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Reduction of Stroke Events With Pravastatin
The Prospective Pravastatin Pooling (PPP) Project
Robert P. Byington, PhD; Barry R. Davis, MD, PhD; Jonathan F. Plehn, MD; Harvey D. White, DSc; Jennifer Baker, MSc, MB; Stuart M. Cobbe, MD; James Shepherd, MD; for the PPP Investigators* Background—Stroke is a leading cause of death and disability. Although clinical trials of the early lipid-lowering therapies
did not demonstrate a reduction in the rates of stroke, data from recently completed statin trials strongly suggest benefit.
Methods and Results—The 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 559person-years of follow-up. In all, 598 participants had a stroke during Ϸ5 years of follow-up. The 2 secondaryprevention trials (CARE [Cholesterol And Recurrent Events] and LIPID [Long-term Intervention with Pravastatin inIschemic Disease]) individually demonstrated reductions in nonfatal and total stroke rates. When the 13 173 patientsfrom CARE and LIPID were combined, there was a 22% reduction in total strokes (95% CI 7% to 35%, Pϭ0.01) anda 25% reduction in nonfatal stroke (95% CI 10% to 38%). The beneficial effect of pravastatin on total stroke wasobserved across a wide range of patient characteristics. WOSCOPS (West of Scotland Coronary Prevention Study, aprimary prevention trial in hypercholesterolemic men) exhibited a similar, although smaller, trend for a reduction in totalstroke. Among the CARE/LIPID participants, pravastatin was associated with a 23% reduction in nonhemorrhagicstrokes (95% CI 6% to 37%), but there was no statistical treatment group difference in hemorrhagic or unknown type.
Conclusions—Pravastatin 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. (Circulation. 2001;103:387-392.)
Key Words: lipids Ⅲ prevention Ⅲ stroke Ⅲ trials
Cerebrovascular disease is the second leading cause of This report presents the results of a pooled analysis of death in the Americas and Europe, accounting for 10% stroke data from 3 recently completed event trials that used a and 14% of all deaths in these regions,1 and is the leading specific statin, pravastatin. The Prospective Pravastatin Pool- cause of death among the Western Pacific countries, account- ing (PPP) Project included data from WOSCOPS (West Of ing for 14% of all deaths.1 In the United States, strokes killed Scotland Coronary Prevention Study), the CARE (Cholester- almost 160 000 persons in 1997 and ranked third as cause of ol And Recurrent Events) trial, and the LIPID (Long-term death after heart disease and cancer.2 Approximately 600 000 Intervention with Pravastatin in Ischemic Disease) trial.
persons have a stroke each year in the United States.3 It is a Individual patient data from the 3 trials were pooled into a leading cause of disability and increased healthcare costs.3 single database to provide increased power overall and for subgroup analyses. The larger sample size also permitsanalyses by stroke subtype.
Numerous studies have demonstrated that the risk of coronary heart disease events is reduced by lipid-loweringtherapy.4–8 The effect of lipid lowering on stroke events is less well established: meta-analyses of the early clinical trials The PPP Project was initiated in 1992 before completion of any of with older lipid-lowering agents have suggested that modest the constituent trials. The design and rationale for the project havebeen previously described,11 as have been the primary results of the reductions in cholesterol did not reduce stroke.9,10 However, 3 constituent trials6–8 and the pooled mortality and coronary event the introduction of the HMG-CoA reductase inhibitors (or subgroup results.12,13 Each of the 3 studies was a randomized, “statins”) raised the expectation that these agents might double-masked, placebo-controlled trial of 40 mg/d pravastatin.
demonstrate a beneficial effect on stroke.
WOSCOPS, conducted in Scotland, was a primary prevention trial Received June 6, 2000; revision received August 15, 2000; accepted September 8, 2000.
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.
Guest Editor for this article was Paul M. Ridker, MD, MPH, Brigham and Women’s Hospital, Boston, Mass.
Dr Shepherd serves as a consultant to Bristol-Myers Squibb. Dr Byington has an ad hoc consultancy arrangement with Bristol-Myers Squibb.
*A complete list of the Prospective Pravastatin Pooling Project Investigators is given in the Appendix.
Correspondence to Robert P. Byington, PhD, Department of Public Health Sciences, Wake Forest University School of Medicine, Winston-Salem, NC 2001 American Heart Association, Inc.
