1. Gemfibrozil for the Secondary Prevention of Coronary Heart Disease in Men with Low Levels of High-Density Lipoprotein Cholesterol VA-HIT Rubins, HB, et al, for the Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial Study Group N Eng J Med, August 5, 1999 Vol. 341:410-418

2. VA-HIT: Background It is generally accepted that lowering LDL cholesterol in patients with CHD is beneficial.It is generally accepted that lowering LDL cholesterol in patients with CHD is beneficial. Few data exist, however, to guide the treatment of patients whose primary lipid abnormality is low HDL.Few data exist, however, to guide the treatment of patients whose primary lipid abnormality is low HDL. N Eng J Med, August 5, 1999 Vol. 341:410-418

3. VA-HIT: Hypothesis Treatment of men with CHD whose primary lipid abnormality is low HDL-C will reduce the endpoint of CHD death and non-fatal M.I.Treatment of men with CHD whose primary lipid abnormality is low HDL-C will reduce the endpoint of CHD death and non-fatal M.I. Gemfibrozil is the drug most likely to favorably affect HDL-C and triglycerides with the least effect on LDL- cholesterol.Gemfibrozil is the drug most likely to favorably affect HDL-C and triglycerides with the least effect on LDL- cholesterol. N Eng J Med, August 5, 1999 Vol. 341:410-418

4. VA-HIT: Study Design 2,531 men with coronary heart disease2,531 men with coronary heart disease –average age: 64yrs –90% white, 57% with hypertension, 25% diabetic, 61% prior MI, 22% current smokers Double-blind trial comparing:Double-blind trial comparing: –Gemfibrozil 1200 mg/d –placebo HDL < 40 mg/dL (average: ~ 32 mg/dL)HDL < 40 mg/dL (average: ~ 32 mg/dL) LDL-C < 140 mg/dL (average: ~ 111 mg/dL)LDL-C < 140 mg/dL (average: ~ 111 mg/dL) TG < 300 mg/dL (average: ~ 161 mg/dL)TG < 300 mg/dL (average: ~ 161 mg/dL) N Eng J Med, August 5, 1999 Vol. 341:410-418

5. Primary endpoint: nonfatal MI or death from coronary heart diseasePrimary endpoint: nonfatal MI or death from coronary heart disease Secondary endpoints: stroke, death from any cause, TIA, revascularization procedures, carotid endarterectomy, and hospitalization for unstable angina or CHF.Secondary endpoints: stroke, death from any cause, TIA, revascularization procedures, carotid endarterectomy, and hospitalization for unstable angina or CHF. Median follow-up 5.1 yearsMedian follow-up 5.1 years VA-HIT: Study Design N Eng J Med, August 5, 1999 Vol. 341:410-418

6. VA-HIT: Mean Plasma Lipid Changes, Year One N Eng J Med, August 5, 1999 Vol. 341:410-418 6% increase p<0.001 31% decrease p<0.001 4% decrease p<0.001 P=NS

7. VA-HIT: Lipid Effects N Eng J Med, August 5, 1999 Vol. 341:410-418

8. VA-HIT: Lipid Effects N Eng J Med, August 5, 1999 Vol. 341:410-418

9. VA-HIT: Results Increased HDL 6%Increased HDL 6% Decreased TG 31%Decreased TG 31% Decreased TC 4%Decreased TC 4% No change in LDLNo change in LDL Primary event (death from CHD or nonfatal M.I.) occurred in:Primary event (death from CHD or nonfatal M.I.) occurred in: –275 of 1267 patients on placebo (21.7%) –219 of 1264 patients on gemfibrozil (17.3%) N Eng J Med, August 5, 1999 Vol. 341:410-418

