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Ranolazina para la angina de pecho estable

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Referencias

Babalis 2015 {published data only (unpublished sought but not used)}

Babalis D, Tritakis V, Floros G, Mouzarou A, Kafkas N, Bampali K, et al. Effects of ranolazine on left ventricular diastolic and systolic function in patients with chronic coronary disease and stable angina. Hellenic Journal of Cardiology 2015;56(3):237‐41. CENTRAL

CARISA 2004 {published data only (unpublished sought but not used)}

Chaitman BR, Pepine CJ, Parker JO, Skopal J, Chumakova G, Kuch J, et al Combination Assessment of Ranolazine In Stable Angina (CARISA) Investigators. Effects of ranolazine with atenolol, amlodipine, or diltiazem on exercise tolerance and angina frequency in patients with severe chronic angina: a randomized controlled trial. JAMA 2004;291(3):309‐16. CENTRAL

ERICA 2006 {published data only (unpublished sought but not used)}

Stone PH, Gratsiansky NA, Blokhin A, Huang IZ, Meng L. ERICA Investigators. Antianginal efficacy of ranolazine when added to treatment with amlodipine: the ERICA (Efficacy of Ranolazine in Chronic Angina) trial. Journal of the American College of Cardiology 2006;48(3):566‐75. CENTRAL

MARISA 2004 {published data only (unpublished sought but not used)}

Chaitman BR, Skettino SL, Parker JO, Hanley P, Meluzin J, Kuch J, et al. MARISA Investigators. Anti‐ischemic effects and long‐term survival during ranolazine monotherapy in patients with chronic severe angina. Journal of the American College of Cardiology 2004;43(8):1375‐82. CENTRAL

Mehta 2011 {published data only (unpublished sought but not used)}

Mehta PK, Goykhman P, Thomson LE, Shufelt C, Wei J, Yang Y, et al. Ranolazine improves angina in women with evidence of myocardial ischemia but no obstructive coronary artery disease. JACC. Cardiovascular Imaging 2011;4(5):514‐22. CENTRAL

MERLIN‐TIMI 36 2007 {published data only (unpublished sought but not used)}

Wilson SR, Scirica BM, Braunwald E, Murphy SA, Karwatowska‐Prokopczuk E, Buros JL, et al. Efficacy of ranolazine in patients with chronic angina observations from the randomized, double‐blind, placebo‐controlled MERLIN‐TIMI (Metabolic Efficiency With Ranolazine for Less Ischemia in Non‐ST‐Segment Elevation Acute Coronary Syndromes) 36 Trial. Journal of the American College of Cardiology 2009;53(17):1510‐6. CENTRAL

Pelliccia 2012 {published data only (unpublished sought but not used)}

Pelliccia F, Pasceri V, Marazzi G, Rosano G, Greco C, Gaudio C. A pilot randomized study of ranolazine for reduction of myocardial damage during elective percutaneous coronary intervention. American Heart Journal 2012;163(6):1019‐23. CENTRAL

Pepine 1999 {published data only (unpublished sought but not used)}

Pepine CJ, Wolff AA, on behalf of the Ranolazine Study Group. A controlled trial with a novel anti‐ischemic agent, ranolazine, in chronic stable angina pectoris that is responsive to conventional antianginal agents. American Journal of Cardiology 1999;84(1):46‐50. CENTRAL

RAN080 2005 {published data only (unpublished sought but not used)}

Rousseau MF, Pouleur H, Cocco G, Wolff AA. Comparative efficacy of ranolazine versus atenolol for chronic angina pectoris. American Journal of Cardiology 2005;95(3):311‐6. CENTRAL

RIVER‐PCI 2016 {published data only (unpublished sought but not used)}

Alexander KP, Weisz G, Prather K, James S, Mark DB, Anstrom KJ, et al. Effects of ranolazine on angina and quality of life after percutaneous coronary intervention with incomplete revascularization: results from the Ranolazine for Incomplete Vessel Revascularization (RIVER‐PCI) Trial. Circulation 2016;133(1):39‐47. CENTRAL
Weisz G, Généreux P, Iñiguez A, Zurakowski A, Shechter M, Alexander KP, et al. Ranolazine in patients with incomplete revascularisation after percutaneous coronary intervention (RIVER‐PCI): a multicentre, randomised, double‐blind, placebo‐controlled trial. Lancet 2016;387(10014):136‐45. CENTRAL

RWISE 2016 {published data only (unpublished sought but not used)}

Bairey Merz CN, Handberg EM, Shufelt CL, Mehta PK, Minissian MB, Wei J, et al. A randomized, placebo‐controlled trial of late Na current inhibition (ranolazine) in coronary microvascular dysfunction (CMD): impact on angina and myocardial perfusion reserve. European Heart Journal 2016;37(19):1504‐13. CENTRAL

Sandhiya 2015 {published data only (unpublished sought but not used)}

Sandhiya S, Steven AD, Ajith AP, Melvin G, Balachander J, Adithan C. Comparison of ranolazine and trimetazidine on glycemic status in diabetic patients with coronary artery disease – a randomized controlled trial. Journal of Clinical and Diagnostic Research 2015;9(1):OC01–OC05. CENTRAL

Shammas 2015 {published data only (unpublished sought but not used)}

Shammas NW, Shammas GA, Keyes K, Duske S, Kelly R, Jerin M. Ranolazine versus placebo in patients with ischemic cardiomyopathy and persistent chest pain or dyspnea despite optimal medical and revascularization therapy: randomized, double‐blind crossover pilot study. Therapeutics and Clinical Risk Management 2015;11:469‐74. CENTRAL

Tagliamonte 2015 {published data only (unpublished sought but not used)}

Tagliamonte E, Rigo F, Cirillo T, Astarita C, Quaranta G, Marinelli U, et al. Effects of ranolazine on noninvasive coronary flow reserve in patients with myocardial ischemia but without obstructive coronary artery disease. Echocardiography 2015;32(3):516‐21. CENTRAL

TERISA 2013 {published data only (unpublished sought but not used)}

Kosiborod M, Arnold SV, Spertus JA, McGuire DK, Li Y, Yue P, et al. Evaluation of ranolazine in patients with type 2 diabetes mellitus and chronic stable angina: results from the TERISA randomized clinical trial (Type 2 Diabetes Evaluation of Ranolazine in Subjects With Chronic Stable Angina). Journal of the American College of Cardiology 2013;61(20):2038‐45. CENTRAL

Thadani 1994 {published data only (unpublished sought but not used)}

Thadani U, Ezekowitz M, Fenney L, Chiang YK. Double‐blind efficacy and safety study of a novel anti‐ischemic agent, ranolazine, versus placebo in patients with chronic stable angina pectoris. Circulation 1994;90(2):726‐34. CENTRAL

Villano 2013 {published data only (unpublished sought but not used)}

Villano A, Di Franco A, Nerla R, Sestito A, Tarzia P, Lamendola P, et al. Effects of ivabradine and ranolazine in patients with microvascular angina pectoris. American Journal of Cardiology 2013;112(1):8‐13. CENTRAL

Arnold 2014 {published data only}

Arnold SV, Kosiborod M, McGuire DK, Li Y, Yue P, Ben‐Yehuda O, et al. Effects of ranolazine on quality of life among patients with diabetes mellitus and stable angina. JAMA Internal Medicine 2014;174(8):1403‐5. CENTRAL

Cocco 1992 {published data only}

Cocco G, Rousseau MF, Bouvy T, Cheron P, Williams G, Detry JM, et al. Effects of a new metabolic modulator, ranolazine, on exercise tolerance in angina pectoris patients treated with beta‐blocker or diltiazem. Journal of Cardiovascular Pharmacology 1992;20(1):131‐8. CENTRAL

Coleman 2015 {published data only}

Coleman CI, Freemantle N, Kohn CG. Ranolazine for the treatment of chronic stable angina: a cost‐effectiveness analysis from the UK perspective. BMJ Open 2015;5(11):e008861. CENTRAL

Hidalgo‐Vega 2014 {published data only}

Hidalgo‐Vega A, Ramos‐Goñi JM, Villoro R. Cost‐utility of ranolazine for the symptomatic treatment of patients with chronic angina pectoris in Spain. European Journal of Health Economics 2014;15(9):917‐25. CENTRAL

Jain 1990 {published data only (unpublished sought but not used)}

Jain D, Dasgupta P, Hughes LO, Lahiri A, Raftery EB. Ranolazine (RS‐43285): a preliminary study of a new anti‐anginal agent with selective effect on ischaemic myocardium. European Journal of Clinical Pharmacology 1990;38(2):111–4. CENTRAL

Kohn 2014 {published data only}

Kohn CG, Parker MW, Limone BL, Coleman CI. Cost‐effectiveness of ranolazine added to standard‐of‐care treatment in patients with chronic stable angina pectoris. American Journal of Cardiology 2014;113(8):1306‐11. CENTRAL

Lucioni 2009 {published data only}

Lucioni C, Mazzi S. Economic evaluation of add‐on ranolazine in the treatment of chronic stable angina [Una valutazione economica di ranolazina add‐on nel trattamento dell’angina stabile cronica]. Pharmacoeconomics Italian Research Articles 2009;11(3):141‐52. CENTRAL

Rehberger‐Likozar 2015 {published data only}

Rehberger‐Likozar A, Šebeštjen M. Influence of trimetazidine and ranolazine on endothelial function in patients with ischemic heart disease. Coronary Artery Disease 2015;26(8):651‐6. CENTRAL

Rich 2007 {published data only}

Rich MW, Crager M, McKay CR. Safety and efficacy of extended‐release ranolazine in patients aged 70 years or older with chronic stable angina pectoris. American Journal of Geriatric Cardiology 2007;16(4):216‐21. CENTRAL

ROLE 2007 {published data only}

Koren MJ, Crager MR, Sweeney M. Long‐term safety of a novel antianginal agent in patients with severe chronic stable angina: the Ranolazine Open Label Experience (ROLE). Journal of the American College of Cardiology 2007;49(10):1027‐34. CENTRAL

NCT01304095 {published data only}

NCT01304095. Ranolazine, ethnicity and the metabolic syndrome (REMS). https://clinicaltrials.gov/ct2/show/NCT01304095?term=NCT01304095&rank=1 (first received 16 February 2011). CENTRAL

Tagarakis 2013 {published data only}

Tagarakis GI, Aidonidis I, Daskalopoulou SS, Simopoulos V, Liouras V, Daskalopoulos ME, et al. Effect of ranolazine in preventing postoperative atrial fibrillation in patients undergoing coronary revascularization surgery. Current Vascular Pharmacology 2013;11(6):988‐91. CENTRAL

Tian 2012 {published data only}

Tian C, Liu Y. Effect of ranolazine and diltiazem on patients with stable angina pectoris [雷诺拉嗪联合地尔硫对稳定性心绞痛的疗效评价]. 中国现代医生 (Chinese Modern Physician) 2012;50(5):122‐3. CENTRAL

Wang 2012 {published data only}

Wang G, Zhou C. Clinical observation of ranolazine hydrochloride sustained‐release tablets in the treatment of stable angina pectoris [盐酸雷诺嗪缓释片治疗稳定型心绞痛的临床观察]. 中国药房 (Chinese Pharmacy) 2012;23(26):2455‐8. CENTRAL

Calcagno 2014 {published data only}

Calcagno S, Taccheri T, Carnesale R, Nicol S, Lembo M, Bruno P, et al. Complete coronary revascularization in different clinical settings is not enough: role of ranolazine. Journal of the American College of Cardiology. 2014; Vol. 63:12 S. CENTRAL

Calcagno 2015 {published data only}

Calcagno S, Severino P, Taccheri T, Placentino F, Ceccacci A, Cinque A, et al. Complete coronary revascularization in some clinical settings is not enough: comparison of ivabradine, ranolazine and standard medical therapy in term of efficacy and tolerability. Journal of the American College of Cardiology. 2015; Vol. 65:10 S. CENTRAL

CTRI/2014/01/004332 {published data only}

CTRI/2014/01/004332. Effect of ranolazine on improvement of heart function [Effect of ranolazine on improvement of left ventricular dysfunction in patients with chronic stable angina – a randomized controlled clinical trial]. http://ctri.nic.in/Clinicaltrials/showallp.php?mid1=7785&EncHid=&userName=CTRI/2014/01/0043 (first received 22 January 2014). CENTRAL

EUCTR 2011‐001278‐24 {published data only}

EUCTR 2011‐001278‐24. Efficacy of ranolazine in patients with coronary artery disease (CAD). www.clinicaltrialsregister.eu/ctr‐search/search?query=Efficacy+of+ranolazine+in+patients+with+coronary+artery+disease+%28CAD%29 (first received 18 July 2011). CENTRAL

EUCTR 2012‐001584‐77 {published data only}

EUCTR 2012‐001584‐77. Effect of ranolazine in ischemic patients with indication of staged interventional therapy. www.clinicaltrialsregister.eu/ctr‐search/search?query=A+study+to+investigate+the+effect+of+a+drug+to+treat+angina+pectoris (first received 18 July 2012). CENTRAL

Gupta 2014 {published data only}

Gupta G, Varma CM, Thakur R, Bhardwaj RPS, Ahmad M, Bansal RK, et al. Effect of ranolazine on angina frequency in patients with type 2 DM and chronic stable angina. Indian Heart Journal. 2014; Vol. 66 (Suppl 2):S11. CENTRAL

NCT01495520 {published data only}

NCT01495520. Ranolazine for improving symptoms of palpitations (RYPPLE). https://clinicaltrials.gov/ct2/show/NCT01495520 (first received 15 December 2011). CENTRAL

NCT01558830 {published data only}

NCT01558830. Safety of amiodarone and ranolazine together in patients with angina (SARA). https://clinicaltrials.gov/ct2/show/NCT01558830 (first received 18 March 2012). CENTRAL

NCT01754259 {published data only}

NCT01754259. Effects of ranolazine on coronary flow reserve in symptomatic diabetic patients and CAD (RAND‐CFR). https://clinicaltrials.gov/ct2/show/NCT01754259 (first received 12 December 2012). CENTRAL

NCT01948310 {published data only}

NCT01948310. Effects of ranolazine and exercise on daily physical activity trial (EREDA). https://clinicaltrials.gov/ct2/show/NCT01948310 (first received 17 September 2013). CENTRAL

NCT02052011 {published data only}

NCT02052011. Ranolazine and microvascular angina by PET in the emergency department (RAMP‐ED). https://clinicaltrials.gov/ct2/show/NCT02052011 (first received 30 January 2014). CENTRAL

NCT02147067 {published data only}

NCT02147067. Microvascular assessment of ranolazine in non‐obstructive atherosclerosis (MARINA). https://clinicaltrials.gov/ct2/show/NCT02147067 (first received 22 May 2014). CENTRAL

NCT02147834 {published data only}

NCT02147834. Effectiveness of ranolazine on reducing chest pain in patients with blockage but no stents (IMWELL3). https://clinicaltrials.gov/ct2/show/NCT02147834 (first received 22 May 2014). CENTRAL

NCT02252406 {published data only}

NCT02252406. Impact of ranolazine in blood markers in women with angina and metabolic syndrome (IRMA). https://clinicaltrials.gov/ct2/show/NCT02252406 (first received 11 August 2014). CENTRAL

NCT02265796 {published data only}

NCT02265796. Improvement of subjective well‐being by ranolazine among unrevascularized chronic stable coronary artery disease patients (IMWELL). https://clinicaltrials.gov/ct2/show/NCT02265796 (first received 10 October 2014). CENTRAL

NCT02423265 {published data only}

NCT02423265. Efficacy of ranolazine in patients with chronic total occlusions of coronary arteries. https://clinicaltrials.gov/ct2/show/NCT02423265 (first received 12 April 2015). CENTRAL

Šebeštjen 2014 {published data only}

Šebeštjen M, Rehberjer‐Likozar A, Vrtovec B, Poglajen G. Both trimetazidine and ranolazine improve arterial vasoreactivity in patients with ischemic heart disease (Abstract 14057). Circulation. 2014; Vol. 130:A14057. CENTRAL

ACC/AHA 2012

Fihn SD, Gardin JM, Abrams J, Berra K, Blankenship JC, Dallas AP, et al. 2012 ACCF/AHA/ACP/AATS/PCNA/SCAI/STS guideline for the diagnosis and management of patients with stable ischemic heart disease: a report of the American College of Cardiology Foundation/American Heart Association task force on practice guidelines, and the American College of Physicians, American Association for Thoracic Surgery, Preventive Cardiovascular Nurses Association, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons. Circulation 2012;126(25):e354‐471.

Banon 2014

Banon D, Filion KB, Budlovsky T, Franck C, Eisenberg MJ. The usefulness of ranolazine for the treatment of refractory chronic stable angina pectoris as determined from a systematic review of randomized controlled trials. American Journal of Cardiology 2014;113(6):1075‐82.

Belsey 2015

Belsey J, Savelieva I, Mugelli A, Camm AJ. Relative efficacy of antianginal drugs used as add‐on therapy in patients with stable angina: A systematic review and meta‐analysis. European Journal of Preventive Cardiology 2015;22(7):837‐48.

Cattaneo 2015

Cattaneo M, Porretta AP, Gallino A. Ranolazine: Drug overview and possible role in primary microvascular angina management. International Journal of Cardiology 2015;181:376‐81.

Chaitman 2011

Chaitman BR, Laddu AA. Stable angina pectoris: antianginal therapies and future directions. Nature Reviews. Cardiology 2011;9(1):40‐52.

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Characteristics of studies

Characteristics of included studies [ordered by study ID]

Babalis 2015

Methods

Study design: parallel‐group trial

Total study duration: 3 months

Duration of follow‐up: no follow‐up beyond treatment phase

Method of randomisation: not described

Method of concealment of allocation: not mentioned

Blinding: not mentioned

Power calculation: not mentioned

Phases of the study: 1 (treatment phase)

Number of patients randomised: 40 (20/20 for placebo/ranolazine group)

Exclusions post‐randomisation: not reported

Withdrawals (and reasons): not reported

Participants

Total number: 40

Country of enrolment: Greece

Setting/location: not specified

Diagnostic criteria (stable angina pectoris): symptoms of stable angina and coronary artery disease (CAD) established by coronary stenosis > 70% in one or more vessels documented by angiography (macrovascular angina)

Comorbidities: none (non suitability for invasive treatment)

Age (mean): 69 ± 7 years

Gender (male %): 75%

Inclusion criteria:

  • Adult patient

  • Symptomatic stable angina despite optimised anti‐anginal treatment, not suitable for further invasive treatment

  • Coronary disease (coronary stenosis > 70% in one or more vessels, as documented by angiography)

Exclusion criteria:

  • Severe ischaemic heart failure (New York Heart Association class [NYHA] III or IV)

  • Unstable angina

  • Recent (< 1 month) myocardial infarction

  • Ongoing treatment with drugs that might prolong the QT interval on the ECG

Interventions

Number of intervention groups: 2

Concomitant medications: optimised anti‐anginal treatment (not further specified)

Excluded medications: none

Placebo group

Intervention: placebo

Duration of intervention: 3 months

Ranolazine group

Intervention: ranolazine (type of formulation not specified) 500 mg twice daily

Duration of intervention: 3 months

Outcomes

Total number of outcomes: 1

  • According to study protocol: no published protocol; according to the "Patients and Methods" section: 3 (exercise treadmill test (ETT) measurements, left ventricular (LV) function measurements, safety evaluations)

  • Reported: 2 (results for ETT measurements were not reported)

OUTCOMES

Adverse events incidence

  • Outcome definition: events related to medications

  • Method and unit of measurement: number of patients

  • Time points reported: 3 months

RESULTS

Adverse events incidence

  • Sample size: 40 (intention‐to‐treat analysis)

  • Missing participants: none

  • Summary data: 0/20‐0/20 for Placebo group‐Ranolazine group (type of analysis not specified)

  • Subgroup analyses: not performed

Notes

Relevant observations for the data provided before: It is worth mentioning that two ranolazine group participants and four placebo group participants were not eligible for revascularisation because of complicated coronary anatomy or lack of grafts

Source of funding: not stated

Notable conflicts of interest: the authors declare that they have no conflict of interest

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Randomisation is stated but described only as "in a 1:1 ratio"

Allocation concealment (selection bias)

Unclear risk

Not mentioned

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Not mentioned

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Not mentioned

Incomplete outcome data (attrition bias)
All outcomes

Low risk

No exclusion or withdrawal is reported, it is stated that no patient withdrew from the study because of ranolazine‐related adverse reactions. We assume that all patients completed the study

Selective reporting (reporting bias)

Unclear risk

There is no published protocol. Exercise capacity and duration and time to appearance of angina results were not reported in spite they were mentioned among the study benchmarks

Other bias

Unclear risk

The authors declare that they have no conflict of interest. However, the source of funding is not stated. Furthermore, editorial assistance for the preparation of the manuscript was provided by Luca Giacomelli, PhD, on behalf of Content Ed Net; this assistance was funded by Menarini International, an Italian pharmaceutical company.

CARISA 2004

Methods

Study design: parallel‐group trial

Total study duration: 14 weeks plus follow‐up (around 14 months). Patients were enrolled from July 1999 to August 2001

Duration of follow‐up: from August 2001 to 31 October 2002

Method of randomisation: randomisation schedules generated by Quintiles (UK) Limited in SAS version 6.12, stratified by the 3 background anti‐anginal therapies using a block size of 6

Method of concealment of allocation: drug packaging with code break envelopes provided by Brecon Pharmaceuticals Ltd.

Blinding: double‐blind, not described but presumably referred to participants and study personnel

Power calculation: 90% to detect a difference of 30s in the primary end point

Phases of the study: 3 (qualifying phase, treatment phase, open‐label follow‐up phase)

Number of patients randomised: 823 (269/279/275 for placebo/ranolazine 750 mg/ranolazine 1000 mg group)

Exclusions post‐randomisation (for each phase): Qualifying phase: 32 (11/7/14 from placebo/ranolazine 750 mg/ranolazine 1000 mg group). Treatment phase: 54 (14/18/22 from placebo/ranolazine 750 mg/ranolazine 1000 mg group)

Withdrawals (and reasons): not reported (excluded patients were reported only as "dropped out")

Participants

Total number: 823

Country of enrolment: 15 (Canada, Czech Republic, Georgia, Greece, Ireland, Israel, Italy, New Zealand, Poland, Romania, Russia, Spain, United Kingdom, United States)

Setting/location: ambulatory outpatient

Diagnostic criteria (stable angina pectoris): minimum 3 month history of exertional angina with CAD confirmed by angiography, documented prior myocardial infarction, or a diagnostic stress myocardial imaging study (macrovascular angina)

Comorbidities: none

Age (mean, SD): 63.7(8.9)/64.3(9.3)/63.9(9.3) for placebo/ranolazine 750 mg/ranolazine 1000 mg group

Gender (male %): 75.1/77.8/79.6 for placebo/ranolazine 750 mg/ranolazine 1000 mg group

Inclusion criteria:

  • Minimum 3‐month history of exertional angina

  • Coronary artery disease

  • Reproducible angina on exercise treadmill test while receiving required background anti‐anginal treatment

Exclusion criteria:

  • Factors that precluded satisfactory interpretation of the ECG

  • Class III or IV heart failure

  • Acute coronary syndrome or coronary revascularisation procedure within the prior two months

Interventions

Number of intervention groups: 3

Concomitant medications: background anti‐anginal treatment (atenolol 50 mg once daily, diltiazem 180 mg once daily, or amlodipine 5m g once daily)

Excluded medications: none

Placebo group

Intervention: placebo twice daily

Duration of intervention: 12 weeks

Ranolazine 750 mg group

Intervention: ranolazine ER 750 mg twice daily

Duration of intervention: 12 weeks

Ranolazine 1000 mg group

Intervention: ranolazine ER 1000 mg twice daily

Duration of intervention: 12 weeks

Outcomes

Total number of outcomes:

  • According to study protocol: no published protocol; according to the "Methods" section: 9 (exercise duration at through levels, exercise duration at peak levels, time to angina at peak and trough levels, time to 1‐mm ST segment depression at peak and through levels, frequency of angina attacks, frequency of nitroglycerin use, drug tolerability and safety)

  • Reported: 11 (including heart rate and blood pressure, mortality deemed to be part of the safety outcome)

All‐cause mortality

Outcome definition: number of deaths

Method and unit of measurement: absolute frequency, survival rate

Time points reported: 12 weeks (plus the 14‐day safety follow‐up), 17 months (including follow‐up phase)

Angina episodes frequency

  • Outcome definition: average angina attacks per week

  • Method and unit of measurement: number per week

  • Time points reported: 12 weeks

Adverse events incidence

  • Outcome definition: not described

  • Method and unit of measurement: percentage

  • Time points reported: 12 weeks

RESULTS

All‐cause mortality

  • Sample size: 823 (intention‐to‐treat analysis), 750 (open‐label follow‐up phase)

  • Missing participants: none

  • Summary data: 3/269‐2/279‐1/275 for placebo‐ranolazine 750 mg ranolazine 1000 mg group. Survival rates are reported for the open‐label long‐term follow‐up phase

  • Subgroup analyses: not performed

Angina episodes frequency

  • Sample size: 791 (intention‐to‐treat analysis)

  • Missing participants: 32 (exclusion post‐randomisation during the qualifying phase)

  • Summary data: mean (SE) 3.3(0.3) / 2.5(0.2) / 2.1 (0.2) for placebo/ranolazine 750 mg/ranolazine 1000 mg group

  • Subgroup analyses: not performed

Adverse events incidence

  • Sample size: 823 (intention‐to‐treat analysis)

  • Missing participants: none

  • Summary data: 26.4%/31.2%/32.7% for placebo/ranolazine 750 mg/ranolazine 1000 mg group. The most common dose‐related adverse effects were constipation, dizziness, nausea and asthenia (≤ 7.3% in both ranolazine groups; ≥ 0.7% in the placebo group)

  • Subgroup analyses: not performed

Notes

Relevant observations for the data provided before: none

Source of funding: CV Therapeutics Inc.

Notable conflicts of interest: six of the authors have financial relationships with CV Therapeutics

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Computer‐generated random sequence. Randomisation schedules generated by Quintiles (UK) Limited in SAS version 6.12, stratified by the 3 background anti‐anginal therapies using a block size of 6

Allocation concealment (selection bias)

Low risk

Drug packaging with code break envelopes made by Brecon Pharmaceuticals Ltd. The medication assignment was provided to the principal investigator in a sealed envelope.

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Treatment phase is declared to be double‐blinded, but no description is provided. Drug packages were made with code break envelopes and provided to the clinical units, so patients and personnel were not aware of the treatment assigned.

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Exercise treadmill test ECGs were interpreted by a core EGC laboratory blinded to treatment assignment using customised software. Although this is stated only for the single‐blind qualifying phase, we assume it also applies for the double‐blind treatment phase. However, for outcomes such as all‐cause mortality, angina frequency and adverse events incidence blinding measures have not been described

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Number of patients dropped out during the qualifying and treatment phases are reported, but reasons and explanations are not provided

Selective reporting (reporting bias)

Unclear risk

There is no published protocol. Results for all the outcomes stated in the "Methods" section of the paper are reported, but results for some additional outcomes (haemodynamics) are also reported.

Other bias

High risk

The study was supported by CV Therapeutics Inc. Furthermore, six of the authors have financial relationships with CV Therapeutics.

ERICA 2006

Methods

Study design: parallel‐group trial

Total study duration: 9 weeks; recruitment from July 30, 2004 to February 16, 2005

Duration of follow‐up: no follow‐up beyond treatment phase

Method of randomisation: randomisation in a 1:1 ratio, centralised and not stratified by centre

Method of concealment of allocation: not mentioned

Blinding: double‐blind, not described

Power calculation: not mentioned

Phases of the study: 2 (qualifying phase, treatment phase), treatment phase made up by 1‐week run‐in phase and 6‐week full‐dose treatment phase

Number of patients randomised: 565 (284/281 for placebo/ranolazine group)

Exclusions post‐randomisation: run‐in phase: 1 withdrawal before study drug treatment (placebo group), 3 exclusions from placebo group because not beginning full‐dose treatment phase, 4 exclusions from ranolazine group, 1 because not beginning full‐dose treatment phase, 3 because not having any diary data in the full‐dose treatment phase

Withdrawals (and reasons): ranolazine group (3 adverse events, 1 death, 3 withdrew consent), placebo group (5 adverse events (4 according to the text), 1 death)

Participants

Total number: 564

Country of enrolment: Eastern Europe, United States, Canada

Setting/location: not specified

Diagnostic criteria (stable angina pectoris): history of chronic stable angina ≥3 months, documented history of CAD (macrovascular angina)

Comorbidities: none

Age (mean ± SD): 61.3±9.0 / 62.0±8.7 for placebo / ranolazine group

Gender (male %): 73% / 72% for placebo / ranolazine group

Inclusion criteria:

  • Age ≥ 18 years

  • Chronic stable angina ≥ 3 months, and ≥ 3 episodes of angina per week during a ≥2‐week qualification period despite treatment with 10 mg/day amlodipine

  • Documented history of CAD (angiographic evidence of ≥ 60% stenosis of at least 1 major coronary artery, history of previous myocardial infarction and/or a stress‐induced reversible perfusion defect identified by radionuclide or echocardiographic imaging)

Exclusion criteria:

  • NYHA functional class IV congestive heart failure

  • History of myocardial infarction or unstable angina within the previous 2 months

  • Active acute myocarditis, pericarditis, hypertrophic cardiomyopathy, or uncontrolled hypertension

  • History of torsades de pointes

  • Receiving agents known to prolong the QTc interval

  • QTc interval measurement > 500 ms at study entry

  • Clinically significant hepatic disease, creatinine clearance < 30 mL/min, or chronic illness likely to interfere with protocol compliance

Interventions

Number of intervention groups: 2

Concomitant medications: amlodipine 10 mg/day; LANs and sublingual nitroglycerin as required

Excluded medications: inhibitors of cytochrome P450‐3A4, digitalis preparation, perhexiline, trimetazidine, beta‐blockers, calcium cannel blockers other than amlodipine

Placebo group

  • Intervention: placebo

  • Duration of intervention: 6 weeks (full‐dose treatment phase)

Ranolazine group

  • Intervention: ranolazine ER 1000 mg twice daily

  • Duration of intervention: 6 weeks (full‐dose treatment phase)

Outcomes

Total number of outcomes:

  • According to study protocol: no published protocol (registered data in clinicaltrials.gov is not available any more); according to the "Methods" section: 7 (average weekly frequency of self‐reported angina episodes, average weekly nitroglycerin consumption, change from baseline of the 5 dimensions of the Seattle Angina Questionnaire (SAQ), reported adverse events, haemodynamics, routine clinical laboratory measures, 12‐lead electrocardiograms)

  • Reported: 7

All‐cause mortality

  • Outcome definition: number of deaths

  • Method and unit of measurement: absolute frequency

  • Time points reported: 9 weeks

Quality of life

  • Outcome definition: change from baseline of the 5 dimensions of the Seattle Angina Questionnaire (SAQ), reported separately

  • Upper and lower limits and whether a high or low score is good: each dimension (anginal frequency, physical limitation, anginal stability, disease perception, and treatment satisfaction) was scored on a scale of 0 to 100

  • Method and unit of measurement: score difference

  • Time points reported: 6 weeks

Acute myocardial infarction incidence (fatal and non‐fatal)

  • Outcome definition: not described

  • Method and unit of measurement: percentage

  • Time points reported: 9 weeks

Angina episodes frequency

  • Outcome definition: average weekly angina episodes frequency

  • Method and unit of measurement: number per week

  • Time points reported: 6 weeks

Adverse events incidence

  • Outcome definition: number of patients that reported any adverse event

  • Method and unit of measurement: percentage

  • Time points reported: 9 weeks

RESULTS

All‐cause mortality

  • Sample size: 565 (Intention‐to‐treat analysis)

  • Missing participants: none

  • Summary data: 1/284‐1/281 for placebo‐ranolazine group

  • Subgroup analyses: not performed

Quality of life

  • Sample size: 558 (Intention‐to‐treat analysis)

  • Missing participants: 7 (3 from placebo group, 4 from ranolazine group)

  • Summary data: SAQ dimension 1 (anginal frequency) 22.5 ± 19.0/18.5 ± 18.8 for ranolazine/placebo group

  • Subgroup analyses: significant improvement of SAQ anginal frequency only for patients with baseline angina frequency > 4.5 per week

Acute myocardial infarction incidence (fatal and non‐fatal)

  • Sample size: 565 (Intention‐to‐treat analysis)

  • Missing participants: none

  • Summary data: 0.7%/0.4% for placebo/ranolazine group

  • Subgroup analyses: not performed

Angina episodes frequency

  • Sample size: 558 (intention‐to‐treat analysis)

  • Missing participants: 7 (3 from placebo group, 4 from ranolazine group)

  • Summary data: arithmetic means ± SE: 4.3 ± 0.64/3.29 ± 0.26 for placebo/ranolazine group; trimmed means ± SE: 3.31 ± 0.22/2.88 ± 0.19 for placebo/ranolazine group

  • Subgroup analyses: significant reductions of angina frequency for patients with baseline angina frequency > 4.5 per week and for ≤ 4.5 per week

Adverse events incidence

  • Sample size: 565 (Intention‐to‐treat analysis)

  • Missing participants: none

  • Summary data: 35.3%/39.9% for placebo/ranolazine group. The most frequently reported adverse events in the ranolazine group were constipation (25/281), peripheral edema (16/281), dizziness (11/281), nausea (8/281) and headache (8/281); in the placebo group were peripheral edema (8/284), dizziness (7/284), headache (7/284), constipation (5/284) and nausea (2/284).

