Supplementary Online Content Gutierrez J, Ramirez G, Rundek T, Sacco RL. Statin therapy in the prevention of recurrent cardiovascular events: a sex-based meta-analysis. Arch Intern Med. 2012;172(12):IRA120005. eappendix. Included trials description ereferences efigure 1. Coronary mortality efigure 2. Any myocardial infarction (fatal or nonfatal) efigure 3. Cardiac intervention (CABG or PCI) This supplementary material has been provided by the authors to give readers additional information about their work.
eappendix INCLUDED TRIALS DESCRIPTION ASCOT-LLA: 1-4 Participants were spontaneously referred from community clinics to study centers. Duration of follow up: 3.7 years. Interventions: Atorvastatin 10 mg daily vs. placebo. Factorial design, 2x2, performed under protocol PROBE by an independent randomization center. The statistical analysis was performed by an independent third party. Outcomes: Combined endpoint of non-fatal myocardial infarction, including so-called silent myocardial infarction, and fatal CHD. The secondary endpoints of the lipid-lowering arm were the primary outcome without silent events, all-cause mortality, total cardiovascular mortality, fatal and non-fatal stroke, fatal and non-fatal heart failure, total coronary endpoints, and total cardiovascular events. Conflict of interest: Several authors received benefits from pharmaceutical companies involved in manufacturing cholesterol-reducing medications. They also received financial support from Pfizer to cover administrative and staffing costs of ASCOT, and travel, accommodation expenses or both incurred by attending relevant meetings. The steering committee included two non-voting representatives from the pharmaceutical company manufacturing the tested intervention. ASCOT-LLA was the lipid lowering part of a larger trail testing anti-hypertensive medications. In a different publication, the interaction between cholesterol lowering medications and anti-hypertensive was evaluated and a significant interaction among treatments was not found. 5 CARE: 6-10 The participants from a hospital-based sample with diagnosis of MI were included in a 5 year follow up study. Interventions: Pravastatin 40 mg daily. Randomization scheme: The randomization into the 2 treatment groups was stratified by the center so that there was a balance in therapy assignment within each of the participating centers. Outcomes: The primary end point of the trial was death from coronary heart disease (including fatal MI, either definite or probable; sudden death; death during a coronary intervention; and death from other coronary causes) or a symptomatic (unless during non-cardiac surgery) non-fatal MI confirmed by serum creatine kinase measurements. Conflict of Interest: This study was supported by a grant from Bristol-Myers Squibb. The sponsor had no access to the data on lipid changes or end points. CCAIT: 11,12 it was identified in our initial search and qualified for analysis, but no other citation was found among the results. Participants were patients referred to study centers with the clinical indication for cardiac angiography. Duration: 24 months. Interventions: Lovastatin 20 mg daily vs. placebo. If treatment subjects failed to achieve LDL goal, lovastatin was increased to 40 mg daily. Similar changes in placebo group to preserve blinding. Statistical analysis was performed by a sponsoring company. Outcomes: The primary end point was per-patient mean of the minimum lumen diameter changes in coronary arteries. Secondary outcomes: (1) proportion of patients classified as progressors, (2) proportion of patients classified as regressors, (3) proportion of patients with one or more new lesions, (4) proportion of patients with one or more new total occlusions, and (5) coronary change score, including only lesions in diameter stenosis at baseline and (6) clinical events. Conflict of interest: Sponsored by Merck Frosst Canada Inc. manufacturer of a lovastatin presentation at the time of the study. FLORIDA: 13 The participants from a hospital-based sample of patient with an acute myocardial infarction were enrolled. Interventions: Fluvastatin 40 mg twice a day vs. placebo. Follow up: 52 weeks. Outcomes: Major clinical events were defined as cardiovascular death (sudden death, fatal recurrent AMI, fatal stroke or other cardiovascular death), non-cardiovascular death, recurrent AMI or recurrent ischemia necessitating hospitalization or revascularization (PCI, CABG). Rates per sex were obtained by a personal communication with the authors. No funding disclosed. Fluvastatin on CE: 14 Unclear source of population. Interventions: Fluvastatin 40 mg daily vs. placebo. If active treatment subjects did not reach goal 6 -weeks of randomization, then dose of fluvastatin was increased to 80 mg daily. The same changes made in a placebo case to preserve blinding. Outcomes: The primary efficacy variable (combined endpoint) was the incidence of cardiac events during the 52-week treatment period. Cardiac events included death from cardiovascular cause (fatal MI, sudden cardiac death),nonfatal MI, CABG, and unstable angina. Funding not disclosed.
