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Throughout its history, the DCRI has designed and performed
cutting-edge research projects. Besides innovation in the
design and completion of clinical trials, the DCRI has also
contributed extensively to clinical knowledge and advances
in clinical practice. The following projects are a sample
of those that have been particularly influential in both their
innovations in clinical trial design and their contributions
to the practice of medicine. Results slides for selected projects
can be found here.
ASSENT-II
This international trial of 16,949 patients with acute coronary
syndromes showed that an easily injected drug known as tenecteplase
(TNK) could be as effective as the standard 90-minute infusion
of alteplase in reducing mortality. Lancet 1999;354:716-722.
CARS
This 8,803-patient trial found that low, fixed doses of warfarin
(an oral anti-clotting drug) combined with aspirin offered
no benefit in preventing repeat heart attacks, among patients
who had survived a heart attack, beyond that of aspirin alone.
Lancet 1997;350:389-396.
CAVEAT-I
CAVEAT-I was the first major randomized trial of two cardiac
devices. At 35 sites in the U.S. and Europe, 1012 patients
were assigned to either atherectomy or angioplasty. Immediately
after the procedure, the blockage in the coronary blood vessel
was reduced to 50% or less significantly more often with atherectomy
than with angioplasty (89% vs. 80%), and the immediate increase
in vessel diameter was significantly increased with atherectomy.
However, early complications and in-hospital costs were significantly
increased with atherectomy, as was the risk of death or heart
attack at 6 months (8.6% vs. 4.6%). The rate of repeat blockage
also was similar between groups at 6 months. Thus although
atherectomy was associated with better short-term results,
it also was associated with more early complications, increased
costs, and no apparent clinical benefit after 6 months. N
Engl J Med 1993;329:221-227.
EPIC
This study showed that the use of a platelet glycoprotein
IIb/IIIa blocker (abciximab) could substantially reduce the
need for angioplasty or bypass surgery in patients with a
heart attack or angina, and other high-risk patients, offering
a more cost-effective approach and a benefit lasting up to
3 years. N Engl J Med 1994;330:956-961.
EPILOG
The follow-up trial to EPIC, EPILOG was intended to identify
the best dosages for combination heparin and abciximab therapy.
Using lower doses of heparin than in EPIC resulted in the
same degree of benefit, with less bleeding than in EPIC. N
Engl J Med 1997;336:1689-1696.
GUSTO-I
This "megatrial" of 41,021 patients set the standard
for the modern clinical trial. The analysis of four thrombolytic
treatments found that a regimen of alteplase (a clot-busting
drug) and intravenous heparin (a clot-preventing drug) was
superior to the more standard treatment, streptokinase, in
reducing mortality after heart attack. The GUSTO-I study showed
that the newer therapy could save the lives of thousands of
heart-attack victims each year. It has produced more than
100 published manuscripts so far and spawned dozens of influential
substudies. N Engl J Med 1993;329:673-682.
GUSTO Angiographic Substudy
The key finding of this 2431-patient GUSTO-I substudy was
that blood flow to the heart muscle at 90 minutes mirrors
outcomes at 30 days; that is, alteplase resulted in both superior
blood flow and superior outcomes compared with other therapies.
This finding provided hard evidence that restoring blood flow
to the heart muscle more quickly and completely corresponds
directly with favorable outcomes. N Engl J Med 1993;329:1615-1622.
GUSTO-IIa and –IIb
GUSTO-II compared recombinant hirudin versus heparin in acute
coronary syndromes. GUSTO-IIa was stopped after given hirudin
had a higher rate of hemorrhagic stroke, but GUSTO-IIb continued
the study at a lower dose of hirudin. This dose of hirudin
was found to reduce rates of repeat heart attack. In addition,
GUSTO-IIa highlighted the need to have large numbers of patients
in a trial: because hemorrhagic stroke occurs very rarely,
only a trial of this size would have captured enough events
to detect this potential problem. GUSTO-IIb was at the time
the largest trial to date in non-ST elevation acute coronary
syndromes. GUSTO-IIa: Circulation 1994;90:1631-1637.
GUSTO-IIb: N Engl J Med 1996;335:775-782.
GUSTO-II Angioplasty Substudy
In this substudy, angioplasty was found to be superior to
alteplase in reducing the rates of death, heart attack and
stroke, and stroke at 30 days, although this difference had
diminished by 6 months. This study helped establish angioplasty
as an acceptable treatment alternative to clot-busting therapy
alone. N Engl J Med 1997:336:1621-1628.
GUSTO-III
The third GUSTO trial was the first Phase III trial to evaluate
reteplase versus alteplase, two clot-busting drugs. It enrolled
15,060 patients with heart attack. Reteplase was associated
with slightly higher rates of mortality and bleeding at 30
days. Designed as a superiority trial, GUSTO-III raised the
question of how to define equivalence in a clinical trial.
N Engl J Med 1997;337:1118-1123.
Hypericum
This study randomized 340 people with major depressive disorder
to receive Hypericum perforatum (St. John's wort)
, sertraline (Zoloft), or placebo for 8 weeks. Neither patients
nor physicians knew which treatment had been assigned. At
8 weeks, the depression scores among people given Hypericum
or sertraline did not differ significnatly from those of patients
given placebo, nor did the rate of "full response."
Sertraline did show superiority over placebo on the Clinical
Global Impressions scale, a secondary measure in this study.
