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.
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
HYPE
Homocysteine and CAD
Homocysteine and
Heart Disease
Evidence from Prospective Trials
SEARCH
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
Mean (SD) baseline: 13.5 (5) µmol/l
Reduction
µmol/l
percent
Month 4
4.2
31%
Year 1
4.0
30%
Year 5
3.7
27%
AVERAGE
3.8
28%
SEARCH: FOLATE/B12 on MAJOR
VASCULAR EVENTS
Event
Folate allocation
Risk ratio & 95% CI
Active
Placebo Active better Placebo better
(n=6033)
(n=6031)
Non-fatal MI
Coronary revascularisation
CHD death
431
590
463
Major coronary events
(7.1%)
(9.8%)
(7.7%)
429
591
422
(7.1%)
(9.8%)
(7.0%)
1229 (20.4%) 1185 (19.6%)
4.7% SE 4.2
increase
Fatal stroke
Non-fatal stroke
59
218
(1.0%)
(3.6%)
65
222
(1.1%)
(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 by year of follow-up
Year of follow-up
1
2
3
4
5
6
7+
Folate allocation
Active
Placebo
265 /6033
220 /5751
232 /5483
192 /5202
221 /4958
192 /4680
215 /4400
(4.4%)
(3.8%)
(4.2%)
(3.7%)
(4.5%)
(4.1%)
(4.9%)
228 /6031
236 /5783
197 /5511
194 /5257
192 /5010
209 /4749
237 /4467
Risk ratio & 95% CI
Active better Placebo better
(3.8%)
(4.1%)
(3.6%)
(3.7%)
(3.8%)
(4.4%)
(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
SEARCH: FOLATE/B12 on MAJOR
VASCULAR EVENTS
by baseline HOMOCYSTEINE
Folate allocation
Active
Placebo
Risk ratio & 95% CI
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
SEARCH: Effects of Folate/B12 on
Mortality
Cause of death
Folate allocation
Active
Placebo
(n=6033)
(n=6031)
CHD
463
(7.7%) 422
(7.0%)
59
51
(1.0%)
(0.8%)
65
58
(1.1%)
(1.0%)
All vascular
573
(9.5%)
545
(9.0%)
Neoplastic
Respiratory
Other medical
Non-medical
260
67
67
16
(4.3%) 251
(1.1%) 65
(1.1%) 78
(0.3%) 11
(4.2%)
(1.1%)
(1.3%)
(0.2%)
All non-vascular
410
(6.8%)
(6.7%)
All causes
983 (16.3%)
Stroke
Other vascular
405
Risk ratio & 95% CI
Active better Placebo better
5.5% SE 6.1
increase
1.6% SE 7.0
increase
3.8% SE 4.6
increase
950 (15.8%)
0.6
0.8
1.0
1.2
1.4
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
BVTT
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
Events (%)
Treatment
Control
(n=11,658)
(n=11,707)
(n=17,691)
(n=17,691)
Risk ratio (CI)
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)
99% CI
95% CI
0.5
Treatment
better
1.0
Control
better
2.0
Effects of BVTT of B-vitamins on
Figure 1: Effects BVTT of B-vitamins on coronary events,
coronary in
events,
in published
trials
published
trials
Events (%)
Treatment
Control
(n=17,783) (n=17,820)
HOST
129 (12.5)
WENBIT
135
(8.8)
VISP
114
(6.2)
NORVIT
RR (CI)
150 (14.6)
0.92 (0.78- 1.07)
113
(7.3)
1.22 (0.87- 1.72)
123
(6.6)
0.91 (0.54- 1.52)
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:
2
6
5.91; p=0.4
0.5
99% CI
95% CI
Treatment
better
1.0
Control
better
2.0
Effects of BVTT of B-vitamins on stroke
Figure 2: Effects BVTT of B-vitamins on stroke events,
events, in
in published
published
trials
trials
Events (%)
Treatment Control
(n=17,783) (n=17,820)
RR (CI)
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)
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)
VISP
Heterogeneity:
2
6
7.52; p=0.3
0.5
99% CI
95% CI
Treatment
better
1.0
Control
better
2.0
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
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)
1521 (9.1) 1450 (8.6)
1.05 (0.98- 1.13)
Total
2
Test for trend : c1 = 0.04; p=0.9
99% CI
95% CI
0.5
Treatment
better
1.0
Control
better
2.0
Effects of BVTT of B-vitamins on
Figure 3: Effects
of B-vitamins
on trials
cancer events,
cancerBVTT
events,
in published
in published trials
Events (%)
Treatment
Control
(n=14,924) (n=14,943)
RR (CI)
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
Heterogeneity:
2
4
(9.3) 1305
2.31; p=0.7
0.5
99% CI
95% CI
1.08 (0.99- 1.17)
(8.7)
Treatment
better
1.0
Control
better
2.0
BVTT meta-analysis: Effects of
FOLATE on CANCER SUBTYPES
Events (%)
Treatment Control
(n=16,751) (n=16,796)
HR (CI)
Cancer Subtypes
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)
320 (1.9)
302 (1.8)
1.07 (0.87- 1.31)
1521 (9.1)
1450 (8.6)
1.05 (0.98- 1.13)
Colorectal
Other
ALL
99% CI
95% CI
0.5
Treatment
better
1.0
Control
better
2.0
Effects of BVTT of B-vitamins on
Figure 4: Effects BVTT of B-vitamins on mortality,
in published
trials trials
mortality,
in published
Events (%)
Treatment
Control
(n=18,723) (n=18,762)
CHAOS-2
74
(7.9)
448 (43.4)
HOST
RR (CI)
(7.9)
1.00 (0.41- 2.49)
436 (42.6)
1.02 (0.91- 1.13)
74
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)
2581 (13.8) 2547 (13.6)
1.02 (0.97- 1.07)
ALL
Heterogeneity:
2
7
3.7; p=0.8
0.5
99% CI
95% CI
Treatment
better
1.0
Control
better
2.0
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….
Our lab
Isabelle
Racine- Miousse
David
Watkins
David
Rosenblatt
Natascia
Anastasio
Junhui Liu
Lama
Yamani
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