  • Subgroup analyses: performed for the following variables: long acting nitrates (LAN) user state, gender, age

Notes

Relevant observations for the data provided before: given that 4 placebo patients and 3 ranolazine patients discontinued the study because of adverse events but 5 placebo patients are reported not to have terminated the trial because of adverse events and 3 more ranolazine patients are reported not to have terminated the trial because of withdrawing consent, it is not clear which patients were finally included in the efficacy analysis

Source of funding: CV Therapeutics

Notable conflicts of interest: all the authors have received some kind of reward or support for participating in this trial from several pharmaceutical companies

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Randomisation is stated but described only as "in a 1:1 ratio, centralized but not stratified"

Allocation concealment (selection bias)

Unclear risk

Not mentioned

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Treatment phase is declared to be double‐blinded, but not description is provided

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Treatment phase is declared to be double‐blinded, but not description is provided

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Patients who did not complete the trial are described clearly, however, there is an inconsistency in the data provided for terminating patients in the placebo group for only one case and it is not clear which patients were finally included in the efficacy analysis

Selective reporting (reporting bias)

Unclear risk

There is no published protocol. Results for all the outcomes mentioned in the "Methods" section of the paper are reported

Other bias

High risk

The study was supported by CV Therapeutics Inc. All the authors have received some kind of reward or support for participating in this trial from several pharmaceutical companies

MARISA 2004

Methods

Study design: cross‐over trial

Total study duration: 6 weeks plus follow‐up, the study began in December 1997 and ended in May 1999

Duration of follow‐up: about 2 years; to October 15, 2001

Method of randomisation: not described

Method of concealment of allocation: not mentioned

Blinding: double‐blind, not described

Power calculation: not mentioned

Phases of the study: 3 (qualifying phase, treatment phase, open‐label follow‐up phase)

Number of patients randomised: 191

Exclusions post‐randomisation: 16 (treatment phase, those who did not complete at least three treatment periods)

Withdrawals (and reasons): 23 patients (12%) discontinued the study before completing all treatment periods: 15 patients (7.9%) for adverse events, 4 patients (2.1%) by elective withdrawal, 2 patients (1.0%) for other reasons, 1 patient (˂ 1%) because of death and 1 patient (˂ 1%) because of inappropriate enrolment

Participants

Total number: 191

Country of enrolment: 4 (Canada, Czech Republic, Poland, United States)

Setting/location: not specified

Diagnostic criteria (stable angina pectoris): at least a three‐month history of effort angina responding to beta‐blockers, calcium channel blockers and/or long‐acting nitrates with well‐documented CAD (macrovascular angina)

Comorbidities: none

Age (mean ± SD): 64.3 ± 9.4 years

Gender (male %): 73.3%

Inclusion criteria:

  • Patients were at least 21 years of age

  • Well‐documented coronary artery disease

  • At least a three‐month history of effort angina responding to beta‐blockers, calcium channel blockers, and/or long‐acting nitrates

  • All patients discontinued anti‐anginal treatment during the study (except sublingual nitroglycerin as needed) and provided written informed consent

Exclusion criteria:

  • Conditions that might compromise electrocardiogram (ECG) or ETT interpretation (e.g. treatment with digoxin, 1 mm ST‐segment depression at rest, left bundle branch block, pacemaker rhythm)

  • New York Heart Association functional class III or IV congestive heart failure

  • Unstable angina

  • Myocardial infarction

  • Any coronary revascularisation procedure within two months of enrolment

  • Corrected QT interval (QTc) ˃ 500 ms or any medication known to prolong the QTc interval

  • Requirement for medication or food known to affect metabolism by cytochrome P450 3A4

Interventions

Number of intervention groups: 4

Concomitant medications: sublingual nitroglycerin

Excluded medications: anti‐anginal treatment except sublingual nitroglycerin

Placebo group

Intervention: placebo twice daily

Duration of intervention: 1 week

Ranolazine 500 mg group

Intervention: ranolazine SR 500 mg twice daily

Duration of intervention: 1 week

Ranolazine 1000 mg group

Intervention: ranolazine SR 1000 mg twice daily

Duration of intervention: 1 week

Ranolazine 1500 mg group

Intervention: ranolazine SR 1500 mg twice daily

Duration of intervention: 1 week

Outcomes

Total number of outcomes:

  • According to study protocol: no published protocol; according to the "Methods" section: 10 (ETT duration (through and peak), ETT time to onset of angina (through and peak), ETT time to 1mm ST‐segment depression (through and peak), haemodynamics (through and peak), laboratory, safety evaluations)

  • Reported: 10

Adverse events incidence

Outcome definition: number of patients who report any adverse event

Method and unit of measurement: percentage

Time points reported: 1 week

RESULTS

Adverse events incidence

Sample size: 191 (intention‐to‐treat analysis)

Missing participants: none

Summary data: 15.6%/16.0%/21.7%/34.2% for placebo/ranolazine 500 mg/ranolazine 1000 mg/ranolazine 1500 mg group. Over a total of 191 participants, the adverse events most frequently reported were dizziness (2/2/10/23), nausea (0/1/2/16), asthenia (4/0/3/12), constipation (0/0/3/8), angina (10/10/3/6), headache (4/1/2/5) and sweating (0/0/0/5) for placebo/ranolazine 500 mg/ranolazine 1000 mg/ranolazine 1500 mg group.

Subgroup analyses: not performed

Notes

Relevant observations for the data provided before: none

Source of funding: CV Therapeutics

Notable conflicts of interest: three of the authors have financial relationships with CV Therapeutics

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Randomisation is stated but not described

Allocation concealment (selection bias)

Unclear risk

Not mentioned

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Study is declared to be double‐blinded, but no description is provided

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Exercise treadmill test ECGs were interpreted by a core EGC laboratory blinded to treatment assignment using customised software. However, for outcomes such as adverse events incidence, blinding measures have not been described

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Patients who did not complete the trial are described, but the treatment they were receiving is not specified

Selective reporting (reporting bias)

Unclear risk

There is no published protocol. Results for all the outcomes stated in the "Methods" section of the paper are reported

Other bias

High risk

The study was supported by CV Therapeutics. Three of the authors have financial relationships with CV Therapeutics

Mehta 2011

Methods

Study design: cross‐over trial

Total study duration: 10 weeks plus up to 24 months of qualifying phase

Duration of follow‐up: no follow‐up beyond treatment phase

Method of randomisation: not described

Method of concealment of allocation: not mentioned

Blinding: double‐blind, not described

Power calculation: not mentioned

Phases of the study: 2 (qualifying phase, treatment phase)

Number of patients randomised: 20

Exclusions post‐randomisation: not reported

Withdrawals (and reasons): not reported

Participants

Total number: 20

Country of enrolment: United States

Setting/location: not specified

Diagnostic criteria (stable angina pectoris): chest pain and abnormal routine stress testing without obstructive CAD (< 50% epicardial coronary stenosis in all epicardial coronary arteries) on clinically indicated coronary angiography (microvascular angina)

Comorbidities: none

Age (mean): 57 ± 11 years

Gender (male %): 0%

Inclusion criteria:

  • Women with signs and symptoms of myocardial ischaemia (chest pain and abnormal routine stress testing)

  • No obstructive CAD (< 50% epicardial coronary stenosis in all epicardial coronary arteries) on clinically indicated coronary angiography

  • Abnormal adenosine stress CMR (≥ 10% ischaemic myocardium) within the previous 12 months

Exclusion criteria:

  • Contraindications to withholding nitrates, calcium channel agents, and alpha and beta‐adrenergic blockers for 24 hours before testing

  • Contraindications to CMR including implantable cardioverter‐defibrillators, pacemakers, and severe claustrophobia

  • Hepatic insufficiency, prolonged QT, renal failure

  • Use of drugs that inhibit CYP3A such as diltiazem, verapamil, ketoconazole, macrolides, and HIV protease inhibitors

  • Women younger than 18 years of age, pregnant, or breastfeeding

  • Taking drugs that prolong the QT interval

  • Life expectancy < 6 months

Interventions

Number of intervention groups: 2

Concomitant medications: usual anti‐anginal medication

Excluded medications: none (apart from those mentioned in the exclusion criteria)

Placebo group

Intervention: placebo twice daily

Duration of intervention: 4 weeks (plus 2 weeks of washout)

Ranolazine group

Intervention: ranolazine (type of formulation not specified) 500/1000 mg twice daily (the dose was increased from 500 mg to 1000 mg twice daily during the second half of treatment period if tolerated)

Duration of intervention: 4 weeks (plus 2 weeks of washout)

Outcomes

Total number of outcomes:

  • According to study protocol (published in clinicaltrials.gov): 3 (quality of life assessed by the Seattle Angina Questionnaire ‐SAQ and Duke Activity Status Index‐DASI; cardiac magnetic resonance (CMR) studies)

  • Reported: 3

Quality of life

1. Seattle Angina Questionnaire (SAQ)

Outcome definition: score in the 5 sub‐scales, reported separately

(For scales) upper and lower limits and whether a high or low score is good: higher scores are better, upper and lower limits are not described

Method and unit of measurement: score

Time points reported: 4 weeks

2. Duke Activity Status Index (DASI)

Outcome definition: functional capacity scale, not further described

(For scales) upper and lower limits and whether a high or low score is good: not described

Method and unit of measurement: score

Time points reported: 4 weeks

RESULTS

Quality of life

1. Seattle Angina Questionnaire (SAQ)

Sample size: 47 (intention‐to‐treat analysis)

Missing participants: none

Summary data: reported as mean (minimum, maximum)
i) Physical functioning: 83.3 (66.6, 97.2) /91.7 (79.2, 97.9) for placebo/ranolazine group;
ii) Angina stability: 50.0 (25.0, 75.0)/75.0 (50.0, 100.0) for placebo/ranolazine group;
iii) angina frequency: 75.0 (60.0, 87.5)/80.0 (50.0, 100.0) for placebo/ranolazine group;
iv) Treatment satisfaction: 93.8 (75.0, 100.0)/87.5 (75.0, 100.0) for placebo/ranolazine group
v) Quality of life: 66.7 (58.3, 75.0)/75.0 (60.4, 83.3) for placebo/ranolazine group

Subgroup analyses: not performed

2. Duke Activity Status Index (DASI)

Sample size: 20 (intention‐to‐treat analysis)

Missing participants: none

Summary data: 8.9 (5.4 minimum, 12.1 maximum) METS / 8.6 (3.7 minimum, 11.5 maximum) METS for placebo/ranolazine group

Subgroup analyses: not performed

Notes

Relevant observations for the data provided before: details about the qualifying phase are not provided

Source of funding: grants and contracts from several public and private organisations in the United States.

Notable conflicts of interest: the authors reported they have no relationships to disclose.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Randomisation is stated, but no description is provided

Allocation concealment (selection bias)

Unclear risk

Not mentioned

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Study is declared to be double‐blinded. Participants and investigators.

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Cardiac magnetic resonance imaging outcomes were measured by readers blinded to treatment assignment. However, for outcomes such as quality of life, blinding measures have not been described

Incomplete outcome data (attrition bias)
All outcomes

Low risk

All patients completed the study.

Selective reporting (reporting bias)

Low risk

There is published protocol in clinical trials. Results for all the outcomes stated in the "Methods" section of the paper are reported.

Other bias

Unclear risk

The study received grants and contracts from several public and private organisations in the United States. The authors reported they have no relationships to disclose.

MERLIN‐TIMI 36 2007

Methods

Study design: parallel‐group trial

Total study duration: mean of 350 days

Duration of follow‐up: no follow‐up beyond treatment phase

Method of randomisation: via a central computerised telephone system with stratification by the responsible physician’s intended management strategy (early invasive versus conservative)

Method of concealment of allocation: not mentioned

Blinding: double‐blind, not described

Power calculation: 90% to detect a significant difference between treatment groups at 2‐sided 5% significance level

Phases of the study: 1, treatment phase

Number of patients randomised: 6560 in the original trial, 3565 in the sub‐study on stable angina patients (1789/1776 for ranolazine/placebo group)

Exclusions post‐randomisation: 5 lost to follow‐up

Withdrawals (and reasons): 8.1%/4.1% discontinued ranolazine due to an adverse event in ranolazine/placebo group

Participants

Total number: 3565

Country of enrolment: 17 (Australia, France, Germany, Poland, United Kingdom, United States, Spain, Israel, Austria, Switzerland, Italy, The Netherlands, South Africa, Hungary, Czech Republic, Canada, Belgium)

Setting/location: hospitalisation

Diagnostic criteria (stable angina pectoris): history of prior stable angina before and separate from the presenting ACS

Comorbidities: Acute coronary syndrome: clinical presentation consistent with an ACS with at least 1 indicator of moderate to high risk of death or recurrent ischaemic events

Age (mean (25th, 75th)): 65 (57,73)/66 (56/73) for ranolazine/placebo group

Gender (male %): 1149/1789(64.2%)‐1083/1776(61.0%) for ranolazine‐placebo group

Inclusion criteria:

  • Aged ≥ 18 years

  • Hospitalised with NSTE‐ACS defined as chest discomfort or anginal equivalent occurring at rest, lasting ≥ 10 min and consistent with myocardial ischaemia

  • Presence of ischaemic symptoms (≥ 5 minutes) at rest within 48 hours of enrolment (may include index episode)

  • At least one indicator of moderate to high risk (elevated cardiac troponin or CK‐MB, ST depression ≥ 0.1 mV, diabetes mellitus, TIMI risk score for UA/NSTEMI ≥ 3)

  • Willing and able to provide written informed consent

Exclusion criteria:

  • Persistent (> 20 minutes) acute ST‐segment elevation ≥ 0.1 mV in ≥ 2 continuous leads

  • Successful revascularisation of the culprit stenosis during qualifying hospitalisation before randomisation

  • Acute pulmonary edema requiring endotracheal intubation, sustained systolic blood pressure < 90 mm Hg, or evidence of cardiogenic shock

  • Left bundle branch block, electronic pacemaker, or left ventricular hypertrophy with severe repolarisation abnormality that would interfere with the interpretation of the Holter

  • Pregnant or lactating women

  • Use at randomisation of agents that are strong inhibitors of cytochrome P450 pathway isoform 3A4

  • Need for ongoing or anticipated need for chronic treatment during the study period with any of the following agents that might interfere with the evaluation of the therapeutic response or safety of the study drug: agents known to prolong the QT interval, any digitalis preparation

  • Clinically significant hepatic disease

  • End‐stage kidney disease requiring dialysis

  • Participation in another trial of an investigational drug or device within 30d (or longer as per local requirements) or treatment with ranolazine or previous participation in MERLIN

  • Inability to comply with the protocol and follow‐up visits

  • Any serious medical comorbidity such the patients life expectancy is < 12 months

  • Any condition that might increase the risk to the patient or decrease the chance of obtaining satisfactory data to achieve the objectives of the study

Interventions

Number of intervention groups: 2

Concomitant medications: intravenous ranolazine 12 hours to 96 hours before intervention

Excluded medications: none (apart from those mentioned in the exclusion criteria)

Placebo group

Intervention: placebo twice daily

Duration of intervention: mean of 350 days

Ranolazine group

Intervention: ranolazine ER 1000 mg twice daily (500 mg twice daily for renal insufficiency patients)

Duration of intervention: mean of 350 days

Outcomes

Total number of outcomes:

  • According to study protocol: 7 (composite of cardiovascular (CV) death, myocardial infarction (MI) and recurrent ischaemia, rate of major cardiovascular events (composite of CV death, MI and severe recurrent ischaemia), rate of failure of therapy (composite of CV death, MI, recurrent ischaemia, positive Holter for ischaemia, hospitalisation for new/worsening heart failure, or early positive ETT), rate of CV death, MI, severe recurrent ischaemia or positive Holter for ischaemia through 30 days, quality of life at 4 months, duration of exercise on ETT at 8 months, total duration of ischaemia on Holter monitoring between randomisation and 72 h, death from any cause, composite of death from any cause or any cardiovascular hospitalisation, frequency of symptomatic documented arrhythmia, frequency of clinically significant arrhythmias detected during protocol‐related Holter monitoring, serious adverse events related to study drug and clinically significant laboratory abnormalities)

  • Reported: 6 (composite of cardiovascular death, myocardial infarction, or recurrent ischaemia; worsening angina; need for an increase of anti‐anginal therapy; exercise duration on ETT; Holted‐detected arrhythmias; adverse events)

All‐cause mortality

Outcome definition: number of deaths

Method and unit of measurement: absolute frequency

Time points reported: overall study duration (mean of 350 days)

RESULTS

All‐cause mortality

Sample size: 3560 (1785 + 1775) (intention‐to‐treat analysis)

Missing participants: 5

Summary data: 114/1775 ‐ 111/1785 for placebo‐ranolazine group

Subgroup analyses: not performed

Adverse events

The most common adverse effects that were more frequent in the ranolazine group compared with placebo were dizziness (12.4% versus 7.4%), nausea (9.7% versus 6.1%) and constipation (8.5% versus 3,3%).

Notes

Relevant observations for the data provided before: sub‐study of the MERLIN TIMI 36 trial not considered in the protocol

Source of funding: CV Therapeutics (CVT), Inc.

Notable conflicts of interest: five of the authors have financial relationships with CVT

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Via a central computerised telephone system

Allocation concealment (selection bias)

Low risk

Not mentioned. However, given the use of a centralised telephone system for randomization (and allocation), it can be assumed that study personnel was blinded until the moment of assignment.

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Study is declared to be double‐blinded, but no description is provided

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

All elements of the primary composite and major secondary efficacy end points as well as hospitalisation for new or worsening heart failure were adjudicated by members of a Clinical Events Committee blinded to treatment allocation. Exercise treadmill test results were also interpreted by a core laboratory blinded to treatment allocation

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Patients who did not complete the trial are described, but the treatment they were receiving or the reasons for withdrawal are not specified

Selective reporting (reporting bias)

High risk

This sub‐study of the MERLIN TIMI 36 trial included in this review was not pre‐specified in the published protocol. Furthermore, results for some outcomes (laboratory abnormalities) included in the protocol are not reported in the paper while results for some other outcomes (worsening angina, need for an increase of anti‐anginal therapy) not mentioned in the protocol are reported in the paper.

Other bias

High risk

The study was supported by CV Therapeutics (CVT), Inc. Five of the authors have financial relationships with CVT

Pelliccia 2012

Methods

Study design: parallel‐group trial

Total study duration: 37 days

Duration of follow‐up: 30 days

Method of randomisation: not described

Method of concealment of allocation: not mentioned

Blinding: double‐blind, not described

Power calculation: not mentioned

Phases of the study: 2 (treatment phase, 30‐day follow‐up phase)

Number of patients randomised: 70 (35/35 for placebo/ranolazine group)

Exclusions post‐randomisation: not reported

Withdrawals (and reasons): not reported

Participants

Total number: 70

Country of enrolment: Italy

Setting/location: not specified

Diagnostic criteria (stable angina pectoris): typical stable effort angina with positive stress test, with indication for PCI

Comorbidities: none

Age (mean ± SD): 60 ± 18/64 ± 17 for placebo/ranolazine group

Gender (male %): 57%/63% for placebo/ranolazine group

Inclusion criteria:

  • Presence of typical stable effort angina

  • Positive stress test (exercise stress test, stress myocardial scintigraphy, or dobutamine stress echocardiography)

  • Indication for PCI

Exclusion criteria:

  • Acute myocardial infarction (< 3 months)

  • Unstable angina

  • Any increase in CK‐MB, troponin I, or myoglobin above ULN at the time of randomisation

  • Any increase in liver enzymes

  • Left ventricular ejection fraction < 40%

  • Renal failure with estimated glomerular filtration rate < 60 mL/min per 1.73 m²

  • History of liver or muscle disease

Interventions

Number of intervention groups: 2

Concomitant medications: aspirin 100 mg/d, loading dose of clopidogrel 600 mg or ticlopidine 250 mg bid (before the procedure), and clopidogrel 75 mg/d or ticlopidine 250 mg bid for 1 or 12 months. Other medications such as β‐blockers, calcium antagonists, statins, and angiotensin‐converting enzyme inhibitors given as appropriate

Excluded medications: none

Placebo group

Intervention: placebo as pretreatment for PCI

Duration of intervention: 1 week

Ranolazine group

Intervention: ranolazine (type of formulation not specified) 1000 mg twice daily as pretreatment for PCI

Duration of intervention: 1 week

Outcomes

Total number of outcomes:

  • According to study protocol: no published protocol; according to the "Methods" section: 2 (periprocedural myocardial infarction, incidence of MACE by 30 days (death, myocardial infarction, target‐vessel revascularisation))

  • Reported: 2

All‐cause mortality

Outcome definition: number of deaths

Method and unit of measurement: absolute frequency

Time points reported: 37 days

Acute myocardial infarction incidence (fatal and non‐fatal)

Outcome definition: (periprocedural) postprocedural increase of CK‐MB ≥ 3 times above the upper limit of normal, number of cases

Method and unit of measurement: absolute frequency

Time points reported: 7 days (periprocedural), 37 days (periprocedural plus spontaneous)

Need for revascularisation procedure

Outcome definition: target‐vessel revascularisation, number of cases

Method and unit of measurement: absolute frequency

Time points reported: 37 days

RESULTS

All‐cause mortality

Sample size: 70 (intention‐to‐treat analysis)

Missing participants: none

Summary data: 1/35‐0/35 for placebo‐ranolazine group

Subgroup analyses: not performed

Acute myocardial infarction incidence (fatal and non‐fatal)

Sample size: 70 (intention‐to‐treat analysis)

Missing participants: none

Summary data: 9/35‐2/35 for placebo/ranolazine group (37 days)

Subgroup analyses: not performed

Need for revascularisation procedure

Sample size: 70 (intention‐to‐treat analysis)

Missing participants: none

Summary data: 1/35‐1/35 for placebo‐ranolazine group

Subgroup analyses: not performed

Notes

Relevant observations for the data provided before: none

Source of funding: no extramural funding

Notable conflicts of interest: no conflicts of interest to declare.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Randomisation is stated but not described

Allocation concealment (selection bias)

Unclear risk

Not mentioned

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Study declared to be double‐blinded, but no description is provided

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Study declared to be double‐blinded, but no description is provided

Incomplete outcome data (attrition bias)
All outcomes

Low risk

No exclusion or withdrawal is reported, we assume that all patients completed the study

Selective reporting (reporting bias)

Unclear risk

There is no published protocol. Results for all the outcomes stated in the "Methods" section of the paper are reported

Other bias

Low risk

The authors declare that the study was not supported by any external source of funding. Furthermore, there were no conflicts of interest to declare.

Pepine 1999

Methods

Study design: cross‐over trial

Total study duration: 8 weeks

Duration of follow‐up: no follow‐up beyond treatment phase

Method of randomisation: not described

Method of concealment of allocation: not mentioned

Blinding: double‐blind (with "double dummy" technique)

Power calculation: not mentioned

Phases of the study: 2 (qualifying phase, treatment phase)

Number of patients randomised: 318

Exclusions post‐randomisation: 6 (not described)

Withdrawals (and reasons): premature withdrawals due to adverse events are declared to have been very similar for all treatments, but no details are provided

Participants

Total number: 312

Country of enrolment: United States, Canada.

Setting/location: not specified

Diagnostic criteria (stable angina pectoris): chronic (≥ 3 months) stable angina pectoris that had responded to conventional anti‐anginal therapy

Comorbidities: none

Age (mean, range): 64.3 (33‐85) years

Gender (male %): 226 (72%)

Inclusion criteria:

  • Chronic (≥ 3 months) stable angina pectoris that had responded to conventional anti‐anginal therapy

  • Exercise‐induced ischaemia, defined as horizontal or down‐sloping ≥1 mm ST‐segment depression persisting in 3 consecutive beats

Exclusion criteria:

  • Left ventricular hypertrophy

  • Preexcitation

  • Conduction abnormalities

  • Pacemaker rhythm

  • Unstable angina

  • Myocardial infarction within the preceding 3 months

  • Heart failure (New York Heart Association class III or IV)

  • Uncorrected valvular

  • Congenital heart disease

  • Need for digoxin or long‐acting nitrates

  • Labile diabetes

  • Conditions that would confuse follow‐up evaluation

Interventions

Number of intervention groups: 4

Concomitant medications: β‐blockers and/or calcium antagonists (minimum medication needed during qualifying phase)

Excluded medications: long‐acting nitrates

Placebo group

Intervention: placebo

Duration of intervention: 1 week (5 double‐blind treatment periods in an extended period Latin square design)

Ranolazine 400 mg bid group

Intervention: ranolazine IR 400 mg twice daily

Duration of intervention: 1 week (5 double‐blind treatment periods in an extended period Latin square design)

Ranolazine 267 mg tid group

Intervention: ranolazine IR 267 mg thrice daily

Duration of intervention: 1 week (5 double‐blind treatment periods in an extended period Latin square design)

Ranolazine 400 mg tid group

Intervention: ranolazine IR 400 mg thrice daily

Duration of intervention: 1 week (5 double‐blind treatment periods in an extended period Latin square design)

Outcomes

Total number of outcomes:

  • According to study protocol: no published protocol; according to the "Methods" section: 9 (ETT time to onset of angina (peak and through), ETT duration of exercise (peak and through), ETT time to onset of ischaemic‐type ST‐segment depression (peak and through), haemodynamic, laboratory, adverse events)

  • Reported: 9

Adverse events incidence

Outcome definition: number of patients experiencing an adverse event

Method and unit of measurement: percentage

Time points reported: 1 week

RESULTS

Adverse events incidence

Sample size: 312 (intention‐to‐treat)

Missing participants: 6

Summary data: it is stated that adverse events rates were similar for all ranolazine and placebo regimens and approximately 25%, but data for each group is not reported. It is stated that only minor gastrointestinal complaints tended to occur more often with ranolazine (6.6% to 10.7%) than with placebo (3,2%).

Subgroup analyses: not performed

Notes

Relevant observations for the data provided before: "all patients" (intention‐to‐treat) (N = 312) and per‐protocol (N = 260) analysis were performed for ETT variables

Source of funding: in part by a grant from Syntex Research

Notable conflicts of interest: not stated

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Randomisation is stated but no described

Allocation concealment (selection bias)

Unclear risk

Not mentioned

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Study is declared to be double‐blinded, but no description is provided

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Study is declared to be double‐blinded, but no description is provided

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Exclusions and withdrawals are reported, but no reasons or explanations are provided

Selective reporting (reporting bias)

Unclear risk

There is no published protocol. Results for all the outcomes stated in the "Methods" section of the paper are reported

Other bias

Unclear risk

The study was supported in part by a grant from Syntex Research. The authors did not stated any conflicts of interest.

RAN080 2005

Methods

Study design: cross‐over trial

Total study duration: 28 to 40 days

Duration of follow‐up: no follow‐up beyond treatment phase

Method of randomisation: not described

Method of concealment of allocation: not mentioned

Blinding: double‐blind (with 'double‐dummy' technique), not described

Power calculation: not mentioned

Phases of the study: 2 (qualifying phase, treatment phase)

Number of patients randomised: 158

Exclusions post‐randomisation: 4 (did not perform ≥ 1 exercise test in the treatment phase)

Withdrawals (and reasons): 6, 4 withdrawals attributed to adverse events (2 during ranolazine therapy, 1 because of hematologic abnormality, 1 because of asthenia, nausea and chest pain; 2 during placebo therapy, due to exacerbation of angina)

Participants

Total number: 158

Country of enrolment: Europe and Canada

Setting/location: not specified

Diagnostic criteria (stable angina pectoris): symptoms and exercise test results that support the diagnosis of chronic angina with evidence of CAD (macrovascular angina)

Comorbidities: none

Age (mean ± SD): 59 ± 8 years

Gender (male %): 89%

Inclusion criteria:

  • Age 18 to 75 years

  • Evidence of coronary artery disease consisting of a well‐documented medical history of myocardial infarction or significant coronary artery disease (defined by the presence of ≥ 50% diameter stenosis accompanied by ischaemic electrocardiographic signs and angina during exercise), ideally within 12 months of study entry

  • Symptoms that supported the diagnosis of chronic angina and a bicycle or modified Bruce’s protocol treadmill exercise electrocardiogram that showed ≥1‐mm ST‐segment depression 3 to 9 min after the start of exercise

  • Documented improvement in anginal symptoms and ST‐segment depression during exercise testing after administration of standard anti‐anginal medical therapy (β blockers, long‐acting nitrates, and/or calcium channel blockers)

Exclusion criteria:

  • Clinically significant arrhythmias

  • Implanted pacemaker

  • Pre‐exercise ST‐segment depression ≥1mm in any lead, left bundle branch block, digoxin therapy, or other factors that could reasonably interfere with exercise electrocardiographic interpretation

  • History of congestive heart failure, unstable angina, or myocardial infarction at any time ≤1 month before study entry

  • Clinically significant comorbidities, including hepatic or renal dysfunction, pulmonary hypertension, chronic obstructive pulmonary disease, a history of cerebral haemorrhage, or seizure disorder that required anticonvulsant medication

  • Pregnancy or lactation

  • Verapamil therapy

  • Inability to discontinue β‐blocker therapy

Interventions

Number of intervention groups: 3

Concomitant medications: (permitted) short‐acting nitrates, calcium cannel blockers (except those that are cardiodepressants)

Excluded medications: β‐blockers, verapamil

Placebo group

Intervention: Placebo

Duration of intervention: 7 to 10 days

Atenolol group

Intervention: atenolol 100 mg/d

Duration of intervention: 7 to 10 days

Ranolazine group

Intervention: ranolazine IR 400 mg thrice daily

Duration of intervention: 7 to 10 days

Outcomes

Total number of outcomes:

  • According to study protocol: no published protocol; according to the "Methods" section: 6 (time to onset of angina, time to 1‐mm ST segment depression, total exercise duration, heart rate x systolic blood pressure, angina frequency, nitroglycerin consumption)

  • Reported: 9 (including heart rate, blood pressure, and safety and adverse events)

Acute myocardial infarction incidence (fatal and non‐fatal)

Outcome definition: mentioned as “serious adverse events”, number of cases

Method and unit of measurement: absolute frequency

Time points reported: 28 to 40 days (total study duration)

Angina episodes frequency

Outcome definition: average number of episodes per week

Method and unit of measurement: number per week

Time points reported: 28 to 40 days (total study duration)

Adverse events incidence

Outcome definition: number of patients that reported ≥ 1 adverse event

Method and unit of measurement: absolute frequency

Time points reported: 28 to 40 days

RESULTS

Acute myocardial infarction incidence (fatal and non‐fatal)

Sample size: 155 (intention‐to‐treat analysis)

Missing participants: 3

Summary data (for each intervention group) (according to type of analysis) (for the largest time point): 1/154 – 0/154 – 0/155 for placebo – atenolol – ranolazine group

Subgroup analyses: not performed

Angina episodes frequency

Sample size: not specified (presumably 154)

Missing participants: not specified (presumably 4)

Summary data: numerical data not reported

Subgroup analyses: not performed

Adverse events incidence

Sample size: 155 (intention‐to‐treat analysis)

Missing participants: 3

Summary data: 26/154 – 39/154 – 45/155 for placebo – atenolol – ranolazine group. The most frequently reported adverse events were asthenia (19/26/4), dizziness (2/9/4), headache (6/0/5), nausea (6/0/2), palpitations (4/2/3), dyspepsia (7/0/2), pain (1/2/2), constipation (5/0/1), malaise (1/1/2) and dyspnoea (0/1/3) for ranolazine/atenolol/placebo group.

Subgroup analyses: not performed

Notes

Relevant observations for the data provided before: none

Source of funding: CV Therapeutics, Inc.

