(Circulation. 1997;96:2155-2161.)
© 1997 American Heart Association, Inc.
Articles |
Randomized, Double-blind Comparison of Hirulog Versus Heparin in Patients Receiving Streptokinase and Aspirin for Acute Myocardial Infarction (HERO)
From Green Lane Hospital (H.D.W., J.K.F.), Auckland, New Zealand; Flinders Cardiovascular Centre (P.E.A.), Adelaide, South Australia; Heart Center of Sarasota (M.J.F.), Fla; Royal Victoria Hospital (A.A.J.A.), Belfast, Northern Ireland; University Hospital of Cleveland (R.N.), Ohio; Western Infirmary (W.S.H.), Glasgow, Scotland; Sinai Samaritan Medical Center (Y.S.), Milwaukee, Wis; Royal Adelaide Hospital (M.A.B.), South Australia; Radcliffe Infirmary (R.C.), Oxford, England; and Biogen Inc (J.M., B.A.), Boston, Mass.
Correspondence to Professor Harvey White, Cardiology Department, Green Lane Hospital, Private Bag 92 189, Auckland 1030, New Zealand. E-mail white002{at}msn.com
 |
Abstract |
|---|
 Top Abstract IntroductionMethodsResultsDiscussionAppendix 1References |
|---|
Background Thrombolytic therapy improves survival after myocardial infarction through reperfusion of the infarct-related artery. Thrombin generated during thrombolytic administration may reduce the efficacy of thrombolysis. A direct thrombin inhibitor may improve early patency rates.
Methods and Results Four hundred twelve patients presenting within 12 hours with ST-segment elevation were given aspirin and streptokinase and randomized in a double-blind manner to receive up to 60 hours of either heparin (5000 U bolus followed by 1000 to 1200 U/h), low-dose hirulog (0.125 mg/kg bolus followed by 0.25 mg · kg-1 · h-1 for 12 hours then 0.125 mg · kg-1 · h-1), or high-dose hirulog (0.25 mg/kg bolus followed by 0.5 mg · kg-1 · h-1 for 12 hours then 0.25 mg · kg-1 · h-1). The primary outcome was Thrombolysis In Myocardial Infarction trial (TIMI) grade 3 flow of the infarct-related artery at 90 to 120 minutes. TIMI 3 flow was 35% (95% CI, 28% to 44%) with heparin, 46% (95% CI, 38% to 55%) with low-dose hirulog, and 48% (95% CI, 40% to 57%) with high-dose hirulog (heparin versus hirulog, P=.023; heparin versus high-dose hirulog, P=.03). At 48 hours, reocclusion had occurred in 7% of heparin, 5% of low-dose hirulog, and 1% of high-dose hirulog patients (P=NS). By 35 days, death, cardiogenic shock, or reinfarction had occurred in 25 heparin (17.9%), 19 low-dose hirulog (14%), and 17 high-dose hirulog patients (12.5%) (P=NS). Two strokes occurred with heparin, none with low-dose hirulog, and two with high-dose hirulog. Major bleeding (40% from the groin site) occurred in 28% of heparin, 14% of low-dose hirulog, and 19% of high-dose hirulog patients (heparin versus low-dose hirulog, P<.01).
Conclusions Hirulog was more effective than heparin in producing early patency in patients treated with aspirin and streptokinase without increasing the risk of major bleeding. Direct thrombin inhibition may improve clinical outcome.
Key Words: myocardial infarction • heparin • hirulog • streptokinase
|
Introduction |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionAppendix 1References |
|---|
The administration of aspirin and thrombolytic therapy has been a major advance in the management of acute myocardial infarction, with several large studies demonstrating improved survival and preservation of left ventricular function.1 2 3 4 5 6 Early, complete reperfusion is associated with lower mortality. In the angiographic substudy of the GUSTO-I trial,7 mortality at 30 days was 4.4% among patients with TIMI grade 3 flow8 (complete perfusion) in the infarct-related artery at 90 minutes, 7.4% among patients with TIMI 2 flow (partial perfusion), and 8.9% among patients with TIMI 1 or 0 flow (occlusion). TIMI 3 flow was also associated with significant improvement in left ventricular function.9 Despite the clinical benefits of all the fibrinolytic regimens studied in the GUSTO-I trial, TIMI 3 flow at 90 minutes in the infarct-related artery was achieved in only 33% of patients treated with streptokinase, aspirin, and intravenous heparin and 54% of those treated with accelerated TPA, aspirin, and intravenous heparin.9 Reocclusion may occur in the first week in 5% to 15% of reperfused infarct-related arteries, with approximately half occurring in the first 24 hours,9 10 and is associated with a marked increase in morbidity and mortality.11
Thrombolysis and thrombosis are simultaneously occurring processes,12 and a number of factors affect thrombosis during and after thrombolytic therapy. A residual mural thrombus containing fibrin-bound thrombin can promote local fibrin formation and is the most potent stimulus for platelet aggregation,13 and this potentiation is not inhibited by aspirin. Thrombolytic therapy generates plasmin, which is procoagulant, by activating factor V to Va and accelerating thrombin generation via the prothrombinase complex.14 Both streptokinase and TPA may activate platelets,15 16 17 and antibodies to streptokinase may also promote platelet aggregation.18 During effective thrombolytic therapy, the dynamic balance of lysis and rethrombosis is pivoted in favor of lysis. Adjuvant heparin therapy has not been shown to improve 90-minute patency with streptokinase7 or TPA19 and has several limitations apart from the small risk of bleeding. It has only a small effect on fibrin-bound thrombin,20 and factor Xa in the prothrombinase complex is protected from heparin–antithrombin III.21 Furthermore, platelet factor 4 neutralizes heparin, and fibrin monomer II inhibits heparin–antithrombin III.21
Hirulog is a 20–amino acid synthetic peptide that directly inhibits free and clot-bound thrombin22 and, when used in appropriate regimens as an adjuvant during thrombolytic therapy, may prevent clot formation and extension and facilitate clot lysis. The present report is of the double-blind HERO trial, in which the safety and efficacy of two hirulog regimens for achieving early and complete flow of the infarct-related artery were compared with heparin among patients with acute myocardial infarction receiving streptokinase and aspirin.
|
Methods |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionAppendix 1References |
|---|
Study Population
Patients were eligible if they presented within 12 hours of the onset of symptoms of infarction with
1 mm of ST-segment
elevation in 2 limb leads and/or leads V4 through
V6 of a 12-lead ECG or 2 mm of ST-segment elevation
in 2 contiguous precordial V1 through V3
leads. Exclusion criteria included previous administration of
streptokinase; history of systemic, gastrointestinal, or genitourinary
bleeding within 3 months; history of cerebrovascular disease including
stroke or transient ischemic attack within 6 months; history of
intracranial neoplasm, arteriovenous malformation, or aneurysm;
severe trauma or major surgery within the previous 3 months; puncture
of noncompressible vessels within the previous 10 days; traumatic
cardiopulmonary resuscitation within the previous month; severe
and uncontrolled hypertension; and cardiogenic shock. The study design was approved by the ethics committees at the participating centers, and all patients gave written, informed consent.
