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Plasma Homocysteine and Coronary Heart Disease David S. Rosenblatt, MD Department of Human Genetics McGill University.

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Presentation on theme: "Plasma Homocysteine and Coronary Heart Disease David S. Rosenblatt, MD Department of Human Genetics McGill University."— Presentation transcript:

1 Plasma Homocysteine and Coronary Heart Disease David S. Rosenblatt, MD Department of Human Genetics McGill University

2 OBJECTIVES 1)To describe the evidence for a role for homocysteine in coronary artery and vascular disease 2)To present evidence from recent prospective trials

3 Homocysteine and Heart Disease Evidence from Inborn Errors of Metabolism

4 In 1969, Kilmer McCully proposed the homocysteine hypothesis of vascular disease based on autopsy findings of extensive atherosclerosis and arterial thrombosis in two children-one with classical homocystinuria and one with an inborn error of vitamin B 12 metabolism.

5 Homocysteine and Heart Disease CYSTATHIONINE SYNTHASE DEFICIENCY CLASSIC HOMOCYSTINURIA

6 Glycine

7 Homocysteine and Heart Disease COMBINED HOMOCYSTINURIA AND METHYLMALONIC ACIDURIA cblC

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11 Homocysteine and Heart Disease Evidence from Observational Studies

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13 Homocysteine and Heart Disease H Y P E

14 Homocysteine and CAD

15 Homocysteine and Heart Disease Evidence from Prospective Trials

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17 S E A R C H Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine (Circulation 118: 2310, 2008)

18 Homocysteine and Heart Disease SEARCH results slides provided by Dr. Jacques Genest, McGill University

19 SEARCH: 2 separate randomised treatment comparisons in 12,064 post-MI patients Homocysteine-lowering comparison Folic acid 2mg + Vitamin B 12 1mg daily vs Placebo Mean (SD) duration: 6.7 (1.5) years

20 SEARCH: Reduction in HOMOCYSTEINE with allocation to FOLATE/B 12 versus placebo Reduction µmol/lpercent Month 44.231% Year 14.030% Year 53.727% AVERAGE3.828% Mean (SD) baseline: 13.5 (5) µmol/l

21 Folate allocationRisk ratio & 95% CI EventPlaceboActiveActive betterPlacebo better (n=6031)(n=6033) Non-fatal MI431(7.1%)429(7.1%) Coronary revascularisation590(9.8%)591(9.8%) CHD death463(7.7%)422(7.0%) Major coronary events1229(20.4%)1185(19.6%)4.7% SE 4.2 increase Fatal stroke59(1.0%)65(1.1%) Non-fatal stroke218(3.6%)222(3.7%) Total stroke269(4.5%)265(4.4%)1.8% SE 8.7 increase Non-coronary revascularisation178(3.0%)153(2.5%)16.9% SE 11.9 increase MAJOR VASCULAR EVENTS1537(25.5%)1493(24.8%)4.0% SE 3.7 increase 0.60.81.01.21.4 SEARCH: FOLATE/B 12 on MAJOR VASCULAR EVENTS

22 Folate allocationRisk ratio & 95% CI Year of follow-upPlaceboActiveActive betterPlacebo better 1265/6033(4.4%)228/6031(3.8%) 2220/5751(3.8%)236/5783(4.1%) 3232/5483(4.2%)197/5511(3.6%) 4192/5202(3.7%)194/5257(3.7%) 5221/4958(4.5%)192/5010(3.8%) 6192/4680(4.1%)209/4749(4.4%) 7+215/4400(4.9%)237/4467(5.3%) 2+1272/5751(22.1%)1265/5783(21.9%)1.8% SE 4.0 increase ALL FOLLOW-UP1537/6033(25.5%)1493/6031(24.8%)4.0% SE 3.7 increase 0.60.81.01.21.4 SEARCH: FOLATE/B 12 on MAJOR VASCULAR EVENTS by year of follow-up

23 Folate allocationRisk ratio & 95% CI PlaceboActiveActive betterPlacebo better Homocysteine (µmol/L) <11363/1735(20.9%)377/1736(21.7%) ≥11 <14563/2255(25.0%)521/2315(22.5%) ≥14611/2043(29.9%)595/1980(30.1%) ALL PATIENTS1537/6033(25.5%)1493/6031(24.8%)4.0% SE 3.7 increase 0.60.81.01.21.4 SEARCH: FOLATE/B 12 on MAJOR VASCULAR EVENTS by baseline HOMOCYSTEINE

