From the Interventional Cardiology Laboratories and Department of
Medicine, Montreal Heart Institute, Québec, Canada.
Correspondence to Jean-Claude Tardif, MD, Montreal Heart Institute, Research Center, 5000 Belanger St, Montreal, Quebec, Canada, H1T 1C8.
Methods and Results—We studied a subgroup of 189 patients
included in the MVP trial who underwent successful balloon angioplasty
of at least one coronary segment with a reference diameter
< 3.0 mm. One month before angioplasty, patients were randomly
assigned to one of four treatments: placebo, probucol (500 mg),
multivitamins (beta-carotene 30 000 IU, vitamin C 500 mg, and vitamin
E 700 IU), or probucol plus multivitamins twice daily. The treatment
was maintained until follow-up angiography was performed at 6 months.
The mean reference diameter of this study population was
2.49±0.34 mm. Lumen loss was 0.12±0.34 mm for probucol,
0.25±0.43 mm for the combined treatment, 0.35±0.56 mm for
vitamins, and 0.38±0.51 mm for placebo (P=.005 for
probucol). Restenosis rates per segment were 20.0% for
probucol, 28.6% for the combined treatment, 45.1% for vitamins, and
37.3% for placebo (P=.006 for probucol).
Conclusions—Probucol reduces lumen loss and restenosis
rate after balloon angioplasty in small coronary arteries.
We have shown in the MultiVitamins and Probucol (MVP) study
that probucol, a potent antioxidant, significantly reduces
coronary restenosis after balloon
angioplasty.15 Interestingly, these results were
obtained without imposing any restriction relative to vessel size at
entry into the trial. Whether the benefit of probucol therapy was
maintained in the subgroup of patients with small vessels is not known.
Therefore the purpose of this study was to assess the effectiveness of
drugs with antioxidant properties (probucol and/or multivitamins) in
reducing late lumen loss and preventing restenosis after
balloon angioplasty in small coronary arteries (vessels with
reference diameter <3.0 mm).
Angioplasty and Angiographic Methods
Quantitative Coronary Angiography and Definition of
Restenosis
All measurements were determined by off-line quantitative angiographic
methods. Successful angioplasty was defined as a final diameter
narrowing <50% fifteen minutes after final angioplasty, with
Clinical Follow-up
Diet assessment and intervention in the MVP study has previously been
described.15 The American Heart Association Step
1 diet was taught to all patients. Specific dietary counseling was
given at each visit. Daily dietary intake of vitamins E and C and
beta-carotene was limited, and patients were instructed to avoid
vitamin and mineral supplements.
Major secondary clinical end points were death, myocardial infarction,
coronary bypass surgery, and repeat angioplasty.
Statistical Methods
Nine patients discharged after successful angioplasty did not undergo
final angiography. Causes for early termination included 1 death, 1
myocardial infarction, and 1 dropout. Three patients underwent surgical
revascularization and 3 patients had repeat
angioplasty despite not having reached quantitative criteria for
restenosis at early angiography. Seven patients were not
adequately compliant to study medications (2 in the probucol group, 2
in the vitamins, 3 in the combined treatment, and none in the placebo
group).
Angiographic Analysis
Restenosis rates per segment were 20.0% for probucol, 28.6%
for the combined treatment, 45.1% for vitamins alone, and 37.3% for
placebo (P=.006 for probucol versus no probucol and 0.370
for vitamins versus no vitamins) (Fig 2
Since there is no consensus on the definition of a small
coronary artery, we also performed angiographic
analysis of segments with reference diameters <2.7 mm. A
total of 131 patients presented at least one successfully
dilated segment <2.7 mm (n=34, 33, 34, and 30 in the placebo,
vitamins alone, combined treatment, and probucol alone groups,
respectively). The mean reference diameter of this subgroup of patients
was 2.31±0.27 mm (range, 1.48 to 2.69 mm), with no
differences between groups. The four groups were also comparable for
the minimal lumen diameter before (0.77±0.21 mm) and 15 minutes
after percutaneous transluminal coronary
angioplasty (PTCA) (1.57±0.28 mm), and the acute gain immediately
(0.86±0.36 mm) and at 15 minutes (0.84±0.40 mm) after PTCA.