Study Design
Aspirin 150 to 325 mg was administered as soon as possible after
admission and continued daily. Eligible patients were then randomized
by telephoning a 24-hour service at the Clinical Trial Service Unit,
Oxford, England. All patients were to receive 1.5 million units of
streptokinase over a period of 30 to 60 minutes and were randomly
allocated, in a double-blind manner, to receive either active heparin
and placebo hirulog or one of two different blinded active hirulog
regimens and placebo heparin (ie, a "double dummy"
procedure):
1. Heparin regimen—5000 U intravenous bolus followed by
an infusion of 1000 U/h in patients weighing <80 kg and 1200 U/h in
patients weighing 80 kg for up to 60 hours. At 11 and at 24
hours, the heparin/placebo infusion could be adjusted upward according
to a nomogram.
2. Low-dose hirulog regimen—0.125 mg/kg intravenous bolus followed by an infusion of 0.25 mg · kg-1 · h-1 for 12 hours and then 0.125 mg · kg-1 · h-1 for up to 60 hours.
3. High-dose hirulog regimen—0.25 mg/kg intravenous bolus followed by an infusion of 0.5 mg · kg-1 · h-1 for 12 hours and then 0.25 mg · kg-1 · h-1 for up to 60 hours.
The infusions were not to be adjusted downward during the first 24 hours unless there was bleeding. If clinically indicated (eg, aPTT >120 seconds or excessive oozing) after the first 24 hours of dosing, the rate of both infusions could be reduced by one third and maintained for 36 to 60 hours until the second angiogram (see below).
It was recommended that oral ß-blocker therapy be commenced in patients without contraindications and that aspirin and oral ß-blocker therapy be continued at discharge. Other medications could be given according to local practice.
Evaluation of Efficacy
The primary outcome was patency at 90 to 120 minutes as measured
by TIMI 3 flow. Secondary outcomes were patency at 2 to 3 days; left
ventricular function, global ejection fraction,
end-systolic volume, and regional wall motion at 2 to 3 days in
patients without a prior history of myocardial infarction; and
incidence of death, stroke, reinfarction and cardiogenic shock at 35
days after treatment.
Cardiac Catheterization
Angiograms were performed 90 to 120 minutes after the
commencement of the thrombolytic infusion. Infusion of
study drugs was continued during the procedure. The infarct-related
artery was imaged first, with the initial imaging aimed at optimizing
assessment of TIMI flow by visualizing the entire vessel. Three LAO and
two RAO views were taken of the left coronary artery, and at
least one LAO and one RAO view were taken of the right coronary
artery. Additional views were also taken to clearly image the
infarct-related stenosis without overlapping vessels. A second
angiogram was to be performed 36 to 60 hours after the start of the
study infusion, unless rescue angioplasty was performed. The same views
used in the first angiogram were duplicated, and left ventriculography
in the 40° RAO projection with a grid or sphere for volume
measurements was also performed.
All angiograms were analyzed at the Green Lane Hospital quantitative angiography laboratory using the Cardiovascular Measurement System. The film sequence and identification were blinded by an independent technician who cut the dates off the films. Patency was assessed by use of the TIMI flow scoring system8 on the first injection of contrast by two independent, experienced core laboratory reviewers. A third cardiologist became involved in the review process if agreement was not reached by the first two reviewers, and consensus was then reached by all three reviewers. Ventriculograms were analyzed separately by use of the Cardiovascular Measurement System for regional wall-motion analysis.
Bleeding
Patients were carefully monitored for bleeding. Bleeding was
defined as major if it was clinically overt, with either a fall in the
hemoglobin level of 3 g/dL or requirement for transfusion of
two or more units of blood, or if it was retroperitoneal or
intracranial. Bleeding was defined as minor if it was clinically overt
but did not meet these criteria.
Reinfarction
Reinfarction within 18 hours after commencement of
thrombolytic therapy was defined as recurrent, severe
ischemic chest discomfort lasting >30 minutes accompanied by
new or recurrent ST-segment elevation of 1 mm (0.1 mV) in at
least two contiguous leads. Reinfarction after 18 hours was defined as
development of new Q waves in two or more leads or reelevation of
creatine kinase by 50% to above the upper limit of normal.
Statistical Analysis
Sample-size calculations were based on having 80% power at
P<.05 to detect improvements in TIMI 3 flow at 90 to 120
minutes from 30% with heparin23 24 to 46% with the
combination of the two hirulog regimens (1:2 comparison) or to 48%
with one of the hirulog regimens (1:1 comparison). It was estimated
that 375 patients would be required (125 in each of the three groups).
The independent data safety monitoring committee was to review interim
results on the first 75 and 150 patients. All patients were to be
included in intention-to-treat analyses. ANOVA and tests of
trend were used to compare outcome, with probability values <.05
considered significant for primary outcome measures. Data are
presented as mean±SD.
|
Results |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionAppendix 1References |
|---|
Four hundred twelve patients were randomized from 26 hospitals in five countries (see "Appendix"). The baseline characteristics of the three groups of patients were similar, as shown in Table 1
. The mean age was 62±12 years, and
75% of the patients were men. All patients received aspirin. The time
from symptom onset to streptokinase initiation was similar in the three
treatment groups, as was the duration of the streptokinase infusion and
the time to initiation of the study drugs.
|
Angiographic Results
Four hundred patients (97%) had an early angiogram. The reasons
for patients not having an angiogram included death in one, technical
or equipment failure in two, withdrawal of consent in one,
hemodynamic stability in four, and miscellaneous
reasons in four patients. TIMI flow was assessable in 393 patients.
