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.

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.

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

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

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.

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

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.

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.

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.

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.

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

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 HbA_1c>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.

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.

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.

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, p_interaction = 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

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.

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