you were saying that even if mc-1 works people could just buy b-6
New England Journal of Medicine. B-6 doesn't work
original article
The new england journal o f medicine
n engl j med 354;1578 15 www.nejm.org april 13, 2006
Homocysteine Lowering and Cardiovascular
Events after Acute Myocardial Infarction
Kaare Harald Bønaa, M.D., Ph.D., Inger Njølstad, M.D., Ph.D.,
Per Magne Ueland, M.D., Ph.D., Henrik Schirmer, M.D., Ph.D., Aage Tverdal, Ph.D.,
Terje Steigen, M.D., Ph.D., Harald Wang, M.D., Jan Erik Nordrehaug, M.D., Ph.D.,
Egil Arnesen, M.D., and Knut Rasmussen, M.D., Ph.D.,
for the NORVIT Trial Investigators*
From the Institute of Community Medicine,
University of Tromsø, Tromsø (K.H.B., I.N.,
H.S., E.A.); the Locus for Homocysteine
and Related Vitamins and the Section for
Pharmacology, Institute of Medicine, University
of Bergen, Bergen (P.M.U.); the Norwegian
Institute of Public Health, Oslo
(A.T.); the Department of Heart Disease,
University Hospital of Northern Norway,
Tromsø (T.S., H.W., K.R.); and the Department
of Heart Disease, Haukeland University
Hospital, Bergen (J.E.N.) — all in Norway.
Address reprint requests to Dr. Bønaa
at the Institute of Community Medicine,
University of Tromsø, N-9037 Tromsø, Norway,
or at kaare.bonaa@stolav.no.
*The investigators and study centers participating
in the Norwegian Vitamin
(NORVIT) trial are listed in the Appendix.
This article was published at www.nejm.org
on March 12, 2006.
N Engl J Med 2006;354:1578-88.
Copyright © 2006 Massachusetts Medical Society.
ABSTRACT
BACKGROUND
Homocysteine is a risk factor for cardiovascular disease. We evaluated the efficacy
of homocysteine-lowering treatment with B vitamins for secondary prevention in
patients who had had an acute myocardial infarction.
METHODS
The trial included 3749 men and women who had had an acute myocardial infarction
within seven days before randomization. Patients were randomly assigned, in a twoby-
two factorial design, to receive one of the following four daily treatments: 0.8 mg
of folic acid, 0.4 mg of vitamin B12, and 40 mg of vitamin B6; 0.8 mg of folic acid and
0.4 mg of vitamin B12; 40 mg of vitamin B6; or placebo. The primary end point during
a median follow-up of 40 months was a composite of recurrent myocardial infarction,
stroke, and sudden death attributed to coronary artery disease.
RESULTS
The mean total homocysteine level was lowered by 27 percent among patients given
folic acid plus vitamin B12, but such treatment had no significant effect on the primary
end point (risk ratio, 1.08; 95 percent confidence interval, 0.93 to 1.25; P = 0.31).
Also, treatment with vitamin B6 was not associated with any significant benefit
with regard to the primary end point (relative risk of the primary end point, 1.14;
95 percent confidence interval, 0.98 to 1.32; P = 0.09). In the group given folic acid,
vitamin B12, and vitamin B6, there was a trend toward an increased risk (relative risk,
1.22; 95 percent confidence interval, 1.00 to 1.50; P = 0.05).
CONCLUSIONS
Treatment with B vitamins did not lower the risk of recurrent cardiovascular disease
after acute myocardial infarction. A harmful effect from combined B vitamin
treatment was suggested. Such treatment should therefore not be recommended.
(ClinicalTrials.gov number, NCT00266487.)
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homocysteine lowering after acute myocardial infarction
1579
Case–control as well as prospective
studies have demonstrated that the plasma
total homocysteine level is a strong,
graded, and independent risk factor for coronary
heart disease (CHD) and stroke.1-3 Evidence from
studies involving so-called mendelian randomization,
4 demonstrating an association between
CHD and the 677C?T methylenetetrahydrofolate
reductase polymorphism, has provided additional
support for a causal relation between homocysteine
and CHD.5,6
Plasma total homocysteine can be lowered
with the B vitamins folic acid and vitamin B12,7
and persons with high plasma levels or dietary
intake of folate and vitamin B6 have a decreased
risk of CHD.8-11 The lowering of the population
mean level of total homocysteine in the United
States by fortifying food with folic acid12 is
estimated to have prevented 17,000 deaths from
coronary causes each year,13 and the inclusion
of folic acid in a combination pill has been
suggested as a means to prevent cardiovascular
disease.14
In contrast to what was expected on the basis
of epidemiologic evidence, the first large, randomized
trial found that lowering the total homocysteine
level with B vitamins failed to prevent recurrent
stroke, myocardial infarction, or death in
patients who had had a recent stroke.15 A post hoc
efficacy analysis indicated, however, that a large
subgroup of the participants in the trial might
have benefited from B vitamin treatment.16 Studies
of the effects of B vitamins on the risk of restenosis
after percutaneous coronary intervention
have also yielded inconsistent results.17,18 We conducted
a large trial to evaluate the potential benefit
of such therapy in patients after acute myocardial
infarction.
