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

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Presentation transcript:

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

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

Homocysteine and Heart Disease Evidence from Inborn Errors of Metabolism

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.

Homocysteine and Heart Disease CYSTATHIONINE SYNTHASE DEFICIENCY CLASSIC HOMOCYSTINURIA

Glycine

Homocysteine and Heart Disease COMBINED HOMOCYSTINURIA AND METHYLMALONIC ACIDURIA cblC

Homocysteine and Heart Disease Evidence from Observational Studies

Homocysteine and Heart Disease H Y P E

Homocysteine and CAD

Homocysteine and Heart Disease Evidence from Prospective Trials

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

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

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

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

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 SEARCH: FOLATE/B 12 on MAJOR VASCULAR EVENTS

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%) /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 SEARCH: FOLATE/B 12 on MAJOR VASCULAR EVENTS by year of follow-up

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 SEARCH: FOLATE/B 12 on MAJOR VASCULAR EVENTS by baseline HOMOCYSTEINE

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 SEARCH: Effects of Folate/B 12 on Mortality

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

B V T T B-Vitamin Treatment Trialists’ Collaboration

Homocysteine and Heart Disease BVVT unpublished meta-analysis results provided by Dr.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

BVTT meta-analysis: Effects of FOLATE on MAJOR VASCULAR EVENTS by trial % 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 ( ) WENBIT327(21.2)313(20.2) 1.06 ( ) VISP300(16.4)300(16.2) 1.01 ( ) NORVIT978(52.2)1011(53.9) 0.96 ( ) WAFACS376(13.8)366(13.5) 1.02 ( ) HOPE-2790(28.7)796(28.8) 1.01 ( ) SEARCH1537(25.5)1493(24.8) 1.04 ( ) Total4419(25.0)4374(24.7) 1.02 ( ) (n=17,691)

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

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

BVTT meta-analysis: Effects of FOLATE on CANCER by year of follow-up % 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 ( ) Year 2 323(2.0)279(1.7) 1.16 ( ) Year 3 244(1.7)219(1.5) 1.12 ( ) Year 4 212(1.7)193(1.5) 1.11 ( ) Year (1.9) 193 (1.8) 1.02 ( ) Years (3.0)257(3.0) 1.02 ( ) Total1521(9.1)1450(8.6) 1.05 ( ) Test for trend :  1 2  0.04; p=0.9

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

BVTT meta-analysis: Effects of FOLATE on CANCER SUBTYPES % 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 ( ) Other gastrointestinal 129(0.8)123(0.7) 1.05 ( ) Prostate265(1.6)233(1.4) 1.14 ( ) Other genitourinary 178(1.1)173(1.0) 1.02 ( ) Lung 206(1.2)186(1.1) 1.11 ( ) Breast111(0.7)132(0.8) 0.83 ( ) Melanoma44(0.3)46(0.3) 0.96 ( ) Haematological 93 (0.6) 95 (0.6) 0.98 ( ) Other320(1.9)302(1.8) 1.07 ( ) ALL1521(9.1)1450(8.6) 1.05 ( ) (n=16,751)(n=16,796)

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

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

So don’t fear the hype just yet….

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

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