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Circulation. 1996;94:911-921

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(Circulation. 1996;94:911-921.)
© 1996 American Heart Association, Inc.

Articles

Hirudin in Acute Myocardial Infarction

Thrombolysis and Thrombin Inhibition in Myocardial Infarction (TIMI) 9B Trial

Elliott M. Antman, MD; for the TIMI 9B Investigators*

the Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Boston, Mass.

Correspondence to Elliott M. Antman, MD, Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, 75 Francis St, Boston, MA 02115.


*    Abstract
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 *Abstract
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Background The TIMI 9 trial evaluated whether the direct antithrombin hirudin is more effective than an indirect-acting antithrombin, heparin, as adjunctive therapy for thrombolysis in myocardial infarction.

Methods and Results Patients (n=3002) with acute myocardial infarction were treated with aspirin and either accelerated-dose tissue plasminogen activator (TPA) or streptokinase. They were randomized within 12 hours of symptoms to receive either intravenous heparin (5000 U bolus followed by infusion of 1000 U/h) or hirudin (0.1 mg/kg bolus followed by infusion of 0.1 mg/kg per hour). The infusions of both antithrombins were titrated to a target activated partial thromboplastin time (aPTT) of 55 to 85 seconds and were administered for 96 hours. Patients randomized to hirudin were significantly more likely to have an aPTT measurement in the target range (P<.0001). The primary end point (death, recurrent nonfatal myocardial infarction, or development of severe congestive heart failure or cardiogenic shock by 30 days) occurred in 11.9% of the 1491 patients in the heparin group and 12.9% of the 1511 patients in the hirudin group (P=NS). Subgroup analyses did not reveal any profile of patients who benefited more from one of the antithrombins. The rate of major hemorrhage was similar in the heparin (5.3%) and hirudin (4.6%) groups; intracranial hemorrhage occurred in 0.9% of the heparin and 0.4% of the hirudin patients.

Conclusions Heparin and hirudin have an equal effect as adjunctive therapy to TPA and streptokinase in preventing unsatisfactory outcome in patients with acute myocardial infarction. Similar rates of major bleeding were observed for patients in the heparin and hirudin groups.


Key Words: heparin • thrombolysis • myocardial infarction


*    Introduction
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 *Introduction
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Contemporary thrombolytic reperfusion regimens, while providing an important survival benefit for patients with acute myocardial infarction (AMI) presenting with ST-segment elevation, continue to suffer from several deficiencies. Depending on the agent prescribed, patency of the infarct-related artery is established by 90 minutes in only 60% to 80% of patients1 2 3 ; full antegrade perfusion (TIMI grade 3 flow) is achieved in only 30% to 55% of patients.2 3 After initially successful thrombolysis, {approx}5% to 10% of patients experience reocclusion of the culprit coronary vessel. When it occurs, reocclusion may be associated with recurrent infarction and an increased risk of mortality and morbidity.4 Although aspirin acts synergistically with thrombolytic therapy to reduce mortality5 6 and may also be helpful in preventing reocclusion,7 it is largely ineffective at inhibiting thrombin, a central molecule in the pathophysiology of coronary artery occlusion in AMI with ST-segment elevation.8

Thrombin molecules exist both in the fluid phase and bound within the thrombus in the infarct-related coronary artery. Heparin, the current antithrombin used widely in clinical practice, is an indirectly acting drug that catalyzes the inactivation of fluid-phase thrombin by antithrombin III but is unable to inhibit clot-bound thrombin, which therefore remains enzymatically active.9 In addition to this deficiency, heparin has several other theoretical disadvantages including inhibition by platelet factor IV and marked heterogeneity of its pharmacokinetic and pharmacodynamic properties.10

The availability of direct-acting antithrombins in sufficient quantity for clinical investigation has provided the opportunity to test the hypothesis that more complete and consistent inhibition of thrombin activity is associated with a reduced rate of adverse clinical events after thrombolysis for AMI.8 11 12 13 The prototypic direct antithrombin is hirudin, a 65–amino acid compound derived from the medicinal leech, which binds selectively via its carboxy terminus to the substrate recognition site of thrombin and via its amino terminus to the catalytic center of thrombin.14 Recombinant desulfatohirudin (CGP 39393; REVASC, Ciba-Geigy Corp)15 is identical to wild-type hirudin except for a missing sulfate group on tyrosine number 63. It has been shown in previous in vitro and animal investigations to be a potent inhibitor of thrombin, capable of facilitating thrombolysis with tissue plasminogen activator (TPA)16 and streptokinase17 in experimental models of coronary thrombosis. These observations coupled with promising pilot data from the Thrombolysis in Myocardial Infarction (TIMI) 5 (TPA)18 and TIMI 6 (streptokinase)19 trials led to its selection for study in a phase III trial, TIMI 9.

The purpose of TIMI 9 was to compare the efficacy and safety of intravenous recombinant desulfatohirudin (hereafter referred to as hirudin) to intravenous heparin as adjunctive therapy to thrombolysis with either accelerated-dose TPA or streptokinase for AMI. As described in a previous report,20 the doses of heparin (5000 U bolus followed by infusion of 1300 U/h in patients who weighed >=80 kg and 1000 U/h for patients who weighed <80 kg) and hirudin (0.6 mg/kg bolus followed by infusion of 0.2 mg/kg per hour) initially selected were associated with higher than expected bleeding rates after 757 patients had been enrolled in what is now referred to as TIMI 9A. After reduction of the doses of both study drugs and institution of additional safety measures (eg, titration of both antithrombins to a reduced target activated partial thromboplastin time [aPTT] range of 55 to 85 seconds) the TIMI 9B trial was undertaken.


