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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
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.
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 B12 1mg daily
vs
Placebo
Mean (SD) duration: 6.7 (1.5) years
SEARCH: Reduction in HOMOCYSTEINE with allocation to
FOLATE/B12 versus placebo
Reduction
µmol/l percent
Month 4 4.2 31%
Year 1 4.0 30%
Year 5 3.7 27%
AVERAGE 3.8 28%
Mean (SD) baseline: 13.5 (5) µmol/l
Folate allocation Risk ratio & 95% CIEvent PlaceboActive Active better Placebo better
(n=6031)(n=6033)
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 4.2increase
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 8.7increase
Non-coronary revascularisation 178 (3.0%) 153 (2.5%) 16.9% SE 11.9increase
MAJOR VASCULAR EVENTS 1537 (25.5%) 1493 (24.8%) 4.0% SE 3.7increase
0.6 0.8 1.0 1.2 1.4
SEARCH: FOLATE/B12 on MAJOR VASCULAR EVENTS
Folate allocation Risk ratio & 95% CIYear of follow-up PlaceboActive 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 4.0increase
ALL FOLLOW-UP 1537 /6033 (25.5%) 1493 /6031(24.8%) 4.0% SE 3.7increase
0.6 0.8 1.0 1.2 1.4
SEARCH: FOLATE/B12 on MAJOR VASCULAR EVENTS by year of follow-up
Folate allocation Risk ratio & 95% CIPlaceboActive 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 3.7increase
0.6 0.8 1.0 1.2 1.4
SEARCH: FOLATE/B12 on MAJOR VASCULAR EVENTS
by baseline HOMOCYSTEINE
Folate allocation Risk ratio & 95% CICause of death PlaceboActive Active better Placebo better
(n=6031)(n=6033)
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 6.1increase
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 7.0increase
All causes 983 (16.3%) 950 (15.8%) 3.8% SE 4.6increase
0.6 0.8 1.0 1.2 1.4
SEARCH: Effects of Folate/B12 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
Homocysteine and Heart Disease
BVVT unpublished meta-analysis results provided by Dr. Robert Clarke, University of Oxford
BVTT meta-analysis: Effects of FOLATEon MAJOR VASCULAR EVENTS by trial
0.5 1.0 2.099% CI95% CI99% CI95% CI
Events (%)Treatment Control(n=11,658) (n=11,707) Risk ratio (CI)
Treatmentbetter
Controlbetter
Trial
CHAOS-2 111 (11.8) 95 (10.1) 1.21 (0.84- 1.73)
WENBIT 327 (21.2) 313 (20.2) 1.06 (0.86- 1.30)
VISP 300 (16.4) 300 (16.2) 1.01 (0.82- 1.25)
NORVIT 978 (52.2) 1011 (53.9) 0.96 (0.86- 1.08)
WAFACS 376 (13.8) 366 (13.5) 1.02 (0.84- 1.23)
HOPE-2 790 (28.7) 796 (28.8) 1.01 (0.89- 1.15)
SEARCH 1537 (25.5) 1493 (24.8) 1.04 (0.95- 1.14)
Total 4419 (25.0) 4374 (24.7) 1.02 (0.98- 1.06)
(n=17,691) (n=17,691)
Figure 1: Effects BVTT of B-vitamins on coronary events,in published trials
0.5 1.0 2.099% CI95% CI99% CI95% CI
Events (%)Treatment Control(n=17,783) (n=17,820) RR (CI)
Treatmentbetter
Controlbetter
HOST 129 (12.5) 150 (14.6) 0.92 (0.78- 1.07)
WENBIT 135 (8.8) 113 (7.3) 1.22 (0.87- 1.72)
VISP 114 (6.2) 123 (6.6) 0.91 (0.54- 1.52)
NORVIT 329 (17.6) 314 (16.7) 1.05 (0.86- 1.29)
WAFACS 283 (10.4) 280 (10.3) 1.01 (0.80- 1.27)
HOPE-2 341 (12.4) 349 (12.6) 0.97 (0.73- 1.29)