The Figure and Table 2 show early TIMI 3 flow for the three
treatment groups. Patients allocated hirulog had TIMI 3 flow more
frequently than those allocated heparin (P=.024). TIMI 3
patency was achieved in 35% of patients allocated heparin (95% CI,
28% to 44%) versus 46% with low-dose hirulog (95% CI, 38% to 55%)
and 48% with high-dose hirulog (95% CI, 40% to 57%). Patients
treated with high-dose hirulog showed a significant increase in early
TIMI 3 flow patency compared with heparin that represented
a 37% relative improvement (P=.03). No significant
difference was observed in the combination of TIMI 2 and 3 flow (69%
heparin versus 76% low-dose hirulog versus 68% high-dose
hirulog).
|
|
The differences in TIMI 3 flow between high-dose hirulog, low-dose
hirulog, and heparin appeared to be greater among patients treated
earlier after the onset of symptoms (Table 2
). Among patients treated
within 3 hours after symptom onset, the rate of TIMI 3 patency was 52%
in those treated with heparin versus 56% in those treated with
low-dose hirulog and 70% in those treated with high-dose hirulog. The
effect observed with hirulog compared with heparin among patients
treated within 3 hours was not statistically significantly different
from that observed among those treated later. For patients treated
within 6 hours, the rate of TIMI 3 patency was 53% with high-dose
hirulog.
Two- to Three-Day Angiogram
A second angiogram was performed in 323 patients (81%).
Because of a higher death rate, a greater need for rescue angioplasty
(13 heparin, 4 low-dose hirulog, and 6 high-dose hirulog patients), and
a higher incidence of bleeding, fewer patients in the heparin group
underwent a second angiogram. Sustained patency (maintenance of
TIMI 3 flow, excluding patients undergoing angioplasty) was similar in
the three treatment groups: heparin 70%, low-dose hirulog 78%, and
high-dose hirulog 77% (probability value for trend, .18). Reocclusion
(TIMI 2 or 3 flow reducing to TIMI 0 or 1 flow) occurred in 7% of
patients treated with heparin, 4.6% of patients treated with low-dose
hirulog, and 1.3% of patients treated with high-dose hirulog
(probability value for trend, .09) (Table 3).
|
There were 262 patients with first infarctions who underwent assessment
of left ventricular function at the angiogram on the second
or third day (Table 4). No differences in
ejection fraction, end-systolic volume, or regional wall motion
were observed between the treatment groups.
|
Laboratory Results
Patients treated with low-dose or high-dose hirulog had less
variability and lower aPTTs at both 11 hours (136±66 seconds for
heparin versus 96±30 seconds for low-dose hirulog and 117±35 seconds
for high-dose hirulog; P<.001 for aPTT levels in heparin
versus hirulog patients) and 24 hours after commencement of
streptokinase (95±51 seconds for heparin versus 67±21 seconds for
low-dose hirulog and 83±23 seconds for high-dose hirulog;
P<.001). The peak creatine kinase levels were similar:
heparin 1944±140 U/L, low-dose hirulog 2220±237 U/L, and high-dose
hirulog 1934±156 U/L.
Clinical Events
Table 5 shows the frequency of major
clinical events. There were slightly fewer deaths and cases of
cardiogenic shock and/or recurrent myocardial infarction among patients
treated with high-dose hirulog, but these differences were not
significant. For the combined end point of death or nonfatal myocardial
infarction at 35 days, the rates were 15% with heparin, 11% with
low-dose hirulog, and 8.8% with high-dose hirulog (P=.26).
|
Safety
There were two strokes in the heparin group (neither considered to
be hemorrhagic), none in the low-dose hirulog group, and two (one of
which was confirmed to be hemorrhagic) in the high-dose hirulog group
(Table 6). Major bleeding and the need
for transfusion occurred less frequently in patients treated with
hirulog than in those treated with heparin (P<.05). Among
patients receiving the high-dose hirulog regimen, there were
nonsignificantly fewer major bleeds than with heparin. The main cause
of bleeding was the catheterization site (42% of
bleeds among heparin-allocated patients versus 40% of low-dose hirulog
bleeds and 38% of high-dose hirulog bleeds).
|
|
Discussion |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionAppendix 1References |
|---|
This study demonstrates that hirulog is more effective at achieving early TIMI 3 flow than heparin as an adjunct to streptokinase and aspirin in acute myocardial infarction and that the effect of hirulog may be dose dependent. The improved efficacy of hirulog was achieved at lower aPTT levels without increased bleeding.
Although hirulog and other agents have been shown to improve patency in animal models,25 26 this is the first time that improved TIMI 3 flow has been shown with these agents in humans. For patients treated within 3 hours of symptom onset, the difference in TIMI 3 flow between hirulog and heparin appeared to be greater than among those treated later, but this was a post hoc analysis, and the effects of early and later treatment were not significantly different from each other. For patients randomized within 6 hours, the TIMI 3 flow rate with streptokinase and high-dose hirulog was similar to that observed with accelerated TPA and heparin in the GUSTO-I trial,23 and there was a trend toward fewer major bleeds with high-dose hirulog than with heparin. As expected, because of the effects of hypercontractility of the noninfarct zones and myocardial stunning affecting contractility in the first few days after myocardial infarction,27 there was no effect on global or regional left ventricular function.
Timing of Administration of Hirulog
Early administration of a direct thrombin inhibitor,
either before administration of a thrombolytic agent or
soon after, might be expected to inhibit more effectively the
procoagulant effects of thrombolytic therapy. This is
difficult to achieve in a trial setting because investigators want to
provide thrombolytic therapy as soon as possible, and
delays occur in obtaining consent, in randomization, and in preparation
of blinded infusions.
In the recent TIMI-9B28 and GUSTO-IIB29 trials, which compared hirudin with heparin, the delays after initiation of thrombolytic therapy were 50 minutes and 35 minutes, respectively, and the combined results for the comparison of hirudin versus heparin did not indicate any difference in the 30-day rates of death and nonfatal myocardial infarction. These results in patients receiving thrombolytic therapy might have been importantly affected by the delay between administration of thrombolytic therapy and commencement of heparin or hirudin. In the HERO study, hirulog or heparin was administered at a mean time of 24 minutes after the infusion of streptokinase was begun, and consequently the effects of earlier initiation of antithrombin therapy may also have been underestimated.
