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(Circulation. 2001;103:2828.)
© 2001 American Heart Association, Inc.

Clinical Investigation and Reports

Reduction in Stroke With Gemfibrozil in Men With Coronary Heart Disease and Low HDL Cholesterol

The Veterans Affairs HDL Intervention Trial (VA-HIT)

Hanna Bloomfield Rubins, MD, MPH; John Davenport, MD; Viken Babikian, MD; Lawrence M. Brass, MD; Dorothea Collins, ScD; Laura Wexler, MD; Stephen Wagner, MD; Vassilios Papademetriou, MD; Gale Rutan, MD; Sander J. Robins, MD; for the VA-HIT Study Group

From the Center for Chronic Disease Outcomes Research, VAMC, Minneapolis (H.B.R.), and Department of Neurology, Park Nicollet Clinic, St Louis Park (J.D.), Minn; Department of Neurology, VAMC (V.B.), and Department of Medicine, Boston University School of Medicine (S.J.R.), Boston, Mass; Department of Neurology, VAMC (L.M.B.), and Department of Veterans Affairs Cooperative Studies Program Coordinating Center (D.C.), West Haven, Conn; Department of Medicine, VAMC, Cincinnati, Ohio (L.W.); Department of Medicine, VAMC, Louisville, Ky (S.W.); Department of Medicine, VAMC, Washington, DC (V.P.); and Department of Medicine, VAMC, Memphis, Tenn (G.R.). Dr Rutan is now at Roudebush VAMC, Indianapolis, Ind.

	Abstract

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Background—A low level of HDL cholesterol has been identified as a risk factor for stroke in observational studies.

Methods and Results—Our objective was to determine whether treatment aimed at raising HDL cholesterol and lowering triglycerides reduces stroke in men with coronary heart disease and low levels of both HDL and LDL cholesterol. The study was a placebo-controlled, randomized trial conducted in 20 Veterans Affairs medical centers. A total of 2531 men with coronary heart disease, with mean HDL cholesterol 0.82 mmol/L (31.5 mg/dL) and mean LDL cholesterol 2.9 mmol/L (111 mg/dL), were randomized to gemfibrozil 1200 mg/d or placebo and were followed up for 5 years. Strokes were confirmed by a blinded adjudication committee. Relative risks were derived from Cox proportional hazards models. There were 134 confirmed strokes, 90% of which were ischemic. Seventy-six occurred in the placebo group (9 fatal) and 58 in the gemfibrozil group (3 fatal), for a relative risk reduction, adjusted for baseline variables, of 31% (95% CI, 2% to 52%, P=0.036). The reduction in risk was evident after 6 to 12 months. Patients with baseline HDL cholesterol below the median may have been more likely to benefit from treatment than those with higher HDL cholesterol.

Conclusions—In men with coronary heart disease, low HDL cholesterol, and low LDL cholesterol, gemfibrozil reduces stroke incidence.

Key Words: coronary disease • stroke • gemfibrozil • cholesterol

	Introduction

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Alow level of HDL cholesterol is a known risk factor for coronary heart disease (CHD),¹ and several prospective cohort studies suggest that HDL cholesterol is a significant, independent risk factor for stroke.^{2 3 4} Confirmatory clinical trial data, however, have not been available, because until recently there were no trials with a specific focus on HDL cholesterol. The VA HDL Intervention Trial (VA-HIT) was the first major trial to assess the effect of raising HDL cholesterol and lowering triglycerides in patients with CHD whose predominant lipid abnormality was low HDL cholesterol.⁵ In VA-HIT, treatment with gemfibrozil resulted in significant changes in HDL cholesterol, total cholesterol, and triglycerides, which were 6% higher and 4% and 31% lower, respectively, in the gemfibrozil than the placebo group (all P<0.001). The mean LDL cholesterol was not affected by treatment.⁵ The primary end point in VA-HIT was CHD death and nonfatal myocardial infarction. Cerebrovascular events were prespecified secondary end points, however, and all clinically suspected strokes were formally adjudicated during the trial. The purpose of the present report is to describe the effect of gemfibrozil on stroke incidence in VA-HIT.

