Effect of Homocysteine-Lowering Therapy
With Folic Acid, Vitamin B12, and Vitamin B6 on Clinical
Outcome After Percutaneous Coronary Intervention
The Swiss Heart Study: A Randomized
Controlled Trial
JAMA Vol. 288 No. 8,
August 28, 2002
Guido Schnyder, MD; Marco Roffi, MD; Yvonne Flammer, MD; Riccardo Pin,
MD; Otto Martin Hess, MD
Context Plasma homocysteine level has been recognized as an important
cardiovascular risk factor that predicts adverse cardiac events in patients with
established coronary atherosclerosis and influences restenosis rate after
percutaneous coronary intervention.
Objective To evaluate the effect of homocysteine-lowering therapy on
clinical outcome after percutaneous coronary intervention.
Design, Setting, and
Participants Randomized, double-blind
placebo-controlled trial involving 553 patients referred to the University
Hospital in Bern, Switzerland, from May 1998 to April 1999 and enrolled after
successful angioplasty of at least 1 significant coronary stenosis (50%).
Intervention Participants were randomly assigned to receive a combination of
folic acid (1 mg/d), vitamin B12 (cyanocobalamin, 400 µg/d), and
vitamin B6 (pyridoxine hydrochloride, 10 mg/d) (n = 272) or placebo
(n = 281) for 6 months.
Main Outcome
Measure Composite end point of
major adverse events defined as death, nonfatal myocardial infarction, and need
for repeat revascularization, evaluated at 6 months and 1 year.
Results After a mean (SD) follow-up of 11 (3) months, the composite end
point was significantly lower at 1 year in patients treated with
homocysteine-lowering therapy (15.4% vs 22.8%; relative risk [RR], 0.68; 95%
confidence interval [CI], 0.48-0.96; P
= .03), primarily due to a reduced rate of target lesion revascularization
(9.9% vs 16.0%; RR, 0.62; 95% CI, 0.40-0.97; P
= .03). A nonsignificant trend was seen toward fewer deaths (1.5% vs 2.8%; RR,
0.54; 95% CI, 0.16-1.70; P = .27)
and nonfatal myocardial infarctions (2.6% vs 4.3%; RR, 0.60; 95% CI, 0.24-1.51;
P = .27) with
homocysteine-lowering therapy. These findings remained unchanged after
adjustment for potential confounders.
Conclusion Homocysteine-lowering therapy with folic acid, vitamin B12,
and vitamin B6 significantly decreases the incidence of major
adverse events after percutaneous coronary intervention.
JAMA. 2002;288:973-979
Despite technical improvements, restenosis and
overall adverse events after percutaneous coronary interventions remain
important limitations of this procedure.1 Epidemiological
evidence suggests that total plasma homocysteine level is an independent
cardiovascular risk factor,2, 3 correlates with the
severity of coronary artery disease,4, 5 predicts mortality in
patients with established coronary atherosclerosis,6, 7 and may have a
potential role with regard to outcome after coronary interventions. Studies on
the pathogenesis of homocysteine-induced vascular damage have suggested adverse
interaction with vascular smooth muscle cells,8, 9 endothelium function,10, 11 plasma lipoproteins,12 and coagulation
cascade,13-16 which may
contribute to homocysteine-induced atherogenesis, restenosis, and overall
adverse events after coronary interventions, such as angioplasty.
Previous reports have documented that plasma
homocysteine levels predict outcome after coronary angioplasty17, 18 and our group has
shown that homocysteine-lowering therapy significantly decreases restenosis
rate after coronary angioplasty.19 Based on those
results, we now report in an extension of our original study, the effect of
homocysteine-lowering therapy with folic acid, vitamin B12
(cyanocobalamin), and vitamin B6 (pyridoxine hydrochloride) on
clinical outcome after successful coronary angioplasty and, in particular,
whether the previously described 6 months' benefit is maintained at 1 year
despite cessation of homocysteine-lowering therapy at 6 months.