Lumen loss per patient was then 0.08±0.30 mm for the probucol
only group, 0.27±0.49 mm for the combined treatment,
0.24±0.45 mm for vitamins alone, and 0.34±0.53 mm for
placebo alone (P=.09 for probucol versus no probucol and
0.42 for vitamins versus no vitamins). Restenosis rate per
segment was 21.6% in the probucol only group, 29.3% for probucol plus
vitamins, 44.4% for vitamins alone, and 32.4% for placebo
(P=.055 for probucol vs no probucol and 0.322 for vitamins
versus no vitamins).
Clinical End Points
Total cholesterol, LDL cholesterol, HDL
cholesterol, and triglycerides levels, as well
as
The effectiveness of probucol on the prevention of restenosis
has been previously suggested by several small
studies28 29 30 31 and recently confirmed by the MVP
trial.15 This substudy of the MVP trial is the
first to demonstrate a reduction of restenosis after balloon
angioplasty in coronary arteries <3.0 mm, with a mean
vessel reference diameter of 2.49 mm. Compared with placebo,
probucol given alone resulted in reductions of 68% in late lumen loss
and of 46% in the restenosis rate per segment. This translates
into a restenosis rate per patient as low as 21.7% in the
group treated with probucol alone. When arteries <2.7 mm were
evaluated (mean reference diameter, 2.31 mm), restenosis
rate per segment remained similarly low (21.6%). The beneficial effect
of probucol on the prevention of restenosis in small
coronary arteries has also been suggested by one other study
involving a limited number of patients (n=78). In that study, the
effectiveness of probucol was restricted to arteries
Probucol has powerful antioxidant effects33 that
may control the oxidative stress occurring after angioplasty. Oxidizing
species generated by damaged endothelium,
activated platelets, and neutrophils at the angioplasty
site can induce chain reactions which result in
endothelial dysfunction34 and LDL
oxidation.35 Activation of macrophages by
oxidized LDL and dysfunction of the endothelium can
result in the release of growth factors promoting tissue proliferation.
Secretion of metalloproteinases by endothelial and
smooth muscle cells and of new extracellular matrix also occurs as part
of the unaltered remodeling process,36 with
collagen cross-linking presumably causing arterial
constriction37 and endothelial
dysfunction possibly limiting positive chronic flow-dependent changes
in vessel dimensions.38 Thus the antioxidant
probucol may prevent endothelial
dysfunction39 40 and LDL
oxidation41 and in turn modify
neointimal formation42 and vascular
remodeling involved in restenosis.43
Probucol also has weak lipid-lowering properties, which probably cannot
account for its antirestenotic effect especially in light of
the fact that the more potent lovastatin failed to prevent
restenosis in one large clinical trial.44
On the other hand, it has been demonstrated that probucol also inhibits
the secretion of interleukin-1 by
macrophages.45 This effect may be
clinically important, since inhibition of interleukin-1 secretion may
result in a decreased production of matrix metalloproteinases
by smooth muscle cells46 and thus modify
remodeling of the extracellular matrix.
There was a tendency for probucol to have better results when given
alone than when it was combined with vitamins. The interaction between
probucol and vitamins for late lumen loss in coronary arteries
<3.0 mm was not significant (P=.19), but the power to
detect such an interaction was low in this substudy (39%). The
possible pro-oxidant effects of the very high doses of vitamins used in
the MVP study may explain this observation.
Limitations
Clinical Implications
Received July 31, 1997;
revision received October 8, 1997;
accepted October 10, 1997.
© 1998 American Heart Association, Inc.
Clinical Investigation and Reports
Prevention of Restenosis After Angioplasty in Small Coronary Arteries With Probucol
Abstract
Top
Abstract
Introduction
Methods
Results
Discussion
References
Background—Restenosis
remains the major limitation of coronary angioplasty.
Coronary stents have reduced the incidence of
restenosis in selected patients with relatively large vessels.
No strategies to date have demonstrated a beneficial effect in
vessels < 3.0 mm in diameter. We have shown in the
MultiVitamins and Probucol (MVP) Trial that probucol, a potent
antioxidant, reduces restenosis after balloon angioplasty. The
purpose of this study was to determine whether the benefit of probucol
therapy is maintained in the subgroup of patients with smaller
coronary vessels.