*    Methods
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 *Methods
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The trial was conducted between May 1994 and September 1995 at 150 enrolling centers in the United States, Canada, the United Kingdom, Israel, and Germany and was supported by two central units as described in the "Appendix."

Eligibility Criteria
To be eligible for inclusion in the trial, patients were required to have an episode of ischemic discomfort that lasted at least 30 minutes and occurred within 12 hours of enrollment (Fig 1Down). In addition, an ECG with >=0.1 mV ST-segment elevation in at least two leads or new or presumably new left bundle branch block was required. Patients were excluded if they had contraindications to thrombolytic therapy (active bleeding, history of stroke, major surgery within 2 months, confirmed blood pressure >190/110 mm Hg), were <21 years of age (no upper age limit for enrollment), had a serum creatinine level >2.0 mg/dL, were in cardiogenic shock, were a female of child-bearing potential, or were receiving therapeutic doses of anticoagulants (prothrombin time [PT] >=14 seconds, aPTT >=60 seconds). (Fig 1Down)



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  		Figure 1. Protocol design of the Thrombolysis and Thrombin Inhibition (TIMI) 9 Trial. AMI indicates acute myocardial infarction; aPTT, activated partial thromboplastin time; CHF, congestive heart failure; Inf, infusion; SK, streptokinase; ST elev, ST-segment elevation; and TPA, tissue plasminogen activator.

Study Protocol
Selection of the thrombolytic agent was at the treating physician's discretion and consisted either of front-loaded, weight-adjusted TPA (maximum, 100 mg) over 90 minutes or 1.5 million units of streptokinase over 1 hour. Patients received 150 to 325 mg of aspirin immediately (followed by daily therapy thereafter) and were randomized in a 1:1 fashion through a central telephone system to either unfractionated heparin or hirudin (Fig 1). A permuted block design was used to ensure balanced randomization at each enrolling center. A consistent formulation of porcine heparin from a single manufacturer (Elkins-Scinn) was used throughout the trial. ß-Blockers, nitrates, calcium antagonists, and other medications were administered at the discretion of the treating physician, as were decisions regarding catheterization and revascularization.

The study drug was to be administered either before or as soon as possible (not to exceed 60 minutes) after thrombolysis and continued for 96 hours. The dose of heparin was a bolus of 5000 U followed by a continuous infusion of 1000 U/h for patients of any weight. The dose of hirudin was a bolus of 0.1 mg/kg (not to exceed 15 mg) followed by a continuous infusion of 0.1 mg/kg per hour (not to exceed 15 mg/h). The target aPTT was 55 to 85 seconds with dose adjustments for both study drugs made according to a specified nomogram modified from the one published by Hirsh.21

Blood samples were obtained at 12 and 24 hours after initiation of study drug and daily thereafter during study drug infusion for measurement of aPTT. All aPTT measurements were performed locally at the enrolling center with the use of either a hospital anticoagulation laboratory or a bedside aPTT monitoring system. The same method of aPTT measurement (eg, laboratory versus bedside) was used for all patients enrolled at each center. Within 6 hours of thrombolytic therapy, the infusion rate of the study drug was only adjusted upward for an aPTT <55 seconds. At the investigator's discretion, the rate of study drug infusion could be adjusted according to the study nomogram between 6 and 12 hours after thrombolysis in individual patients.

ECGs were obtained on admission, for any episodes of recurrent ischemic discomfort >=30 minutes during the index hospitalization, at hospital discharge, and for any episodes of recurrent ischemic discomfort >=30 minutes between hospital discharge and 30 days after randomization. Creatine kinase (CK) and isoenzyme (CK-MB) levels were measured at admission and during the subsequent 24 hours, at the time of and for 24 hours after episodes of recurrent ischemic discomfort, and 12 to 24 hours after coronary angioplasty or coronary artery bypass surgery.

If during the 96-hour infusion of study drug the patient required coronary arteriography or angioplasty, the procedure was supported by blinded study drug to an activated clotting time of >=350 seconds. After the initial 96 hours, diagnostic and interventional catheterization procedures were supported by blinded study drug to the extent that supplies were available and then by open-label unfractionated heparin if further antithrombotic therapy was considered necessary. Patients who were referred for coronary artery bypass surgery had their study drug discontinued 3 to 6 hours before the operation, which was performed with antithrombotic therapy according to local institutional practices.

Study End Points
Efficacy
The primary efficacy end point was a composite of "unsatisfactory outcome" consisting of any one of the following events through 30 days after randomization: (1) death (all-cause mortality), (2) recurrent infarction, or (3) the development at least 4 hours after the start of thrombolytic therapy of severe congestive heart failure (rales over more than half of the lung fields and pulmonary congestion on chest radiograph) or cardiogenic shock (end-organ hypoperfusion, systolic pressure <90 mm Hg without inotropic or intra-aortic balloon support or >90 mm Hg requiring inotropic or intra-aortic balloon support in the setting of adequate volume expansion) (Fig 1).