24 Folate allocationRisk ratio & 95% CI Cause of deathPlaceboActiveActive betterPlacebo better (n=6031)(n=6033) CHD463(7.7%)422(7.0%) Stroke59(1.0%)65(1.1%) Other vascular51(0.8%)58(1.0%) All vascular573(9.5%)545(9.0%)5.5% SE 6.1 increase Neoplastic260(4.3%)251(4.2%) Respiratory67(1.1%)65(1.1%) Other medical67(1.1%)78(1.3%) Non-medical16(0.3%)11(0.2%) All non-vascular410(6.8%)405(6.7%)1.6% SE 7.0 increase All causes983(16.3%)950(15.8%)3.8% SE 4.6 increase 0.60.81.0 1.2 1.4 SEARCH: Effects of Folate/B 12 on Mortality

25 Summary of SEARCH findings in context of meta-analyses of previous trials Lowering homocysteine with folic acid supplementation is safe, but does not reduce the risk of vascular events

26 B V T T B-Vitamin Treatment Trialists’ Collaboration

27 Homocysteine and Heart Disease BVVT unpublished meta-analysis results provided by Dr. Robert Clarke, University of Oxford

28 BVTT meta-analysis: Effects of FOLATE on MAJOR VASCULAR EVENTS by trial 0.51.02.0 99% CI 95% CI 99% CI 95% CI Events (%) TreatmentControl (n=11,658)(n=11,707)Risk ratio (CI) Treatment better Control better Trial CHAOS-2111(11.8)95(10.1) 1.21 (0.84- 1.73) WENBIT327(21.2)313(20.2) 1.06 (0.86- 1.30) VISP300(16.4)300(16.2) 1.01 (0.82- 1.25) NORVIT978(52.2)1011(53.9) 0.96 (0.86- 1.08) WAFACS376(13.8)366(13.5) 1.02 (0.84- 1.23) HOPE-2790(28.7)796(28.8) 1.01 (0.89- 1.15) SEARCH1537(25.5)1493(24.8) 1.04 (0.95- 1.14) Total4419(25.0)4374(24.7) 1.02 (0.98- 1.06) (n=17,691)

29 Effects of BVTT of B-vitamins on coronary events, in published trials

30 Effects of BVTT of B-vitamins on stroke events, in published trials

31 BVTT meta-analysis: Effects of FOLATE on CANCER by year of follow-up 0.51.02.0 99% CI 95% CI 99% CI 95% CI Events (%) TreatmentControl (n=16,751)(n=16,796)HR (CI) Treatment better Control better Year of follow-up Year 1 286(1.7)309(1.8) 0.93 (0.75- 1.15) Year 2 323(2.0)279(1.7) 1.16 (0.94- 1.43) Year 3 244(1.7)219(1.5) 1.12 (0.88- 1.42) Year 4 212(1.7)193(1.5) 1.11 (0.86- 1.43) Year 5 196 (1.9) 193 (1.8) 1.02 (0.79- 1.33) Years 6+ 260(3.0)257(3.0) 1.02 (0.81- 1.28) Total1521(9.1)1450(8.6) 1.05 (0.98- 1.13) Test for trend :  1 2  0.04; p=0.9

32 Effects of BVTT of B-vitamins on cancer events, in published trials

33 BVTT meta-analysis: Effects of FOLATE on CANCER SUBTYPES 0.51.02.0 99% CI 95% CI 99% CI 95% CI Events (%) TreatmentControl HR (CI) Treatment better Control better Cancer Subtypes Colorectal175(1.0)160(1.0) 1.10 (0.83- 1.46) Other gastrointestinal 129(0.8)123(0.7) 1.05 (0.76- 1.46) Prostate265(1.6)233(1.4) 1.14 (0.91- 1.44) Other genitourinary 178(1.1)173(1.0) 1.02 (0.78- 1.35) Lung 206(1.2)186(1.1) 1.11 (0.85- 1.44) Breast111(0.7)132(0.8) 0.83 (0.60- 1.16) Melanoma44(0.3)46(0.3) 0.96 (0.56- 1.65) Haematological 93 (0.6) 95 (0.6) 0.98 (0.67- 1.43) Other320(1.9)302(1.8) 1.07 (0.87- 1.31) ALL1521(9.1)1450(8.6) 1.05 (0.98- 1.13) (n=16,751)(n=16,796)

34 Effects of BVTT of B-vitamins on mortality, in published trials

35 Summary of BVVT Meta-Analysis and overall CONCLUSIONS Lowering homocysteine with folic acid supplementation is safe, but does not reduce the risk of vascular events

36 So don’t fear the hype just yet….

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39 Lama Yamani Isabelle Racine- Miousse Junhui Liu Our lab David Watkins David Rosenblatt Natascia Anastasio

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45 Summary of SEARCH findings in context of meta-analyses of previous trials More versus less LDL-lowering comparison: SEARCH results are consistent with previous trials of statin vs control and of more vs less statin Larger reductions in LDL cholesterol with statin therapy produces larger reductions in major vascular events

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