	Methods

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Overview
The design and major results of VA-HIT have been reported previously.^{5 6 7} Briefly, men <74 years old were eligible if they had an established diagnosis of CHD and an HDL cholesterol <1.03 mmol/L (40 mg/dL), an LDL cholesterol <3.6 mmol/L (140 mg/dL), and triglycerides <3.39 mmol/L (300 mg/dL). During 1991 to 1993, 2531 patients were randomized to either gemfibrozil 1200 mg/d or matching placebo and were then followed up for an average of 5.1 years.

Ascertainment of Cerebrovascular Events
Patients were seen every 3 months by the study coordinator, who reviewed the patient’s medical record and inquired about new events, including transient ischemic attacks (TIAs), strokes, surgeries, and hospitalizations. TIAs and carotid endarterectomies were included only if confirmed by physician notes in the written medical record.

Adjudication of Strokes
Two of a panel of 3 neurologists (J.D., V.B., L.B.), blinded to treatment assignment, reviewed the records for each investigator-designated stroke. Using preset criteria, reviewers determined the presence or absence of a stroke using all available notes, consultations, laboratory information, and x-ray CT or MRI studies. In the event of initial disagreement between the 2 reviewers, the materials were reviewed by all 3 neurologists, and disagreements were resolved by consensus.

Ischemic stroke subtypes followed established definitions.⁸ Atherothrombotic stroke was defined as a territorial brain infarct in any distribution, with stenosis or occlusion of a large extracranial or intracranial artery serving that territory. Lacunar stroke was defined as one of the more common syndromes of pure motor or sensory hemideficit or the less common hemiataxia or dysarthria, with or without a small, deep cerebral or brain stem imaging abnormality, and the absence of large-vessel pathology or cardiac source of embolism. Cardioembolic stroke was defined by the presence of any high-probability cardiac source of embolism (eg, atrial fibrillation, valvulopathy, endocarditis, cardiac surgical procedure, major left ventricular akinesis) in the presence of a nonlacunar, territorial clinical syndrome. Ischemic strokes were classified as unknown subtype if the clinical deficit was nonlacunar and there was no cardioembolic source. Ischemic strokes with inadequate or conflicting clinical data were also designated as of unknown subtype. Hemorrhagic stroke (subarachnoid or primary intraparenchymal) was designated exclusively by brain imaging confirmation. Strokes were classified as undetermined type if there were no imaging studies to determine hemorrhage status. A stroke was determined to be fatal by consensus of the panel of neurologists and the primary end-points committee, which adjudicated all deaths.

Statistical Analysis
Baseline variables are compared in subjects with and without confirmed stroke by ² and t tests. Cox proportional hazards analyses, adjusting for treatment effect, were used to derive the relative risk of a stroke for each baseline characteristic. To determine the magnitude of the treatment effect, adjusting for all baseline variables shown in Table 1, we used multivariate Cox analysis. To determine relative risk reductions in subgroups, we ran separate univariate Cox models for each patient subgroup, with treatment group as the sole independent variable and time to first stroke as the dependent variable. Similar models were used, with an interaction term, to assess the homogeneity of the treatment effect across the subgroup categories. Analyses were performed separately for all strokes and for ischemic strokes only. Because results were virtually identical, only the former are shown.

View this table: [in this window] [in a new window]   Table 1. Risk Factors for Stroke

Informed Consent
This study was approved by the Human Rights Committee of the Cooperative Studies Program Coordinating Center and by each center’s institutional review board. All patients gave written informed consent.

	Results

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Baseline characteristics of patients with and without stroke are shown in Table 1. Overall, the population had a mean age of 64 years, with >70% >60 years old, and a high prevalence of hypertension, diabetes, and obesity. More than 80% were taking aspirin. Patients who experienced a confirmed stroke were older and were more likely to be nonwhite and to have hypertension, diabetes, and prior stroke than patients without stroke. They were also more likely to be on digoxin, possibly a marker for atrial fibrillation, because patients with chronic heart failure were excluded from the trial. We have no data, however, on atrial fibrillation in our population.

As previously reported, gemfibrozil was associated with a 59% reduction in TIAs (95% CI, 33% to 75%, P<0.001) and a 65% reduction in carotid endarterectomies (95% CI, 37% to 80%, P<0.001).⁵ The remainder of this article discusses strokes.