Key Words: angioplasty • antioxidants • restenosis
Introduction
Top
Abstract
Introduction
Methods
Results
Discussion
References
Restenosis
remains the major limitation of the long-term success of
coronary angioplasty.1 The introduction
of stents has significantly reduced the incidence of
restenosis,2 3 but these results were
obtained in selected patients with relatively large vessels (diameter
3.0 mm). Coronary stenting has initially been limited to
such arteries because of the increased risk of subacute thrombosis
observed in smaller vessels.4 Nevertheless, a
large number of percutaneous interventions are
performed in patients with small coronary arteries. A few
preliminary studies of coronary stents implanted in vessels
<3.0 mm have provided conflicting
results,5 6 7 8 9 10 11 12 13 14 and no strategies to date have
definitively demonstrated a significant reduction of restenosis
in small coronary vessels.
Methods
Top
Abstract
Introduction
Methods
Results
Discussion
References
Study Population and Randomization Procedure
We studied a subgroup of patients included in the MVP trial who
underwent balloon angioplasty of at least one coronary segment
with a reference diameter <3.0 mm. Details of the MVP trial have
been recently published.15 Briefly, the MVP study
was a double-blind, placebo-controlled randomized trial designed to
test the hypothesis that probucol and/or multivitamins (a combination
of vitamins E and C and beta-carotene) could reduce the rate and
severity of restenosis after coronary balloon
angioplasty. Patients were eligible if they were scheduled to have
standard balloon angioplasty on 1 native coronary artery and
had 1 target lesion with luminal narrowing of 50% by caliper
measurements. Patients were excluded if any of the following occurred:
inability to comply with pretreatment or to return for follow-up,
recent myocardial infarction (
7 days), planned stenting or
atherectomy, coronary angioplasty for a restenotic
lesion or for another lesion in the preceding 6 months, or angioplasty
of a bypass graft or of a bypassed native vessel with a patent graft.
Beginning 30 days before scheduled angioplasty, patients were randomly
assigned to receive either probucol alone (500 mg twice daily),
multivitamins alone (beta-carotene 30 000 IU, vitamin C 500 mg, and
vitamin E 700 IU, twice daily), the combination of probucol and
multivitamins, or placebo. All patients received an extra dose of
vitamin E 2000 IU and/or probucol 1000 mg and/or matched placebos 12
hours before angioplasty, according to randomization assignment. All
successfully dilated patients who did not present a periprocedural
complication were maintained on their assigned study regimen until
follow-up angiography was performed at 5 to 7 months.
All patients received aspirin 325 mg daily for the entire study
period. Coronary angiography and balloon angioplasty were
performed according to standard techniques. ECGs were taken before
angioplasty, immediately afterward, and daily until discharge. Creatine
kinase level and MB fraction were measured on the evening after the
procedure and the following morning. Patients were excluded from the
study if there was inability to dilate the stenosis, if an
initially successful angioplasty was followed by persistent abrupt
closure, if the procedure was complicated by a Q-wave infarction in the
dilated territory, if failed angioplasty required emergency bypass
surgery, or if suboptimal angioplasty result was treated with stenting.
Intracoronary nitroglycerin (0.3 mg) was given
for each target artery for both before and after dilatation angiography
and at follow-up. Angiograms were performed before angioplasty,
immediately after dilatation, 15 minutes after final balloon inflation
and at 5- to 7-month follow-up. Patients in whom coronary
angiography was performed for clinical reasons before the fifth month
returned for repeat angiographic examination at 5 to 7 months if no
definite restenosis was present on 1 dilated site.
The four coronary angiograms (before, immediately after,
15 minutes after the procedure, and final follow-up) were
analyzed together by experienced technicians supervised by a
cardiovascular radiologist blinded to treatment
assignment, using the Coronary Measurement
System.16 Measurements were made in a single
projection, showing the most severe stenosis. The
projection showing the arterial segment with good
opacification, as nearly perpendicular to the x-ray beam as possible,
was selected for analysis. Whenever possible, all four
measurements were made in the same projection for more accurate
comparison. Variability for repeated measurements of percent
stenosis in our laboratory is 8.6% when analyzing frames
recorded 1 to 6 months apart.17 A change of
15% or roughly 2 SD of this variability was taken to indicate a
clinically important change. 15%
reduction in diameter stenosis compared with the preangioplasty
angiogram. The 15-minute postangioplasty angiogram was used as the
final result to at least partly exclude early elastic recoil from the
assessment of restenosis. For the purpose of this MVP substudy,
only patients with 1 successfully dilated lesion with a reference
diameter <3.0 mm were included in the analysis of
restenosis. If a patient underwent angioplasty on more than one
segment, those with a reference diameter 3.0 mm were excluded
from the analysis. Restenosis was evaluated per patient
and per segment dilated. The primary efficacy end point was the extent
of restenosis defined as the loss in minimal lumen diameter
between the angiogram performed 15 minutes after final angioplasty and
at follow-up. In patients undergoing angioplasty on more than one
lesion with a reference diameter <3.0 mm, mean minimal luminal
diameters for all sites successfully dilated were computed at 15
minutes after angioplasty and at follow-up. Restenosis was also
defined as a dichotomous outcome and analyzed in terms of
change in percent stenosis. A patient was defined as having
restenosis if 1 dilated segment had a diameter
stenosis 50% at follow-up angiography, with a 15% change
in diameter stenosis compared with the angiogram performed 15
minutes after angioplasty. Only successfully dilated segments with
reference diameter <3.0 mm were considered in the evaluation per
segment, with a similar definition for restenosis
(stenosis 50% at final angiography with 15% change in
stenosis compared to baseline).
