CARDIOVASCULAR NEWS
The Clopidogrel for the Reduction
of Events During Observation (CREDO) trial investigators
evaluated the benefit of long-term (12-month)
treatment with clopidogrel after PCI and the benefit
of initiating clopidogrel with a preprocedure
loading dose, both in addition to aspirin therapy.
The study, double-blind and placebo-controlled,
randomized 2116 patients who were to undergo elective
percutaneous coronary revascularization (PCI)
or were deemed at high likelihood of undergoing
PCI. The study participants were enrolled in 99
centers in North America from June 1999 to April
2001.
Patients were randomly assigned to receive
a 300-mg clopidogrel loading dose (n = 1053) or
placebo (n = 1063) 3 to 24 hours before PCI. Thereafter,
all patients received clopidogrel, 75 mg/d, through
day 28. From day 29 through 12 months, patients
in the loading-dose group received clopidogrel,
75 mg/d, and those in the control group received
placebo. Both groups received aspirin throughout
the study. At 1 year, long-term clopidogrel therapy
was associated with a 26.9% relative reduction
in the combined risk of death, MI, or stroke.
Clopidogrel pretreatment did not significantly
reduce the combined risk of death, MI, or urgent
target vessel revascularization at 28 days. However,
in a prespecified subgroup analysis, patients
who received clopidogrel at least 6 hours before
PCI experienced a relative risk reduction of 38.6%
for this end point compared with no reduction
with treatment less than 6 hours before PCI.
Risk
of major bleeding at 1 year increased, but not
significantly (8.8% with clopidogrel vs 6.7% with
placebo; P=0.07).
The study concluded that following
PCI, long-term (1-year) clopidogrel therapy significantly
reduced the risk of adverse ischemic events. A
loading dose of clopidogrel given at least 3 hours
before the procedure did not reduce events at
28 days, but subgroup analyses suggest that longer
intervals between the loading dose and PCI may
reduce events.
The findings from this trial (CREDO)
and the previously published PCI-CURE trial suggest
that dual antiplatelet therapy with clopidogrel
and aspirin in patients undergoing PCI for at
least one year instead of the current standard
of 2-4 weeks leads to significant reduction in
clinical complications. The study also suggests
that when clopidogrel loading of 300 mg is administered
more than 6 hours before PCI it may well offer
substantial benefit.
JAMA. 2002; 288:2411-2420
A pooled analysis of 5 randomized
intravenous GP IIb/IIIa inhibitor trials (EPIC,
EPILOG, EPISTENT, IMPACT II, and PURSUIT) was
performed to evaluate the utility of using platelet
glycoprotein (GP) IIb/IIIa receptor inhibitors
for percutaneous coronary interventions (PCI)
of bypass grafts. Outcomes of graft interventions
were assessed at 30 days and 6 months.
Compared
with PCI of native circulation (n=13 158), graft
interventions (n=627) were associated with worse
outcomes and in particular with a doubling of
mortality at 30 days (2.1% versus 1.0%, P=0.006)
and 6 months (4.7% versus 2.0%, P<0.001). Revascularization
of a graft was identified as an independent predictor
of death, myocardial infarction, or revascularization
at 6 months (hazard ratio, 1.42; 95% CI, 1.24
to 1.63; P<0.001). Among patients undergoing graft
PCI, the incidence of the triple end point at
30 days was 16.5% in the platelet GP IIb/IIIa
inhibitor group and 12.6% in the placebo group
(odds ratio, 1.38; 95% CI, 0.85 to 2.24; P=0.18).
At 6 months, 39.4% of patients randomized to GP
IIb/IIIa inhibitors and 32.7% of patients allocated
to placebo had an ischemic event (hazard ratio,
1.29; 95% CI, 0.97 to 1.72; P=0.07).
The investigators
concluded that intravenous platelet GP IIb/IIIa
receptor inhibition does not improve outcomes
after PCI of bypass grafts. In the absence of
mechanical emboli protection, this procedure is
associated with high incidence of death and nonfatal
ischemic events.
Circulation 2002 106: 3063 – 3067
The investigators examined the
associations between genetic variants and myocardial
infarction. A fluorescence- or colorimetry-based
allele-specific DNA-primer–probe assay system
was used to determine the genotypes of 112 polymorphisms
of 71 candidate genes in 2819 unrelated Japanese
patients with myocardial infarction (2003 men
and 816 women) and 2242 unrelated Japanese controls
(1306 men and 936 women).