There were a total of 174 reported strokes in 152 patients. Of the 152 reported first strokes, 134 were confirmed by the adjudication committee, 76 in the placebo group (6%) and 58 in the gemfibrozil group (4.6%). This represents an absolute risk reduction of 1.4% and a relative risk reduction, adjusted for all the baseline variables shown in Table 1, of 31% (95% CI, 2% to 52%, P=0.036). In the unadjusted analysis previously reported, the relative risk reduction was 25% (95% CI, -6% to 47%, P=0.098).⁵

The vast majority (90%) of strokes were ischemic, and the beneficial effect of gemfibrozil was largely confined to these strokes, specifically to atherothrombotic strokes (Table 2). There was no difference between treatment groups in incidence of lacunar or cardioembolic strokes. A total of 12 strokes were fatal, 9 in the placebo group and 3 in the gemfibrozil group. Overall, 38 strokes (evenly divided by treatment groups) were preceded by a cardiovascular event (myocardial infarction, hospitalization for unstable angina, or coronary revascularization). Only 4 strokes were preceded by a TIA and 1 by a carotid endarterectomy. As shown in the Figure, the time-to-event curves for strokes began to separate early, within 6 to 12 months after the initiation of therapy.

View this table: [in this window] [in a new window]   Table 2. Stroke Types by Treatment Group

View larger version (13K): [in this window] [in a new window]   Figure 1. Cumulative incidence of confirmed strokes by treatment group.

Table 3 shows the results of the subgroup analysis designed to explore whether the efficacy of gemfibrozil varied by baseline characteristics. For all variables, the test for heterogeneity was not significant, indicating that the treatment effect did not differ between levels of any of the baseline variables. For baseline HDL cholesterol, however, the interaction term was of borderline significance (P=0.05), suggesting that persons with HDL cholesterol <0.81 mmol/L (31.5 mg/dL) may have benefited more from gemfibrozil treatment than those with higher HDL cholesterol.

View this table: [in this window] [in a new window]   Table 3. Effect of Gemfibrozil on Confirmed Strokes in Subgroups

	Discussion

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This report shows that gemfibrozil reduced strokes by 31% (95% CI, 2% to 52%, P=0.036) in men with CHD whose predominant lipid abnormality was low HDL cholesterol. This is the first major trial to show that therapy aimed at raising HDL cholesterol and lowering triglycerides reduces stroke incidence. The reduction in confirmed strokes was due to a reduction in ischemic, specifically atherothrombotic, strokes. Gemfibrozil also appeared to be particularly effective in preventing fatal strokes.

Several clinical trials using statins for the primary or secondary prevention of CHD in people with moderate to high levels of cholesterol have reported a significantly decreased incidence of cerebrovascular events.^{9 10} These trials suggest that treatment with statins is associated with a significant 25% to 30% reduction in the incidence of strokes among patients with preexisting CHD and with a nonsignificant reduction in strokes in patients without preexisting CHD.^{11 12 13 14} Also noted was a slight but nonsignificant excess in fatal strokes in patients treated with statins.^{12 13} More recently, the large Long Term Intervention with Pravastatin in Ischemic Disease (LIPID) study reported a 19% reduction in total strokes (P=0.05), a 23% reduction in ischemic strokes (P=0.02), and no excess in fatal strokes in the pravastatin group.¹⁵ It is important to recognize, however, that the results of the statin trials apply to patients with a high-risk LDL cholesterol. Statins have never been tested in patients with the VA-HIT lipid profile, ie, low HDL cholesterol with low-risk LDL cholesterol.

Reduction in strokes and TIAs was also reported in the niacin arm of the Coronary Drug Project, an older secondary-prevention trial.¹⁶ We are aware of only 1 previous report, however, of the effect of gemfibrozil on cerebrovascular events. In the Helsinki Heart Study, a 5-year primary prevention trial in 4000 middle-aged men with high levels of non-HDL cholesterol, there were a total of 10 fatal cerebrovascular events, 6 in the gemfibrozil group and 4 in the placebo group.¹⁷ Thus, in this population, which was at very low risk of strokes because of young age, low prevalence of risk factors, and absence of preexisting heart disease, there was no evidence that gemfibrozil was either beneficial or harmful. This absence of benefit in the primary prevention setting has also been noted in the statin trials.