This study failed to support the efficacy of this popular
supplement in moderately severe major depression. JAMA.
2002;287:1807-1814.
IMPACT-II
A study of 4010 patients who underwent procedures for unstable
angina, IMPACT-II found that the platelet glycoprotein IIb/IIIa
blocker eptifibatide was associated with fewer outcome events
than placebo when used with aspirin and heparin. IMPACT-II
also highlighted the importance of monitoring therapy, when
it was found that platelet testing in the lab overestimated
the drug's effectiveness, leading to underdosing. Circulation
1995;91:2151-2157.
MAGIC
This study compared magnesium and placebo in 156 patients
who were in cardiac arrest. This was the first clinical trial
of any standard advanced life-support drug in humans. Previous
guidelines had been based only on retrospective case reports.
MAGIC also was the first trial to enroll patients who were
actually in cardiac arrest, an innovation made possible by
"waived consent" in accordance with FDA guidelines.
Lancet 1997;350:1272-1276.
OPTIME CHF
This was the first large clinical trial in acute heart failure,
which kills as many people as heart attacks. It compared early
interventional treatment with milrinone, an intravenous drug,
versus placebo in addition to standard care among 1005 patients
hospitalized for worsening, severe congestive heart failure.
The main outcome measure was the reduction in the total number
of days hospitalized for cardiovascular events within 60 days
after therapy. Although patients did not appear to benefit
from milrinone treatment overall, those with nonischemic cardiomyopathy
and those with low sodium levels did show some benefit. JAMA
2002;287:1541-1547.
PURSUIT
This study in 10,948 patients proved the benefits of eptifibatide
in the treatment of certain acute coronary syndromes. PURSUIT
was an excellent example of the “Large, Simple Trial”
concept, enrolling geographically dispersed patients with
a wide variety of symptoms, allowing useful comparisons of
patient characteristics and practice patterns. N Engl
J Med 1998;339:436-443.
SADHART
This study was the first to evaluate the effects of 24 weeks
of sertraline (Zoloft) or placebo treatment for major depressive
disorder in 369 patients with unstable angina or recent heart
attack, which can occur in up to 25% of such patients. Sertraline
had no significant effects on ejection fraction, a measure
of how well the heart is pumping blood, or on heart beat.
Severe cardiovascular events were much more uncommon with
sertraline (14.5%) than with placebo (22.4%). Among patients
with previous depression and those with severe current depression,
sertraline was associated with much greater improvement on
both depression scores. Thus sertraline appeared to be a safe,
effective treatment for recurrent depression in patients with
recent heart attack or unstable angina and without other life-threatening
medical conditions. JAMA 2002;288:701-709 (erratum
in JAMA 2002;288:1720).
SCD-HeFT
The Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT)
found that single-chamber implantable cardioverter defibrillators
(ICDs) reduced the rate of sudden death within 5 years by
23% compared with a placebo or amiodarone, a drug that corrects
abnormal heart rhythms. A cost-effectiveness analysis was
incorporated into the design of the SCH-HeFT study, and found
that the less-costly ICD devices represent a good value for
most patients who need them. N Engl J Med 2005;352:225-237.
SYMPHONY
SYMPHONY tested two doses of sibrafiban, an oral platelet
glycoprotein IIb/IIIa inhibitor, against aspirin to prevent
future cardiac events in 9233 patients with acute coronary
syndromes. The primary endpoint — the composite of death,
nonfatal heart attack, or severe recurrent ischemia at 90
days — did not differ significantly among the groups,
but major bleeding was more frequent with high-dose sibrafiban
than with aspirin or low-dose sibrafiban. Lancet 2000;335:337-345.
SYNERGY
This trial of two anticoagulants randomized 10,027 patients
with high-risk acute coronary syndromes to receive subcutaneous
enoxaparin every 12 hours or intravenous heparin, until symptoms
resolved or the patient underwent a coronary revascularization
procedure. Enoxaparin was neither superior nor inferior compared
with intravenous heparin—14% of patients given enoxaparin
died or had a heart attack by 30 days, as did 14.5% of those
given heparin. Similar proportions of patients had a procedure
to increase coronary blood flow, but bleeding was more common
among patients given enoxaparin. Among patients who had not
received anticoagulant therapy before enrollment, however,
outcomes were better and bleeding was reduced with enoxaparin
versus heparin treatment. JAMA 2004;292:45-54.
VALIANT
This was the largest trial among survivors of acute myocardial
infarction (MI), enrolling 14,808 patients at 931 centers
in 24 countries. The study randomly assigned these patients—who
had had an MI within 10 days previously and who also had heart
failure or pumping difficulty—to receive valsartan (an
angiotensin II receptor blocker, or ARB), captopril (an angiotensin-converting-enzyme
inhibitor, or ACEI), or their combination. There was a unique,
2-stage plan to analyze the primary endpoint, all-cause mortality:
1) the superiority of valsartan vs. captopril and combination
treatment vs. captopril, and, if no superiority was evident,
2) the noninferiority of valsartan vs. captopril. Over 2 years,
19.9% of patients in the valsartan group died, as did 19.5%
of patients in the captopril group and 19.3% of patients in
the combination group, differences that were not statistically
significant. Valsartan treatment was shown to be noninferior
to captopril with regard to mortality and a composite of fatal
and nonfatal cardiovascular events. N Engl J Med 2003;349:1893-1906.
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