ascot trial

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;19:1139-1147 Sever PS, Dahlöf B, Poulter N, Wedel H et al, for the ASCOT Investigators. Lancet. 2003;361:1149-58

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;19:1139-1147

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;361:1149-58

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


Sample Size and Statistical Power (LLA)

Cholesterol reduction with statin 30%

Relative effect on end point of statin vs placebo 30%

Cumulative end point rate on placebo for 5 years 6.35%

Significance level 1 %

Power 90%

Total sample size 9000

Primary End Point: Nonfatal MI and Fatal CHD


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


ASCOT Study Design

Sever PS, et al, for the ASCOT Investigators. J Hypertens. 2001;19:1139-1147

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)

4000 TC >6.5 mmol/L (>250 mg/dL)

5000 TC 6.5 mmol/L (250

mg/dL)

R

500 open lipid lowering

4500

2250 statin

2250 placebo

2250 placebo

2250 statin

R

4500500

open lipid lowering

+

8000 open lipid lowering

18,000 patientsR = Randomized

Therapeutic Interventions and Targets (LLA)

Atorvastatin 10 mg vs placebo

No fixed lipid-lowering target


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

876876

13141314

10311031

22292229

48554855

Total = 10,305


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

Characteristic Atorvastatin (n=5168)

Baseline Characteristics

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

Placebo (n=5137)

*Mean ± SD


ASCOT LLA: Patient Population Risk Factor Profile

All patients in ASCOT have hypertension plus 3 risk factors for CHD

Patients with risk factor (%)


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


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 1st Oct 2002 4 alive before 1st Oct 2002 5 withdrew consent 7 lost to follow-up

212 dead with complete information

5137 placebo

4861 alive with complete information

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


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


Blood Pressure Changes

130

140

150

160

170

0 1 2 3

Atorvastatin 10 mg Placebo

75

80

85

90

95

100

0 1 2 3Years

SB

P (

mm

Hg

)D

BP

(m

m H

g)

Baseline 164/95Treated 138/80


Close-out

Close-out

Reductions in Total and LDL Cholesterol

2

4

6

0 1 2 3

Atorvastatin 10 mg Placebo

1

2

3

4

0 1 2 3

200

150

150

75

125

100

100

(mg

/dL

)(m

g/d

L)

To

tal c

ho

lest

ero

l (m

mo

l/L)

LD

L c

ho

lest

ero

l (m

mo

l/L)

Years

1.3 mmol/L 1.0 mmol/L

1.2 mmol/L 1.0 mmol/L


Close-out

0

1

2

3

4

0,0 0,5 1,0 1,5 2,0 2,5 3,0 3,5

Years

Cu

mu

lati

ve

Inc

ide

nc

e (

%)

36% reduction

Primary End Point: Nonfatal MI and Fatal CHD

HR = 0.64 (0.50-0.83)

Atorvastatin 10 mg Number of events 100

Placebo Number of events 154

p=0.0005


Secondary End Point: Fatal and Nonfatal Stroke

27% reduction

HR = 0.73 (0.56-0.96) p=0.0236



0

1

2

3

0,0 0,5 1,0 1,5 2,0 2,5 3,0 3,5

Years

Cu

mu

lati

ve In

cid

ence

(%

)


0

2

4

6

8

10

12

0,0 0,5 1,0 1,5 2,0 2,5 3,0 3,5

Years

Cu

mu

lati

ve

Inc

ide

nc

e (

%)

Secondary End Point: All CV Events and Procedures

21% reduction

HR= 0.79 (0.69-0.90) p=0.0005




0

1

2

3

4

5

6

0,0 0,5 1,0 1,5 2,0 2,5 3,0 3,5

Years

Cu

mu

lati

ve

Inc

ide

nc

e (

%)

HR=0.71 (0.59-0.86)

Secondary Endpoint: All Coronary Events

29% reduction

p=0.0005




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)

End Points

Area of squares is proportional to the amount of statistical information

0.5 1.0 1.5

Atorvastatin better Placebo better

Primary End PointsNonfatal MI (incl silent) + fatal CHD

Secondary End PointsTotal CV events and proceduresTotal coronary eventsNonfatal MI (excl silent) + fatal CHDAll-cause mortalityCardiovascular mortalityFatal and nonfatal strokeFatal and nonfatal heart failure

Tertiary End PointsSilent MIUnstable anginaChronic stable anginaPeripheral arterial diseaseDevelopment of diabetes mellitusDevelopment of renal impairment

Risk Ratio


Pre-specified Subgroups: Primary End Point

Area of squares is proportional to the amount of statistical information

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)

Hazard Ratio

DiabetesNondiabetesCurrent smokerNoncurrent smokerObeseNonobeseLVHNo LVHOlder (>60 years)Younger (≤60 years)FemaleMalePrevious vascular diseaseNo previous vascular diseaseRenal dysfunctionNo renal dysfunctionWith metabolic syndromeWithout metabolic syndrome

All patients

0.5 1.0 1.5

Atorvastatin better Placebo better

Risk Ratio


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)


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


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


ascot trial

Documents

ascot investigators

poulter n

dahlf b

ascot study designsever

targetsever ps

uksever ps

mgdlsever ps

dyslipidaemicsever ps