P Sever (Co-chair), B Dahlöf (Co-chair), N Poulter (Secretary), H Wedel (Statistician), G Beevers, M Caulfield, R Collins, SE Kjeldsen, A Kristinsson, J Mehlsen, G McInnes, M Nieminen, E O’Brien, J Östergren On behalf of the ASCOT Investigators

Rationale CHD incidence remains a major unresolved problem in BP management High prevalence of dyslipidaemia in hypertensive patients Combinations of risk factors synergistic for CHD No trial has specifically addressed benefits of lipid lowering in primary prevention of CHD in hypertensive patients not conventionally deemed dyslipidaemic Sever PS, et al, for the ASCOT Investigators. J Hypertens. 2001;19: Sever PS, Dahlöf B, Poulter N, Wedel H et al, for the ASCOT Investigators. Lancet. 2003;361:

Rationale The Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) is a multicentre, international trial, which involves 2 treatment comparisons in a factorial design –A prospective, randomized, open, blinded end point (PROBE) design comparing 2 antihypertensive regimens –A double-blind, placebo-controlled trial of a lipid-lowering agent in a subsample of those hypertensive patients studied (lipid-lowering arm [LLA]) Sever PS, et al, for the ASCOT Investigators. J Hypertens. 2001;19:

Lipid-Lowering Arm (LLA) Primary Objective To compare the effects on the combined outcome of nonfatal MI (including silent MI) and fatal CHD of atorvastatin 10 mg with those of placebo in hypertensive patients with TC levels of  6.5 mmol/L (  250 mg/dL) Sever PS, Dahlöf B, Poulter N, Wedel H, et al, for the ASCOT Investigators. Lancet. 2003;361:

Secondary and Tertiary End Points Secondary Primary outcome without silent MI All-cause mortality CV mortality Fatal + nonfatal stroke Fatal + nonfatal heart failure Total coronary end points All CV events and procedures Tertiary Silent MI Unstable angina Chronic stable angina Peripheral vascular disease Development of diabetes Development of renal impairment Major study end points in specific subpopulations Sever PS, Dahlöf B, Poulter N, Wedel H, et al, for the ASCOT Investigators. Lancet. 2003;361:

Sample Size and Statistical Power (LLA) Cholesterol reduction with statin30% Relative effect on end point of statin vs placebo30% Cumulative end point rate on placebo for 5 years6.35% Significance level1 % Power90% Total sample size 9000 Primary End Point: Nonfatal MI and Fatal CHD Sever PS, Dahlöf B, Poulter N, Wedel H, et al, for the ASCOT Investigators. Lancet. 2003;361:

Patient Population: LLA Eligibility criteria SBP  160 mm Hg and/or DBP  100 mm Hg (untreated) or SBP  140 mm Hg and/or DBP  90 mm Hg (treated) TC  6.5 mmol/L (250 mg/dL) and TGs  4.5 mmol/L (400 mg/dL) years of age 3+ CVD risk factors No history of CHD Sever PS, Dahlöf B, Poulter N, Wedel H, et al, for the ASCOT Investigators. Lancet. 2003;361:

ASCOT Study Design Sever PS, et al, for the ASCOT Investigators. J Hypertens. 2001;19: R 9000  -blocker ± diuretic 9000 CCB ± ACEI 5000 TC  6.5 mmol/L (  250 mg/dL) 4000 TC >6.5 mmol/L (>250 mg/dL) 5000 TC  6.5 mmol/L (  250 mg/dL) R 500 open lipid lowering statin 2250 placebo 2250 statin R open lipid lowering open lipid lowering 18,000 patients R = Randomized

Therapeutic Interventions and Targets (LLA) Atorvastatin 10 mg vs placebo No fixed lipid-lowering target Sever PS, Dahlöf B, Poulter N, Wedel H, et al, for the ASCOT Investigators. Lancet. 2003;361:

Recruitment: February 1998 – May centers, including 686 general practices in Denmark, Finland, Iceland, Norway, and Sweden and 32 regional centres in Ireland and the UK Total = 10,305 Sever PS, Dahlöf B, Poulter N, Wedel H, et al, for the ASCOT Investigators. Lancet. 2003;361:

Age* (years) Male (%) Caucasian (%) SBP* (mm Hg) DBP* (mm Hg) TC* (mmol/L [mg/dL]) LDL-C* (mmol/L [mg/dL]) TG* (mmol/L [mg/dL]) HDL-C* (mmol/L [mg/dL]) Number of risk factors* 63.1 ± ± ± ± 0.8 (213 ± 31) 3.4 ± 0.7 (131 ± 27) 1.7 ± 0.9 (150 ± 80) 1.3 ± 0.4 (50 ± 27) 3.7 ± 0.9 Characteristic Atorvastatin (n=5168) Baseline Characteristics 63.2 ± ± ± ± 0.8 (213 ± 31) 3.4 ± 0.7 (131 ± 27) 1.6 ± 0.9 (142 ± 80) 1.3 ± 0.4 (50 ± 27) 3.7 ± 0.9 Placebo (n=5137) *Mean ± SD Sever PS, Dahlöf B, Poulter N, Wedel H, et al, for the ASCOT Investigators. Lancet. 2003;361:

ASCOT LLA: Patient Population Risk Factor Profile All patients in ASCOT have hypertension plus  3 risk factors for CHD Patients with risk factor (%) Sever PS, Dahlöf B, Poulter N, Wedel H, et al, for the ASCOT Investigators. Lancet. 2003;361:

Lipid arm closure The DSMB in September 2002 reported that in the lipid arm of ASCOT there was a highly significant reduction in the primary end point as well as a significant reduction in stroke The DSMB recommended that the double-blind cholesterol lowering study treatment arm be terminated since the results were outside of the stopping rules of the trial The Steering Committee endorsed the recommendation of the DSMB, and the lipid arm was closed after a median follow-up period of 3.3 years Sever PS, Dahlöf B, Poulter N, Wedel H, et al, for the ASCOT Investigators. Lancet. 2003;361:

ASCOT LLA: Patient Inclusion and Follow-Up Status 19,342 patients randomized to antihypertensive treatment 10,305 randomized in lipid-lowering arm 5168 atorvastatin 4928 alive with complete information 185 dead with complete information Incomplete information: 39 alive after 1 st Oct alive before 1 st Oct withdrew consent 7 lost to follow-up 212 dead with complete information 5137 placebo 4861 alive with complete information Incomplete information: 42 alive after 1 st Oct alive before 1 st Oct withdrew consent 10 lost to follow-up Complete information obtained on 98.8% of patients Sever PS, Dahlöf B, Poulter N, Wedel H, et al, for the ASCOT Investigators. Lancet. 2003;361:

ASCOT Statistical Methods Based on an Intention-to-Treat Analysis Time to first primary event Log-Rank Procedure and Cox’s Proportional Hazards were used to calculate confidence intervals Cumulative Incidence Curves generated by using the Kaplan-Meier method Sever PS, Dahlöf B, Poulter N, Wedel H, et al, for the ASCOT Investigators. Lancet. 2003;361:

Blood Pressure Changes SBP (mm Hg) DBP (mm Hg) Baseline164/95 Treated138/80 Sever PS, Dahlöf B, Poulter N, Wedel H, et al, for the ASCOT Investigators. Lancet. 2003;361: Close-out

Reductions in Total and LDL Cholesterol (mg/dL) Total cholesterol (mmol/L) LDL cholesterol (mmol/L) Years 1.3 mmol/L 1.0 mmol/L 1.2 mmol/L 1.0 mmol/L Sever PS, Dahlöf B, Poulter N, Wedel H, et al, for the ASCOT Investigators. Lancet. 2003;361: Close-out

36% reduction Primary End Point: Nonfatal MI and Fatal CHD HR = 0.64 ( ) Atorvastatin 10 mgNumber of events100 PlaceboNumber of events 154 p= Sever PS, Dahlöf B, Poulter N, Wedel H, et al, for the ASCOT Investigators. Lancet. 2003;361:

Secondary End Point: Fatal and Nonfatal Stroke 27% reduction HR = 0.73 ( )p= Atorvastatin 10 mgNumber of events 89 PlaceboNumber of events121 Sever PS, Dahlöf B, Poulter N, Wedel H, et al, for the ASCOT Investigators. Lancet. 2003;361:

Secondary End Point: All CV Events and Procedures 21% reduction HR= 0.79 ( )p= Atorvastatin 10 mgNumber of events389 PlaceboNumber of events 486 Sever PS, Dahlöf B, Poulter N, Wedel H, et al, for the ASCOT Investigators. Lancet. 2003;361:

HR=0.71 ( ) Secondary Endpoint: All Coronary Events 29% reduction p= Atorvastatin 10 mgNumber of events178 PlaceboNumber of events 247 Sever PS, Dahlöf B, Poulter N, Wedel H, et al, for the ASCOT Investigators. Lancet. 2003;361:

Hazard Ratio 0.64 ( ) 0.79 ( ) 0.71 ( ) 0.62 ( ) 0.87 ( ) 0.90 ( ) 0.73 ( ) 1.13 ( ) 0.82 ( ) 0.87 ( ) 0.59 ( ) 1.02 ( ) 1.15 ( ) 1.29 ( ) End Points Area of squares is proportional to the amount of statistical information Atorvastatin betterPlacebo better Primary End Points Nonfatal MI (incl silent) + fatal CHD Secondary End Points Total CV events and procedures Total coronary events Nonfatal MI (excl silent) + fatal CHD All-cause mortality Cardiovascular mortality Fatal and nonfatal stroke Fatal and nonfatal heart failure Tertiary End Points Silent MI Unstable angina Chronic stable angina Peripheral arterial disease Development of diabetes mellitus Development of renal impairment Risk Ratio Sever PS, Dahlöf B, Poulter N, Wedel H, et al, for the ASCOT Investigators. Lancet. 2003;361:

Pre-specified Subgroups: Primary End Point Area of squares is proportional to the amount of statistical information 0.84 ( ) 0.56 ( ) 0.56 ( ) 0.70 ( ) 0.59 ( ) 0.67 ( ) 0.67 ( ) 0.64 ( ) 0.64 ( ) 0.66 ( ) 1.10 ( ) 0.59 ( ) 0.80 ( ) 0.61 ( ) 0.61 ( ) 0.70 ( ) 0.77 ( ) 0.56 ( ) 0.64 ( ) Hazard Ratio Sever PS, Dahlöf B, Poulter N, Wedel H, et al, for the ASCOT Investigators. Lancet. 2003;361:

Safety Evaluations Numbers of non-CV deaths were similar (111 atorvastatin, 130 placebo) No significant difference between atorvastatin and placebo in: –Incidence of fatal cancers –Incidence of serious adverse events –Incidence of liver enzyme abnormalities 1 nonfatal case of rhabdomyolysis in a patient receiving atorvastatin (causation confounded by alcohol abuse and recent febrile illness) Sever PS, Dahlöf B, Poulter N, Wedel H, et al, for the ASCOT Investigators. Lancet. 2003;361:

Summary and Conclusions In hypertensive patients at modest risk of CHD, atorvastatin is associated with a highly significant reduction in the primary end point of CHD, together with significant reductions in the secondary end points of stroke, all cardiovascular events and procedures, and total coronary events These reductions in major cardiovascular events are large given the short follow-up time and occurred earlier than in many other statin trials There was no significant heterogeneity among pre-specified subgroups Sever PS, Dahlöf B, Poulter N, Wedel H, et al, for the ASCOT Investigators. Lancet. 2003;361:

Summary and Conclusions (continued) Risk reductions in CHD events were unrelated to baseline cholesterol levels and were consistent across the whole range of cholesterol Were the trial to have continue to its planned duration of 5 years, it is estimated that atorvastatin would have reduced CHD incidence by approximately 50% Benefits occurred in the absence of any increased risk of non-cardiovascular disease, including fatal cancer These findings have implications for future lipid- lowering guidelines, particularly with reference to hypertensive patients Sever PS, Dahlöf B, Poulter N, Wedel H, et al, for the ASCOT Investigators. Lancet. 2003;361: