| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
(Circulation. 2001;103:387.)
© 2001 American Heart Association, Inc.
Clinical Investigation and Reports |
Reduction of Stroke Events With Pravastatin
The Prospective Pravastatin Pooling (PPP) Project
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 |
|---|
 Top Abstract IntroductionMethodsResultsDiscussionAppendix 1References |
|---|
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 102 559
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.
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.
Key Words: lipids • prevention • stroke • trials
|
Introduction |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionAppendix 1References |
|---|
Cerebrovascular disease is the second leading cause of death in the Americas and Europe, accounting for 10% and 14% of all deaths in these regions,1 and is the leading cause of death among the Western Pacific countries, accounting for 14% of all deaths.1 In the United States, strokes killed almost 160 000 persons in 1997 and ranked third as cause of death after heart disease and cancer.2 Approximately 600 000 persons have a stroke each year in the United States.3 It is a leading cause of disability and increased healthcare costs.3
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 |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionAppendix 1References |
|---|
The PPP Project was initiated in 1992 before completion of any of the constituent trials. The design and rationale for the project have been previously described,11 as have been the primary results of the 3 constituent trials6 7 8 and the pooled mortality and coronary event subgroup results.12 13 Each of the 3 studies was a randomized, double-masked, placebo-controlled trial of 40 mg/d pravastatin. WOSCOPS, conducted in Scotland, was a primary prevention trial that evaluated the effectiveness of pravastatin in the prevention of fatal and nonfatal coronary events in 6595 men aged 45 to 64 years with hyperlipidemia and no history of myocardial infarction (MI).6 WOSCOPS patients were followed for a mean of 4.8 years. CARE, conducted in the United States and Canada, was a secondary prevention trial that evaluated the effectiveness of pravastatin in the prevention of fatal and nonfatal coronary events in 4159 men and women aged 21 to 75 years with average lipid levels and an MI 3 to 20 months before randomization.7 CARE patients were followed for a mean of 4.8 years. LIPID, conducted in Australia and New Zealand, was also a secondary prevention trial. It evaluated the effectiveness of pravastatin in the prevention of coronary deaths in 9014 men and women aged 31 to 75 years with a history of MI or unstable angina and a wider lipid range than CARE.8 LIPID patients were followed for a mean of 6.1 years.
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 |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionAppendix 1References |
|---|
The baseline descriptions of the 3 trials and the treatment group comparisons are presented in Table 1
. Collectively, there were 19 768 patients
in the PPP database with 102 559 patient-years of
follow-up.
|
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.
|
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.
|
|
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.
|
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.
|
|
Discussion |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionAppendix 1References |
|---|
For decades, there had been considerable doubt regarding the value of lipid lowering in stroke prevention. This was because total stroke incidence (in which hemorrhagic and nonhemorrhagic strokes were combined together) had only been weakly associated, if at all, with increased cholesterol levels in observational studies17 and because of the observed lack of benefit of lipid lowering on stroke incidence in the early cholesterol-lowering trials.9 10 Even as late as 1995, a meta-analysis of cholesterol-lowering trials (none of which used a statin) reported that patients assigned to cholesterol lowering experienced no reduction in total stroke.10 In that report, summarizing the stroke results from 11 randomized trials of lipid lowering, the relative risk for total fatal/nonfatal stroke in participants assigned to treatment compared with controls was 1.0 (95% CI 0.8 to 1.2).
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 pressure–lowering 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 |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionAppendix 1References |
|---|
PPP Project Investigators
Wake Forest University School of Medicine, Winston-Salem, NC: Curt D. Furberg, Robert P. Byington, Timothy E. Craven; Brigham & Women’s Hospital, Harvard Medical School, Boston, Mass: Eugene Braunwald, Marc A. Pfeffer, Frank M. Sacks; University of Texas School of Public Health, Houston, Tex: Barry R. Davis, C. Morton Hawkins, Lemuel A. Moyé; National Heart Foundation, Victoria, Australia: Andrew Tonkin; University of Sydney, Sydney, Australia: Anthony C. Keech, R. John Simes; University of Queensland, Herston Old, Australia: Paul Glaziou; University of Glasgow, Glasgow, Scotland: Stuart M. Cobbe, Ian Ford, Christopher J. Packard, James Shepherd; and Bristol-Myers Squibb Co, Pharmaceutical Research Institute, Princeton, NJ (sponsor): Rene Belder, Sharon Anderson, Kannan Natarajan, Chen-Sheng Lin.
|
Acknowledgments |
|---|
The PPP Project is funded by a grant from Bristol-Myers Squibb, Princeton, NJ.
|
Footnotes |
|---|
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.
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 |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionAppendix 1References |
|---|
1. World Health Organization. World Health Report 1999–Making a Difference. Geneva, Switzerland: World Health Organization; 1999.
2. National Center for Health Statistics. Health United States 1999, With Health and Aging Chartbook. Hyattsville, Md: National Center for Health Statistics; 1999.
3. American Heart Association. 2000 Heart and Stroke Statistical Update. Dallas, Tex: American Heart Association; 1999.
4.
Byington RP, Jukema
JW, Salonen JT, et al. Reduction in cardiovascular events during
pravastatin therapy: pooled analysis of clinical events in the
Pravastatin Atherosclerosis Intervention Program.
Circulation. 1995;92:2419–2425.
5. Scandinavian Simvastatin Survival Study Group. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet. 1994;344:1383–1389.[Medline] [Order article via Infotrieve]
6.
Shepherd J, Cobbe
SM, Ford I, et al, for the West of Scotland Coronary Prevention Study
Group. Prevention of coronary disease with pravastatin in men with
hypercholesterolemia. N Engl J
Med. 1995;333:1301–1307.
7.
Sacks FM, Pfeffer
MA, Moye LA, et al, for the Cholesterol and Recurrent Events Trial
Investigators. The effect of pravastatin on coronary events after
myocardial infarction in patients with average cholesterol
levels. N Engl J Med. 1996;335:1001–1009.
8.
Long-term
Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group.
Prevention of cardiovascular events and death with pravastatin in
patients with coronary heart disease and a broad range of initial
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.
10.
Hebert PR,
Gaziano JM, Hennekens CH. An overview of trials of cholesterol lowering
and risk of stroke. Arch Intern
Med. 1995;155:50–55.
11. PPP Project Investigators. Design, rationale, and baseline characteristics of the Prospective Pravastatin Pooling (PPP) Project: a combined analysis of three large-scale randomized trials: Long-term Intervention with Pravastatin in Ischemic Disease (LIPID), Cholesterol And Recurrent Events (CARE), and West of Scotland Coronary Prevention Study (WOSCOPS). Am J Cardiol. 1995;76:899–905.[Medline] [Order article via Infotrieve]
12. Simes J, Braunwald E, Shepherd J, et al, for the PPP Investigators. Pravastatin reduces mortality in patients with a broad range of lipid levels with or without prior coronary heart disease: the Prospective Pravastatin Pooling Project. Circulation. 1999;100(suppl I):I-825. Abstract.
13.
Sacks FM, Tonkin
A, Shepherd J, et al, for the Prospective Pravastatin Pooling Project
Investigators Group. The effect of pravastatin on coronary disease
events in subgroups defined by coronary risk factors: the Prospective
Pravastatin Pooling Project.
Circulation. 2000;102:1893–1900.
14.
Plehn JF, Davis
BR, Sacks FM, et al, for the CARE Investigators. Reduction of stroke
incidence after myocardial infarction with pravastatin: the Cholesterol
and Recurrent Events (CARE) Study.
Circulation. 1999;99:216–223.
15. White HD, Simes RJ, Anderson NE, et al. Impact of pravastatin therapy on the risk of stroke: results from the LIPID Study. N Engl J Med. In press.
16. Kalbfleisch JD, Prentice RL. The Statistical Analysis of Failure Time Data. New York, NY: John Wiley & Sons Inc; 1980.
17. Prospective Studies Collaboration. Cholesterol, diastolic blood pressure and stroke: 13,000 strokes in 450,000 people in 45 prospective cohorts. Lancet. 1995;346:1647–1653.[Medline] [Order article via Infotrieve]
18.
Crouse JR,
Byington RP, Hoen HM, et al. Reductase inhibitor monotherapy and stroke
prevention. Arch Intern Med. 1997;157:1305–1310.
19.
Blauw GJ, Lagaay
AM, Smelt AHM, et al. Stroke, statins, and cholesterol: a meta-analysis
of randomized, placebo-controlled, double-blind trials with HMG-CoA
reductase inhibitors. Stroke. 1997;28:946–950.
20.
Hebert PR,
Gaziano JM, Chan KS, et al. Cholesterol lowering with statin drugs,
risk of stroke, and total mortality.
JAMA. 1997;278:313–321.
21. Crouse JR, Byington RP, Furberg CD. HMG-CoA reductase inhibitor therapy and stroke reduction: an analysis of clinical trial data. Atherosclerosis. 1998;138:11–24.[Medline] [Order article via Infotrieve]
22. Kjekshus J, Pedersen TR, for the Scandinavian Simvastatin Survival Study Group. Reducing the risk of coronary events: evidence from the Scandinavian Simvastatin Survival Group. Am J Cardiol. 1995;76:64C–68C.[Medline] [Order article via Infotrieve]
23. Crouse JR, Byington RP, Bond MG, et al. Pravastatin, Lipids, and Atherosclerosis in the Carotid Arteries (PLAC-II). Am J Cardiol. 1995;75:455–459.[Medline] [Order article via Infotrieve]
24.
Salonen R,
Nyyssönen K, Porkkala E, et al. Kuopio Prevention Study (KAPS): a
population-based primary prevention trial of the effects of LDL
lowering on atherosclerotic progression in carotid and femoral
arteries. Circulation. 1995;92:1758–1764.
25.
MacMahon S,
Sharpe N, Gamble G, et al, on behalf of the LIPID Trial Research Group.
Effects of lowering average or below-average cholesterol levels on the
progression of carotid atherosclerosis: results of the LIPID
Atherosclerosis Substudy.
Circulation. 1998;97:1784–1790.
26.
Antiplatelet
Trialists’ Collaboration. Collaborative overview of randomised trials
of antiplatelet therapy, I: prevention of death, myocardial infarction,
and stroke by prolonged antiplatelet therapy in various categories of
patients. Br Med J. 1994;308:81–106.
27.
Papadakis JA,
Mikhailidis DP, Winder AF. Lipids and stroke: neglect of a useful
preventive measure? Cardiovasc
Res. 1998;40:265–271.
28. Iso H, Jacobs DR, Wentworth D, et al, for the MRFIT Research Group. Serum cholesterol levels and six-year mortality from stroke in 350,977 men screened for the Multiple Risk Factor Intervention Trial. N Engl J Med. 1989;320:904–910. [Abstract]
This article has been cited by other articles:
 |
|
 |
|
  N. Meier, K. Nedeltchev, C. Brekenfeld, A. Galimanis, U. Fischer, O. Findling, L. Remonda, G. Schroth, H. P. Mattle, and M. Arnold Prior Statin Use, Intracranial Hemorrhage, and Outcome After Intra-Arterial Thrombolysis for Acute Ischemic Stroke Stroke, May 1, 2009; 40(5): 1729 - 1737. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Kushiro, K. Mizuno, N. Nakaya, Y. Ohashi, N. Tajima, T. Teramoto, S. Uchiyama, H. Nakamura, and for the Management of Elevated Cholesterol in the Pravastatin for Cardiovascular Event Primary Prevention in Patients With Mild-to-Moderate Hypertension in the Management of Elevated Cholesterol in the Primary Prevention Group of Adult Japanese (MEGA) Study Hypertension, February 1, 2009; 53(2): 135 - 141. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. B. Goldstein, P. Amarenco, M. LaMonte, S. Gilbert, M. Messig, A. Callahan, M. Hennerici, H. Sillesen, K. M. A. Welch, and on behalf of the SPARCL Investigators Relative Effects of Statin Therapy on Stroke and Cardiovascular Events in Men and Women: Secondary Analysis of the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) Study Stroke, September 1, 2008; 39(9): 2444 - 2448. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. A. Golomb, J. E. Dimsdale, H. L. White, J. B. Ritchie, and M. H. Criqui Reduction in Blood Pressure With Statins: Results From the UCSD Statin Study, a Randomized Trial Arch Intern Med, April 14, 2008; 168(7): 721 - 727. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Nassief and J. D. Marsh Statin Therapy for Stroke Prevention Stroke, March 1, 2008; 39(3): 1042 - 1048. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Gnavi, A. Migliardi, M. Demaria, A. Petrelli, A. Caprioglio, and G. Costa Statins prescribing for the secondary prevention of ischaemic heart disease in Torino, Italy. A case of ageism and social inequalities Eur J Public Health, October 1, 2007; 17(5): 492 - 496. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. K. Wenger, S. J. Lewis, D. M. Herrington, V. Bittner, F. K. Welty, and for the Treating to New Targets Study Steering Com Outcomes of Using High- or Low-Dose Atorvastatin in Patients 65 Years of Age or Older with Stable Coronary Heart Disease Ann Intern Med, July 3, 2007; 147(1): 1 - 9. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. S. Dhamoon, W. Tai, B. Boden-Albala, T. Rundek, M. C. Paik, R. L. Sacco, and M. S.V. Elkind Risk of Myocardial Infarction or Vascular Death After First Ischemic Stroke: The Northern Manhattan Study Stroke, June 1, 2007; 38(6): 1752 - 1758. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 V. Khurana, H. R. Bejjanki, G. Caldito, and M. W. Owens Statins Reduce the Risk of Lung Cancer in Humans: A Large Case-Control Study of US Veterans Chest, May 1, 2007; 131(5): 1282 - 1288. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 V. J. Dzau, E. M. Antman, H. R. Black, D. L. Hayes, J. E. Manson, J. Plutzky, J. J. Popma, and W. Stevenson The Cardiovascular Disease Continuum Validated: Clinical Evidence of Improved Patient Outcomes: Part II: Clinical Trial Evidence (Acute Coronary Syndromes Through Renal Disease) and Future Directions Circulation, December 19, 2006; 114(25): 2871 - 2891. [Full Text] [PDF]
|
|
|
|
|
|
C. D. Bushnell, J. Griffin, L. K. Newby, L. B. Goldstein, K. W. Mahaffey, C. A. Graffagnino, R. A. Harrington, H. D. White, R. J. Simes, R. M. Califf, et al. Statin Use and Sex-Specific Stroke Outcomes in Patients With Vascular Disease Stroke, June 1, 2006; 37(6): 1427 - 1431. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. Rief, J. Avorn, and A. J. Barsky Medication-Attributed Adverse Effects in Placebo Groups: Implications for Assessment of Adverse Effects Arch Intern Med, January 23, 2006; 166(2): 155 - 160. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Kennedy, H. Quan, A. M. Buchan, W. A. Ghali, and T. E. Feasby Statins Are Associated With Better Outcomes After Carotid Endarterectomy in Symptomatic Patients Stroke, October 1, 2005; 36(10): 2072 - 2076. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Patel, M. Woodward, D. J. Campbell, D. R. Sullivan, S. Colman, J. Chalmers, B. Neal, and S. MacMahon Plasma lipids predict myocardial infarction, but not stroke, in patients with established cerebrovascular disease Eur. Heart J., September 2, 2005; 26(18): 1910 - 1915. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. S.V. Elkind, A. C. Flint, R. R. Sciacca, and R. L. Sacco Lipid-lowering agent use at ischemic stroke onset is associated with decreased mortality Neurology, July 26, 2005; 65(2): 253 - 258. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Amarenco, J. Labreuche, P. Lavallee, and P.-J. Touboul Statins in Stroke Prevention and Carotid Atherosclerosis: Systematic Review and Up-to-Date Meta-Analysis Stroke, December 1, 2004; 35(12): 2902 - 2909. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. L. Tirschwell, N. L. Smith, S. R. Heckbert, R. N. Lemaitre, W. T. Longstreth Jr., and B. M. Psaty Association of cholesterol with stroke risk varies in stroke subtypes and patient subgroups Neurology, November 23, 2004; 63(10): 1868 - 1875. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Becker and M. Chopp Role of Statins in the Treatment and Prevention of Stroke: Introduction Stroke, November 1, 2004; 35(11_suppl_1): 2706 - 2707. [Full Text] [PDF]
|
|
|
|
|
|
P. Amarenco and A. M. Tonkin Statins for Stroke Prevention: Disappointment and Hope Circulation, June 15, 2004; 109(23_suppl_1): III-44 - III-49. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Marti-Fabregas, M. Gomis, A. Arboix, A. Aleu, J. Pagonabarraga, R. Belvis, D. Cocho, J. Roquer, A. Rodriguez, M. D. Garcia, et al. Favorable Outcome of Ischemic Stroke in Patients Pretreated with Statins Stroke, May 1, 2004; 35(5): 1117 - 1121. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. O'Rourke, N. Dean, N. Akhtar, and A. Shuaib Current and future concepts in stroke prevention Can. Med. Assoc. J., March 30, 2004; 170(7): 1123 - 1133. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. P. Broderick William M. Feinberg Lecture: Stroke Therapy in the Year 2025: Burden, Breakthroughs, and Barriers to Progress Stroke, January 1, 2004; 35(1): 205 - 211. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. E. Ho, F. Paultre, and L. Mosca Is Diabetes Mellitus a Cardiovascular Disease Risk Equivalent for Fatal Stroke in Women?: Data From the Women's Pooling Project Stroke, December 1, 2003; 34(12): 2812 - 2816. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. M Buckley Review: Lipids and stroke The British Journal of Diabetes & Vascular Disease, May 1, 2003; 3(3): 170 - 176. [Abstract] [PDF]
|
|
|
|
 |
|
 K. K. W. Chan, A. M. Oza, and L. L. Siu The Statins as Anticancer Agents Clin. Cancer Res., January 1, 2003; 9(1): 10 - 19. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. Lalouschek, W. Lang, S. Greisenegger, and M. Mullner Determination of Lipid Profiles and Use of Statins in Patients With Ischemic Stroke or Transient Ischemic Attack Stroke, January 1, 2003; 34(1): 105 - 110. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. M. Sacks Low-density lipoprotein lowering therapy: an analysis of the options J. Am. Coll. Cardiol., December 18, 2002; 40(12): 2135 - 2138. [Full Text] [PDF]
|
|
|
|
 |
|
 S. C. Johnston Transient Ischemic Attack N. Engl. J. Med., November 21, 2002; 347(21): 1687 - 1692. [Full Text] [PDF]
|
|
|
|
|
|
C. A. Allen Maycock, J. B. Muhlestein, B. D. Horne, J. F. Carlquist, T. L. Bair, R. R. Pearson, Q. Li, J. L. Anderson, and Intermountain Heart Collaborative Study Statin therapy is associated with reduced mortality across all age groups of individuals with significant coronary disease, including very elderly patients J. Am. Coll. Cardiol., November 20, 2002; 40(10): 1777 - 1785. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Garnero, C. Jamin, C.-L. Benhamou, C. Pelissier, and C. Roux Effects of tibolone and combined 17{beta}-estradiol and norethisterone acetate on serum C-reactive protein in healthy post-menopausal women: a randomized trial Hum. Reprod., October 1, 2002; 17(10): 2748 - 2753. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. M. Gotto Jr and J. A. Farmer Reducing the Risk for Stroke in Patients With Myocardial Infarction: A Myocardial Ischemia Reduction With Aggressive Cholesterol Lowering (MIRACL) Substudy Circulation, September 24, 2002; 106(13): 1595 - 1598. [Full Text] [PDF]
|
|
|
|
|
|
J. P. Broderick and W. Hacke Treatment of Acute Ischemic Stroke: Part II: Neuroprotection and Medical Management Circulation, September 24, 2002; 106(13): 1736 - 1740. [Full Text] [PDF]
|
|
|
|
 |
|
 S. E. Straus, S. R. Majumdar, and F. A. McAlister New Evidence for Stroke Prevention: Scientific Review JAMA, September 18, 2002; 288(11): 1388 - 1395. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. M. Ridker Inflammatory Biomarkers, Statins, and the Risk of Stroke: Cracking a Clinical Conundrum Circulation, June 4, 2002; 105(22): 2583 - 2585. [Full Text] [PDF]
|
|
|
|
|
|
G. Engstrom, P. Lind, B. Hedblad, L. Stavenow, L. Janzon, and F. Lindgarde Effects of Cholesterol and Inflammation-Sensitive Plasma Proteins on Incidence of Myocardial Infarction and Stroke in Men Circulation, June 4, 2002; 105(22): 2632 - 2637. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. S. Mouradian, S. R. Majumdar, A. Senthilselvan, K. Khan, and A. Shuaib How Well Are Hypertension, Hyperlipidemia, Diabetes, and Smoking Managed After a Stroke or Transient Ischemic Attack? Stroke, June 1, 2002; 33(6): 1656 - 1659. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. A. Pfeffer, A. Keech, F. M. Sacks, S. M. Cobbe, A. Tonkin, R. P. Byington, B. R. Davis, C. P. Friedman, and E. Braunwald Safety and Tolerability of Pravastatin in Long-Term Clinical Trials: Prospective Pravastatin Pooling (PPP) Project Circulation, May 21, 2002; 105(20): 2341 - 2346. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Koren-Morag, D. Tanne, E. Graff, U. Goldbourt, and for the Bezafibrate Infarction Prevention Study Gr Low- and High-Density Lipoprotein Cholesterol and Ischemic Cerebrovascular Disease: The Bezafibrate Infarction Prevention Registry Arch Intern Med, May 13, 2002; 162(9): 993 - 999. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 I. Loftus and M. Thompson The role of matrix metalloproteinases in vascular disease Vascular Medicine, May 1, 2002; 7(2): 117 - 133. [Abstract] [PDF]
|
|
|
|
|
|
P. B. Gorelick Stroke Prevention Therapy Beyond Antithrombotics: Unifying Mechanisms in Ischemic Stroke Pathogenesis and Implications for Therapy: An Invited Review Stroke, March 1, 2002; 33(3): 862 - 875. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. A. Kreisberg and A. Oberman Lipids and Atherosclerosis: Lessons Learned from Randomized Controlled Trials of Lipid Lowering and Other Relevant Studies J. Clin. Endocrinol. Metab., February 1, 2002; 87(2): 423 - 437. [Full Text] [PDF]
|
|
|
|
|
|
M. A. Albert, E. Danielson, N. Rifai, P. M Ridker, and for the PRINCE Investigators Effect of Statin Therapy on C-Reactive Protein Levels: The Pravastatin Inflammation/CRP Evaluation (PRINCE): A Randomized Trial and Cohort Study JAMA, July 4, 2001; 286(1): 64 - 70. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Mulcahy Statins and cardiovascular disease--major therapeutic advances but are we seizing the moment? Eur. Heart J., July 1, 2001; 22(13): 1065 - 1066. [PDF]
|
|
|
|
|
|
J. Plutzky and P. M. Ridker Statins for Stroke: The Second Story? Circulation, January 23, 2001; 103(3): 348 - 350. [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||