From St Luke's Episcopal Hospital, Texas Heart Institute, Baylor
College of Medicine, and the University of Texas Health Science Center at
Houston.
The
following trials were presented at the 70th Scientific Sessions
of the American Heart Association, November 10–13, 1997, in Orlando,
Fla.
Lipid-Lowering Therapy
The Trial: AFCAPS/TEXCAPS
The study: A randomized, placebo-controlled trial of the
HMG-CoA reductase inhibitor lovastatin in 6605
patients with average LDL cholesterol (130 to 190 mg/dL)
and relatively low HDL (<50 mg/dL), with an HDL/LDL ratio of <0.5. No
patients had clinical evidence of coronary artery disease.
Patients were randomized to placebo or lovastatin (mean
dose, 30 mg) and followed up. The primary end point of the trial was
the new development of unstable angina, fatal or nonfatal MI, or sudden
cardiac death. The study was stopped when the result crossed the
prespecified stopping boundaries after a total of 267 events.
The results: Overall, treatment with lovastatin
resulted in a 36% relative decrease in the incidence of
primary-end-point events. In the placebo group, the total number of
primary-end-point events at long-term follow-up (
Summary: In men and women free of clinical signs of
cardiovascular disease, with average total
cholesterol and LDL and low HDL, treatment with
lovastatin results in a significant decrease in the
incidence of new cardiovascular events.
The Trial: LIPID
The study: A multicenter, randomized, placebo-controlled
trial of the HMG-CoA reductase inhibitor
pravastatin in patients (men and women 31 to 75 years old)
after a heart attack or those admitted with unstable angina with
average (155 to 270 mg/dL) cholesterol levels. A total of
9014 patients were randomized to pravastatin (40 mg/d) or
placebo. The primary end point of the trial was coronary heart
disease mortality. The study was originally designed to take place over
a 7-year period. However, at a mean follow-up of 60 months, the
mortality curves crossed the prespecified boundary (3 SD) for stopping
the trial, and the study was terminated.
The results: Pravastatin therapy was associated
with significant reductions in death from coronary heart
disease (6.4% versus 8.3%, 24% relative decrease), total mortality
(11.0% versus 14.1%, 23% relative decrease), stroke (20% relative
decrease), need for CABG (8.9% versus 11.3%, 24% relative decrease),
and fatal and nonfatal MI (7.4% versus 10.1%, 29% relative
decrease).
Summary: In patients with unstable angina or a history of MI
with average cholesterol levels,
cholesterol-lowering therapy with pravastatin
significantly reduces mortality.
Acute MI
The Trial: PAMI Stent Pilot
The study: An open-label pilot trial of the safety and
efficacy of primary stenting (stenting all target lesions possible) in
patients with acute MI. There were no age restrictions, and treatment
of both native vessels and saphenous vein grafts was allowed.
In-hospital outcomes were compared with the outcomes of primary PTCA in
the PAMI-2 study.
The results: Of 312 consecutively enrolled patients, 240
(77%) underwent successful stent implantation. Procedural success
(TIMI-3 flow with <50% stenosis) was slightly but not
significantly better in the PAMI stent pilot than in PAMI-2 (95%
versus 92%, P=.08). PAMI stent patients had a significantly
lower incidence of reinfarction (1.3% versus 4.8%), recurrent
ischemia (3.5% versus 11.8%), and in-hospital mortality
(0.6% versus 2.8%). There was also a nonsignificant trend toward
lower repeat target lesion PTCA (2.9% versus 6.0%, P=.06)
and similar rates of CABG (5.1% versus 6.9%) and stroke (0.3% versus
0.8%).
Summary: A primary stent strategy in patients with acute MI
is safe and feasible and results in better in-hospital outcomes than
primary PTCA in previous studies.
The Trial: TIMI 14
The study: A prospective, multicenter, randomized,
controlled trial of combined therapy with thrombolytic
agents and the platelet GP IIb/IIIa antagonist
abciximab in patients with acute MI. An interim report was
presented on a total of 444 patients who were randomized to
standard front-loaded t-PA (100 mg), low-dose t-PA (20, 35, or 50 mg)
plus abciximab, low-dose streptokinase (500 000, 750 000, or
1 250 000 U) plus abciximab, or abciximab alone. The primary end
point of the study is the incidence of TIMI grade III flow at 90-minute
angiography.
The results: At 90 minutes, the incidence of TIMI III flow
was 52% in the t-PA–alone arm; 32% in the abciximab-alone arm; 53%,
63%, and 61% in the respective t-PA plus abciximab groups; and 42%,
38%, and 48% in the respective streptokinase plus abciximab groups.
The incidence of major hemorrhage was 7% in the t-PA–alone
arm; 6% in the abciximab-alone arm; 5%, 0%, and 8% in the
respective t-PA plus abciximab groups; and 5%, 8%, and 12% in the
respective streptokinase plus abciximab groups.
