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January 26, 2005 — The drug reviparin (a low molecular weight heparin
anticoagulant), when administered to patients with a heart attack, is effective
in reducing the risk of death and the risk of a subsequent heart attack,
according to a study in the January 26 issue of the Journal of the American
Medical Association.
Approximately 15.5 million cardiovascular deaths
occur every year, according to background information in the article. Of these,
about half are likely to be due to acute myocardial infarction (MI, [heart
attack]). Although reperfusion therapy (restoration of blood flow), aspirin,
beta-blockers, and angiotensin-converting enzyme (ACE) inhibitors reduce the
risk of death when used early in patients after a heart attack, the rate of
death and illness remains high. No antithrombotic or newer antiplatelet drug has
been shown to reduce the risk of death after a heart attack.
Salim Yusuf,
D.Phil., F.R.C.P.C., of Hamilton General Hospital and McMaster University,
Ontario, Hamilton, Canada, and colleagues evaluated the effects of reviparin on
the composite outcome of death, heart attack, and stroke at seven and 30 days.
The randomized, double-blind, placebo-controlled trial (Clinical Trial of
Reviparin and Metabolic Modulation in Acute Myocardial Infarction Treatment
Evaluation [CREATE]), included 15,570 patients with ST-segment elevation (a
specific finding on the electrocardiogram ) or new left bundle-branch block (a
slowing in the flow of electrical pulses that drive the heart beat). The
patients presented within 12 hours of symptom onset at 341 hospitals in India
and China from July 2001 through July 2004. Patients received reviparin (n =
7,780) or placebo (n = 7,790) subcutaneously twice daily for seven
days.
The researchers found that the primary composite outcome was
significantly reduced from 11.0 percent of patients in the placebo group to 9.6
percent in the reviparin group, a 13 percent lowered risk. These benefits
persisted at 30 days (13.6 percent vs. 11.8 percent) patients, a 13 percent
lowered risk; with significant reductions in the 30-day death rate (11.3 percent
vs. 9.8 percent), 13 percent lower rate; and additional heart attack (2.6
percent vs. 2.0 percent), a 23 percent lower rate; and no significant
differences in strokes (0.8 percent vs. 1.0 percent).
Reviparin
treatment was significantly better when it was initiated very early after
symptom onset at seven days (less than two hours: 30 percent reduced risk; 30 of
1,000 events prevented; between two to four hours: 19 percent reduced risk; 21
of 1,000 events prevented; between four to eight hours: 15 percent reduced risk;
16 of 1,000 events prevented; and greater than eight hours: 6 percent increased
risk. There was an increase in life-threatening bleeding at seven days with
reviparin and placebo (17 [0.2 percent] vs. 7 [0.1 percent], respectively); but
the absolute excess was small (one more event per 1,000) compared with the
reductions in the primary outcome (18 fewer per 1,000) or mortality (15 fewer
per 1,000).
“Reviparin is considerably less expensive than other
antithrombotic agents, such as bivalirudin, … and can be given subcutaneously.
Its use is relatively straightforward and can be used in both developed and
developing countries. Therefore, the benefits of reviparin represent a moderate
but important globally applicable advance in the management of patients with
acute MI,” the authors conclude.
Editor’s Note: The study had no
external funding. Reviparin and placebo were donated by Abbott Laboratories. Dr.
Yusuf has received research grants and honoraria for lectures from Knoll and
Abbott Laboratories.
Therapy With Glucose-Insulin-Potassium
Infusion Not Beneficial for Treating Heart Attack
In a related study
in this week’s JAMA, a widely applicable, inexpensive therapy was found
to have no effect on death rates when treating patients who had an acute
ST-segment elevation myocardial infarction (STEMI), a heart attack with a
specific finding on the electrocardiogram.
Shamir R. Mehta, M.D., M.Sc.,
of McMaster University and Hamilton Health Sciences, Hamilton, Ontario, Canada,
and colleagues evaluated the effects of high-dose glucose-insulin-potassium
(GIK) infusion on patients with acute STEMI. GIK is a low-cost therapy that has
been speculated to improve mortality in heart attack patients.
The study
(a merger of CREATE and Estudios Cardiologicas Latin America Study Group, ECLA
[CREATE-ECLA]) was conducted in 470 centers worldwide among 20,201 patients with
STEMI who presented within 12 hours of symptom onset. The average age of
patients was 58.6 years, and evidence-based therapies were commonly used.
Patients were randomly assigned to receive GIK intravenous infusion for 24 hours
plus usual care (n = 10,091) or to receive usual care alone (controls; n =
10,110).
The researchers found: “The CREATE-ECLA trial demonstrated that
high-dose GIK solution given for 24 hours in patients presenting with acute
STEMI has a neutral effect on mortality, cardiac arrest, and cardiogenic shock.
The goal of our study was to reliably assess the effects of high-dose GIK in
preventing mortality and major cardiovascular events in patients with STEMI.
Given that there were more than 1,900 deaths in the study, it was well powered
to detect even a moderate effect on mortality,” the authors write. “The very
high adherence to the protocol and the excellent 30-day follow-up (99.85
percent) provide confidence in the validity of our findings and suggest that it
is very unlikely that the current regimen of high-dose GIK is of any material
benefit in reducing mortality in patients with STEMI.”
Editor’s Note:
This study had no external funding. Aventis Pharma donated human insulin in
India. Aventis Pharma had no role in the design and conduct of the study, in the
collection, analysis, and interpretation of the data, or in the preparation,
review, or approval of the manuscript.
Editorial: Simple
Principles of Clinical Trials Remain Powerful
In an accompanying
editorial, Robert M. Califf, M.D., of Duke Clinical Research Institute, Durham,
N.C., discusses the CREATE trials.
“What does [the CREATE-ECLA] trial
show about GIK infusion? This ‘generic’ therapy has survived decades of clinical
practice without a definitive test of its safety and effectiveness. The
conceptual basis for its use is sound, and its rationale has been delineated in
a variety of publications cited by the CREATE investigators. Unfortunately,
regardless of its scientific rationale and the positive results of small
studies, this definitive trial, combined with a previous overview that showed
only a modest potential benefit, answers the question beyond reasonable doubt:
there is no benefit of GIK therapy. Societal resources would be better spent on
evaluating other approaches in clinical trials and using other therapies in
practice.”
“What does [the CREATE] trial show about reviparin?
Antithrombotic therapy has become a mainstay of treatment of acute coronary
syndromes (ACS), but the accrual of definitive evidence has been hampered by the
fact that unfractionated heparin (UFH) became standard before the era of
definitive clinical outcome trials,” Dr. Califf writes. “CREATE advances the
field by demonstrating that the recommendation for antithrombotic therapy can
now be made with confidence that the evidence is not built like a house of cards
on a series of neutral ‘equivalence trials or small outcome trials. Given the
modest advantage of low-molecular-weight heparin in general in the broader range
of ACS, including non-ST elevation ACS, CREATE enhances the case for its
preference over UFH.”
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