112 polymorphisms were
crosschecked in 909 patients with myocardial infarction
(MI). After adjustment for age, body-mass index,
and the prevalence of smoking, hypertension, diabetes
mellitus, hypercholesterolemia, and hyperuricemia,
19 polymorphisms were selected in men and 18 in
women by means of logistic-regression analysis.
In a large-scale study involving the selected
polymorphisms and the remaining 4152 subjects,
similar logistic-regression analysis revealed
that the risk of myocardial infarction was significantly
associated with the C1019T polymorphism in the
connexin 37 gene (P<0.001) in men and the 4G–668/5G
polymorphism in the plasminogen-activator inhibitor
type 1 gene (P<0.001) whereas the 5A–1171/6A polymorphism
in the stromelysin-1 gene (P<0.001) was strongly
implicated in women.
The authors conclude that
determination of the genotypes of the connexin
37, plasminogen-activator inhibitor type 1, and
stromelysin-1 genes may prove reliable in predicting
the genetic risk of myocardial infarction and
might thus contribute to the primary prevention
of this condition.
An editorial accompanying the
article recommended further studies aimed at replication
and elucidation of the underlying mechanisms of
disease. Advice to individual patients or recommendations
for primary prevention cannot be based on these
findings at present.
N Eng J Med.2002; 347:1916-1923
The Atrial Fibrillation Follow-up
Investigation of Rhythm Management (AFFIRM) trial
compared the two approaches to the treatment of
atrial fibrillation: (1) cardioversion and treatment
with antiarrhythmic drugs to maintain sinus rhythm,
and (2) the use of rate-controlling drugs, allowing
atrial fibrillation to persist. The study was
a randomized, multicenter comparison of these
two treatment strategies in patients with atrial
fibrillation and a high risk of stroke or death.
The primary end point was overall mortality. In
both approaches, the use of anticoagulant drugs
is recommended. A total of 4060 patients (mean
[±SD] age, 69.7±9.0 years) were enrolled in the
study; 70.8 percent had a history of hypertension,
and 38.2 percent had coronary artery disease.
Of the 3311 patients with echocardiograms, the
left atrium was enlarged in 64.7 percent and left
ventricular function was depressed in 26.0 percent.
There were 356 deaths among the patients assigned
to rhythm-control therapy and 310 deaths among
those assigned to rate-control therapy (mortality
at five years, 23.8 percent and 21.3 percent,
respectively; P=0.08).
More patients in the rhythm-control
group than in the rate-control group were hospitalized,
and there were more adverse drug effects in the
rhythm-control group as well. In both groups,
the majority of strokes occurred after warfarin
had been stopped or when the international normalized
ratio (INR) was subtherapeutic.
The study concluded
that management of atrial fibrillation with the
rhythm-control strategy offers no survival advantage
over the rate-control strategy. A potential advantage
in the rate-control strategy was lower risk of
adverse drug effects. Anticoagulation should be
continued in high-risk patients.
N Engl J Med 2002; 347:1825-1833
The purpose of the trial was similar
to the AFFIRM trial. 522 patients who had persistent
atrial fibrillation after a previous electrical
cardioversion were randomly assigned to receive
treatment aimed at rate control or rhythm control.
Patients in the rate-control group received oral
anticoagulant drugs and rate-slowing medication.
Patients in the rhythm-control group underwent
serial cardioversions and received antiarrhythmic
drugs and oral anticoagulant drugs. The end point
was a composite of death from cardiovascular causes,
heart failure, thromboembolic complications, bleeding,
implantation of a pacemaker, and severe adverse
effects of drugs. After a mean (±SD) of 2.3±0.6
years, 39 percent of the 266 patients in the rhythm-control
group had sinus rhythm, as compared with 10 percent
of the 256 patients in the rate-control group.
The primary end point occurred in 44 patients
(17.2 percent) in the rate-control group and in
60 (22.6 percent) in the rhythm-control group.
The 90 percent (two-sided) upper boundary of the
absolute difference in the primary end point was
0.4 percent (the prespecified criterion for noninferiority
was 10 percent or less). The distribution of the
various components of the primary end point was
similar in the rate-control and rhythm-control
groups.
