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1 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):IRA 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.

2 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.

3 Four S: 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: 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: 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):

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