The definition of recurrent infarction within or after 18 hours of thrombolytic therapy was established on the basis of ECG and enzyme criteria as previously described.18 22 Within 18 hours, recurrent ischemic discomfort >=30 minutes and new or recurrent ST-segment elevation >=0.1 mV were required. After 18 hours, a criterion of reelevation of CK-MB to above the upper limit of normal and increased by >=50% over the previous value was added. If quantitative CK-MB was not available, it was required that the total CK be reelevated to more than twice the upper limit of normal and increased by >=25% or >=200 U/mL over the previous value; if reelevated to less than twice normal, the CK was required to exceed the upper limit of normal by >=50% and the previous value by twofold or >=200 U/mL. After coronary angioplasty, the definition of recurrent infarction was new Q waves in two or more leads and reelevation of the CK-MB (or total CK if CK-MB was not available) to at least twice normal and >=50% above the previous value; after coronary artery bypass surgery, the latter criterion was set at a CK-MB elevation at least five times normal.

For any episode of suspected recurrent infarction (ie, ischemic discomfort >=30 minutes) after the qualifying episode, the relevant ECGs and cardiac enzyme results were submitted to a Morbidity and Mortality Classification Committee (MMCC) that was unaware of treatment assignment and confirmed the presence or absence of recurrent AMI according to the criteria specified above.

Safety
The primary safety end point was ascertained during hospitalization and consisted of major hemorrhage (defined as overt bleeding associated with an absolute decrease in hematocrit >=15% or a decrease in hemoglobin of >=5 g/dL, or any intracranial or retroperitoneal bleed) or severe anaphylaxis. All bleeding end points were reviewed and classified by the MMCC.

Statistical Methods
Statistical comparisons of the characteristics of the heparin and hirudin groups were performed by the {chi}2 test for categorical variables and either two-sample t tests or Wilcoxon rank-sum tests for continuous variables. The incidence of the primary efficacy and safety end points were analyzed on an intention-to-treat basis with the use of the Cochran-Mantel-Haenszel test adjusted for the following strata: thrombolytic, age (<65, >=65 years) and time from onset of ischemic discomfort to initiation of thrombolytic (<4, >=4 hours). Differences in treatment effect across the stratifying variables were evaluated with the Breslow-Day procedure. Odds ratios and 95% confidence intervals were used to compare the two treatments in prespecified subgroups. Comparisons of the time to events during the 30-day follow-up were performed with the use of the Kaplan-Meier method23 and analyzed with a log rank statistic. A multivariate logistic regression model was constructed to evaluate the response to treatment with hirudin and heparin after adjusting for other variables previously shown to correlate with the risk of adverse clinical outcome.

A sample size of 3000 patients was estimated on the basis of an anticipated event rate for the primary end point in the heparin group of 18%3 18 and the desire to detect a 25% reduction in events with hirudin with 90% power and a two-sided {alpha}-level of 5%. An independent Data Safety Monitoring Board monitored the trial using a prespecified interim testing scheme based on a group sequential design with three interim analyses and one final analysis.


*    Results
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Baseline Characteristics
A total of 3002 patients were enrolled in the trial. Of these, 1765 (59%) were from North America, 754 (25%) from Israel, 334 (11%) from the United Kingdom, and 149 (5%) from Germany. Selected baseline characteristics of the two patient groups are shown in Table 1Down. No significant differences were observed between the patients allocated to heparin (n=1491) versus hirudin (n=1511). The mean age was 60 years and the patient population consisted predominantly of white men. Approximately one sixth of the patients had a prior myocardial infarction. The presenting infarction was anterior in location in {approx}40% of the population, and three quarters of the patients were classified as "not low risk."24 The median time from symptoms to initiation of thrombolytic therapy was slightly less than 3 hours; two thirds of patients were treated with TPA. The median time from symptoms to administration of study drug was similar in the two treatment groups (heparin, 3.5 hours; hirudin, 3.7 hours). The assigned study drug was received by 97.2% of patients randomized in the trial.


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  		Table 1. Baseline Characteristics of Patients

Results of aPTT Measurements
The ability of the two study drugs to maintain the aPTT in the desired target range of 55 to 85 seconds is summarized in Table 2Down. For each of the five time intervals shown, the first aPTT measurement in that interval was categorized as to whether it was <55 seconds (below the target range), between 55 and 85 seconds (within target range), or >85 seconds (above the target range). At each of the time intervals shown, twice as many hirudin-treated patients achieved an aPTT within the target range as compared with heparin (P<.001). Furthermore, only 15% of hirudin patients compared with 34% of heparin patients had aPTT values below the target range within the first 24 hours.


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  		Table 2. Activated Partial Thromboplastin Time Measurements in Response to Study Drug

Efficacy Analyses
The primary end point was ascertained in 99.5% of patients. The composite event rate for unsatisfactory outcome in the heparin group was 11.9% and in the hirudin group was 12.9% (P=NS) (Table 3Down). There was no statistically significant difference in the unadjusted rate of the primary end point in the two treatment groups or when analyzed after stratifying for age, time to treatment, and thrombolytic administered. In addition, no significant differences were seen in comparisons of individual elements of the composite end point or when the sum of death and recurrent nonfatal myocardial infarction was compared between the two treatment groups at 24 hours, during hospitalization, or by 30 days (Table 3Down).


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  		Table 3. Clinical Outcome

Kaplan-Meier plots of the time to development of the composite unsatisfactory outcome end point (Fig 2Down) as well as the secondary end point of the sum of death and reinfarction showed no significant differences between the treatment groups. All curves exhibited a similar pattern, with the greatest frequency of events occurring within the first 7 days after randomization followed by a slower rate of the development of events over the ensuing 3 weeks.



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  		Figure 2. Time to development of unsatisfactory outcome. Kaplan-Meier plot of time to occurrence of any element of the unsatisfactory outcome composite end point in the heparin (broken line) and hirudin (solid line) groups. No difference in the timing of events was observed (P=NS by log rank test). Similarly, no difference was seen in the rate of occurrence of the sum of death and recurrent infarction.

To determine whether there were any patient characteristics that would identify a subgroup that might benefit to a greater degree from one of the antithrombins, several subgroup analyses were performed on the basis of demographic features, prior cardiac history, cardiac medications at the time of enrollment, thrombolytic prescribed, or time to treatment (Fig 3Down). In each subgroup analysis, either the point estimate was near unity or the 95% confidence intervals overlapped unity. Thus, no subgroup emerged as clearly benefiting from one of the drug regimens.



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  		Figure 3. Comparison of unsatisfactory outcome at 30 days in heparin and hirudin groups. The odds ratios and 95% confidence intervals for unsatisfactory outcome (hirudin:heparin) in the two treatment groups is shown by the filled squares and horizontal lines. The subgroups analyzed are arranged vertically and the overall treatment effect is summarized in the large square at the bottom of the plot. No significant difference in the odds of unsatisfactory outcome was observed for any patient group. C.P. indicates onset of chest pain; H/O Htn, history of hypertension; Study Rx, study drug; MI, myocardial infarction; and CABG, coronary artery bypass surgery.

The response to antithrombin therapy was also analyzed according to the following strata of the first aPTT measurement obtained within 12 to 24 hours (second row of Table 2Up): below target range (<55 seconds), within target range (55 to 85 seconds), and above target range (>85 seconds). Across the aPTT strata, unsatisfactory outcome occurred in 9.3%, 7.0%, and 13.8% of heparin-treated patients, respectively, versus 12.6%, 10.8%, and 8.8% of hirudin-treated patients. Across the same aPTT strata, the sum of death and nonfatal reinfarction occurred in 8.0%, 4.8%, and 10.7% of heparin-treated patients versus 9.6%, 7.4%, and 6.8% of hirudin-treated patients.

The multivariate logistic regression analysis shown in Table 4Down indicates that the baseline variables associated with unsatisfactory outcome by 30 days included age, sex, weight, systolic blood pressure, heart rate, location of infarction, and history of prior infarction. After adjusting for these variables there was no significant incremental contribution to the model of the antithrombin to which the patient was randomized, or time to treatment with either the thrombolytic or time from thrombolytic to study drug. A similar observation of the lack of statistical significance of time to treatment or antithrombin to which the patient was randomized was made for the secondary end point of death and nonfatal reinfarction.


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  		Table 4. Multivariate Analysis of Independent Factors Predictive of Clinical Outcome

The incidence of revascularization procedures in the subgroup of patients who received trial drug is shown in Table 5Down. The rates of percutaneous revascularization procedures and coronary artery bypass graft surgery were not different between the two treatment groups either during the initial hospitalization or within 30 days of randomization.


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  		Table 5. Incidence of Revascularization Procedures in Patients Receiving Study Drug

There was no significant difference between the hirudin and heparin groups by 30 days with respect to the rate of death or myocardial infarction (6.0% versus 6.0%) or unsatisfactory outcome (6.5% versus 6.9%) after emergency cardiac interventional procedures. There was also no significant difference between the treatment groups by 30 days with respect to the net clinical benefit of death plus nonfatal stroke with major residual neurological deficit (heparin, 5.4%; hirudin, 5.9%; odds ratio, 1.12 [0.81 to 1.54]).

Safety Analyses
In the heparin-treated patients, the rate of major hemorrhage was 5.3%, including an intracranial hemorrhage (ICH) rate of 0.9% and major spontaneous hemorrhage rate of 1.1% (Table 6Down). In the hirudin-treated patients, the rate of major hemorrhage was 4.6% (ICH, 0.4%; spontaneous hemorrhage, 1.8%), which was not statistically different from that seen in heparin-treated patients.


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  		Table 6. Major Hemorrhagic Events (All Patients Who Received Trial Drug)

In the heparin-treated patients, the rate of major hemorrhage when streptokinase was prescribed was 3.9% and was 6.1% when TPA was prescribed (P=.07). For hirudin-treated patients, the major hemorrhage rate was 3.9% with streptokinase and 4.9% with TPA (P=NS). No confirmed episodes of anaphylaxis were reported during the trial.


