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Figure 1.

 Meta-analysis of the effect of lipid-lowering therapies on stroke incidence (all trials). Relative risk is given for all strokes (fatal plus nonfatal) for individual trials, all trials #1total), and in primary or secondary prevention subgroups; all lipid-lowering therapies providing information on all strokes are represented. CI indicates confidence interval.

Meta-analysis of the effect of lipid-lowering therapies on stroke incidence (all trials). Relative risk is given for all strokes (fatal plus nonfatal) for individual trials, all trials #1total), and in primary or secondary prevention subgroups; all lipid-lowering therapies providing information on all strokes are represented. CI indicates confidence interval.

Figure 2.

 Subgroup meta-analysis by type of treatment on stroke incidence. Relative risk (RR) is given for all strokes #1fatal plus nonfatal) by type of treatment subgroups. P values represent the result of the χ2 test for association. CI indicates confidence interval.

Subgroup meta-analysis by type of treatment on stroke incidence. Relative risk (RR) is given for all strokes #1fatal plus nonfatal) by type of treatment subgroups. P values represent the result of the χ2 test for association. CI indicates confidence interval.

Figure 3.

 Meta-analysis of the effect of statins on stroke incidence by type of prevention subgroups. Relative risk is given for all strokes (fatal plus nonfatal) for individual trials, for all trials testing statin therapy (total), and in primary or secondary prevention subgroups. CI indicates confidence interval.

Meta-analysis of the effect of statins on stroke incidence by type of prevention subgroups. Relative risk is given for all strokes (fatal plus nonfatal) for individual trials, for all trials testing statin therapy (total), and in primary or secondary prevention subgroups. CI indicates confidence interval.

Figure 4.

 Summary of the meta-analysis end points. Overall relative risk (RR) of each end point (all strokes, fatal stroke, and fatal plus nonfatal myocardial infarction [MI]) with all trials providing data for these end points is given. P values represent the result of the χ2 test for association.

Summary of the meta-analysis end points. Overall relative risk (RR) of each end point (all strokes, fatal stroke, and fatal plus nonfatal myocardial infarction [MI]) with all trials providing data for these end points is given. P values represent the result of the χ2 test for association.

Figure 5.

 Effect model analysis of lipid-lowering therapies on stroke prevention. Weighted regression line is shown between annual incidence of stroke in the placebo group (risk in the control group) and annual incidence of stroke in the lipid-lowering therapy group (risk in the experimental group); for purposes of diagram presentation, the points corresponding to the MIRACL (risk in the control group, 0.052; experimental group, 0.026) and VA-HIT (risk in the control group, 0.012; experimental group, 0.009) trials are not indicated. CI indicates confidence interval.

Effect model analysis of lipid-lowering therapies on stroke prevention. Weighted regression line is shown between annual incidence of stroke in the placebo group (risk in the control group) and annual incidence of stroke in the lipid-lowering therapy group (risk in the experimental group); for purposes of diagram presentation, the points corresponding to the MIRACL (risk in the control group, 0.052; experimental group, 0.026) and VA-HIT (risk in the control group, 0.012; experimental group, 0.009) trials are not indicated. CI indicates confidence interval.

Figure 6.

 Relationships between final cholesterol level and effect of lipid-lowering therapies on stroke and myocardial infarction. Inverse variance weighted regression line (plain line) with the 95% confidence interval (CI) (dotted lines) are shown between final total cholesterol level and relative risk reduction of stroke (A) and myocardial infarction (B) in trials testing lipid-lowering therapies; diameter of the symbol for each trial is proportional to its weight (inverse variance of relative risk). To convert cholesterol values to millimoles per liter, multiply by 0.0259.

Relationships between final cholesterol level and effect of lipid-lowering therapies on stroke and myocardial infarction. Inverse variance weighted regression line (plain line) with the 95% confidence interval (CI) (dotted lines) are shown between final total cholesterol level and relative risk reduction of stroke (A) and myocardial infarction (B) in trials testing lipid-lowering therapies; diameter of the symbol for each trial is proportional to its weight (inverse variance of relative risk). To convert cholesterol values to millimoles per liter, multiply by 0.0259.

Table 1. 
Characteristics of the Trials*
Characteristics of the Trials*
Table 2. 
Relationships Between Relative Risk Reduction of Stroke or Myocardial Infarction and Cholesterol Measures
Relationships Between Relative Risk Reduction of Stroke or Myocardial Infarction and Cholesterol Measures
1.
Williams  GRJiang  JGMatchar  DBSamsa  GP Incidence and occurrence of total (first-ever and recurrent) stroke. Stroke. 1999;302523- 2528Article
2.
Prospective Studies Collaboration, Cholesterol, diastolic blood pressure, and stroke: 13,000 strokes in 450,000 people in 45 prospective cohorts. Lancet. 1995;3461647- 1653Article
3.
Blauw  GJLagaay  AMSmelt  AHWestendorp  RG Stroke, statins, and cholesterol: a meta-analysis of randomized, placebo-controlled, double-blind trials with HMG-CoA reductase inhibitors. Stroke. 1997;28946- 950Article
4.
Hebert  PRGaziano  JMChan  KSHennekens  CH Cholesterol lowering with statin drugs, risk of stroke, and total mortality: an overview of randomized trials. JAMA. 1997;278313- 321Article
5.
Hebert  PRGaziano  JMHennekens  CH An overview of trials of cholesterol lowering and risk of stroke. Arch Intern Med. 1995;15550- 55Article
6.
Di Mascio  RMarchioli  RTognoni  G Cholesterol reduction and stroke occurrence: an overview of randomized clinical trials. Cerebrovasc Dis. 2000;1085- 92Article
7.
Atkins  DPsaty  BMKoepsell  TDLongstreth  WT  JrLarson  EB Cholesterol reduction and the risk for stroke in men: a meta-analysis of randomized, controlled trials. Ann Intern Med. 1993;119136- 145Article
8.
Not Available, Secondary prevention by raising HDL cholesterol and reducing triglycerides in patients with coronary artery disease: the Bezafibrate Infarction Prevention #1BIP) study Circulation. 2000;10221- 27Article
9.
Rubins  HBRobins  SJCollins  D  et al. for the Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial Study Group, Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high-density lipoprotein cholesterol. N Engl J Med. 1999;341410- 418Article
10.
Schwartz  GGOlsson  AGEzekowitz  MD  et al.  Effects of atorvastatin on early recurrent ischemic events in acute coronary syndromes: the MIRACL study: a randomized controlled trial. JAMA. 2001;2851711- 1718Article
11.
Teo  KKBurton  JRBuller  CE  et al.  Long-term effects of cholesterol lowering and angiotensin-converting enzyme inhibition on coronary atherosclerosis: the Simvastatin/Enalapril Coronary Atherosclerosis Trial (SCAT). Circulation. 2000;1021748- 1754Article
12.
Delanty  NVaughan  CJ Vascular effects of statins in stroke. Stroke. 1997;282315- 2320Article
13.
Kwak  BMulhaupt  FMyit  SMach  F Statins as a newly recognized type of immunomodulator. Nat Med. 2000;61399- 1402Article
14.
Rosenson  RSTangney  CC Antiatherothrombotic properties of statins: implications for cardiovascular event reduction. JAMA. 1998;2791643- 1650Article
15.
Vaughan  CJDelanty  N Neuroprotective properties of statins in cerebral ischemia and stroke. Stroke. 1999;301969- 1973Article
16.
Maron  DJFazio  SLinton  MF Current perspectives on statins. Circulation. 2000;101207- 213Article
17.
Seiler  CSuter  TMHess  OM Exercise-induced vasomotion of angiographically normal and stenotic coronary arteries improves after cholesterol-lowering drug therapy with bezafibrate. J Am Coll Cardiol. 1995;261615- 1622Article
18.
Staels  BKoenig  WHabib  A  et al.  Activation of human aortic smooth-muscle cells is inhibited by PPARα but not by PPARγ activators. Nature. 1998;393790- 793Article
19.
Marx  NSukhova  GKCollins  TLibby  PPlutzky  J PPARα activators inhibit cytokine-induced vascular cell adhesion molecule-1 expression in human endothelial cells. Circulation. 1999;993125- 3131Article
20.
Fujii  SSobel  BE Direct effects of gemfibrozil on the fibrinolytic system: diminution of synthesis of plasminogen activator inhibitor type 1. Circulation. 1992;851888- 1893Article
21.
Miettinen  TAHuttunen  JKNaukkarinen  V  et al.  Multifactorial primary prevention of cardiovascular diseases in middle-aged men: risk factor changes, incidence, and mortality. JAMA. 1985;2542097- 2102Article
22.
Kroon  AAAengevaeren  WRvan der Werf  T  et al.  LDL-Apheresis Atherosclerosis Regression Study (LAARS): effect of aggressive versus conventional lipid lowering treatment on coronary atherosclerosis. Circulation. 1996;931826- 1835Article
23.
Acheson  JHutchinson  EC Controlled trial of clofibrate in cerebral vascular disease. Atherosclerosis. 1972;15177- 183Article
24.
Bradford  RHShear  CLChremos  AN  et al.  Expanded Clinical Evaluation of Lovastatin (EXCEL) study results, I: efficacy in modifying plasma lipoproteins and adverse event profile in 8245 patients with moderate hypercholesterolemia. Arch Intern Med. 1991;15143- 49Article
25.
Walter  SD Variation in baseline risk as an explanation of heterogeneity in meta-analysis. Stat Med. 1997;162883- 2900Article
26.
Salonen  RNyyssonen  KPorkkala  E  et al.  Kuopio Atherosclerosis Prevention Study (KAPS): a population-based primary preventive trial of the effect of LDL lowering on atherosclerotic progression in carotid and femoral arteries. Circulation. 1995;921758- 1764Article
27.
The Pravastatin Multinational Study Group for Cardiac Risk Patients, Effects of pravastatin in patients with serum total cholesterol levels from 5.2 to 7.8 mmol/liter (200 to 300 mg/dl) plus two additional atherosclerotic risk factors. Am J Cardiol. 1993;721031- 1037Article
28.
Shepherd  JCobbe  SMFord  I  et al. for the West of Scotland Coronary Prevention Study Group, Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. N Engl J Med. 1995;3331301- 1307Article
29.
Jukema  JWBruschke  AVvan Boven  AJ  et al.  Effects of lipid lowering by pravastatin on progression and regression of coronary artery disease in symptomatic men with normal to moderately elevated serum cholesterol levels: the Regression Growth Evaluation Statin Study (REGRESS). Circulation. 1995;912528- 2540Article
30.
Crouse III  JRByington  RPBond  MG  et al.  Pravastatin, Lipids, and Atherosclerosis in the Carotid Arteries (PLAC-II). Am J Cardiol. 1995;75455- 459Article
31.
Pitt  BMancini  GBEllis  SGRosman  HSPark  JSMcGovern  MEfor the PLAC I Investigation, Pravastatin limitation of atherosclerosis in the coronary arteries #1PLAC I): reduction in atherosclerosis progression and clinical events. J Am Coll Cardiol. 1995;261133- 1139Article
32.
Sacks  FMPfeffer  MAMoye  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;3351001- 1009Article
33.
The 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;3391349- 1357Article
34.
Furberg  CDAdams  HP  JrApplegate  WB  et al. for the Asymptomatic Carotid Artery Progression Study (ACAPS) Research Group, Effect of lovastatin on early carotid atherosclerosis and cardiovascular events. Circulation. 1994;901679- 1687Article
35.
Blankenhorn  DHAzen  SPKramsch  DM  et al. for the MARS Research Group, Coronary angiographic changes with lovastatin therapy: the Monitored Atherosclerosis Regression Study (MARS). Ann Intern Med. 1993;119969- 976Article
36.
Weintraub  WSBoccuzzi  SJKlein  JL  et al. for the Lovastatin Restenosis Trial Study Group, Lack of effect of lovastatin on restenosis after coronary angioplasty. N Engl J Med. 1994;3311331- 1337Article
37.
Not Available, Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet 1994;3441383- 1389
38.
Not Available, Effect of simvastatin on coronary atheroma: the Multicentre Anti-Atheroma Study (MAAS). Lancet. 1994;344633- 638Article
39.
Not Available, A co-operative trial in the primary prevention of ischaemic heart disease using clofibrate: report from the Committee of Principal Investigators. Br Heart J 1978;401069- 1118Article
40.
Not Available, Ischaemic heart disease: a secondary prevention trial using clofibrate: report by a research committee of the Scottish Society of Physicians. BMJ. 1971;4775- 784Article
41.
Not Available, Trial of clofibrate in the treatment of ischaemic heart disease: five-year study by a group of physicians of the Newcastle upon Tyne region. BMJ. 1971;4767- 775Article
42.
Not Available, The Lipid Research Clinics Coronary Primary Prevention Trial results I: reduction in incidence of coronary heart disease. JAMA. 1984;251351- 364Article
43.
Not Available, The Lipid Research Clinics Coronary Primary Prevention Trial results, II: the relationship of reduction in incidence of coronary heart disease to cholesterol lowering. JAMA. 1984;251365- 374Article
44.
Watts  GFLewis  BBrunt  JN  et al.  Effects on coronary artery disease of lipid-lowering diet, or diet plus cholestyramine, in the St Thomas' Atherosclerosis Regression Study (STARS). Lancet. 1992;339563- 569Article
45.