Notable conflicts of interest: not stated

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Randomisation is stated but not described

Allocation concealment (selection bias)

Unclear risk

Not mentioned

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Study declared to be double‐blinded, but no description is provided

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Study declared to be double‐blinded, but no description is provided

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Six patients are reported not to have completed the study. Reasons for withdrawal and treatment assigned are not described for two of them

Selective reporting (reporting bias)

High risk

There is no published protocol. Results for all the outcomes stated in the "Methods" section of the paper are reported, but results for some additional outcomes (haemodynamics and safety and adverse events) are also reported

Other bias

High risk

The study was supported by CV Therapeutics, Inc. Conflicts of interest were not stated.

RIVER‐PCI 2016

Methods

Study design: parallel‐group trial

Total study duration: about 3.5 years

Duration of follow‐up: mean of 643 days

Method of randomisation: interactive web‐based block randomisation system (block sizes of 10), with randomisation stratified by diabetes history (presence versus absence) and acute coronary syndrome presentation (acute versus non‐acute)

Method of concealment of allocation: not described in enough detail, it is just mentioned that investigators and patients were masked to treatment allocation

Blinding: double‐blind, referred to participants, clinicians ("masked to treatment allocation"), data collectors (independent Data Safety Monitoring Board, independent on‐site clinical monitors, independent angiographic core laboratory), outcome adjudicators (independent Clinical Endpoint Committee) and data analysts (independent statistical data analysis group, Duke Clinical Research Institute for quality of life and economic analyses)

Power calculation: 85% power using a 2‐sided log‐rank test at the 5% significance level, with regard to the primary end point events

Phases of the study: 1 (treatment phase, including a 7‐day run‐in period)

Number of patients randomised: 2651 (1319/1332 for placebo/ranolazine group)

Exclusions post‐randomisation: 32 exclusions in the placebo group (19 not treated, 3 scientific misconduct, 10 no qualifying PCI), 15 exclusions in the ranolazine group (7 not treated, 3 scientific misconduct, 5 no qualifying PCI). Additionally, for the quality of life sub‐study, there were 105 exclusions in the placebo group (97 questionnaires invalid, 8 questionnaires not done) and 110 exclusions in the ranolazine group (103 questionnaires invalid, 7 questionnaires not done)

Withdrawals (and reasons): 463/1287 ‐ 529/1317 for placebo ‐ ranolazine group, reasons detailed in the appendix of the study report

Participants

Total number: 2651

Country of enrolment: 15 countries (Europe, Israel, Russia, USA)

Setting/location: inpatient and outpatient

Diagnostic criteria (stable angina pectoris): symptoms of stable angina

Comorbidities: incomplete revascularisation (ICR) post‐PCI

Age (mean): 63.3±10 / 63.3±10.4 years for placebo/ranolazine group

Gender (male %): 80.3% / 79.7% for placebo/ranolazine group

Inclusion criteria:

  • Men and women aged ≥18 years

  • History of chronic angina, defined as ≥ 2 episodes of angina pain or discomfort in the chest, jaw, shoulder, back, neck, or arm that is precipitated by exertion or emotional stress and relieved by rest or sublingual nitroglycerin, occurring on ≥ 2 separate days and ≥14 d before PCI (in the case of staged PCI procedures, a history of angina has to have occurred at least 14 days before the first PCI in the series)

  • PCI for any indication (ACS or non‐ACS)

  • Evidence of ICR post‐PCI. ICR is defined as the presence of ≥ 1 lesion with visually estimated ≥50% diameter stenosis in any coronary artery (including branch vessels) with reference vessel diameter ≥2.0 mm, whether in the target vessel or in a non‐target vessel. In the case of a participant post‐CABG, ICR is defined as the presence of ≥ 1 lesion with visually estimated ≥ 50% diameter stenosis in a non bypassed epicardial vessel ≥ 2.0 mm in diameter, or ≥1 visually estimated ≥ 50% diameter stenosis in a bypass graft supplying an otherwise non revascularised myocardial territory

  • Clinically stable post‐PCI. Participants randomised in hospital on the day of planned discharge or in clinic are considered stable. Participants randomised in hospital before the day of planned discharge must meet all of the following criteria:

    • CK‐MB < 3 times the upper limit of normal (ULN) ≥3 hours after PCI, or with evidence of decreasing CK‐MB (by at least 20% from the prior measurement) if ≥3 times the ULN, each as reported by local laboratory. If CK‐MB is not available, the participant must have evidence of normal or decreasing troponin levels (by at least 20% from the prior measurement) ≥3 hours after PCI, as reported by local laboratory

    • Systolic blood pressure ≥ 90 mm Hg and not receiving pressors or inotropes

    • No current requirement for an intra‐aortic balloon pump or any left ventricular assist device

    • No current requirement for intravenous (IV) nitroglycerin

  • Women of childbearing potential must have a negative pregnancy test result at screening (unless surgically sterile or postmenopausal) and must agree to use highly effective contraception methods from screening throughout the duration of study treatment and for 14 d after the last dose of study drug

  • Ability and willingness to comply with all study procedures during the course of the study

Exclusion criteria:

  • Any future planned revascularisation (including staged procedures) or possible planned revascularisation (e.g. planned stress test to assess the imminent need for additional revascularisation). Future planned stress tests for purposes of monitoring are permitted but strongly discouraged. Participants may be enrolled after the last PCI in the staged series or once a decision is made not to perform a follow‐up PCI, as long as randomisation occurs within 14 d from the last PCI. If a participant has had a stress test after PCI and before randomisation and no further intervention is planned, the participant may be enrolled within 14 days from the last PCI.

  • Unrevascularised left main coronary artery lesion with diameter stenosis ≥ 50%. Participants with a history of CABG to the left coronary system will be considered to have a revascularised left main if at least 1 graft is patent.

  • Major complication during or after the index PCI (in the case of staged PCI, the last in the series) including any of the following:

    • TIMI major bleeding or any bleeding requiring blood transfusion of ≥ 2 units of red blood cells

    • Coronary perforation requiring treatment

    • Procedural complication requiring surgery (including CABG or peripheral vascular surgery)

  • Stroke within 90 days before randomisation or any history of stroke with permanent major neurologic disability Cardiogenic shock within 90 d before randomisation (transient decreases in blood pressure without clinical sequelae are not considered to be cardiogenic shock)

  • New York Heart Association class III or IV heart failure

  • Severe renal insufficiency as defined by an estimated GFR 30 mL/min per 1.73 m² using the 4 variable modification of diet in renal disease equation (based on the last available measurement before randomisation, collected within 1 mo before the index PCI [or in the case of staged PCI, the last in the series])

  • Liver cirrhosis

  • Use of class Ia, Ic, or class III anti‐arrhythmic agents, except for amiodarone

  • Current treatment with strong inhibitors of CYP3A

  • Current treatment with cytochrome P450 3A4 inducers or P‐gp inducers

  • Participants taking > 20 mg simvastatin daily or > 40 mg lovastatin daily who cannot reduce the dose to 20 mg once daily for simvastatin or 40 mg once daily for lovastatin, or who cannot switch to another statin

  • Participants taking > 1000 mg daily of metformin who cannot reduce the dose to a maximum total of 1000 mg daily (additional antidiabetic medications may be added as clinically indicated to allow participants to decrease their metformin dose and maintain glycaemic control)

  • Previous treatment with ranolazine for > 7 consecutive days within 30 d before randomisation, or known hypersensitivity or intolerance to ranolazine or to any of the excipients

  • Participation in another investigational drug or investigational device study within 30 d before randomisation (participation in registries is allowed)

  • Women who are pregnant or breast‐feeding

  • Non–coronary artery disease–related comorbid conditions (e.g. advanced malignancy, severe aortic stenosis), which are likely to result in death within 2 years of randomisation

Interventions

Number of intervention groups: 2

Concomitant medications: per the discretion of the investigator

Excluded medications: those mentioned in exclusion criteria

Placebo group

Intervention: placebo

Duration of intervention: mean (IQR) of 642 (575‐561) days

Ranolazine group

Intervention: ranolazine (type of formulation not specified) 1000 mg twice daily

Duration of intervention: mean (IQR) of 644 (575‐757) days

Outcomes

Total number of outcomes: 1

  • According to study protocol: 14 (time from randomisation to the occurrence of ischemia‐driven revascularisation/hospitalisation, sudden cardiac death, cardiovascular death, myocardial infarction; all‐cause mortality; incidence of major adverse cardiovascular events: stroke, transient ischaemic attack, hospitalisation for heart failure; SAQ score, DASI score, symptoms by Rose Dyspnea Scale score (quality of life sub‐study);cumulative total US medical costs, health care costs and resource use, cost per life‐year added and cost per quality‐adjusted life‐year added (health economics sub study))

  • Reported: 16 (including incidence of ischemia‐driven revascularisation/hospitalisation, sudden cardiac death, cardiovascular death, myocardial infarction, missing time to event for sudden cardiac death, cardiovascular death and myocardial infarction)

Cardiovascular mortality

  • Outcome definition: death from cardiac disease, stroke, pulmonary embolism (in the absence of conditions such as malignancy), peripheral artery disease or cardiovascular intervention/surgery

  • Method and unit of measurement: absolute frequency

  • Time points reported: overall study duration

All‐cause mortality

  • Outcome definition: number of deaths

  • Method and unit of measurement: absolute frequency

  • Time points reported: overall study duration

Quality of life

1. Seattle Angina Questionnaire (SAQ)

  • Outcome definition: includes 5 domains: angina frequency, angina stability, angina‐related treatment satisfaction, angina‐related physical functioning and QOL

  • Upper and lower limits and whether a high or low score is good: each domain is scored separately from 0 to 100, with higher scores indicating better health status

  • Method and unit of measurement: score for each domain

  • Time points reported: 1, 6, 12 months

2. Duke Activity Satuts Index (DASI)

  • Outcome definition:12‐item scale which focuses on physical activity ranging from self‐care to strenuous physical work; each activity is weighted by the metabolic output associated with its performance, and a final score weights the performed activities

  • Upper and lower limits and whether a high or low score is good: score ranges from 0 (worst) to 58.2 (best)

  • Method and unit of measurement: score

  • Time points reported: 1, 6, 12 months

3. Mental Health Inventory‐5 (MHI‐5)

  • Outcome definition: 5‐question scale derived from the 36‐item Short Form Health Survey (SF‐36) version 2.0

  • Upper and lower limits and whether a high or low score is good: not described

  • Method and unit of measurement: score

  • Time points reported: 1, 6, 12 months

4. European QOL Five Dimension Three‐Level Scale (EuroQOL‐5D‐3 L)

  • Outcome definition: 5‐item instrument assessing specific domains of mobility, self‐care, usual activities, pain/discomfort, and anxiety/depression

  • Upper and lower limits and whether a high or low score is good: not described

  • Method and unit of measurement: score

  • Time points reported: 1, 6, 12 months

5. Rose Dyspnea Scale (RDS)

  • Outcome definition: not described

  • Upper and lower limits and whether a high or low score is good: not described

  • Method and unit of measurement: score

  • Time points reported: 1, 6, 12 months

Acute myocardial infarction incidence (fatal and non‐fatal)

  • Outcome definition: episodes defined by symptoms suggestive of ischaemia/infarction in association with ECG, cardiac biomarker, or pathologic evidence of infarction

  • Method and unit of measurement: absolute frequency

  • Time points reported: overall study duration

Need for revascularisation procedure

  • Outcome definition: any PCI or CABG surgery occurring after randomisation for angina or angina equivalent symptoms, with or without documented ischaemia. PCI is defined as an attempt to cross a lesion with a wire with the intention of performing revascularisation

  • Method and unit of measurement: absolute frequency

  • Time points reported: overall study duration

RESULTS

Cardiovascular mortality

  • Sample size: 2604 (intention‐to‐treat analysis)

  • Missing participants: 47 (32/15 for placebo/ranolazine group)

  • Summary data: 20/1287 ‐ 21/1317 for placebo ‐ ranolazine group

  • Subgroup analyses: not performed

All‐cause mortality

  • Sample size: 823 (intention‐to‐treat analysis)

  • Missing participants: 32 (22/10 for placebo/ranolazine group)

  • Summary data: 36/1297 ‐ 42/1322 for placebo ‐ ranolazine group

  • Subgroup analyses: not performed

Quality of life 1182 1207

1. Seattle Angina Questionnaire (SAQ)

  • Sample size: 1958 (980/978 for the placebo/ranolazine group) (intention‐to‐treat analysis)

  • Missing participants: 202/229 for placebo/ranolazine group

  • Summary data: baseline/12‐month (mean ± SD) score in the QOL domain: 49.5 ± 22.8 / 70.4 ± 22.2 for placebo group, 48.3 ± 22.3 / 70.3 ± 22.5 for ranolazine group

  • Subgroup analyses: performed for the following variables: age, sex, indication for the qualifying PCI, baseline anti‐anginal use, diabetes mellitus, baseline angina

2. Duke Activity Satuts Index (DASI)

  • Sample size: 1957 (980/977 for the placebo/ranolazine group) (intention‐to‐treat analysis)

  • Missing participants: 202/230 for the placebo/ranolazine group

  • Summary data: baseline/12‐month (mean±SD) score: 18.7±14.3 / 23.3±16.1 for placebo group, 18.7±14.9 / 22.5±15.8 for ranolazine group

  • Subgroup analyses: performed for the following variables: age, sex, indication for the qualifying PCI, baseline anti‐anginal use, diabetes mellitus, baseline angina

3. Mental Health Inventory‐5 (MHI‐5)

  • Sample size: 1954 (978/976 for the placebo/ranolazine group) (intention‐to‐treat analysis)

  • Missing participants: 204/231 for placebo/ranolazine group

  • Summary data: baseline/12‐month (mean±SD) score: 64.1 ± 19.6 / 70.4 ± 18.0 for placebo group, 64.9±19.2 / 70.3 ± 18.1 for ranolazine group

  • Subgroup analyses: performed for the following variables: age, sex, indication for the qualifying PCI, baseline anti‐anginal use, diabetes mellitus, baseline angina

4. European QOL Five Dimension Three‐Level Scale (EuroQOL‐5D‐3 L)

  • Sample size: 1934 (973/961 for the placebo/ranolazine group) (intention‐to‐treat analysis)

  • Missing participants: 209/246 for placebo/ranolazine group

  • Summary data: baseline/12‐month (mean±SD) score: 0.75 ± 0.23 / 0.78 ± 0.23 for placebo group, 0.75 ± 0.23 / 0.79 ± 0.22 for ranolazine group

  • Subgroup analyses: performed for the following variables: age, sex, indication for the qualifying PCI, baseline anti‐anginal use, diabetes mellitus, baseline angina

5. Rose Dyspnea Scale (RDS)

  • Sample size: 1939 (971/968 for the placebo/ranolazine group) (intention‐to‐treat analysis)

  • Missing participants: 211/239 for placebo/ranolazine group

  • Summary data: baseline/12‐month (mean ± SD) score: 1.7 ± 1.4 / 1.0 ± 1.3 for placebo group, 1.7±1.4 / 1.1 ± 1.3 for ranolazine group

  • Subgroup analyses: performed for the following variables: age, sex, indication for the qualifying PCI, baseline anti‐anginal use, diabetes mellitus, baseline angina

Acute myocardial infarction incidence (fatal and non‐fatal)

  • Sample size: 2604 (intention‐to‐treat analysis)

  • Missing participants: 47 (32/15 for placebo/ranolazine group)

  • Summary data: 116/1287 ‐ 111/1317 for placebo ‐ ranolazine group

  • Subgroup analyses: not performed

Need for revascularisation procedure

  • Sample size: 2604 (intention‐to‐treat analysis)

  • Missing participants: 47 (32/15 for placebo/ranolazine group)

  • Summary data: 200/1287 ‐ 201/1317 for placebo ‐ ranolazine group

  • Subgroup analyses: performed for the following variables: sex, age, precedence, diabetes mellitus, indication for PCI, type of vessel disease, residual SYNTAX score, type of PCI device, total occlusion, previous CABG, baseline BNP and baseline LVEF

Adverse events

Dizziness, constipation, nausea, hypotension, vomiting and vertigo were reported more often in the ranolazine group than in the placebo group.

Notes

Relevant observations for the data provided before: none

Source of funding: Gilead Sciences, Menarini Group

Notable conflicts of interest: seven of the authors declare current of past financial relationships with Gilead Sciences

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Computer‐generated random sequence. Random sequence generated by an interactive web‐based block randomisation system with block sizes of ten

Allocation concealment (selection bias)

Low risk

Described for participants and clinicians as "masked to treatment allocation". The use of a web‐based system for randomization (and allocation) can be considered sufficient to mantain blinded the study personnel until the momment of assignment.

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Treatment phase is declared to be double‐blinded, but no description for participants and personnel is provided. However, the subjects idea about study arm was measured, and study data was collected by independent groups, then presumably both participants and investigators were blinded

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Data for events and quality of life/economic analyses were collected by independent outcome adjudication groups

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Exclusions and withdrawals are described, and reason are reported

Selective reporting (reporting bias)

High risk

There are two sub studies (quality of life and health economics) besides the main study for the RIVER‐PCI trial, and all the main endpoints considered in the protocol were reported (the health economics sub study has not yet been published). Of note, for the events under study, time to event occurrence was stated to be the endpoint rather than the rate/incidence of the event; however, results for the secondary endpoint events were reported only as rate/incidence, and no data about time to event occurrence was provided

Other bias

High risk

The study was supported by Gilead Sciences and Menarini Group. Seven of the authors declare current or past financial relationships with Gilead Sciences.

RWISE 2016

Methods

Study design: cross‐over trial

Total study duration: recruitment was undertaken since 12 May 2011 to 10 Aug 2015, treatment phase duration was of 6 weeks (including 2 periods of treatment of 2 weeks and 1 period of washout of 1 week)

Duration of follow‐up: 2 weeks

Method of randomisation: performed at a 1:1 ratio blocked by clinical site, not further described

Method of concealment of allocation: not mentioned

Blinding: double‐blind, not described

Power calculation: 90% power to detect a mean difference of 15 in SAQ score using a two‐sided t‐test at the 0.017 Holm‐Bonferroni corrected level of significance

Phases of the study: 1 (treatment phase)

Number of patients randomised: 142

Exclusions post‐randomisation: 4 participants were excluded because they received incomplete treatment

Withdrawals (and reasons): number differ between the text (subject characteristics) and figure 1, data from the later was deemed to be more coherent. Five participants dropped‐out during ranolazine treatment and 4 during placebo washout (no dropouts during ranolazine washout), reasons not described

Participants

Total number: 128

Country of enrolment: USA

Setting/location: not specified

Diagnostic criteria (stable angina pectoris): chronic angina or its equivalent with coronary angiogram revealing coronary microvascular dysfunction (CMD) with no obstructive CAD (microvascular angina)

Comorbidities: none

Age (mean ± SD): 55.2 ± 9.2 years

Gender (male %): 4%

Inclusion criteria:

  1. Men or women age > 18 years from diverse racial/ethnic groups;

  2. Competent to give informed consent;

  3. Patients with chronic angina or its equivalent;

  4. Coronary angiogram revealing CMD with no obstructive CAD (epicardial coronary stenosis <50% luminal diameter stenosis); or measured noninvasively using the Society of Cardiovascular Computed Tomography threshold of < 50% stenosis.

  5. Left ventricular ejection fraction ≥ 45%;

  6. Objective evidence of ischaemia by noninvasive methods such as exercise stress test, stress Echo, CMRI or single photon emission tomography (SPECT);

  7. Patients with CMD defined as an invasive measured CFR < 2.5 or acetylcholine (ACH) response of no dilation or constriction, determined by local site read, or a CMRI derived MPRI ≤ 2.0**.

  8. Patients must have withdrawn from ranolazine at least 2 weeks prior to study entry.

  9. Either a qualifying WISE or clinical CMRI scan must be completed within 2.5 years ± 1 month of study participation.

  10. Qualifying angiograms must have been within 2.5 years ± 1 month of study enrolment.

Exclusion criteria:

  1. Acute coronary syndrome (defined by World Health Organization [WHO]), cardiogenic shock or requiring inotropic or intra‐aortic balloon support;

  2. Planned percutaneous coronary intervention or coronary bypass surgery or established obstructive CAD with ischaemia eligible for revascularisation, acute myocardial infarction (MI);

  3. Prior non‐cardiac illness with estimated life expectancy < 4 years;

  4. Unable to give informed consent;

  5. Allergy or contra‐indication to CMRI testing, including renal failure, claustrophobia, and asthma, uncontrolled moderate hypertension (sitting blood pressure (BP) > 160/95 mm Hg with measurements recorded on at least 2 occasions), other conditions likely to influence outcomes: Severe lung, creatinine > 1.8 or creatinine clearance [CrCl] ≤ 50 mL/min) or hepatic disease;

  6. Surgically uncorrected significant congenital or valvular heart disease and other disease likely to be fatal or require frequent hospitalisation within the next six months;

  7. Adherence or retention reasons;

  8. Unwilling to complete follow‐up evaluation including repeat testing, documented obstructive hypertrophic cardiomyopathy;

  9. Aortic stenosis (valve area < 1.5 cm);

  10. LV dysfunction (ejection fraction < 45%);

  11. History of significant cocaine or amphetamine abuse;

  12. Taking potent CYP3A4 inhibitors (ketoconazole, itraconazole, nefazodone, troleandomycin, clarithromycin, ritonavir, nelfinavir)

  13. Women who are pregnant

Interventions

Number of intervention groups: 2

Concomitant medications: (permitted) anti‐anginals, antihypertensives, statins, hormone replacement therapy

Excluded medications: those mentioned in exclusion criteria

Placebo group

Intervention: placebo twice daily

Duration of intervention: 2 weeks

Ranolazine group

Intervention: ranolazine ER 500/1000 mg twice daily

Duration of intervention: 2 weeks

Outcomes

Total number of outcomes:

  • According to study protocol (published in clinicaltrials.gov; published as Online Exhibit A): 7 (angina frequency, nitroglycerine use frequency, quality of life, healthcare costs, cardiac MRI perfusion and diastolic function, biochemical parameters, correlation between quality of life and cardiac MRI myocardial ischaemia improvements)

  • Reported: 6 (missing healthcare costs and biochemical parameters, including adverse events incidence)

Quality of life

1. Seattle Angina Questionnaire (SAQ and SAQ‐7)

  • Outcome definition: includes 5 domains: angina frequency, angina stability, treatment satisfaction, physical limitation and QoL

  • Upper and lower limits and whether a high or low score is good: not described

  • Method and unit of measurement: score for each domain and overall

  • Time points reported: 2 weeks

2. Duke Activity Satuts Index (DASI)

  • Outcome definition: measure of functional status

  • Upper and lower limits and whether a high or low score is good: not described

  • Method and unit of measurement: score

  • Time points reported: 2 weeks

3. QOL

  • Outcome definition: selected questions from the Medical Outcomes Study(MOS)‐Short Form‐36 Health Survey (SF‐36, energy/fatigue and emotional domains), the MOS‐116 (moody and low spirits domains), and the HIS‐GWB Mental Health (depressed and strain domains)

  • Method and unit of measurement: score separately for each domain

  • Time points reported: 2 weeks

Angina episodes frequency

  • Outcome definition: average number of episodes per week

  • Method and unit of measurement: number per week

  • Time points reported: 2 weeks

Adverse events incidence

  • Outcome definition: number of patients that reported ≥1 adverse event

  • Method and unit of measurement: absolute frequency

  • Time points reported: 2 weeks

RESULTS

Quality of life

1. Seattle Angina Questionnaire (SAQ)

  • Sample size: 128 (per‐protocol analysis)

  • Missing participants: 5/5 for placebo/ranolazine group

  • Summary data: score (mean±SD) in the QOL domain: 54.17±23.31 / 56.05±23.09 for placebo / ranolazine group

  • Subgroup analyses: not reported

2. Duke Activity Satuts Index (DASI)

  • Sample size: 128 (per‐protocol analysis)

  • Missing participants: 5/5 for placebo/ranolazine group

  • Summary data: score (mean±SD): 6.20±5.05 / 6.35±4.83 for placebo / ranolazine group

  • Subgroup analyses: not reported

3. QOL

  • Sample size: 128 (per‐protocol analysis)

  • Missing participants: 5/5‐6 for placebo/ranolazine group

  • Summary data: score (mean±SD) for each scale and domain mentioned above

  • Subgroup analyses: not reported

Angina episodes frequency

  • Sample size: 128 (per‐protocol analysis)

  • Missing participants: 5/5 for placebo/ranolazine group

  • Summary data: number/week (mean ± SD): 4.88 ± 7.75 / 4.78 ± 8.20 for placebo/ranolazine group

  • Subgroup analyses: not performed

Adverse events incidence

  • Sample size: 128 (per‐protocol analysis)

  • Missing participants: 5/5 for placebo/ranolazine group

  • Summary data: 6/128 – 7/128 for placebo – ranolazine group. The adverse events reported for the ranolazine treatment group were nausea and dizziness (3/128), arm shaking (1/128), back pain (1/128), renal abnormality (1/128) and throat swelling (1/128), for the placebo treatment group were chest pain (3(128), throat swelling (1/128), cough (1/128) and sinus infection (1/128).

  • Subgroup analyses: not performed

Notes

Relevant observations for the data provided before: none

Source of funding: unrestricted research grant from Gilead and contracts from several public (USA) entities

Notable conflicts of interest: seven of the authors declare financial relationships with private pharmaceutical organisations (Gilead among others) and public (USA) entities

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Randomisation is stated but described only as "in a 1:1 ratio, blocked by clinical site"

Allocation concealment (selection bias)

Unclear risk

Not mentioned

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Study declared to be double‐blinded, but no description is provided

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Study declared to be double‐blinded, but no description is provided

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Exclusions and withdrawals are reported, but no reasons or explanations are provided. Furthermore, inconsistencies among the data provided were observed

Selective reporting (reporting bias)

Unclear risk

Protocol published in clinicaltrials.gov and as Online Exhibit adjoined to the results publication. Healthcare costs and biochemical parameters were not reported, adverse events incidence was reported but not included among the study outcomes in protocol

Other bias

High risk

The study was supported by Gilead and several public organisations. Seven authors declared financial relationships with private pharmaceutical organisations

Sandhiya 2015

Methods

Study design: parallel‐group trial

Total study duration: from 1 January 2012 to 11 April 2013

Duration of follow‐up: no follow‐up beyond treatment phase

Method of randomisation: not described, performed in a 1:1 ratio

Method of concealment of allocation: drugs distributed using sequentially numbered opaque sealed envelopes

Blinding: not mentioned

Power calculation: not mentioned

Phases of the study: 1 (treatment phase)

Number of patients randomised: 47 (24/23 for trimetazidine/ranolazine group)

Exclusions post‐randomisation: not reported

Withdrawals (and reasons): not reported

Participants

Total number: 40

Country of enrolment: Greece

Setting/location: outpatient

Diagnostic criteria (stable angina pectoris): history of exertional angina and CAD documented by coronary angiography (macrovascular angina)

Comorbidities: diabetes mellitus

Age (mean): 57.4 ± 9.1 / 58 ± 8.1 years for trimetazidine/ranolazine group

Gender (male %): 83% (87.5/78.3 for trimetazidine/ranolazine group)

Inclusion criteria:

  • Aged ≥ 18 years

  • Diagnosis of CAD: documented by coronary angiography/minimum three months history of exertional angina

  • Diagnosis of diabetes mellitus with HbA1c>7%

Exclusion criteria:

  • History of myocardial infarction in the previous three months

  • Heart failure

  • Valvular heart diseases

  • Alcoholic cardiomyopathy

  • Renal failure

  • Chronic lung diseases

  • Hepatic failure

  • Baseline ECG abnormalities

  • Hyperthyroidism

  • Secondary causes of angina

  • Pregnancy/absence of contraceptive use in women of childbearing age/lactating mothers

  • Patients on P‐glycoprotein inhibitors, drugs known to prolong QT interval, CYP3A4 inhibitors, CYP3A4 inducers, pacemaker

  • Patients participating in other clinical trials or those who participated in any clinical trial within the last three months

Interventions

Number of intervention groups: 2

Concomitant medications: statins

Excluded medications: those mentioned in exclusion criteria

Trimetazidine group

  • Intervention: trimetazidine 35 mg twice daily

  • Duration of intervention: 3 months

Ranolazine group

  • Intervention: ranolazine (type of formulation not specified) 500 mg twice daily

  • Duration of intervention: 3 months

Outcomes

Total number of outcomes: 1

  • According to study protocol: no published protocol; according to the "Materials and Methods" section: 5 (angina episodes frequency, adverse events, biochemical diabetes assessment, QTc interval, haemodynamic parameters)

  • Reported: 6 (including sublingual nitrate consumption frequency)

Angina episodes frequency

  • Outcome definition: average angina attacks per week

  • Method and unit of measurement: number per week

  • Time points reported: 12 weeks

RESULTS

Angina episodes frequency

  • Sample size: 47 (intention‐to‐treat analysis)

  • Missing participants: none

  • Summary data: mean (SD) 1.4(2.2) / 1.2(1.7) for trimetazidine/ranolazine group (baseline values are also reported)

  • Subgroup analyses: not performed

Adverse events

The adverse events reported for the ranolazine group included angina, constipation, postural hypotension, headache, dizziness, nausea and weakness; for the trimetazidine group were constipation, weakness, palpitations, angina, dizziness, nausea, dyspepsia, headache, gastric discomfort and joint pain.

Notes

Relevant observations for the data provided before: none

Source of funding: no external source of funding

Notable conflicts of interest: the authors declare that they have no conflict of interest

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Randomisation is stated but described only as "in a 1:1 ratio"

Allocation concealment (selection bias)

Low risk

Study drugs were provided in sequentially numbered opaque sealed envelopes

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Study declared to be double‐blinded, but no description is provided. However, it can be presumed that participants and personnel were blinded since drugs were provided in sealed envelopes

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Study declared to be double‐blinded, but no description is provided

Incomplete outcome data (attrition bias)
All outcomes

Low risk

No exclusion or withdrawal is reported, we assume that all patients completed the study

Selective reporting (reporting bias)

Unclear risk

There is no published protocol. Results for all the outcomes stated in the "Methods" section of the paper are reported

Other bias

Low risk

The authors declare that the study was not supported by external source of funding. Also, they declared that they had no conflict of interest.