The protocol was approved by the Institutional
Research Ethics Committee of the University Hospital in Bern, Switzerland. Each
patient gave written informed consent. This was a prospective study enrolling
553 consecutive patients from May 1998 to April 1999 who had undergone
angioplasty of at least 1 significant coronary stenosis (50%) (Figure 1).
After successful coronary angioplasty, patients were randomly assigned in
double-blind fashion to receive folic acid (1 mg/d), vitamin B12
(400 µg/d), and vitamin B6 (10 mg/d) or placebo daily for 6 months.
The study medication was formulated to obtain a maximal homocysteine-lowering
effect with a minimal risk of adverse effects.20 The study population
included a subgroup of 205 patients independently randomized and scheduled for
follow-up angiography at 6 months; the quantitative angiography results of this
subgroup have been published.19
Patients with unstable angina, subacute
myocardial infarction (<2 weeks), renal insufficiency (serum creatinine
level >1.8 mg/dL [160 µmol/L]), or taking vitamin supplements were not
included. Patients were asked to withhold any multivitamin intake for the
entire study duration. Fasting total plasma homocysteine levels were measured
on admission and at 6 months follow-up using a rapid high-performance liquid
chromatographic assay.21 Coronary angioplasty
was performed according to standard clinical practice, with success defined as
residual diameter stenosis less than 35% with normal flow pattern (Thrombolysis
in Myocardial Ischemia [TIMI] III trial criteria).22
Angiographic Evaluation
Quantitative evaluation was carried out in monoplane projection after
predilatation with nitrates. Two orthogonal views were averaged for biplane
assessment. Data analysis was performed using an automated edge-detection
system (Philips Integris-BH-3000, Version 2 [if online] or Philips
View-Station-CDM-3500, Version 2 [if offline]; Philips, Best, the Netherlands)
with an institutional intraobserver variability of 0.15 mm for minimal luminal
diameter and 7% for stenosis severity.19 The tip of the
diagnostic or guiding catheter (positioned at the coronary ostium) was used for
calibration purposes. The same views and calibration techniques were used for
target lesion revascularization. End-diastolic frames in the 2 orthogonal views
that demonstrated maximal stenosis severity were used for luminal diameter measurement.
Reference vessel diameter, minimal luminal diameter, diameter stenosis, and
lesion length were calculated as the average value of the 2 views. Angiograms
were reviewed by an experienced interventional cardiologist blinded to
patients' homocysteine level and treatment assignments.
Follow-up and Study End Points
Clinical follow-up, including noninvasive stress test and resting
electrocardiogram, was performed at 6 months and 1 year, or earlier if symptoms
recurred. Adverse events were defined prospectively as (1) death; (2) cardiac
death, defined as sudden, unexplained death or death related to myocardial
infarction; (3) nonfatal myocardial infarction, defined as new Q waves (>40
ms; >0.2 mV) in 2 or more contiguous electrocardiographic leads; (4) need
for repeat revascularization for proven ischemia demonstrated by either
follow-up cardiac events or a positive noninvasive stress test with significant
angiographic stenosis of at least 50%; and (5) a composite of major adverse
events defined as any of the above events. Patients with more than 1 event had
only the first occurring event computed for overall major adverse events
determination.
Statistical Analysis
The target sample size of 555 patients was based on the assumption that the
rate of major adverse events would be 25% or more in the placebo-treated group
and less than 15% in the group treated with folate+B12+B6.17, 19 Assuming a 10%
dropout rate, the planned sample size would yield 500 patients with complete
follow-up and give the study a statistical power of 80% at a significance level
of .05.23 All analyses
were performed with the intent-to-treat principle, and patients lost to
follow-up were censored at the time clinical data became no longer available.
Plasma homocysteine levels were positively
skewed and therefore log-transformed prior to analysis. Results are shown in
natural units. Categorical variables are reported as counts (percentages) and
continuous variables as mean (SD). Categorical variables were examined by 2
test. Continuous variables were examined by a 2-tailed t test or by the Mann-Whitney U test if
skewed. The Spearman rank correlation coefficient was used to estimate the
correlation between homocysteine levels and different continuous variables.
