(Circulation. 2001;103:387.)
© 2001 American Heart Association, Inc.
Clinical Investigation and Reports |
From the Wake Forest University School of Medicine (R.P.B.), Winston-Salem, NC; University of Texas School of Public Health (B.R.D.), Houston; St Francis Hospital (J.F.P.), Roslyn, NY; Green Lane Hospital (H.D.W.), Auckland, New Zealand; Therapeutic Goods Administration (J.B.), Canberra, Australia; and University of Glasgow (S.M.C., J.S.), Glasgow, Scotland.
Correspondence to Robert P. Byington, PhD, Department of Public Health Sciences, Wake Forest University School of Medicine, Winston-Salem, NC 27157-1063. E-mail bbyingto{at}wfubmc.edu
| Abstract |
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Methods and ResultsThe
effect of pravastatin 40 mg/d on stroke events was investigated in a
prospectively defined pooled analysis of 3 large, placebo-controlled,
randomized trials that included 19 768 patients with 102 559
person-years of follow-up. In all, 598 participants had a stroke during
5 years of follow-up. The 2 secondary prevention trials (CARE
[Cholesterol And Recurrent Events] and LIPID [Long-term Intervention
with Pravastatin in Ischemic Disease]) individually demonstrated
reductions in nonfatal and total stroke rates. When the 13 173
patients from CARE and LIPID were combined, there was a 22% reduction
in total strokes (95% CI 7% to 35%,
P=0.01) and a 25% reduction in
nonfatal stroke (95% CI 10% to 38%). The beneficial effect of
pravastatin on total stroke was observed across a wide range of patient
characteristics. WOSCOPS (West of Scotland Coronary Prevention Study, a
primary prevention trial in hypercholesterolemic men) exhibited a
similar, although smaller, trend for a reduction in total stroke. Among
the CARE/LIPID participants, pravastatin was associated with a 23%
reduction in nonhemorrhagic strokes (95% CI 6% to 37%), but there
was no statistical treatment group difference in hemorrhagic or unknown
type.
ConclusionsPravastatin reduced the risk of stroke over a wide range of lipid values among patients with documented coronary disease. This effect was due to a reduction in nonfatal nonhemorrhagic strokes.
Key Words: lipids prevention stroke trials
| Introduction |
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Numerous studies have demonstrated that the risk of coronary heart disease events is reduced by lipid-lowering therapy.4 5 6 7 8 The effect of lipid lowering on stroke events is less well established: meta-analyses of the early clinical trials with older lipid-lowering agents have suggested that modest reductions in cholesterol did not reduce stroke.9 10 However, the introduction of the HMG-CoA reductase inhibitors (or "statins") raised the expectation that these agents might demonstrate a beneficial effect on stroke.
This report presents the results of a pooled analysis of stroke data from 3 recently completed event trials that used a specific statin, pravastatin. The Prospective Pravastatin Pooling (PPP) Project included data from WOSCOPS (West Of Scotland Coronary Prevention Study), the CARE (Cholesterol And Recurrent Events) trial, and the LIPID (Long-term Intervention with Pravastatin in Ischemic Disease) trial. Individual patient data from the 3 trials were pooled into a single database to provide increased power overall and for subgroup analyses. The larger sample size also permits analyses by stroke subtype.
| Methods |
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Strokes in WOSCOPS were monitored with national computerized record linking,6 reviewed by an adverse events committee, and defined as episodes of motor paralysis, sensory or speech dysfunction, diplopia, or visual disturbance lasting >1 hour. CARE and LIPID used an end points committee to predefine and blindly classify strokes. Stroke was defined as a new acute disturbance of focal neurological or monocular function that resulted in either death or signs and/or symptoms of presumed vascular origin.14 15 Strokes for CARE and LIPID were categorized in the pooled database as hemorrhagic, nonhemorrhagic, and unknown.
Following the PPP protocol, the specific objectives for the analyses presented here were to determine the effect of pravastatin on the rate of total stroke both for the 3 trials combined and for the combination of CARE and LIPID. Analyses of time to first event were performed using log-rank statistics and proportional hazards models.16 In the pooled analyses, tests were stratified by trial. The absolute event rates presented in the tables used the mean follow-up as the unit of time. Interactions between treatment and baseline characteristics were explored in stratified analyses and proportional hazard models. Simple tests of proportions and means were conducted to evaluate treatment group differences in baseline characteristics. All analyses followed the intention-to-treat principle. Hazard ratios and 95% CIs are presented as indications of relative effect sizes.
| Results |
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The effects of pravastatin on all stroke events occurring
during the entire follow-up period are presented in
Table 2
. Overall, 598 of the participants had a fatal or
nonfatal stroke during follow-up. More than half of these were from
LIPID, although LIPID and CARE had similar placebo group event rates
(8.0 and 7.6 strokes · 1000
patients-1 · y-1,
respectively). WOSCOPS had the fewest strokes and the lowest rate of
strokes. Each trial individually demonstrated a reduction in total
stroke, although the CI for the WOSCOPS hazard ratio was large and
crossed 1.00
(Table 2
, top). CARE had a 32% reduction (4% to 52%
reduction) and LIPID had an 18% reduction (0% to 33% reduction).