Circulation is available at http://www.circulationaha.org
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Baseline Descriptions
BP indicates blood pressure; LDL-C, LDL cholesterol; HDL-C, HDL cholesterol; NA, not available.
*Includes ␤-blockers, calcium channel blockers, ACE inhibitors, and diuretics.
that evaluated the effectiveness of pravastatin in the prevention of CARE and LIPID were categorized in the pooled database as fatal and nonfatal coronary events in 6595 men aged 45 to 64 years hemorrhagic, nonhemorrhagic, and unknown.
with hyperlipidemia and no history of myocardial infarction (MI).6 Following the PPP protocol, the specific objectives for the WOSCOPS patients were followed for a mean of 4.8 years. CARE, analyses presented here were to determine the effect of pravastatin conducted in the United States and Canada, was a secondary on the rate of total stroke both for the 3 trials combined and for the prevention trial that evaluated the effectiveness of pravastatin in the combination of CARE and LIPID. Analyses of time to first event prevention of fatal and nonfatal coronary events in 4159 men and were performed using log-rank statistics and proportional hazards women aged 21 to 75 years with average lipid levels and an MI 3 to models.16 In the pooled analyses, tests were stratified by trial. The 20 months before randomization.7 CARE patients were followed for absolute event rates presented in the tables used the mean follow-up a mean of 4.8 years. LIPID, conducted in Australia and New as the unit of time. Interactions between treatment and baseline Zealand, was also a secondary prevention trial. It evaluated the characteristics were explored in stratified analyses and proportional effectiveness of pravastatin in the prevention of coronary deaths in hazard models. Simple tests of proportions and means were con- 9014 men and women aged 31 to 75 years with a history of MI or ducted to evaluate treatment group differences in baseline character- unstable angina and a wider lipid range than CARE.8 LIPID patients istics. All analyses followed the intention-to-treat principle. Hazard were followed for a mean of 6.1 years.
ratios and 95% CIs are presented as indications of relative effect Strokes in WOSCOPS were monitored with national computer- ized record linking,6 reviewed by an adverse events committee, anddefined as episodes of motor paralysis, sensory or speech dysfunc- tion, diplopia, or visual disturbance lasting Ͼ1 hour. CARE and The baseline descriptions of the 3 trials and the treatment LIPID used an end points committee to predefine and blindly classify group comparisons are presented in Table 1. Collectively, strokes. Stroke was defined as a new acute disturbance of focalneurological or monocular function that resulted in either death or there were 19 768 patients in the PPP database with 102 559 signs and/or symptoms of presumed vascular origin.14,15 Strokes for Byington et al
Pravastatin and Stroke
389
Effect of Pravastatin on Stroke Events
*From proportional hazards model.
†From log-rank model, reported only for “total stroke.” The effects of pravastatin on all stroke events occurring no clear overall benefit attributable to pravastatin. Among the during the entire follow-up period are presented in Table 2.
2 secondary prevention trials (CARE and LIPID), the stroke Overall, 598 of the participants had a fatal or nonfatal stroke rates were generally consistent, both in terms of the long-term during follow-up. More than half of these were from LIPID, absolute risks of stroke and the benefit attributable to prava- although LIPID and CARE had similar placebo group event statin. Figure 2 presents the cumulative treatment-specific rates (8.0 and 7.6 strokes ⅐ 1000 patientsϪ1 ⅐ yϪ1, respectively).
stroke curves for the combined CARE and LIPID population, WOSCOPS had the fewest strokes and the lowest rate of in which it is noted that the curves diverge after 1 year of strokes. Each trial individually demonstrated a reduction in total stroke, although the CI for the WOSCOPS hazard ratio The effect of pravastatin on total stroke was examined in was large and crossed 1.00 (Table 2, top). CARE had a 32% various baseline subgroups in the combined CARE/LIPID reduction (4% to 52% reduction) and LIPID had an 18% group. The beneficial effect of pravastatin in reducing strokes reduction (0% to 33% reduction). Combining all 3 trials was evident and consistent across subgroups (Figure 3).
resulted in a 20% reduction in total stroke with pravastatin There was no evidence of a statistical interaction (at PϽ0.05) (7% to 32% reduction, Pϭ0.01). This difference in totalstrokes was maintained if WOSCOPS was removed from thecalculations: CARE and LIPID combined had a 22% reduc-tion (7% to 35% reduction, Pϭ0.01). In the combinedCARE/LIPID database, it was estimated that 588 patientswould have to be treated per year to avert 1 stroke event; inWOSCOPS, 3333 patients would have to be treated.
