Landmark Statin Trials Across the Spectrum of Risk: Secondary Stroke Prevention

Simvastatin in Patients With Prior Cerebrovascular Disease: HPS 29.8 Simvastatin Placebo 24.7* 10.3 10.4 In the Heart Protection Study (HPS ) of simvastatin 40 mg versus placebo in high-risk patients, the incidence of stroke was significantly reduced in patients randomized to simvastatin 40 mg with no prior cerebrovascular disease (275 first stroke events in simvastatin-treated patients vs 415 first stroke events for placebo), but was not significant in patients with prior cerebrovascular disease (169 first stroke events in simvastatin-treated patients vs 170 first stroke events for placebo). The heterogeneity test for the effect of stroke in patients with and without prior cerebrovascular disease was significant (P = 0.002). Heart Protection Study Collaborative Group. Effects of cholesterol-lowering with simvastatin on stroke and other major vascular events in 20 536 people with cerebrovascular disease or other high-risk conditions. Lancet. 2004;363:757-767. (N=488) N=406 N=169 N=170 Major Vasular Events Stroke *29% RRR, p=0.001 Heart Protection Study Collaborative Group. Lancet. 2004;363:757-767.

SPARCL Trial of Secondary Stroke Prevention: Study Design Double-Blind Period Patient Population Atorvastatin 80 mg/day 205 sites worldwide Previously documented stroke or TIA within 6 months No history of CHD LDL-C levels ≥100 mg/dL and ≤190 mg/dL 4731 Patients Pravastatin 40 mg TNT randomized 10,001 patients to either atorvastatin 10 mg with a goal of an average LDL-C of 100 mg/dL versus atorvastatin 80 mg with an average LDL-C of 80 mg/dL after an 8-week open-label run-in on atorvastatin 10 mg. The primary end point was time to first occurrence of a major CV event (CHD death, nonfatal non–procedure-related MI, resuscitated cardiac arrest, fatal or nonfatal stroke). Patients were followed for 5 years. During the open-label period, the LDL-C level was reduced by 35% from a mean of 152 mg/dL (3.9 mmol/L) to a mean of 98 mg/dL (2.6 mmol/L). After randomization, mean LDL-C levels during the study were 77 mg/dL (2 mmol/L) among patients receiving atorvastatin 80 mg and 101 mg/dL (2.6 mmol/L) among those receiving atorvastatin 10 mg . LaRosa JC, Grundy, Waters DD, et al; for the Treating to New Targets (TNT) Investigators. Intensive lipid lowering with atorvastatin in patients with stable coronary disease. N Engl J Med. 2005;352:1425-1435. 540 Primary End Points Primary End Point Time to the First Occurrence of a Fatal or Nonfatal Stroke SPARCL Investigators. Cerebrovasc Dis. 2003;16:389-395.

SPARCL Primary End Point: Time to Fatal or Nonfatal Stroke 16% Placebo Placebo (n= 2366) Mean LDL-C = 128 mg/dL (3.3 mmol/L) 16% RR Atorvastatin 12% Fatal or Non-Fatal Stroke, % Atorvastatin 80 mg (n= 2635) Mean LDL-C = 73 mg/dL (1.9 mmol/L) 8% During the course of the study, the mean LDL-C values were 128 mg/dL (3.3 mmol/L) in the placebo group and 73 mg/dL (1.9 mmol/L) in the atorvastatin 80 mg group. The primary end point (any nonfatal or fatal stroke) occurred in 265 patients in the atorvastatin group and 311 in the placebo group (unadjusted P = 0.05). The absolute difference in Kaplan-Meier rates at 5 years was 2.2% (95% CI, 0.2%-4.2%). Atorvastatin 80 mg was associated with a 16% relative risk reduction of the primary end point of fatal or nonfatal stroke. The hazard ratio from a Cox proportional hazards model with adjustments for geographical region, entry event, time since entry event, gender, and baseline age was 0.84 (95% CI, 0.71-0.99; P = 0.03). The Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) Investigators. High-dose atorvastatin after stroke or transient ischemic attack. N Engl J Med. 2006;355:549-559. 4% Adjusted HR (95% CI)* = 0.84 (0.71, 0.99), p = 0.03 0% 1 2 3 4 5 6 Years Since Randomization * Treatment effect from Cox proportional hazards models with prespecified adjustment for geographical region, entry event, time since entry event, gender, and baseline age. Amarenco P et al. N Engl J Med. 2006;355:549-559.

SPARCL Secondary End Point: Time to Major Coronary Event Years Since Randomization Adjusted HR (95% CI)* = 0.65 (0.49, 0.87), p = 0.003 35% RR Major Coronary Event, % 1 2 3 4 5 6 0% 2% 4% 6% 8% Placebo Atorvastatin The secondary end point of time to major coronary events was reduced by 35% with atorvastatin 80 mg versus placebo. The Cox proportional hazards models with prespecified adjustment for geographical region, entry event, time since entry event, gender, and baseline age was 0.65 (95% CI, 0.49-0.87; P = 0.003). The Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) Investigators. High-dose atorvastatin after stroke or transient ischemic attack. N Engl J Med. 2006;355:549-559. * Treatment effect from Cox proportional hazards models with prespecified adjustment for geographical region, entry event, time since entry event, gender, and baseline age. 5 Amarenco P et al. N Engl J Med. 2006;355:549-559.