Shammas 2015

Methods

Study design: cross‐over trial

Total study duration: 16 weeks

Duration of follow‐up: no follow‐up beyond treatment phase

Method of randomisation: not described

Method of concealment of allocation: not described

Blinding: double‐blind, it is stated that the investigators and the patient remained blinded to the treatment until the completion of the trial, but no details are provided

Power calculation: not performed (pilot study)

Phases of the study: 1 (treatment phase)

Number of patients randomised: 28

Exclusions post‐randomisation: 4

Withdrawals (and reasons): 5 (3 withdrew voluntarily, 1 lost to follow‐up, 1 withdrew involuntarily) (only 4 patients were excluded from the analysis)

Participants

Total number: 28

Country of enrolment: United States

Setting/location: not specified

Diagnostic criteria (stable angina pectoris): symptomatic (exertional angina or dyspnoea) ischaemic cardiomyopathy (ICM) with angiographic documentation of CAD (macrovascular angina)

Comorbidities: none (not treatable by further revascularisation)

Age (mean ± SD): 71.5 ± 8.4 years

Gender (male %): 82.1%

Inclusion criteria:

  • ICM with continued symptoms on guideline‐directed medical treatment, where optimal medical treatment was defined as treatment with two anti‐ischaemic agents (amlodipine or long‐acting nitrates on top of beta blockers) as well as an ACEI/ARB unless contraindicated, and continued symptoms defined as significant exertional angina or dyspnoea, interfering with the patient’s daily activity

  • Angiographic documentation of coronary artery disease that was not amenable to treatment by coronary intervention (already treated or non treatable)

  • A recent ejection fraction (EF) of less than or equal to 40% within 6 months of enrolment, as assessed by echocardiography or isotope ventriculography

  • Able to sign an informed consent before enrolment

Exclusion criteria:

  • Dyalisis patients

  • There was no prespecified exclusion based on QTc or renal function

Interventions

Number of intervention groups: 2

Concomitant medications: angiotensin‐converting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB), a beta blocker, and at least one additional anti‐ischaemic drug (amlodipine or long‐acting nitrate)

Excluded medications: none

Placebo group

Intervention: placebo

Duration of intervention: 6 weeks (plus 2 weeks of washout)

Ranolazine group

Intervention: ranolazine (type of formulation not specified) 500 mg/1000 mg twice daily

Duration of intervention: 6 weeks (plus 2 weeks of washout)

Outcomes

Total number of outcomes:

  • According to study protocol: no published protocol; according to the "Methods" section: 2 (SAQ and Rose Dyspnea Scale (RDS) scores)

  • Reported: 3 (including adverse events incidence)

Quality of life

1. Seattle Angina Questionnaire (SAQ)

  • Outcome definition: level of functioning scale, measured by the scores in the 5 sub scales, reported separately and as a mean score

  • Upper and lower limits and whether a high or low score is good: higher scores are better, upper and lower limits are not described

  • Method and unit of measurement: score

  • Time points reported: 6 weeks

2. Rose Dyspnea Scale (RDS)

  • Outcome definition: scale for dyspnoea with regular activities, measured by a total score

  • Upper and lower limits and whether a high or low score is good: higher scores indicate dyspnoea leading to more physical limitation (worse)

  • Method and unit of measurement: change from baseline, score

  • Time points reported: 6 weeks

Adverse events incidence

  • Outcome definition: number of adverse events (serious and non serious) reported

  • Method and unit of measurement: frequency

  • Time points reported: 6 weeks

RESULTS

Quality of life

1. Seattle Angina Questionnaire (SAQ)

  • Sample size: 24 (intention‐to‐treat analysis)

  • Missing participants: 4

  • Summary data: baseline/post‐intervention score:

    • i) physical limitation 62.35/58.02 ‐ 62.19/64.35,

    • ii) anginal stability 50/63.89 ‐ 61.11/61.11,

    • iii) anginal frequency 74.44/74.44 ‐ 71.11/86.67,

    • iv) treatment satisfaction 89.58/87.5 ‐ 88.89/92.36,

    • v) quality of life 68.52/66.67 ‐ 58.33/72.22 for placebo‐ranolazine group

  • Subgroup analyses: not performed

2. Rose Dyspnea Scale (SAQ)

  • Sample size: 20 (intention‐to‐treat analysis)

  • Missing participants: 8 (4 because of not having dyspnoea)

  • Summary data: ‐0.34/‐0.45 for placebo/ranolazine group

  • Subgroup analyses: not performed

Adverse events incidence

  • Sample size: 24 (intention‐to‐treat analysis)

  • Missing participants: 4

  • Summary data: neither the frequency of each adverse event nor the number of patients who report any adverse event were reported, but it is stated that the most common side effects reported in the ranolazine arm included nausea, dizziness, constipation, headache, hypotension and dyspepsia; while in the placebo patients, dizziness was reported.

  • Subgroup analyses: not performed

Notes

Relevant observations for the data provided before: none

Source of funding: research grant from Gilead

Notable conflicts of interest: Dr Shammas is a speaker for and is on the advisory board of Gilead

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Randomisation is stated but not described

Allocation concealment (selection bias)

Unclear risk

It is stated that the investigators remained blinded to the treatment (allocation) until the completion of the trial, but no details are provided

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Study declared to be double‐blinded, with blinding corresponding to investigators and patients

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

A core laboratory blinded to patient treatment determined the SAQ scores

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Withdrawals and reasons are described; however, there is an inconsistency in the number of patients who did not complete the trial (5) and the number of patients excluded from the analysis (4)

Selective reporting (reporting bias)

Unclear risk

There is no published protocol. Results for all the outcomes stated in the "Methods" section of the paper are reported

Other bias

High risk

The study was supported by a research grant from Gilead Science. Dr Shammas is a speaker for and is on the advisory board of Gilead.

Tagliamonte 2015

Methods

Study design: parallel‐group trial

Total study duration: 8 weeks

Duration of follow‐up: no follow‐up beyond treatment phase

Method of randomisation: not described

Method of concealment of allocation: not mentioned

Blinding: double‐blind, not described

Power calculation: not mentioned

Phases of the study: 1 (treatment phase)

Number of patients randomised: 58 (29/29 for placebo/ranolazine group)

Exclusions post‐randomisation: none

Withdrawals (and reasons): none

Participants

Total number: 58

Country of enrolment: Italy

Setting/location: not specified

Diagnostic criteria: sings and symptoms of myocardial ischaemia without obstructive CAD (microvascular angina)

Comorbidities: none

Age (mean ± SD): 66 ± 10 years

Gender (male %): 67%

Inclusion criteria:

  • Signs and symptoms of myocardial ischaemia but no obstructive CAD (< 70% coronary stenosis in all epicardial coronary arteries)

Exclusion criteria:

  • Hepatic insufficiency

  • Prolonged QT

  • Renal failure

  • Use of drugs that inhibit CYP3A such as diltiazem, verapamil, ketoconazole, macrolides, HIV protease inhibitors

  • life expectancy < 6 months

  • Atrial fibrillation, left bundle branch block on ECG, primary valvular heart disease, hypertrophic cardiomyopathy, previous acute coronary syndrome, left ventricular systolic dysfunction with ejection fraction < 55%

Interventions

Number of intervention groups: 2

Concomitant medications: aspirin

Excluded medications: those mentioned in exclusion criteria

Placebo group

  • Intervention: placebo twice daily

  • Duration of intervention: 8 weeks

Ranolazine group

  • Intervention: ranolazine (type of formulation not specified) 500 mg twice daily (increased from 350 mg twice daily for 4 weeks)

  • Duration of intervention: 8 weeks

Outcomes

Total number of outcomes: 3

According to study protocol: no published protocol; according to the "Methods" section: 3 (coronary flow reserve, left ventricular ejection fraction, SAQ score)

Reported: 3

Quality of life

  • Outcome definition: score in the 5 dimensions of the Seattle Angina Questionnaire (SAQ), reported separately

  • Upper and lower limits and whether a high or low score is good: not described

  • Method and unit of measurement: average score

  • Time points reported: 8 weeks

RESULTS

Quality of life

  • Sample size: 58 (Intention‐to‐treat analysis)

  • Missing participants: 0

  • Summary data: reported as mean (minimum, maximum) i) Physical functioning: 82.2 (71.1, 88.9) / 87.4 (73.3, 97.9) for placebo / ranolazine group; ii) Angina stability: 58.6 (25.0, 75.0) / 77.6 (50.0, 100.0) for placebo/ranolazine group; iii) Angina frequency: 64.8 (40.0, 80.0) / 80.7 (50.0, 100.0) for placebo / ranolazine group; iv) Treatment satisfaction: 90.3 (76.5, 100.0) / 86.4 (70.6, 100.0) for placebo / ranolazine group v) Quality of life: 62.9 (50.0, 75.0) / 77.6 (58.3, 91.7) for placebo / ranolazine group. Baseline data measured but not reported

Notes

Relevant observations for the data provided before: none

Source of funding: not stated

Notable conflicts of interest: not stated

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Randomisation is stated but not described

Allocation concealment (selection bias)

Unclear risk

Not mentioned

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Study declared to be double‐blinded, but no description is provided

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Study declared to be double‐blinded, but no description is provided

Incomplete outcome data (attrition bias)
All outcomes

Low risk

It is reported that no patient withdrew the study

Selective reporting (reporting bias)

Unclear risk

There is no published protocol. Results for all the outcomes stated in the "Methods" section of the paper are reported

Other bias

Unclear risk

The source of funding was not stated. Conflicts of interest were not stated.

TERISA 2013

Methods

Study design: parallel‐group trial

Total study duration: 12 weeks

Duration of follow‐up: no follow‐up beyond treatment phase

Method of randomisation: Interactive Voice/Web Response System (IVRS/IWRS)

Method of concealment of allocation: blinded study drug bottle assigned by the IVRS/IWRS

Blinding: double‐blind, participants and clinicians were blinded by using study drug bottles assigned by the IVRS/IWRS

Power calculation: 90% to show a relative reduction of 20% in weekly angina frequency

Phases of the study: 2 (qualifying phase, treatment phase)

Number of patients randomised: 949 (476/473 for placebo/ranolazine group)

Exclusions post‐randomisation: 22 (11 in the ranolazine arm, 11 in the placebo arm)

Withdrawals (and reasons): 20 (9 withdrawals, 3 deaths in the ranolazine group, 11 withdrawals, 2 deaths in the placebo group)

Participants

Total number: 949

Country of enrolment: 14 (United States, Belarus, Bulgaria, Canada, Czech Republic, Georgia, Germany, Israel, Poland, Russian Federation, Serbia, Slovakia, Slovenia, Ukraine)

Setting/location: not specified

Diagnostic criteria (stable angina pectoris): at least a three‐month history of chronic stable angina that remain symptomatic despite treatment with 1 or 2 anti‐anginal, with documented history of CAD (macrovascular angina)

Comorbidities: type 2 diabetes mellitus

Age (mean ± SD): 64 ± 8.5 years

Gender (male %): 61%

Inclusion criteria:

  • Aged at least 18 years

  • At least a 3‐month history of chronic stable angina triggered by physical effort and relieved by rest and/or sublingual nitroglycerin

  • CAD documented by one or more of the following:

    • Angiographic evidence of ≥ 50% stenosis of one or more major coronary arteries

    • History of myocardial infarction (MI) documented by positive myocardial muscle creatine kinase (CK‐MB) enzymes, troponins, or electrocardiogram (ECG) changes

    • Cardiac imaging study or exercise test diagnostic for CAD

  • Treatment with up to 2 anti‐anginal therapies at a stable dose for at least 2 weeks prior to the qualifying period.

  • Documented history of T2DM

  • Willing to maintain stable tobacco usage habits throughout the study

  • Willing to maintain stable activity levels throughout the study

  • Females of childbearing potential must agree to use highly effective contraception methods from Screening throughout the duration of study treatment and for 14 days following the last dose of study drug

Exclusion criteria:

  • New York Heart Association (NYHA) Class III and IV

  • Acute coronary syndrome in the prior 2 months or planned coronary revascularisation during the study period

  • Stroke or transient ischaemic attack within 6 months prior to screening

  • QTc > 500 ms

  • Uncontrolled hypertension (seated systolic blood pressure > 180 mm Hg or diastolic blood pressure > 110 mm Hg)

  • Systolic blood pressure < 100 mm Hg

  • Clinically significant hepatic impairment

  • Prior treatment with ranolazine, or known hypersensitivity or intolerance to ranolazine

  • Females who are breastfeeding

  • Positive serum pregnancy test

  • Participation in another investigational drug or device study within 1 month prior to Screening

  • Current treatment with trimetazidine, ivabradine, or nicorandil. Subjects will need to discontinue these medications 2 weeks prior to the qualifying period

  • Current treatment with potent inhibitors of cytochrome (CYP)3A (e.g. ketoconazole, itraconazole, clarithromycin, nefazodone, nelfinavir, ritonavir, indinavir, and saquinavir)

  • Current treatment with CYP3A and P glycoprotein (Pgp) inducers (e.g. rifampicin/rifampin, carbamazepine, and St. John's wort [Hypericum perforatum])

  • Current treatment with CYP3A4 substrates with a narrow therapeutic range (e.g. cyclosporine, tacrolimus, and sirolimus)

  • Subjects taking simvastatin who cannot reduce the dose to 20 mg once daily or who cannot switch to another statin

  • Current treatment with Class I or III anti‐arrhythmic medications

  • History of illicit drug use or alcohol abuse within 1 year of Screening

  • Any other conditions that, in the opinion of the investigator, are likely to prevent compliance with the study protocol or pose a safety concern if the subject participates in the study

Interventions

Number of intervention groups: 2

Concomitant medications: Anti‐anginal: beta blockers, calcium channel blockers, long‐acting nitrates; other cardiovascular medications: statins, antiplatelet agents, ACE‐I/ARB; antidiabetic medications: glucose‐lowering medications, insulin

Excluded medications: none (apart from those mentioned in the exclusion criteria)

Placebo group

  • Intervention: placebo

  • Duration of intervention: 8 weeks

Ranolazine group

  • Intervention: ranolazine ER 1000 mg twice daily

  • Duration of intervention: 8 weeks

Outcomes

Total number of outcomes:

  • According to study protocol: 6 (angina episodes frequency, sublingual nitroglycerin use frequency, number of angina‐free days, proportion of subjects with ≥50% reduction in average weekly angina frequency, health‐related quality of life, adverse events incidence)

  • Reported: 6

All‐cause mortality

  • Outcome definition: number of deaths

  • Method and unit of measurement: absolute frequency

  • Time points reported: 8 weeks

Quality of life

1. Medical Outcomes Short Form‐36 (SF‐36)

  • Outcome definition: health state scale, change from baseline in the Mental and Physical Components

  • Upper and lower limits and whether a high or low score is good: the range of each health domain score is 0‐100, with 0 indicating a poorer health state and 100 indicating a better health state

  • Method and unit of measurement: change from baseline, score

  • Time points reported: 8 weeks

2. Patient’s Global Impression of Change (PGIC)

  • Outcome definition: change in overall status scale, total score

  • Upper and lower limits and whether a high or low score is good: ranging from 1 (no change or worse) to 7 (very much improved)

  • Method and unit of measurement: score

  • Time points reported: 8 weeks

Acute myocardial infarction incidence (non‐fatal)

  • Outcome definition: number non‐fatal myocardial infarction cases

  • Method and unit of measurement: absolute frequency

  • Time points reported: 8 weeks

Angina episodes frequency

  • Outcome definition: average number of angina episodes per week from weeks 2 to 8 of treatment

  • Method and unit of measurement: number of angina episodes per week

  • Time points reported: 8 weeks

Adverse events incidence

  • Outcome definition: number of patients who report any non serious adverse event

  • Method and unit of measurement: absolute frequency

  • Time points reported: 8 weeks plus 30 days

RESULTS

All‐cause mortality

  • Sample size: 944 (intention‐to‐treat analysis)

  • Missing participants: 5

  • Summary data: 2/474‐3/470 for placebo‐ranolazine group

  • Subgroup analyses: not performed

Quality of life

1. Medical Outcomes Short Form‐36 (SF‐36)

  • Sample size: 927 (intention‐to‐treat analysis)

  • Missing participants: 22

  • Summary data: Physical component: 1.9 (1.3‐2.5) / 2.9 (2.3‐3.5) for placebo/ranolazine group; mental component: 1.1 (0.28‐1.92) / 1.0 (0.18‐1.82) for placebo/ranolazine group

  • Subgroup analyses: not performed

2. Patient’s Global Impression of Change (PGIC)

  • Sample size: 927 (intention‐to‐treat analysis)

  • Missing participants: 22

  • Summary data: 3.9 (3.74‐4.10) / 4.0 (3.82‐4.19) for placebo/ranolazine group

  • Subgroup analyses: not performed

Acute myocardial infarction incidence (non‐fatal)

  • Sample size: 944 (intention‐to‐treat analysis)

  • Missing participants: 5

  • Summary data: 3/474 ‐ 1/470 for placebo‐ranolazine group

  • Subgroup analyses: not performed

Angina episodes frequency

  • Sample size: 927 (intention‐to‐treat analysis)

  • Missing participants: 22

  • Summary data: 4.3 (4.01‐4.52) / 3.8 (3.57‐4.05) for placebo/ranolazine group

  • Subgroup analyses: several pre‐specified subset analyses, all are reported, significant interaction in the effect of ranolazine versus placebo was found only by the geographic region of enrolment (Russia, Ukraine, Belarus versus Other, pinteraction = 0.016). Russia, Ukraine and Belarus: 4.3 (4.1‐4.6) / 4.1 (3.9‐4.4) for placebo/ranolazine group; Other: 4.1 (3.7‐4.6) / 3.1 (2.8‐3.5) for placebo/ranolazine group

Adverse events incidence:

  • Sample size: 944 (intention‐to‐treat analysis)

  • Missing participants: 5

  • Summary data: 85/474 ‐ 110/470 for placebo‐ranolazine group. The most common adverse events reported in the ranolazine group were dizziness (17/462), nausea (17/462), headache (7/462), constipation (8/462), hypoglycaemia (3/462); and in the placebo group were dizziness (6/465), nausea (2/465), headache (9/465) and constipation (2/465), hypoglycaemia = 0/465.

  • Subgroup analyses: not performed

Notes

Relevant observations for the data provided before: none

Source of funding: Gilead Sciences

Notable conflicts of interest: all the authors have financial relationships with Gilead Sciences

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Randomisation undertaken by the IVRS/IWRS

Allocation concealment (selection bias)

Low risk

Intervention was provided to personnel in blinded study drug bottles assigned by the IVRS/IWRS

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Study declared to be double‐blinded, but no description is provided. Intervention was provided to personnel and patients in blinded drug bottles, so they were unaware of the treatment assigned

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Study declared to be double‐blinded, but no description about the blinding of data collectors/outcome adjudicators is provided

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Withdrawals are reported, but no description is provided

Selective reporting (reporting bias)

Low risk

According to the protocol published in Clinicaltrials.gov, results for all the outcomes are reported

Other bias

High risk

The study was supported by Gilead Sciences. All the authors have financial relationships with Gilead Sciences

Thadani 1994

Methods

Study design: parallel‐group trial

Total study duration: 35‐40 days

Duration of follow‐up: no follow‐up beyond treatment phase

Method of randomisation: not described

Method of concealment of allocation: not mentioned

Blinding: double‐blind, not described

Power calculation: not mentioned

Phases of the study: 2 (qualifying phase, treatment phase)

Number of patients randomised: 319 (79, 81, 81 and 78 for placebo, ranolazine 30 mg, ranolazine 60 mg and ranolazine 120 mg groups)

Exclusions post‐randomisation: 20

Withdrawals (and reasons): 31 (15 because of adverse events, new intercurrent illnesses, or new laboratory abnormalities, 4 because of unsatisfactory therapeutic response, 2 because of study administration problems, 10 for 'other' reasons (4 did not take study medication in compliance with the protocol, 2 elected to have surgical intervention, 2 declined to finish the study, 1 violated the protocol, and 1 required medication to control ventricular ectopy)). Withdrawals were similarly distributed among the study groups: 9/79, 9/81, 7/81 and 6/78 for placebo, ranolazine 30 mg, ranolazine 60 mg and ranolazine 120 mg groups

Participants

Total number: 319

Country of enrolment: United States

Setting/location: not specified

Diagnostic criteria: at least a 3‐month history of symptomatic chronic stable angina triggered by physical effort and relieved by rest or nitroglycerin

Comorbidities: none

Age (mean ± SD): 65 ± 8 years

Gender (male %): 74.7%/80.2%/81.5%/79.5% for placebo/ranolazine 30 mg/ranolazine 60 mg/ranolazine 120 mg group

Inclusion criteria:

  • At least a 3‐month history of symptomatic chronic stable angina triggered by physical effort and relieved by rest or nitroglycerin

  • Having ECG evidence of exercise‐induced myocardial ischaemia (ST segment depression of >1 mm from baseline) and a resting ECG pattern that would not interfere with the interpretation of ST changes during exercise.

  • Patients entered the 4‐week double‐blind phase if they met the following entry criteria:

    • The duration of exercise for each of two qualifying ETTs had been 3 to 9 minutes

    • The difference between the two qualifying ETTs was not more than 15% of the duration of the longer ETT

    • All qualifying ETTs had evidence of myocardial ischaemia, as diagnosed by ST depression of 1 mm or more, measured 80 milliseconds from the J point

    • The Holter monitor had at least 36 hours of readable ECG tracings

    • The patient reported at least one anginal episode during the week before randomisation

Exclusion criteria:

  • Patients with pacemakers

  • Standing systolic blood pressure < 95 mm Hg

  • Patients with conditions that would hinder or confuse follow‐up evaluations

  • Patients unable to undergo the protocol requirements for the study (e.g. stress testing)

Interventions

Number of intervention groups: 4

Concomitant medications: (permitted) sublingual nitroglycerin (0.4mg tablets), taken for anginal pain and not as a prophylactic agent; hydrochlorothiazide and potassium supplementation for the treatment of hypertension

Excluded medications: all anti‐anginal medication with the exception of sublingual nitroglycerin

Placebo group

  • Intervention: placebo thrice daily

  • Duration of intervention: 4 weeks

Ranolazine 30 mg group

  • Intervention: ranolazine (type of formulation not specified) 30 mg thrice daily

  • Duration of intervention: 4 weeks

Ranolazine 60 mg group

  • Intervention: ranolazine (type of formulation not specified) 60 mg thrice daily

  • Duration of intervention: 4 weeks

Ranolazine 120 mg group

  • Intervention: ranolazine (type of formulation not specified) 120 mg thrice daily

  • Duration of intervention: 4 weeks

Outcomes

Total number of outcomes: 6

According to study protocol: no published protocol; according to the "Methods" section: 10 (change from baseline in ETT total exercise duration, time to onset of angina and time to 1‐mm ST segment depression (peak and through), change from baseline in the number and duration of ST segment depression episodes (by Holter monitoring), change from baseline in the weekly rate of NTG consumption and anginal attacks, adverse events incidence)

Reported: 12 (including circulatory data at peak and through)

Angina episodes frequency

  • Outcome definition: weekly rate of anginal attacks, change from baseline

  • Method and unit of measurement: number per week

  • Time points reported: 4 weeks

Adverse events incidence

  • Outcome definition: number of adverse events reported

  • Method and unit of measurement: absolute frequency

  • Time points reported: 4 weeks

RESULTS

Angina episodes frequency

  • Sample size: 283 (intention‐to‐treat analysis)

  • Missing participants: 36

  • Summary data (mean, 95% CI ‐2.24 ‐3.04 to ‐1.58) / ‐2.32 (‐3.34 to ‐1.71) / ‐2.67 (‐3.38 to ‐2.05) / ‐2.11 (‐3.03 to ‐1.50) for placebo/ranolazine 30 mg/ranolazine 60 mg/ranolazine 120 mg group

  • Subgroup analyses: not performed

Adverse events incidence

  • Sample size: 299 (intention‐to‐treat analysis)

  • Missing participants: 20

  • Summary data: it is stated that the rates of adverse events were similar among the study groups, but incidence for each one is not reported. It is stated that the 3 adverse events reported most frequently in the ranolazine groups were headache, dizziness and asthenia. No description is provided for the ranolazine group.

  • Subgroup analyses: not performed

Notes

Relevant observations for the data provided before: 'all patients' (intention‐to‐treat) (N = 299) and per‐protocol (N = 258) analysis were performed for ETT variables

Source of funding: Syntex Research, Palo Alto, CA, USA

Notable conflicts of interest: not stated

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Randomisation is stated but not described

Allocation concealment (selection bias)

Unclear risk

Not mentioned

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Study declared to be double‐blinded, but no description is provided

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Study declared to be double‐blinded, but no description is provided

Incomplete outcome data (attrition bias)
All outcomes

High risk

Withdrawals and reasons are provided and similarly distributed among the study groups, however, number of withdrawals is nearly 10% of total number of randomised patients

Selective reporting (reporting bias)

Unclear risk

There is no published protocol. Results for all the outcomes stated in the "Methods" section of the paper are reported

Other bias

High risk

The study was supported by Syntex Research. Authors did not state conflicts of interest.

Villano 2013

Methods

Study design: parallel‐group trial

Total study duration: 4 weeks

Duration of follow‐up: no follow‐up beyond treatment phase

Method of randomisation: computer‐generated table of random numbers

Method of concealment of allocation: drugs were given to patients in anonymous drug packages by three of the authors who were not involved in the clinical assessment of patients. Cardiologists involved in the clinical and laboratory assessment of patients and/or analyses of data were blinded to the allocation of treatment

Blinding: not mentioned, but presumably involving participants and data collectors/outcome adjudicators

Power calculation: 90% to detect a significant difference of 15 points (SD 10) between each active drug versus placebo in any SAQ item and in the EuroQoL score

Phases of the study: 1 (treatment phase)

Number of patients randomised: 46

Exclusions post‐randomisation: not reported

Withdrawals (and reasons): not reported

Participants

Total number: 46

Country of enrolment: Italy

Setting/location: ambulatory patients

Diagnostic criteria (stable angina pectoris): history of typical effort angina with exercise‐induced ST‐segment depression ≥ 1 mm, normal coronary angiography and absence of any specific cardiac disease including vasospastic angina (microvascular angina) which remains symptomatic despite anti‐ischaemic therapy

Comorbidities: none

Age (mean, interval): 57 ± 12/57 ± 11/60 ± 9 years for ivabradine/ranolazine/placebo group

Gender (male %): 2/16, 3/15, 4/15 for ivabradine‐ranolazine‐placebo group

Inclusion criteria:

  • Diagnosis of stable primary MVA based on the presence of

    • A history of typical effort angina

    • Exercise‐induced ST‐segment depression ≥ 1 mm

    • Normal coronary angiography

    • Absence of any specific cardiac disease including vasospastic angina

    • Normal echocardiographic examination including absence of left ventricular hypertrophy

    • A coronary flow reserve < 2.5 in the left anterior descending coronary artery

  • Suboptimal control of symptoms on conventional anti‐ischaemic therapy, as indicated by the occurrence of ≥1 episode per week of angina

  • No previous consumption of the drugs under investigation

  • No apparent contraindications to ivabradine and ranolazine administration

Exclusion criteria: Not described

Interventions

Number of intervention groups: 3

Concomitant medications: anti‐anginals, antihypertensives, anti‐aggregants, statins

Excluded medications: none

Placebo group

  • Intervention: placebo twice daily

  • Duration of intervention: 4 weeks

Ivabradine group

  • Intervention: ivabradine 5 mg twice daily

  • Duration of intervention: 4 weeks

Ranolazine group

  • Intervention: ranolazine (type of formulation not specified) 375 mg twice daily

  • Duration of intervention: 4 weeks

Outcomes

Total number of outcomes:

  • According to study protocol: no published protocol; according to the "Methods" section: 5 (angina status, quality of life, exercise stress tests, coronary microvascular dilation, peripheral vascular dilation)

  • Reported: 5

Quality of life

1. Seattle Angina Questionnaire (SAQ)

  • Outcome definition: angina status scale, five components

  • Upper and lower limits and whether a high or low score is good: each component is scored on a 0 to 100 scale, with higher scores indicating better functional status

  • Method and unit of measurement: score

  • Time points reported: 4 weeks

2. EuroQoL visual analogue scale (VAS)

  • Outcome definition: quality of life scale, measured as a total score

  • Upper and lower limits and whether a high or low score is good: scored from 0 (worst condition) to 100 (best condition)

  • Method and unit of measurement: score

  • Time points reported: 4 weeks

Adverse events incidence

  • Outcome definition: number of adverse events reported

  • Method and unit of measurement: absolute frequency

  • Time points reported: 4 weeks

RESULTS

Quality of life

1. Seattle Angina Questionnaire (SAQ)

  • Sample size: 46 (intention‐to‐treat analysis)

  • Missing participants: none

  • Summary data: baseline/post‐intervention for placebo‐ivabradine‐ranolazine group

    • (i) physical limitation: 68.2 ± 20/67.0 ± 21 ‐ 65.4 ± 15/76.5 ± 16 ‐ 69.8 ± 16/84.1 ± 12,

    • (ii) angina stability: 56.7 ± 26/55.0 ± 25 ‐ 43.8 ± 30/56.3 ± 33 ‐ 40.0 ± 25/90.0 ± 18,

    • (iii) angina frequency: 72.7 ± 17/71.3 ± 18 ‐ 64.4 ± 14/73.1 ± 18 ‐ 61.3 ± 12/81.3 ±1 7,

    • (iv) treatment satisfaction: 75.8 ± 15/74.2 ± 14 ‐ 75.8 ± 15/84.4 ± 14 ‐ 68.8 ± 16/90.8 ± 9,

    • (v) disease perception: 60.0 ± 22/57.2 ± 23 ‐ 49.5 ± 23/62.5 ± 26 ‐ 45.0 ± 17/79.4 ± 14

  • Subgroup analyses: not performed

2. EuroQoL visual analogue scale (VAS)

  • Sample size: 46 (intention‐to‐treat analysis)

  • Missing participants: none

  • Summary data: baseline/post‐intervention for placebo‐ivabradine‐ranolazine group 65.7 ± 17/64.3 ± 19 ‐ 66.6 ± 14/72.5 ± 17 ‐ 61.3 ± 17/79.3 ± 13

  • Subgroup analyses: not performed

Adverse events incidence

  • Sample size: 46 (intention‐to‐treat analysis)

  • Missing participants: none

  • Summary data: 0/15 ‐ 0/16 ‐ 0/15 for placebo‐ivabradine‐ranolazine group

  • Subgroup analyses: not performed

Notes

Relevant observations for the data provided before: none

Source of funding: not stated

Notable conflicts of interest: no conflicts of interest to disclose

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Computer‐generated table of random numbers

Allocation concealment (selection bias)

Low risk

Drugs were given to patients in anonymous drug packages by three of the authors who were not involved in the clinical assessment of patients.