Methods
Study Population and Design
The Norwegian Vitamin (NORVIT) trial was a multicenter,
prospective, randomized, double-blind,
placebo-controlled evaluation of the potential benefit
of B vitamin therapy in patients with an acute
myocardial infarction. Study medication was provided
without charge by Alpharma. The sponsors
had no role in the design, conduct, or reporting of
the study. The protocol was approved by the regional
committee for research ethics. All participants
provided written informed consent.
Men and women 30 to 85 years of age who had
had an acute myocardial infarction within seven
days before randomization were eligible to participate.
Exclusion criteria were the presence of
coexisting disease associated with a life expectancy
of less than four years, prescribed treatment
with B vitamins or untreated vitamin B deficiency,
or inability to follow the protocol, as judged by the
investigator.
Participants were randomly assigned, in a twoby-
two factorial design, to receive one of the following
four treatments: 0.8 mg of folic acid, 0.4 mg
of vitamin B12, and 40 mg of vitamin B6 per day
(referred to as combination therapy); 0.8 mg of folic
acid plus 0.4 mg of vitamin B12 per day; 40 mg of
vitamin B6 per day; or placebo. Study medication
was given in a single capsule, taken once per
day. For the first two weeks after enrollment,
the combination-therapy group and the group
given folic acid and vitamin B12 received a loading
dose of 5 mg of folic acid per day, whereas the
other two groups received placebo for the first
two weeks. Capsule formulations were manufactured
(Alpharma) to be indistinguishable by color,
weight, or their ability to dissolve in water.
The randomization was performed in blocks
of 20 by Alpharma. Each study center received
whole blocks of study medication and assigned it
to patients in numerical order. All study personnel
and participants were unaware of the treatment
assignments.
Participants were given standard post–myocardial
infarction therapy and were seen at a followup
visit at 2 months and at a final visit after 2.0 to
3.5 years. Every six months after enrollment, study
medication and a questionnaire were mailed to
the participants. They were asked about study
outcomes, compliance, and adverse effects. Those
who did not return the questionnaire were interviewed
by telephone by study personnel, or records
were consulted to determine their vital status.
Staff members at the coordinating center visited
all participating hospitals to monitor data quality.
Smerud Medical Research, on behalf of the Norwegian
Research Council, conducted an audit of
the trial and approved it.
Blood samples were obtained from all available
participants at baseline, at two months, and at the
final visit for the measurement of plasma total
homocysteine, serum folate, and serum cobalamin.
Levels of these vitamins were determined with the
use of published methods.19-22
n engl j med 354;15 www.nejm.org april 13, 2006
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The new england journal o f medicine
1580
Definition and Ascertainment of End Points
The primary end point was a composite of new
nonfatal and fatal myocardial infarction, nonfatal
and fatal stroke, and sudden death attributed
to CHD. Patients who were resuscitated after cardiac
arrest were included in the analysis of the
primary end point, whereas those with a silent
myocardial infarction were not. For each participant,
only the first of all such events was included
in the analysis of the primary end point. If death
occurred within 28 days after the onset of an event,
the event was classified as fatal.
Secondary end points were myocardial infarction,
unstable angina pectoris requiring hospitalization,
coronary revascularization with percutaneous
coronary intervention or coronary-artery
bypass grafting, stroke, and death from any cause.
Incident cases of cancer were recorded as a measure
of safety.
Acute coronary events were categorized according
to symptoms, new changes on electrocardiography,
and levels of cardiac biomarkers. An
unequivocal global or focal neurologic deficit that
occurred suddenly and lasted more than 24 hours
was required for the diagnosis of stroke. A detailed
description of the end-point definitions of
myocardial infarction, unstable angina pectoris,
and stroke is available in the Supplementary Appendix
(available with the full text of this article
at www.nejm.org).
All end points were adjudicated by members
of the end-points committee, who were unaware
of patients’ treatment assignments. Data on possible
events were collected at the hospitals by study
nurses, who filled in forms and submitted relevant
discharge letters and medical-record notes.
For deaths that occurred outside the hospital, a
copy of the death certificate was retrieved from
the Causes of Death Registry. If deemed necessary
by the end-points committee, additional information
on the death was requested from the physician
in charge. We obtained information on incident
cancer (except basal-cell skin cancer) by using
the Norwegian unique 11-digit person-number for
each patient to search the National Cancer Registry.
Patients completed forms every six months
providing information on specified cardiovascular
events. Finally, the study nurses filled in a
questionnaire at the last follow-up visit.
Statistical Analysis
The calculation of the sample size was based on
data from previous Scandinavian trials, assuming
the three-year rate of the primary end point would
be 25 percent in the placebo group. The planned
enrollment of 3500 patients, with an average follow-
up of 3.0 years, was expected to result in 750
primary events and give the study a statistical power
of more than 90 percent to detect a 20 percent
relative reduction in the rate of the primary end
point, given a two-sided alpha value of 0.05.