Kaplan-Meier survival curves were used to
evaluate freedom from major adverse events, and treatment effect differences
were assessed with the Mantel-Cox log-rank test. Cox proportional hazards
regression models were used to examine the relation between treatment groups
and the different end points, after adjustment for multiple clinical and
angiographic covariates including age, sex, use or nonuse of stent, treatment
of restenotic or de novo lesions, vessel size, postprocedural minimal luminal
diameter, target lesion location, and use or nonuse of glycoprotein IIb/IIIa
inhibitors. Selected variables were those that were associated with at least 1
of the end points in unadjusted analysis. Cardiovascular risk factors (diabetes
mellitus, hypertension, hypercholesterolemia, smoking status) and statin use
were not associated with the different end points in unadjusted analysis.
Furthermore, adjustment for those variables did not significantly modify the
Cox proportional hazards regression analysis and were thus not included in the
model. Patients with a history of renal failure (serum creatinine level,
>1.8 mg/dL [160 µmol/L]) were not included to avoid elevated creatinine
values as confounders for increased plasma homocysteine levels. P<.05 was considered statistically
significant. Data were prospectively collected and analyzed using StatView
Version 4.5 (SAS Institute, Cary, NC).
Five hundred fifty-three patients were randomly
assigned either to receive folate+B12+B6 (n = 272) or
placebo (n = 281), with a total of 741 successfully treated lesions (Figure 1).
Seventy patients (110 lesions) were lost to follow-up or did not comply with
the study protocol: 14 (6 in the folate+B12+B6 group)
discontinued study medication, 37 (15 in the folate+B12+B6
group) refused noninvasive stress testing, 17 (8 in the folate+B12+B6
group) with proven ischemia refused reangiography, and 2 (1 in the folate+B12+B6
group) developed reversible contrast agent nephropathy. Two patients randomized
to receive folate+B12+B6 discontinued study medication
because of pruritus. No other adverse effect was reported. The baseline
clinical, laboratory, and angiographic characteristics of the 70 patients
without complete follow-up did not significantly differ from the remaining
study population. Given that clinical outcomes were the primary end points in
this study, all analyses were performed with the intent-to-treat principle.
Baseline Characteristics
Patients in the 2 groups were well matched at baseline with regard to
demographic variables and cardiovascular risk factors (Table 1).
Severity of coronary artery disease (as measured by a history of previous
myocardial infarction, previous revascularization, and the number of treated
lesions per patient), baseline laboratory values, and discharge drug therapy
were not significantly different between study groups. As expected, mean
homocysteine levels (SD) at 6 months were significantly lower with folate+B12+B6
therapy compared with placebo (1.01 [0.34] mg/L [7.5 (2.5) µmol/L] vs 1.36
[0.57] mg/L [10.1 (4.2) µmol/L], P<.001).
Mild to moderate elevation of homocysteine levels (>1.62 mg/L [12 µmol/L])
was present in 29% of patients at baseline. None of the patients had severe
hyperhomocysteinemia (>13.5 mg/L [100 µmol/L]). Baseline homocysteine levels
correlated with age (Spearman r =
0.212, P<.001), serum
creatinine levels (Spearman r =
0.251, P<.001), and
high-density lipoprotein (HDL) cholesterol levels (Spearman r = -0.128, P = .004).
Lesion location was independent of study group:
40% of all lesions were located in the left anterior descending coronary artery
and about 30% each in the circumflex coronary artery and the right coronary
artery (Table 2).24 Lesion severity
(lesion complexity, lesion length, vessel size, minimal luminal diameter, and
diameter stenosis) before and after coronary angioplasty was comparable between
study groups. The use of stents and glycoprotein IIb/IIIa inhibitors was also
identical between study groups.