Stroke and Major Coronary Events SPARCL: Benefit/Risk P=0.002 P = 0.03 17.2% Major Coronary Event Ischemic Stroke Hemorrhagic Stroke Unclassified Stroke 14.1% 13.1% 11.2% Incidence (%) This analysis shows the benefit-to-risk profile of atorvastatin 80 mg in SPARCL, based on the reduction in total stroke or stroke and major coronary events. Amarenco. Atorvastatin in prevention of stroke and transiet ischeamic attack. Expert Opin Pharmacother. 2007;8:2789-2797. Atorvastatin n = 2365 Placebo n = 2366 Atorvastatin n = 2365 Placebo n = 2366 Stroke Stroke and Major Coronary Events Amarenco P. Exp Op Pharmacotherapy. 2007;8:2789-2797.

Effect of Atorvastatin on Stroke In SPARCL Patients with Diabetes 70 100 90 80 Percentage of Patients Free of EndPoints Placebo Atorvastatin 80 mg 1 2 3 4 5 Years Since Randomization 6 HR = 0.70 (95% CI, 0.50, 0.98), P = 0.0387* Log-rank P = 0.0377 RR: 30% In a subgroup analysis of patients with diabetes in the SPARCL trial, atorvastatin 80 mg was associated with a 30% relative risk reduction (adjusted HR = 0.70; 95% CI, 0.50-0.98; P = 0.0387). Amarenco P, Bogousslavsky MD, Callahan A III, et al; on behalf of the SPARCL Investigators. A placebo-controlled trial of high-dose atorvastatin in patients with recent stroke or transient ischemic attack. Publication pending. *Adjusted for entry event, time since entry event, gender, age, and geographic region Callahan A, Welch KMA, Amarenco P, et al.

SPARCL: Stroke in Patients With Carotid Stenosis 100 Atorvastatin Placebo 90 Patients Free of Fatal or Non-Fatal Stroke, % RR: 33% 80 The SPARCL study included a prespecified analysis of the subpopulation of patients within the SPARCL trial who had investigator-identified carotid stenosis at study entry to see whether atorvastatin had a greater impact in patients with stroke or TIA and carotid stenosis than in patients without. Of the SPARCL population 1007 patients had carotid stenosis. Patients with carotid stenosis were older and the proportion of men, smokers, and patients with diabetes was higher as compared with the group without carotid stenosis. The average degree of stenosis was 51% (±29%), although only given in 966 of the 1007 (96%) patients. Among the subjects with carotid stenosis, a primary end point (fatal or nonfatal stroke) occurred in 55 patients randomized to treatment with atorvastatin and in 83 of those randomized to placebo. Randomization to treatment with atorvastatin reduced the risk of stroke by 33% (HR = 0.67; 95% CI, 0.47-0.94; P = 0.02) and the risk of TIA or stroke by 34% (HR = 0.66; 95% CI, 0.50-0.89; P = 0.005). AAmarenco P, Bogousslavsky MD, Callahan A III, et al; on behalf of the SPARCL Investigators. A placebo-controlled trial of high-dose atorvastatin in patients with recent stroke or transient ischemic attack. Publication pending. HR=0.67 (95% CI 0.47, 0.94), P=.02* 70 1 2 3 4 5 Years Since Randomization * Adjusted for entry event, time since entry event, gender, age, and geographical region. Sillesen H et al. Stroke. 2008;39;3297-3302.

SPARCL: Carotid Endarterectomy in Patients with Carotid Stenosis 100 Atorvastatin (n=16/493) Placebo (n=37/514) 98 RR: 56% Patients Free of Carotid Endarterectomy, % 96 Among the 1007 patients in SPARCL who had carotid stenosis, carotid revascularizations were reduced by 56% (HR = 0.44; 95% CI, 0.24-0.79; P = 0.006). Amarenco P, Bogousslavsky MD, Callahan A III, et al; on behalf of the SPARCL Investigators. A placebo-controlled trial of high-dose atorvastatin in patients with recent stroke or transient ischemic attack. Publication pending. 94 HR=0.44 (95% CI 0.24, 0.79), P=.006 92 1 2 3 4 5 Years Since Randomization * Adjusted for entry event, time since entry event, gender, age, and geographical region. Sillesen H et al. Stroke. 2008;39;3297-3302.