Four S: 15-24 The participants were referred to study center with diagnosis of clinical coronary heart disease. Interventions: Simvastatin 20 mg daily or placebo. If LDL goal was not achieved, the simvastatin was increased to 40 mg daily. If LDL goal was achieved, simvastatin was decreased to 10 mg daily. Similar changes were performed in controls to preserve blinding. Randomization scheme: Sequential allocation stratified per center and then per qualifying event. Duration: 5.4 years. Outcomes: All-cause mortality and major coronary events (CHD death, nonfatal myocardial infarction, or resuscitated cardiac arrest) were the primary and secondary end points of the study, respectively. Any CHD-related event, any atherosclerosis-related event, and coronary revascularization procedures were tertiary end points. Conflict of Interest: Supported by Merck Research Laboratories, manufacturer of a product containing simvastatin. LIPID: 18,25-33 The participants referral is unclear. Interventions: Pravastatin 40 mg daily vs. placebo. Duration: 6.1 year. Randomization was stratified by qualifying event, and then blocked to keep a ratio of 2:1, acute myocardial infarction: unstable angina, respectively. Outcomes: Primary end point: Coronary mortality. Secondary outcomes included effect of treatment on (1) total mortality; (2) the incidence of AMI (fatal and nonfatal); (3) total days of hospitalization; and (4) serum lipid fractions, and the relationship of changes in them to changes in CAD mortality. Conflict of interest: This study was conducted under the auspices of the National Heart Foundation of Australia and funded by a grant from Bristol-Myers Squibb (Pharmaceuticals). MIRACL: 34-40 Duration: 16 weeks. Participants were enrolled from a hospital-based sample referred with acute chest pain. Interventions: Atorvastatin 80 mg daily vs. placebo. Outcomes: Primary outcomes were death, cardiac arrest, reinfarction, or readmission for recurrent symptomatic ischemia. A secondary outcome was the need for coronary revascularization. Conflict of interest: Supported by a grant from Pfizer Inc. Pfizer provided the atorvastatin and matching placebo used in this study. PLAC-I: 41 The participants were obtained from a hospital-based sample of patient who had clinical indication to have a cardiac angiography. Interventions: Pravastatin 40 mg daily vs. placebo. Duration: 36 months. Outcomes: Rate of progression for mean diameter averaged over coronary vessel segments as primary outcome, secondary outcomes include myocardial infarction, stroke, angioplasty and coronary artery bypass graft surgery, and total and cause-specific mortality. Conflict of interest: Sponsored by Bristol-Myers Squibb Pharmaceutical Research Institute, manufacturer of a pravastatin presentation. PROSPER: 42,43 The participants were old individuals referred from primary care physicians based on eligibility criteria. Interventions: Pravastatin 40 mg daily vs. placebo. Duration: 3.2 years. Outcomes: Combined end point of coronary heart disease death (definite plus suspect), nonfatal myocardial infarction (definite plus suspect), and fatal plus nonfatal stroke. Conflict of interest: This study is supported by a research grant from the Bristol-Myers Squibb Pharmaceutical Research Institute, manufacturer of the tested drug at the time of the trial. SPARCL: 44-48 Participants were referrals to a neurologist at the study center for acute or subacute stroke. Interventions: Atorvastatin 80 mg daily vs. placebo. Duration: 4.9 years. Outcomes: The primary outcome was the time from randomization to a first nonfatal or fatal stroke. Secondary composite outcomes: stroke or TIA, major coronary event (death from cardiac causes, nonfatal myocardial infarction, or resuscitation after cardiac arrest), major cardiovascular event (stroke plus any major coronary event), acute coronary event (major coronary event or unstable angina), any coronary event (acute coronary event plus a coronary revascularization procedure, unstable angina, or angina or ischemia requiring emergency hospitalizations), revascularization procedure (coronary, carotid, or peripheral), and any cardiovascular event (any of the former plus clinically significant peripheral vascular disease). Conflict of interest: The trial was supported by Pfizer, and several authors and steering committee members have received consultations fees from multiple pharmaceutical companies including some that manufacture cholesterol lowering medications. ereferences 1. Manisty C, Mayet J, Tapp RJ, et al. Atorvastatin treatment is associated with less augmentation of the carotid pressure waveform in hypertension: a substudy of the Anglo-Scandinavian Cardiac Outcome Trial (ASCOT). Hypertension. 2009;54(5):1009-1013.