Study End Points
After a mean (SD) follow-up of 11 (3) months, 14.0% of patients treated with
folate+B12+B6 underwent repeat revascularization vs 19.9%
of control patients (relative risk [RR], 0.70; 95% confidence interval [CI],
0.49-1.01; P = .06) (Table 3).
This difference was primarily due to the number of patients with repeat target
lesion revascularization, as 4.0% of patients in the folate+B12+B6
group and 3.9% in the placebo group had revascularization of a lesion other
than a target lesion (RR, 1.03; 95% CI, 0.45-2.34; P = .94). Among patients who received folate+B12+B6,
9.9% had repeat target lesion revascularization vs 16.0% in the placebo group,
a relative reduction of 38% (RR, 0.62; 95% CI, 0.40-0.97; P = .03). The need for target lesion
revascularization was also significantly associated with smaller vessel size
(SD) (2.91 [0.78] mm vs 3.16 [0.79] mm, P
= .02), smaller postprocedural minimal luminal diameter (SD) (2.22 [0.53] mm vs
2.45 [0.78] mm, P = .03), and the
restenotic nature of previously treated lesions (RR, 3.36; 95% CI, 1.67-6.76; P = .002). Adjustment for multiple risk
factors including age, sex, and variables known to influence the need for
target lesion revascularization after coronary angioplasty (use of stents,
treatment of restenotic lesions, vessel size, postprocedural minimal luminal
diameter, target lesion location, use of IIb/IIIa inhibitors) did not
significantly change the association between homocysteine-lowering therapy and
the need for repeat target lesion revascularization. In Cox proportional
hazards regression analysis, only folate+B12+B6 therapy (P = .02), the restenotic nature of
previously treated lesions (P =
.005), and postprocedural minimal luminal diameter (P = .01) retained statistical significance.
The need for target lesion revascularization was
independent of cholesterol levels, but the benefit of folate+B12+B6
therapy was most apparent for patients in the highest cholesterol tertile.
Compared with controls, patients treated with folate+B12+B6
with cholesterol levels in the highest (>228 mg/dL [5.90 mmol/L]) tertile
had the largest risk reduction in terms of target lesion revascularization (RR,
0.44; 95% CI, 0.21-0.92; P =
.04). This benefit was not significant among patients treated with folate+B12+B6
in the middle (189-228 mg/dL [4.89-5.90 mmol/L]) tertile (RR, 0.55; 95% CI,
0.25-1.23; P = .20) and was
smallest in the lowest (<189 mg/dL [4.89 mmol/L]) tertile (RR, 0.72; 95% CI,
0.33-1.55; P = .53). A similar
trend was seen for low-density lipoprotein (LDL) cholesterol levels ([highest
tertile: >145 mg/dL (3.75 mmol/L); RR, 0.50; 95% CI, 0.26-0.91; P = .03] [middle tertile: 108-145 mg/dL
(2.80-3.75 mmol/L); RR, 0.58; 95% CI, 0.32-1.14; P = .29] [lowest tertile: <108 mg/dL (2.80 mmol/L); RR,
0.66; 95% CI, 0.25-1.74; P =
.39], respectively). Adjustment for statin use did not significantly change
those associations.
There was a nonsignificant trend for a lower
incidence of nonfatal myocardial infarction (RR, 0.60; 95% CI, 0.24-1.51; P = .27), cardiac deaths (RR, 0.52; 95%
CI, 0.13-2.04; P = .34), and
overall deaths (RR, 0.54; 95% CI, 0.16-1.70; P
= .27) in patients receiving folate+B12+B6 therapy. Older
age (SD) was the only variable significantly associated with mortality (65.4
[11.5] years vs 61.2 [10.8] years, P
= .002).
The incidence of major adverse events was
significantly lower in patients receiving folate+B12+B6
therapy at 6 months (11.4% vs 18.9%; RR, 0.60; 95% CI, 0.40-0.91; P = .02) and at 1 year follow-up (15.4% vs
22.8%; RR, 0.68; 95% CI, 0.48-0.96; P
= .03) (Figure 2).