The progress of the trial was monitored by
the data and safety monitoring board. Because the
incidence of the primary end point in the study
group as a whole was lower than expected, the
executive committee decided in March 2001 to extend
the follow-up for those enrolled before June
30, 2001, to 3.5 years; to increase the total enrollment
by 250 patients; and to follow those enrolled
after June 30, 2001, until the date of their exit assessment,
to be conducted between January 1 and
March 31, 2004.
A chi-square value of more than 9 (corresponding
to a P value of approximately 0.003) for the
difference in mortality rates between treatment
regimens was used to guide a decision to stop the
study earlier than planned. The data and safety
monitoring board evaluated the mortality rates after
about 250 and 500 primary events had occurred,
recommending that the trial should continue.
All analyses were conducted according to the
intention-to-treat principle. The main focus was
on comparison of treatment with folic acid and
vitamin B12 with control (the combination-therapy
group and the group given folic acid and vitamin
B12 vs. the vitamin B6 and placebo groups)
and comparison of treatment with vitamin B6 with
control (the combination-therapy group and the
group given vitamin B6 vs. the group given folic
acid and vitamin B12 and the placebo group). The
factorial design also allowed a comparison of the
combination-therapy group with the placebo
group. Estimates of the hazard ratios and 95 percent
confidence intervals were obtained with the
use of Cox proportional-hazards models. Interactions
were identified by applying the likelihoodratio
test to models with the interaction term and
those without the interaction term and comparing
the result. Kaplan–Meier survival analysis was
used to compare the cumulative incidence of the
primary end point in the four groups. Differences
between groups in baseline characteristics were
tested with analysis of variance. Study center was
included as a covariate in all analyses. The reported
P values are two-sided and are not adjusted for
multiple comparisons.
n engl j med 354;15 www.nejm.org april 13, 2006
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homocysteine lowering after acute myocardial infarction
1581
Table 1. Baseline Characteristics of the Patients and Use of Concomitant Medications.*
Characteristic
Folic Acid, B12,
and B6
(N = 937)
Folic Acid
and B12
(N = 935)
B6
(N = 934)
Placebo
(N = 943) P Value
Age — yr 63.6±11.9 63.2±11.6 62.5±11.7 62.6±11.4 0.11
Male sex — no. (%) 684 (73) 696 (74) 686 (73) 705 (75) 0.80
Total cholesterol — mmol/liter 5.8±1.2 5.8±1.2 5.8±1.3 5.7±1.3 0.49
Creatinine — µmol/liter 91±27 91±26 90±25 91±24 0.57
Systolic blood pressure — mm Hg 126±21 126±20 125±20 125±20 0.27
Diastolic blood pressure — mm Hg 73±13 73±13 72±13 72±13 0.25
Body-mass index† 26.5±4.0 26.2±3.5 26.3±3.8 26.3±3.8 0.66
Medical history — no. (%)
Myocardial infarction 171 (18) 155 (17) 149 (16) 153 (16) 0.54
Angina pectoris 262 (28) 225 (24) 243 (26) 240 (26) 0.28
Stroke 50 (5) 36 (4) 38 (4) 33 (3) 0.21
Diabetes mellitus 103 (11) 83 (9) 86 (9) 96 (10) 0.40
Coronary-artery bypass surgery 55 (6) 40 (4) 38 (4) 44 (5) 0.26
Percutaneous coronary intervention
44 (5) 45 (5) 43 (5) 49 (5) 0.94
Receiving treatment for hypertension
— no. (%)
281 (30) 250 (27) 268 (29) 275 (29) 0.46
Current smoker — no. (%) 429 (46) 405 (43) 460 (49) 453 (48) 0.05
Use of vitamin supplements
— no./total no. (%)
271/931 (29) 275/930 (30) 257/928 (28) 263/935 (28) 0.78
Qualifying myocardial infarction
Received primary or rescue PCI
— no.(%)
59 (6) 61 (7) 54 (6) 54 (6) 0.86
Received thrombolysis
— no./total no. (%)
383/932 (41) 403/931 (43) 405/929 (44) 381/942 (40) 0.42
Q-wave — no./total no. (%) 403/906 (44) 420/906 (46) 411/894 (46) 417/904 (46) 0.85
Peak creatine kinase — U/liter‡
Median 969 1043 1004 929 0.62
Interquartile range 425–2156 461–2136 489–2084 457–2095
Concomitant medication
— no./total no. (%)
Acetylsalicylic acid 757/874 (87) 789/880 (90) 764/853 (90) 778/880 (88) 0.16
Beta-blockers 797/873 (91) 808/879 (92) 768/853 (90) 802/881 (91) 0.58
Statins 690/873 (79) 721/879 (82) 704/856 (82) 712/880 (81) 0.30
ACE inhibitors 283/868 (33) 264/875 (30) 263/851 (31) 262/880 (30) 0.59
Angiotensin II–receptor
antagonists
38/866 (4) 46/873 (5) 37/849 (4) 48/879 (6) 0.60
Diuretics 162/869 (19) 153/874 (18) 147/851 (17) 152/879 (17) 0.86
Warfarin 123/868 (14) 89/873 (10) 88/851 (10) 104/879 (12) 0.04
* Plus–minus values are means ±SD. To convert values for cholesterol to milligrams per deciliter, divide by 0.02586. To
convert values for creatinine to milligrams per deciliter, divide by 88.4. PCI denotes percutaneous coronary intervention,
and ACE angiotensin-converting enzyme.
† Body-mass index is the weight in kilograms divided by the square of the height in meters.
‡ Information was available on 673 patients in the combination-therapy group, 678 in the group given folic acid and vitamin
B12, 671 in the group given vitamin B6, and 669 in the placebo group.
n engl j med 354;15 www.nejm.org april 13, 2006
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The new england journal o f medicine
1582
Results
Between December 12, 1998, and March 31, 2002,
3749 patients were enrolled in the trial at 35 Norwegian
hospitals and assigned to one of the four treatment
groups. The four groups were well balanced
with regard to baseline characteristics, prognostic
factors, and concomitant medications (Table 1).
The mean length of follow-up was 36 months
(median, 40). Five participants withdrew their informed
consent and did not receive the assigned
treatment, and 404 (11 percent) stopped taking
study medication during the trial. The percentages
stopping treatment were similar in the four
study groups. A total of 94 percent of all surviving
patients attended the final visit. Outcomes
among those who did not attend the final visit
were assessed by examining relevant medical records
and by direct contact. No patients were lost
to follow-up in the mortality analysis, but a total
of 20 (3 to 8 in each group) had incomplete follow-
up data on nonfatal events.
Compliance and Side Effects
The questionnaires on compliance and side effects
were returned by 99 percent, 94 percent, and
93 percent of the participants after one, two, and
three years, respectively. The response rates were
similar in the four treatment groups. About 98
percent of those who returned the questionnaire
reported that they complied with the study protocol
or had missed taking study medication only
a few times. This percentage was similar in the
four groups at one, two, and three years.
The participants were asked whether they had
had adverse effects related to the study medication
(yes or no). The percentages who responded
“yes” were similar (18 to 24 percent) in the four
treatment groups throughout the study. No serious
adverse events were reported.
Effect of Intervention on B Vitamin Status
In the two groups that received folic acid and vitamin
B12, the mean total homocysteine level
was reduced by a mean of 27 percent, from 13.0
µmol per liter (1.8 mg per liter) at baseline to 9.6
µmol per liter (1.3 mg per liter) at the end of the
intervention (Table 2). Among those who received
folic acid, the mean total homocysteine level was
a mean of 4.2 µmol per liter (0.57 mg per liter)
lower than the level in the group that did not receive
folic acid after two months (a difference of 31
Table 2. Plasma Levels of Total Homocysteine and B Vitamins at Baseline, after Two Months, and at the End
of the Intervention.*
Variable
Folic Acid, B12,
and B6
(N = 937)†
Folic Acid and B12
(N = 935)‡
B6
(N = 934)§
Placebo
(N = 943)¶
Total homocysteine (µmol/liter)
Baseline 13.1±5.0 12.9±4.3 13.3±6.1 13.2±5.2
2 Mo 9.4±3.0 9.5±2.8 13.7±5.7 13.7±5.6
End of intervention 9.5±3.6 9.8±4.0 13.3±5.4 13.6±6.2
Folate (nmol/liter)
Baseline 13.1±27.5 11.7±28.4 9.4±6.6 9.6±6.0
2 Mo 59.9±29.5 68.2±30.0 7.9±7.1 9.9±6.3
End of intervention 61.8±31.7 70.4±36.4 10.4±9.6 13.1±14.5
Vitamin B12 (pmol/liter)
Baseline 388±161 400±311 388±167 383±182
2 Mo 571±212 578±372 398±158 393±143
End of intervention 638±370 648±414 398±320 390±171
* Values are means ±SD. To convert values for homocysteine to millligrams per liter, divide by 7.396. To convert values
for folate to nanograms per milliliter, divide by 2.266. To convert values for vitamin B12 to picograms per milliliter, divide
by 0.7378.
† Blood samples were available from 935 patients at baseline, 855 at two months, and 750 at the end of the intervention.
‡ Blood samples were available from 933 patients at baseline, 849 at two months, and 770 at the end of the intervention.
§ Blood samples were available from 930 patients at baseline, 819 at two months, and 747 at the end of the intervention.
¶ Blood samples were available from 935 patients at baseline, 851 at two months, and 760 at the end of the intervention.
n engl j med 354;15 www.nejm.org april 13, 2006
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homocysteine lowering after acute myocardial infarction
1583
Table 3. Clinical Outcomes and Rate Ratios.
Variable Total No.
Folic Acid,
B12, and B6
(N = 937)
Folic Acid
and B12
(N = 935)
B6
(N = 934)
Placebo
(N = 943)
Folic Acid and B12 vs. No Folic
Acid and B12* B6 vs. No B6†
Folic Acid, B12, and B6
vs. Placebo‡
Rate Ratio
(95% CI)§ P Value
Rate Ratio
(95% CI)§ P Value
Rate Ratio
(95% CI)§ P Value
no. of cases (rate/1000 observation-yr)
Primary end point¶ 716 201 (81.6) 168 (66.9) 175 (70.1) 172 (67.2) 1.08 (0.93–1.25) 0.31 1.14 (0.98–1.32) 0.09 1.22 (1.00–1.50) 0.05
Myocardial infarction? 643 182 (73.0) 147 (57.5) 161 (64.0) 153 (59.2) 1.06 (0.91–1.24) 0.47 1.17 (1.00–1.37) 0.05 1.23 (0.99–1.52) 0.06
Fatal** 235 68 (24.5) 47 (16.8) 61 (22.1) 59 (21.0) 0.96 (0.74–1.24) 0.75 1.24 (0.96–1.61) 0.10 1.19 (0.84–1.69) 0.34
Nonfatal 462 132 (53.0) 113 (44.2) 113 (44.9) 104 (40.2) 1.14 (0.95–1.37) 0.16 1.15 (0.96–1.38) 0.14 1.30 (1.00–1.68) 0.05
Stroke 98 21 (7.7) 28 (10.2) 22 (8.1) 27 (9.7) 1.02 (0.68–1.51) 0.94 0.81 (0.54–1.20) 0.29 0.83 (0.47–1.47) 0.52
Death from any cause 365 104 (37.5) 80 (28.7) 92 (33.4) 89 (31.7) 1.02 (0.83–1.26) 0.82 1.19 (0.96–1.46) 0.11 1.21 (0.91–1.61) 0.19
Hospitalization for unstable
angina
pectoris
488 125 (50.5) 126 (50.6) 105 (41.6) 132 (53.0) 1.06 (0.89–1.27) 0.50 0.88 (0.74–1.05) 0.17 0.93 (0.73–1.19) 0.57
Coronary-artery bypass
surgery
584 138 (57.1) 139 (57.0) 150 (63.3) 157 (65.0) 0.90 (0.76–1.05) 0.18 0.99 (0.84–1.17) 0.91 0.89 (0.71–1.13) 0.34
Percutaneous coronary
intervention
1096 257 (122.6) 270 (129.4) 279 (135.0) 290 (141.6) 0.92 (0.82–1.03) 0.16 0.94 (0.83–1.05) 0.27 0.86 (0.72–1.02) 0.08
Cancer 144 40 (15.5) 39 (14.9) 25 (9.8) 40 (15.2) 1.22 (0.88–1.70) 0.23 0.84 (0.60–1.16) 0.29 1.02 (0.65–1.58) 0.94
* The comparison is for the combination-therapy group and the group given folic acid and vitamin B12 with the group given vitamin B6 and the placebo group.
† The comparison is for the combination-therapy group and the group given vitamin B6 with the group given folic acid and vitamin B12 and the placebo group.
‡ The comparison is for the combination-therapy group with the placebo group.
§ Values were adjusted for study center. CI denotes confidence interval.
¶ The primary end point was a composite of nonfatal or fatal myocardial infarction (including sudden death attributed to coronary heart disease) and nonfatal or fatal stroke. Only the
first event is included in the composite primary end point.
? If a participant first had a nonfatal myocardial infarction and then a fatal myocardial infarction, only the nonfatal myocardial infarction was included in the category of myocardial infarction.
** The category includes sudden death attributed to coronary heart disease.
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The new england journal o f medicine
1584
percent, P<0.001) and 3.8 µmol per liter (0.51 mg
per liter) lower at the end of the intervention (a
difference of 28 percent, P<0.001). The mean total
homocysteine level did not change significantly
in the group treated with vitamin B6 alone. Treatment
with folic acid and vitamin B12 led to significant
increases, by a factor of 5 to 6, in the mean
levels of plasma folate and increases in plasma
vitamin B12 by approximately 60 percent.
Clinical End Points
Table 3 shows the number of primary and secondary
end points and event rates in the treatment
groups and the rate ratios. Treatment with folic
acid in combination with vitamin B12 — with or
without vitamin B6 — did not significantly reduce
the risk of the primary end point, as compared
with placebo. Both treatment regimens were associated
with a nonsignificant increase in risk, mainly
driven by an event rate that was 22 percent higher
in the combination-therapy group than in the
placebo group (P = 0.05). Figure 1 shows Kaplan–
Meier curves of the event rates for the primary
end point in the treatment groups. The cumulative
hazard ratio for the combination-therapy group,
as compared with the other three groups, was
1.20 (95 percent confidence interval, 1.02 to 1.41;
P = 0.03). Adjusting for the use of warfarin at baseline
(which differed among the four groups, as
shown in Table 1) did not alter the rate ratios significantly.
The risk of the secondary end points was not
significantly influenced by treatment with folic
acid and vitamin B12. Vitamin B6 therapy was
associated with a 17 percent increase in the risk
of myocardial infarction (P = 0.05), and combination
therapy was associated with a 30 percent
increase in the risk of nonfatal myocardial infarction
(P = 0.05) (Table 3). Given, however, that
these analyses were not adjusted for multiple comparisons,
these apparent associations could readily
be explained by chance. There was a numerical
increase in the risk of cancer among patients
assigned to folic acid, but this difference was not
significant (Table 3).
Subgroup analyses of the primary end point
are shown in Table 4. Treatment with B vitamins
was not associated with a significant benefit in
any subgroup. An increased risk associated with
treatment was observed among patients with
higher baseline levels of total homocysteine (more
than 13 µmol per liter, vs. 13 µmol per liter or
less) who received combination therapy (P = 0.04)
and among those with a myocardial infarction
without ST-segment elevation who received folic
acid and vitamin B12 (P = 0.04).
The baseline level of total homocysteine was
a significant predictor of the primary end point
(relative risk associated with a 3-µmol difference
in the total homocysteine level, 1.05; 95 percent
confidence interval, 1.01 to 1.09; P = 0.01) after
adjustment for study center, age, sex, systolic blood
pressure, total cholesterol level, and smoking status.
After additional adjustment for the creatinine
level, the relative risk was 1.03 (P = 0.10).
Discussion
We did not find that secondary intervention with
folic acid (plus vitamin B12) and vitamin B6, alone
or in combination, decreased the risk of complications
and death from cardiovascular causes
among patients with a recent myocardial infarction,
despite a substantial reduction in plasma total
homocysteine levels in patients receiving folic
acid. Contrary to expectations, there was a trend
No. at Risk
Folic acid,
B12, and B6
Folic acid
and B12
B6
Placebo
517
518
511
523
745
764
766
771
795
812
805
823
937
935
934
943
Probability of Primary End Point
0.20
0.25
0.15
0.10
0.05
0.00
0 1 2 3 4
Years of Follow-up
Folic acid, B12, and B6
Folic acid
and B12
Placebo
0.30
B6
Figure 1. Kaplan–Meier Estimates of the Probability
of Reaching the Primary End Point during Follow-up.
The primary end point was a composite of fatal and
nonfatal myocardial infarction, fatal and nonfatal
stroke, and sudden death attributed to coronary heart
disease.
n engl j med 354;15 www.nejm.org april 13, 2006
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homocysteine lowering after acute myocardial infarction
1585
toward an increased rate of events among patients
receiving B vitamins, in particular the combination
of folic acid, vitamin B6, and vitamin B12.
Noncompliance is not a likely explanation for
these negative findings, because the high rate of
compliance, although probably overreported, was
corroborated by a biochemical assessment of vitamin
status. The power of the trial was slightly
less than planned. However, it had a power of 0.80
to detect an 18 percent reduction in the risk of
the primary end point and a power of 0.87 to detect
the prespecified, hypothesized 20 percent reduction
in risk with vitamin therapy.
Our trial was large and included patients from
community and referral hospitals in different regions
of Norway; we used liberal entry criteria to
increase the generalizability of the results, and the
baseline characteristics of NORVIT participants
were similar to those of patients with acute myocardial
infarction who have participated in recent
trials conducted worldwide.23 We therefore believe
our results are applicable to the majority of
patients who present with acute myocardial infarction.
Many observational studies have demonstrated
that the plasma total homocysteine level is a
Table 4. Rate Ratios for the Primary End Point in Various Subgroups.*
Characteristic Total No.
Folic Acid and B12 vs.
No Folic Acid and B12† B6 vs. No B6‡
Folic Acid, B12, and B6
vs. Placebo§
rate ratio (95% confidence interval)
Sex
Male 2771 1.06 (0.89–1.27) 1.14 (0.96–1.36) 1.23 (0.96–1.57)
Female 978 1.07 (0.82–1.41) 1.11 (0.85–1.46) 1.10 (0.75–1.61)
Age
=65 yr 2068 1.17 (0.92–1.51) 1.11 (0.87–1.42) 1.26 (0.89–1.80)
>65 yr 1681 0.97 (0.80–1.16) 1.12 (0.93–1.34) 1.05 (0.81–1.36)
Total homocysteine
=13 µmol/liter 2237 0.97 (0.79–1.20) 1.03 (0.84–1.27) 1.02 (0.75–1.37)
>13 µmol/liter 1496 1.27 (1.02–1.66) 1.26 (1.02–1.55) 1.56 (1.16–2.09)
Creatinine
=100 µmol/liter 2845 1.05 (0.88–1.25) 1.04 (0.87–1.25) 1.09 (0.85–1.46)
>100 µmol/liter 891 1.13 (0.87–1.47) 1.32 (1.01–1.71) 1.44 (0.98–2.11)
History of CVD or diabetes¶
No 1641 1.28 (0.95–1.73) 0.92 (0.68–1.24) 1.15 (0.76–1.75)
Yes 2108 1.04 (0.88–1.23) 1.22 (1.03–1.45) 1.28 (1.01–1.62)
Current smoker
No 2002 1.08 (0.90–1.30) 1.06 (0.88–1.27) 1.12 (0.86–1.45)
Yes 1747 1.04 (0.81–1.32) 1.28 (1.01–1.63) 1.34 (0.95–1.88)
Qualifying myocardial infarction
No ST-segment elevation 1959 1.25 (1.03–1.51) 1.12 (0.92–1.35) 1.40 (1.07–1.82)
ST-segment elevation 1651 0.90 (0.71–1.15) 1.11 (0.87–1.41) 1.07 (0.76–1.51)
* Values were adjusted for study center. Information on total homocysteine was available for 3733 patients, information
on creatinine was available for 3736 patients, and information on ST-segment elevation was available for 3610 patients.
To convert values for homocysteine to milligrams per liter, divide by 7.396. To convert values for cholesterol to milligrams
per deciliter, divide by 0.02586.
† The comparison is for the combination-therapy group and the group given folic acid and vitamin B12 with the group
given vitamin B6 and the placebo group.
‡ The comparison is for the combination-therapy group and the group given vitamin B6 with the group given folic acid
and vitamin B12 and the placebo group.
§ The comparison is for the combination-therapy group with the placebo group.
¶ CVD denotes cardiovascular disease (i.e., myocardial infarction, angina pectoris, stroke, coronary-artery bypass surgery,
or percutaneous coronary intervention).
n engl j med 354;15 www.nejm.org april 13, 2006
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The new england journal o f medicine
1586
predictor of cardiovascular events1 in the general
population2 as well as in patients with a diagnosis
of cardiovascular disease,3 but no causative
role of homocysteine has been substantiated by
the results of intervention trials involving homocysteine-
reducing treatment. Results from a
large secondary intervention trial15 and three
smaller studies24-26 suggest that treatment with
B vitamins has no effect on stroke recurrence
or on complications and death from cardiovascular
causes. Similar findings were noted in the
Heart Outcomes Prevention Evaluation (HOPE)
2 trial of B vitamin therapy in high-risk patients,
which is reported elsewhere in this issue of the
Journal.27
Folic acid in combination with vitamin B6 may
reduce the rate of restenosis in patients undergoing
coronary balloon angioplasty,17 but it may
increase the rate after coronary stenting.18 The
latter finding came from a study that used a dose
of B vitamins similar to that of the combination
therapy in our study, and the results resemble
our findings of increased event rates among patients
receiving folic acid plus a high dose of vitamin
B6. Thus, secondary intervention trials with
high doses of B vitamins in patients with cardiovascular
disease have mostly shown no effect, not
unlike the failure to prevent heart disease with
high doses of single nutrients like vitamins E, C,
and A. These findings should encourage trials
with physiologic and more balanced doses of micronutrients.
28
The effects of folate and homocysteine-lowering
therapy have been evaluated with the use of
cardiovascular surrogate markers, including endothelium-
dependent vascular reactivity and markers
of vascular dysfunction and inflammation.
Improved function has been demonstrated in
some8,29-32 but not all33-38 studies. The lack of benefit
of homocysteine-lowering therapy in the clinical
setting suggests that such treatment may have
effects that promote atherothrombosis. Folic acid
may affect endothelial function8 and support cell
growth through mechanisms that are independent
of homocysteine.39 Increased proliferation
of vascular smooth-muscle cells and matrix formation
have been suggested as possible mechanisms
behind the increased risk of in-stent restenosis
in patients given folic acid and vitamin B6.18
Furthermore, vitamin B6 is involved in numerous
enzymatic reactions and biologic functions, including
cell growth, immunocompetence, and
cholesterol metabolism,40 and high levels may
inhibit angiogenesis.41 Conceivably, high doses of
vitamin B6 may adversely affect vascular remodeling
and myocardial repair, leading to increased
rates of complications and death among patients
with cardiovascular disease.
In summary, the NORVIT trial demonstrated
that intervention with folic acid, with or without
high doses of vitamin B6, did not lower the risk
of recurrent cardiovascular disease or death after
an acute myocardial infarction. Such therapy may
even be harmful after acute myocardial infarction
or coronary stenting18 and should therefore
not be recommended.
Supported by the Norwegian Research Council, the Council
on Health and Rehabilitation, the University of Tromsø, the
Norwegian Council on Cardiovascular Disease, the Northern Norway
Regional Health Authority, the Norwegian Red Cross, the
Foundation to Promote Research into Functional Vitamin B12 Deficiency,
and an unrestricted private donation.
Presented in part at the European Society of Cardiology Congress,
Stockholm, September 3–7, 2005.
Dr. Ueland reports having received consulting fees from
Nycomed and is a member of the steering board of both the
nonprofit Foundation to Promote Research into Functional Vitamin
B12 Deficiency and Bevital, a company owned by the foundation.
A provisional application (62924 [52365]) for a patent entitled
“Determination of folate in fresh and stored serum or
plasma as paraaminobenzoylglutamate” was filed on March 4,
2005; Dr. Ueland is listed as one of the inventors. The patent is
owned by Bevital. No other potential conflict of interest relevant
to this article was reported.
We are indebted to Alpharma for providing the study medication
free of charge, to all investigators and the nursing staff at
the participating hospitals, to Sissel Andersen and Anna-Kirsti
Jenssen for database management, and to all the patients who
participated in the trial.
appendix
The following investigators and institutions, all in Norway, participated in the NORVIT trial: Investigators (listed in descending order
of the number of randomized patients, with the number of patients shown in parentheses) — Sentralsykehuset i Akershus, Nordbyhagen
(357): J. Eriksen, I. Sletten Løvik, G. Hofset, U. Hågensen; Universitetssykehuset Nord-Norge, Tromsø (339): F. Saleh, H. Wang, W. Gamst,
J. Aarsland, F. Johnsen; Vest-Agder sentralsykehus, Kristiansand (275): F.T. Gjestvang, G. Eidvinsson, S.H. Schou; Sentralsykehuset i Møre og
Romsdal, Aalesund (206): T. Hole, Ø. Kaarbøe, L. Gjerde, L. Walderhaug; Buskerud sentralsykehus, Drammen (200): S. Ritland, B. Aakervik,
MG. Ødegaard, I. Mikalsen, E.-M. Christiansen; Sentralsjukehuset i Hedmark, Hamar (194): K. Andersen, M. Ekelund Thørud, T.K. Dalsbakken;
Nordland sentralsykehus, Bodø (191): K.T. Lappegård, A. Sivertsen, B. Tegnander, J.H. Flage, V. Andreasson, L. Stolpen; St. Olav’s
Hospital, Universitetsklinikken i Trondheim, Trondheim (175): J.D. Solli, H. Thürmer, F. Alstad Berg, S. Holst; Lovisenberg Diakonale sykehus, Oslo
(147): K.A. Langerød, G. Vollan; Hammerfest sykehus, Hammerfest (137): S. Høybjør, B. Rystad, R. Hjertø; Kongsvinger sykehus, Kongsvinger
(133): J. Aaseth, E. Melbye; Harstad sykehus, Harstad (115): K. Hofsøy, A. Karlsen; Fylkessjukehuset på Voss, Voss (115): F. Bergo, G.-O. Nedreberg;
Kongsberg sykehus, Kongsberg (106): K. Berget, A. Sagosen, A. Fulsebakk, N. Wangestad; Oppland sentralsykehus, Gjøvik (106): I. Stokland, P.
n engl j med 354;15 www.nejm.org april 13, 2006
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homocysteine lowering after acute myocardial infarction
1587
Vandvik, T. Roterud; Haukeland sykehus, Bergen (96): J.E. Nordrehaug, Ø. Bleie, S. Færevåg; Notodden sykehus, Notodden (83): N.O. Lied, M.
Sand, G. Bjerke-Dalen, R. Innvær; Fylkessjukehuset i Nordfjordeid, Nordfjordeid (81): H. Berg, M. Berg; Telemark sentralsykehus, Skien (80): P.
Urdal, M. Gundersen; Rjukan sykehus, Rjukan (75): O. Øygarden, A. Lien; Lofoten sykehus, Gravdal (62): J. Liljedal, V. Hausler, L. Møllre
Ofstad; Aker sykehus, Oslo (59): T. Bruun Wyller, A. Hodt, H. Claussen; Vefsn Sykehus, Mosjøen (53): T. Haugnes, B. Øvrehus; Kirkenes sykehus,
Kirkenes (48): H. Søndenå, M. Tverland; Tynset Sykehus, Tynset (47): V. Høeg; Fylkessjukehuset i Haugesund, Haugesund (46): K. Waage, P.
Rebhan, T. Stene Mo; Sentralsjukehuset i Sogn og Fjordane, Førde (44): F.J. Halvorsen, D.J. Fadnes, S. Landro; Sandnessjøen Sykehus, Sandnessjøen
(41): M. Noursadeghi, E. Aagnes, T. Vartdal, A. Bauer; Vestfold sentralsykehus, Horten (37): M. Bækkevar, E. Røkås, T. Nordby; Fylkessjukehuset
på Stord, Stord (31): E. Hodneland, J. Halwe, J. Njøsen; Orkdal Sanitetsforenings sykehus, Orkdal (30): K. Selsås, B. Gustavsson, M. Stenbacka,
A.-G. Snildal; Stokmarknes sykehus, Stokmarknes (18): A.F. Eide, U. Spreng; Rana sykehus, Mo i Rana (14): P. Nesje, R.T. Hansen;
Narvik sykehus, Narvik (5): S. Njålla; Rikshospitalet, Oslo (3): J. Offstad; End-Points Committee — I. Njølstad (chair), H. Wang, T. Steigen,
H. Schirmer; Executive Committee — K. Rasmussen (chair), J. Eriksen, P.M. Ueland, J.E. Nordrehaug, E. Arnesen, A. Nordøy, K.H.
Bønaa; Coordinating Center — K.H. Bønaa (principal investigator), S. Andersen, A.K. Jenssen, H. Jacobsen; Data and Safety Monitoring
Board — T. Pedersen (chair), D. Thelle, A. Tverdal; Core Laboratory Staff — P.M. Ueland, G. Kvalheim.
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