Summary: The combination of thrombolytic
therapy and GP IIb/IIIa receptor blockade appears to result in
facilitated thrombolysis. Abciximab alone was not as
effective as t-PA alone. Bleeding may be somewhat increased with
combination therapy when higher doses of streptokinase are used.
The Trial: HIT 4
The study: A multicenter, randomized, controlled trial of
heparin versus r-hirudin (a direct thrombin inhibitor) in
1211 patients with acute MI treated with streptokinase. An angiographic
substudy examined patency rates in 447 patients undergoing 90-minute
angiography.
The results: There were no significant differences in 30-day
mortality (6.8% with r-hirudin versus 6.4% with heparin) or
reinfarction (4.4% with r-hirudin versus 4.9% with heparin). There
were no significant differences in TIMI 3 flow rates between groups
(40.7% with r-hirudin versus 33.5% with heparin). The r-hirudin group
had more complete resolution of ST-segment changes (28% versus
22%).
Summary: The combination of r-hirudin and streptokinase does
not dramatically enhance the efficacy of thrombolytic
therapy as assessed by mortality, reinfarction, and 90-minute
angiographic patency.
The Trial: PRIME
The study: A prospective, multicenter, randomized,
controlled trial of the direct thrombin inhibitor efegatran
versus heparin in patients with acute MI after
thrombolytic therapy. A total of 336 MI patients
treated with t-PA were randomized to heparin or efegatran. All patients
underwent 90-minute angiography; a subset of 152 patients without
previous intervention had follow-up angiography a median of 5 days
later.
The results: Efegatran-treated patients had shorter
activated partial thromboplastin times but longer peak thrombin
times. In patients with matched studies, the 90-minute TIMI III flow
rates (66% versus 73%; P=.4) and reduction in infarct
artery stenosis at follow-up (4% versus 1%; P=.16)
were not significantly different for heparin and efegatran. There was
no significant difference in reocclusion rates for heparin and
efegatran (8% versus 10%; P=1.0).
Summary: In patients with acute MI treated with accelerated
t-PA, efegatran appears to provide no angiographic improvement in acute
or subsequent infarct artery stenosis.
The Trial: AMISTAD
The study: A multicenter, randomized, placebo-controlled
trial of adenosine (70 µg ·
kg-1 · min-1 for 3
hours) in 236 patients with acute MI treated with
thrombolytic therapy. To qualify for the study,
patients had to be enrolled within 6 hours of their MI; patients in
cardiogenic shock were excluded. Separate randomization schemes were
used for anterior and nonanterior infarcts. The primary end point of
the study was myocardial infarct size (adjusted for covariates), as
determined by 99mTc-sestamibi single-photon
emission computed tomographic imaging 6±1 days after enrollment.
Clinical follow-up was also obtained at 4 to 6 weeks.
The results: The principal finding was a 33% relative
reduction in infarct size (P=.03 using prespecified
multivariable regression modeling that adjusted for covariate (22
adenosine patients vs 16 placebo patients). There was a 67% (15 vs
45.5%; P=.014) relative reduction in infarct size in
patients with anterior infarcts, but no reduction (11.5 vs 11.5%) in
infarct size in patients with nonanterior infarcts. There was a
tendency toward more adverse clinical events (death, infarction, CHF,
shock, and/or stroke) in the adenosine group, although the overall
number of events was small.
Summary: Adenosine may significantly reduce infarct
size; the results of this study are encouraging and support the need
for a large clinical outcome study.
Interventional Cardiology
The Trial: ERASER
The study: A prospective, randomized, placebo-controlled,
multicenter study of the platelet GP IIb/IIIa receptor
antagonist abciximab in patients undergoing
coronary stent placement. After successful stent placement, a
total of 225 patients were randomized to receive either placebo, a
bolus and 12-hour infusion of abciximab, or a bolus and 24-hour
infusion of abciximab. The primary end point of the study was the
percent volume obstruction by IVUS at 6-month follow-up
catheterization; 152 patients underwent 6-month
follow-up IVUS examination.
The results: At 6 months, the mean IVUS percent volume
obstruction was 32.4% in the placebo group, 32.7% in the 12-hour
abciximab group, and 34.2% in the 24-hour abciximab group. The
incidence of death, MI, and target vessel
revascularization at 6 months was 25.4% in the
placebo group, 20.3% in the 12-hour abciximab group, and 22.7% in the
24-hour abciximab group.
Summary: Treatment with abciximab did not result in a
significant decrease in intimal hyperplasia after intracoronary
stent placement.