Adjustment for the previously mentioned variables did not significantly change
this association (P = .01). These
findings were reproduced in subgroups of patients stratified according to the
traditional cardiovascular risk factors (sex, diabetes mellitus, hypertension,
hypercholesterolemia, and smoking) (Figure 3).
The only other variable independently associated with the incidence of major
adverse events was the restenotic nature of previously treated lesions (P = .008).
This study provides evidence that
homocysteine-lowering therapy with folic acid, vitamin B12, and
vitamin B6 improves outcome after percutaneous coronary intervention
by reducing the need for repeat revascularization and decreasing the overall
incidence of major adverse events 1 year after successful coronary angioplasty.
This benefit is primarily related to a decrease in target lesion
revascularization, as the need for revascularization of lesions other than a
target lesion was almost identical between study groups. Furthermore, these
findings were reproduced in subgroups of patients stratified according to the
traditional cardiovascular risk factors. Vessel size, postprocedural minimal
luminal diameter, and treatment of restenotic lesions are known to influence
the need for target lesion revascularization.25, 26 These parameters were
equally distributed between study groups and the benefit of folate+B12+B6
therapy on the outcome after coronary angioplasty remained unaltered after
adjustment for those risk factors. These results are consistent with those of
recent randomized trials with homocysteine-lowering therapy showing decreased
risk of atherosclerotic coronary events among healthy patients,27 halting in the
progression of carotid plaque,28 improved arterial
endothelial function,29-31 and significant
benefit on restenosis rate after coronary angioplasty.19
This study further suggests that the benefit
obtained with homocysteine-lowering therapy at 6 months is maintained at 1 year
despite cessation of folate+B12+B6 therapy at 6 months.
Our previously reported significant decrease in restenosis rate after coronary
angioplasty19 could have
been questioned as a temporary benefit triggered by a homocysteine-lowering
therapy–related delay of the restenosis process. The current study confirms
that a 6-month course of this inexpensive treatment has minimal adverse effects
and helps to control excessive restenosis mechanisms. Nevertheless, it is
unclear whether a longer treatment course (ie, up to 12 months) would have
benefited the other end points, such as death or myocardial infarction, for
which only a trend in favor of homocysteine-lowering therapy was found. These
issues should be answered by several ongoing clinical trials: the Norwegian
Vitamin Interventional Trial (NORVIT) and the Western Norway B-vitamin
Intervention Trial (WENBIT) will assess the effects of homocysteine-lowering
therapy in patients with coronary artery disease; the Vitamin Intervention for
Stroke Prevention (VISP) study in the United States will report the effect of B
vitamins on stroke recurrence in patients with cardiovascular disease; and the
Prevention with a Combined Inhibitor and Folate in Coronary Heart Disease
(PACIFIC) study in Australia and the Study of Effectiveness of Additional
Reduction in Cholesterol and Homocysteine (SEARCH) in the United Kingdom will
address similar issues.32
The mechanisms by which elevated homocysteine
levels impair vascular function and possibly influence outcome after
percutaneous coronary intervention are not clearly understood, although several
hypotheses have been suggested. Elevated homocysteine levels stimulate vascular
smooth muscle cell growth8, 9 and collagen
synthesis,33 which promote
intimal-medial thickening.34 Elevated homocysteine
levels may also have a procoagulant effect through interaction with coagulation
factor V,13 protein C,14 tissue plasminogen
activator,15 and tissue
factor activity.16 However,
increasing evidence suggests that the primary mechanism may be
oxidative-endothelial injury and dysfunction.10, 11 Elevated homocysteine
levels decrease the release of nitric oxide35, 36 and promote the
generation and accumulation of hydrogen peroxide, thus rendering nitric oxide
more susceptible to oxidative inactivation.34 Furthermore, elevated
plasma homocysteine levels promote lipid peroxidation,37 which alters growth
factor production and influences smooth muscle cell proliferation.38 Oxidized LDL
cholesterol has been shown to increase smooth muscle cells proliferation and
chemoattraction39, 40 and enhance
platelet-derived growth factor gene expression and receptor formation in
vascular smooth muscle cell.41 Therefore,
homocysteine-induced endothelial dysfunction and lipid peroxidation may promote
smooth muscle cell proliferation, extracellular matrix formation, and
ultimately increase the need for repeat target lesion revascularization. Our
findings that the benefit of homocysteine-lowering therapy increases with
higher levels of LDL cholesterol supports this possible mechanism.
