Statin Landmark Trials Across the Spectrum of Risk: Primary CV Prevention

Cholesterol quintile (mg/dL) Over Time Additional Risk Factors Can Progress: Effect of Cholesterol and BP on CHD Risk in MRFIT Trial Neaton p56, Abstract Deaths/10,000 patient-years 34 21 13 6 23 12 8 10 18 11 9 4 17 3 14 5 Increasing Risk Neaton p59, Figure 8 N = 316,099 An examination of data from the Multiple Risk Factor Intervention Trial (MRFIT) assessed the combined influence of blood pressure, serum cholesterol level, and smoking on age-adjusted CHD mortality in 316,099 white males aged 35 to 57 years. In a subset of 202,620 nonsmokers with total cholesterol and systolic blood pressure (SBP) risk factors, an increase in serum cholesterol levels from 182 mg/dL to ≥245 mg/dL raised CHD death rates from 3.1 to 12.2 per 10,000 person-years. Increases in SBP from 118 mm Hg to ≥142 mm Hg raised CHD death rates from 3.1 to 13.7 per 10,000 person-years. As a midrange example, with 2 slightly elevated risk factors (SBP of 142 mm Hg and serum cholesterol of 203 mg/dL), the death rate per 10,000 patient-years is ~17%. The combined effect of these risk factors (serum cholesterol ≥245 mg/dL and SBP ≥142 mm Hg) more than doubled the CHD death rate to 33.7 per 10,000 person-years. Neaton JD, Wentworth D; for the Multiple Risk Factor Intervention Trial Research Group. Serum cholesterol, blood pressure, cigarette smoking, and death from coronary heart disease. Overall findings and differences by age for 316,009 white men. Arch Intern Med. 1992;152:56-64. 245+ 142+ 132-141 221-244 125-131 Cholesterol quintile (mg/dL) 203-220 SBP quintile (mm Hg) 182-202 118-124 <182 <118 BP = blood pressure; CHD = coronary heart disease. Neaton JD et al. Arch Intern Med. 1992;152:56-64. .

All patients in ASCOT have hypertension plus 3 risk factors for CHD ASCOT LLA Trial of Statin in Hypertensive Patients With Additional Risk Factors: Patient Population Sever, p 1146, T8 All patients in ASCOT have hypertension plus 3 risk factors for CHD Patients With Risk Factor, % 10 20 30 40 50 60 70 80 90 100 Peripheral vascular disease Previous cerebrovascular events LVH Certain ECG abnormalities Plasma TC:HDL-C ≥6 Type 2 diabetes Family history of coronary disease Smoker Microalbumin/proteinuria Male Age ≥55 years Hypertension 84 81 62 33 26 24 14 5 The ASCOT trial was designed as a prospective randomized 2  2 factorial trial that randomized 19,342 patients to amlodipine-based antihypertensive treatment versus beta-blocker–based treatment. A group of 10,305 of these patients, who had controlled hypertension and additional risk factors as well as average or below average cholesterol levels, were further randomized in a double-blinded manner to atorvastatin 10 mg versus placebo. The study was terminated early after a median follow-up of 3.3 years on the recommendation of the Data and Safety Monitoring Committee, due to the high significant reduction in the primary end point observed with atorvastatin therapy. Men and women aged 40 to 79 years were eligible to participate in the ASCOT trial if they had hypertension and at least 3 of the CVrisk factors listed on this slide. Here, you can see a breakdown of the percentages of patients in the lipid-lowering arm who had each individual risk factor. Sever PS, Dahlöf B, Poulter NR, et al; for the ASCOT Investigators. Rationale, design, methods and baseline demography of participants of the Anglo-Scandinavian Cardiac Outcomes Trial. J Hypertens. 2001;19:1139-1147. Sever PS et al. J Hypertens. 2001;19:1139-1147.

ASCOT LLA Primary End Point: Nonfatal MI and Fatal CHD Sever, p 1152, F2 1 2 3 4 Atorvastatin 10 mg Placebo Number of Events 100 Number of Events 154 36% relative risk reduction Cumulative Incidence, % ASCOT-LLA was stopped early after a median follow-up of 3.3 years. Compared with placebo at end of study, in the atorvastatin group, total cholesterol and calculated LDL-C were both around 1 mmol/L lower. The primary end point of nonfatal MI (including silent MI) and fatal CHD was significantly lower by 36% (HR = 0.64; 95% CI, 0.5-0.83; P = 0.005) in the atorvastatin group compared with the placebo group. Sever PS, Dahlöf B, Poulter NR, et al; for the ASCOT Investigators. 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. Lancet. 2003;361:1149-1158. HR = 0.64 (95% CI, 0.50 – 0.83) P = .0005 0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 Years Sever PS et al. Lancet. 2003;361:1149-1158.

ASCOT LLA Secondary End Point: Fatal and Nonfatal Stroke Sever, p 1154, F24 3 Atorvastatin 10 mg Placebo Number of Events 89 Number of Events 121 27% relative risk reduction 2 Cumulative Incidence, % 1 The secondary end point of fatal and nonfatal stroke was significantly lowered by 27% (HR = 0.73, 95% CI, 0.56-0.96; P = 0.0236) in the atorvastatin group compared with the placebo group. Sever PS, Dahlöf B, Poulter NR, et al; for the ASCOT Investigators. 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. Lancet. 2003;361:1149-1158. HR = 0.73 (0.56 – 0.96) P = .0236 0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 Years Sever PS et al. Lancet. 2003;361:1149-1158.

