Rationale

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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. 2001191139-1147 Sever PS, Dahlöf B,
Poulter N, Wedel H et al, for the ASCOT
Investigators. Lancet. 20033611149-58
3
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. 2001191139-1147
4
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.
20033611149-58
5
Secondary and Tertiary End Points
Sever PS, Dahlöf B, Poulter N, Wedel H, et al,
for the ASCOT Investigators. Lancet.
20033611149-58
6
Sample Size and Statistical Power (LLA)
Primary End Point Nonfatal MI and Fatal CHD
Sever PS, Dahlöf B, Poulter N, Wedel H, et al,
for the ASCOT Investigators. Lancet.
20033611149-58
7
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)
• 40-79 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.
20033611149-58
8
ASCOT Study Design
R Randomized
18,000 patients
R
9000 ?-blocker diuretic
9000 CCB ACEI

5000 TC ?6.5 mmol/L (?250 mg/dL)
4000 TC gt6.5 mmol/L (gt250 mg/dL)
4000 TC gt6.5 mmol/L (gt250 mg/dL)
5000 TC ?6.5 mmol/L (?250 mg/dL)
500 open lipid lowering
4500
4500
500 open lipid lowering
R
R
2250 statin
2250 placebo
2250 placebo
2250 statin
8000 open lipid lowering
Sever PS, et al, for the ASCOT Investigators. J
Hypertens. 2001191139-1147
9
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.
20033611149-58
10
Recruitment February 1998 May 2000

• 718 centers, including 686 general practices
  in Denmark, Finland, Iceland, Norway, and Sweden
  and 32 regional centres in Ireland and the UK

Sever PS, Dahlöf B, Poulter N, Wedel H, et al,
for the ASCOT Investigators. Lancet.
20033611149-58
11
Baseline Characteristics
Atorvastatin (n5168)
Placebo (n5137)
Characteristic
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 8.5 81.1 94.6 164.2 17.7 95.0 10.3 5.5
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
63.2 8.6 81.3 94.7 164.2 18.0 95.0 10.3 5.5
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
Mean SD
Sever PS, Dahlöf B, Poulter N, Wedel H, et al,
for the ASCOT Investigators. Lancet.
20033611149-58
12
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.
20033611149-58
13
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.
20033611149-58
14
ASCOT LLA Patient Inclusion and Follow-Up Status
10,305 randomized in lipid-lowering arm
19,342 patients randomized to antihypertensive
treatment
5168 atorvastatin
5137 placebo
4928 alive with complete information
185 dead with complete information
212 dead with complete information
4861 alive with complete information
Incomplete information 39 alive after 1st
Oct 2002 4 alive before 1st Oct 2002 5
withdrew consent 7 lost to follow-up
Incomplete information 42 alive after 1st
Oct 2002 3 alive before 1st Oct 2002 9
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.
20033611149-58
15
ASCOT Statistical Methods

• Based on an Intention-to-Treat Analysis
• Time to first primary event
• Log-Rank Procedure and Coxs 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.
20033611149-58
16
Blood Pressure Changes
Baseline 164/95 Treated 138/80
SBP (mm Hg)
Close-out
DBP (mm Hg)
Close-out
Sever PS, Dahlöf B, Poulter N, Wedel H, et al,
for the ASCOT Investigators. Lancet.
20033611149-58
17
Reductions in Total and LDL Cholesterol
1.3 mmol/L
1.0 mmol/L
1.2 mmol/L
1.0 mmol/L
Close-out
Sever PS, Dahlöf B, Poulter N, Wedel H, et al,
for the ASCOT Investigators. Lancet.
20033611149-58
18
Primary End Point Nonfatal MI and Fatal CHD
Atorvastatin 10 mg Number of events 100 Placebo Nu
mber of events 154
36 reduction
HR 0.64 (0.50-0.83)
p0.0005
Sever PS, Dahlöf B, Poulter N, Wedel H, et al,
for the ASCOT Investigators. Lancet.
20033611149-58
19
Secondary End Point Fatal and Nonfatal Stroke
Atorvastatin 10 mg Number of events
89 Placebo Number of events 121
27 reduction
HR 0.73 (0.56-0.96)
p0.0236
Sever PS, Dahlöf B, Poulter N, Wedel H, et al,
for the ASCOT Investigators. Lancet.
20033611149-58
20
Secondary End Point All CV Events and Procedures
Atorvastatin 10 mg Number of events 389 Placebo Nu
mber of events 486
21 reduction
HR 0.79 (0.69-0.90)
p0.0005
Sever PS, Dahlöf B, Poulter N, Wedel H, et al,
for the ASCOT Investigators. Lancet.
20033611149-58
21
Secondary Endpoint All Coronary Events
Atorvastatin 10 mg Number of events 178 Placebo Nu
mber of events 247
29 reduction
HR0.71 (0.59-0.86)
p0.0005
Sever PS, Dahlöf B, Poulter N, Wedel H, et al,
for the ASCOT Investigators. Lancet.
20033611149-58
22
End Points
Hazard Ratio 0.64 (0.50-0.83) 0.79
(0.69-0.90) 0.71 (0.59-0.86) 0.62
(0.47-0.81) 0.87 (0.71-1.06) 0.90
(0.66-1.23) 0.73 (0.56-0.96) 1.13 (0.73-1.78)
0.82 (0.40-1.66) 0.87 (0.49-1.57) 0.59
(0.38-0.90) 1.02 (0.66-1.57) 1.15
(0.91-1.44) 1.29 (0.76-2.19)
Sever PS, Dahlöf B, Poulter N, Wedel H, et al,
for the ASCOT Investigators. Lancet.
20033611149-58
23
Pre-specified Subgroups Primary End Point
Hazard Ratio
0.84 (0.55-1.29) 0.56 (0.41-0.77) 0.56
(0.37-0.85) 0.70 (0.51-0.96) 0.59
(0.39-0.90) 0.67 (0.49-0.92) 0.67
(0.35-1.29) 0.64 (0.49-0.84) 0.64
(0.47-0.86) 0.66 (0.41-1.06) 1.10
(0.57-2.12) 0.59 (0.44-0.77) 0.80
(0.45-1.42) 0.61 (0.46-0.81) 0.61
(0.44-0.84) 0.70 (0.47-1.04) 0.77
(0.52-1.12) 0.56 (0.40-0.79) 0.64 (0.50-0.83)
Area of squares is proportional to the amount of
statistical information
Sever PS, Dahlöf B, Poulter N, Wedel H, et al,
for the ASCOT Investigators. Lancet.
20033611149-58
24
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.
20033611149-58
25
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.
20033611149-58
26
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.
20033611149-58