2. Sever PS, Poulter NR, Dahlof B, et al. Reduction in cardiovascular events with atorvastatin in 2,532 patients with type 2 diabetes: Anglo-Scandinavian Cardiac Outcomes Trial--lipid-lowering arm (ASCOT- LLA). Diabetes Care. 2005;28(5):1151-1157. 3. Sever PS, Dahlof B, Poulter NR, et al. Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than-average cholesterol concentrations, in the Anglo- Scandinavian Cardiac Outcomes Trial--Lipid Lowering Arm (ASCOT-LLA): a multicentre randomised controlled trial. Drugs. 2004;64 Suppl 2:43-60. 4. Sever PS, Dahlof B, Poulter NR, et al. Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than-average cholesterol concentrations, in the Anglo- Scandinavian Cardiac Outcomes Trial--Lipid Lowering Arm (ASCOT-LLA): a multicenter randomised controlled trial. Lancet. 2003;361(9364):1149-1158. 5. Sever P, Dahlof B, Poulter N, et al. Potential synergy between lipid-lowering and blood-pressure-lowering in the Anglo-Scandinavian Cardiac Outcomes Trial. Eur Heart J. Dec 2006;27(24):2982-2988. 6. Pfeffer MA, Sacks FM, Moye LA, et al. Influence of baseline lipids on effectiveness of pravastatin in the CARE Trial. Cholesterol And Recurrent Events. Journal of the American College of Cardiology. 1999;33(1):125-130. 7. Lewis SJ, Sacks FM, Mitchell JS, et al. Effect of pravastatin on cardiovascular events in women after myocardial infarction: the cholesterol and recurrent events (CARE) trial. Journal of the American College of Cardiology. 1998;32(1):140-146. 8. Lewis SJ, Moye LA, Sacks FM, et al. Effect of pravastatin on cardiovascular events in older patients with myocardial infarction and cholesterol levels in the average range. Results of the Cholesterol and Recurrent Events (CARE) trial. Annals of internal medicine. 1998;129(9):681-689. 9. Pfeffer MA, Sacks FM, Moye LA, et al. Cholesterol and Recurrent Events: a secondary prevention trial for normolipidemic patients. CARE Investigators. The American journal of cardiology. 1995;76(9):98C-106C. 10. Sacks FM, Pfeffer MA, Moye L, et al. Rationale and design of a secondary prevention trial of lowering normal plasma cholesterol levels after acute myocardial infarction: the Cholesterol and Recurrent Events trial (CARE). The American journal of cardiology. 1991;68(15):1436-1446. 11. Waters D, Higginson L, Gladstone P, Boccuzzi SJ, Cook T, Lespérance J. Effects of cholesterol lowering on the progression of coronary atherosclerosis in women. A Canadian Coronary Atherosclerosis Intervention Trial (CCAIT) substudy. Circulation. 1995;92(9):2404-2410. 12. Waters D, Higginson L, Gladstone P, Kimball B, LeMay M, Lesperance J. Design features of a controlled clinical trial to assess the effect of an HMG CoA reductase inhibitor on the progression of coronary artery disease. Canadian Coronary Atherosclerosis Intervention Trial Investigators Montreal, Ottawa, and Toronto, Canada. Controlled clinical trials. 1993;14(1):45-74. 13. Liem AH, van Boven AJ, Veeger NJ, et al. Effect of fluvastatin on ischaemia following acute myocardial infarction: a randomized trial. European heart journal. 2002;23(24):1931-1937. 14. Riegger G, Abletshauser C, Ludwig M, et al. The effect of fluvastatin on cardiac events in patients with symptomatic coronary artery disease during one year of treatment. Atherosclerosis. 1999;144(1):263-270. 15. Design and baseline results of the Scandinavian Simvastatin Survival Study of patients with stable angina and/or previous myocardial infarction. The American journal of cardiology. 1993;71(5):393-400. 16. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet. 1994;344(8934):1383-1389. 17. Baseline serum cholesterol and treatment effect in the Scandinavian Simvastatin Survival Study (4S). Lancet. 1995;345(8960):1274-1275. 18. Tonkin AM. Management of the Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) study after the Scandinavian Simvastatin Survival Study (4S). The American journal of cardiology. 1995;76(9):107C-112C. 19. Kjekshus J, Pedersen TR. Reducing the risk of coronary events: evidence from the Scandinavian Simvastatin Survival Study (4S). The American journal of cardiology. 1995;76(9):64C-68C. 20. Pyorala K, Pedersen TR, Kjekshus J, Faergeman O, Olsson AG, Thorgeirsson G. Cholesterol lowering with simvastatin improves prognosis of diabetic patients with coronary heart disease. A subgroup analysis of the Scandinavian Simvastatin Survival Study (4S). Diabetes Care. 1997;20(4):614-620. 21. Miettinen TA, Pyorala K, Olsson AG, et al. Cholesterol-lowering therapy in women and elderly patients with myocardial infarction or angina pectoris: findings from the Scandinavian Simvastatin Survival Study (4S). Circulation. 1997;96(12):4211-4218.
22. Pedersen TR, Olsson AG, Faergeman O, et al. Lipoprotein changes and reduction in the incidence of major coronary heart disease events in the Scandinavian Simvastatin Survival Study (4S). Circulation. 1998;97(15):1453-1460. 23. Ballantyne CM, Olsson AG, Cook TJ, Mercuri MF, Pedersen TR, Kjekshus J. Influence of low highdensity lipoprotein cholesterol and elevated triglyceride on coronary heart disease events and response to simvastatin therapy in 4S. Circulation. 2001;104(25):3046-3051. 24. Wilhelmsen L, Pyorala K, Wedel H, Cook T, Pedersen T, Kjekshus J. Risk factors for a major coronary event after myocardial infarction in the Scandinavian Simvastatin Survival Study (4S). Impact of predicted risk on the benefit of cholesterol-lowering treatment. European heart journal. 2001;22(13):1119-1127. 25. Design features and baseline characteristics of the LIPID (Long-Term Intervention with Pravastatin in Ischemic Disease) Study: a randomized trial in patients with previous acute myocardial infarction and/or unstable angina pectoris. The American journal of cardiology. 1995;76(7):474-479. 26. Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. The Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group. The New England journal of medicine. 1998;339(19):1349-1357. 27. Goldberg RB, Mellies MJ, Sacks FM, et al. Cardiovascular events and their reduction with pravastatin in diabetic and glucose-intolerant myocardial infarction survivors with average cholesterol levels: subgroup analyses in the cholesterol and recurrent events (CARE) trial. The Care Investigators. Circulation. 1998;98(23):2513-2519. 28. Tonkin AM, Colquhoun D, Emberson J, et al. Effects of pravastatin in 3260 patients with unstable angina: results from the LIPID study. Lancet. 2000;356(9245):1871-1875. 29. Marschner IC, Colquhoun D, Simes RJ, et al. Long-term risk stratification for survivors of acute coronary syndromes. Results from the Long-term Intervention with Pravastatin in Ischemic Disease (LIPID) Study. LIPID Study Investigators. Journal of the American College of Cardiology. 2001;38(1):56-63. 30. Hunt D, Young P, Simes J, et al. Benefits of pravastatin on cardiovascular events and mortality in older patients with coronary heart disease are equal to or exceed those seen in younger patients: Results from the LIPID trial. Annals of internal medicine. 2001;134(10):931-940. 31. Hague W, Forder P, Simes J, Hunt D, Tonkin A. Effect of pravastatin on cardiovascular events and mortality in 1516 women with coronary heart disease: results from the Long-Term Intervention with Pravastatin in Ischemic Disease (LIPID) study. American heart journal. 2003;145(4):643-651. 32. Keech A, Colquhoun D, Best J, et al. Secondary prevention of cardiovascular events with long-term pravastatin in patients with diabetes or impaired fasting glucose: results from the LIPID trial. Diabetes Care. 2003;26(10):2713-2721. 33. Colquhoun D, Keech A, Hunt D, et al. Effects of pravastatin on coronary events in 2073 patients with low levels of both low-density lipoprotein cholesterol and high-density lipoprotein cholesterol: results from the LIPID study. European heart journal. 2004;25(9):771-777. 34. Schwartz GG, Olsson AG, Ezekowitz MD, et al. Effects of atorvastatin on early recurrent ischemic events in acute coronary syndromes: the MIRACL study: a randomized controlled trial. JAMA : the journal of the American Medical Association. 2001;285(13):1711-1718. 35. Waters DD, Schwartz GG, Olsson AG, et al. Effects of atorvastatin on stroke in patients with unstable angina or non-q-wave myocardial infarction: a Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) substudy. Circulation. 