The study concluded that rate control
is not inferior to rhythm control for the prevention
of death and morbidity from cardiovascular causes
and may be appropriate therapy in patients with
a recurrence of persistent atrial fibrillation
after electrical cardioversion.
N Engl J Med 2002;347:1834-1840
An accompanying editorial of the
two trials, (affirm AND RACE) pointed out that
all RACE patients and most AFFIRM participants
had already had an episode of AF before enrollment,
pointing to the propensity of recurrent arrhythmias.
As such the findings from these two trials may
not apply to people with first episode of arrhythmia.
N Engl J Med 2002;347:1883-1844
Experimental studies suggest that
transplantation of blood-derived or bone marrow–derived
progenitor cells beneficially affects postinfarction
remodeling. The safety and feasibility of autologous
progenitor cell transplantation in patients with
ischemic heart disease is unknown and hence was
studied by Hoelzer et al.
20 patients with reperfused
acute myocardial infarction (AMI) were randomized
to receive intracoronary infusion of either bone
marrow–derived (n=9) or circulating blood–derived
progenitor cells (n=11) into the infarct artery
4.3±1.5 days after AMI. Transplantation of progenitor
cells was associated with a significant increase
in global left ventricular ejection fraction from
51.6±9.6% to 60.1±8.6% (P=0.003), improved regional
wall motion in the infarct zone (P<0.001), and
profoundly reduced end-systolic left ventricular
volumes (56.1±20 mL to 42.2±15.1 mL; P=0.01) at
4-month follow-up.
In contrast, in a nonrandomized
matched reference group, left ventricular ejection
fraction only slightly increased from 51±10% to
53.5±7.9%, and end-systolic volumes remained unchanged.
Echocardiography revealed a profound enhancement
of regional contractile function (wall motion
score index 1.4±0.2 at baseline versus 1.19±0.2
at follow-up; P<0.001). At 4 months, coronary
blood flow reserve was significantly (P<0.001)
increased in the infarct artery. Quantitative
F-18-fluorodeoxyglucose–positron emission tomography
analysis revealed a significant (P<0.01) increase
in myocardial viability in the infarct zone. There
were no differences for any measured parameter
between blood-derived or bone marrow–derived progenitor
cells. No signs of an inflammatory response or
malignant arrhythmias were observed.
In patients
with AMI, intracoronary infusion of autologous
progenitor cells appears to be feasible and safe
and may beneficially affect postinfarction remodeling
processes.
Circulation 2002 106: 3009 – 3017
The design of a percutaneous implantable
prosthetic heart valve has become an important
area for investigation. A percutaneously implanted
heart valve (PHV) composed of 3 bovine pericardial
leaflets mounted within a balloon-expandable stent
was developed. After ex vivo testing and animal
implantation studies, the first human implantation
was performed in a 57-year-old man with calcific
aortic stenosis, cardiogenic shock, subacute leg
ischemia, and other associated noncardiac diseases.
Valve replacement had been declined for this patient,
and balloon valvuloplasty had been performed with
nonsustained results.
With the use of an antegrade
transseptal approach, the PHV was successfully
implanted within the diseased native aortic valve.
With accurate and stable PHV positioning, there
was no impairment of the coronary artery blood
flow or of the mitral valve function. There was
mild paravalvular aortic regurgitation. Immediately
and at 48 hours after implantation, valve function
was excellent, resulting in marked hemodynamic
improvement. Over a follow-up period of 4 months,
the valvular function remained satisfactory as
assessed by sequential transesophageal echocardiography,
and there was no recurrence of heart failure.
However, severe noncardiac complications occurred,
including a progressive worsening of the leg ischemia,
leading to leg amputation with lack of healing,
infection, and death 17 weeks after PHV implantation.
Nonsurgical implantation of a prosthetic heart
valve can be successfully achieved with immediate
and midterm hemodynamic and clinical improvement.
After further device modifications, additional
durability tests, and confirmatory clinical implantations,
PHV might become an important therapeutic alternative
for the treatment of selected patients with nonsurgical
aortic stenosis.®
Circulation 2002 106: 3006 – 3008
Compiled by: Dr. Jassim Al-Suwaidi
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GHA
PRESIDENT'S 