*    Discussion
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 up arrowAbstract
 up arrowIntroduction
 up arrowMethods
 up arrowResults
 *Discussion
down arrowReferences
 
The principal goal of adjunctive treatment with antithrombin agents in AMI is to facilitate prompt restoration of antegrade flow and help maintain patency of the infarct-related artery.25 The degree to which this goal is achieved determines in large part how effectively antithrombin therapy contributes to reduction of mortality and morbidity due to recurrent infarction and left ventricular dysfunction after AMI. The results of TIMI 9B indicate that in AMI patients receiving thrombolytic therapy relatively early after the onset of symptoms (75% within <=4 hours), treatment with hirudin is not incrementally better than treatment with heparin either in preventing adverse clinical outcome or the need for revascularization procedures. The mortality rate and the rate of development of severe congestive heart failure or cardiogenic shock were slightly higher with hirudin at 24 hours, during hospitalization, and by 30 days. Although there was a trend toward a reduction in the rate of recurrent nonfatal AMI within the first 24 hours with hirudin, evidence of this possible early benefit of hirudin at preventing reinfarction was progressively less striking by 30 days (Table 3Up).

The process of local generation of thrombin begins when tissue factor is exposed at the site of a ruptured atherosclerotic plaque.26 27 After thrombolysis, additional thrombin is generated, in part because of the procoagulant activity of thrombolytic agents that convert plasminogen to plasmin, which in turn activates critical coagulation factors such as factor V and prothrombin.28 29 Platelet activation also increases after thrombolysis.30 31 Thrombin in both the fluid phase and clot-bound is the most potent stimulant of platelet aggregation. In addition, it is responsible for the generation of fibrin and a stable cross-linked network of fibrin strands, amplifies the coagulation cascade, and releases endothelin from damaged endothelium.32 Therefore, reperfusion strategies that have been evaluated to date typically have included the standard antithrombin heparin, either alone33 or in conjunction with aspirin.3 25 34 35 36 Despite a large number of randomized trials, controversy exists regarding the precise role of adjunctive therapy with heparin in AMI patients receiving thrombolytic therapy and aspirin.25 34 35 37 38 39 Nevertheless, consensus panels have recommended immediate intravenous heparin for patients receiving TPA.25 Some authors have suggested that a benefit to heparin may also exist in patients receiving streptokinase,39 and recent registries of clinical practice reveal that the majority of AMI patients treated with thrombolytic therapy in the United States receive intravenous heparin.40 41

Given the marked pharmacodynamic and pharmacokinetic variability of unfractionated heparin10 coupled with its inability to inhibit clot-bound thrombin9 and prevent increases in thrombin activity after thrombolysis,42 considerable interest has centered around the novel direct antithrombins.8 11 12 13 In addition to inhibition of both fluid-phase and clot-bound thrombin, hirudin is more effective than heparin in inhibiting thrombin-mediated platelet activation.43 44 Initial pilot dose-ranging experience with hirudin in patients receiving accelerated-dose TPA in the TIMI 5 trial suggested that it provided a more stable prolongation of the aPTT and might be effective for improving patency of and preventing reocclusion of the infarct-related artery.18 The rate of major spontaneous hemorrhage in hirudin-treated patients in TIMI 518 and TIMI 6 (streptokinase)19 was similar to that observed in heparin-treated patients. It subsequently became clear from the TIMI 9A,20 GUSTO 2A,45 and HIT-III46 trials that treatment of higher-risk patients with aggressive regimens of hirudin that were not adjusted in response to aPTT measurements were associated with unacceptable levels of bleeding. Similarly, it was observed in TIMI 9A and GUSTO 2A that high-dose heparin infusions and a target aPTT range of 60 to 90 seconds was also associated with excessive bleeding risk.20 45

The TIMI 9B trial therefore represents a test of whether a lower dose of hirudin than that used in TIMI 9A is superior to heparin for preventing unsatisfactory outcome after thrombolysis, with the use of a dose of hirudin believed to be effective but not associated with an increased bleeding risk. Indeed, there was a significant reduction in major hemorrhage in TIMI 9B compared with TIMI 9A. The dose of hirudin administered in TIMI 9B was also significantly more effective than heparin at maintaining the aPTT in the therapeutic range (Table 2Up). However, on the basis of the event rates summarized in Table 3Up and Fig 2Up, it appears that heparin and hirudin have an equal effect as adjunctive therapy to TPA and streptokinase in preventing unsatisfactory outcome in patients with AMI. No subgroup could be identified that showed statistically significant benefit of hirudin over heparin; nor was there a difference between the treatment groups in the time to development of elements of the unsatisfactory outcome end point or the secondary end point of death plus recurrent infarction.

Possible Explanations for Results
One possible explanation for the similar rates of unsatisfactory outcome was a lack of superiority in early TIMI grade 3 flow of the infarct related artery in hirudin-treated patients. The predominant factor determining early patency may be the timeliness and potency of the thrombolytic agent; adjunctive therapy with hirudin and heparin may have had an equivalent impact (or lack thereof) on the extent of and rapidity of achievement of initial TIMI grade 3 flow. In addition, although the TIMI 5 trial18 suggested that hirudin was more effective than heparin in preventing reocclusion (angiographic and clinical) of reperfused infarct related arteries, this might not have translated into a clinical benefit in TIMI 9B. It is possible that the infarct-related arteries undergoing late reocclusion in heparin-treated patients supplied zones of infarcted and nonsalvageable myocardium.