Frick  MHElo  OHaapa  K  et al.  Helsinki Heart Study: primary-prevention trial with gemfibrozil in middle-aged men with dyslipidemia: safety of treatment, changes in risk factors, and incidence of coronary heart disease. N Engl J Med. 1987;3171237- 1245Article
46.
Frick  MHHeinonen  OPHuttunen  JKKoskinen  PManttari  MManninen  V Efficacy of gemfibrozil in dyslipidaemic subjects with suspected heart disease: an ancillary study in the Helsinki Heart Study frame population. Ann Med. 1993;2541- 45Article
47.
Dorr  AEGundersen  KSchneider  JCSpencer  TWMartin  WB Colestipol hydrochloride in hypercholesterolemic patients: effect on serum cholesterol and mortality. J Chronic Dis. 1978;315- 14Article
48.
Carlson  LARosenhamer  G Reduction of mortality in the Stockholm Ischaemic Heart Disease Secondary Prevention Study by combined treatment with clofibrate and nicotinic acid. Acta Med Scand. 1988;223405- 418Article
49.
Not Available, Clofibrate and niacin in coronary heart disease. JAMA. 1975;231360- 381Article
50.
Dayton  SPearce  MLHashimoto  SDixon  WJTomiyasu  U A controlled clinical trial of a diet high in unsaturated fat in preventing complications of atherosclerosis. Circulation. 1969;39/40(suppl 2)1- 63
51.
Frantz  IDDawson  EAAshman  PL  et al.  Test of effect of lipid lowering by diet on cardiovascular risk: the Minnesota Coronary Survey. Arteriosclerosis. 1989;9129- 135Article
52.
Leren  P The Oslo Diet-Heart Study: eleven-year report. Circulation. 1970;42935- 942Article
53.
Not Available, Controlled trial of soya-bean oil in myocardial infarction. Lancet. 1968;2693- 699
54.
Singh  RBRastogi  SSVerma  R  et al.  Randomised controlled trial of cardioprotective diet in patients with recent acute myocardial infarction: results of one year follow up. BMJ. 1992;3041015- 1019Article
55.
de Lorgeril  MRenaud  SMamelle  N  et al.  Mediterranean alpha-linolenic acid–rich diet in secondary prevention of coronary heart disease. Lancet. 1994;3431454- 1459Article
56.
The Post Coronary Artery Bypass Graft Trial Investigators, The effect of aggressive lowering of low-density lipoprotein cholesterol levels and low-dose anticoagulation on obstructive changes in saphenous-vein coronary-artery bypass grafts. N Engl J Med. 1997;336153- 162Article
57.
Hjermann  IVelve Byre  KHolme  ILeren  P Effect of diet and smoking intervention on the incidence of coronary heart disease: report from the Oslo Study Group of a randomised trial in healthy men. Lancet. 1981;21303- 1310Article
58.
Buchwald  HVarco  RLMatts  JP  et al.  Effect of partial ileal bypass surgery on mortality and morbidity from coronary heart disease in patients with hypercholesterolemia: report of the Program on the Surgical Control of the Hyperlipidemias (POSCH). N Engl J Med. 1990;323946- 955Article
59.
Heart Protection Study Collaborative Group, MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet. 2002;3607- 22Article
60.
Hier  DBFoulkes  MASwiontoniowski  M  et al.  Stroke recurrence within 2 years after ischemic infarction. Stroke. 1991;22155- 161Article
61.
Jorgensen  HSNakayama  HReith  JRaaschou  HOOlsen  TS Stroke recurrence: predictors, severity, and prognosis: the Copenhagen Stroke Study. Neurology. 1997;48891- 895Article
62.
Moroney  JTBagiella  EPaik  MCSacco  RLDesmond  DW Risk factors for early recurrence after ischemic stroke: the role of stroke syndrome and subtype. Stroke. 1998;292118- 2124Article
63.
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64.
Bousser  MGEschwege  EHaguenau  M  et al.  "AICLA" controlled trial of aspirin and dipyridamole in the secondary prevention of athero-thrombotic cerebral ischemia. Stroke. 1983;145- 14Article
65.
Bloomfield Rubins  HDavenport  JBabikian  V  et al.  Reduction in stroke with gemfibrozil in men with coronary heart disease and low HDL cholesterol: the Veterans Affairs HDL Intervention Trial (VA-HIT). Circulation. 2001;1032828- 2833Article
66.
Thomas  HE  JrKannel  WBDawber  TRMcNamara  PM Cholesterol-phospholipid ratio in the prediction of coronary heart disease: the Framingham study. N Engl J Med. 1966;274701- 705Article
67.
Tanne  DYaari  SGoldbourt  U High-density lipoprotein cholesterol and risk of ischemic stroke mortality: a 21-year follow-up of 8586 men from the Israeli Ischemic Heart Disease Study. Stroke. 1997;2883- 87Article
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Review Article
March 24, 2003

Differential Effects of Lipid-Lowering Therapies on Stroke PreventionA Meta-analysis of Randomized Trials

Author Affiliations

From the Service de Pharmacologie, Centre Hospitalo-Universitaire Pitié-Salpêtrière, Paris, France.

Arch Intern Med. 2003;163(6):669-676. doi:10.1001/archinte.163.6.669
Abstract

Background  Previous overviews suggested that hydroxymethyl glutaryl coenzyme A reductase inhibitors (statins), but not other lipid-lowering therapy (LLT), may reduce stroke incidence in coronary patients.

Objective  To investigate the amplitude and sources of heterogeneity of LLT effects on stroke prevention.

Methods  We searched the literature from 1966 to 2001 and then conducted a meta-analysis including randomized trials of primary and secondary coronary heart disease prevention, testing statins, nonstatin drugs, diet, or other interventions and providing data on stroke incidence.

Results  The meta-analysis (38 trials, 83 161 patients, mean follow-up of 4.7 years) showed a significant relative risk reduction (RRR) of strokes by LLT of 17% (P<.001), without significant heterogeneity between trials and between subgroups according to either the type of prevention #1primary or secondary) or the type of LLT. The most substantial effects were obtained, however, with statins (RRR, 26%). Effect model analysis showed that treatment benefit appeared constant whatever the risk of stroke, suggesting that LLT may be effective in a population with a higher risk of stroke. Weighted regression showed a significant correlation between RRR of stroke and total cholesterol levels (baseline, final, and change). Only final cholesterol allowed clear separation between benefit (RRR>0) and no effect (RRR<0) of LLT on stroke incidence, with a cutoff for benefit of 232 mg/dL (6.0 mmol/L).

Conclusion  Lipid-lowering therapy reduces stroke incidence in coronary patients, especially when total cholesterol level is lowered to less than 232 mg/dL #16.0 mmol/L), which explains the best results being obtained with statins.

REDUCING STROKE incidence in industrialized countries is a major challenge,1 since stroke is the third leading cause of mortality after coronary heart disease and cancer, and the leading cause of disability. Although lowering blood cholesterol level decreases the risk of coronary heart disease, whether it decreases the risk of stroke remains unclear.2 To date, no large randomized trial with stroke as the primary end point has been completed to establish whether cholesterol reduction reduces stroke incidence. Indeed, primary end points in clinical trials using lipid-lowering therapies (LLTs) were usually coronary events and/or mortality. Previous overviews of these randomized trials had suggested that cholesterol lowering could be effective in reduction of stroke incidence.36 Particularly, only the newest class of cholesterol-lowering drug, the hydroxymethyl glutaryl coenzyme A reductase inhibitors (statins), were efficient in stroke reduction in these meta-analyses.6,7 However, these overviews did not include 4 large randomized trials recently published: 2 trials testing fibrates8,9 and 2 trials testing statins.10,11

Moreover, why only statins and not the other LLT drugs or diets are successful in stroke prevention remains unresolved. It has been suggested that statins could prevent stroke by a mechanism other than cholesterol lowering.12 Indeed, in addition to their lipid-lowering effects, statins have been demonstrated to have a wide variety of effects, such as anti-inflammatory,13 antithrombotic,14 neuroprotective,15 and direct properties on endothelial cells and plaque stability,16 which may act on stroke prevention. However, fibrates have also been shown to improve endothelial function,17 to have anti-inflammatory effects,18,19 and to have favorable effects on several hemostatic variables.20

We then conducted a new meta-analysis of all randomized clinical trials testing LLT in primary or secondary prevention of coronary events, and providing information on stroke.

METHODS

Our study used a meta-analysis of all published randomized trials that examined the cardiovascular effects of any LLT. We initially conducted a computerized PubMed search of the literature to identify all trials testing LLTs limited to English-language articles published between 1966 and 2001. In addition, we searched the reference lists of published trials testing statins, other cholesterol-lowering drugs, diets, and previously conducted overviews. Criteria for inclusion of trials in the meta-analysis were (1) randomized and controlled trials testing LLT vs placebo and (2) trials providing data on stroke incidence #1fatal and/or nonfatal strokes). Strokes included ischemic and hemorrhagic strokes. Transient ischemic attacks were not considered because diagnostic criteria for such events were variable and not always reported in the trials. We included trials enrolling participants free of heart disease at baseline #1primary prevention) and trials selecting participants with heart disease history (secondary prevention). We included trials with interventions in addition to lipid lowering (multiple intervention). We excluded crossover trials21 and short-term efficacy trials using serum cholesterol level as the primary end point. To ensure comparability of the included studies, we excluded 3 trials: 1 trial in which patients in both the control and intervention groups received simvastatin22; 1 trial that was restricted to patients with previous stroke, with a small number of patients and a much higher risk of stroke than all other trials23; and 1 trial because lovastatin was given at different dosages to patients and data were not provided for each group.24 In the selected trials, we studied also the effect of LLT on myocardial infarction #1MI) (fatal and nonfatal) and compared both effects on MI and stroke.

The pooled estimate of the overall relative risk (RR) was calculated by using, for each study, the inverse variance weighted RR. As is usual in meta-analysis, a χ2 test for association on the pooled estimate of overall RR and a χ2 test for homogeneity of RR between trials and between subgroups were performed. P values for significance were set at .05 for χ2 test for association and at .10 for χ2 test for homogeneity.

Means of age, follow-up, baseline and final total cholesterol levels, and total cholesterol reduction were expressed as arithmetic means weighted with the number of randomized patients in each trial. Baseline cholesterol level was defined as the average of total plasma cholesterol level in the control and treated groups before treatment. Final cholesterol level was defined as the average of the last value of total cholesterol provided in the treated group. The percentage of total cholesterol reduction (TCr) for each trial was calculated as the percentage of total cholesterol reduction during the study (variable delay according to available data for each study) between the treated (t) and control (c) groups: TCr = TCr(t) − TCr(c). We investigated relationships between annual stroke rate in the placebo and in the treated groups of trials testing LLTs in primary or secondary prevention, according to the "effect model" analysis described by Walter.25 Briefly, 3 possibilities can occur: (1) the effect model is multiplicative when the regression line slope is different from 1 and the 95% confidence interval #1CI) of the intercept includes the origin, meaning that the relative risk reduction (RRR) is constant whatever the incidence of event in the placebo group; (2) the effect model is additive when the slope is close to 1 and the 95% CI of the intercept does not include the origin, meaning that absolute risk reduction is constant; and (3) the effect model is mixed when the slope is different from 1 and the 95% CI of the intercept does not include the origin; in this last case neither the RRR nor the absolute risk reduction is constant with the incidence of the disease in the placebo group. This method allows one to investigate whether the treatment effect is dependent on the baseline risk in the studied population, ie, virtually the disease severity.

Finally, to test a dose-response relationship between the treatment effect on stroke incidence and its effect on cholesterol reduction, we used an inverse variance weighted linear regression between the RRR and baseline cholesterol level, percentage of cholesterol reduction, or final cholesterol level. Trials in which baseline cholesterol level, final cholesterol level, or cholesterol reduction data were not available were excluded from this analysis. The statistical analysis for the meta-analysis was performed with EasyMA software #1Department of Clinical Pharmacology, Cardiological Hospital, Lyon, France; available at: http://www.spc.univ-lyon1.fr/~mcu/easyma/) and, for the regression, with STATISTICA 5.1 software (StatSoft, Tulsa, Okla).

RESULTS
TRIAL CHARACTERISTICS

We found 38 independent trials of LLT that fit our criteria (Table 1). All of these studies were primary #110 trials) or secondary (28 trials) coronary heart disease prevention trials. Interventions for lipid lowering were classified as follows: (1) statins, including 15 studies (8 with pravastatin sodium,2633 3 with lovastatin,3436 3 with simvastatin,11,37,38 and 1 with atorvastatin calcium10); (2) nonstatin drugs, including 13 trials (3 with clofibrate,3941 2 with cholestyramine resin,4244 3 with gemfibrozil,9,45,46 1 with bezafibrate,8 1 with colestipol hydrochloride,47 1 with clofibrate plus niacin,48 and 1 trial testing clofibrate with or without niacin49 [see next sentence]); (3) diet, including 7 trials44,5055; and (4) 3 other interventions, including 1 trial testing LLT with various drugs vs placebo,56 1 trial testing multifactorial advice (stop smoking and diet),57 and 1 trial testing ileal bypass.58 Two trials included 3 groups: the Coronary Drug Project (CDP) trial49 included 1 group treated with clofibrate alone, 1 group treated with niacin, and a placebo group; and the St Thomas' Atherosclerosis Regression Study trial44 randomized patients in 1 placebo group, 1 diet group, and 1 cholestyramine group. For the meta-analysis, each intervention group for these 2 trials was separately analyzed vs placebo.

Altogether, the data represented 83 161 patients (39 943 and 43 218 patients in the treatment and placebo groups, respectively), with 672 and 939 fatal and nonfatal strokes in the treatment and placebo groups, respectively. The average baseline total cholesterol level was 240 mg/dL (6.2 mmol/L), and the mean total cholesterol reduction in the treated group was 14.6%. This cholesterol reduction was dramatically higher than that in a previous meta-analysis performed 8 years earlier (only 7.3%), before the use of statins.7 The mean follow-up for all the trials was 4.7 years.

META-ANALYSIS ON STROKE INCIDENCE

The meta-analysis of all trials showed that LLTs significantly reduced all stroke incidence (fatal plus nonfatal strokes) by 17% (P<.001; Figure 1) without significant heterogeneity either between trials (P = .80) or between the different studied subgroups (type of treatment, P = .15; type of prevention, P = .24). However, best efficacy was obtained with statin treatment (RRR, 24%; RR, 0.76; 95% CI, 0.66-0.87; Figure 2) and in secondary prevention (RRR, 26%; RR, 0.74; 95% CI, 0.64-0.86; Figure 3). The LLTs did not reduce fatal stroke incidence (RR, 1.09; 95% CI, 0.86-1.38; Figure 4).

Information on incidence of hemorrhagic stroke was provided in 10 trials #130 766 patients). Hemorrhagic stroke occurred in 31 patients among control groups and 45 in LLT groups. The use of LLT did not significantly modify such incidence (RR, 1.16; 95% CI, 0.75-1.80).

The RRR of fatal and nonfatal MI by LLT was 22% (P<.001; Figure 4). Given the annual incidence of stroke (0.8%) and MI (4.8%), and the overall RRR obtained with LLT on these 2 outcomes (17% and 22%, respectively), the calculated number of patients to be treated during 1 year (number needed to treat [NNT] = 1/[incidence × RRR]) to avoid 1 stroke (NNT = 735) was dramatically higher than for MI (NNT = 95).

EFFECT MODEL ANALYSIS

To investigate whether the effect of LLTs on stroke risk reduction was related to the incidence of stroke in the studied population, we performed an effect model analysis with the use of the Walter weighted regression model,25 testing the relationship between the annual stroke rate in the placebo and LLT groups for each trial (Figure 5). The slope of the regression line was different from 1 #10.75; 95% CI, 0.64-0.87) and the 95% CI of the intercept included the origin #1intercept, 0.000; 95% CI, 0.000-0.001), demonstrating that the effect model was multiplicative (see the "Methods" section). This result indicates that the RRR of stroke was constant whatever the incidence of event in the placebo group, and predicts that LLT effect on stroke incidence should be the same #1in terms of RRR) in a population with a higher risk of stroke (ie, in stroke secondary prevention).

RELATIONSHIP BETWEEN CHOLESTEROL AND STROKE INCIDENCE

Our results showed that different classes of lipid-lowering drugs, statins and nonstatin drugs (but also other LLTs such as diet), did not have the same effect on stroke prevention (see Figure 2). Statins and nonstatin drugs also did not have the same efficacy on cholesterol lowering: statins induced an average total cholesterol reduction of 21.8% as opposed to only 8.3% with nonstatin drugs. We then studied the relationship between total cholesterol levels (baseline, final, and change) and stroke incidence reduction (RRR). The weighted linear correlation between these variables provided the following results (Table 2).

Stroke incidence RRR was significantly correlated with cholesterol reduction #1r = 0.46; P<.001), baseline cholesterol level (r = −0.47; P<.001), and final cholesterol level (r = −0.69; P<.001). The threshold of cholesterol reduction to induce a beneficial effect on stroke incidence (RRR>0) was around 2%. However, the strongest correlation was found between RRR and the final cholesterol level (r2 = 0.48). More important, only the final cholesterol level allowed a clear separation between absence and presence of stroke reduction (RRR>0 and RRR<0). The cutoff value of such final cholesterol level appeared around 232 mg/dL (6.0 mmol/L) (Figure 6A).

Results for the relationship between RRR for MI and cholesterol measures were different from those for stroke. The RRR of MI was significantly correlated with cholesterol reduction (r = 0.50; P<.001) and final cholesterol level (r = −0.39; P<.001) but not with baseline cholesterol level (r = −0.03; P = .22). The strongest correlation was found between RRR and cholesterol reduction and not final cholesterol level. Final cholesterol value did not allow the clear separation of treatment efficacy for MI that was observed with stroke, since RRR was positive for MI whatever the cholesterol level (Figure 6B).

COMMENT

The results of this meta-analysis provide strong evidence in favor of the potential of LLTs to prevent stroke. Such preventive effect appears related to efficacy of LLT to lower blood cholesterol levels, explaining why the most convincing results are obtained with statins. Indeed, optimal prevention appears to be obtained when cholesterol level is lowered to less than 232 mg/dL (6.0 mmol/L).

Our results confirm previous overviews,37 adding the new published trials MIRACL (Myocardial Ischemia Reduction With Aggressive Cholesterol Lowering), SCAT (Simvastatin/Enalapril Coronary Atherosclerosis Trial), BIP (Bezafibrate Infarction Prevention Study), and VA-HIT (Veterans Affairs High-Density Lipoprotein Intervention Trial). The recently completed HPS (Heart Protection Study) provides similar results.59 However, all of these clinical trials included patients with or without coronary disease, and their main objective was not stroke reduction but death, cardiovascular death, and recurrence of MI. Stroke was included as a secondary end point. Therefore, no controlled trial had stroke prevention as a primary end point. Such trials are, however, ongoing and including a much more aged population at higher risk of stroke. This explains why in all trials in this overview incidence of stroke was very low, especially in the case of primary cardiovascular disease prevention, reducing the power of the comparison. Therefore, stroke reduction was significant only in cardiovascular secondary prevention (19%) and not in cardiovascular primary prevention (5%).

