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www.RxFiles.ca – April 2003
RxFiles – Q&A Supplement
An Overview of ASCOT-LLA 1,7 - Atorvastatin in Primary Prevention
ASCOT-LLA Trial Overview
♦
a multi-center randomized placebo-controlled trial to determine effects of atorvastatin on ‘non-fatal MI and fatal CHD’
in high risk (eg. diabetes 24%), hypertensive patients without previous heart disease and a total cholesterol ≤6.5 mmol/l
♦
two treatment arms: M atorvastatin (LIPITOR) 10mg daily plus antihypertensive medications (n=5,168)
M placebo plus antihypertensive medications (n=5,137)
♦
10,305 patients with the following characteristics:
- hypertension (mean BP 164.2/95 mmHg)
- total cholesterol (mean 5.5mmol/l→4.2 mmol/L), LDL (mean 3.4mmol/l→ 2.3mmol/l)
- risk factors: hypertension plus ≥3 additional CHD risk factors (Average 3.7 additional risk factors/patient)
(age ≥ 55 84%, male 81%, microalbuminuria/proteinuria 62%, smoking 33%, family history of CHD 26%, type 2 diabetes 24%,
TC/HDL ≥6 14%, other ECG abnormalities 14%, LVH 14%, previous stroke/TIA 10% or peripheral artery disease 5%).
age 40-79 (mean 63 years); 81% male (evenly distributed)
♦
trial halted after 3.3 years due to morbidity benefits (e.g. significant reduction in ‘non-fatal MI & fatal CHD’ & stroke)
Table 1: ASCOT-LLA results (atorvastatin 10mg daily vs placebo)
Endpoints
1°° fatal CHD & non-fatal MI
2°°
total CVD events & procedures
2°°
total coronary events
2°°
non-fatal MI plus fatal CHD*
2°°
mortality-all cause
2°°
CVD mortality
2°°
fatal & non-fatal stroke
2°°
fatal & non-fatal heart failure
3°°
chronic stable angina
atorvastatin %
1.9
placebo %
3.0
(100 events)
(154 events)
7.5
3.4
1.7
3.6
1.4
1.7
0.8
0.6
9.5
4.8
2.7
4.1
1.6
2.4
0.7
1.1
ARR %
1.1
RRR %
36
NNT
91
p value
0.0005
2.0
1.4
1.0
0.5
0.2
0.7
0.5
21
29
37
12
13
29
45
50
72
100
NS
NS
143
200
0.0005
0.0005
0.0005
0.1649
0.5066
0.0236
0.5794
0.0135
* not including silent MI 1o=primary outcome 2o=secondary outcome 3o=tertiary outcome ARR=absolute risk reduction CHD=coronary heart disease
CVD=cardiovascular disease MI=myocardial infarction NS=not significant NNT=number needed to treat to benefit 1 patient RRR=relative risk reduction
Of Note:
♦ study did not provide risk/benefit data for higher atorvastatin doses or for more aggressive treatment to target
♦ short trial; lack data on long term effects; reduction in all-cause death did not reach statistical significance
♦ adverse event data lacking in the publication (1 case of non-fatal rhabdomyolysis in atorvastatin arm reported)
n=1942
♦ benefits only in men (no benefit seen in women
; rate of 1° outcome non-fatal MI & fatal CHD 1.9% atorvastatin vs 1.8% placebo p>0.7)
♦ lack of significant risk reduction in diabetes; may relate to study design; 14% of diabetes-placebo arm received a statin
(similar limitation seen in ALLHAT-LLT 2 trial with pravastatin 40mg daily where 26% of control group received a statin)
Comparison to WOSCOPS 3
♦ a primary prevention study of pravastatin 40mg od vs placebo in Scottish males age 45-64 with cholesterol ≥7 mmol/l
♦ both had relative reductions in the primary outcome of non-fatal MI and fatal CHD (RRR= ASCOT: 36% at 3.3yrs; WOSCOPS: 31% at 4.9yrs)
♦ both had favorable all-cause mortality trends (ASCOT 4.1% ð 3.6% at 3.3yrs; WOSCOPS 4.1% ð 3.2 % at 4.9 yrs)
♦ LDL reduction (ASCOT 3.4 mmol/l ð 2.3 mmol/l at 3.3yrs; WOSCOPS 5.0 mmol/l ð 4.1 mmol/l at 4.9 yrs)
What we knew and what these results add to that knowledge:
♦ 1o prevention: previous evidence supported benefit of statins (pravastatin 3 & lovastatin 4) in primary prevention of CHD in
o
moderate to high risk male patients with dyslipidemia. 1 & 2o prevention: in PROSPER 5, pravastatin 40mg daily reduced fatal
(age 70-82yrs)
with or at high risk of CVD; in HPS 6, simvastatin 40mg daily reduced
MI & non-fatal CHD in elderly male patients
(age 40-80yrs)
morbidity & mortality in male and female patients
with or at high risk of CVD.