2002;106(13):1690-1695. 36. Kinlay S, Schwartz GG, Olsson AG, et al. High-dose atorvastatin enhances the decline in inflammatory markers in patients with acute coronary syndromes in the MIRACL study. Circulation. 2003;108(13):1560-1566. 37. Kinlay S, Schwartz GG, Olsson AG, et al. Effect of atorvastatin on risk of recurrent cardiovascular events after an acute coronary syndrome associated with high soluble CD40 ligand in the Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) Study. Circulation. 2004;110(4):386-391. 38. Schwartz GG, Olsson AG, Szarek M, Sasiela WJ. Relation of characteristics of metabolic syndrome to short-term prognosis and effects of intensive statin therapy after acute coronary syndrome: an analysis of the Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) trial. Diabetes Care. 2005;28(10):2508-2513. 39. Olsson AG, Schwartz GG, Szarek M, Luo D, Jamieson MJ. Effects of high-dose atorvastatin in patients > or =65 years of age with acute coronary syndrome (from the myocardial ischemia reduction with aggressive cholesterol lowering [MIRACL] study). The American journal of cardiology. 2007;99(5):632-635.
40. Fraley AE, Schwartz GG, Olsson AG, et al. Relationship of oxidized phospholipids and biomarkers of oxidized low-density lipoprotein with cardiovascular risk factors, inflammatory biomarkers, and effect of statin therapy in patients with acute coronary syndromes: Results from the MIRACL (Myocardial Ischemia Reduction With Aggressive Cholesterol Lowering) trial. Journal of the American College of Cardiology. 2009;53(23):2186-2196. 41. Pitt B, Mancini GB, Ellis SG, Rosman HS, Park JS, McGovern ME. Pravastatin limitation of atherosclerosis in the coronary arteries (PLAC I): reduction in atherosclerosis progression and clinical events. PLAC I investigation. Journal of the American College of Cardiology. 1995;26(5):1133-1139. 42. Shepherd J, Blauw GJ, Murphy MB, et al. The design of a prospective study of Pravastatin in the Elderly at Risk (PROSPER). PROSPER Study Group. PROspective Study of Pravastatin in the Elderly at Risk. The American journal of cardiology. 1999;84(10):1192-1197. 43. Shepherd J, Blauw GJ, Murphy MB, et al. Pravastatin in elderly individuals at risk of vascular disease (PROSPER): a randomised controlled trial. Lancet. 2002;360(9346):1623-1630. 44. Goldstein LB, Amarenco P, Lamonte M, et al. Relative effects of statin therapy on stroke and cardiovascular events in men and women: secondary analysis of the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) Study. Stroke; a journal of cerebral circulation. 2008;39(9):2444-2448. 45. Sillesen H, Amarenco P, Hennerici MG, et al. Atorvastatin reduces the risk of cardiovascular events in patients with carotid atherosclerosis: a secondary analysis of the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial. Stroke; a journal of cerebral circulation. 2008;39(12):3297-3302. 46. Amarenco P, Goldstein LB, Callahan A rd, et al. Baseline blood pressure, low- and high-density lipoproteins, and triglycerides and the risk of vascular events in the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial. Atherosclerosis. 2009;204(2):515-520. 47. Amarenco P, Benavente O, Goldstein LB, et al. Results of the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial by stroke subtypes. Stroke; a journal of cerebral circulation. 2009;40(4):1405-1409. 48. Goldstein LB, Amarenco P, Zivin J, et al. Statin treatment and stroke outcome in the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial. Stroke; a journal of cerebral circulation. 2009;40(11):3526-3531.