A critical question is whether the benefit of
homocysteine-lowering therapy on the outcome after coronary intervention
reflects causality. In the current study, the treatment of restenotic lesions,
the treatment of lesions in smaller vessels, and smaller postprocedural minimal
luminal diameter were all significantly associated with a worse outcome after
coronary angioplasty. Adjustment for these factors did not weaken the benefit
of homocysteine-lowering therapy, suggesting an independent association.
A limitation of the study design was that it
precluded assessment of the separate effects of folic acid, vitamin B12,
and vitamin B6, and the effect of different doses of these vitamins.
Furthermore, we cannot exclude the possibility that the benefit seen was not
also influenced by other homocysteine-independent treatment effects.
Specifically, folic acid likely improves nitric oxide availability
independently of its homocysteine-lowering effect,42 and vitamin B6
deficiency appears to be an independent predictor of coronary artery disease43 and further has been
shown to alter platelet function.44 Therefore, and
despite the findings of the Homocysteine Lowering Trialists' Collaboration
group that vitamin B6 does not significantly lower homocysteine
levels,20 the inclusion
of vitamin B6 in the homocysteine-lowering therapy or possibly
another homocysteine-unrelated effect of folic acid or vitamin B12
could have contributed to the improvement seen in the patients treated with
folate+B12+B6. In conclusion, the findings in this study,
in conjunction with our previously described association between homocysteine
levels and restenosis rate,17 support the
conclusion that the combination of folic acid, vitamin B12, and
vitamin B6, at least partially by lowering of homocysteine levels,
is an effective therapy for improving outcome in patients undergoing coronary
angioplasty.
Author/Article Information
Author Affiliations: Division of
Cardiology, Swiss Cardiovascular Center Bern, University Hospital, Bern,
Switzerland (Drs Flammer, Pin, and Hess); Department of Cardiovascular
Medicine/F25, The Cleveland Clinic Foundation, Cleveland, Ohio (Dr Roffi); and
the Division of Cardiology, UCSD Medical Center, University of California, San Diego
(Dr Schnyder).
Corresponding Author and Reprints:
Guido Schnyder, MD, Division of Cardiology, UCSD Medical Center, University of
California, San Diego, 200 West Arbor Dr, San Diego, CA 92103-8784 (e-mail: [log in to unmask]).
Author Contributions: Study concept and design:
Schnyder, Hess.
Acquisition of data: Schnyder, Roffi, Flammer, Pin.
Analysis and interpretation of
data: Schnyder, Roffi,
Flammer, Pin, Hess.
Drafting of the manuscript: Schnyder.
Critical revision of the
manuscript for important intellectual content: Roffi, Flammer, Pin, Hess.
Statistical expertise: Schnyder, Hess.
Obtained funding: Schnyder.
Administrative, technical, or
material support: Schnyder, Roffi,
Flammer, Pin.
Study supervision: Hess.
Funding/Support: Dr Schnyder is supported by a career development grant from the
Swiss National Science Foundation and by the University Hospital, Bern,
Switzerland.
Acknowledgment: We would like to thank the patients and their physicians for participation
in this study. We are grateful for the cooperation of the Coronary
Catheterization Laboratory staff and the nursing staff of the Swiss
Cardiovascular Center in Bern.
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Edward E.
Rylander, M.D.
Diplomat American
Board of Family Practice.
Diplomat American
Board of Palliative Medicine.