In contrast to observations regarding the lack of a significant time dependency of the treatment effect of heparin in thrombolytic-treated patients,47 the time to treatment with hirudin has been proposed as an important determinant of its effectiveness.48 In TIMI 9B, 75% of patients received adjunctive antithrombin therapy in <60 minutes from initiation of thrombolysis. The multivariate analysis in Table 4Up suggests that baseline factors previously shown to correlate with the risk of adverse outcome24 49 are of paramount importance, and no statistical evidence can be found that the time between thrombolytic and study drug nor the study drug to which the patient was randomized correlated with outcome.

The event rate in the heparin group was lower than anticipated, probably in part because of continued general improvement in the prognosis of patients after AMI.50 To determine the likelihood that a true relative superiority of hirudin over heparin failed to be detected in TIMI 9B, several calculations were made comparing the observed results with those expected for a specified treatment effect.51 Given the observed results in TIMI 9B, the likelihood that a 25% relative superiority of hirudin failed to be detected is less than 1 in 1000. In addition, there is about a 1 in 20 chance that even a 10% relative superiority of hirudin failed to be detected. Thus, it is unlikely that a clinically significant treatment benefit of hirudin over heparin failed to be detected.

An additional consideration relates to the possible mechanisms by which heparin and hirudin decrease thrombus formation in the infarct-related coronary artery. On the basis of experimental and clinical data, it appears that for equivalent levels of fibrinopeptide A (FPA) (reflecting thrombin activity), a greater reduction in prothrombin fragment F1.2 levels (reflecting thrombin generation) is seen with heparin compared with hirudin (even in high doses).52 In contrast, for equivalent levels of F1.2, a greater reduction in FPA levels is seen with hirudin compared with heparin.53 Thus, heparin appears to have a greater ability to decrease thrombin generation than to inhibit thrombin activity, whereas hirudin has a greater ability to decrease thrombin activity than to inhibit thrombin generation. The net result of this balance of activities is that both antithrombins result in an equivalent decrement in thrombus formation in the culprit infarct-related coronary artery. It is possible that the differences cited above may be potentiated by the ability of thrombolytics to increase the generation of thrombin.

Clinical Implications
Hirudin and heparin appear to be therapeutically equivalent as adjunctive therapy for AMI patients receiving thrombolytics. Hirudin has the advantage of a more consistent anticoagulant effect and may require fewer adjustments of the infusion rate. In addition, hirudin may be an attractive alternative for patients who have a history of heparin sensitivity or who develop heparin-induced thrombocytopenia.54

Given that there is considerable redundancy of biological systems, perturbing the system at predominantly one point (eg, thrombin generation or thrombin inhibition) may have only a limited impact on downstream events (eg, thrombus formation in culprit coronary artery). Evidence is emerging that inhibition of tissue factor by tissue factor pathway inhibitor55 or factor Xa by tick anticoagulant peptide may be useful as adjunctive therapy to thrombolytic regimens.56 Platelet aggregation that occurs despite the effects of aspirin may contribute to resistance to thrombolysis.57 This resistance may be overcome by new glycoprotein IIbIIIa receptor antagonists.58 59 Although it is highly speculative, a carefully titrated combination of multiple antithrombotic agents capable of inhibiting the coagulation cascade and thrombin as well as activated platelets may be the optimal adjunctive regimen.8 60 The challenge for clinical investigators will be to identify an effective regimen with an acceptable safety profile.


*    Acknowledgments
 
This study was supported by Ciba-Geigy Corp (Summit, NJ). Additional support was provided by Genentech, Inc (South San Francisco).


*    Footnotes
 
*A list of the TIMI 9B Investigators is found in the "Appendix."

TIMI 9B Participants
Study chairman's office: Harvard Medical School, Boston, Mass. Study chairman: Eugene Braunwald, MD; Principal investigator: Elliott M. Antman, MD; Project director: Carolyn H. McCabe, BS; Coinvestigators: Christopher P. Cannon, MD; L. Veronica Lee, MD, Susan Marble, RN, MS.

Sponsor: Ciba-Geigy Pharmaceuticals, Summit, NJ. Chairman, Hirudin Studies: Marc Henis, MD; Biostatistician: Paul Gallo, PhD; Associate Director: Susan Edwards; Project Manager: Donna Hornyak.

Data coordinating center: G.H. Besselaar Associates, Princeton, NJ. Project director: Larry Meinert, MD, MPH; Biostatistician: Jeffrey Griffiths, PhD; Coordinator: Iris Houlihan.

Data and safety monitoring board: J. Ward Kennedy, MD, Chairman; Joel Karliner, MD; Sheryl Kelsey, PhD; Andrew Schafer; MD, Lewis Becker, MD.

Morbidity and mortality classification committee: C. Michael Gibson, MD, Geoffrey Tofler, MD, Douglas Losordo, MD, Richard Becker, MD, Theresa Palabrica, MD, Rob Piana, MD, George McKendall, MD, Cliff Berger, MD, Marc Schweiger, MD.

Drug distribution center: Blis-Tech Corporation, Fairfield, NJ. Investigators: Joseph D'Elia, Robert Armenti, Lucy Ayra.

Steering committee: The members of the steering committee include the Study Chairman and the principal investigators from the TIMI 9 clinical centers and core laboratories.

Clinical Centers in Order of Number of Patients Enrolled (Principal Investigator Is First Individual Listed)
North America
Albert Einstein College of Medicine, Montefiore Medical Center, Bronx, NY. Hiltrud S. Mueller, MD; Mark H. Goldberger, MD; Mark A. Menegus, MD; Joseph Cosico, RN; Linda Kunkel, RN.