About 90% of the strokes were nonfatal (Table 2, middle), and there was an overall 24% reduction in nonfatal strokeattributable to pravastatin. This treatment benefit on nonfatalstrokes was maintained when only the 2 secondary preventiontrials are combined. Less than 10% of the strokes reported inthe trials were fatal (Table 2, bottom).
Figure 1 presents the cumulative fatal/nonfatal stroke curves. There was no statistical evidence that the proportionalhazards assumption was violated. Event rates in the primary Figure 1. Occurrence of any stroke (fatal or nonfatal) by clinical
prevention trial (WOSCOPS) were consistently lower, with 390
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orrhagic stroke (6% to 37% reduction), primarily a functionof its effect on nonfatal nonhemorrhagic strokes (24% reduc-tion). There is no evidence that pravastatin had an effect onhemorrhagic strokes.
Discussion
For decades, there had been considerable doubt regarding thevalue of lipid lowering in stroke prevention. This was becausetotal stroke incidence (in which hemorrhagic and nonhemor-rhagic strokes were combined together) had only been weaklyassociated, if at all, with increased cholesterol levels inobservational studies17 and because of the observed lack ofbenefit of lipid lowering on stroke incidence in the earlycholesterol-lowering trials.9,10 Even as late as 1995, a meta- Figure 2. Occurrence of any stroke (fatal or nonfatal) by treat-
analysis of cholesterol-lowering trials (none of which used a ment assignment (CARE and LIPID combined).
statin) reported that patients assigned to cholesterol loweringexperienced no reduction in total stroke.10 In that report, between any baseline characteristic and treatment group summarizing the stroke results from 11 randomized trials of lipid lowering, the relative risk for total fatal/nonfatal stroke The rates of hemorrhagic and nonhemorrhagic stroke from in participants assigned to treatment compared with controls CARE/LIPID are presented in Table 3. Seventy percent of all stroke events were nonfatal nonhemorrhagic strokes. Prava- However, this doubt began to evaporate with the publica- statin was associated with a 23% reduction in total nonhem- tion of the results of the secondary prevention statin tri-als.18–21 For example, the Scandinavian Simvastatin SurvivalStudy reported in 1995 the post hoc finding that there was a30% reduction in any cerebrovascular event attributable tosimvastatin.22 In another post hoc analysis that same year, apooled analysis of 4 regression trials conducted primarily incoronary patients reported a 62% lower rate of total strokeattributable to pravastatin (Pϭ0.054).4 Subsequently, andwith stroke as a prespecified outcome, CARE and LIPIDindividually reported fewer strokes among patients assignedto pravastatin therapy compared with placebo.7,8 CARE andLIPID remain the only trials to publish the results ofprospectively defined stroke end points. Supporting thesefindings were the results from the B-mode ultrasound regres-sion trials that documented the effectiveness of pravastatin inslowing and/or reversing carotid atherosclerosis.23–25 The analyses presented here clearly demonstrate that prav- astatin is more effective than the older, nonstatin lipid-lowering therapies in reducing stroke rates. The consistentreductions across the trials and subgroups are striking. Atten-tion is drawn to the beneficial effect of pravastatin amongpatients on aspirin and on or not on blood pressure–loweringmedications. It is also noted that the 22% reduction in relativerisk and the 1.7 ⅐ 1000 patientsϪ1 ⅐ yϪ1 reduction in absoluterisk in CARE/LIPID are comparable to those reported forstroke with antiplatelet therapies given to post-MI patients.26 In observational studies, higher lipid levels have been associated with higher rates of nonhemorrhagic stroke andlower lipid levels associated with higher rates of hemorrhagic Figure 3. Effect of pravastatin on total stroke (fatal or nonfatal)
stroke.27,28 Therefore, analyses should be stratified by type of according to baseline characteristic (95% CIs around hazard stroke. Moreover, an overall benefit is more likely to be ratios: CARE/LIPID only). Cholesterol, 214.5 mg/dLϭ5.5 mmol/L; observed in populations in which nonhemorrhagic strokes LDL cholesterol (LDL-c), 144.4 mg/dLϭ3.7 mmol/L; HDL choles-terol (HDL-c), 36.2 mg/dLϭ0.9 mmol/L; and triglycerides, 141.5 greatly outnumber hemorrhagic strokes. It has also been mg/dLϭ1.6 mmol/L. Vertical bar indicates hazard ratio point estimated from observational studies that hemorrhagic stroke estimate. DBP indicates diastolic blood pressure; SBP, systolic rates may increase if the LDL cholesterol levels are Ͻ70 blood pressure; BMI, body mass index; Hx, history of; HTN, hypertension; BP, blood pressure; Med, medication; and ASA, Ͻ1.8 mmol/L),21 a level not usually attained with a 40 mg/d dosage of pravastatin. Therefore, the observed PPP Byington et al
Pravastatin and Stroke
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Effect of Pravastatin on Stroke Type
Data are available for only CARE and LIPID.