The Trial: ORBIT
The study: A phase II, multicenter, randomized,
placebo-controlled trial of the oral platelet GP IIb/IIIa
antagonist xemilofiban in patients after
percutaneous coronary intervention. A total of
549 patients were randomized to one of three treatment groups:
xemilofiban 15 mg TID for 2 weeks, then BID for 2 weeks; xemilofiban 20
mg TID for 2 weeks, then BID for 2 weeks; or placebo. Abciximab
patients were included but received lower doses of xemilofiban (10 mg
TID) for the first 2 weeks. All patients received aspirin (325 mg/d).
The primary end points of the study were
pharmacokinetic/pharmacodynamic parameters and the safety
and tolerability of xemilofiban.
The results: There was a dose-dependent increase in plasma
concentration and degree of platelet inhibition; both xemilofiban
doses were able to achieve between 50% and 80% inhibition of
platelet aggregation in response to 20 µmol/L ADP. There was
no increase in serious bleeding events in the xemilofiban groups.
Xemilofiban was associated with an increase in insignificant and mild
bleeding events that did not require discontinuation of study drug or
treatment. There were no significant differences in clinical outcome
events at 90 days for the entire study population.
Summary: After percutaneous coronary
intervention, prolonged (1-month) therapy with xemilofiban does not
increase the incidence of major bleeding complications, although
insignificant and minor bleeding complications are more common.
Although clinical events were not significantly different at 90 days,
the trial was not powered for a clinical events end point; longer-term
outcomes will be assessed in larger phase III trials.
The Trial: Argatroban in HIT Patients Undergoing
PTCA
The study: A controlled, open-label trial of the direct
thrombin inhibitor argatroban in 50 patients with a history
of HIT undergoing PTCA. Outcomes were compared with a registry control
of 5832 non-HIT patients undergoing PTCA who were treated with
heparin.
The results: Adequate procedural anticoagulation
(activated coagulation time >300 seconds) with argatroban was
achieved in 98% of the HIT patients. Among HIT patients, there were 1
patient who developed abrupt closure requiring bypass surgery and 1
patient with a retroperitoneal hematoma. Acute procedural success was
slightly better in the argatroban/HIT group (98% versus 94%;
P=.03).
Summary: Argatroban anticoagulation for PTCA in patients
with a history of HIT appears to be comparable to heparin
anticoagulation in non-HIT patients.
The Trial: ACUTE
The study: A prospective, uncontrolled, multicenter trial of
percutaneous coronary ultrasound
thrombolysis in 31 consecutive patients presenting
with acute anterior MI.
The results: Patency was achieved in 29 of 31 patients
(94%); TIMI 3 flow was achieved in 26 (84%). The mean residual
stenosis after ultrasound therapy alone was 54±26%. There
were no dissections, perforations, embolism, no-reflow, or spasm.
Subsequent adjunct PTCA resulted in a mean residual stenosis of
15%. Stents were deployed in 7 patients (22%). After the procedure, 1
patient (3%) developed reinfarction and 3 patients (10%) had
recurrent ischemia and repeat target-vessel
revascularization.
Summary: Ultrasound thrombolysis appears to
be a useful reperfusion technique in patients with acute MI.
Arrhythmias
The Trial: ARREST
The study: A prospective, double-blind study of
amiodarone in patients with nontraumatic out-of-hospital
cardiac arrest and refractory ventricular
arrhythmias not responding to three initial shocks. A total of
3954 patients were screened for the study; 667 met study inclusion
criteria, and 504 were enrolled. Of these, 246 received
amiodarone and 258 received placebo. All patients were
pulseless at the time of treatment with amiodarone or placebo,
and all patients were subsequently treated with standard advanced
cardiac life support protocols. The primary end point of the study was
the number of patients admitted alive to the hospital.
The results: Of the patients treated with
amiodarone, 44% survived to hospital admission, compared with
35% of the placebo-treated patients, a relative increase of 27%. One
subgroup with particular benefit was those patients who transiently had
a return of spontaneous cardiac function before treatment with the
study drug. In these patients, 64% of the amiodarone patients
survived to hospital admission, compared with 41% of the
placebo-treated patients.
Summary: Amiodarone appears to be an effective form
of therapy in patients with cardiac arrest due to shock-refractory
ventricular fibrillation.
The Trial: CABG-PATCH
The study: A multicenter, randomized, controlled trial of
ICD therapy in high-risk patients (ejection fraction <36%, abnormal
signal-averaged ECG) undergoing CABG surgery. A total of 900 patients
were randomized to ICD (n=446) or no ICD (n=454) and followed
clinically for an average of 3 years. The primary end point of the
trial was all-cause mortality.
The results: There was no difference between the two
treatment groups in all-cause mortality. The use of drugs for angina,
heart failure, and arrhythmias did not differ between groups;
there were no differences in the use of antiarrhythmic drugs and
ß-blockers.
Summary: In the high-risk group of patients studied in this
trial, who were undergoing CABP, ICD therapy did not decrease
mortality. ICD prophylaxis does not appear to benefit all high-risk
subgroups.