Albert Einstein Hospital, Bronx, NY. E. Scott Monrad, MD; Ira S. Blaufarb, MD; Jeffrey T. Shapiro, MD; William Gotsis, MD; Beth Spinogatti, RN.

Downstate University Hospital/SUNY, Brooklyn, NY. Tak Kwan, MD; Rosa Julien.

Nyack Hospital, Pearl River, NY. Richard Edelstein, MD; Amy Dachille, RN.

Brookdale Hospital, Brookdale, NY. Hal Chadow, MD; Lorraine Giarraffa, RN.

Winthrop University Hospital, Mineola, NY. Richard M. Steingart, MD; Suzanne E. Bilodeau, RN; Mary Ellen Coglianese, RN.

Mercy Medical Center, Rockville Centre, NY. Gary R. Friedman, MD; Agnes Bedor, RN; Joanne Scarlato, RN.

Central Suffolk Hospital, Riverhead, NY. Thomas Falco, MD; Katie Rush, RN; Cindy Zaleski, RN.

St. John's Queens Hospital, Elmhurst, NY. Gregory Macina, MD; Marie Kikel, RN; Marya Pier, RN.

Jamaica Hospital, Jamaica NY. Robert Mendelson, MD.

Brunswick Hospital, Amityville, NY. Mathew Chengot, MD; Patricia Eidenbach, RN; Kathy Morimando, RN.

Flushing Hospital, Flushing, NY. John Hsueh, MD; Dorren Heffernan, BA.

Rhode Island Hospital, Providence, RI. David O. Williams, MD; George McKendall, MD; Mary Jane McDonald, RN.

South County Hospital, Narragansett, RI. Steven Fera, MD; Bobby Fay, RN; Patricia Towle, RN.

Roger Williams Hospital, Providence, RI. Mark Travin, MD; Jean Fisk, RN.

University of Maryland Hospital, Baltimore, Md. Washington County Hospital, Hagerstown, Md. Gary Papuchis, MD; Deborah Chamberlain, RN; Sharon Etter, RN.

Mercy Medical Center, Baltimore, Md. Deborah Barbour, MD; Linda Goetz, RN.

Baystate Medical Center, Springfield, Mass. Marc J. Schweiger, MD; Barbara Burkott, RN; Deborah Warwick, RN.

Hennepin County Medical Center, Minneapolis, Minn. Timothy D. Henry, MD; Charlene Boisjolie, RN; Lorri Knox, RN.

Methodist Hospital, St Louis Park, Minn. J. Mark Haugland, MD; Ruth M. Slivken, RN.

United Hospital, St Paul, Minn. Kenneth Baran, MD; Roseann Pitzen Kolb, RN.

Fairview Riverside Hospital, Minneapolis, Minn. Timothy D. Henry, MD; Mary Maier, RN.

Krannert-Indiana University Hospital, Indianapolis, Ind. Wishard Memorial Hospital, Roudebush VA Hospital, Indianapolis, Ind. Robert Wilensky, MD; Laura Perkins, RN.

Henry County Memorial Hospital, New Castle, Ind. Cloyd C. Dye, MD; Laura Perkins, RN.

University of Massachusetts Medical School, Worcester, Mass. Richard C. Becker, MD; Steven P. Ball, RN.

St Vincent's Hospital, Worcester, Mass. Richard L. Bishop, MD; Tammy Brunelle, RN; Patricia Arsenault, RN.

Robert Wood Johnson Medical School, Brunswick, NJ. Sebastian Palmeri, MD; Laurie Casazza, RN.

Hunterdon Medical Center, Flemington, NJ. Austin Kutscher, Jr, MD; Janet McMahon, RN.

Jackson Memorial Hospital/University of Miami, Miami, Fla. Rafael Sequeira, MD; Pura Teixeiro.

Veterans Affairs Medical Center, Miami, Fla. Simon Chakko, MD.

Sarasota Memorial Hospital, Sarasota, Fla. Martin Frey, MD; Mary Healy, RN.

St Luke's/Roosevelt Hospital Center, New York, NY. Judith Hochman, MD; Angela Palazzo, MD; Mary McAnulty, RN.

Roosevelt Hospital Center, New York, NY. Anthony Pepe, MD; Robert Leber, MD; James Slater, MD.

Kaiser Permanente Medical Center, Los Angeles, Calif. Peter Mahrer, MD; Robert Browning, RN; Joni Noceda, RN. Kaiser coordinator: Robert Browning, RN. Kaiser Panorama City Medical Center, Panorama City, Calif. Terry Talkin, MD; Robert Browning, RN; Joni Noceda, RN. Kaiser Permanente Medical Center, Woodland Hills, Calif. Kathleen Ryman, MD; Robert Browning, RN.

LDS Hospital, Salt Lake City, Utah. Jeffrey L. Anderson, MD; Labros Karagounis, MD; Ann Allen, RN.

Utah Valley Regional Medical Center, Provo, Utah. Charles Dahl, MD; Mary Saldutte, RN.

Alta Bates Medical Center, Berkeley, Calif. Robert Greene, MD; Eileen Healy, RN; Vickie Perry.

Hospital of the University of Pennsylvania, Philadelphia, Pa. Joseph McClellan, MD; Kimberly Craig, RN.