Patients had a clinical evaluation at 1, 3, and 6 months that
included an assessment for ischemic symptoms or any symptoms
related or not to the study medication or the angioplasty procedure.
Compliance with study medications was evaluated by pill counts and drug
level measurements at each visit.15 Drug levels
were not made available during the trial to keep investigators
blinded.
For the per-protocol population (patients completing trial
without protocol violations, including compliance with study
medications >80%), the primary efficacy end point (late lumen loss)
was analyzed with a two-way ANCOVA on follow-up luminal
diameter, controlling for postangioplasty luminal diameter and for
target vessel distribution extracting treatment effects and
interaction. In the intent-to-treat population, the dichotomous outcome
was analyzed similarly by using multiple logistic regression.
All early termination patients were considered as having
restenosis for the intent-to-treat analysis. Patients
who completed the trial with protocol violations were considered as
"restenosis" or "no restenosis," depending on
results of their efficacy end points. The restenosis rate per
segment was analyzed by the generalized estimating equations
technique,18 which takes into account potential
dependence between segments in the same patient. All secondary end
points were analyzed similarly to the primary efficacy end
point; depending on the nature of the outcome, ANCOVA, or multiple
logistic regressions were used. Baseline characteristics and major
clinical events of the four study groups were compared using
2 tests for categorical variables and
ANOVA for continuous variables. A value of P.05 was
considered to indicate statistical significance.
Results
Top
Abstract
Introduction
Methods
Results
Discussion
References
A total of 317 patients had been included in the MVP trial. From
this population, 189 patients with at least one successfully dilated
vessel with reference diameter <3.0 mm were selected for this
study. Patients were distributed in the four groups of treatment as
follows: 46 received probucol alone, 45 multivitamins alone, 51
probucol plus multivitamins, and 47 placebo alone. Baseline
demographic, clinical, and angiographic characteristics are shown in
Table 1
. The only statistically
significant baseline difference was target vessel distribution, with a
greater number of dilated left anterior descending arteries in the
vitamins only group. This variable did not show associations with
the efficacy end points.
View this table:
[in a new window]
Table 1. Baseline Demographic, Clinical, and Angiographic
Characteristics of the Four Study Groups
Quantitative angiographic findings in the per-protocol population
are shown in Table 2. The mean reference
diameter for this population was 2.49±0.34 mm (range, 1.48 to
2.99 mm), with no differences between groups. Lumen loss per
patient was 0.12±0.34 mm in the probucol only group,
0.25±0.43 mm for combined treatment, 0.35±0.56 mm for
vitamins only, and 0.38±0.51 mm for placebo (P=.005
for probucol versus no probucol and 0.325 for vitamins vs no vitamins).
Fig 1 represents the cumulative
frequency curves of minimal lumen diameter in all study groups.
View this table:
[in a new window]
Table 2. Quantitative Angiographic Analysis of
Per-Protocol Population
View larger version (32K):
[in a new window]
Figure 1. Cumulative distribution curves of the minimum
lumen diameter before and 15 minutes after angioplasty (PTCA,
percutaneous transluminal coronary angioplasty)
and at follow-up for the four study groups of the per-protocol
population. ).
Restenosis rates per patient were 21.7% for probucol, 33.3%
for probucol plus vitamins, 46.7% for vitamins, and 40.4% for placebo
(P=.005 for probucol versus no probucol and 0.374 for
vitamins versus no vitamins).