10. VA-HIT: Results Primary endpoint:Primary endpoint: –22 % risk reduction in nonfatal MI or death from CHD (p=0.006) Secondary endpoints:Secondary endpoints: –24% risk reduction in CHD death, nonfatal MI and confirmed stroke combined (p< 0.001) –22% risk reduction in CHD death (p = 0.07) –23% risk reduction in nonfatal MI (p = 0.02) –25% risk reduction in confirmed stroke (p = 0.10) –59% risk reduction in TIA (p<0.001) –65% risk reduction in carotid endarterectomy (p<0.001) N Eng J Med, August 5, 1999 Vol. 341:410-418

11. There was no significant difference in rates of coronary revascularization, hospitalization for unstable angina, death from any cause, and cancer between patients randomized to gemfibrozil or placebo.There was no significant difference in rates of coronary revascularization, hospitalization for unstable angina, death from any cause, and cancer between patients randomized to gemfibrozil or placebo. Gemfibrozil was generally well tolerated. Dyspepsia occurred in 40% of patients taking gemfibrozil and 34% of patients taking placebo (p=0.002)Gemfibrozil was generally well tolerated. Dyspepsia occurred in 40% of patients taking gemfibrozil and 34% of patients taking placebo (p=0.002) The beneficial effects of gemfibrozil did not become apparent until 2 years after randomization.The beneficial effects of gemfibrozil did not become apparent until 2 years after randomization. VA-HIT: Results N Eng J Med, August 5, 1999 Vol. 341:410-418

12. VA-HIT: Primary Endpoint Results 22% Relative Risk Reduction (p = 0.006) Nonfatal M.I. or CHD Death, % N Eng J Med, August 5, 1999 Vol. 341:410-418

13. VA-HIT: Results by Baseline HDL-C Death due to CHD, Nonfatal MI or Confirmed Stroke 30% risk reduction p=0.003 24% risk reduction p=0.03 N Eng J Med, August 5, 1999 Vol. 341:410-418

14. VA-HIT: Results by Baseline LDL-C Death due to CHD, Nonfatal MI or Confirmed Stroke P< 0.04 P< 0.003 P< 0.46 P< 0.008 P< 0.02 N Eng J Med, August 5, 1999 Vol. 341:410-418

15. VA-HIT: Results by Prespecified Subgroup CHD Death, Nonfatal MI, or Confirmed Stroke Risk Reduction (%): 22 26 24 27 25 24 P value: 0.04 0.007 0.002 0.20 0.11 0.004 P value: 0.04 0.007 0.002 0.20 0.11 0.004 N Eng J Med, August 5, 1999 Vol. 341:410-418

16. VA-HIT: Results by Prespecified Subgroup CHD Death, Nonfatal MI, or Confirmed Stroke Risk Reduction (%): -16 34 24 24 17 34 P value: 0.41 0.001 0.05 0.009 0.09 0.002 P value: 0.41 0.001 0.05 0.009 0.09 0.002 N Eng J Med, August 5, 1999 Vol. 341:410-418

17. VA-HIT: Results by Prespecified Subgroup CHD Death, Nonfatal MI, or Confirmed Stroke Risk Reduction (%): 27 19 20 42 14 31 P value: 0.002 0.17 0.02 0.007 0.24 0.001 P value: 0.002 0.17 0.02 0.007 0.24 0.001 N Eng J Med, August 5, 1999 Vol. 341:410-418

18. VA-HIT: Conclusions The results of this study suggest that raising HDL cholesterol and lowering levels of TG, without lowering LDL cholesterol level, reduces major coronary events in patients whose primary lipid abnormality is a low HDL cholesterol levelThe results of this study suggest that raising HDL cholesterol and lowering levels of TG, without lowering LDL cholesterol level, reduces major coronary events in patients whose primary lipid abnormality is a low HDL cholesterol level A 6% increase in HDL and a 31% decrease in TG resulted in 24% decrease in CHD death, nonfatal MI and stroke combined.A 6% increase in HDL and a 31% decrease in TG resulted in 24% decrease in CHD death, nonfatal MI and stroke combined. N Eng J Med, August 5, 1999 Vol. 341:410-418