♦ ASCOT-LLA supports the use of atorvastatin 10mg daily for primary prevention of CHD & stroke in hypertensive male
patients (especially >60years of age) with multiple risk factors for CHD and total cholesterol levels ≤6.5 mmol/L.
Magnitude of benefit was “one less fatal CHD event or non-fatal MI for every 91 patients treated over 3.3 years”;
additional reductions seen in other endpoints such as stroke.
References:
1) Peter S Sever, Björn Dahlöf et al. 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: 1149-58. Online April 2, 2003.
2) Major Outcomes in Moderately Hypercholesterolemic, Hypertensive Patients Randomized to Pravastatin vs Usual Care. The Antihypertensive and Lipid-Lowering Treatment to Prevent
Heart Attack Trial (ALLHAT-LLT). The ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. JAMA. 2002;288:2998-3007.
3) Shepherd J, Cobbe SM, Ford I et al. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia (WOSCOPS). N Engl J Med 1995;333:1383-9.
4) Downs JR, Clearfield M et al. Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels. Results of (AFCAPS/TexCAPS). JAMA 1998;279:1615-22.
5) Shepherd J, Blauw G et al. Pravastatin in elderly individuals at risk of vascular disease (PROSPER): a randomised controlled trial. Lancet 2002 Nov 23;360(9346):1623-30.
6) Heart Protection Study Group.MRC/BHF HPS study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet 2002 Jul 6;360(9326):7-22.
7) http://www.ascotstudy.co.uk
Prepared by: Brad Rath Pharmacy Student, Brent Jensen BSP, Loren Regier BSP BA
www.RxFiles.ca – ASCOT-LLA Overview – April 2003 – Page 2
S ta tin s
(th e o n ly g ro u p w ith a ll-c a u se m o rta lity e vid e n c e)
W h o b e n e fits m o s t?
D iffe re n ce s : E v id e n c e?
■
■
2 ° P r eve n tio n
S im v a sta tin 2 0 -4 0 m g /d
%
p
a
t
i
e
n
t
s
30
8.2
1 ° P r ev e n tio n
P ra v a sta tin 4 0 m g /d
Drug Tx
22.6
30
Placebo
15.9
20
20
11.5
5.5
4.1
10
N N T = 30
N N T = 12
4S-death
4S-CVevents
4 /1 0 /03
7.9
3.2
10
0
W atc h fo r to x ic ity :
h e p a tic /m y o p a th y .
D I’s ? P o t en c y ?
0
N N T = ?1 1 1
N N T = 42
WOSCOPS-death
WOSCOPS- CVevents
R x F iles-L ip id A g en ts-H ig h lig h ts
1
H PS
Lancet, July 2002
•No benefit for V itam ins E 600m g, C 250m g, or beta-carotene
•Evidence for sim vastatin 40m g in 2 O & very high risk 1 O
prevention in diabetes, stroke, age<80, w om en, LD L<3
•Questions rem aining: safety/efficacy of aggressive pursuit of
targets, com bination therapies, low-risk patients with ↑ LDL.
2°° & H igh-risk Prevention
(CH D ,PV D,Diabetes,H T N,M ale/F em ale,A ge40-80)
%
p
a
t
i
e
n
t
s
Sim vastatin 40m g/d
50
40
30
20
10
0
2 5 .4
1 2 .9 1 4 .6
1 9 .9
N N T =59
N N T =18
A ll-D e a th
M a jV a s c E v e nts
4/10/03
N N T =62
D rug T x
P la c e bo
6
4 .4
0 .8
S tro k e
0 .6
ALT > 3X ULN
R xFiles-Lipid A gents-Highlights
2
ASCOT Lancet, April 2003
•Trial provided evidence for primary prevention of CHD and
stroke in hypertensive male patients with multiple CHD risk factors
with total cholesterol ≤6.5mmol/L
•Questions remaining: women, adverse effects, long term effects,
safety and efficacy of titrating dose to attain targets, magnitude/$
% pts
1 o Prevention in high risk
(HTN, male/female, age 40-79, TC<6.5mmol/L)
Atorvastatin 10mg/d over average 3.3yrs
5
4
3
2
1
0
NNT=91
M I & C HD
4/10/03
3 .6
3
1.9
4.1
2 .4
1. 7
NNT=143
Stroke
NNT=NS
Drug Tx
Placebo
A ll-D e ath
RxFiles-Lipid Agents-Highlights
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