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Drug‐eluting stents versus bare‐metal stents for acute coronary syndrome

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Appendices

Appendix 1. Glossary

Ischaemic: reduced blood supply to an organ.

ST: ST is short for the ST‐segment, which is a specific segment of the printout when recording an electrocardiogram. It is used to differentiate between ST and non‐ST myocardial infarction.

Angina pectoris: medical term for chest pain or discomfort due to ischaemic heart disease.

Myocardial ischaemia: reduced blood supply to the heart.

Cardiomyocyte necrosis: undesirable death of the cells of the heart.

Non‐ST‐elevation myocardial infarction: a kind of heart attack which does not show ST‐segment elevation on an electrocardiogram.

ST‐elevation myocardial infarction: a kind of heart attack which shows ST‐segment elevation on an electrocardiogram.

Troponin I: a cardiac protein which is released during a heart attack

Troponin T: a cardiac protein which is released during a heart attack

Myocardial band isoenzyme of creatine kinase (CK‐MB): a specific type of the enzyme creatine kinase, which is highly specific for the heart.

Atherosclerosis: arterial wall‐thickening due to build up of plaque.

Intraluminal thrombus: formation of a clot inside a vessel.

Arrhythmias: deviation from the normal heart rhythm.

Hypertension: increased pressure typically inside the arteries.

Hypotension: decreased pressure typically inside the arteries.

Percutaneous: through the skin.

Stent thrombosis: blockage of the stent by a blood clot.

Angiography: visualisation of the blood vessels typically by injection of contrast and using x‐ray.

Ventricular arrhythmias: deviation from the normal heart rhythm involving the ventricles of the heart.

Myocyte: a heart muscle cell.

Continuous ischaemia: prolonged reduced blood supply (to the heart).

Myocardium: the muscle tissue of the heart.

Myocardial necrosis: death of the muscle tissue of the heart.

Acute decompensated heart failure: heart failure where the heart is unable to overcome the pressure in the blood vessels and results in symptoms such as difficulty breathing, edema, and fatigue.

Systolic: the time period in which the ventricles of the heart contract.

Diastolic: the time period in which the ventricles of the heart relax.

Nonocclusive thrombus: the blood clot does not completely prevent blood flow through the vessel.

Coronary vasoconstriction: narrowing due to muscle contraction of the blood vessels of the heart.

Restenosis: narrowing of a previously narrowed blood vessel due to a blood clot.

Thyrotoxicosis: excessive levels of the hormone produced by the thyroid gland resulting in unwanted symptoms.

Tachycardia: a faster than normal heart beat typically above 100 beats per minute.

Biolimus: the trade name of the drug Umirolimus. The mechanism of action is believed to be anti proliferation of smooth muscle cells.

Atheroembolism: embolism originating from an atherosclerotic plaque.

Retroperitoneal bleeding: bleeding behind the peritoneum, a membrane lining the abdominal cavity.

Stenosis: narrowing of a vessel.

Neointimal: scar tissue formed in a vessel after an injury.

Revascularisation: removing the cause of the stenosed blood vessel, allowing blood flow to resume.

Sirolimus stent: a stent using the sirolimus drug, a drug used in stents with the aim of reducing restenosis.

Paclitaxcel stent: a stent using the paclitaxel drug, a drug used in stents with the aim of reducing restenosis.

Bifurcation: when a blood vessel splits into two different blood vessels.

Saphenous vein grafts: when performing bypass surgery, one may use the saphenous vein (located in the leg) to bypass the occluded vessel, ultimately reestablishing heart flow.

Bioresorbable stents: stents that are absorbed after initial placement with the intent of reducing restenosis.

Percutaneous coronary intervention: an intervention where a balloon is guided up to the heart through an access sheath penetrating the skin to reduce a narrowing of a blood vessel.

Balloon angioplasty: using a balloon to open a narrowed vessel.

Re‐endothelialisation: regrowth of endothelium after injury.

Everolimus: a drug used in stents with the aim of reducing restenosis.

Zotarolimus: a drug used in stents with the aim of reducing restenosis

Paclitaxel: a drug used in stents with the aim of reducing restenosis

Sirolimus: a drug used in stents with the aim of reducing restenosis

Level of evidence A: data derived from multiple randomized clinical trials or meta‐analyses.

Level of evidence B: data derived from a single randomized clinical trial or large non‐randomized studies.

Level of evidence C: consensus of opinion of the experts and/ or small studies, retrospective studies, registries.

Appendix 2. Preliminary MEDLINE Ovid search strategy

1. Stents/
2. stent*.tw.
3. 1 or 2
4. drug elut*.tw.
5. Sirolimus/
6. sirolimus.tw.
7. rapamycin.tw.
8. paclitaxel.tw.
9. taxol.tw.
10. exp Immunosuppressive Agents/
11. coat* stent*.tw.
12. exp Taxoids/
13. taxane*.tw.
14. qp2.tw.
15. hexanoyltaxol.tw.
16. everolimus.tw.
17. abt‐578.tw.
18. Tacrolimus/
19. Dactinomycin/
20. actinomycin.tw.
21. batimastat.tw.
22. exp Dexamethasone/
23. dexamethasone.tw.
24. exp Estradiol/
25. estradiol.tw.
26. praxel.tw.
27. paxene.tw.
28. onxol.tw.
29. anzatax.tw.
30. immunosuppress*.tw.
31. prograf*.tw.
32. meractinomycin.tw.
33. cosmegen.tw.
34. dactinomycin.tw.
35. millicorten.tw.
36. maxidex.tw.
37. decaspray.tw
38. dexpak.tw.
39. dexasone.tw.
40. oradexon.tw.
41. hexadecadrol.tw.
42. decaject.tw.
43. hexadrol.tw.
44. decameth.tw.
45. methylfluorprednisolone.tw.
46. vivelle.tw.
47. oestradiol.tw.
48. estrace.tw.
49. aerodiol.tw.
50. estraderm.tw.
51. ovocyclin.tw.
52. estramustin*.tw.
53. estracyt.tw.
54. emcyt.tw.
55. tacrolimus.tw.
56. taxoids.tw.
57. zotarolimus.tw.
58. umirolimus.tw.
59. biolimus.tw.
60. pimecrolimus.tw.
61. elidel.tw.
62. or/4‐61
63. 3 and 62
64. eluting stent*.tw.
65. 63 or 64
66. exp Angioplasty, Balloon, Coronary/ or exp Percutaneous Coronary Intervention/
67. balloon angioplast*.tw.
68. (percutaneous adj6 coronary intervention*).tw.
69. PCI.tw.
70. (intervention* adj6 percutaneous coronary).tw.
71. (revascularization* adj6 percutaneous coronary).tw.
72. (angioplast* adj6 coronary).tw.
73. percutaneous coronary.tw.
74. ((transluminal or trans‐luminal) adj6 coronary).tw.
75. or/66‐74
76. exp Myocardial Ischemia/
77. ((myocardial or myocardium or subendocardial or transmural or cardiac or cardial or coronary or heart) adj2 (infarct* or postinfarct* or hypoxi* or anoxi* or failure* or decompensation or insufficien*)).tw.
78. (heart disease* or coronary disease* or IHD or CIHD or CHD).tw.
79. (myocardial dysfunction or angina or stenocardia).tw.
80. ((ischemi* or ischaemi*) adj2 (myocardium or myocardial or heart or coronary or cardiac or cardial or subendocardial or cardiomyopath*)).tw.
81. ((artery occlusion* or artery disease* or arterioscleros* or atheroscleros*) adj2 coronary).tw.
82. or/76‐81
83. Acute Coronary Syndrome/
84. exp Myocardial Infarction/
85. exp Coronary Thrombosis/
86. coronary thrombosis.tw.
87. acute coronary.tw.
88. exp Angina, Unstable/
89. myocardial infarct*. tw.
90. heart infarct*.tw.
91. acs.tw.
92. ami.tw.
93. (coronary adj3 syndrome*).tw.
94. acute angina.tw.
95. (unstable adj3 angina).tw.
96. unstable coronary.tw.
97. or/83‐96
98. randomized controlled trial.pt.
99. controlled clinical trial.pt.
100. randomized.ab.
101. placebo.ab.
102. drug therapy.fs.
103. randomly.ab.
104. trial.ab.
105. groups.ab.
106. or/98‐105
107. exp animals/ not humans.sh.
108. 106 not 107
109. 65 or 75
110. 82 or 97
111. 108 and 109 and 110

Appendix 3. Details on assessment of risk of bias

We will classify each trial according to the domains below for each outcome result.

Random sequence generation

  • Low risk: if sequence generation is achieved using a computer random number generator or a random numbers table. We will also consider drawing lots, tossing a coin, shuffling cards, and throwing dice as adequate if an independent adjudicator performs these methods.

  • Unclear risk: if there is insufficient information to permit judgement of 'low risk' or 'high risk'.

  • High risk: if the allocation sequence is not randomised or only quasi‐randomised.

Allocation sequence concealment

  • Low risk: if the allocation of participants results from a central independent unit, on‐site locked computer, identical‐looking numbered sealed opaque envelopes, drug bottles or containers prepared by an independent investigator.

  • Unclear risk: if there is insufficient information to permit judgement of 'low risk' or 'high risk'.

  • High risk: if the allocation sequence is known to the investigators who assigned participants.

Blinding of participants and personnel

  • Low risk: if the participants and the personnel are blinded to treatment allocation and this is described.

  • Unclear risk: if there is insufficient information to permit judgement of 'low risk' or 'high risk'.

  • High risk: if blinding of participants and personnel is not performed.

Blinding of outcome assessment

  • Low risk: if the trial investigators performing the outcome assessments, analyses, and calculations are blinded to the intervention.

  • Unclear risk: if there is insufficient information to permit judgement of 'low risk' or 'high risk'.

  • High risk: if blinding of outcome assessment is not performed.

Incomplete outcome data

  • Low risk: (1) there are no dropouts or withdrawals for all outcomes, or (2) the numbers and reasons for the withdrawals and dropouts for all outcomes are clearly stated, can be described as being similar in both groups, and the trial handles missing data appropriately in intention‐to‐treat analysis using proper methodology, e.g. multiple imputations*. As a general rule, we will judge the trial as at low risk of bias due to incomplete outcome data if the number of dropouts is less than five per cent. However, the five per cent cut off is not definitive.

  • Unclear risk: if there is insufficient information to permit judgement of 'low risk' or 'high risk'.

  • High risk: the pattern of dropouts can be described as being different in the two intervention groups or the trial uses improper methodology in dealing with the missing data, e.g. last observation carried forward.

*Multiple imputation is a general approach to the problem of missing data. It aims to allow for the uncertainty about the missing data by creating several different plausible imputed data sets and appropriately combining results obtained from each of them. The first stage is to create multiple copies of the dataset, with the missing values replaced by imputed values. These are sampled from their predictive distribution based on the observed data; thus, multiple imputation is based on a bayesian approach. The imputation procedure must fully account for all uncertainty in predicting the missing values by injecting appropriate variability into the multiple imputed values. The second stage is to use standard statistical methods to fit the model of interest to each of the imputed datasets. The estimated associations from the imputed datasets will differ and are only useful when averaged together to give overall estimated associations. Valid inferences are obtained because we are averaging over the distribution of the missing data given the observed data (Sterne 2009).

Selective outcome reporting

  • Low risk: a protocol is published before or at the time the trial begins and the outcomes called for in the protocol are reported on. If there is no protocol or the protocol is published after the trial begins, reporting of the primary outcomes will grant the trial a grade of low risk of bias.

  • Unclear risk: if there is no protocol and the primary outcomes are not reported on.

  • High risk: if the outcomes that are called on in a protocol are not reported on.

Other bias risk

  • Low risk of bias: the trial appears to be free of other components (for example, academic bias or for‐profit bias) that could put it at risk of bias.

  • Unclear risk of bias: the trial may or may not be free of other components that could put it at risk of bias.

  • High risk of bias: there are other factors in the trial that could put it at risk of bias (for example, authors have conducted trials on the same topic, for‐profit bias, etc).

Overall risk of bias

  • Low risk of bias: we will classify the outcome result as overall 'low' risk of bias only if we classify all of the bias domains described in the aforementioned text as low risk of bias. Due to the nature of the PCI procedure, we do not expect to find any trials at low risk of bias. We provide a description of how we will deal with this scenario in Data synthesis.

  • High risk of bias: we will classify the outcome result as 'high' risk of bias if we classify any of the bias risk domains in the aforementioned text as 'unclear' or 'high' risk of bias.

We will grade each potential source of bias as high, low, or unclear and provide a quote from the study report together with a justification for our judgment in the 'Risk of bias' table. We will summarise the 'Risk of bias' judgements across different studies for each of the domains listed. Where information on risk of bias relates to unpublished data or correspondence with a trialist, we will note this in the 'Risk of bias' table.

When considering treatment effects, we will take into account the risk of bias for the studies that contribute to that outcome.