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Blinding design is not stated. It is mentioned that study drugs were provided in anonymous packages, so it could be assumed that patients and personnel were blinded to the allocation of treatment

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Blinding design is not stated. It is mentioned that the cardiologists involved in the clinical and laboratory assessment of patients and/or analyses of data were blinded to the allocation of treatment. However, for outcomes such as quality of life, blinding measures have not been described

Incomplete outcome data (attrition bias)
All outcomes

Low risk

No exclusions or withdrawals were reported. We assumed that all patients completed the study

Selective reporting (reporting bias)

Unclear risk

There was no published protocol. Results for all outcomes in the 'Methods' section were reported

Other bias

Unclear risk

Funding source not stated. The authors declared no conflicts of interest

Characteristics of excluded studies [ordered by study ID]

Study

Reason for exclusion

Arnold 2014

Substudy of RCT: substudy of the TERISA 2013 trial on quality of life

Cocco 1992

Wrong intervention: ranolazine given in single dose

Coleman 2015

Not RCT: health economics study not conducted alongside a RCT

Hidalgo‐Vega 2014

Not RCT: health economics study not conducted alongside a RCT

Jain 1990

Not RCT: three‐period cross‐over trial with only one group of participants, no randomisation method stated

Kohn 2014

Not RCT: health economics study not conducted alongside a RCT

Lucioni 2009

Not RCT: health economics study not conducted alongside a RCT

Rehberger‐Likozar 2015

No angina population: condition studied did not meet inclusion criteria

Rich 2007

Substudy of RCT: subgroup analysis of the CARISA 2004 and ERICA 2006 trials

ROLE 2007

Not RCT: open‐label follow‐up study of the CARISA 2004 and MARISA 2004 trials, including only participants treated with ranolazine (without comparator)

Characteristics of studies awaiting assessment [ordered by study ID]

NCT01304095

Methods

Study design: parallel‐group trial

Duration of follow‐up: 6 months

Method of randomisation: not described

Method of concealment of allocation: not described

Blinding: open‐label

Power calculation: not mentioned

Phases of the study: 1 (treatment phase)

Participants

Total number: 160 (estimated)

Country of enrolment: USA

Setting/location: not specified

Diagnostic criteria (stable angina pectoris): symptoms of angina with evidence of stable CAD (macrovascular angina)

Comorbidities: metabolic syndrome

Inclusion criteria:

  • Evidence of stable Coronary Artery Disease

    • MI > 30 days prior to enrolment

    • PCI > 30 days prior to enrolment

    • CABG > 30 days prior to enrolment

    • Angiography showing > 50% stenosis in a major vessel, branch or bypass graft > 30 days prior to enrolment

  • Metabolic Syndrome as evidenced by at least one of the following risk factors:

    • Abdominal Obesity (elevated waist circumference)

      • Men ‐ waist circumference ≥ 40 inches (102 cm) Asians/Asian Americans ≥ 35.5 inches (90 cm)

      • Women ‐ waist circumference ≥ 35 inches (88 cm) Asians/Asian Americans ≥ 31.5 inches (80 cm)

    • Atherogenic dyslipidaemia (either one or both)

      • Triglycerides ≥ 150 mg/dL

      • Reduced HDL Men ‐ HDL ≤ 40 mg/dL Women ‐ HDL ≤ 50 mg/dL

    • Elevated Blood Pressure (equal to or greater than 130/85)

    • Elevated fasting glucose (equal to or greater than 100 mg/dL)

Interventions

Number of intervention groups: 2

Concomitant medications: standard medical therapy

Excluded medications: those mentioned in exclusion criteria

Control group

Intervention: no treatment

Duration of intervention: 6 months

Ranolazine group

Intervention: ranolazine (type of formulation not specified) 500/1000 mg twice daily

Duration of intervention: 6 months

Outcomes

Total number of outcomes: 6 (ETT parameters, fasting glucose, angina (SAQ scale), concomitant medications, lipid profile, HbA1c)

OUTCOMES

No outcome meets inclusion criteria

Notes

Tagarakis 2013

Methods

Study design: parallel‐group trial

Duration of follow‐up: not reported

Method of randomisation: not described

Method of concealment of allocation: not described

Blinding: single‐blind (outcome assessors)

Power calculation: not mentioned

Phases of the study: 1 (treatment phase)

Participants

Country of enrolment: Greece

Setting/location: inpatient

Diagnostic criteria (stable angina pectoris): not described

Comorbidities: patients scheduled for elective on‐pump CABG

Inclusion criteria: not described

Exclusion criteria: not described

Interventions

Number of intervention groups: 2

Concomitant medications: not described

Excluded medications: not described

Control group

Intervention: no treatment

Duration of intervention: not reported

Ranolazine group

Intervention: ranolazine (type of formulation not specified) 375 mg twice daily for 3 days prior to surgery and until discharge

Duration of intervention: not reported

Outcomes

Total number of outcomes: 3 (post‐operative atrial fibrillation, left atrial diameter, left ventricular ejection fraction)

OUTCOMES

No outcome meets the inclusion criteria

Notes

Tian 2012

Methods

Study design: parallel‐group trial

Duration of follow‐up:

Method of randomisation: not described

Method of concealment of allocation: not described

Blinding: not mentioned

Power calculation: not mentioned

Phases of the study: 1 (treatment phase)

Participants

Total number: 86

Country of enrolment: China

Setting/location: not specified

Diagnostic criteria (stable angina pectoris): not described

Comorbidities: none

Inclusion criteria: not described

Exclusion criteria: not described

Interventions

Number of intervention groups: 2

Concomitant medications: diltiazem

Excluded medications: not described

Control group

Intervention: no treatment

Duration of intervention: not reported

Ranolazine group

Intervention: ranolazine (type of formulation not specified) (dosage not reported)

Duration of intervention: not reported

Outcomes

Total number of outcomes: 2 (ECG total effective rate, adverse events incidence)

OUTCOMES

Adverse events incidence

Outcome definition: not described

Method and unit of measurement: absolute frequency

Time points to report: not reported

Notes

Wang 2012

Methods

Study design: parallel‐group trial

Duration of follow‐up: 8 weeks

Method of randomisation: not described

Method of concealment of allocation: not described

Blinding: not mentioned

Power calculation: not mentioned

Phases of the study: 1 (treatment phase)

Participants

Country of enrolment: China

Setting/location: not specified

Diagnostic criteria (stable angina pectoris): stable angina with coronary heart disease (macrovascular angina)

Comorbidities: none

Inclusion criteria: not described

Exclusion criteria: not described

Interventions

Number of intervention groups: 3

Concomitant medications: conventional therapy (aspirin, cholesterol lowering agents, metoprolol)

Excluded medications: not described

Placebo group

Intervention: placebo

Duration of intervention: 8 weeks

Ranolazine 500 mg group

Intervention: ranolazine SR 500 mg twice daily

Duration of intervention: 8 weeks

Ranolazine 1000 mg group

Intervention: ranolazine SR 1000 mg twice daily

Duration of intervention: 8 weeks

Outcomes

Total number of outcomes: 5 (angina frequency, nitroglycerin consumption frequency, ECG total effective rate, ADR, liver/kidney function)

OUTCOMES

Angina episodes frequency

Outcome definition: not described

Method and unit of measurement: not described

Time points to report: 8 weeks

Notes

Characteristics of ongoing studies [ordered by study ID]

Calcagno 2014

Trial name or title

Not stated

Methods

Study design: parallel‐group trial

Duration of follow‐up: 12 months

Method of randomisation: not described

Method of concealment of allocation: not described

Blinding: not mentioned

Power calculation: not mentioned

Phases of the study: 2 (treatment phase, follow‐up phase)

Participants

Country of enrolment: not described

Setting/location: not specified

Diagnostic criteria (stable angina pectoris): not described

Comorbidities: percutaneous coronary intervention plus stent implantation

Inclusion criteria: not described

Exclusion criteria: not described

Interventions

Number of intervention groups: 2

Concomitant medications: medical therapy (not described)

Excluded medications: not mentioned

No treatment group

Intervention: none

Duration of intervention: 30 days

Ranolazine group

Intervention: ranolazine (type of formulation not specified) (dose not reported)

Duration of intervention: 30 days

Outcomes

Total number of outcomes: 5 (ETT parameters, symptoms, arrhythmia, angina during moderate exercises, re‐hospitalisation)

OUTCOMES

No outcome appears to meet the inclusion criteria

Starting date

Not reported

Contact information

Not provided

Notes

Calcagno 2015

Trial name or title

Not stated

Methods

Study design: parallel‐group trial

Duration of follow‐up: 12 months

Method of randomisation: not described

Method of concealment of allocation: not described

Blinding: not mentioned

Power calculation: not mentioned

Phases of the study: 2 (treatment phase, follow‐up phase)

Participants

Country of enrolment: not described

Setting/location: not specified

Diagnostic criteria (stable angina pectoris): not described

Comorbidities: percutaneous coronary intervention plus stent implantation

Inclusion criteria: not described

Exclusion criteria: not described

Interventions

Number of intervention groups: 3

Concomitant medications: standard therapy (not described)

Excluded medications: not mentioned

No treatment group

Intervention: none

Duration of intervention: 30 days

Ivabradine group

Intervention: ivabradine (dose not reported)

Duration of intervention: 30 days

Ranolazine group

Intervention: ranolazine (type of formulation not specified) (dose not reported)

Duration of intervention: 30 days

Outcomes

Total number of outcomes: 3 (ETT parameters, weekly angina during daily moderate exercises, re‐hospitalisation)

OUTCOMES

No outcome meets the inclusion criteria

Starting date

Not reported

Contact information

Not provided

Notes

CTRI/2014/01/004332

Trial name or title

CTRI/2014/01/004332

Methods

Study design: parallel‐group trial

Duration of follow‐up: 8 weeks

Method of randomisation: computer generated randomisation

Method of concealment of allocation: sequentially numbered, sealed, opaque envelopes

Blinding: not specified ("Investigator Blinded")

Power calculation: not mentioned

Phases of the study: 1 (treatment phase)

Participants

Total number: 50 (estimated)

Country of enrolment: India

Setting/location: not specified

Diagnostic criteria (stable angina pectoris): not described

Comorbidities: sustained STEMI

Inclusion criteria:

  • Age from 18 to 75 years

  • Patients who have sustained STEMI more than 12 weeks ago

  • Left ventricular ejection fraction ≤40%

Exclusion criteria:

  • H/o undergoing CABG or stenting procedure within the last 12 weeks

  • Co‐existing end‐stage pulmonary, or hepatic disease

  • Valvular heart disease

  • Patient consumed other study medication in the last 3 months

  • Unwilling to comply with study related procedures

Interventions

Number of intervention groups: 2

Concomitant medications: those indicated by the patient's cardiologist

Excluded medications: not mentioned

Trimetazidine group

Intervention: trimetazidine 35 mg twice daily

Duration of intervention: 8 weeks

Ranolazine group

Intervention: ranolazine (type of formulation not specified) 500 mg twice daily

Duration of intervention: 8 weeks

Outcomes

Total number of outcomes: 3 (changes in LV systolic and diastolic function, improvement in angina symptoms, ADR)

OUTCOMES

No outcome meets the inclusion criteria

Starting date

28/10/2013

Contact information

Dr Melvin George

Assistant Professor Cardiac Research

SRM Medical College Hospital

Dept of Cardiology SRM MCH RC Kattankulathur Kancheepuram

Kancheepuram
TAMIL NADU
603203
India

9894133697

[email protected]

Notes

Source of funding: SRM Medical College Hospital

EUCTR 2011‐001278‐24

Trial name or title

2011‐001278‐24 / MEIN/10/Ran‐Cad/003

Methods

Study design: parallel‐group trial

Duration of follow‐up: 24 weeks

Method of randomisation: not described

Method of concealment of allocation: not described

Blinding: double‐blind

Power calculation: not mentioned

Phases of the study: 1 (treatment phase)

Participants

Total number: 1460 (estimated)

Country of enrolment: Greece, Switzerland

Setting/location: not specified

Diagnostic criteria (stable angina pectoris): exercise angina in patients with CAD (macrovascular angina)

Comorbidities: none

Inclusion criteria:

  • Male and female patients (females of childbearing potential must be using adequate contraceptive precautions such as implants, injectables, combined oral contraceptives, intrauterine devices, sexual abstinence or vasectomised partner)

  • Patients aged ≥ 18 years

  • Patients with coronary artery disease confirmed by angiography, prior MI, prior revascularisation (PCI, CABG) and with exercise angina not controlled by the standard therapy

  • ST‐segment depression ≥ 1mm during exercise ECG

  • Capacity to perform the exercise test

  • Able and willing to sign informed consent and to comply with study procedures

  • Females of childbearing potential or within two years from the menopause must have a negative urine pregnancy test

  • Reproducible ST‐segment depression ≥ 1mm during two exercise tests performed 1 week apart (difference in exercise no more than 20%) (at first visit)

Exclusion criteria:

  • Angina at rest

  • ECG abnormalities at rest (left bundle‐branch block, resting ST‐segment depression ≥ 1mm, tachyarrhythmia)

  • Presence of factors that preclude satisfactory interpretation of the ECG (e.g. resting ST‐segment depression ≥ 1 mm in any lead, left bundle‐branch block, digoxin therapy) or repolarisation and conduction abnormalities

  • Heart failure (class III or IV NYHA)

  • Moderate‐severe hypertension (SBP > 160 mmHg and/or DBP > 100 mmHg)

  • Hypotension

  • Acute coronary syndrome or coronary revascularisation procedure within the prior 3 months before enrolment

  • Females who are pregnant or nursing

  • Any clinically relevant haematological or biochemical abnormality on routine screening, according to Investigator’s judgment

  • Severe concurrent pathology, including terminal illness (cancer, AIDS, etc.)

  • Renal impairment defined as creatinine clearance< 30 mL/min

  • Mild, moderate or severe hepatic impairment or hepatic insufficiency defined as: SGOT or SGPT > 3 times ULN or total serum bilirubin > 1.5 times greater than normal upper limit

  • Pre‐existing QT prolongation (including congenital long QT syndrome, uncorrected hypokalaemia)

  • Patients on QT‐prolonging drugs such as Class Ia (e.g. quinidine) and Class III (e.g. dofetilide, sotalol, dronedarone) anti‐arrhythmics, and antipsychotics (e.g. thioridazine, ziprasidone)

  • Existing contraindications for exercise testing (e.g. acute myocarditis or pericarditis, DVT, severe aortic stenosis)

  • Dementia, psychosis, alcoholism (>350 g ethanol/week) or chronic abuse of medicines, drugs or psychoactive substances

  • Conditions which in the Investigator’s opinion may interfere with the study’s execution or due to which the patient should not participate for safety reasons

  • Risk of low patient cooperation

Interventions

Number of intervention groups: 2

Concomitant medications: not described

Excluded medications: those mentioned in exclusion criteria

Placebo group

Intervention: placebo

Duration of intervention: 24 weeks

Ranolazine group

Intervention: ranolazine (type of formulation not specified) 750 mg twice daily

Duration of intervention: 24 weeks

Outcomes

Total number of outcomes: 5 (ETT parameters, angina frequency, nitroglycerin consumption frequency, adverse events incidence, laboratory findings)

OUTCOMES

Angina episodes frequency

Outcome definition: weekly frequency

Method and unit of measurement: number/week

Time points to report: 4, 12 and 24 weeks

Adverse events incidence

Outcome definition: not described

Method and unit of measurement: absolute frequency

Time points to report: 4, 12 and 24 weeks

Starting date

Not reported

Contact information

Study Medical Expert (SME)

Via Walter Tobagi, 8

Peschiera Borromeo ‐ Italy

003902516555236

[email protected]

Notes

Source of funding: Menarini International Operations Luxembourg SA

EUCTR 2012‐001584‐77

Trial name or title

EUCTR2012‐001584‐77‐DE / MEIN/10/Ran‐PCI/005

Methods

Study design: parallel‐group trial

Duration of follow‐up: 5 weeks

Method of randomisation: not described

Method of concealment of allocation: not described

Blinding: double‐blind

Power calculation: not mentioned

Phases of the study: 1 (treatment phase)

Participants

Country of enrolment: Germany

Setting/location: not specified

Diagnostic criteria (stable angina pectoris):history of chronic stable angina and coronary stenosis by angiography (macrovascular angina)

Comorbidities: none

Inclusion criteria:

  • Male and female patients (females of childbearing potential must have a negative urine pregnancy test and must be using adequate contraceptive precautions

  • Performed coronary angiography with or without initial PCI more than 24 hours before MRI

  • Remaining ≥ 70% stenosis of a coronary artery bigger than 2 mm diameter (not corrected by PCI)

  • Indication of further interventional treatment

  • Wall motion abnormalities in at least one segment; if segment 17 is affected, an additional segment has to show wall motion abnormalities

  • History of chronic angina pectoris

  • Age ≥ 18 years

  • Normalised blood pressure < 140/90 mmHg and heart rate < 70 bpm and ≥ 50 bpm at rest

  • Sinus rhythm

  • Standard therapy: beta‐blocker and/or calcium channel blocker (stable for 4 weeks)

Exclusion criteria:

  • Cardiac instability, e.g. acute coronary syndrome as indication for the coronary angiography (ST‐elevation or positive troponin testing)

  • Contraindication for MRI (e.g. implanted pace maker, internal defibrillator, MRI incompatible devices or metals)

  • Contraindication for dobutamine, atropine, gadolinium based contrast agent, or metoprolol

  • Patients with heart failure classification NYHA III and NYHA IV

  • Myocardial infarction during the last 3 days prior to treatment with ranolazine

  • Severe renal impairment (GFR < 30 ml/min)

  • Moderate or severe hepatic impairment (ALT or AST > 2.5 × upper normal limit)

  • Allergic asthma bronchiale

  • Hyperthyroidism or Hashimoto thyroiditis

  • Myocarditis or inflammatory heart disease

  • Concomitant administration of class Ia (e.g. quinidine) or class III (e.g. dofetilide, sotalol) anti‐arrhythmics, except for amiodarone

  • Long acting nitrates

  • Concomitant treatment with potent inhibitors of CYP3A

  • Concomitant treatment with CYP3A inducers

  • Dronedarone

  • Use of greater than 1000 mg daily dose of metformin during the study

  • Hypersensitivity to the active substance or to any of the excipients

  • Hypersensitivity to dobutamine, atropine, gadolinium based contrast agent, or metoprolol

  • Concomitant administration of > 20 mg simvastatin/day

  • History of ECG abnormalities that, in the opinion of the investigator, render the patient unsuitable for the trial, e.g. history of long QT syndrome or significant prolonged QT interval (> 120%)

  • Participation in another trial of an investigational drug or device within 30 days prior to screening

  • Pregnant and breast‐feeding women (females of childbearing potential or within two years from the menopause must have a negative urine pregnancy test)

  • Less than 3 months since delivery, abortion, or lactation before the first screening/examination vis

  • Severe psychiatric disorders/neurological disorders

  • Suspected abuse of alcohol, analgesics or psychotropic drugs

  • Disabling or terminal illness

Interventions

Number of intervention groups: 2

Concomitant medications: standard therapy (beta‐blocker and/or calcium channel blocker)

Excluded medications: those mentioned in exclusion criteria

Placebo group

Intervention: film‐coated tablet

Duration of intervention: 5 weeks

Ranolazine group

Intervention: ranolazine ER (dose not reported)

Duration of intervention: 5 weeks

Outcomes

Total number of outcomes: 2 (changes of the wall motion abnormalities, heart’s perfusion deficit and related variables)

OUTCOMES

No outcome meets the inclusion criteria

Starting date

Not reported

Contact information

Dr. Notghi Contract Research GmbH

Zimmerstraße 55 ‐ Berlin

004903046064780

[email protected]

Notes

Source of funding: Menarini International Operations Luxembourg S.A.

Reported as Prematurely ended

Gupta 2014

Trial name or title

Not stated

Methods

Study design: parallel‐group

Duration of follow‐up: 6 weeks

Method of randomisation: not described

Method of concealment of allocation: not described

Blinding: not specified

Power calculation: not mentioned

Phases of the study: 1 (treatment phase)

Participants

Total number: 185

Country of enrolment: India

Setting/location: not specified

Diagnostic criteria (stable angina pectoris): not described

Comorbidities: type 2 diabetes

Inclusion criteria: not described

Exclusion criteria: not described

Interventions

Number of intervention groups: 2

Concomitant medication: 1 or 2 anti‐anginals

Excluded medications: not described

Placebo group

Intervention: placebo

Duration of intervention: 6 weeks

Ranolazine group

Intervention: ranolazine (type of formulation not specified) (dose not reported)

Duration of intervention: 6 weeks

Outcomes

Total number of outcomes: 2 (weekly angina frequency, weekly sublingual nitrate use)

OUTCOMES

Angina episodes frequency

Outcome definition: not described

Method and unit of measurement: number per week

Time points reported: 6 weeks

Starting date

Not reported

Contact information

Not provided

Notes

NCT01495520

Trial name or title

NCT01495520

Methods

Study design: cross‐over trial

Duration of follow‐up: 30 days

Method of randomisation: not described

Method of concealment of allocation: not described

Blinding: double‐blind (Subject, Caregiver, Investigator)

Power calculation: not mentioned

Phases of the study: 1 (treatment phase)

Participants

Total number: 100 (estimated)

Country of enrolment: Italy

Setting/location: not specified

Diagnostic criteria (stable angina pectoris): coronary artery disease (macrovascular angina)

Comorbidities: none

Inclusion criteria:

  • Symptoms of palpitations

  • Angiographically‐proven coronary artery disease

  • Stable conditions

  • No recent acute coronary syndromes

  • Able to understand and willing to sign the informed consent form

  • Symptomatic patients (palpitation) with stable angina pectoris already on therapy with beta‐blockers and/or calcium antagonists

Exclusion criteria:

  • Women of child bearing potential patients must demonstrate a negative pregnancy test performed within 24 hours

  • Severe renal failure

  • Severe hepatic failure

Interventions

Number of intervention groups: 2

Concomitant medications: not described

Excluded medications: not described

Placebo group

Intervention: placebo

Duration of intervention: 30 days

Ranolazine group

Intervention: ranolazine (type of formulation not specified) 750 mg twice daily

Duration of intervention: 30 days

Outcomes

Total number of outcomes: 2 (occurrence of symptoms of palpitations, occurrence of arrhythmia in case of symptoms of palpitations)

OUTCOMES

No outcome meets the inclusion criteria

Starting date

January 2014

Contact information

Francesco Pelliccia, MD

+39064997

[email protected]

Notes

Source of funding: University of Roma La Sapienza

NCT01558830

Trial name or title

NCT01558830

Methods

Study design: parallel‐group

Duration of follow‐up: 3 months

Method of randomisation: not described

Method of concealment of allocation: not described

Blinding: single‐blind (subject)

Power calculation: not mentioned

Phases of the study: 1 (treatment phase)

Participants

Country of enrolment: United States

Setting/location: not specified

Diagnostic criteria (stable angina pectoris): history of stable angina

Comorbidities: other cardiac conditions (such as atrial fibrillation)

Inclusion criteria:

  • Ischemic cardiac disease

  • Chronic anginal symptoms

  • On amiodarone therapy for other cardiac conditions

Exclusion criteria:

  • Pregnant

  • Non‐English speaking

  • Unstable angina

  • Baseline electrocardiogram (EKG) corrected QT (QTc)>490ms

  • Severe thyroid dysfunction

  • Heart block without a pacer system

  • Liver disease

Interventions

Number of intervention groups: 2

Concomitant medications: amiodarone

Excluded medications: not described

Placebo group

Intervention: sugar pill

Duration of intervention: 3 months

Ranolazine group

Intervention: ranolazine (type of formulation not specified) 500/1000 mg twice daily

Duration of intervention: 3 months

Outcomes

Total number of outcomes: 6 (ventricular arrhythmia burden, atrial arrhythmia burden, QTc interval measurement, hospitalisation rate, syncope hospitalisation rate, liver function assay)

OUTCOMES

No outcomes meets inclusion criteria

Starting date

Not reported

Contact information

Erik J Sirulnick, MD

702‐731‐8224

[email protected]

Notes

Source of funding: Cardiovascular Consultants of Nevada, Gilead Sciences

NCT01754259

Trial name or title

NCT01754259

Methods

Study design: cross‐over trial

Duration of follow‐up: 4 weeks

Method of randomisation: not described

Method of concealment of allocation: "labelled" bottles provided by the sponsor

Blinding: double‐blind (Subject, Investigator)

Power calculation: not mentioned

Phases of the study: 1 (treatment phase)

Participants

Total number: 70 (estimated)

Country of enrolment: United States

Setting/location: not specified

Diagnostic criteria (stable angina pectoris): symptoms of stable angina and CAD (criteria for diagnosis not described) (macrovascular angina)

Comorbidities: type 1 and 2 diabetes mellitus

Inclusion criteria:

  • Type 1 or 2 diabetes mellitus

  • Anginal symptoms and/or exertional dyspnoea

  • Ability to exercise and achieve an exercise tolerance of at least 3 METS but not higher than 9 METS either on a treadmill or bicycle exercise tolerance test

  • Perfusion sum stress score (SSS) ≤ 6, as assessed by initial PET

Exclusion criteria:

  • Patients not fulfilling inclusion criteria

  • Patients with evidence of unprotected left main coronary artery stenosis >50%

  • Patients with evidence of new obstructive CAD not on optimal medical therapy

  • Evidence of angiographic disease and/or inducible myocardial ischaemia on stress testing planning to undergo revascularisation within the following 3 months

  • History of cardiomyopathy (LVEF <40%) or significant valvular heart disease

  • Uncontrolled hypertension (SBP >180 mm Hg at screening)

  • Gait instability, lower extremity amputations preventing exercise

  • Significant liver dysfunction (LFTs >3x upper limits of normal), including cirrhosis

  • Prolonged QT (QTc >450 and >470 ms for men and women, respectively) or concomitant use of drugs that prolong QT interval (including methadone and anti‐arrhythmics such as sotalol, amiodarone, and quinidine)

  • Use of drugs that inhibit CYP3A such as ketoconazole, itraconazole, fluconazole, clarithromycin, erythromycin, diltiazem, verapamil, nefazodone, nelfinavir, ritonavir, lopinavir, ritonavir, indinavir, and saquinavir

  • Use of drugs that induce CYP3A such rifampin, rifabutin, rifapentine, phenobarbital, phenytoin, carbamazepine, and St. John's wort 13. atrial fibrillation / inability to hold breath for ≥ 10 seconds (in patients in whom CTA will be performed)

  • eGFR < 50 ml/min or end stage renal disease on dialysis

  • Allergy to intravenous contrast

  • Pregnant or lactating women, or women of childbearing potential not using an acceptable form of birth control (negative pregnancy test also required)

  • Inability to fit safely in PET/CT scanner

Interventions

Number of intervention groups: 2

Concomitant medications: anti‐anginals (not described)

Excluded medications: those mentioned in exclusion criteria

Placebo group

Intervention: placebo

Duration of intervention: 4 weeks

Ranolazine group

Intervention: ranolazine (type of formulation not specified) (dosage not reported)

Duration of intervention: 4 weeks

Outcomes

Total number of outcomes: 9 (post‐exercise coronary vasodilator reserve, symptoms of exertional angina and/or dyspnoea (SAQ/RDS scales), left ventricular systolic function, post‐exercise global myocardial blood flow, post‐exercise global coronary vascular resistance, serum biomarkers of myocardial strain, LV diastolic function, correlation between multimodality imaging parameters)

OUTCOMES

No outcome meets the inclusion criteria

Starting date

April 2013

Contact information

Ron Blankstein, MDBrigham and Women's Hospital

Notes

Source of funding: Brigham and Women's Hospital

NCT01948310

Trial name or title

NCT01948310

Methods

Study design: parallel‐group

Duration of follow‐up: not stated

Method of randomisation: not described

Method of concealment of allocation: not described

Blinding: double‐blind (Subject, Caregiver, Investigator, Outcomes Assessor)

Power calculation: not mentioned

Phases of the study: 1 (treatment phase)

Participants

Total number: 40 (estimated)

Country of enrolment: United States

Setting/location: not specified

Diagnostic criteria (stable angina pectoris): stable angina for at least 3 months with documented CAD (macrovascular angina)

Comorbidities: none

Inclusion criteria:

  • Documented CAD diagnosis

  • Stable angina ≥ 3 months

Exclusion criteria:

  • Class III or IV heart failure

  • Myocardial Infarction or coronary revascularisation procedure within 2 months

  • QT interval > 500 ms or prescribed medication known to prolong the QTc interval

Contraindicated medications

  • Metformin dose > 1700 mg/day

  • Class Ia, Ic and III anti‐arrhythmics

  • CYP3A inhibitors

  • Simvastatin > 20 mg/day

  • Severe renal disease (< 30ml/min creatinine clearance)

  • Currently on dialysis

  • Lack of transportation to the exercise and testing facilities

  • Implanted pacemaker that is not rate responsive

Interventions

Number of intervention groups: 2

Concomitant therapy: aerobic exercise three times per week, 45 minutes per session at an intensity of 10‐20 beats per minute below the angina threshold

Excluded medications: those mentioned in exclusion criteria

Placebo group

Intervention: placebo

Duration of intervention: 13 weeks (not explicitly stated)

Ranolazine group

Intervention: ranolazine (type of formulation not specified) 1000 mg twice daily

Duration of intervention: 13 weeks (not explicitly stated)

Outcomes

Total number of outcomes: 3 (change in peak oxygen consumption, change in treatment satisfaction (SAQ scale), change in total daily energy expenditure)

Adverse events incidence

No outcome meets the inclusion criteria

Starting date

December 2013

Contact information

Leslie H Willis, MS

9196606782

leslie.willisduke.edu

Notes

Source of funding: Duke University, Gilead Sciences

NCT02052011

Trial name or title

NCT02052011

Methods

Study design: parallel‐group trial

Duration of follow‐up: 4 weeks

Method of randomisation: not described

Method of concealment of allocation: not described

Blinding: double‐blind (Subject, Caregiver, Investigator, Outcomes Assessor)

Power calculation: not mentioned

Phases of the study: 1 (treatment phase)

Participants

Total number: 30 (estimated)

Country of enrolment: United States

Setting/location: emergency patients

Diagnostic criteria (stable angina pectoris): microvascular angina

Comorbidities: none

Inclusion criteria:

  • Patients admitted to the Yale ED CPC

  • ≥ 30 years age

  • Chest pain or angina equivalent as their chief complaint within 24 hours of enrolment

  • Coronary Flow Reserve(CFR) <2.5 on PET scan in the ED

Exclusion criteria:

  • Acute coronary syndrome

  • Prior evidence of obstructive heart disease (history of Percutaneous Transluminal Coronary Angioplasty (PTCA), Coronary Artery Bypass Grafting (CABG) or calcium score > 10 on PET scan)

  • Resting blood pressure of systolic >180/110 mm Hg or <100/40

  • Known cardiomyopathy or heart failure

  • Currently on dialysis

  • Creatinine clearance <30 ml/min

  • Liver cirrhosis

  • Significant aortic stenosis (murmur on exam)

  • Active use of cocaine or amphetamine

  • Current use of potent CYP3A4 inducers or inhibitors (such as ketoconazole, clarithromycin, HIV protease inhibitors)

  • Baseline QTc > 580 msec

  • Use of drugs that prolong QTc (Haldol, erythromycin)

  • Pregnancy

  • Inability to read or understand English

  • Suffering from a condition that precludes interview (i.e. cognitive or communication impairment)

Interventions

Number of intervention groups: 2

Concomitant medications: not mentioned

Excluded medications: those mentioned in exclusion criteria

Placebo group

Intervention: placebo

Duration of intervention: 4 weeks

Ranolazine group

Intervention: ranolazine ER 1000 mg twice daily (up‐titrated from 500 mg twice daily for 1 week)

Duration of intervention: 4 weeks

Outcomes

Total number of outcomes: 3 (Coronary Flow Reserve, quality of life (SAQ scale), return visits)

OUTCOMES

Quality of life

Outcome definition: not described

Method and unit of measurement: score

Time points reported: 4 weeks

Starting date

April 2014

Contact information

Matthew Naftilan, MS

203‐785‐4676

[email protected]

Notes

Source of funding: Yale University, Gilead Sciences

NCT02147067

Trial name or title

NCT02147067

Methods

Study design: parallel‐group trial

Duration of follow‐up: 12 weeks

Method of randomisation: not described

Method of concealment of allocation: not described

Blinding: double‐blind (Subject, Caregiver, Investigator, Outcomes Assessor)

Power calculation: not mentioned

Phases of the study: 1 (treatment phase)

Participants

Total number: 50 (estimated)

Country of enrolment: not described

Setting/location: not specified

Diagnostic criteria (stable angina pectoris): symptoms of stable angina and no evidence of CAD (microvascular angina)

Comorbidities: none

Inclusion criteria:

  • History of typical angina or effort‐induced anginal symptoms and are currently experiencing angina at least once per week

  • Abnormal stress ECG, exercise stress imaging, or pharmacological stress imaging

  • Non‐obstructive coronary artery disease as defined by lesion stenosis ≤ 50% in any artery as visualised by diagnostic angiography

Exclusion criteria:

  • Inability to provide informed consent

  • Active Myocardial Infarction

  • History of coronary artery bypass grafting

  • Diagnosis of other specific cardiac disease such as severe valvular heart disease, cardiomyopathy, or variant angina

  • Left Ventricular Ejection Fraction (LVEF) < 30%

  • Known renal insufficiency (CrCl < 30 mL/min) or on dialysis

  • Contraindications to the use of Ranolazine

Interventions

Number of intervention groups: 2

Concomitant medications: not described

Excluded medications: not described

Placebo group

Intervention: placebo

Duration of intervention: 12 weeks

Ranolazine group

Intervention: ranolazine (type of formulation not specified) 1000 mg twice daily

Duration of intervention: 12 weeks

Outcomes

Total number of outcomes: 5 (quality of life (SAQ scale), peak rate of oxygen consumption, ETT parameters, Coronary Flow Velocity Reserve (CFR), Hyperemic Microcirculatory Resistance (HMR))

OUTCOMES

Quality of life

Outcome definition: Seattle Angina Questionnaire score regarding angina frequency, physical functioning, treatment satisfaction, angina stability, and quality of life

Method and unit of measurement: score (change from baseline)

Time points reported: 12 weeks

Starting date

September 2014

Contact information

Habib Samady, MD

(404) 778‐1237

[email protected]

Notes

Source of funding: Emory University, Gilead Sciences

NCT02147834

Trial name or title

NCT02147834

Methods

Study design: parallel‐group trial

Duration of follow‐up: 4 months

Method of randomisation: not described

Method of concealment of allocation: not described

Blinding: double‐blind (Subject, Caregiver, Investigator, Outcomes Assessor)

Power calculation: not mentioned

Phases of the study: 1 (treatment phase)

Participants

Total number: 250 (estimated)

Country of enrolment: United States

Setting/location: not specified

Diagnostic criteria (stable angina pectoris): not described, patients deferred from having a PCI

Comorbidities: none

Inclusion criteria:

  • Stable patients aged ≥ 18 years referred for cardiac catheterisation for evaluation of cardiac symptoms (angina, fatigue, or shortness of breath)

  • At least 1 indeterminate stenosis (20% to 80%), fractional flow reserve (FFR) ≥ 0.8 and PCI deferred

Exclusion criteria:

  • Coronary revascularisation (percutaneous coronary intervention or coronary artery bypass grafting) during the index procedure or anticipated within the next month

  • Acute coronary syndrome or cardiogenic shock

  • Use of strong inhibitors of CTP3A (i.e. ketoconazole, itraconazole, clarithromycin,nefazodone, nelfinavir, ritonavir, indinavir and saquinavir)

  • Use of inducers of CYP3A (i.e. rifampin, rifabutin, rifapentine, phenobarbital, phenytoin, carbamazepine, and St. John's wort)

  • Liver cirrhosis

  • Severe renal insufficiency (i.e. creatinine clearance < 30 mL/min/1.73 m²)

  • QTc > 500 milliseconds

Interventions

Number of intervention groups: 2

Concomitant medications: not described

Excluded medications: those mentioned in exclusion criteria

Placebo group

Intervention: sugar pill twice daily

Duration of intervention: 16 weeks

Ranolazine group

Intervention: ranolazine (type of formulation not specified) 1000 mg twice daily (up‐titrated from 500 mg twice daily for 1 week)

Duration of intervention: 16 weeks

Outcomes

Total number of outcomes: 3 (quality of life (SAQ scale), subjective well being, ischemia‐driven revascularisation or hospitalisation)

