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Plasma Homocysteine and Coronary Heart Disease

Plasma Homocysteine and Coronary Heart Disease. David S. Rosenblatt, MD Department of Human Genetics McGill University. OBJECTIVES. To describe the evidence for a role for homocysteine in coronary artery and vascular disease To present evidence from recent prospective trials.

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Plasma Homocysteine and Coronary Heart Disease

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

  2. OBJECTIVES • To describe the evidence for a role for homocysteine in coronary artery and vascular disease • 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 B12 metabolism.

  5. Homocysteine and Heart Disease CYSTATHIONINE SYNTHASE DEFICIENCY CLASSIC HOMOCYSTINURIA

  6. Glycine

  7. Homocysteine and Heart Disease COMBINED HOMOCYSTINURIA AND METHYLMALONIC ACIDURIA cblC

  8. Homocysteine and Heart Disease Evidence from Observational Studies

  9. Homocysteine and Heart Disease H Y P E

  10. Homocysteine and CAD

  11. Homocysteine and Heart Disease Evidence from Prospective Trials

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

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

  14. SEARCH: 2 separate randomised treatment comparisons in 12,064 post-MI patients Homocysteine-lowering comparison Folic acid 2mg + Vitamin B12 1mg daily vs Placebo Mean (SD) duration: 6.7 (1.5) years

  15. SEARCH: Reduction in HOMOCYSTEINE with allocation to FOLATE/B12 versus placebo Mean (SD) baseline: 13.5 (5) µmol/l

  16. Folate allocation Risk ratio & 95% CI Event Active Placebo Active better Placebo better (n=6033) (n=6031) Non-fatal MI 431 (7.1%) 429 (7.1%) Coronary revascularisation 590 (9.8%) 591 (9.8%) CHD death 463 (7.7%) 422 (7.0%) Major coronary events 1229 (20.4%) 1185 (19.6%) 4.7% SE 4.2 increase Fatal stroke 59 (1.0%) 65 (1.1%) Non-fatal stroke 218 (3.6%) 222 (3.7%) Total stroke 269 (4.5%) 265 (4.4%) 1.8% SE 8.7 increase Non-coronary revascularisation 178 (3.0%) 153 (2.5%) 16.9% SE 11.9 increase MAJOR VASCULAR EVENTS 1537 (25.5%) 1493 (24.8%) 4.0% SE 3.7 increase 0.6 0.8 1.0 1.2 1.4 SEARCH: FOLATE/B12 on MAJOR VASCULAR EVENTS

  17. SEARCH: FOLATE/B12 on MAJOR VASCULAR EVENTS by year of follow-up Folate allocation Risk ratio & 95% CI Year of follow-up Active Placebo Active better Placebo better 1 265 /6033 (4.4%) 228 /6031 (3.8%) 2 220 /5751 (3.8%) 236 /5783 (4.1%) 3 232 /5483 (4.2%) 197 /5511 (3.6%) 4 192 /5202 (3.7%) 194 /5257 (3.7%) 5 221 /4958 (4.5%) 192 /5010 (3.8%) 6 192 /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-UP 1537 /6033 (25.5%) 1493 /6031 (24.8%) 4.0% SE 3.7 increase 0.6 0.8 1.0 1.2 1.4

  18. SEARCH: FOLATE/B12 on MAJOR VASCULAR EVENTS by baseline HOMOCYSTEINE Folate allocation Risk ratio & 95% CI Active Placebo Active better Placebo better Homocysteine (µmol/L) <11 363 /1735 (20.9%) 377 /1736 (21.7%) ≥11 <14 563 /2255 (25.0%) 521 /2315 (22.5%) ≥14 611 /2043 (29.9%) 595 /1980 (30.1%) ALL PATIENTS 1537 /6033 (25.5%) 1493 /6031 (24.8%) 4.0% SE 3.7 increase 0.6 0.8 1.0 1.2 1.4

