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

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 B12 metabolism.


CYSTATHIONINE SYNTHASE DEFICIENCY

CLASSIC HOMOCYSTINURIA

Glycine


COMBINED HOMOCYSTINURIA AND METHYLMALONIC ACIDURIA

cblC


Evidence from Observational Studies


H Y P E

Homocysteine and CAD


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)


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

B V T T

B-Vitamin Treatment Trialists’

Collaboration


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


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


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


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

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

Documents

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