OUTCOMES

Quality of life

Outcome definition: the Seattle Angina Questionnaire is a valid and reliable instrument that measures five clinically important dimensions of health in patients with CAD (physical limitation, anginal stability, anginal frequency, treatment satisfaction, and disease perception)

Method and unit of measurement: score (change from baseline)

Time points reported: 4 months

Need for revascularisation procedure

Outcome definition: frequency of the number of reported adverse events for ischaemia driven revascularisation

Method and unit of measurement: absolute frequency

Time points reported: 4 months

Starting date

August 2015

Contact information

Anthony A Bavry, MD MPH

352‐376‐1611 ext 4726

[email protected]

Notes

Source of funding: North Florida Foundation for Research and Education, Gilead Sciences, University of Florida

NCT02252406

Trial name or title

NCT02252406

Methods

Study design: parallel‐group

Duration of follow‐up: 24 weeks

Method of randomisation: not described

Method of concealment of allocation: not described

Blinding: double‐blind (Subject, Caregiver, Investigator, Outcomes Assessor)

Power calculation: not mentioned

Phases of the study: 1 (treatment phase)

Participants

Total number: 40 (estimated)

Country of enrolment: not described

Setting/location: not specified

Diagnostic criteria (stable angina pectoris): symptoms of chronic stable angina and evidence of CAD (macrovascular angina)

Comorbidities: Metabolic Syndrome

Inclusion criteria:

  • Patients with chronic stable angina (> 3 months) and symptomatic >=3 attacks/week on evidence based adequate therapy

  • Evidence of stable coronary artery disease by any of these:

    • MI, PCI or CABG > 30 days prior to enrolment or

    • Angiography showing > 50% stenosis in major vessel, branch or bypass graft > 30 days of Enrollment or

    • Abnormal stress MPI nuclear study, or DBA stress echo where the decision has been to treat medically and where angina has remained stable for >= 3 months

  • Evidence of the Metabolic Syndrome: As defined by ATP III criteria i.e. 3/5 of following Abdominal circumference F > 88 cm (35 in), M > 102 cm (40 in) Hypertriglyceridemia ≥ 150 mg/dl HDL F < 50 mg/dl M < 40 mg/dl Blood Pressure ≥130/85 Fasting Glucose ≥100 mg/dl For reproductive age women, a negative urine pregnancy test is required if all other inclusion criteria are met

Exclusion criteria:

  • Contraindications to use of Ranexa, including patients on CYP3A4 inducers/potent inhibitors, and patients with liver cirrhosis

  • Patients with CrCl < 30 mL/min

  • Limit dose of Ranexa to 500 mg BID in patients on concurrent diltiazem/verapamil

  • Limit concurrent simvastatin to 20 mg/day

  • Limit concurrent metformin to 1000 mg/day

Additional exclusion

  • Patients with variable ‐inconsistent symptoms

  • Patients with unstable coronary artery disease or revascularisation within 30 days of enrolment

  • Patients who have known severe liver disease

  • Patients already receiving maximal ranolazine therapy for more than 4 weeks

  • Presence of diabetes, hypothyroidism, active infection, cancer and/or recent major surgery or illness

  • Patients with any contraindication to ranolazine see above

  • Women of reproductive age are excluded if they are planning to become pregnant in the next 6 ‐12 months after randomisation

  • Patients who are pregnant or lactating

  • Documented allergic reaction to ranolazine in the past

  • Unexplained prolongation of the QTc > 500 milliseconds

  • Current or planned co‐administration of moderate CYP3A inhibitors (e.g. diltiazem, verapamil, aprepitant, erythromycin, fluconazole, and grapefruit juice or grapefruit‐containing products) is not a full contraindication, if meet inclusion criteria otherwise, these patients could be accepted in trial but dose will be limited to 500 mg BID as stated previously

  • Current or planned co‐administration of strong CYP3A inhibitors (e.g. ketoconazole, itraconazole, clarithromycin, nefazodone, nelfinavir, ritonavir, indinavir, and saquinavir) OR strong CYP3A inducers (e.g. rifampin, rifabutin, rifapentine, phenobarbital, phenytoin,carbamazepine, and St. John's Wort) is a contraindication

Interventions

Number of intervention groups: 2

Concomitant medications: not described

Excluded medications: those mentioned in exclusion criteria

Placebo group

Intervention: placebo

Duration of intervention: 24 weeks

Ranolazine group

Intervention: ranolazine (type of formulation not specified) 500 mg twice daily

Duration of intervention: 24 weeks

Outcomes

Total number of outcomes: (angina frequency (SAQ scale), biomarkers)

OUTCOMES

No outcome meets the inclusion criteria

Starting date

September 2015

Contact information

Gladys Velarde, MD

904‐244‐43095

[email protected]

Notes

Source of funding: University of Florida

NCT02265796

Trial name or title

NCT02265796

Methods

Study design: parallel‐group trial

Duration of follow‐up: 16 weeks

Method of randomisation: not described

Method of concealment of allocation: not described

Blinding: double‐blind (Subject, Caregiver, Investigator, Outcomes Assessor)

Power calculation: not mentioned

Phases of the study: 1 (treatment phase)

Participants

Total number: 50 (estimated)

Country of enrolment: United States

Setting/location: not specified

Diagnostic criteria (stable angina pectoris): not described

Comorbidities: none

Inclusion criteria:

  • Adult patients aged ≥ 18 years referred for cardiac catheterisation for evaluation of cardiac symptoms (angina, fatigue, or shortness of breath)

  • At least 1 indeterminate stenosis (20% to 80%)

  • Fractional flow reserve (FFR) ≤ 0.8 and PCI deferred

Exclusion criteria:

  • Coronary revascularisation (percutaneous coronary intervention or coronary artery bypass grafting) during the index procedure or anticipated within the next month

  • Acute coronary syndrome or cardiogenic shock

  • QTc > 500 milliseconds

  • Use of strong inhibitors of CTP3A (i.e. ketoconazole, itraconazole, clarithromycin,nefazodone, nelfinavir, ritonavir, indinavir and saquinavir)

  • Use of inducers of CYP3A (i.e. rifampin, rifabutin, rifapentine, phenobarbital, phenytoin, carbamazepine, and St. John's wort)

  • Liver cirrhosis

  • Severe renal insufficiency (i.e. creatinine clearance < 30mL/min/1.73 m2)

Interventions

Number of intervention groups: 2

Concomitant medications: not described

Excluded medications: those mentioned in exclusion criteria

Placebo group

Intervention: sugar pill twice daily

Duration of intervention: 16 weeks

Ranolazine group

Intervention: ranolazine (type of formulation not specified) 1000 mg twice daily (up‐titrated from 500 mg twice daily for 1 week)

Duration of intervention: 16 weeks

Outcomes

Total number of outcomes: 3 (quality of life (SAQ scale), subjective well being, ischemia‐driven revascularisation or hospitalisation)

OUTCOMES

Quality of life

Outcome definition: the Seattle Angina Questionnaire is a valid and reliable instrument that measures five clinically important dimensions of health in patients with coronary artery disease (physical limitation, anginal stability, anginal frequency, treatment satisfaction, and disease perception)

Method and unit of measurement: score (change from baseline)

Time points reported: 16 weeks

Need for revascularisation procedure

Outcome definition: frequency of the number of reported adverse events for ischaemia driven revascularisation

Method and unit of measurement: absolute frequency

Time points reported: 16 weeks

Starting date

September 2014

Contact information

Anthony A Bavry, MD, MPH

352‐376‐1611 ext 4726

[email protected]

Notes

Source of funding: North Florida Foundation for Research and Education, Gilead Sciences

NCT02423265

Trial name or title

NCT02423265

Methods

Study design: parallel‐group trial

Duration of follow‐up: 9 weeks

Method of randomisation: not described

Method of concealment of allocation: not described

Blinding: Double‐blind (Subject, Investigator, Outcomes Assessor)

Power calculation: not mentioned

Phases of the study: 2 (treatment phase, follow‐up phase)

Participants

Country of enrolment: not described

Setting/location: not specified

Diagnostic criteria (stable angina pectoris): not described

Comorbidities: percutaneous coronary intervention plus stent implantation

Inclusion criteria:

  • Angiographically proven coronary artery disease with chronic stable angina for at least 3 months.

  • Abnormal stress test (treadmill ECG, nuclear stress test, dobutamine stress echocardiogram or stress perfusion cardiac MRI)

  • ≥ 1 chronically occluded coronary artery of a dominant coronary vessel or the left anterior descending artery and/or ≥ 1 occluded vein graft to chronically occluded native coronary vessel

  • Subjects must be taking a minimum of 2 anti‐anginal agents

Exclusion criteria:

  • LVEF < 40

  • Terminal illness such as cancer

  • Occluded recessive coronary vessel

  • Hepatic insufficiency,

  • Liver cirrhosis,

  • Prolonged QT interval on ECG,

  • Severe renal failure (see below), Excluding patients with CrCl < 30

  • Drugs that are strong inhibitors of CYP3A such as, ketoconazole, macrolide antibiotics and HIV protease inhibitors.

  • Limit Ranolazine to 500 mg BID in patients on concurrent diltiazem/verapamil

  • Limit concurrent simvastatin to 20 mg/day

  • Limit concurrent metformin to 1700 mg/day

  • Inability to have an MRI scan/known claustrophobia

Interventions

Number of intervention groups: 3

Concomitant medications: standard therapy (not described)

Excluded medications: not mentioned

Placebo group

Intervention:placebo with up‐titration after 1 week

Duration of intervention: 9 weeks

Ranolazine group

Intervention: ranolazine (type of formulation not specified) 1000 mg twice daily (up‐titrated after 1‐week 500 mg twice daily)

Duration of intervention: 9 weeks

Outcomes

Total number of outcomes: 4 (cardiac MRI strain, dobutamine wall motion scoring index, quality of life, ETT parameters)

OUTCOMES

Quality of life

Outcome definition: measured with 3 scales (SAQ, DASI, SF‐12)

Method and unit of measurement: total score

Time points to report: 9 weeks

Starting date

June 2015

Contact information

Ashesh N Buch, MB.ChB, M.D. [email protected]

Notes

Šebeštjen 2014

Trial name or title

Methods

Study design: parallel‐group trial

Duration of follow‐up: 12 weeks

Method of randomisation: not described

Method of concealment of allocation: not described

Blinding: double‐blind

Power calculation: not mentioned

Phases of the study: 1 (treatment phase)

Participants

Total number: 52

Country of enrolment: not mentioned

Setting/location: not specified

Diagnostic criteria (stable angina pectoris): not described

Comorbidities: none

Inclusion criteria: not described

Exclusion criteria: not described

Interventions

Number of intervention groups: 2

Concomitant medications: not described

Excluded medications: not described

Trimetazidine group

Intervention: trimetazidine 35 mg twice daily

Duration of intervention: 12 weeks

Ranolazine group

Intervention: ranolazine (type of formulation not specified) 375/500 mg twice daily

Duration of intervention: 12 weeks

Outcomes

Total number of outcomes: 2 (flow‐mediated (endothelium‐dependent) dilation (FMD) of brachial artery, nitroglycerin‐induced (endothelium‐independent) (GTN) dilation of brachial artery)

OUTCOMES

No outcomes meets inclusion criteria

Starting date

Not reported

Contact information

Not provided

Notes

Data and analyses

Open in table viewer
Comparison 1. Ranolazine (monotherapy) 1000 mg twice daily versus placebo

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Cardiovascular mortality Show forest plot

1

2604

Risk Ratio (M‐H, Fixed, 95% CI)

1.03 [0.56, 1.88]

Analysis 1.1

Comparison 1 Ranolazine (monotherapy) 1000 mg twice daily versus placebo, Outcome 1 Cardiovascular mortality.

Comparison 1 Ranolazine (monotherapy) 1000 mg twice daily versus placebo, Outcome 1 Cardiovascular mortality.

2 All‐cause mortality Show forest plot

3

6249

Risk Ratio (M‐H, Fixed, 95% CI)

1.00 [0.81, 1.25]

Analysis 1.2

Comparison 1 Ranolazine (monotherapy) 1000 mg twice daily versus placebo, Outcome 2 All‐cause mortality.

Comparison 1 Ranolazine (monotherapy) 1000 mg twice daily versus placebo, Outcome 2 All‐cause mortality.

3 Quality of life Show forest plot

3

2254

Mean Difference (IV, Fixed, 95% CI)

0.28 [‐1.57, 2.13]

Analysis 1.3

Comparison 1 Ranolazine (monotherapy) 1000 mg twice daily versus placebo, Outcome 3 Quality of life.

Comparison 1 Ranolazine (monotherapy) 1000 mg twice daily versus placebo, Outcome 3 Quality of life.

4 AMI incidence Show forest plot

2

2674

Risk Ratio (M‐H, Random, 95% CI)

0.55 [0.14, 2.15]

Analysis 1.4

Comparison 1 Ranolazine (monotherapy) 1000 mg twice daily versus placebo, Outcome 4 AMI incidence.

Comparison 1 Ranolazine (monotherapy) 1000 mg twice daily versus placebo, Outcome 4 AMI incidence.

5 Need for revascularisation procedure Show forest plot

2

2674

Risk Ratio (M‐H, Fixed, 95% CI)

0.98 [0.82, 1.18]

Analysis 1.5

Comparison 1 Ranolazine (monotherapy) 1000 mg twice daily versus placebo, Outcome 5 Need for revascularisation procedure.

Comparison 1 Ranolazine (monotherapy) 1000 mg twice daily versus placebo, Outcome 5 Need for revascularisation procedure.

6 Adverse events incidence Show forest plot

2

638

Risk Ratio (M‐H, Fixed, 95% CI)

1.33 [0.90, 1.98]

Analysis 1.6

Comparison 1 Ranolazine (monotherapy) 1000 mg twice daily versus placebo, Outcome 6 Adverse events incidence.

Comparison 1 Ranolazine (monotherapy) 1000 mg twice daily versus placebo, Outcome 6 Adverse events incidence.

Open in table viewer
Comparison 2. Ranolazine (monotherapy) any dose versus placebo

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 AMI incidence Show forest plot

3

2983

Risk Ratio (M‐H, Fixed, 95% CI)

0.88 [0.69, 1.12]

Analysis 2.1

Comparison 2 Ranolazine (monotherapy) any dose versus placebo, Outcome 1 AMI incidence.

Comparison 2 Ranolazine (monotherapy) any dose versus placebo, Outcome 1 AMI incidence.

2 Angina episodes frequency Show forest plot

2

402

Mean Difference (IV, Fixed, 95% CI)

0.08 [‐0.85, 1.01]

Analysis 2.2

Comparison 2 Ranolazine (monotherapy) any dose versus placebo, Outcome 2 Angina episodes frequency.

Comparison 2 Ranolazine (monotherapy) any dose versus placebo, Outcome 2 Angina episodes frequency.

3 Adverse events incidence Show forest plot

3

947

Risk Ratio (M‐H, Fixed, 95% CI)

1.50 [1.12, 2.00]

Analysis 2.3

Comparison 2 Ranolazine (monotherapy) any dose versus placebo, Outcome 3 Adverse events incidence.

Comparison 2 Ranolazine (monotherapy) any dose versus placebo, Outcome 3 Adverse events incidence.

3.1 Macrovascular angina

2

691

Risk Ratio (M‐H, Fixed, 95% CI)

1.53 [1.13, 2.07]

3.2 Microvascular angina

1

256

Risk Ratio (M‐H, Fixed, 95% CI)

1.17 [0.40, 3.38]

Open in table viewer
Comparison 3. Ranolazine (add‐on therapy) 1000 mg twice daily versus placebo

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 All‐cause mortality Show forest plot

3

2053

Risk Ratio (M‐H, Fixed, 95% CI)

0.83 [0.26, 2.71]

Analysis 3.1

Comparison 3 Ranolazine (add‐on therapy) 1000 mg twice daily versus placebo, Outcome 1 All‐cause mortality.

Comparison 3 Ranolazine (add‐on therapy) 1000 mg twice daily versus placebo, Outcome 1 All‐cause mortality.

2 Quality of life Show forest plot

3

1533

Std. Mean Difference (IV, Random, 95% CI)

0.13 [‐0.05, 0.32]

Analysis 3.2

Comparison 3 Ranolazine (add‐on therapy) 1000 mg twice daily versus placebo, Outcome 2 Quality of life.

Comparison 3 Ranolazine (add‐on therapy) 1000 mg twice daily versus placebo, Outcome 2 Quality of life.

3 AMI incidence (fatal) Show forest plot

2

1509

Risk Ratio (M‐H, Fixed, 95% CI)

1.51 [0.25, 9.05]

Analysis 3.3

Comparison 3 Ranolazine (add‐on therapy) 1000 mg twice daily versus placebo, Outcome 3 AMI incidence (fatal).

Comparison 3 Ranolazine (add‐on therapy) 1000 mg twice daily versus placebo, Outcome 3 AMI incidence (fatal).

4 AMI incidence (non‐fatal) Show forest plot

2

1509

Risk Ratio (M‐H, Fixed, 95% CI)

0.40 [0.08, 2.07]

Analysis 3.4

Comparison 3 Ranolazine (add‐on therapy) 1000 mg twice daily versus placebo, Outcome 4 AMI incidence (non‐fatal).

Comparison 3 Ranolazine (add‐on therapy) 1000 mg twice daily versus placebo, Outcome 4 AMI incidence (non‐fatal).

5 Angina episodes frequency Show forest plot

3

2004

Mean Difference (IV, Fixed, 95% CI)

‐0.66 [‐0.97, ‐0.35]

Analysis 3.5

Comparison 3 Ranolazine (add‐on therapy) 1000 mg twice daily versus placebo, Outcome 5 Angina episodes frequency.

Comparison 3 Ranolazine (add‐on therapy) 1000 mg twice daily versus placebo, Outcome 5 Angina episodes frequency.

6 Adverse events incidence Show forest plot

3

2053

Risk Ratio (M‐H, Fixed, 95% CI)

1.22 [1.06, 1.40]

Analysis 3.6

Comparison 3 Ranolazine (add‐on therapy) 1000 mg twice daily versus placebo, Outcome 6 Adverse events incidence.

Comparison 3 Ranolazine (add‐on therapy) 1000 mg twice daily versus placebo, Outcome 6 Adverse events incidence.

Open in table viewer
Comparison 4. Ranolazine (add‐on therapy) any dose versus placebo

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Quality of life Show forest plot

4

1563

Std. Mean Difference (IV, Random, 95% CI)

0.25 [‐0.01, 0.52]

Analysis 4.1

Comparison 4 Ranolazine (add‐on therapy) any dose versus placebo, Outcome 1 Quality of life.

Comparison 4 Ranolazine (add‐on therapy) any dose versus placebo, Outcome 1 Quality of life.

1.1 Macrovascular angina

3

1533

Std. Mean Difference (IV, Random, 95% CI)

0.13 [‐0.05, 0.32]

1.2 Microvascular angina

1

30

Std. Mean Difference (IV, Random, 95% CI)

1.13 [0.36, 1.91]

2 Time to 1‐mm ST‐segment depression Show forest plot

3

1165

Mean Difference (Fixed, 95% CI)

34.62 [33.08, 36.16]

Analysis 4.2

Comparison 4 Ranolazine (add‐on therapy) any dose versus placebo, Outcome 2 Time to 1‐mm ST‐segment depression.

Comparison 4 Ranolazine (add‐on therapy) any dose versus placebo, Outcome 2 Time to 1‐mm ST‐segment depression.

Open in table viewer
Comparison 5. Sensitivity analysis 1: Studies at low risk of bias

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Comparison 1 ‐ All‐cause mortality Show forest plot

2

6179

Risk Ratio (M‐H, Fixed, 95% CI)

1.01 [0.81, 1.26]

Analysis 5.1

Comparison 5 Sensitivity analysis 1: Studies at low risk of bias, Outcome 1 Comparison 1 ‐ All‐cause mortality.

Comparison 5 Sensitivity analysis 1: Studies at low risk of bias, Outcome 1 Comparison 1 ‐ All‐cause mortality.

2 Comparison 1 ‐ Quality of life Show forest plot

2

1998

Mean Difference (IV, Fixed, 95% CI)

0.09 [‐1.86, 2.05]

Analysis 5.2

Comparison 5 Sensitivity analysis 1: Studies at low risk of bias, Outcome 2 Comparison 1 ‐ Quality of life.

Comparison 5 Sensitivity analysis 1: Studies at low risk of bias, Outcome 2 Comparison 1 ‐ Quality of life.

3 Comparison 1 ‐ AMI incidence Show forest plot

1

2604

Risk Ratio (M‐H, Random, 95% CI)

0.94 [0.73, 1.20]

Analysis 5.3

Comparison 5 Sensitivity analysis 1: Studies at low risk of bias, Outcome 3 Comparison 1 ‐ AMI incidence.

Comparison 5 Sensitivity analysis 1: Studies at low risk of bias, Outcome 3 Comparison 1 ‐ AMI incidence.

4 Comparison 1 ‐ Need for revascularisation procedure Show forest plot

1

2604

Risk Ratio (M‐H, Fixed, 95% CI)

0.98 [0.82, 1.18]

Analysis 5.4

Comparison 5 Sensitivity analysis 1: Studies at low risk of bias, Outcome 4 Comparison 1 ‐ Need for revascularisation procedure.

Comparison 5 Sensitivity analysis 1: Studies at low risk of bias, Outcome 4 Comparison 1 ‐ Need for revascularisation procedure.

5 Comparison 2 ‐ AMI incidence Show forest plot

1

2604

Risk Ratio (M‐H, Fixed, 95% CI)

0.94 [0.73, 1.20]

Analysis 5.5

Comparison 5 Sensitivity analysis 1: Studies at low risk of bias, Outcome 5 Comparison 2 ‐ AMI incidence.

Comparison 5 Sensitivity analysis 1: Studies at low risk of bias, Outcome 5 Comparison 2 ‐ AMI incidence.

6 Comparison 3 ‐ All‐cause mortality Show forest plot

2

1488

Risk Ratio (M‐H, Fixed, 95% CI)

0.80 [0.22, 2.95]

Analysis 5.6

Comparison 5 Sensitivity analysis 1: Studies at low risk of bias, Outcome 6 Comparison 3 ‐ All‐cause mortality.

Comparison 5 Sensitivity analysis 1: Studies at low risk of bias, Outcome 6 Comparison 3 ‐ All‐cause mortality.

7 Comparison 3 ‐ Quality of life Show forest plot

2

975

Std. Mean Difference (IV, Random, 95% CI)

0.30 [‐0.13, 0.73]

Analysis 5.7

Comparison 5 Sensitivity analysis 1: Studies at low risk of bias, Outcome 7 Comparison 3 ‐ Quality of life.

Comparison 5 Sensitivity analysis 1: Studies at low risk of bias, Outcome 7 Comparison 3 ‐ Quality of life.

8 Comparison 3 ‐ AMI incidence (fatal) Show forest plot

1

944

Risk Ratio (M‐H, Fixed, 95% CI)

5.04 [0.24, 104.75]

Analysis 5.8

Comparison 5 Sensitivity analysis 1: Studies at low risk of bias, Outcome 8 Comparison 3 ‐ AMI incidence (fatal).

Comparison 5 Sensitivity analysis 1: Studies at low risk of bias, Outcome 8 Comparison 3 ‐ AMI incidence (fatal).

9 Comparison 3 ‐ AMI incidence (non‐fatal) Show forest plot

1

944

Risk Ratio (M‐H, Fixed, 95% CI)

0.34 [0.04, 3.22]

Analysis 5.9

Comparison 5 Sensitivity analysis 1: Studies at low risk of bias, Outcome 9 Comparison 3 ‐ AMI incidence (non‐fatal).

Comparison 5 Sensitivity analysis 1: Studies at low risk of bias, Outcome 9 Comparison 3 ‐ AMI incidence (non‐fatal).

10 Comparison 3 ‐ Angina episodes frequency Show forest plot

2

1446

Mean Difference (IV, Fixed, 95% CI)

‐0.64 [‐0.96, ‐0.32]

Analysis 5.10

Comparison 5 Sensitivity analysis 1: Studies at low risk of bias, Outcome 10 Comparison 3 ‐ Angina episodes frequency.

Comparison 5 Sensitivity analysis 1: Studies at low risk of bias, Outcome 10 Comparison 3 ‐ Angina episodes frequency.

11 Comparison 3 ‐ Adverse events incidence Show forest plot

2

1488

Risk Ratio (M‐H, Fixed, 95% CI)

1.28 [1.06, 1.53]

Analysis 5.11

Comparison 5 Sensitivity analysis 1: Studies at low risk of bias, Outcome 11 Comparison 3 ‐ Adverse events incidence.

Comparison 5 Sensitivity analysis 1: Studies at low risk of bias, Outcome 11 Comparison 3 ‐ Adverse events incidence.

12 Comparison 4 ‐ Quality of life Show forest plot

3

1005

Std. Mean Difference (IV, Random, 95% CI)

0.54 [‐0.03, 1.10]

Analysis 5.12

Comparison 5 Sensitivity analysis 1: Studies at low risk of bias, Outcome 12 Comparison 4 ‐ Quality of life.

Comparison 5 Sensitivity analysis 1: Studies at low risk of bias, Outcome 12 Comparison 4 ‐ Quality of life.

12.1 Macrovascular angina

2

975

Std. Mean Difference (IV, Random, 95% CI)

0.30 [‐0.13, 0.73]

12.2 Microvascular angina

1

30

Std. Mean Difference (IV, Random, 95% CI)

1.13 [0.36, 1.91]

13 Comparison 4 ‐ Time to 1‐mm ST‐segment depression Show forest plot

2

Mean Difference (Fixed, 95% CI)

34.62 [33.08, 36.16]

Analysis 5.13

Comparison 5 Sensitivity analysis 1: Studies at low risk of bias, Outcome 13 Comparison 4 ‐ Time to 1‐mm ST‐segment depression.

Comparison 5 Sensitivity analysis 1: Studies at low risk of bias, Outcome 13 Comparison 4 ‐ Time to 1‐mm ST‐segment depression.

Open in table viewer
Comparison 6. Sensitivity analysis 2: Exchange of model for data synthesis

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Comparison 1 ‐ All‐cause mortality Show forest plot

3

6249

Risk Ratio (M‐H, Random, 95% CI)

1.00 [0.81, 1.25]

Analysis 6.1

Comparison 6 Sensitivity analysis 2: Exchange of model for data synthesis, Outcome 1 Comparison 1 ‐ All‐cause mortality.

Comparison 6 Sensitivity analysis 2: Exchange of model for data synthesis, Outcome 1 Comparison 1 ‐ All‐cause mortality.

2 Comparison 1 ‐ Quality of life Show forest plot

3

2254

Mean Difference (IV, Random, 95% CI)

0.28 [‐1.57, 2.13]

Analysis 6.2

Comparison 6 Sensitivity analysis 2: Exchange of model for data synthesis, Outcome 2 Comparison 1 ‐ Quality of life.

Comparison 6 Sensitivity analysis 2: Exchange of model for data synthesis, Outcome 2 Comparison 1 ‐ Quality of life.

3 Comparison 1 ‐ AMI incidence Show forest plot

2

2674

Risk Ratio (M‐H, Fixed, 95% CI)

0.88 [0.69, 1.13]

Analysis 6.3

Comparison 6 Sensitivity analysis 2: Exchange of model for data synthesis, Outcome 3 Comparison 1 ‐ AMI incidence.

Comparison 6 Sensitivity analysis 2: Exchange of model for data synthesis, Outcome 3 Comparison 1 ‐ AMI incidence.

4 Comparison 1 ‐ Need for revascularisation procedure Show forest plot

2

2674

Risk Ratio (M‐H, Random, 95% CI)

0.98 [0.82, 1.18]

Analysis 6.4

Comparison 6 Sensitivity analysis 2: Exchange of model for data synthesis, Outcome 4 Comparison 1 ‐ Need for revascularisation procedure.

Comparison 6 Sensitivity analysis 2: Exchange of model for data synthesis, Outcome 4 Comparison 1 ‐ Need for revascularisation procedure.

5 Comparison 1 ‐ Adverse events incidence Show forest plot

2

638

Risk Ratio (M‐H, Random, 95% CI)

1.34 [0.90, 1.99]

Analysis 6.5

Comparison 6 Sensitivity analysis 2: Exchange of model for data synthesis, Outcome 5 Comparison 1 ‐ Adverse events incidence.

Comparison 6 Sensitivity analysis 2: Exchange of model for data synthesis, Outcome 5 Comparison 1 ‐ Adverse events incidence.

6 Comparison 2 ‐ AMI incidence Show forest plot

3

2983

Risk Ratio (M‐H, Random, 95% CI)

0.56 [0.19, 1.63]

Analysis 6.6

Comparison 6 Sensitivity analysis 2: Exchange of model for data synthesis, Outcome 6 Comparison 2 ‐ AMI incidence.

Comparison 6 Sensitivity analysis 2: Exchange of model for data synthesis, Outcome 6 Comparison 2 ‐ AMI incidence.

7 Comparison 2 ‐ Angina episodes frequency Show forest plot

2

402

Mean Difference (IV, Random, 95% CI)

0.08 [‐0.85, 1.01]

Analysis 6.7

Comparison 6 Sensitivity analysis 2: Exchange of model for data synthesis, Outcome 7 Comparison 2 ‐ Angina episodes frequency.

Comparison 6 Sensitivity analysis 2: Exchange of model for data synthesis, Outcome 7 Comparison 2 ‐ Angina episodes frequency.

8 Comparison 2 ‐ Adverse events incidence Show forest plot

3

947

Risk Ratio (M‐H, Random, 95% CI)

1.50 [1.12, 2.01]

Analysis 6.8

Comparison 6 Sensitivity analysis 2: Exchange of model for data synthesis, Outcome 8 Comparison 2 ‐ Adverse events incidence.

Comparison 6 Sensitivity analysis 2: Exchange of model for data synthesis, Outcome 8 Comparison 2 ‐ Adverse events incidence.

8.1 Macrovascular angina

2

691

Risk Ratio (M‐H, Random, 95% CI)

1.53 [1.13, 2.07]

8.2 Microvascular angina

1

256

Risk Ratio (M‐H, Random, 95% CI)

1.17 [0.40, 3.38]

9 Comparison 3 ‐ All‐cause mortality Show forest plot

3

2053

Risk Ratio (M‐H, Random, 95% CI)

0.87 [0.25, 3.04]

Analysis 6.9

Comparison 6 Sensitivity analysis 2: Exchange of model for data synthesis, Outcome 9 Comparison 3 ‐ All‐cause mortality.

Comparison 6 Sensitivity analysis 2: Exchange of model for data synthesis, Outcome 9 Comparison 3 ‐ All‐cause mortality.

10 Comparison 3 ‐ Quality of life Show forest plot

3

1533

Std. Mean Difference (IV, Fixed, 95% CI)

0.11 [0.01, 0.22]

Analysis 6.10

Comparison 6 Sensitivity analysis 2: Exchange of model for data synthesis, Outcome 10 Comparison 3 ‐ Quality of life.

Comparison 6 Sensitivity analysis 2: Exchange of model for data synthesis, Outcome 10 Comparison 3 ‐ Quality of life.

11 Comparison 3 ‐ AMI incidence (fatal) Show forest plot

2

1509

Risk Ratio (M‐H, Random, 95% CI)

1.37 [0.10, 19.46]

Analysis 6.11

Comparison 6 Sensitivity analysis 2: Exchange of model for data synthesis, Outcome 11 Comparison 3 ‐ AMI incidence (fatal).

Comparison 6 Sensitivity analysis 2: Exchange of model for data synthesis, Outcome 11 Comparison 3 ‐ AMI incidence (fatal).

12 Comparison 3 ‐ AMI incidence (non‐fatal) Show forest plot

2

1509

Risk Ratio (M‐H, Random, 95% CI)

0.41 [0.08, 2.11]

Analysis 6.12

Comparison 6 Sensitivity analysis 2: Exchange of model for data synthesis, Outcome 12 Comparison 3 ‐ AMI incidence (non‐fatal).

Comparison 6 Sensitivity analysis 2: Exchange of model for data synthesis, Outcome 12 Comparison 3 ‐ AMI incidence (non‐fatal).

13 Comparison 3 ‐ Angina episodes frequency Show forest plot

3

2004

Mean Difference (IV, Random, 95% CI)

‐0.78 [‐1.28, ‐0.27]

Analysis 6.13

Comparison 6 Sensitivity analysis 2: Exchange of model for data synthesis, Outcome 13 Comparison 3 ‐ Angina episodes frequency.