There are several possible pathophysiological mechanisms whereby gemfibrozil might prevent cerebrovascular disease. Gemfibrozil has been shown to decrease progression of atherosclerotic lesions in coronary arteries,¹⁸ and it is possible that a similar effect also occurs in the carotid arteries. Our finding of a substantial drop in atherothrombotic strokes is consistent with such a mechanism. A gemfibrozil effect on carotid atherosclerosis might have been mediated either through the increase in HDL cholesterol, the decrease in triglycerides, or other mechanisms. In some but not all studies, low HDL cholesterol, high fasting and postprandial triglycerides, and elevations of chylomicron and VLDL remnants have been associated with ultrasound-detected carotid atherosclerosis.^{19 20}

Fibrates have also been shown to improve endothelial function,²¹ to have anti-inflammatory effects that may stabilize atherosclerotic plaque,^{22 23 24} and to have favorable effects on several hemostatic parameters. Endothelial dysfunction and plaque destabilization are thought to be important mechanisms for coronary events, but their significance for stroke has not been well established. With regard to hemostasis, fibrates may cause reductions in factor VII, thrombin, white blood cell count, fibrinogen, and platelet reactivity and increases in fibrinolytic capacity.^{25 26} Several of these parameters have been identified in epidemiological studies as risk factors for stroke.^{27 28}

Effects on plaque stabilization, endothelial function, and hemostasis are attractive possible mechanisms for the favorable impact of gemfibrozil, because these would be consistent with the observation of an early reduction in events. This, incidentally, is in marked contrast to the statin trials, in which the lag time between initiation of therapy and evidence of benefit for cerebrovascular events was 3 to 3.5 years.^{29 30} Plaque stabilization, which influences large-vessel atherothrombosis preferentially, might also explain the observation that atherothrombotic but not lacunar strokes were reduced by gemfibrozil.

Interpretation of the results of this study should take into account the limitations of the study design. The primary purpose of VA-HIT was to determine the effect of gemfibrozil on CHD events in CHD patients with a unique lipid profile; strokes were secondary, albeit prespecified, end points. Nevertheless, strokes were adjudicated by rigorous procedures by an expert committee blinded to treatment assignment.

In conclusion, we have shown that gemfibrozil reduces the incidence of stroke in men with established CHD who have low levels of HDL cholesterol and low-risk LDL cholesterol. All subgroups examined appeared to benefit, including diabetics, the elderly, and patients on aspirin. To the best of our knowledge, this is the first trial to show that lipid therapy aimed at raising HDL cholesterol and lowering triglycerides reduces stroke incidence. Although gemfibrozil cannot be recommended specifically for prevention of stroke on the basis of this study, this may be an additional benefit for those patients in whom the drug is indicated for secondary prevention of CHD.

	Acknowledgments

 
VA-HIT was supported by the Cooperative Studies Program of the Department of Veterans Affairs Office of Research and Development and by a supplemental grant from Parke-Davis, a division of Warner-Lambert. We wish to acknowledge the VA-HIT patients and study personnel for their participation in this trial and Lucy Kraml for manuscript preparation.

	Footnotes

 
Reprint requests to Hanna Bloomfield Rubins, MD, MPH, Section of General Internal Medicine (1110), VAMC, Minneapolis, MN 55417.

The views expressed in this article do not necessarily represent the views of the Department of Veterans Affairs.

Members of the VA-HIT study group are listed in N Engl J Med. 1999;341:410–418.

Received December 18, 2000; revision received March 19, 2001; accepted March 28, 2001.