View larger version (28K):
[in a new window]
Figure 2. Restenosis rates for the four study groups
of the intent-to-treat population. A, Restenosis rates per
segment. B, Restenosis rates per patient.
The major clinical events were distributed as follows: One
myocardial infarction and one death occurred (both in the combined
treatment group), and there were four coronary artery bypass
grafts surgeries (three in the vitamins alone group and one in
the probucol group). Rates of repeat angioplasty were 13.0%, 19.6%,
26.7%, and 27.7% in the probucol, combined treatment, vitamins and
placebo groups, respectively (P=.07 for probucol versus no
probucol and 0.63 for vitamins versus no vitamins). 
-tocopherol and probucol levels for the four study
groups are provided in Table 3.
View this table:
[in a new window]
Table 3. Lipid and Drug Levels for the Four Study Groups
Discussion
Top
Abstract
Introduction
Methods
Results
Discussion
References
Few studies have analyzed the possible influence of vessel
size on restenosis after coronary balloon angioplasty.
Hirshfeld et al19 reported a reduced
restenosis rate in vessels 2.9 mm (34%) compared with
smaller vessels (44%). This inverse relation between vessel size and
restenosis has also been observed in the balloon angioplasty
arm of two stent trials5 14 and in one
intravascular ultrasound study.20 Balloon
oversizing in small coronary arteries resulting in greater
vascular injury may explain this observation. However, other studies
have failed to show the same relationship21 22 or
even suggested a negative effect of increased vessel
size.23 Although the potential role of vessel
diameter on restenosis after balloon angioplasty remains
unclear, small vessel size remains a major limitation of
coronary stenting. The use of stents has initially been
restricted to vessels with a reference diameter 3.0 mm because
of the increased risk of thrombotic occlusion in smaller
vessels.4 In addition to early experiences with
stent implantation,24 25 a substudy of the
Benestent trial emphasized the high risk of subacute thrombosis
when stents were implanted in small arteries (6.9%) compared with
vessels >3.0 mm (0.9%).8 However, there
have been recent preliminary reports involving a limited number of
patients in which stenting coronary arteries slightly
<3.0 mm in size was attempted.9 10 11 Most of
these studies have suggested that this approach could be safe when high
pressure inflations were performed to improve stent
expansion.10 11 Unfortunately, as shown by
intravascular ultrasound studies, a high percentage of stents are
inadequately deployed even after high pressure
inflations.26 Furthermore, there are no
angiographic parameters that can predict the adequate
expansion of stents.27 The long-term risk of
leaving an inadequately deployed stent in a small coronary
artery is unknown. Also, the effectiveness of coronary stenting
for the reduction of restenosis in small vessels has not been
clearly demonstrated. Subgroup analyses from the Stress and
Start trials have both reported a reduction in the restenosis
rate with stenting compared with balloon angioplasty in patients with
coronary arteries smaller than 3.0
mm.5 14 In addition, a meta-analysis of
the angiographic outcomes in the Benestent-1 and Stress-1 and 2 trials
has suggested that stenting had a greater impact on lowering
restenosis if vessels were between 2.6 and 3.4 mm in
diameter.13 In vessels <2.6 mm,
restenosis rates for stenting (38%) and balloon angioplasty
(42%) were comparable.13 Furthermore, other
studies have found restenosis rates as high as 45% when stents
were deployed in coronary arteries <3.0
mm.7 12 However, it is important to note that
there has been no large randomized trial conducted specifically to
determine whether stenting reduces restenosis in small
coronary arteries. Thus the data on the use of stents in small
coronary arteries are incomplete and conflicting and the issue
remains unresolved at the present time. 2.7 mm,
with a resultant restenosis rate of 24% in the probucol group
compared with 75% in the control group.32
The MVP trial was not specifically designed to address the issue
of balloon angioplasty in small coronary arteries.
Nevertheless, this analysis of 189 subjects well distributed in
each of the four study groups offers strong evidence that the positive
overall results obtained in the main trial also apply to this
clinically important subgroup of patients.
Percutaneous revascularization
of small coronary arteries presents major shortcomings. Our
study demonstrates a significant reduction in restenosis with
the use of the antioxidant probucol when started 1 month before balloon
angioplasty in stable angina patients with coronary arteries
<3.0 mm in diameter. It remains to be determined if the high
restenosis rate after balloon angioplasty can also be reduced
by stenting such vessels. Further research addressing this question
will help to determine the respective roles of stenting and of an
effective pharmacological agent such as probucol for the prevention of
restenosis in patients with small coronary
arteries.