Comparison 6 Sensitivity analysis 2: Exchange of model for data synthesis, Outcome 13 Comparison 3 ‐ Angina episodes frequency.

14 Comparison 3 ‐ Adverse events incidence Show forest plot

3

2053

Risk Ratio (M‐H, Random, 95% CI)

1.21 [1.06, 1.39]

Analysis 6.14

Comparison 6 Sensitivity analysis 2: Exchange of model for data synthesis, Outcome 14 Comparison 3 ‐ Adverse events incidence.

Comparison 6 Sensitivity analysis 2: Exchange of model for data synthesis, Outcome 14 Comparison 3 ‐ Adverse events incidence.

15 Comparison 4 ‐ Quality of life Show forest plot

4

1563

Std. Mean Difference (IV, Fixed, 95% CI)

0.13 [0.03, 0.23]

Analysis 6.15

Comparison 6 Sensitivity analysis 2: Exchange of model for data synthesis, Outcome 15 Comparison 4 ‐ Quality of life.

Comparison 6 Sensitivity analysis 2: Exchange of model for data synthesis, Outcome 15 Comparison 4 ‐ Quality of life.

15.1 Macrovascular angina

3

1533

Std. Mean Difference (IV, Fixed, 95% CI)

0.11 [0.01, 0.22]

15.2 Microvascular angina

1

30

Std. Mean Difference (IV, Fixed, 95% CI)

1.13 [0.36, 1.91]

16 Comparison 4 ‐ Time to 1‐mm ST‐segment depression Show forest plot

3

Mean Difference (Random, 95% CI)

51.05 [4.05, 98.04]

Analysis 6.16

Comparison 6 Sensitivity analysis 2: Exchange of model for data synthesis, Outcome 16 Comparison 4 ‐ Time to 1‐mm ST‐segment depression.

Comparison 6 Sensitivity analysis 2: Exchange of model for data synthesis, Outcome 16 Comparison 4 ‐ Time to 1‐mm ST‐segment depression.

Open in table viewer
Comparison 7. Sensitivity analysis 3: Change of the measure of treatment effect

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Comparison 1 ‐ All‐cause mortality Show forest plot

3

6249

Odds Ratio (M‐H, Fixed, 95% CI)

1.00 [0.80, 1.27]

Analysis 7.1

Comparison 7 Sensitivity analysis 3: Change of the measure of treatment effect, Outcome 1 Comparison 1 ‐ All‐cause mortality.

Comparison 7 Sensitivity analysis 3: Change of the measure of treatment effect, Outcome 1 Comparison 1 ‐ All‐cause mortality.

2 Comparison 1 ‐ Quality of life Show forest plot

3

2254

Std. Mean Difference (IV, Fixed, 95% CI)

0.01 [‐0.07, 0.09]

Analysis 7.2

Comparison 7 Sensitivity analysis 3: Change of the measure of treatment effect, Outcome 2 Comparison 1 ‐ Quality of life.

Comparison 7 Sensitivity analysis 3: Change of the measure of treatment effect, Outcome 2 Comparison 1 ‐ Quality of life.

3 Comparison 1 ‐ AMI incidence Show forest plot

2

2674

Odds Ratio (M‐H, Random, 95% CI)

0.49 [0.10, 2.41]

Analysis 7.3

Comparison 7 Sensitivity analysis 3: Change of the measure of treatment effect, Outcome 3 Comparison 1 ‐ AMI incidence.

Comparison 7 Sensitivity analysis 3: Change of the measure of treatment effect, Outcome 3 Comparison 1 ‐ AMI incidence.

4 Comparison 1 ‐ Need for revascularisation procedure Show forest plot

2

2674

Odds Ratio (M‐H, Fixed, 95% CI)

0.98 [0.79, 1.21]

Analysis 7.4

Comparison 7 Sensitivity analysis 3: Change of the measure of treatment effect, Outcome 4 Comparison 1 ‐ Need for revascularisation procedure.

Comparison 7 Sensitivity analysis 3: Change of the measure of treatment effect, Outcome 4 Comparison 1 ‐ Need for revascularisation procedure.

5 Comparison 1 ‐ Adverse events incidence Show forest plot

2

638

Odds Ratio (M‐H, Fixed, 95% CI)

1.41 [0.88, 2.26]

Analysis 7.5

Comparison 7 Sensitivity analysis 3: Change of the measure of treatment effect, Outcome 5 Comparison 1 ‐ Adverse events incidence.

Comparison 7 Sensitivity analysis 3: Change of the measure of treatment effect, Outcome 5 Comparison 1 ‐ Adverse events incidence.

6 Comparison 2 ‐ AMI incidence Show forest plot

3

2983

Odds Ratio (M‐H, Fixed, 95% CI)

0.87 [0.67, 1.13]

Analysis 7.6

Comparison 7 Sensitivity analysis 3: Change of the measure of treatment effect, Outcome 6 Comparison 2 ‐ AMI incidence.

Comparison 7 Sensitivity analysis 3: Change of the measure of treatment effect, Outcome 6 Comparison 2 ‐ AMI incidence.

7 Comparison 2 ‐ Angina episodes frequency Show forest plot

2

402

Std. Mean Difference (IV, Fixed, 95% CI)

0.01 [‐0.19, 0.20]

Analysis 7.7

Comparison 7 Sensitivity analysis 3: Change of the measure of treatment effect, Outcome 7 Comparison 2 ‐ Angina episodes frequency.

Comparison 7 Sensitivity analysis 3: Change of the measure of treatment effect, Outcome 7 Comparison 2 ‐ Angina episodes frequency.

8 Comparison 2 ‐ Adverse events incidence Show forest plot

3

947

Odds Ratio (M‐H, Fixed, 95% CI)

1.64 [1.15, 2.35]

Analysis 7.8

Comparison 7 Sensitivity analysis 3: Change of the measure of treatment effect, Outcome 8 Comparison 2 ‐ Adverse events incidence.

Comparison 7 Sensitivity analysis 3: Change of the measure of treatment effect, Outcome 8 Comparison 2 ‐ Adverse events incidence.

8.1 Macrovascular angina

2

691

Odds Ratio (M‐H, Fixed, 95% CI)

1.71 [1.17, 2.49]

8.2 Microvascular angina

1

256

Odds Ratio (M‐H, Fixed, 95% CI)

1.18 [0.38, 3.60]

9 Comparison 3 ‐ All‐cause mortality Show forest plot

3

2053

Odds Ratio (M‐H, Fixed, 95% CI)

0.83 [0.25, 2.73]

Analysis 7.9

Comparison 7 Sensitivity analysis 3: Change of the measure of treatment effect, Outcome 9 Comparison 3 ‐ All‐cause mortality.

Comparison 7 Sensitivity analysis 3: Change of the measure of treatment effect, Outcome 9 Comparison 3 ‐ All‐cause mortality.

10 Comparison 3 ‐ Quality of life Show forest plot

3

1533

Mean Difference (IV, Random, 95% CI)

5.91 [‐5.52, 17.34]

Analysis 7.10

Comparison 7 Sensitivity analysis 3: Change of the measure of treatment effect, Outcome 10 Comparison 3 ‐ Quality of life.

Comparison 7 Sensitivity analysis 3: Change of the measure of treatment effect, Outcome 10 Comparison 3 ‐ Quality of life.

11 Comparison 3 ‐ AMI incidence (fatal) Show forest plot

2

1509

Odds Ratio (M‐H, Fixed, 95% CI)

1.52 [0.25, 9.09]

Analysis 7.11

Comparison 7 Sensitivity analysis 3: Change of the measure of treatment effect, Outcome 11 Comparison 3 ‐ AMI incidence (fatal).

Comparison 7 Sensitivity analysis 3: Change of the measure of treatment effect, Outcome 11 Comparison 3 ‐ AMI incidence (fatal).

12 Comparison 3 ‐ AMI incidence (non‐fatal) Show forest plot

2

1509

Odds Ratio (M‐H, Fixed, 95% CI)

0.40 [0.08, 2.08]

Analysis 7.12

Comparison 7 Sensitivity analysis 3: Change of the measure of treatment effect, Outcome 12 Comparison 3 ‐ AMI incidence (non‐fatal).

Comparison 7 Sensitivity analysis 3: Change of the measure of treatment effect, Outcome 12 Comparison 3 ‐ AMI incidence (non‐fatal).

13 Comparison 3 ‐ Angina episodes frequency Show forest plot

3

2004

Std. Mean Difference (IV, Fixed, 95% CI)

‐0.19 [‐0.28, ‐0.11]

Analysis 7.13

Comparison 7 Sensitivity analysis 3: Change of the measure of treatment effect, Outcome 13 Comparison 3 ‐ Angina episodes frequency.

Comparison 7 Sensitivity analysis 3: Change of the measure of treatment effect, Outcome 13 Comparison 3 ‐ Angina episodes frequency.

14 Comparison 3 ‐ Adverse events incidence Show forest plot

3

2053

Odds Ratio (M‐H, Fixed, 95% CI)

1.32 [1.09, 1.61]

Analysis 7.14

Comparison 7 Sensitivity analysis 3: Change of the measure of treatment effect, Outcome 14 Comparison 3 ‐ Adverse events incidence.

Comparison 7 Sensitivity analysis 3: Change of the measure of treatment effect, Outcome 14 Comparison 3 ‐ Adverse events incidence.

15 Comparison 4 ‐ Quality of life Show forest plot

4

1563

Mean Difference (IV, Random, 95% CI)

11.17 [‐2.54, 24.87]

Analysis 7.15

Comparison 7 Sensitivity analysis 3: Change of the measure of treatment effect, Outcome 15 Comparison 4 ‐ Quality of life.

Comparison 7 Sensitivity analysis 3: Change of the measure of treatment effect, Outcome 15 Comparison 4 ‐ Quality of life.

15.1 Macrovascular angina

3

1533

Mean Difference (IV, Random, 95% CI)

5.91 [‐5.52, 17.34]

15.2 Microvascular angina

1

30

Mean Difference (IV, Random, 95% CI)

22.20 [8.57, 35.83]

Open in table viewer
Comparison 8. Sensitivity analysis 4: follow‐up ≥ 6 weeks

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Comparison 1 ‐ All‐cause mortality Show forest plot

2

6179

Risk Ratio (M‐H, Fixed, 95% CI)

1.01 [0.81, 1.26]

Analysis 8.1

Comparison 8 Sensitivity analysis 4: follow‐up ≥ 6 weeks, Outcome 1 Comparison 1 ‐ All‐cause mortality.

Comparison 8 Sensitivity analysis 4: follow‐up ≥ 6 weeks, Outcome 1 Comparison 1 ‐ All‐cause mortality.

2 Comparison 1 ‐ Quality of life Show forest plot

1

1958

Mean Difference (IV, Fixed, 95% CI)

‐0.10 [‐2.08, 1.88]

Analysis 8.2

Comparison 8 Sensitivity analysis 4: follow‐up ≥ 6 weeks, Outcome 2 Comparison 1 ‐ Quality of life.

Comparison 8 Sensitivity analysis 4: follow‐up ≥ 6 weeks, Outcome 2 Comparison 1 ‐ Quality of life.

3 Comparison 1 ‐ AMI incidence Show forest plot

1

2604

Risk Ratio (M‐H, Random, 95% CI)

0.94 [0.73, 1.20]

Analysis 8.3

Comparison 8 Sensitivity analysis 4: follow‐up ≥ 6 weeks, Outcome 3 Comparison 1 ‐ AMI incidence.

Comparison 8 Sensitivity analysis 4: follow‐up ≥ 6 weeks, Outcome 3 Comparison 1 ‐ AMI incidence.

4 Comparison 1 ‐ Need for revascularisation procedure Show forest plot

1

2604

Risk Ratio (M‐H, Fixed, 95% CI)

0.98 [0.82, 1.18]

Analysis 8.4

Comparison 8 Sensitivity analysis 4: follow‐up ≥ 6 weeks, Outcome 4 Comparison 1 ‐ Need for revascularisation procedure.

Comparison 8 Sensitivity analysis 4: follow‐up ≥ 6 weeks, Outcome 4 Comparison 1 ‐ Need for revascularisation procedure.

5 Comparison 2 ‐ AMI incidence Show forest plot

1

2604

Risk Ratio (M‐H, Fixed, 95% CI)

0.94 [0.73, 1.20]

Analysis 8.5

Comparison 8 Sensitivity analysis 4: follow‐up ≥ 6 weeks, Outcome 5 Comparison 2 ‐ AMI incidence.

Comparison 8 Sensitivity analysis 4: follow‐up ≥ 6 weeks, Outcome 5 Comparison 2 ‐ AMI incidence.

6 Comparison 3 ‐ All‐cause mortality Show forest plot

3

2053

Risk Ratio (M‐H, Fixed, 95% CI)

0.83 [0.26, 2.71]

Analysis 8.6

Comparison 8 Sensitivity analysis 4: follow‐up ≥ 6 weeks, Outcome 6 Comparison 3 ‐ All‐cause mortality.

Comparison 8 Sensitivity analysis 4: follow‐up ≥ 6 weeks, Outcome 6 Comparison 3 ‐ All‐cause mortality.

7 Comparison 3 ‐ Quality of life Show forest plot

3

1533

Std. Mean Difference (IV, Random, 95% CI)

0.13 [‐0.05, 0.32]

Analysis 8.7

Comparison 8 Sensitivity analysis 4: follow‐up ≥ 6 weeks, Outcome 7 Comparison 3 ‐ Quality of life.

Comparison 8 Sensitivity analysis 4: follow‐up ≥ 6 weeks, Outcome 7 Comparison 3 ‐ Quality of life.

8 Comparison 3 ‐ AMI incidence (fatal) Show forest plot

2

1509

Risk Ratio (M‐H, Fixed, 95% CI)

1.51 [0.25, 9.05]

Analysis 8.8

Comparison 8 Sensitivity analysis 4: follow‐up ≥ 6 weeks, Outcome 8 Comparison 3 ‐ AMI incidence (fatal).

Comparison 8 Sensitivity analysis 4: follow‐up ≥ 6 weeks, Outcome 8 Comparison 3 ‐ AMI incidence (fatal).

9 Comparison 3 ‐ AMI incidence (non‐fatal) Show forest plot

2

1509

Risk Ratio (M‐H, Fixed, 95% CI)

0.40 [0.08, 2.07]

Analysis 8.9

Comparison 8 Sensitivity analysis 4: follow‐up ≥ 6 weeks, Outcome 9 Comparison 3 ‐ AMI incidence (non‐fatal).

Comparison 8 Sensitivity analysis 4: follow‐up ≥ 6 weeks, Outcome 9 Comparison 3 ‐ AMI incidence (non‐fatal).

10 Comparison 3 ‐ Angina episodes frequency Show forest plot

3

2004

Mean Difference (IV, Fixed, 95% CI)

‐0.66 [‐0.97, ‐0.35]

Analysis 8.10

Comparison 8 Sensitivity analysis 4: follow‐up ≥ 6 weeks, Outcome 10 Comparison 3 ‐ Angina episodes frequency.

Comparison 8 Sensitivity analysis 4: follow‐up ≥ 6 weeks, Outcome 10 Comparison 3 ‐ Angina episodes frequency.

11 Comparison 3 ‐ Adverse events incidence Show forest plot

3

2053

Risk Ratio (M‐H, Fixed, 95% CI)

1.22 [1.06, 1.40]

Analysis 8.11

Comparison 8 Sensitivity analysis 4: follow‐up ≥ 6 weeks, Outcome 11 Comparison 3 ‐ Adverse events incidence.

Comparison 8 Sensitivity analysis 4: follow‐up ≥ 6 weeks, Outcome 11 Comparison 3 ‐ Adverse events incidence.

12 Comparison 4 ‐ Quality of life Show forest plot

3

1533

Std. Mean Difference (IV, Random, 95% CI)

0.13 [‐0.05, 0.32]

Analysis 8.12

Comparison 8 Sensitivity analysis 4: follow‐up ≥ 6 weeks, Outcome 12 Comparison 4 ‐ Quality of life.

Comparison 8 Sensitivity analysis 4: follow‐up ≥ 6 weeks, Outcome 12 Comparison 4 ‐ Quality of life.

12.1 Macrovascular angina

3

1533

Std. Mean Difference (IV, Random, 95% CI)

0.13 [‐0.05, 0.32]

13 Comparison 4 ‐ Time to 1‐mm ST‐segment depression Show forest plot

1

Mean Difference (Fixed, 95% CI)

34.6 [33.06, 36.14]

Analysis 8.13

Comparison 8 Sensitivity analysis 4: follow‐up ≥ 6 weeks, Outcome 13 Comparison 4 ‐ Time to 1‐mm ST‐segment depression.

Comparison 8 Sensitivity analysis 4: follow‐up ≥ 6 weeks, Outcome 13 Comparison 4 ‐ Time to 1‐mm ST‐segment depression.

Study flow diagram†Two included articles report data from the RIVER‐PCI trial
Figuras y tablas -
Figure 1

Study flow diagram

Two included articles report data from the RIVER‐PCI trial

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies
Figuras y tablas -
Figure 2

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies

Risk of bias summary: review authors' judgements about each risk of bias item for each included study. Other bias criteria: we considered the source of funding in this section, we scored high risk of bias if the source of funding was solely from private organisations, unclear risk of bias if it was mixed (private and public) and low risk of bias if it was solely not external or from public organisations.
Figuras y tablas -
Figure 3

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

Other bias criteria: we considered the source of funding in this section, we scored high risk of bias if the source of funding was solely from private organisations, unclear risk of bias if it was mixed (private and public) and low risk of bias if it was solely not external or from public organisations.

Comparison 1 Ranolazine (monotherapy) 1000 mg twice daily versus placebo, Outcome 1 Cardiovascular mortality.
Figuras y tablas -
Analysis 1.1

Comparison 1 Ranolazine (monotherapy) 1000 mg twice daily versus placebo, Outcome 1 Cardiovascular mortality.

Comparison 1 Ranolazine (monotherapy) 1000 mg twice daily versus placebo, Outcome 2 All‐cause mortality.
Figuras y tablas -
Analysis 1.2

Comparison 1 Ranolazine (monotherapy) 1000 mg twice daily versus placebo, Outcome 2 All‐cause mortality.

Comparison 1 Ranolazine (monotherapy) 1000 mg twice daily versus placebo, Outcome 3 Quality of life.
Figuras y tablas -
Analysis 1.3

Comparison 1 Ranolazine (monotherapy) 1000 mg twice daily versus placebo, Outcome 3 Quality of life.

Comparison 1 Ranolazine (monotherapy) 1000 mg twice daily versus placebo, Outcome 4 AMI incidence.
Figuras y tablas -
Analysis 1.4

Comparison 1 Ranolazine (monotherapy) 1000 mg twice daily versus placebo, Outcome 4 AMI incidence.

Comparison 1 Ranolazine (monotherapy) 1000 mg twice daily versus placebo, Outcome 5 Need for revascularisation procedure.
Figuras y tablas -
Analysis 1.5

Comparison 1 Ranolazine (monotherapy) 1000 mg twice daily versus placebo, Outcome 5 Need for revascularisation procedure.

Comparison 1 Ranolazine (monotherapy) 1000 mg twice daily versus placebo, Outcome 6 Adverse events incidence.
Figuras y tablas -
Analysis 1.6

Comparison 1 Ranolazine (monotherapy) 1000 mg twice daily versus placebo, Outcome 6 Adverse events incidence.

Comparison 2 Ranolazine (monotherapy) any dose versus placebo, Outcome 1 AMI incidence.
Figuras y tablas -
Analysis 2.1

Comparison 2 Ranolazine (monotherapy) any dose versus placebo, Outcome 1 AMI incidence.

Comparison 2 Ranolazine (monotherapy) any dose versus placebo, Outcome 2 Angina episodes frequency.
Figuras y tablas -
Analysis 2.2

Comparison 2 Ranolazine (monotherapy) any dose versus placebo, Outcome 2 Angina episodes frequency.

Comparison 2 Ranolazine (monotherapy) any dose versus placebo, Outcome 3 Adverse events incidence.
Figuras y tablas -
Analysis 2.3

Comparison 2 Ranolazine (monotherapy) any dose versus placebo, Outcome 3 Adverse events incidence.

Comparison 3 Ranolazine (add‐on therapy) 1000 mg twice daily versus placebo, Outcome 1 All‐cause mortality.
Figuras y tablas -
Analysis 3.1

Comparison 3 Ranolazine (add‐on therapy) 1000 mg twice daily versus placebo, Outcome 1 All‐cause mortality.

Comparison 3 Ranolazine (add‐on therapy) 1000 mg twice daily versus placebo, Outcome 2 Quality of life.
Figuras y tablas -
Analysis 3.2

Comparison 3 Ranolazine (add‐on therapy) 1000 mg twice daily versus placebo, Outcome 2 Quality of life.

Comparison 3 Ranolazine (add‐on therapy) 1000 mg twice daily versus placebo, Outcome 3 AMI incidence (fatal).
Figuras y tablas -
Analysis 3.3

Comparison 3 Ranolazine (add‐on therapy) 1000 mg twice daily versus placebo, Outcome 3 AMI incidence (fatal).

Comparison 3 Ranolazine (add‐on therapy) 1000 mg twice daily versus placebo, Outcome 4 AMI incidence (non‐fatal).
Figuras y tablas -
Analysis 3.4

Comparison 3 Ranolazine (add‐on therapy) 1000 mg twice daily versus placebo, Outcome 4 AMI incidence (non‐fatal).

Comparison 3 Ranolazine (add‐on therapy) 1000 mg twice daily versus placebo, Outcome 5 Angina episodes frequency.
Figuras y tablas -
Analysis 3.5

Comparison 3 Ranolazine (add‐on therapy) 1000 mg twice daily versus placebo, Outcome 5 Angina episodes frequency.

Comparison 3 Ranolazine (add‐on therapy) 1000 mg twice daily versus placebo, Outcome 6 Adverse events incidence.
Figuras y tablas -
Analysis 3.6

Comparison 3 Ranolazine (add‐on therapy) 1000 mg twice daily versus placebo, Outcome 6 Adverse events incidence.

Comparison 4 Ranolazine (add‐on therapy) any dose versus placebo, Outcome 1 Quality of life.
Figuras y tablas -
Analysis 4.1

Comparison 4 Ranolazine (add‐on therapy) any dose versus placebo, Outcome 1 Quality of life.

Comparison 4 Ranolazine (add‐on therapy) any dose versus placebo, Outcome 2 Time to 1‐mm ST‐segment depression.
Figuras y tablas -
Analysis 4.2

Comparison 4 Ranolazine (add‐on therapy) any dose versus placebo, Outcome 2 Time to 1‐mm ST‐segment depression.

Comparison 5 Sensitivity analysis 1: Studies at low risk of bias, Outcome 1 Comparison 1 ‐ All‐cause mortality.
Figuras y tablas -
Analysis 5.1

Comparison 5 Sensitivity analysis 1: Studies at low risk of bias, Outcome 1 Comparison 1 ‐ All‐cause mortality.

Comparison 5 Sensitivity analysis 1: Studies at low risk of bias, Outcome 2 Comparison 1 ‐ Quality of life.
Figuras y tablas -
Analysis 5.2

Comparison 5 Sensitivity analysis 1: Studies at low risk of bias, Outcome 2 Comparison 1 ‐ Quality of life.

Comparison 5 Sensitivity analysis 1: Studies at low risk of bias, Outcome 3 Comparison 1 ‐ AMI incidence.
Figuras y tablas -
Analysis 5.3

Comparison 5 Sensitivity analysis 1: Studies at low risk of bias, Outcome 3 Comparison 1 ‐ AMI incidence.

Comparison 5 Sensitivity analysis 1: Studies at low risk of bias, Outcome 4 Comparison 1 ‐ Need for revascularisation procedure.
Figuras y tablas -
Analysis 5.4

Comparison 5 Sensitivity analysis 1: Studies at low risk of bias, Outcome 4 Comparison 1 ‐ Need for revascularisation procedure.

Comparison 5 Sensitivity analysis 1: Studies at low risk of bias, Outcome 5 Comparison 2 ‐ AMI incidence.
Figuras y tablas -
Analysis 5.5

Comparison 5 Sensitivity analysis 1: Studies at low risk of bias, Outcome 5 Comparison 2 ‐ AMI incidence.

Comparison 5 Sensitivity analysis 1: Studies at low risk of bias, Outcome 6 Comparison 3 ‐ All‐cause mortality.
Figuras y tablas -
Analysis 5.6

Comparison 5 Sensitivity analysis 1: Studies at low risk of bias, Outcome 6 Comparison 3 ‐ All‐cause mortality.

Comparison 5 Sensitivity analysis 1: Studies at low risk of bias, Outcome 7 Comparison 3 ‐ Quality of life.
Figuras y tablas -
Analysis 5.7

Comparison 5 Sensitivity analysis 1: Studies at low risk of bias, Outcome 7 Comparison 3 ‐ Quality of life.

Comparison 5 Sensitivity analysis 1: Studies at low risk of bias, Outcome 8 Comparison 3 ‐ AMI incidence (fatal).
Figuras y tablas -
Analysis 5.8

Comparison 5 Sensitivity analysis 1: Studies at low risk of bias, Outcome 8 Comparison 3 ‐ AMI incidence (fatal).

Comparison 5 Sensitivity analysis 1: Studies at low risk of bias, Outcome 9 Comparison 3 ‐ AMI incidence (non‐fatal).
Figuras y tablas -
Analysis 5.9

Comparison 5 Sensitivity analysis 1: Studies at low risk of bias, Outcome 9 Comparison 3 ‐ AMI incidence (non‐fatal).

Comparison 5 Sensitivity analysis 1: Studies at low risk of bias, Outcome 10 Comparison 3 ‐ Angina episodes frequency.
Figuras y tablas -
Analysis 5.10

Comparison 5 Sensitivity analysis 1: Studies at low risk of bias, Outcome 10 Comparison 3 ‐ Angina episodes frequency.

Comparison 5 Sensitivity analysis 1: Studies at low risk of bias, Outcome 11 Comparison 3 ‐ Adverse events incidence.
Figuras y tablas -
Analysis 5.11

Comparison 5 Sensitivity analysis 1: Studies at low risk of bias, Outcome 11 Comparison 3 ‐ Adverse events incidence.

Comparison 5 Sensitivity analysis 1: Studies at low risk of bias, Outcome 12 Comparison 4 ‐ Quality of life.
Figuras y tablas -
Analysis 5.12

Comparison 5 Sensitivity analysis 1: Studies at low risk of bias, Outcome 12 Comparison 4 ‐ Quality of life.

Comparison 5 Sensitivity analysis 1: Studies at low risk of bias, Outcome 13 Comparison 4 ‐ Time to 1‐mm ST‐segment depression.
Figuras y tablas -
Analysis 5.13

Comparison 5 Sensitivity analysis 1: Studies at low risk of bias, Outcome 13 Comparison 4 ‐ Time to 1‐mm ST‐segment depression.

Comparison 6 Sensitivity analysis 2: Exchange of model for data synthesis, Outcome 1 Comparison 1 ‐ All‐cause mortality.
Figuras y tablas -
Analysis 6.1

Comparison 6 Sensitivity analysis 2: Exchange of model for data synthesis, Outcome 1 Comparison 1 ‐ All‐cause mortality.

Comparison 6 Sensitivity analysis 2: Exchange of model for data synthesis, Outcome 2 Comparison 1 ‐ Quality of life.
Figuras y tablas -
Analysis 6.2

Comparison 6 Sensitivity analysis 2: Exchange of model for data synthesis, Outcome 2 Comparison 1 ‐ Quality of life.

Comparison 6 Sensitivity analysis 2: Exchange of model for data synthesis, Outcome 3 Comparison 1 ‐ AMI incidence.
Figuras y tablas -
Analysis 6.3

Comparison 6 Sensitivity analysis 2: Exchange of model for data synthesis, Outcome 3 Comparison 1 ‐ AMI incidence.

Comparison 6 Sensitivity analysis 2: Exchange of model for data synthesis, Outcome 4 Comparison 1 ‐ Need for revascularisation procedure.
Figuras y tablas -
Analysis 6.4

Comparison 6 Sensitivity analysis 2: Exchange of model for data synthesis, Outcome 4 Comparison 1 ‐ Need for revascularisation procedure.

Comparison 6 Sensitivity analysis 2: Exchange of model for data synthesis, Outcome 5 Comparison 1 ‐ Adverse events incidence.
Figuras y tablas -
Analysis 6.5

Comparison 6 Sensitivity analysis 2: Exchange of model for data synthesis, Outcome 5 Comparison 1 ‐ Adverse events incidence.

Comparison 6 Sensitivity analysis 2: Exchange of model for data synthesis, Outcome 6 Comparison 2 ‐ AMI incidence.
Figuras y tablas -
Analysis 6.6

Comparison 6 Sensitivity analysis 2: Exchange of model for data synthesis, Outcome 6 Comparison 2 ‐ AMI incidence.

Comparison 6 Sensitivity analysis 2: Exchange of model for data synthesis, Outcome 7 Comparison 2 ‐ Angina episodes frequency.
Figuras y tablas -
Analysis 6.7

Comparison 6 Sensitivity analysis 2: Exchange of model for data synthesis, Outcome 7 Comparison 2 ‐ Angina episodes frequency.

Comparison 6 Sensitivity analysis 2: Exchange of model for data synthesis, Outcome 8 Comparison 2 ‐ Adverse events incidence.
Figuras y tablas -
Analysis 6.8

Comparison 6 Sensitivity analysis 2: Exchange of model for data synthesis, Outcome 8 Comparison 2 ‐ Adverse events incidence.

Comparison 6 Sensitivity analysis 2: Exchange of model for data synthesis, Outcome 9 Comparison 3 ‐ All‐cause mortality.
Figuras y tablas -
Analysis 6.9

Comparison 6 Sensitivity analysis 2: Exchange of model for data synthesis, Outcome 9 Comparison 3 ‐ All‐cause mortality.

Comparison 6 Sensitivity analysis 2: Exchange of model for data synthesis, Outcome 10 Comparison 3 ‐ Quality of life.
Figuras y tablas -
Analysis 6.10

Comparison 6 Sensitivity analysis 2: Exchange of model for data synthesis, Outcome 10 Comparison 3 ‐ Quality of life.

Comparison 6 Sensitivity analysis 2: Exchange of model for data synthesis, Outcome 11 Comparison 3 ‐ AMI incidence (fatal).
Figuras y tablas -
Analysis 6.11

Comparison 6 Sensitivity analysis 2: Exchange of model for data synthesis, Outcome 11 Comparison 3 ‐ AMI incidence (fatal).

Comparison 6 Sensitivity analysis 2: Exchange of model for data synthesis, Outcome 12 Comparison 3 ‐ AMI incidence (non‐fatal).
Figuras y tablas -
Analysis 6.12

Comparison 6 Sensitivity analysis 2: Exchange of model for data synthesis, Outcome 12 Comparison 3 ‐ AMI incidence (non‐fatal).

Comparison 6 Sensitivity analysis 2: Exchange of model for data synthesis, Outcome 13 Comparison 3 ‐ Angina episodes frequency.
Figuras y tablas -
Analysis 6.13

Comparison 6 Sensitivity analysis 2: Exchange of model for data synthesis, Outcome 13 Comparison 3 ‐ Angina episodes frequency.

Comparison 6 Sensitivity analysis 2: Exchange of model for data synthesis, Outcome 14 Comparison 3 ‐ Adverse events incidence.
Figuras y tablas -
Analysis 6.14

Comparison 6 Sensitivity analysis 2: Exchange of model for data synthesis, Outcome 14 Comparison 3 ‐ Adverse events incidence.

Comparison 6 Sensitivity analysis 2: Exchange of model for data synthesis, Outcome 15 Comparison 4 ‐ Quality of life.
Figuras y tablas -
Analysis 6.15

Comparison 6 Sensitivity analysis 2: Exchange of model for data synthesis, Outcome 15 Comparison 4 ‐ Quality of life.

Comparison 6 Sensitivity analysis 2: Exchange of model for data synthesis, Outcome 16 Comparison 4 ‐ Time to 1‐mm ST‐segment depression.
Figuras y tablas -
Analysis 6.16

Comparison 6 Sensitivity analysis 2: Exchange of model for data synthesis, Outcome 16 Comparison 4 ‐ Time to 1‐mm ST‐segment depression.

Comparison 7 Sensitivity analysis 3: Change of the measure of treatment effect, Outcome 1 Comparison 1 ‐ All‐cause mortality.
Figuras y tablas -
Analysis 7.1

Comparison 7 Sensitivity analysis 3: Change of the measure of treatment effect, Outcome 1 Comparison 1 ‐ All‐cause mortality.