The Trial: DIAMOND-MI
The study: A multicenter, randomized, placebo-controlled
trial of the class III antiarrhythmic drug dofetilide in patients after
MI. A total of 1510 patients were randomized to dofetilide (n=749;
target dose, 0.5 mg BID) or placebo (n=761) and followed up for at
least 1 year. All randomized patients were continuously monitored by
telemetry for 3 days after therapy was initiated. The primary end point
of the study was all-cause mortality.
The results: There were 230 total deaths in the dofetilide
group, compared with 243 total deaths in the placebo group
(P=NS). There were no differences in cardiac mortality or
arrhythmic death between groups. The drug was generally well tolerated,
although there was a slight increase in the early incidence of torsades
de pointes in the dofetilide group.
Summary: In post-MI patients, dofetilide is well tolerated,
but it has no significant effect on mortality.
Congestive Heart Failure
The Trial: RESOLVD
The study: A multicenter, prospective, randomized,
controlled trial of Candesartan (a direct angiotensin II
subtype I receptor antagonist) in 768 patients with
congestive heart failure. Patients were randomized to 1 of 3 doses of
Candesartan (4, 8, or 16 mg/d), enalapril alone (20 mg/d), enalapril 10
mg/d plus Candesartan 4 mg/d, or enalapril 10 mg/d plus Candesartan 8
mg/d. The primary end point of the study was exercise tolerance; the
secondary end point was ventricular function.
The results: There were no differences among groups in
exercise capacity, symptomatic deterioration, or quality of
life; combination therapy resulted in lower levels of serum
aldosterone, greater blood pressure reduction, improved
ejection fraction, decreased cardiac dilatation, and a reduction in
atrial natriuretic peptide and brain
natriuretic peptide than either therapy alone. There were
no significant differences in mortality, clinical deterioration of
heart failure, or hospitalizations.
Summary: Candesartan appears to be comparable to enalapril
in terms of clinical outcome. Combination therapy results in greater
suppression of aldosterone, prevention of
ventricular dilatation, and a greater reduction in
natriuretic peptides.
Selected Abbreviations and Acronyms
Footnotes
Reprint requests to James J. Ferguson, MD, Cardiology Research, MC1–191, St Luke's Episcopal Hospital, PO Box 20269, Houston, TX 77225.
© 1998 American Heart Association, Inc.
Cardiovascular News
Meeting Highlights
Highlights of the 70th Scientific Sessions of the American Heart Association
Presenter: Antonio Gotto, MD, Cornell University,
New York, NY. 
5 years) was 182,
compared with 105 in the lovastatin group.
Lovastatin therapy was associated with a relative decrease
of 34% in new unstable angina admissions, 35% in fatal or nonfatal
MI, and 33% in revascularization procedures. The
degree of benefit was independent of the absolute level of LDL.
Presenter: Andrew Tonkin, MD, University of
Melbourne and National Heart Foundation of Australia, Melbourne.
Presenter: Gregg W. Stone, MD, El Camino Hospital,
Mountain View, Calif.
Presenter: Elliott Antman, MD, Brigham and
Women's Hospital and Harvard Medical School, Boston, Mass.
Presenter: Professor Karl-Ludwig Neuhaus,
Staedtische Kliniken, Kassel, Germany.
Presenter: Gregory Barsness, MD, Duke University
Medical Center, Durham, NC.
Presenter: Kenneth W. Mahaffey, MD, Duke
University Medical Center, Durham, NC.
Presenter: Stephen Ellis, MD, Cleveland Clinic,
Cleveland, Ohio.
Presenter: Dean Kereiakes, MD, Lindner Center for
Cardiovascular Research, Cincinnati, Ohio.
Presenter: Bruce Lewis, MD, Loyola University,
Chicago, Ill.
Presenter: Uri Rosenschein, MD, The Tel Aviv
Sourasky Medical Center, Tel Aviv, Israel.
Presenter: Peter Kudenchuk, MD, University of
Washington, Seattle.
Presenter: Thomas Bigger, MD, Columbia
University, New York, NY.
Presenter: Poul Erik Bloch-Thomsen, MD, PhD,
University of Copenhagen, Denmark.
Presenter: Salim Yusuf, MD, McMaster University,
Hamilton, Ontario, Canada.
CABG
=
coronary artery bypass graft surgery
GP
=
glycoprotein
HIT
=
heparin-induced thrombocytopenia
HMG-CoA
=
hydroxymethylglutaryl coenzyme A
ICD
=
internal cardioverter-defibrillator
IVUS
=
intravascular ultrasound
MI
=
myocardial infarction
PTCA
=
percutaneous transluminal coronary
angioplasty
r-hirudin
=
recombinant hirudin
t-PA
=
tissue plasminogen activator
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