*From proportional hazards model.
results would be expected: the primary effect of pravastatin Scandinavian Simvastatin Survival Study (4S). Lancet. 1994;344: were to reduce nonhemorrhagic strokes.
6. Shepherd J, Cobbe SM, Ford I, et al, for the West of Scotland Coronary The PPP analyses demonstrate that the long-term use of Prevention Study Group. Prevention of coronary disease with pravastatin pravastatin is associated with a reduction in total stroke inci- in men with hypercholesterolemia. N Engl J Med. 1995;333:1301–1307.
dence in the setting of secondary prevention and across a wide 7. Sacks FM, Pfeffer MA, Moye LA, et al, for the Cholesterol and Recurrent range of patient characteristics. This benefit is seen as a reduc- Events Trial Investigators. The effect of pravastatin on coronary eventsafter myocardial infarction in patients with average cholesterol levels.
tion in nonfatal nonhemorrhagic strokes. There is a suggestion in N Engl J Med. 1996;335:1001–1009.
these data that this benefit occurs after Ϸ1 year of therapy.
8. Long-term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group. Prevention of cardiovascular events and death with prava- Acknowledgment
statin in patients with coronary heart disease and a broad range of initial The PPP Project is funded by a grant from Bristol-Myers Squibb, cholesterol levels. N Engl J Med. 1998;339:1349 –1357.
9. Atkins D, Psaty BM, Koepsell TD, et al. Cholesterol reduction and the risk of stroke in men: a meta-analysis of randomized, controlled trials.
Ann Intern Med. 1993;119:136 –145.
Appendix
10. Hebert PR, Gaziano JM, Hennekens CH. An overview of trials of cho- PPP Project Investigators
lesterol lowering and risk of stroke. Arch Intern Med. 1995;155:50 –55.
11. PPP Project Investigators. Design, rationale, and baseline characteristics Wake Forest University School of Medicine, Winston-Salem, NC: of the Prospective Pravastatin Pooling (PPP) Project: a combined analysis Curt D. Furberg, Robert P. Byington, Timothy E. Craven; Brigham of three large-scale randomized trials: Long-term Intervention with Prav- & Women’s Hospital, Harvard Medical School, Boston, Mass: astatin in Ischemic Disease (LIPID), Cholesterol And Recurrent Events Eugene Braunwald, Marc A. Pfeffer, Frank M. Sacks; University of (CARE), and West of Scotland Coronary Prevention Study (WOSCOPS).
Texas School of Public Health, Houston, Tex: Barry R. Davis, C.
Am J Cardiol. 1995;76:899 –905.
Morton Hawkins, Lemuel A. Moyé; National Heart Foundation, 12. Simes J, Braunwald E, Shepherd J, et al, for the PPP Investigators.
Victoria, Australia: Andrew Tonkin; University of Sydney, Sydney, Pravastatin reduces mortality in patients with a broad range of lipid levels Australia: Anthony C. Keech, R. John Simes; University of Queens- with or without prior coronary heart disease: the Prospective Pravastatin land, Herston Old, Australia: Paul Glaziou; University of Glasgow, Pooling Project. Circulation. 1999;100(suppl I):I-825. Abstract.
Glasgow, Scotland: Stuart M. Cobbe, Ian Ford, Christopher J.
13. Sacks FM, Tonkin A, Shepherd J, et al, for the Prospective Pravastatin Packard, James Shepherd; and Bristol-Myers Squibb Co, Pharma- Pooling Project Investigators Group. The effect of pravastatin on ceutical Research Institute, Princeton, NJ (sponsor): Rene Belder, coronary disease events in subgroups defined by coronary risk factors: the Sharon Anderson, Kannan Natarajan, Chen-Sheng Lin.
Prospective Pravastatin Pooling Project. Circulation. 2000;102:1893–1900.
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