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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

Author Information <http://jama.ama-assn.org/issues/v288n8/rfull/#aainfo>
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
JOC12068
Despite technical improvements, restenosis and overall adverse events after
percutaneous coronary interventions remain important limitations of this
procedure. 1 <http://jama.ama-assn.org/issues/v288n8/rfull/#r1>
Epidemiological evidence suggests that total plasma homocysteine level is an
independent cardiovascular risk factor, 2
<http://jama.ama-assn.org/issues/v288n8/rfull/#r2> , 3
<http://jama.ama-assn.org/issues/v288n8/rfull/#r3>  correlates with the
severity of coronary artery disease, 4
<http://jama.ama-assn.org/issues/v288n8/rfull/#r4> , 5
<http://jama.ama-assn.org/issues/v288n8/rfull/#r5>  predicts mortality in
patients with established coronary atherosclerosis, 6
<http://jama.ama-assn.org/issues/v288n8/rfull/#r6> , 7
<http://jama.ama-assn.org/issues/v288n8/rfull/#r7>  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
<http://jama.ama-assn.org/issues/v288n8/rfull/#r8> , 9
<http://jama.ama-assn.org/issues/v288n8/rfull/#r9>  endothelium function, 10
<http://jama.ama-assn.org/issues/v288n8/rfull/#r10> , 11
<http://jama.ama-assn.org/issues/v288n8/rfull/#r11>  plasma lipoproteins, 12
<http://jama.ama-assn.org/issues/v288n8/rfull/#r12>  and coagulation
cascade, 13-16 <http://jama.ama-assn.org/issues/v288n8/rfull/#r13>  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 angioplasty 17
<http://jama.ama-assn.org/issues/v288n8/rfull/#r17> , 18
<http://jama.ama-assn.org/issues/v288n8/rfull/#r18>  and our group has shown
that homocysteine-lowering therapy significantly decreases restenosis rate
after coronary angioplasty. 19
<http://jama.ama-assn.org/issues/v288n8/rfull/#r19>  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.



METHODS



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
<http://jama.ama-assn.org/issues/v288n8/fig_tab/joc12068_f1.html> ). 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
<http://jama.ama-assn.org/issues/v288n8/rfull/#r20>  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
<http://jama.ama-assn.org/issues/v288n8/rfull/#r19>
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
<http://jama.ama-assn.org/issues/v288n8/rfull/#r21>  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
<http://jama.ama-assn.org/issues/v288n8/rfull/#r22>
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
<http://jama.ama-assn.org/issues/v288n8/rfull/#r19>  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
<http://jama.ama-assn.org/issues/v288n8/rfull/#r17> , 19
<http://jama.ama-assn.org/issues/v288n8/rfull/#r19>  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 <http://jama.ama-assn.org/issues/v288n8/rfull/#r23>  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 chi2 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).



RESULTS



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
<http://jama.ama-assn.org/issues/v288n8/fig_tab/joc12068_f1.html> ). 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
<http://jama.ama-assn.org/issues/v288n8/fig_tab/joc12068_t1.html> ).
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
<http://jama.ama-assn.org/issues/v288n8/fig_tab/joc12068_t2.html> ). 24
<http://jama.ama-assn.org/issues/v288n8/rfull/#r24>  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
<http://jama.ama-assn.org/issues/v288n8/fig_tab/joc12068_t3.html> ). 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
<http://jama.ama-assn.org/issues/v288n8/fig_tab/joc12068_f2.html> ).
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
<http://jama.ama-assn.org/issues/v288n8/fig_tab/joc12068_f3.html> ). The
only other variable independently associated with the incidence of major
adverse events was the restenotic nature of previously treated lesions (P =
.008).



COMMENT



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
<http://jama.ama-assn.org/issues/v288n8/rfull/#r25> , 26
<http://jama.ama-assn.org/issues/v288n8/rfull/#r26>  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
<http://jama.ama-assn.org/issues/v288n8/rfull/#r27>  halting in the
progression of carotid plaque, 28
<http://jama.ama-assn.org/issues/v288n8/rfull/#r28>  improved arterial
endothelial function, 29-31
<http://jama.ama-assn.org/issues/v288n8/rfull/#r29>  and significant benefit
on restenosis rate after coronary angioplasty. 19
<http://jama.ama-assn.org/issues/v288n8/rfull/#r19>
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 angioplasty 19
<http://jama.ama-assn.org/issues/v288n8/rfull/#r19>  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
<http://jama.ama-assn.org/issues/v288n8/rfull/#r32>
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 growth 8 <http://jama.ama-assn.org/issues/v288n8/rfull/#r8> , 9
<http://jama.ama-assn.org/issues/v288n8/rfull/#r9>  and collagen synthesis,
33 <http://jama.ama-assn.org/issues/v288n8/rfull/#r33>  which promote
intimal-medial thickening. 34
<http://jama.ama-assn.org/issues/v288n8/rfull/#r34>  Elevated homocysteine
levels may also have a procoagulant effect through interaction with
coagulation factor V, 13 <http://jama.ama-assn.org/issues/v288n8/rfull/#r13>
protein C, 14 <http://jama.ama-assn.org/issues/v288n8/rfull/#r14>  tissue
plasminogen activator, 15
<http://jama.ama-assn.org/issues/v288n8/rfull/#r15>  and tissue factor
activity. 16 <http://jama.ama-assn.org/issues/v288n8/rfull/#r16>  However,
increasing evidence suggests that the primary mechanism may be
oxidative-endothelial injury and dysfunction. 10
<http://jama.ama-assn.org/issues/v288n8/rfull/#r10> , 11
<http://jama.ama-assn.org/issues/v288n8/rfull/#r11>  Elevated homocysteine
levels decrease the release of nitric oxide 35
<http://jama.ama-assn.org/issues/v288n8/rfull/#r35> , 36
<http://jama.ama-assn.org/issues/v288n8/rfull/#r36>  and promote the
generation and accumulation of hydrogen peroxide, thus rendering nitric
oxide more susceptible to oxidative inactivation. 34
<http://jama.ama-assn.org/issues/v288n8/rfull/#r34>  Furthermore, elevated
plasma homocysteine levels promote lipid peroxidation, 37
<http://jama.ama-assn.org/issues/v288n8/rfull/#r37>  which alters growth
factor production and influences smooth muscle cell proliferation. 38
<http://jama.ama-assn.org/issues/v288n8/rfull/#r38>  Oxidized LDL
cholesterol has been shown to increase smooth muscle cells proliferation and
chemoattraction 39 <http://jama.ama-assn.org/issues/v288n8/rfull/#r39> , 40
<http://jama.ama-assn.org/issues/v288n8/rfull/#r40>  and enhance
platelet-derived growth factor gene expression and receptor formation in
vascular smooth muscle cell. 41
<http://jama.ama-assn.org/issues/v288n8/rfull/#r41>  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
<http://jama.ama-assn.org/issues/v288n8/rfull/#r42>  and vitamin B6
deficiency appears to be an independent predictor of coronary artery disease
43 <http://jama.ama-assn.org/issues/v288n8/rfull/#r43>  and further has been
shown to alter platelet function. 44
<http://jama.ama-assn.org/issues/v288n8/rfull/#r44>  Therefore, and despite
the findings of the Homocysteine Lowering Trialists' Collaboration group
that vitamin B6 does not significantly lower homocysteine levels, 20
<http://jama.ama-assn.org/issues/v288n8/rfull/#r20>  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 <http://jama.ama-assn.org/issues/v288n8/rfull/#r17>
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]
<mailto:[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.