Acknowledgments
Dr Tardif is a clinical investigator of the Fonds de Recherche
en Santé du Québec. The study was also supported in part by
the Medical Research Council of Canada, the Quebec Heart and Stroke
Foundation, and the Fonds de Recherche de l'Institut de Cardiologie
de Montréal.
References
Top
Abstract
Introduction
Methods
Results
Discussion
References
3 mm) and
small (<3 mm) vessels in the Stent REStenosis study.
J Am Coll Cardiol. 1995;25:375A. Abstract.
This article has been cited by other articles:
 |
|
 |
|
  W.-J. Jiang, X.-T. Xu, M. Jin, B. Du, K.-H. Dong, and J.-P. Dai Apollo Stent for Symptomatic Atherosclerotic Intracranial Stenosis: Study Results AJNR Am. J. Neuroradiol., May 1, 2007; 28(5): 830 - 834. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 V. Serebruany, A. Malinin, and R. Scott The In Vitro Effects of a Novel Vascular Protectant, AGI-1067, on Platelet Aggregation and Major Receptor Expression in Subjects With Multiple Risk Factors for Vascular Disease. Journal of Cardiovascular Pharmacology and Therapeutics, September 1, 2006; 11(3): 191 - 196. [Abstract] [PDF]
|
|
|
|
 |
|
 Y.-M. Deng, B. J. Wu, P. K. Witting, and R. Stocker Probucol Protects Against Smooth Muscle Cell Proliferation by Upregulating Heme Oxygenase-1 Circulation, September 28, 2004; 110(13): 1855 - 1860. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. D. Morris and S. Carson Routine Vitamin Supplementation To Prevent Cardiovascular Disease: A Summary of the Evidence for the U.S. Preventive Services Task Force Ann Intern Med, July 1, 2003; 139(1): 56 - 70. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. K. Lau, S. B. Leichtweis, P. Hume, R. Mashima, J. Y. Hou, X. Chaufour, B. Wilkinson, N. H. Hunt, D. S. Celermajer, and R. Stocker Probucol Promotes Functional Reendothelialization in Balloon-Injured Rabbit Aortas Circulation, April 22, 2003; 107(15): 2031 - 2036. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J.-C. Tardif, J. Gregoire, L. Schwartz, L. Title, L. Laramee, F. Reeves, J. Lesperance, M. G. Bourassa, P. L. L'Allier, M. Glass, et al. Effects of AGI-1067 and Probucol After Percutaneous Coronary Interventions Circulation, February 4, 2003; 107(4): 552 - 558. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. C.P. Azevedo, M. d. A. Pedro, L. C. Souza, H. P. de Souza, M. Janiszewski, P. L. da Luz, and F. R.M. Laurindo Oxidative stress as a signaling mechanism of the vascular response to injury: The redox hypothesis of restenosis Cardiovasc Res, August 18, 2000; 47(3): 436 - 445. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. E. Chambers, S. T Riebel, and M. Kozak Interventional Cardiology: Advances in Percutaneous Techniques for the Treatment of Cardiac Disease Seminars in Cardiothoracic and Vascular Anesthesia, July 1, 1999; 3(2): 109 - 125. [Abstract] [PDF]
|
|
|
|
 |
|
 R. J. Gibbons, K. Chatterjee, J. Daley, J. S. Douglas, S. D. Fihn, J. M. Gardin, M. A. Grunwald, D. Levy, B. W. Lytle, R. A. O'Rourke, et al. ACC/AHA/ACP-ASIM guidelines for the management of patients with chronic stable angina: A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on Management of Patients With Chronic Stable Angina) J. Am. Coll. Cardiol., June 1, 1999; 33(7): 2092 - 2197. [Full Text] [PDF]
|
|
|
|
 |
|
 E. M Lonn and S. Yusuf Evidence based cardiology: Emerging approaches in preventing cardiovascular disease BMJ, May 15, 1999; 318(7194): 1337 - 1341. [Full Text]
|
|
|
|
|
|
E. R. Edelman Vessel Size, Antioxidants, and Restenosis : Never Too Small, Not Too Little, but Often Too Late Circulation, February 10, 1998; 97(5): 416 - 420. [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||