SPARCL: Prespecified and Post-Hoc Analyses Prespecified Analysis Atorvastatin (n=2365) n (%) Placebo (n=2366) HR (95% CI) P-value Primary Endpoint 265 (11.2) 311 (13.1) 0.84 (0.71, 0.99) .03 Fatal Stroke 24 (1.0) 41 (1.7) 0.57 (0.35, 0.95) Non-fatal Stroke 247 (10.4) 280 (11.8) 0.57 (0.73, 1.03) .11 Post-Hoc Analysis Ischemic 218 (9.2) 274 (11.6) 0.78 (0.66, 0.94) .01 Hemorrhagic 55 (2.3) 33 (1.4) 1.66 (1.08, 2.55) .02 Reductions in risk for the primary end point of fatal or nonfatal stroke were significant and remained significant when risk of fatal stroke was considered alone (HR = 0.57; 95% CI, 0.35-0.95). Atorvastatin 80 mg was also associated with a 13% reduction in risk of nonfatal stroke, but this did not reach significance (HR = 0.87; 95% CI, 0.73-1.03; P = 0.11). Post hoc analyses indicated a significant difference in treatment effect between ischemic (HR = 0.78; 95% CI, 0.66-0.94; P = 0.78) and hemorrhagic (HR = 1.66; 95% CI, 1.08- 2.55) stroke. Occurrence of fatal hemorrhagic stroke did not differ between groups (17 cases in the atorvastatin group versus 18 cases in the placebo group). The Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) Investigators. High-dose atorvastatin after stroke or transient ischemic attack. N Engl J Med. 2006;355:549-559. *Treatment effect from Cox proportional hazards models with pre-specified adjustment for geographical region, entry event, time since entry event,gender, and baseline age. HR, hazard ratio; CI, confidence interval. The SPARCL Investigators: N Engl J Med: 2006;355:549-559.

SPARCL: Ischemic and Hemorrhagic Stroke Post hoc Analysis Placebo: Ischemic Atorvastatin: Ischemic Placebo: Hemorrhagic Atorvastatin: Hemorrhagic Fatal and Nonfatal Stroke 16 12 Ischemic: HR (95% CI = 0.79 (0.66, 0.95) Ischemic or Hemorrhagic Stroke (%) 8 In the SPARCL study, treatment with atorvastatin 80 mg per day resulted in a 16% reduction in the combined risk of fatal and nonfatal stroke in patients with a recent stroke (within 1 to 6 months) or TIA and no known coronary heart disease (11.2% vs 13.1% over 4.9 years; HR 0.84, 95% CI 0.71 to 0.99, p = 0.03). A post hoc analysis found the overall benefit of treatment included an increase in the numbers of patients having hemorrhagic stroke (n = 55 for active treatment vs n = 33 for placebo; unadjusted HR 1.68, 95% CI 1.09 to 2.59) with no difference in the incidence of fatal hemorrhagic stroke between the groups (17 in the atorvastatin and 18 in the placebo group). Goldstein LB, Amarenco P, Szarek M, et al; on behalf of the SPARCL investigators. Hemorrhagic stroke in the Stroke Prevention by Aggressive Reduction in Cholesterol Levels study. Neurology. 2008;70:2364–2370. 4 Hemorrhagic: HR (95% CI = 1.68 (1.09, 2.59) 1 2 3 4 5 6 Unadjusted HR Years Since Randomization Goldstein LB et al. Neurology. 2008 ;70:2364-2370.

SPARCL: Multivariable Cox Regression Model Baseline Characteristics Risk of hemorrhage OR (95% CI) p Atorvastatin treatment 1.68 (1.09, 2.59) 0.02 Hemorrhage as entry event 5.65 (2.82, 11.30) <0.001 Male sex 1.79 (1.13, 2.84) 0.01 Age (10 yr increments) 1.42 (1.16, 1.74) 0.001 History of Htn 1.41 (0.88, 2.25) 0.15 In a post hoc exploratory analysis, Cox multivariable regression analysis was done to identify predictors of hemorrhagic stroke. The analysis of baseline variables significant in the univariable analysis showed that having a hemorrhagic stroke as the entry event (HR 5.65, 95% CI 2.82 to 11.30, p < 0.001), male sex (HR 1.79, 95% CI 1.13 to 2.84, p = 0.01), atorvastatin treatment (HR 1.68, 95% CI 1.09 to 2.59, p = 0.02), age (10 year increments, HR 1.42, 95% CI 1.16 to 1.74, p = 0.001), but no history of hypertension (HR 1.41, 95% CI 0.88 to 2.25, p = 0.15) were independently associated with the risk of hemorrhagic stroke. These baseline clinical factors apart from randomization to treatment with atorvastatin explained 86% of the increased risk of hemorrhagic stroke found in the model, with having a hemorrhagic stroke as the qualifying event associated with the most risk. Although a history of hypertension was not significant in this model, another analysis that accounted for blood pressure level recorded at the last assessment prior to stroke found that stage 2 hypertension was a significant predictor for hemorrhagic stroke. Goldstein LB er al. Neurology. 2008;70:2364-2370.