Combining all 3 trials resulted in a 20% reduction in total stroke
with pravastatin (7% to 32% reduction,
P=0.01). This difference in
total strokes was maintained if WOSCOPS was removed from the
calculations: CARE and LIPID combined had a 22% reduction (7% to 35%
reduction, P=0.01). In the
combined CARE/LIPID database, it was estimated that 588 patients would
have to be treated per year to avert 1 stroke event; in WOSCOPS, 3333
patients would have to be treated.
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About 90% of the strokes were nonfatal
(Table 2
, middle), and there was an overall 24% reduction
in nonfatal stroke attributable to pravastatin. This treatment benefit
on nonfatal strokes was maintained when only the 2 secondary prevention
trials are combined. Less than 10% of the strokes reported in the
trials were fatal
(Table 2
, bottom).
Figure 1
presents the cumulative fatal/nonfatal stroke
curves. There was no statistical evidence that the proportional hazards
assumption was violated. Event rates in the primary prevention trial
(WOSCOPS) were consistently lower, with no clear overall benefit
attributable to pravastatin. Among the 2 secondary prevention trials
(CARE and LIPID), the stroke rates were generally consistent, both in
terms of the long-term absolute risks of stroke and the benefit
attributable to pravastatin.
Figure 2
presents the cumulative treatment-specific stroke
curves for the combined CARE and LIPID population, in which it is noted
that the curves diverge after 1 year of treatment.
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The effect of pravastatin on total stroke was examined in
various baseline subgroups in the combined CARE/LIPID group. The
beneficial effect of pravastatin in reducing strokes was evident and
consistent across subgroups
(Figure 3
). There was no evidence of a statistical
interaction (at P<0.05)
between any baseline characteristic and treatment group
assignment.
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The rates of hemorrhagic and nonhemorrhagic stroke from
CARE/LIPID are presented in
Table 3
. Seventy percent of all stroke events were nonfatal
nonhemorrhagic strokes. Pravastatin was associated with a 23%
reduction in total nonhemorrhagic stroke (6% to 37% reduction),
primarily a function of its effect on nonfatal nonhemorrhagic strokes
(24% reduction). There is no evidence that pravastatin had an effect
on hemorrhagic strokes.
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| Discussion |
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However, this doubt began to evaporate with the publication of the results of the secondary prevention statin trials.18 19 20 21 For example, the Scandinavian Simvastatin Survival Study reported in 1995 the post hoc finding that there was a 30% reduction in any cerebrovascular event attributable to simvastatin.22 In another post hoc analysis that same year, a pooled analysis of 4 regression trials conducted primarily in coronary patients reported a 62% lower rate of total stroke attributable to pravastatin (P=0.054).4 Subsequently, and with stroke as a prespecified outcome, CARE and LIPID individually reported fewer strokes among patients assigned to pravastatin therapy compared with placebo.7 8 CARE and LIPID remain the only trials to publish the results of prospectively defined stroke end points. Supporting these findings were the results from the B-mode ultrasound regression trials that documented the effectiveness of pravastatin in slowing and/or reversing carotid atherosclerosis.23 24 25
The analyses presented here clearly demonstrate that pravastatin is more effective than the older, nonstatin lipid-lowering therapies in reducing stroke rates. The consistent reductions across the trials and subgroups are striking. Attention is drawn to the beneficial effect of pravastatin among patients on aspirin and on or not on blood pressurelowering medications. It is also noted that the 22% reduction in relative risk and the 1.7 · 1000 patients-1 · y-1 reduction in absolute risk in CARE/LIPID are comparable to those reported for stroke with antiplatelet therapies given to post-MI patients.26
In observational studies, higher lipid levels have been associated with higher rates of nonhemorrhagic stroke and lower lipid levels associated with higher rates of hemorrhagic stroke.27 28 Therefore, analyses should be stratified by type of stroke. Moreover, an overall benefit is more likely to be observed in populations in which nonhemorrhagic strokes greatly outnumber hemorrhagic strokes. It has also been estimated from observational studies that hemorrhagic stroke rates may increase if the LDL cholesterol levels are <70 mg/dL (<1.8 mmol/L),21 a level not usually attained with a 40 mg/d dosage of pravastatin. Therefore, the observed PPP results would be expected: the primary effect of pravastatin were to reduce nonhemorrhagic strokes.
The PPP analyses demonstrate that the long-term use of
pravastatin is associated with a reduction in total stroke incidence in
the setting of secondary prevention and across a wide range of patient
characteristics. This benefit is seen as a reduction in nonfatal
nonhemorrhagic strokes. There is a suggestion in these data that this
benefit occurs after
1 year of
therapy.
| Appendix 1 |
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| Acknowledgments |
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| Footnotes |
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Dr Shepherd serves as a consultant to Bristol-Myers Squibb. Dr Byington has an ad hoc consultancy arrangement with Bristol-Myers Squibb.
1 A complete list of the Prospective Pravastatin Pooling Project Investigators is given in the Appendix. ![]()
Received June 6, 2000; revision received August 15, 2000; accepted September 8, 2000.
| References |
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