Choice of Dose
The choice of an appropriate dose of drug that maximizes
efficacy without inducing unacceptable bleeding is critical for the
clinical development of antithrombotic drugs. In the current study, the
hirulog doses chosen were based on prior experience with hirulog in
various indications (including prevention of deep vein thrombosis,
angioplasty, unstable angina, and acute myocardial
infarction).24 30 31 32 33 34 35 36 A three-part dosing scheme was used:
a bolus infusion, lytic-phase dosing, and reduced-rate
maintenance dosing. Pharmacokinetic data have demonstrated that
bolus dosing is necessary to rapidly attain target steady-state plasma
levels, and the dose was chosen to avoid peak blood levels that might
be associated with bleeding. The lytic-phase dosing used either a dose
of 0.5 mg · kg-1 ·
h-1, which is similar to that used previously
in acute myocardial infarction,24 or a lower dose, 0.25
mg · kg-1 ·
h-1. Experience in unstable angina and
prevention of deep vein thrombosis has demonstrated that doses between
0.12 and 1 mg · kg-1 ·
h-1 actively suppress thrombotic disease
activity,30 31 32 33 and so maintenance doses in this
range were used. A previous trial of patients with acute myocardial
infarction who were given streptokinase reported a higher rate of TIMI
3 flow with a 0.5 mg · kg-1 ·
h-1 dose of hirulog than with a higher dose of
1 mg · kg-1 ·
h-1.24 Only 55 patients were
included in that comparison, and unlike the current trial, bolus doses
of hirulog were not administered. The high and low doses used in the
current trial were half those used in the previous trial, ie, our
high dose was the same as the lower, more effective dose used in the
previous trial.
Bleeding
Even at the higher dose, hirulog was associated with more
stable and lower aPTTs than heparin. The heparin infusion was adjusted
with the use of a nomogram, which may have facilitated achievement of
the target aPTT. The incidence of major bleeding was not increased with
either of the hirulog regimens. Although hirudin and hirulog should
have similar efficacy because they act through similar
mechanisms,26 they may have different risk-benefit ratios
because of differences in elimination (the half-life of hirudin is 2 to
3 hours whereas that of hirulog is 36 minutes).26 Excess
bleeding occurred with high-dose hirudin in the TIMI-9A37
and GUSTO-IIA38 trials. In the GUSTO-IIB29
and TIMI-9B28 trials with a lower dose of hirudin (bolus
reduced from 0.6 to 0.1 mg/kg and infusion reduced from 0.2 to
0.1 mg · kg-1 ·
h-1) and in the absence of protocol-mandated
early cardiac catheterization, the incidence of major
bleeding in thrombolytic-treated patients was similar
with hirudin and heparin.39
Conclusions
Streptokinase continues to be used widely, not only because
it is cheaper but also, at least in part, because it is associated with
a lower incidence of intracerebral bleeding than
TPA.23 40 41 Indeed, even when
thrombolytic therapy was provided free of charge in the
GUSTO-II trial, investigators chose streptokinase as the drug of choice
for 10% of their patients in the United States and 42% elsewhere. The
impact of streptokinase on early patency has greater potential for
improvement than that seen with TPA, and some investigators have found
streptokinase to be more procoagulant than TPA,42 so that
patients treated with streptokinase may be particularly likely to
benefit from adjunctive direct thrombin inhibition therapy. If these
beneficial effects can be achieved without substantially increasing the
risk of intracranial or other major hemorrhage, this might
translate into worthwhile improvement in clinical outcome and,
potentially, lower costs.
The present study shows that early patency achieved with streptokinase can be improved by adjunctive administration of the direct-acting thrombin inhibitor hirulog. The improved antithrombotic effect and the gain in patency were achieved at lower aPTT levels and were not associated with an increased bleeding risk, possibly because of the favorable pharmacokinetic profile of hirulog. Early successful reperfusion of the infarct-related artery is associated with improved survival.7 The present trial was not, however, large enough to reliably assess the effects of hirulog treatment on clinical events, and the trend toward fewer deaths and cases of cardiogenic shock or recurrent infarction with high-dose hirulog was not significant. Also, differences in early angiographic patency and trends for lower rates of reocclusion may not necessarily translate into reduced mortality. Large-scale, randomized trials comparing aspirin plus an appropriate dose of hirulog versus aspirin plus heparin (and/or aspirin alone) among patients receiving thrombolytic therapy are now needed to determine whether these beneficial effects on early patency translate into worthwhile reductions in mortality and other major clinical events that outweigh hemorrhagic risks.
|
Selected Abbreviations and Acronyms |
|---|
|
HERO Trial Personnel
Liaison committee: H. White (chairman), R. Collins, P.
Théroux, B. Adelman, K. Findlen, S. Tremlett, and P. Butera.
Data and safety monitoring committee: C. Hennekens (chairman), R. Peto, D. Julian, and D. Hunt.
Electrocardiographic core laboratory: D. Goodman.
Angiographic core laboratory: H. White, J. French, B. Webber, and B. Williams (Green Lane Hospital, Auckland, New Zealand).
Trial monitoring and data analysis: Corning Besselaar.
Trial investigators (in order of number of patients randomized): P. Aylward (Flinders Medical Centre, Adelaide, Australia), M. Frey (Heart Center of Sarasota, Fla), H. White (Green Lane Hospital, Auckland, New Zealand), J. Adgey (Royal Victoria Hospital, Belfast, Northern Ireland), R. Nair (University Hospital of Cleveland, Ohio), S. Hillis (Western Infirmary, Glasgow, Scotland), Y. Shalev (Sinai Samaritan Medical Center, Milwaukee, Wis), M. Brown (Royal Adelaide Hospital, Adelaide, Australia), H. Ikram (Christchurch Hospital, New Zealand), P. Thompson (Sir Charles Gairdner Hospital, Perth, Australia), J. Machecourt (Centre Hospitalier et Universitaire de Grenoble, France), D. Reid (Freeman Hospital, Newcastle Upon Tyne, England), M. Antoine Slama (Hôpital Béclère, Paris, France), R. Foale (St Mary's Hospital, London, England), G. Nelson (Royal North Shore Hospital, Sydney, Australia), A. Thomson (Royal Hobart Hospital, Australia), H. Charleson (Waikato Hospital, Hamilton, New Zealand), J. Horowitz (Queen Elizabeth Hospital, Adelaide, Australia), J. Puel (Place du Docteur Baylac, Paris, France), G. Timmis (William Beaumont Hospital, Royal Oak, Mich), I. Sarembock (UVA Health Sciences Center, Charlottesville, Va), R. Stomel (Botsford Hospital, Farmington Hills, Mich), M. Schwartz (Cardiology Associates, Annapolis, Md), J. Kaski (St Georges Medical School, London, England), M. Been (Walsgrave Hospital, England), and C. Guerot (Hôpital Boucicaut, Paris, France).