HPS: Effects of Statin on Major Coronary Events and Stroke in Diabetic and Nondiabetic Patients Vascular event Simvastatin Placebo Rate ratio & 95% CI & disease group (10269) (10267) Statin better Placebo better Major coronary events Diabetes 279 (9.4%) 377 (12.6%) No diabetes 619 (8.5%) 835 (11.5%) 27% (95% CI 21-33) reduction (P<0.0001) All patients 898 (8.7%) 1212 (11.8%) Strokes The Heart Protection Study enrolled 5963 individuals with diabetes and 14,573 high-risk patients without diabetes of whom 49% had no previous history of vascular disease. Patients were randomized to simvastatin versus placebo and followed for a mean duration of 4.8 years for the people with diabetes and 5 years for the remaining participants. Simvastatin produced a highly significant 27% (95% CI, 21-33; P < 0.0001) proportional reduction in the incidence of first nonfatal MI or coronary death for the overall population, a significant 27% (95% CI, 15-38; P < 0.0001) reduction in major coronary events among diabetics and a similar 27% (95% CI, 19-34; P < 0.0001) reduction among the other high-risk individuals studied. First nonfatal or fatal stroke was reduced by simvastatin by a significant 25% (95% CI, 15-34; P < 0.0001) in the study overall and by a significant 24% (95% CI, 6-39; P = 0.01) among the diabetic participants with a similar 26% (95% CI, 14-36; P = 0.0002) reduction among the other high-risk individuals studied. Collins R, Armitage J, Parish S, Sleigh P, Peto R; for the Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol-lowering with simvastatin in 5963 people with diabetes: a randomised placebo-controlled trial. Lancet. 2003;361:2005-2016. Diabetes 149 (5.0%) 193 (6.5%) No diabetes 295 (4.0%) 392 (5.4%) 25% (95% CI 15-34) reduction (P<0.0001) All patients 444 (4.3%) 585 (5.7%) 0.4 0.6 0.8 1.0 1.2 1.4 Collins et al. Lancet 2003;361:2005-2016.

Relative Risk Reduction 37% (95% CI, 17–52) P = 0.001 CARDS: Effect of Atorvastatin on the Primary End Point—Major CV Events Including Stroke Relative Risk Reduction 37% (95% CI, 17–52) P = 0.001 15 Placebo 127 events 10 Cumulative Hazard, % 5 Atorvastatin 83 events The CARDS trial randomized 2838 type 2 diabetic patients with no documented previous history of CVD to placebo (n = 1410) or atorvastatin 10 mg daily (n = 1428) to investigate the effect on the primary end point of acute CHD events, coronary revascularization, or stroke. The trial was terminated 2 years earlier than expected because the prespecified early stopping rule for efficacy had been met. Atorvastatin 10 mg significantly reduced the primary end point of acute CHD events, coronary revascularization, or stroke by 37% (relative risk reduction) (95% CI, 17-52; P = 0.001) compared with placebo. Colhoun HM, Betteridge DJ, Durrington PN, et al; for the CARDS Investigators. Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS): multicentre randomised placebo-controlled trial. Lancet. 2004;364:685-696. 1 2 3 4 4.75 Years 1410 1428 1351 1392 Placebo Atorvastatin 1306 1361 1022 1074 651 694 305 328 Colhoun HM et al. Lancet 2004;364:685-696.

CARDS: Component End Points 21 (1.5%) 24 (1.7%) 51 (3.6%) 83 (5.8%) Atorva* 48% (11-69) 39 (2.8%) Stroke 31% (–16-59) 34 (2.4%) Coronary revascularization 36% (9-55) 77 (5.5%) Acute coronary events 37% (17-52) p=0.001 127 (9.0%) Primary end point Hazard Ratio Risk Reduction (95% CI) Placebo* Event When the component end points were assessed separately, acute CHD events were reduced by 36% (–55 to –9), coronary revascularizations by 31% (–59 to 16), and rate of stroke by 48% (–69 to –11). No excess of adverse events was noted in the atorvastatin group. Colhoun HM, Betteridge DJ, Durrington PN, et al; for the CARDS Investigators. Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS): multicentre randomised placebo-controlled trial. Lancet. 2004;364:685-696. * N (% randomized) .2 .4 .6 .8 1 1.2 Favors Atorvastatin Favors Placebo Colhoun HM et al. Lancet. 2004;364:685-696.

JUPITER Trial of Statin in People With Elevated CRP: Primary End Point Ridker, p 2202rt F 1A Time to first occurrence of a CV death, nonfatal stroke, nonfatal MI, unstable angina, or arterial revascularization 0.08 Placebo HR = 0.56 (95% CI, 0.46-0.69) P < .00001 0.06 Rosuvastatin 20 mg Cumulative Incidence 0.04 JUPITER was designed to investigate whether rosuvastatin 20 mg per day would decrease the rate of first major cardiovascular events compared with placebo in men 50 years of age or older and women 60 years of age or older who did not have a history of cardiovascular disease and with low or normal LDL-C but elevated C-reactive protein levels. Rosuvastatin treatment resulted in a 44% relative risk reduction in the primary end point of the occurence of a first major cardiovascular event compared with placebo, which was highly significant. JUPITER, Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin. Ridker P, Danielson E, Fonseca FA, et al; for the JUPITER Study Group. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med. 2008;359:2195-2207. NOTE: COPYRIGHT PERMISSIONS REQUIRED FOR THIS SLIDE 0.02 0.00 1 2 3 4 Follow-up (years) Patients at risk Rosuvastatin Placebo 8901 8631 8412 6540 3893 1958 1353 983 538 157 8621 8353 6508 3872 1963 1333 955 534 174 JUPITER, Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin. Ridker P et al. N Eng J Med. 2008;359:2195-2207.