Similarly, no heterogeneity of LLT effect could be detected between the different types of treatments, but the greatest amplitude of stroke reduction was obtained with statins (RRR, 24%; P<.001; Figure 2). With the other treatment groups, the stroke reduction was nonsignificant: nonstatin drugs (RR, 0.93; 95% CI, 0.79-1.08), diet (RR, 0.60; 95% CI, 0.32-1.13), and other interventions (RR, 1.0; 95% CI, 0.62-1.60).

In cardiovascular secondary prevention trials, representing the subgroup providing the best estimation of treatment effect, statins reduced stroke incidence by 26% (P<.001). Moreover, the effect model predicted a constant RRR of stroke with LLT whatever the stroke incidence. This means that a 26% stroke reduction could be expected with statins in a population of patients with a history of stroke in which the annual incidence of stroke recurrence is much higher and estimated around 8%.6062 Statins in such a population could then prevent 20 strokes for 1000 patients treated during 1 year. This is close to the benefit obtained with antithrombotic drugs in secondary prevention of stroke.63,64 If such a result is confirmed by further studies, this should place statins in the first line of treatment in stroke prevention.

The fact that the best effect was obtained with statins suggests 2 hypotheses3: (1) statins have other properties in addition to cholesterol lowering that may explain their ability to prevent stroke; or #12) stroke prevention by LLT is related to cholesterol lowering, but nonstatin therapies are less efficient than statins in cholesterol lowering. To answer this question, we explored relationships between LLT effects on event prevention #1MI and stroke) and blood lipid measures (total cholesterol levels and change during therapy).

The most meaningful result was the strong correlation between RRR of stroke and final cholesterol level. This correlation could separate beneficial #1RRR>0) from nonbeneficial (RRR<0) effect of LLT on stroke incidence. The cutoff for RRR greater than 0 was around 232 mg/dL (6.0 mmol/L). An a posteriori meta-analysis confirmed this result: stroke incidence was significantly reduced by 19% in the 9 nonstatin trials in which the mean of final cholesterol level was lower than 232 mg/dL (6.0 mmol/L) (RR, 0.82; P = .045; data not shown). Furthermore, a recent subgroup analysis from the VA-HIT trial showed that gemfibrozil may be more effective to reduce stroke incidence in patients with low levels of high-density lipoprotein cholesterol and low levels of low-density lipoprotein cholesterol, ie, patients with low total cholesterol level.65 Altogether, these results suggest that the difference in stroke prevention observed between statins and nonstatin therapies may be due to difficulties to reach the final cholesterol level of 232 mg/dL (6.0 mmol/L) with nonstatin therapies.

The different relationships between RRR of stroke or MI prevention and cholesterol measures (see Table 2) may be explained, in part, by the differences existing in terms of impact of lipid metabolism as a risk factor on stroke and MI. Indeed, high cholesterol level is a stronger risk factor for coronary heart disease66 than for stroke.2 Moreover, high-density lipoprotein cholesterol seems to be a stronger risk factor for stroke than total or low-density lipoprotein cholesterol.67,68 A meta-regression between cholesterol fractions and the RRR of stroke could not be performed because not all trials provided such data, and because the range of high-density lipoprotein and low-density lipoprotein cholesterol levels or change between trials was very low. An individual data analysis with these cholesterol measures should be of interest to investigate this question.

As in any meta-analysis, information bias cannot be totally avoided. Indeed, in some trials, mainly nonstatin trials, information on stroke incidence was not complete. However, the amount of lacking information provided by these trials represents a very low percentage of the total number of included patients and does not significantly influence the overall result. In this meta-analysis, all strokes were considered, which probably underestimates the real impact of LLT. Indeed, LLT should mainly prevent ischemic strokes due to atherosclerosis. Available data from the studied trials did not allow separation of such strokes with strokes from other origins, especially cardioembolic strokes. Incidence of hemorrhagic strokes did not seem to be influenced by LLT. Since these strokes are most often fatal, this result could partly explain the apparent lack of effect of LLT on fatal strokes.

In conclusion, LLT appears to reduce stroke incidence in coronary patients. Such benefit appears to be related to blood cholesterol lowering, which explains why statin drugs provide the most consistent benefit among trials. If a similar stroke incidence reduction (observed in high-risk coronary patients) could be extended to a higher-risk stroke population, LLT will become essential drugs for secondary stroke prevention.

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Article Information

Corresponding author and reprints: Philippe Lechat, MD, PhD, Service de Pharmacologie, CHU Pitié-Salpêtrière, 47-83 Bd de l'Hôpital, 75651 Paris CEDEX 13, France (e-mail: philippe.lechat@psl.ap-hop-paris.fr).

Accepted for publication June 19, 2002.

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