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				J. Okapcova and D. Gabor The Levels of Soluble Adhesion Molecules in Diabetic and Nondiabetic Patients with Combined Hyperlipoproteinemia and the Effect of Ciprofibrate Therapy Angiology, November 1, 2004; 55(6): 629 - 639. [Abstract] [PDF]

				Y. Agmon, B. K. Khandheria, I. Meissner, T. M. Petterson, W. M. O'Fallon, D. O. Wiebers, T. J. H. Christianson, J. P. McConnell, J. P. Whisnant, J. B. Seward, et al. C-Reactive Protein and Atherosclerosis of the Thoracic Aorta: A Population-Based Transesophageal Echocardiographic Study Arch Intern Med, September 13, 2004; 164(16): 1781 - 1787. [Abstract] [Full Text] [PDF]

				J. D. Curb, R. D. Abbott, B. L. Rodriguez, K. H. Masaki, R. Chen, J. S. Popper, H. Petrovitch, G. W. Ross, I. J. Schatz, G. C. Belleau, et al. High Density Lipoprotein Cholesterol and the Risk of Stroke in Elderly Men: The Honolulu Heart Program Am. J. Epidemiol., July 15, 2004; 160(2): 150 - 157. [Abstract] [Full Text] [PDF]

				K. Kuwabara, K. Murakami, M. Todo, T. Aoki, T. Asaki, M. Murai, and J. Yano A Novel Selective Peroxisome Proliferator-Activated Receptor {alpha} Agonist, 2-Methyl-c-5-[4-[5-methyl-2-(4-methylphenyl)-4-oxazolyl]butyl]-1,3-dioxane-r-2-carboxylic acid (NS-220), Potently Decreases Plasma Triglyceride and Glucose Levels and Modifies Lipoprotein Profiles in KK-Ay Mice J. Pharmacol. Exp. Ther., June 1, 2004; 309(3): 970 - 977. [Abstract] [Full Text] [PDF]

				J. P.J. Halcox and J. E. Deanfield Beyond the Laboratory: Clinical Implications for Statin Pleiotropy Circulation, June 1, 2004; 109(21_suppl_1): II-42 - II-48. [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]

				D. N. Muller, J. Theuer, E. Shagdarsuren, E. Kaergel, H. Honeck, J.-K. Park, M. Markovic, E. Barbosa-Sicard, R. Dechend, M. Wellner, et al. A Peroxisome Proliferator-Activated Receptor-{alpha} Activator Induces Renal CYP2C23 Activity and Protects from Angiotensin II-Induced Renal Injury Am. J. Pathol., February 1, 2004; 164(2): 521 - 532. [Abstract] [Full Text] [PDF]

				T. S. Bowman, H. D. Sesso, J. Ma, T. Kurth, C. S. Kase, M. J. Stampfer, and J. M. Gaziano Cholesterol and the Risk of Ischemic Stroke Stroke, December 1, 2003; 34(12): 2930 - 2934. [Abstract] [Full Text] [PDF]

				D. Deplanque, P. Gele, O. Petrault, I. Six, C. Furman, M. Bouly, S. Nion, B. Dupuis, D. Leys, J.-C. Fruchart, et al. Peroxisome Proliferator-Activated Receptor-{alpha} Activation as a Mechanism of Preventive Neuroprotection Induced by Chronic Fenofibrate Treatment J. Neurosci., July 16, 2003; 23(15): 6264 - 6271. [Abstract] [Full Text] [PDF]

				A. W. E. Weverling-Rijnsburger, I. J. A. M. Jonkers, E. van Exel, J. Gussekloo, and R. G. J. Westendorp High-Density vs Low-Density Lipoprotein Cholesterol as the Risk Factor for Coronary Artery Disease and Stroke in Old Age Arch Intern Med, July 14, 2003; 163(13): 1549 - 1554. [Abstract] [Full Text] [PDF]

				J.-C. Corvol, A. Bouzamondo, M. Sirol, J.-S. Hulot, P. Sanchez, and P. Lechat Differential Effects of Lipid-Lowering Therapies on Stroke Prevention: A Meta-analysis of Randomized Trials Arch Intern Med, March 24, 2003; 163(6): 669 - 676. [Abstract] [Full Text] [PDF]

				C. Parolini, G. Chiesa, Y. Zhu, T. Forte, S. Caligari, E. Gianazza, M. G. Sacco, C. R. Sirtori, and E. M. Rubin Targeted Replacement of Mouse Apolipoprotein A-I with Human ApoA-I or the Mutant ApoA-IMilano. EVIDENCE OF APOA-IM IMPAIRED HEPATIC SECRETION J. Biol. Chem., February 7, 2003; 278(7): 4740 - 4746. [Abstract] [Full Text] [PDF]