|
Acknowledgments |
|---|
Financial support for the trial was provided by Biogen Inc (Boston, Mass), Commonwealth Serum Laboratories Limited (Melbourne, Australia), and a grant from the Health Research Council of New Zealand (Auckland, New Zealand). We would like to acknowledge John Varigos (CSL Limited, Melbourne, Australia), Dr David Cross (Royal Brisbane Hospital, Australia), and Dr Marcus Flather (Royal Brompton Hospital, London, England) for their contributions to the design of the study; the many colleagues and nurses who cared for patients in the study; and the patients themselves.
|
Footnotes |
|---|
1 A full list of the HERO trial investigators and participating centers appears in the Appendix
. |
Appendix 1 |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionAppendix 1References |
|---|
Guest editor for this article was David O. Williams, MD, Rhode Island Hospital. Received January 16, 1997; revision received April 24, 1997; accepted May 16, 1997.
|
References |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionAppendix 1References |
|---|
1. Gruppo Italiano per lo Studio della Streptochinasi nell'Infarto Miocardico (GISSI). Effectiveness of intravenous thrombolytic treatment in acute myocardial infarction. Lancet. 1986;1:397-402.[Medline] [Order article via Infotrieve]
2. ISIS-2 (Second International Study of Infarct Survival) Collaborative Group. Randomised trial of intravenous streptokinase, oral aspirin, both, or neither among 17 187 cases of suspected acute myocardial infarction: ISIS-2. Lancet. 1988;2:349-360.[Medline] [Order article via Infotrieve]
3. AIMS Trial Study Group. Effect of intravenous APSAC on mortality after acute myocardial infarction: preliminary report of a placebo-controlled clinical trial. Lancet. 1988;1:545-549.[Medline] [Order article via Infotrieve]
4. Wilcox RG, von der Lippe G, Ollson CG, Jensen G, Skene AM, Hampton JR. Trial of tissue plasminogen activation for mortality reduction in acute myocardial infarction: Anglo-Scandinavian Study of Early Thrombolysis (ASSET). Lancet. 1988;2:525-530.[Medline] [Order article via Infotrieve]
5. White HD, Norris RM, Brown MA, Takayama M, Maslowski A, Bass NM, Ormiston JA, Whitlock T. Effect of intravenous streptokinase on left ventricular function and early survival after acute myocardial infarction. N Engl J Med. 1987;317:850-855.[Abstract]
6. Fibrinolytic Therapy Trialists' (FTT) Collaborative Group. Indications for fibrinolytic therapy in suspected acute myocardial infarction: collaborative overview of early mortality and major morbidity results from all randomised trials of more than 1000 patients. Lancet. 1994;343:311-322.[Medline] [Order article via Infotrieve]
7.
Simes RJ, Topol EJ, Holmes DR, White HD, Rutsch WR,
Vahanian A, Simoons ML, Morris D, Betriu A, Califf RM, Ross AM, for the
GUSTO-I Investigators. Link between the angiographic substudy and
mortality outcomes in a large randomized trial of myocardial
reperfusion: importance of early and complete infarct artery
reperfusion. Circulation. 1995;91:1923-1928.
8.
Chesebro JH, Knatterud G, Roberts R, Borer J, Cohen
LS, Dalen J, Dodge HT, Francis CK, Hillis D, Ludbrook P, Markis JE,
Mueller H, Passamani ER, Powers ER, Rao AK, Robertson T, Ross A, Ryan
TJ, Sobel BE, Willerson J, Williams DO, Zaret BL, Braunwald E.
Thrombolysis In Myocardial Infarction (TIMI) Trial, phase
I: a comparison between intravenous tissue
plasminogen activator and
intravenous streptokinase—clinical findings through
hospital discharge. Circulation. 1987;76:142-154.
9.
The GUSTO Angiographic Investigators. The effects of
tissue plasminogen activator, streptokinase, or
both on coronary-artery patency, ventricular
function, and survival after acute myocardial infarction [published
erratum appears in N Engl J Med. 1994;330:516].
N Engl J Med. 1993;329:1615-1622.
10. Schaer DH, Ross AM, Wasserman AG. Reinfarction, recurrent angina, and reocclusion after thrombolytic therapy. Circulation. 1987;76(suppl II):II-57-II-62.
11.
Ohman EM, Califf RM, Topol EJ, Candela R,
Abbottsmith C, Ellis S, Sigmon KN, Kereiakes D, George B, Stack R, and
the TAMI Study Group. Consequences of reocclusion after successful
reperfusion therapy in acute myocardial infarction.
Circulation. 1990;82:781-791.
12. Hackett D, Davies G, Chierchia S, Maseri A. Intermittent coronary occlusion in acute myocardial infarction: value of combined thrombolytic and vasodilator therapy. N Engl J Med. 1987;317:1055-1059.[Abstract]
13.
Heras M, Chesebro JH, Penny WJ, Bailey KR, Badimon L,
Fuster V. Effects of thrombin inhibition on the development of
acute platelet-thrombus deposition during angioplasty in pigs:
heparin versus recombinant hirudin, a specific thrombin
inhibitor. Circulation. 1989;79:657-665.
14.
Lee CD, Mann KG. Activation/inactivation of
human coagulation factor V by plasmin. Blood. 1989;73:185-190.
15.
Jang IK, Gold HK, Ziskind AA, Leinbach RC, Fallon JT,
Collen D. Prevention of platelet-rich arterial
thrombosis by selective thrombin inhibition.
Circulation. 1990;81:219-225.
16.
Fitzgerald DJ, Catella F, Roy L, Fitzgerald GA.
Marked platelet activation in vivo after intravenous
streptokinase in patients with acute myocardial infarction.
Circulation. 1988;77:142-150.
17.
Kerins DM, Roy L, Fitzgerald GA, Fitzgerald DJ.
Platelet and vascular function during coronary
thrombolysis with tissue-type plasminogen
activator. Circulation. 1989;80:1718-1725.
18. Vaughan DE, Van Houtte E, Declerck PJ, Van de Werf F, Collen D. Prevalence and mechanism of streptokinase-induced platelet aggregation. Circulation. 1989;80(suppl II):II-218. Abstract.
19.
Topol EJ, George BS, Kereiakes DJ, Stump DC, Candela
RJ, Abbottsmith CW, Aronson L, Pickel A, Boswick JM, Lee KL, Ellis SG,
Califf RM, and the TAMI Study Group. A randomized controlled trial of
intravenous tissue plasminogen
activator and early intravenous heparin in
acute myocardial infarction. Circulation. 1989;79:281-286.
20. Weitz JI, Hudoba M, Massel D, Maraganore J, Hirsh J. Clot-bound thrombin is protected from inhibition by heparin-antithrombin III but is susceptible to inactivation by antithrombin III-independent inhibitors. J Clin Invest. 1990;86:385-391.
21. Webster MWI, Chesebro JH, Fuster V. Antithrombotic therapy in acute myocardial infarction: enhancement of thrombolysis, reduction of reocclusion, and prevention of thromboembolism. In: Gersh BJ, Rahimtoola SH, eds. Acute Myocardial Infarction. New York, NY: Elsevier Science Publishing Co Inc; 1991:333-348.
22. Maraganore JM. Preclinical and clinical studies on hirulog: a potent and specific direct thrombin inhibitor. In: Claeson G, Scully MF, Kakkar VV, Deadman J, eds. Design of Synthetic Inhibitors of Thrombin. New York, NY: Plenum Press; 1993:227-236.
23.
The GUSTO Investigators. An international randomized
trial comparing four thrombolytic strategies for acute
myocardial infarction. N Engl J Med. 1993;329:673-682.
24.
Théroux P, Pérez-Villa F, Waters D,
Lespérance J, Shabani F, Bonan R. Randomized double-blind
comparison of two doses of hirulog with heparin as adjunctive therapy
to streptokinase to promote early patency of the infarct-related artery
in acute myocardial infarction. Circulation. 1995;91:2132-2139.
25.
Yao SK, Ober JC, Ferguson JJ, Anderson V, Maraganore J,
Buja LM, Willerson JT. Combination of inhibition of thrombin and
blockade of thromboxane A2 synthetase and receptors
enhances thrombolysis and delays reocclusion in canine
coronary arteries. Circulation. 1992;86:1993-1999.
26. Maraganore JM, Bourdon P, Jablonski I, Ramachandran KL, Kenton JW. Design and characterization of hirulogs: a novel class of bivalent peptide inhibitors of thrombin. Biochem. 1990;29:7095-7101.[Medline] [Order article via Infotrieve]
27.
Braunwald E, Kloner RA. The stunned
myocardium: prolonged, postischemic
ventricular dysfunction. Circulation. 1982;66:1146-1149.
28.
Antman EM, for the TIMI 9B Investigators. Hirudin
in acute myocardial infarction: Thrombolysis and Thrombin
Inhibition in Myocardial Infarction (TIMI) 9B Trial.
Circulation. 1996;94:911-921.
29.
The Global Use of Strategies to Open Occluded
Coronary Arteries (GUSTO) IIb Investigators. A comparison of
recombinant hirudin with heparin for the treatment of acute
coronary syndromes. N Engl J Med. 1996;335:775-782.
30.
Fuchs J, Cannon CP, and the TIMI 7 Investigators.
Hirulog in the treatment of unstable angina: results of the Thrombin
Inhibition in Myocardial Ischemia (TIMI) 7 Trial.
Circulation. 1995;92:727-733.
31.
Lidon RM, Théroux P, Juneau M, Adelman B,
Maraganore J. Initial experience with a direct antithrombin,
hirulog, in unstable angina: anticoagulant, antithrombotic, and
clinical effects. Circulation. 1993;88:1495-1501.
32. Sharma GVRK, Lapsley D, Vita JA, Sharma S, Coccio E, Adelman B, Loscalzo J. Usefulness and tolerability of hirulog, a direct thrombin-inhibitor, in unstable angina pectoris. Am J Cardiol. 1993;72:1357-1360.[Medline] [Order article via Infotrieve]
33.
Ginsberg JS, Nurmohaned MT, Gent M, Nurmohamed
MT, MacKinnon B, Sicurella J, Brill Edwards P, Levine MN, Panju AA,
Powers P, Stevens P. Use of hirulog in the prevention of venous
thrombosis after major hip or knee surgery.
Circulation. 1994;90:2385-2389.
34.
Lidon RM, Theroux P, Lesperance J, Adelman B, Bonan R,
Duval D, Levesque J. A pilot, early angiographic patency study
using a direct thrombin inhibitor as adjunctive therapy to
streptokinase in acute myocardial infarction.
Circulation. 1994;89:1567-1572.
35.
Topol EJ, Bonan R, Jewitt D, Sigwart U, Kakkar VV,
Rothman M, de Bono D, Ferguson J, Willerson JT, Strony J. Use of
a direct antithrombin, hirulog, in place of heparin during
coronary angioplasty. Circulation. 1993;87:1622-1629.
36.
Bittl JA, Strony J, Brinker JA, Ahmed WH, Meckel CR,
Chaitman BR, Maraganore J, Deutsch E, Adelman B, for the Hirulog
Angioplasty Study Investigators. Treatment with bivalirudin (Hirulog)
as compared with heparin during coronary angioplasty for
unstable or postinfarction angina. N Engl J Med. 1995;333:764-769.
37.
Antman EM, for the TIMI 9A Investigators. Hirudin in
acute myocardial infarction: safety report from the
Thrombolysis and Thrombin Inhibition in Myocardial
Infarction (TIMI) 9A trial. Circulation. 1994;90:1624-1630.
38.
The Global Use of Strategies to Open Occluded
Coronary Arteries (GUSTO) IIa Investigators. Randomized trial
of intravenous heparin versus recombinant hirudin for acute
coronary syndromes. Circulation. 1994;90:1631-1637.
39. Simes RJ, Granger CB, Antman EM, Califf RM, Braunwald E, Topol EJ. Impact of hirudin versus heparin on mortality and (re)infarction in patients with acute coronary syndromes: a prospective meta-analysis of the GUSTO-IIb and TIMI 9b Trials. Circulation. 1996;94(suppl I):I-430. Abstract.
40. Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico. GISSI-2: a factorial randomised trial of alteplase versus streptokinase and heparin versus no heparin among 12 490 patients with acute myocardial infarction. Lancet. 1990;336:65-71.[Medline] [Order article via Infotrieve]
41. ISIS-3 (Third International Study of Infarct Survival) Collaborative Group. ISIS-3: a randomised comparison of streptokinase vs tissue plasminogen activator vs anistreplase and of aspirin plus heparin vs aspirin alone among 41 299 cases of suspected acute myocardial infarction. Lancet. 1992;339:753-770.[Medline] [Order article via Infotrieve]
42. Eisenberg PR, Sherman LA, Jaffe AS. Paradoxic elevation of fibrin peptide A after streptokinase: evidence for intense thrombosis despite intense fibrinolysis. J Am Coll Cardiol. 1987;10:527-529.[Abstract]
This article has been cited by other articles:
 |
|
 |
|
  S. Schulman, R. J. Beyth, C. Kearon, and M. N. Levine Hemorrhagic Complications of Anticoagulant and Thrombolytic Treatment: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition) Chest, June 1, 2008; 133(6_suppl): 257S - 298S. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. G. Goodman, V. Menon, C. P. Cannon, G. Steg, E. M. Ohman, and R. A. Harrington Acute ST-Segment Elevation Myocardial Infarction: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition) Chest, June 1, 2008; 133(6_suppl): 708S - 775S. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Singh, J. Molnar, and R. Arora Efficacy and Safety of Bivalirudin Versus Heparins in Reduction of Cardiac Outcomes in Acute Coronary Syndrome and Percutaneous Coronary Interventions Journal of Cardiovascular Pharmacology and Therapeutics, December 1, 2007; 12(4): 283 - 291. [Abstract] [PDF]
|
|
|
|
 |
|
 P. R. Sinnaeve, J. Simes, S. Yusuf, J. Garg, S. Mehta, J. Eikelboom, J. A. Bittl, P. Serruys, E. J. Topol, and C. B. Granger Direct thrombin inhibitors in acute coronary syndromes: effect in patients undergoing early percutaneous coronary intervention Eur. Heart J., November 2, 2005; 26(22): 2396 - 2403. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. Menon, R. A. Harrington, J. S. Hochman, C. P. Cannon, S. D. Goodman, R. G. Wilcox, H. J. Schunemann, and E. M. Ohman Thrombolysis and Adjunctive Therapy in Acute Myocardial Infarction: The Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy Chest, September 1, 2004; 126(3_suppl): 549S - 575S. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Eichler, N. Lubenow, U. Strobel, and A. Greinacher Antibodies against lepirudin are polyspecific and recognize epitopes on bivalirudin Blood, January 15, 2004; 103(2): 613 - 616. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Eikelboom, H. White, and S. Yusuf The evolving role of direct thrombin inhibitors in acute coronary syndromes J. Am. Coll. Cardiol., February 19, 2003; 41(4_Suppl_S): 70S - 78S. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
The Task Force on the Management of Acute Myocardi, F. Van de Werf, D. Ardissino, A. Betriu, D. V. Cokkinos, E. Falk, K. A.A. Fox, D. Julian, M. Lengyel, F.-J. Neumann, et al. Management of acute myocardial infarction in patients presenting with ST-segment elevation Eur. Heart J., January 1, 2003; 24(1): 28 - 66. [Full Text] [PDF]
|
|
|
|
 |
|
 W. F. Baker Jr Thrombolytic Therapy Clinical and Applied Thrombosis/Hemostasis, October 1, 2002; 8(4): 291 - 314. [PDF]
|
|
|
|
|
|
C.-K. Wong, J.K. French, M.W. Krucoff, W. Gao, P.E. Aylward, and H.D. White Slowed ST segment recovery despite early infarct artery patency in patients with Q waves at presentation with a first acute myocardial infarction. Implications of initial Q waves on myocyte reperfusion Eur. Heart J., September 2, 2002; 23(18): 1449 - 1455. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C.-K. Wong, J.K. French, J. Andrews, M.J. Frey, A.A.J. Adgey, P.E. Aylward, and H.D. White Usefulness of the presenting electrocardiogram in predicting myocardial salvage with thrombolytic therapy in patients with a first acute myocardial infarction Eur. Heart J., March 1, 2002; 23(5): 399 - 404. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. W. Armstrong and D. Collen Fibrinolysis for Acute Myocardial Infarction : Current Status and New Horizons for Pharmacological Reperfusion, Part 2 Circulation, June 19, 2001; 103(24): 2987 - 2992. [Full Text] [PDF]
|
|
|
|
 |
|
 G. N. Levine, M. N. Ali, and A. I. Schafer Antithrombotic Therapy in Patients With Acute Coronary Syndromes Arch Intern Med, April 9, 2001; 161(7): 937 - 948. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Greinacher and N. Lubenow Recombinant Hirudin in Clinical Practice : Focus on Lepirudin Circulation, March 13, 2001; 103(10): 1479 - 1484. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. I. Weitz and J. Hirsh New Anticoagulant Drugs Chest, January 1, 2001; 119 (2009): 95S - 107S. [Full Text] [PDF]
|
|
|
|
|
|
E. M. Ohman, R. A. Harrington, C. P. Cannon, G. Agnelli, J. A. Cairns, and J.W. Kennedy Intravenous Thrombolysis in Acute Myocardial Infarction Chest, January 1, 2001; 119 (2009): 253S - 277S. [Full Text] [PDF]
|
|
|
|
|
|
H.D. White Cardiogenic shock: a more aggressive approach is now warranted Eur. Heart J., December 1, 2000; 21(23): 1897 - 1901. [PDF]
|
|
|
|
|
|
P.W. Armstrong Reperfusion synergism: will it be both sustained and safe? Eur. Heart J., December 1, 2000; 21(23): 1913 - 1916. [PDF]
|
|
|
|
|
|
N. S. Van de Water, J. K. French, M. Lund, T. A. Hyde, H. D. White, and P. J. Browett Prevalence of factor v leiden and prothrombin variant g20210a in patients age <50 years with no significant stenoses at angiography three to four weeks after myocardial infarction J. Am. Coll. Cardiol., September 1, 2000; 36(3): 717 - 722. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Andrews, I. T. Straznicky, J. K. French, C. L. Green, A. C. P. Maas, M. Lund, M. W. Krucoff, and H. D. White ST-Segment Recovery Adds to the Assessment of TIMI 2 and 3 Flow in Predicting Infarct Wall Motion After Thrombolytic Therapy Circulation, May 9, 2000; 101(18): 2138 - 2143. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. K. French, T. A. Hyde, I. T. Straznicky, J. Andrews, M. Lund, D. J. Amos, A. Zambanini, C. J. Ellis, B. J. Webber, S. C. McLaughlin, et al. Relationship between corrected TIMI frame counts at three weeks and late survival after myocardial infarction J. Am. Coll. Cardiol., May 1, 2000; 35(6): 1516 - 1524. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
O. Iqbal, H. Messmore, D. Hoppensteadt, J. Fareed, and W. Wehrmacher State-of-the-Art Review : Thrombolytic Drugs in Acute Myocardial Infarction Clinical and Applied Thrombosis/Hemostasis, January 1, 2000; 6(1): 1 - 13. [PDF]
|
|
|
|
|
|
D. F. Kong, E. J. Topol, J. A. Bittl, H. D. White, P. Theroux, V. Hasselblad, and R. M. Califf Clinical Outcomes of Bivalirudin for Ischemic Heart Disease Circulation, November 16, 1999; 100(20): 2049 - 2053. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Klement, P. Liao, and L. Bajzar A Novel Approach to Arterial Thrombolysis Blood, October 15, 1999; 94(8): 2735 - 2743. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
X. Song, G. Huhle, L. Wang, U. Hoffmann, and J. Harenberg Generation of Anti-Hirudin Antibodies in Heparin-Induced Thrombocytopenic Patients Treated With R-Hirudin Circulation, October 5, 1999; 100(14): 1528 - 1532. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K.-L. Neuhaus, G. P. Molhoek, U. Zeymer, U. Tebbe, K. Wegscheider, R. Schroder, A. Camez, G. J. Laarman, G. M. Grollier, D. J. A. Lok, et al. Recombinant hirudin (lepirudin) for the improvement of thrombolysis with streptokinase in patients with acute myocardial infarction: Results of the HIT-4 trial J. Am. Coll. Cardiol., October 1, 1999; 34(4): 966 - 973. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Fareed, B. E. Lewis, D. D. Callas, D. A. Hoppensteadt, J. M. Walenga, and R. L. Bick Antithrombin Agents: The New Class of Anticoagulant and Antithrombotic Drugs Clinical and Applied Thrombosis/Hemostasis, October 1, 1999; 5(1_suppl): S45 - S55. [Abstract] [PDF]
|
|
|
|
|
|
J. K. French, T. A. Hyde, H. Patel, D. J. Amos, S. C. McLaughlin, B. J. Webber, and H. D. White Survival 12 years after randomization to streptokinase: the influence of thrombolysis in myocardial infarction flow at three to four weeks J. Am. Coll. Cardiol., July 1, 1999; 34(1): 62 - 69. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I.-K. Jang, D. F. M. Brown, R. P. Giugliano, H. V. Anderson, D. Losordo, J. C. Nicolau, O. P. Dutra, O. Bazzino, V. M. Viamonte, R. Norbady, et al. A multicenter, randomized study of argatroban versus heparin as adjunct to tissue plasminogen activator (TPA) in acute myocardial infarction: myocardial infarction with Novastan and TPA (MINT) study J. Am. Coll. Cardiol., June 1, 1999; 33(7): 1879 - 1885. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. J. Cook, S. J. Gardell, M. A. Holahan, G. R. Sitko, G. L. Stump, A. A. Wallace, D. B. Gilberto, T. R. Hare, J. A. Krueger, D. L. Dyer, et al. Antithrombotic Efficacy of Thrombin Inhibitor L-374,087: Intravenous Activity in a Primate Model of Venous Thrombus Extension and Oral Activity in a Canine Model of Primary Venous and Coronary Artery Thrombosis J. Pharmacol. Exp. Ther., April 1, 1999; 289(1): 503 - 510. [Abstract] [Full Text]
|
|
|
|
|
|
G. Frostfeldt, G. Ahlberg, G. Gustafsson, G. Helmius, B. Lindahl, A. Nygren, A. Siegbahn, E. Swahn, P. Venge, and L. Wallentin Low molecular weight heparin (dalteparin) as adjuvant treatment to thrombolysis in acute myocardial infarction--a pilot study: Biochemical Markers in Acute Coronary Syndromes (BIOMACS II) J. Am. Coll. Cardiol., March 1, 1999; 33(3): 627 - 633. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J K French, I T Straznicky, B J Webber, P E Aylward, M J Frey, A A J Adgey, B F Williams, S C McLaughlin, and H D White Angiographic frame counts 90 minutes after streptokinase predict left ventricular function at 48 hours following myocardial infarction Heart, February 1, 1999; 81(2): 128 - 133. [Abstract] [Full Text]
|
|
|
|
 |
|
 D. E. Gutstein and V. Fuster Pathophysiology and clinical significance of atherosclerotic plaque rupture Cardiovasc Res, February 1, 1999; 41(2): 323 - 333. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. M. Bates and J. I. Weitz Prevention of activation of blood coagulation during acute coronary ischemic syndromes: beyond aspirin and heparin Cardiovasc Res, February 1, 1999; 41(2): 418 - 432. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. A. Baughman, S. C. Kapoor, R. K. Agarwal, J. Kisicki, F. Catella-Lawson, and G. A. FitzGerald Oral Delivery of Anticoagulant Doses of Heparin : A Randomized, Double-Blind, Controlled Study in Humans Circulation, October 20, 1998; 98(16): 1610 - 1615. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Fareed Antithrombin Agents as Anticoagulants and Antithrombotics: Implications in Drug Development Clinical and Applied Thrombosis/Hemostasis, October 1, 1998; 4(4): 227 - 237. [Abstract] [PDF]
|
|
|
|
 |
|
 V. Fuster, J. J. Badimon, and J. H Chesebro Atherothrombosis: mechanisms and clinical therapeutic approaches Vascular Medicine, August 1, 1998; 3(3): 231 - 239. [Abstract] [PDF]
|
|
|
|
|
|
J. H. Chesebro Direct Thrombin Inhibition Superior to Heparin During and After Thrombolysis : Dose, Duration, and Drug Circulation, October 7, 1997; 96(7): 2118 - 2120. [Full Text]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||