SEARCH 1229 (20.4) 1185 (19.6) 1.05 (0.93- 1.18)
ALL 2560 (14.4) 2514 (14.1) 1.01 (0.96- 1.07)
Heterogeneity: 62 5.91; p=0.4
Effects of BVTT of B-vitamins on coronary events, in published trials
Figure 2: Effects BVTT of B-vitamins on stroke events,in published trials
0.5 1.0 2.099% CI95% CI99% CI95% CI
Events (%)Treatment Control(n=17,783) (n=17,820) RR (CI)
Treatmentbetter
Controlbetter
HOST 37 (3.6) 41 (4.0) 0.95 (0.71- 1.26)
WENBIT 28 (1.8) 39 (2.5) 0.72 (0.38- 1.36)
VISP 152 (8.3) 148 (8.0) 1.07 (0.67- 1.70)
NORVIT 49 (2.6) 49 (2.6) 1.00 (0.62- 1.61)
WAFACS 79 (2.9) 69 (2.5) 1.15 (0.75- 1.77)
HOPE-2 111 (4.0) 147 (5.3) 0.67 (0.43- 1.05)
SEARCH 269 (4.5) 265 (4.4) 1.01 (0.81- 1.28)
ALL 725 (4.1) 758 (4.3) 0.96 (0.87- 1.07)
Heterogeneity: 62 7.52; p=0.3
Effects of BVTT of B-vitamins on stroke events, in published trials
BVTT meta-analysis: Effects of FOLATEon CANCER by year of follow-up
0.5 1.0 2.099% CI95% CI99% CI95% CI
Events (%)Treatment Control(n=16,751) (n=16,796) HR (CI)
Treatmentbetter
Controlbetter
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)
Total 1521 (9.1) 1450 (8.6) 1.05 (0.98- 1.13)
Test for trend : 120.04; p=0.9
Figure 3: Effects BVTT of B-vitamins on cancer events,in published trials
0.5 1.0 2.099% CI95% CI99% CI95% CI
Events (%)Treatment Control(n=14,924) (n=14,943) RR (CI)
Treatmentbetter
Controlbetter
WENBIT 85 (5.5) 69 (4.5) 1.25 (0.82- 1.92)
NORVIT 79 (4.2) 65 (3.5) 1.20 (0.81- 1.78)
WAFACS 187 (6.9) 192 (7.1) 0.97 (0.74- 1.28)
HOPE-2 358 (13.0) 340 (12.3) 1.09 (0.82- 1.45)
SEARCH 678 (11.2) 639 (10.6) 1.07 (0.92- 1.24)
ALL 1387 (9.3) 1305 (8.7) 1.08 (0.99- 1.17)
Heterogeneity: 4
2 2.31; p=0.7
Effects of BVTT of B-vitamins on cancer events, in published trials
BVTT meta-analysis: Effects of FOLATE on CANCER SUBTYPES
0.5 1.0 2.099% CI95% CI99% CI95% CI
Events (%)Treatment Control
HR (CI)
Treatmentbetter
Controlbetter
Cancer Subtypes
Colorectal 175 (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)
Prostate 265 (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)
Breast 111 (0.7) 132 (0.8) 0.83 (0.60- 1.16)
Melanoma 44 (0.3) 46 (0.3) 0.96 (0.56- 1.65)
Haematological 93 (0.6) 95 (0.6) 0.98 (0.67- 1.43)
Other 320 (1.9) 302 (1.8) 1.07 (0.87- 1.31)
ALL 1521 (9.1) 1450 (8.6) 1.05 (0.98- 1.13)
(n=16,751) (n=16,796)
Figure 4: Effects BVTT of B-vitamins on mortality,in published trials
0.5 1.0 2.099% CI95% CI99% CI95% CI
Events (%)Treatment Control(n=18,723) (n=18,762) RR (CI)
Treatmentbetter
Controlbetter
CHAOS-2 74 (7.9) 74 (7.9) 1.00 (0.41- 2.49)
HOST 448 (43.4) 436 (42.6) 1.02 (0.91- 1.13)
WENBIT 73 (4.7) 58 (3.7) 1.28 (0.81- 2.03)
VISP 99 (5.4) 117 (6.3) 0.78 (0.46- 1.35)
NORVIT 184 (9.8) 181 (9.6) 1.02 (0.79- 1.31)
WAFACS 250 (9.2) 256 (9.4) 0.97 (0.77- 1.24)
HOPE-2 470 (17.0) 475 (17.2) 0.99 (0.77- 1.27)
SEARCH 983 (16.3) 950 (15.8) 1.04 (0.92- 1.18)
ALL 2581 (13.8) 2547 (13.6) 1.02 (0.97- 1.07)
Heterogeneity: 7
2 3.7; p=0.8
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
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