  19. Folate allocation Risk ratio & 95% CI Cause of death Active Placebo Active better Placebo better (n=6033) (n=6031) CHD 463 (7.7%) 422 (7.0%) Stroke 59 (1.0%) 65 (1.1%) Other vascular 51 (0.8%) 58 (1.0%) All vascular 573 (9.5%) 545 (9.0%) 5.5% SE 6.1 increase Neoplastic 260 (4.3%) 251 (4.2%) Respiratory 67 (1.1%) 65 (1.1%) Other medical 67 (1.1%) 78 (1.3%) Non-medical 16 (0.3%) 11 (0.2%) All non-vascular 410 (6.8%) 405 (6.7%) 1.6% SE 7.0 increase All causes 983 (16.3%) 950 (15.8%) 3.8% SE 4.6 increase 0.6 0.8 1.0 1.4 1.2 SEARCH: Effects of Folate/B12 on Mortality

  20. 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

  21. B V T T B-Vitamin Treatment Trialists’ Collaboration

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

  23. BVTT meta-analysis: Effects of FOLATE on MAJOR VASCULAR EVENTS by trial Events (%) Treatment Control (n=11,658) (n=11,707) Risk ratio (CI) (n=17,691) (n=17,691) Trial 1.21 (0.84- 1.73) CHAOS-2 111 (11.8) 95 (10.1) 1.06 (0.86- 1.30) WENBIT 327 (21.2) 313 (20.2) 1.01 (0.82- 1.25) VISP 300 (16.4) 300 (16.2) 0.96 (0.86- 1.08) NORVIT 978 (52.2) 1011 (53.9) 1.02 (0.84- 1.23) WAFACS 376 (13.8) 366 (13.5) 1.01 (0.89- 1.15) HOPE-2 790 (28.7) 796 (28.8) 1.04 (0.95- 1.14) SEARCH 1537 (25.5) 1493 (24.8) 1.02 (0.98- 1.06) Total 4419 (25.0) 4374 (24.7) 0.5 1.0 2.0 99% CI 99% CI Treatment Control 95% CI 95% CI better better

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

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

  26. BVTT meta-analysis: Effects of FOLATE on CANCER by year of follow-up Events (%) Treatment Control (n=16,751) (n=16,796) HR (CI) Year of follow-up Year 1 0.93 (0.75- 1.15) 286 (1.7) 309 (1.8) Year 2 1.16 (0.94- 1.43) 323 (2.0) 279 (1.7) Year 3 1.12 (0.88- 1.42) 244 (1.7) 219 (1.5) Year 4 1.11 (0.86- 1.43) 212 (1.7) 193 (1.5) Year 5 1.02 (0.79- 1.33) 196 193 (1.9) (1.8) Years 6+ 1.02 (0.81- 1.28) 260 (3.0) 257 (3.0) 1.05 (0.98- 1.13) Total 1521 (9.1) 1450 (8.6) 2 c = Test for trend : 0.04 ; p=0.9 1 0.5 1.0 2.0 99% CI 99% CI Treatment Control 95% CI 95% CI better better

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

  28. BVTT meta-analysis: Effects of FOLATE on CANCER SUBTYPES Events (%) Treatment Control HR (CI) (n=16,751) (n=16,796) Cancer Subtypes 1.10 (0.83- 1.46) Colorectal 175 (1.0) 160 (1.0) Other gastrointestinal 1.05 (0.76- 1.46) 129 (0.8) 123 (0.7) 1.14 (0.91- 1.44) Prostate 265 (1.6) 233 (1.4) Other genitourinary 1.02 (0.78- 1.35) 178 (1.1) 173 (1.0) Lung 1.11 (0.85- 1.44) 206 (1.2) 186 (1.1) 0.83 (0.60- 1.16) Breast 111 (0.7) 132 (0.8) 0.96 (0.56- 1.65) Melanoma 44 (0.3) 46 (0.3) Haematological 0.98 (0.67- 1.43) 93 95 (0.6) (0.6) 1.07 (0.87- 1.31) Other 320 (1.9) 302 (1.8) 1.05 (0.98- 1.13) ALL 1521 (9.1) 1450 (8.6) 0.5 1.0 2.0 99% CI 99% CI Treatment Control 95% CI 95% CI better better

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

  30. 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

  31. So don’t fear the hype just yet….

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

  33. 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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