Comparison 7 Sensitivity analysis 3: Change of the measure of treatment effect, Outcome 2 Comparison 1 ‐ Quality of life.
Figuras y tablas -
Analysis 7.2

Comparison 7 Sensitivity analysis 3: Change of the measure of treatment effect, Outcome 2 Comparison 1 ‐ Quality of life.

Comparison 7 Sensitivity analysis 3: Change of the measure of treatment effect, Outcome 3 Comparison 1 ‐ AMI incidence.
Figuras y tablas -
Analysis 7.3

Comparison 7 Sensitivity analysis 3: Change of the measure of treatment effect, Outcome 3 Comparison 1 ‐ AMI incidence.

Comparison 7 Sensitivity analysis 3: Change of the measure of treatment effect, Outcome 4 Comparison 1 ‐ Need for revascularisation procedure.
Figuras y tablas -
Analysis 7.4

Comparison 7 Sensitivity analysis 3: Change of the measure of treatment effect, Outcome 4 Comparison 1 ‐ Need for revascularisation procedure.

Comparison 7 Sensitivity analysis 3: Change of the measure of treatment effect, Outcome 5 Comparison 1 ‐ Adverse events incidence.
Figuras y tablas -
Analysis 7.5

Comparison 7 Sensitivity analysis 3: Change of the measure of treatment effect, Outcome 5 Comparison 1 ‐ Adverse events incidence.

Comparison 7 Sensitivity analysis 3: Change of the measure of treatment effect, Outcome 6 Comparison 2 ‐ AMI incidence.
Figuras y tablas -
Analysis 7.6

Comparison 7 Sensitivity analysis 3: Change of the measure of treatment effect, Outcome 6 Comparison 2 ‐ AMI incidence.

Comparison 7 Sensitivity analysis 3: Change of the measure of treatment effect, Outcome 7 Comparison 2 ‐ Angina episodes frequency.
Figuras y tablas -
Analysis 7.7

Comparison 7 Sensitivity analysis 3: Change of the measure of treatment effect, Outcome 7 Comparison 2 ‐ Angina episodes frequency.

Comparison 7 Sensitivity analysis 3: Change of the measure of treatment effect, Outcome 8 Comparison 2 ‐ Adverse events incidence.
Figuras y tablas -
Analysis 7.8

Comparison 7 Sensitivity analysis 3: Change of the measure of treatment effect, Outcome 8 Comparison 2 ‐ Adverse events incidence.

Comparison 7 Sensitivity analysis 3: Change of the measure of treatment effect, Outcome 9 Comparison 3 ‐ All‐cause mortality.
Figuras y tablas -
Analysis 7.9

Comparison 7 Sensitivity analysis 3: Change of the measure of treatment effect, Outcome 9 Comparison 3 ‐ All‐cause mortality.

Comparison 7 Sensitivity analysis 3: Change of the measure of treatment effect, Outcome 10 Comparison 3 ‐ Quality of life.
Figuras y tablas -
Analysis 7.10

Comparison 7 Sensitivity analysis 3: Change of the measure of treatment effect, Outcome 10 Comparison 3 ‐ Quality of life.

Comparison 7 Sensitivity analysis 3: Change of the measure of treatment effect, Outcome 11 Comparison 3 ‐ AMI incidence (fatal).
Figuras y tablas -
Analysis 7.11

Comparison 7 Sensitivity analysis 3: Change of the measure of treatment effect, Outcome 11 Comparison 3 ‐ AMI incidence (fatal).

Comparison 7 Sensitivity analysis 3: Change of the measure of treatment effect, Outcome 12 Comparison 3 ‐ AMI incidence (non‐fatal).
Figuras y tablas -
Analysis 7.12

Comparison 7 Sensitivity analysis 3: Change of the measure of treatment effect, Outcome 12 Comparison 3 ‐ AMI incidence (non‐fatal).

Comparison 7 Sensitivity analysis 3: Change of the measure of treatment effect, Outcome 13 Comparison 3 ‐ Angina episodes frequency.
Figuras y tablas -
Analysis 7.13

Comparison 7 Sensitivity analysis 3: Change of the measure of treatment effect, Outcome 13 Comparison 3 ‐ Angina episodes frequency.

Comparison 7 Sensitivity analysis 3: Change of the measure of treatment effect, Outcome 14 Comparison 3 ‐ Adverse events incidence.
Figuras y tablas -
Analysis 7.14

Comparison 7 Sensitivity analysis 3: Change of the measure of treatment effect, Outcome 14 Comparison 3 ‐ Adverse events incidence.

Comparison 7 Sensitivity analysis 3: Change of the measure of treatment effect, Outcome 15 Comparison 4 ‐ Quality of life.
Figuras y tablas -
Analysis 7.15

Comparison 7 Sensitivity analysis 3: Change of the measure of treatment effect, Outcome 15 Comparison 4 ‐ Quality of life.

Comparison 8 Sensitivity analysis 4: follow‐up ≥ 6 weeks, Outcome 1 Comparison 1 ‐ All‐cause mortality.
Figuras y tablas -
Analysis 8.1

Comparison 8 Sensitivity analysis 4: follow‐up ≥ 6 weeks, Outcome 1 Comparison 1 ‐ All‐cause mortality.

Comparison 8 Sensitivity analysis 4: follow‐up ≥ 6 weeks, Outcome 2 Comparison 1 ‐ Quality of life.
Figuras y tablas -
Analysis 8.2

Comparison 8 Sensitivity analysis 4: follow‐up ≥ 6 weeks, Outcome 2 Comparison 1 ‐ Quality of life.

Comparison 8 Sensitivity analysis 4: follow‐up ≥ 6 weeks, Outcome 3 Comparison 1 ‐ AMI incidence.
Figuras y tablas -
Analysis 8.3

Comparison 8 Sensitivity analysis 4: follow‐up ≥ 6 weeks, Outcome 3 Comparison 1 ‐ AMI incidence.

Comparison 8 Sensitivity analysis 4: follow‐up ≥ 6 weeks, Outcome 4 Comparison 1 ‐ Need for revascularisation procedure.
Figuras y tablas -
Analysis 8.4

Comparison 8 Sensitivity analysis 4: follow‐up ≥ 6 weeks, Outcome 4 Comparison 1 ‐ Need for revascularisation procedure.

Comparison 8 Sensitivity analysis 4: follow‐up ≥ 6 weeks, Outcome 5 Comparison 2 ‐ AMI incidence.
Figuras y tablas -
Analysis 8.5

Comparison 8 Sensitivity analysis 4: follow‐up ≥ 6 weeks, Outcome 5 Comparison 2 ‐ AMI incidence.

Comparison 8 Sensitivity analysis 4: follow‐up ≥ 6 weeks, Outcome 6 Comparison 3 ‐ All‐cause mortality.
Figuras y tablas -
Analysis 8.6

Comparison 8 Sensitivity analysis 4: follow‐up ≥ 6 weeks, Outcome 6 Comparison 3 ‐ All‐cause mortality.

Comparison 8 Sensitivity analysis 4: follow‐up ≥ 6 weeks, Outcome 7 Comparison 3 ‐ Quality of life.
Figuras y tablas -
Analysis 8.7

Comparison 8 Sensitivity analysis 4: follow‐up ≥ 6 weeks, Outcome 7 Comparison 3 ‐ Quality of life.

Comparison 8 Sensitivity analysis 4: follow‐up ≥ 6 weeks, Outcome 8 Comparison 3 ‐ AMI incidence (fatal).
Figuras y tablas -
Analysis 8.8

Comparison 8 Sensitivity analysis 4: follow‐up ≥ 6 weeks, Outcome 8 Comparison 3 ‐ AMI incidence (fatal).

Comparison 8 Sensitivity analysis 4: follow‐up ≥ 6 weeks, Outcome 9 Comparison 3 ‐ AMI incidence (non‐fatal).
Figuras y tablas -
Analysis 8.9

Comparison 8 Sensitivity analysis 4: follow‐up ≥ 6 weeks, Outcome 9 Comparison 3 ‐ AMI incidence (non‐fatal).

Comparison 8 Sensitivity analysis 4: follow‐up ≥ 6 weeks, Outcome 10 Comparison 3 ‐ Angina episodes frequency.
Figuras y tablas -
Analysis 8.10

Comparison 8 Sensitivity analysis 4: follow‐up ≥ 6 weeks, Outcome 10 Comparison 3 ‐ Angina episodes frequency.

Comparison 8 Sensitivity analysis 4: follow‐up ≥ 6 weeks, Outcome 11 Comparison 3 ‐ Adverse events incidence.
Figuras y tablas -
Analysis 8.11

Comparison 8 Sensitivity analysis 4: follow‐up ≥ 6 weeks, Outcome 11 Comparison 3 ‐ Adverse events incidence.

Comparison 8 Sensitivity analysis 4: follow‐up ≥ 6 weeks, Outcome 12 Comparison 4 ‐ Quality of life.
Figuras y tablas -
Analysis 8.12

Comparison 8 Sensitivity analysis 4: follow‐up ≥ 6 weeks, Outcome 12 Comparison 4 ‐ Quality of life.

Comparison 8 Sensitivity analysis 4: follow‐up ≥ 6 weeks, Outcome 13 Comparison 4 ‐ Time to 1‐mm ST‐segment depression.
Figuras y tablas -
Analysis 8.13

Comparison 8 Sensitivity analysis 4: follow‐up ≥ 6 weeks, Outcome 13 Comparison 4 ‐ Time to 1‐mm ST‐segment depression.

Summary of findings for the main comparison. Ranolazine (add‐on therapy) versus placebo for stable angina pectoris

Ranolazine (add‐on therapy) versus placebo for stable angina pectoris*

Patient or population: patients with stable angina pectoris
Settings: not specified
Intervention: ranolazine (add‐on therapy)
Comparison: placebo (add‐on therapy)

Outcomes

Illustrative comparative risks** (95% CI)

Relative effect
(95% CI)

No of Participants
(studies)

Quality of the evidence
(GRADE)

Comments

Assumed risk

Corresponding risk

Placebo

Ranolazine

Cardiovascular mortality ‐ not reported

See comment

See comment

Not estimable

See comment

No data were available for this outcome

Non‐cardiovascular mortality ‐ not reported

See comment

See comment

Not estimable

See comment

No data were available for this outcome

All‐cause mortality
Follow‐up: 42 to 84 days

6 per 1000

5 per 1000
(2 to 16)

RR 0.83
(0.26 to 2.71)

2053
(3 studies)

⊕⊕⊝⊝
low¹ ²

Ranolazine 1000 mg twice daily

Quality of life
Scale: 0 to 100.
Follow‐up: 28 to 56 days

Mean quality of life in control group participants was
44.3 points

Mean quality of life in intervention group participants was
0.25 standard deviations higher
(0.01 lower to 0.52 higher)

1563
(4 studies)

⊕⊕⊕⊝
moderate³

Ranolazine any dose

(SMD 0.25, 95% CI ‐0.01 to 0.52)

AMI incidence
Follow‐up: 42 to 56 days

7 per 1000

3 per 1000
(1 to 14)

RR 0.40
(0.08 to 2.07)

1509
(2 studies)

⊕⊕⊝⊝
low

Ranolazine 1000 mg twice daily

Angina episodes frequency
Follow‐up: 42 to 84 days

Mean angina episode frequency in control group participants was
4.1 episodes per week

Mean angina episodes frequency in intervention group participants was
0.66 lower
(0.97 to 0.35 lower)

2004
(3 studies)

⊕⊕⊕⊝
moderate¹

Ranolazine 1000 mg twice daily

(MD ‐0.66, 95% CI ‐0.97 to ‐0.35)

Adverse events incidence
Follow‐up: 42 to 84 days

241 per 1000

294 per 1000
(256 to 337)

RR 1.22
(1.06 to 1.4)

2123
(3 studies)

⊕⊕⊕⊝
moderate

Ranolazine 1000 mg twice daily

*Add‐on therapy: refers to the addition of ranolazine to an antianginal regimen already in course. The results reported correspond to the comparisons (data and analyses) 3 and 4 of the review (involving ranolazine given at 1000mg twice daily or any dosage); this is specified in the Comments column.

**The assumed risk is based on the median control group risk across studies. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; RR: Risk ratio

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

¹ Quality of evidence was downgraded one level due to unclear risk of bias regarding blinding of outcome assessment and incomplete outcome data
² Quality of evidence was downgraded one level due to insufficient number of events (less than 300), and the 95% confidence interval around the pooled effect includes both 1) no effect and 2) appreciable benefit/harm
³ Quality of evidence was downgraded one level due to substantial heterogeneity
⁴ Quality of evidence was downgraded two levels due to insufficient number of events (less than 300), and the 95% confidence interval around the pooled effect includes both 1) no effect and 2) appreciable benefit/harm
⁵ Quality of evidence was downgraded one level due to unclear risk of bias regarding blinding of outcome assessment and selective reporting

Figuras y tablas -
Summary of findings for the main comparison. Ranolazine (add‐on therapy) versus placebo for stable angina pectoris
Summary of findings 2. Ranolazine (monotherapy) versus placebo for stable angina pectoris

Ranolazine (monotherapy) versus placebo for stable angina pectoris*

Patient or population: patients with stable angina pectoris
Settings: not specified
Intervention: ranolazine (monotherapy)
Comparison: placebo (monotherapy)

Outcomes

Illustrative comparative risks** (95% CI)

Relative effect
(95% CI)

No of Participants
(studies)

Quality of the evidence
(GRADE)

Comments

Assumed risk

Corresponding risk

Placebo

Ranolazine

Cardiovascular mortality
Follow‐up: mean 643 days

16 per 1000

16 per 1000
(9 to 29)

RR 1.03
(0.56 to 1.88)

2604
(1 study)

⊕⊕⊝⊝
low¹ ²

Ranolazine 1000 mg twice daily

Non‐cardiovascular mortality ‐ not reported

See comment

See comment

Not estimable

See comment

No data were available for this outcome

All‐cause mortality
Follow‐up: 37 to 643 days

49 per 1000

49 per 1000
(39 to 61)

RR 1.00
(0.81 to 1.25)

6249
(3 studies)

⊕⊕⊝⊝
low² ³

Ranolazine 1000 mg twice daily

Quality of life
Scale: 0 to 100
Follow‐up: 14 to 643 days

Mean quality of life in control group participants was
68.6 points

Mean quality of life in intervention group participants was
0.28 higher
(1.57 lower to 2.13 higher)

2256
(3 studies)

⊕⊕⊕⊝
moderate

Ranolazine 1000 mg twice daily

(MD 0.28. 95% CI ‐1.57 to 2.13)

AMI incidence
Follow‐up: 7 to 643 days

85 per 1000

75 per 1000
(59 to 96)

RR 0.88
(0.69 to 1.12)

2983
(3 studies)

⊕⊕⊝⊝
low

Ranolazine any dose

Angina episodes frequency
Follow‐up: 14 to 28 days

Mean angina episode frequency in control group participants was
2.08 episodes per week

Mean angina episode frequency in intervention group participants was
0.08 higher
(0.85 lower to 1.01 higher)

402
(2 studies)

⊕⊕⊝⊝
low³ ⁵

Ranolazine any dose

(MD 0.08, 95% CI ‐0.85 to 1.01)

Adverse events incidence
Follow‐up: 7 to 14 days

131 per 1000

197 per 1000
(147 to 262)

RR 1.50
(1.12 to 2)

947
(3 studies)

⊕⊝⊝⊝
very low³ ⁵ ⁶

Ranolazine any dose

*Monotherapy: refers to the administration of ranolazine as the only antianginal drug. The results reported correspond to the comparisons (data and analyses) 1 and 2 of the review (involving ranolazine given at 1000mg twice daily or any dosage); this is specified in the Comments column.

**The assumed risk is based on the median control group risk across studies. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; RR: Risk ratio

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

¹ Quality of evidence was downgraded one level due to unclear risk of bias regarding allocation concealment and high risk of bias regarding selective reporting
² Quality of evidence was downgraded one level due to insufficient numbers of events (< 300), and the 95% CI around the pooled effect includes both 1) no effect and 2) appreciable benefit/harm
³ Quality of evidence was downgraded one level because a group of participants (not quantified) in one or more included studies received ranolazine in addition to usual anti‐anginals (i.e. not as monotherapy)
⁴ Quality of evidence was downgraded one level because the 95% CI around the pooled effect included both 1) no effect and 2) appreciable benefit/harm
⁵ Quality of evidence was downgraded one level due to unclear risk of bias for most criteria
⁶ Quality of evidence was downgraded one level due to insufficient numbers of events (< 300)

Figuras y tablas -
Summary of findings 2. Ranolazine (monotherapy) versus placebo for stable angina pectoris
Comparison 1. Ranolazine (monotherapy) 1000 mg twice daily versus placebo

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Cardiovascular mortality Show forest plot

1

2604

Risk Ratio (M‐H, Fixed, 95% CI)

1.03 [0.56, 1.88]

2 All‐cause mortality Show forest plot

3

6249

Risk Ratio (M‐H, Fixed, 95% CI)

1.00 [0.81, 1.25]

3 Quality of life Show forest plot

3

2254

Mean Difference (IV, Fixed, 95% CI)

0.28 [‐1.57, 2.13]

4 AMI incidence Show forest plot

2

2674

Risk Ratio (M‐H, Random, 95% CI)

0.55 [0.14, 2.15]

5 Need for revascularisation procedure Show forest plot

2

2674

Risk Ratio (M‐H, Fixed, 95% CI)

0.98 [0.82, 1.18]

6 Adverse events incidence Show forest plot

2

638

Risk Ratio (M‐H, Fixed, 95% CI)

1.33 [0.90, 1.98]

Figuras y tablas -
Comparison 1. Ranolazine (monotherapy) 1000 mg twice daily versus placebo
Comparison 2. Ranolazine (monotherapy) any dose versus placebo

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 AMI incidence Show forest plot

3

2983

Risk Ratio (M‐H, Fixed, 95% CI)

0.88 [0.69, 1.12]

2 Angina episodes frequency Show forest plot

2

402

Mean Difference (IV, Fixed, 95% CI)

0.08 [‐0.85, 1.01]

3 Adverse events incidence Show forest plot

3

947

Risk Ratio (M‐H, Fixed, 95% CI)

1.50 [1.12, 2.00]

3.1 Macrovascular angina

2

691

Risk Ratio (M‐H, Fixed, 95% CI)

1.53 [1.13, 2.07]

3.2 Microvascular angina

1

256

Risk Ratio (M‐H, Fixed, 95% CI)

1.17 [0.40, 3.38]

Figuras y tablas -
Comparison 2. Ranolazine (monotherapy) any dose versus placebo
Comparison 3. Ranolazine (add‐on therapy) 1000 mg twice daily versus placebo

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 All‐cause mortality Show forest plot

3

2053

Risk Ratio (M‐H, Fixed, 95% CI)

0.83 [0.26, 2.71]

2 Quality of life Show forest plot

3

1533

Std. Mean Difference (IV, Random, 95% CI)

0.13 [‐0.05, 0.32]

3 AMI incidence (fatal) Show forest plot

2

1509

Risk Ratio (M‐H, Fixed, 95% CI)

1.51 [0.25, 9.05]

4 AMI incidence (non‐fatal) Show forest plot

2

1509

Risk Ratio (M‐H, Fixed, 95% CI)

0.40 [0.08, 2.07]

5 Angina episodes frequency Show forest plot

3

2004

Mean Difference (IV, Fixed, 95% CI)

‐0.66 [‐0.97, ‐0.35]

6 Adverse events incidence Show forest plot

3

2053

Risk Ratio (M‐H, Fixed, 95% CI)

1.22 [1.06, 1.40]

Figuras y tablas -
Comparison 3. Ranolazine (add‐on therapy) 1000 mg twice daily versus placebo
Comparison 4. Ranolazine (add‐on therapy) any dose versus placebo

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Quality of life Show forest plot

4

1563

Std. Mean Difference (IV, Random, 95% CI)

0.25 [‐0.01, 0.52]

1.1 Macrovascular angina

3

1533

Std. Mean Difference (IV, Random, 95% CI)

0.13 [‐0.05, 0.32]

1.2 Microvascular angina

1

30

Std. Mean Difference (IV, Random, 95% CI)

1.13 [0.36, 1.91]

2 Time to 1‐mm ST‐segment depression Show forest plot

3

1165

Mean Difference (Fixed, 95% CI)

34.62 [33.08, 36.16]

Figuras y tablas -
Comparison 4. Ranolazine (add‐on therapy) any dose versus placebo
Comparison 5. Sensitivity analysis 1: Studies at low risk of bias

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Comparison 1 ‐ All‐cause mortality Show forest plot

2

6179

Risk Ratio (M‐H, Fixed, 95% CI)

1.01 [0.81, 1.26]

2 Comparison 1 ‐ Quality of life Show forest plot

2

1998

Mean Difference (IV, Fixed, 95% CI)

0.09 [‐1.86, 2.05]

3 Comparison 1 ‐ AMI incidence Show forest plot

1

2604

Risk Ratio (M‐H, Random, 95% CI)

0.94 [0.73, 1.20]

4 Comparison 1 ‐ Need for revascularisation procedure Show forest plot

1

2604

Risk Ratio (M‐H, Fixed, 95% CI)

0.98 [0.82, 1.18]

5 Comparison 2 ‐ AMI incidence Show forest plot

1

2604

Risk Ratio (M‐H, Fixed, 95% CI)

0.94 [0.73, 1.20]

6 Comparison 3 ‐ All‐cause mortality Show forest plot

2

1488

Risk Ratio (M‐H, Fixed, 95% CI)

0.80 [0.22, 2.95]

7 Comparison 3 ‐ Quality of life Show forest plot

2

975

Std. Mean Difference (IV, Random, 95% CI)

0.30 [‐0.13, 0.73]

8 Comparison 3 ‐ AMI incidence (fatal) Show forest plot

1

944

Risk Ratio (M‐H, Fixed, 95% CI)

5.04 [0.24, 104.75]

9 Comparison 3 ‐ AMI incidence (non‐fatal) Show forest plot

1

944

Risk Ratio (M‐H, Fixed, 95% CI)

0.34 [0.04, 3.22]

10 Comparison 3 ‐ Angina episodes frequency Show forest plot

2

1446

Mean Difference (IV, Fixed, 95% CI)

‐0.64 [‐0.96, ‐0.32]

11 Comparison 3 ‐ Adverse events incidence Show forest plot

2

1488

Risk Ratio (M‐H, Fixed, 95% CI)

1.28 [1.06, 1.53]

12 Comparison 4 ‐ Quality of life Show forest plot

3

1005

Std. Mean Difference (IV, Random, 95% CI)

0.54 [‐0.03, 1.10]

12.1 Macrovascular angina

2

975

Std. Mean Difference (IV, Random, 95% CI)

0.30 [‐0.13, 0.73]

12.2 Microvascular angina

1

30

Std. Mean Difference (IV, Random, 95% CI)

1.13 [0.36, 1.91]

13 Comparison 4 ‐ Time to 1‐mm ST‐segment depression Show forest plot

2

Mean Difference (Fixed, 95% CI)

34.62 [33.08, 36.16]

Figuras y tablas -
Comparison 5. Sensitivity analysis 1: Studies at low risk of bias
Comparison 6. Sensitivity analysis 2: Exchange of model for data synthesis

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Comparison 1 ‐ All‐cause mortality Show forest plot

3

6249

Risk Ratio (M‐H, Random, 95% CI)

1.00 [0.81, 1.25]

2 Comparison 1 ‐ Quality of life Show forest plot

3

2254

Mean Difference (IV, Random, 95% CI)

0.28 [‐1.57, 2.13]

3 Comparison 1 ‐ AMI incidence Show forest plot

2

2674

Risk Ratio (M‐H, Fixed, 95% CI)

0.88 [0.69, 1.13]

4 Comparison 1 ‐ Need for revascularisation procedure Show forest plot

2

2674

Risk Ratio (M‐H, Random, 95% CI)

0.98 [0.82, 1.18]

5 Comparison 1 ‐ Adverse events incidence Show forest plot

2

638

Risk Ratio (M‐H, Random, 95% CI)

1.34 [0.90, 1.99]

6 Comparison 2 ‐ AMI incidence Show forest plot

3

2983

Risk Ratio (M‐H, Random, 95% CI)

0.56 [0.19, 1.63]

7 Comparison 2 ‐ Angina episodes frequency Show forest plot

2

402

Mean Difference (IV, Random, 95% CI)

0.08 [‐0.85, 1.01]

8 Comparison 2 ‐ Adverse events incidence Show forest plot

3

947

Risk Ratio (M‐H, Random, 95% CI)

1.50 [1.12, 2.01]

8.1 Macrovascular angina

2

691

Risk Ratio (M‐H, Random, 95% CI)

1.53 [1.13, 2.07]

8.2 Microvascular angina

1

256

Risk Ratio (M‐H, Random, 95% CI)

1.17 [0.40, 3.38]

9 Comparison 3 ‐ All‐cause mortality Show forest plot

3

2053

Risk Ratio (M‐H, Random, 95% CI)

0.87 [0.25, 3.04]

10 Comparison 3 ‐ Quality of life Show forest plot

3

1533

Std. Mean Difference (IV, Fixed, 95% CI)

0.11 [0.01, 0.22]

11 Comparison 3 ‐ AMI incidence (fatal) Show forest plot

2

1509

Risk Ratio (M‐H, Random, 95% CI)

1.37 [0.10, 19.46]

12 Comparison 3 ‐ AMI incidence (non‐fatal) Show forest plot

2

1509

Risk Ratio (M‐H, Random, 95% CI)

0.41 [0.08, 2.11]

13 Comparison 3 ‐ Angina episodes frequency Show forest plot

3

2004

Mean Difference (IV, Random, 95% CI)

‐0.78 [‐1.28, ‐0.27]

14 Comparison 3 ‐ Adverse events incidence Show forest plot

3

2053

Risk Ratio (M‐H, Random, 95% CI)

1.21 [1.06, 1.39]

15 Comparison 4 ‐ Quality of life Show forest plot

4

1563

Std. Mean Difference (IV, Fixed, 95% CI)

0.13 [0.03, 0.23]

15.1 Macrovascular angina

3

1533

Std. Mean Difference (IV, Fixed, 95% CI)

0.11 [0.01, 0.22]

15.2 Microvascular angina

1

30

Std. Mean Difference (IV, Fixed, 95% CI)

1.13 [0.36, 1.91]

16 Comparison 4 ‐ Time to 1‐mm ST‐segment depression Show forest plot

3

Mean Difference (Random, 95% CI)

51.05 [4.05, 98.04]

Figuras y tablas -
Comparison 6. Sensitivity analysis 2: Exchange of model for data synthesis
Comparison 7. Sensitivity analysis 3: Change of the measure of treatment effect

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Comparison 1 ‐ All‐cause mortality Show forest plot

3

6249

Odds Ratio (M‐H, Fixed, 95% CI)

1.00 [0.80, 1.27]

2 Comparison 1 ‐ Quality of life Show forest plot

3

2254

Std. Mean Difference (IV, Fixed, 95% CI)

0.01 [‐0.07, 0.09]

3 Comparison 1 ‐ AMI incidence Show forest plot

2

2674

Odds Ratio (M‐H, Random, 95% CI)

0.49 [0.10, 2.41]

4 Comparison 1 ‐ Need for revascularisation procedure Show forest plot

2

2674

Odds Ratio (M‐H, Fixed, 95% CI)

0.98 [0.79, 1.21]

5 Comparison 1 ‐ Adverse events incidence Show forest plot

2

638

Odds Ratio (M‐H, Fixed, 95% CI)

1.41 [0.88, 2.26]

6 Comparison 2 ‐ AMI incidence Show forest plot

3

2983

Odds Ratio (M‐H, Fixed, 95% CI)

0.87 [0.67, 1.13]

7 Comparison 2 ‐ Angina episodes frequency Show forest plot

2

402

Std. Mean Difference (IV, Fixed, 95% CI)

0.01 [‐0.19, 0.20]

8 Comparison 2 ‐ Adverse events incidence Show forest plot

3

947

Odds Ratio (M‐H, Fixed, 95% CI)

1.64 [1.15, 2.35]

8.1 Macrovascular angina

2

691

Odds Ratio (M‐H, Fixed, 95% CI)

1.71 [1.17, 2.49]

8.2 Microvascular angina

1

256

Odds Ratio (M‐H, Fixed, 95% CI)

1.18 [0.38, 3.60]

9 Comparison 3 ‐ All‐cause mortality Show forest plot

3

2053

Odds Ratio (M‐H, Fixed, 95% CI)

0.83 [0.25, 2.73]

10 Comparison 3 ‐ Quality of life Show forest plot

3

1533

Mean Difference (IV, Random, 95% CI)

5.91 [‐5.52, 17.34]

11 Comparison 3 ‐ AMI incidence (fatal) Show forest plot

2

1509

Odds Ratio (M‐H, Fixed, 95% CI)

1.52 [0.25, 9.09]

12 Comparison 3 ‐ AMI incidence (non‐fatal) Show forest plot

2

1509

Odds Ratio (M‐H, Fixed, 95% CI)

0.40 [0.08, 2.08]

13 Comparison 3 ‐ Angina episodes frequency Show forest plot

3

2004

Std. Mean Difference (IV, Fixed, 95% CI)

‐0.19 [‐0.28, ‐0.11]

14 Comparison 3 ‐ Adverse events incidence Show forest plot

3

2053

Odds Ratio (M‐H, Fixed, 95% CI)

1.32 [1.09, 1.61]

15 Comparison 4 ‐ Quality of life Show forest plot

4

1563

Mean Difference (IV, Random, 95% CI)

11.17 [‐2.54, 24.87]

15.1 Macrovascular angina

3

1533

Mean Difference (IV, Random, 95% CI)

5.91 [‐5.52, 17.34]

15.2 Microvascular angina

1

30

Mean Difference (IV, Random, 95% CI)

22.20 [8.57, 35.83]

Figuras y tablas -
Comparison 7. Sensitivity analysis 3: Change of the measure of treatment effect
Comparison 8. Sensitivity analysis 4: follow‐up ≥ 6 weeks

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Comparison 1 ‐ All‐cause mortality Show forest plot

2

6179

Risk Ratio (M‐H, Fixed, 95% CI)

1.01 [0.81, 1.26]

2 Comparison 1 ‐ Quality of life Show forest plot

1

1958

Mean Difference (IV, Fixed, 95% CI)

‐0.10 [‐2.08, 1.88]

3 Comparison 1 ‐ AMI incidence Show forest plot

1

2604

Risk Ratio (M‐H, Random, 95% CI)

0.94 [0.73, 1.20]

4 Comparison 1 ‐ Need for revascularisation procedure Show forest plot

1

2604

Risk Ratio (M‐H, Fixed, 95% CI)

0.98 [0.82, 1.18]

5 Comparison 2 ‐ AMI incidence Show forest plot

1

2604

Risk Ratio (M‐H, Fixed, 95% CI)

0.94 [0.73, 1.20]

6 Comparison 3 ‐ All‐cause mortality Show forest plot

3

2053

Risk Ratio (M‐H, Fixed, 95% CI)

0.83 [0.26, 2.71]

7 Comparison 3 ‐ Quality of life Show forest plot

3

1533

Std. Mean Difference (IV, Random, 95% CI)

0.13 [‐0.05, 0.32]

8 Comparison 3 ‐ AMI incidence (fatal) Show forest plot

2

1509

Risk Ratio (M‐H, Fixed, 95% CI)

1.51 [0.25, 9.05]

9 Comparison 3 ‐ AMI incidence (non‐fatal) Show forest plot

2

1509

Risk Ratio (M‐H, Fixed, 95% CI)

0.40 [0.08, 2.07]

10 Comparison 3 ‐ Angina episodes frequency Show forest plot

3

2004

Mean Difference (IV, Fixed, 95% CI)

‐0.66 [‐0.97, ‐0.35]

11 Comparison 3 ‐ Adverse events incidence Show forest plot

3

2053

Risk Ratio (M‐H, Fixed, 95% CI)

1.22 [1.06, 1.40]

12 Comparison 4 ‐ Quality of life Show forest plot

3

1533

Std. Mean Difference (IV, Random, 95% CI)

0.13 [‐0.05, 0.32]

12.1 Macrovascular angina

3

1533

Std. Mean Difference (IV, Random, 95% CI)

0.13 [‐0.05, 0.32]

13 Comparison 4 ‐ Time to 1‐mm ST‐segment depression Show forest plot

1

Mean Difference (Fixed, 95% CI)

34.6 [33.06, 36.14]

Figuras y tablas -
Comparison 8. Sensitivity analysis 4: follow‐up ≥ 6 weeks