Doylestown Hospital, Doylestown, Pa. James Kmetzo, MD; Dawn Shaddinger, RN.

University of Alabama, Birmingham, Ala. William J. Rogers, MD; Douglas J. Pearce, MD; Terri Morgan, RN; Vicki Bannister, RN.

Montgomery Regional Medical Center, Montgomery, Ala. Jackson Hospital and Clinic, Montgomery, Ala. Paul B. Moore, MD; Mark Platt, RN; Gena Henderson, RN.

Baptist Medical Center, Montgomery, Ala. Paul B. Moore, MD; Mark Platt, RN; Gena Henderson, RN.

Miriam Hospital, Providence, RI. Ara Sadaniantz, MD; Betsy Staples, RN.

Sturdy Memorial Hospital, Attleboro, Mass. Charles Peter Rogers, MD; Susan Nordstrom, RN.

Brigham and Women's Hospital, Boston, Mass. James M. Kirshenbaum, MD; Jill Cloutier, BA.

South Shore Hospital, South Weymouth, Mass. Michael Hession, MD; Mary Lou Dorman, RN.

Sacre-Coeur Hospital, Montreal, Quebec, Canada. Donald Palisaitis, MD; Ginette Gaudette, RN; Jocelyn Foquette, RN.

University of Texas, Houston, Tex. Hermann Hospital, Houston, Tex. H. Vernon Anderson, MD; Lynette Weigelt, RN; Julie Manning, RN.

Lyndon B. Johnson General Hospital, Houston, Tex. H. Vernon Anderson, MD; Francis Thandroyen, MD.

Ohio State University Medical Center, Columbus, Ohio. Raymond Magorien, MD; Laurie McCloud, RN; AnnMarie Thomas, RN.

Mary Rutan Hospital, Bellefontaine, Ohio. Evan Dixon, MD; Ronda Neal, RN

University of North Carolina, Chapel Hill, NC. Marcus Williams, MD; Mary Jackson, RN.

Christiana Hospital, Newark, Del. Andrew Doorey, MD; Tracy Hanna, RN; Nancy Gale, RN.

Union Hospital, Elkton, MD. Andrew Doorey, MD; Tracy Hanna, RN.

Danbury Hospital, Danbury, Conn. Jonathan Alexander, MD; Alice Gegeny, RN.

Emerson Hospital, Concord, Mass. Steven Herson, MD; Gail Carey, RN.

Cedars-Sinai Medical Center, Los Angeles, Calif. Prediman K. Shah, MD; Mitchell Gheorghiu, MD.

Glendale Adventist Medical Center, Glendale, Calif. Rene Pidoux, MD; Lorraine Evangelista, RN; Jeanette Abundus, RN.

Columbia-Presbyterian Medical Center, New York, NY. Hal S. Wasserman, MD; Mark Warshofsky, MD; Kenneh Giedd, MD; Edith Escala, RN.

Albany Medical Center, Albany, NY. Andrew Macina, MD; Kim Edmunds, RN.

Michigan Heart and Vascular Institute/St Joseph Mercy Hospital, Ypsilanti, Mich. Kurt Holland, MD; Mary Adolphson, RN.

United Hospital, Grand Forks, ND. Noah Chelliah, MD; Carolyn Gray, BSN.

Merit Care Medical Center, Fargo, ND. Jack Crary, MD; Theresa Theige, RN.

Overlook Hospital, Summit, NJ. John J. Gregory, MD; Judy Romano, RN.

Presbyterian Hospital of Dallas, Dallas, Tex. Darryl L. Kawalsky, MD; Malou Arnold, RN.

Grandview Hospital, Sellersville, Pa. Paul Hermany, MD; Stephanie Smith, RN; Terry Krause, RN.

St Paul's Hospital, Vancouver, British Columbia, Canada. Christopher Thompson, MD; A. Ignaszewski, MD; J.G. Webb, MD; Brenda Mercier, RN; Margot Wilson, RN, BScN.

Washington University, St Louis, Mo. Paul Eisenberg, MD, MPH; Jef E. Faszholz, Jr, RN.

Jewish Hospital, St Louis, Mo. Patricia Cole, MD; Lynne Coulter, RN.

Trinity Mother Frances Hospital, Tyler, Tex. C. Fagg Sanford, MD; Greg Murphy, RPh, CCRC.

University of Pittsburgh/Presbyterian University Hospital, Pittsburgh, Pa. Oakland VAMC, Pittsburgh, Pa. Thomas Smitherman, MD; Mary Kay Margolis, BS.

St Elizabeth's Hospital, Brighton, Mass. Douglas W. Losordo, MD; Nanette Hallet, RN.

Milton Hospital, Milton, Mass. Scott Lutch, MD; Paula Danz, RN.

Hospital of the Good Samaritan, Los Angeles, Calif. Thomas L. Shook, MD; Lucille Junio, RN.

Nassau County Medical Center, East Meadow, NY. Israel Freeman, MD; Lisa Blantz, RN; Laura Teplitz, RN.

Quincy City Hospital, Quincy, Mass. Alan Berrick, MD; Lois Howry, RN.

Northwest Community Hospital, Arlington Heights, Ill. Burton L. Herbstman, MD; Nancy Beck, RN.

Iowa Heart Center, Des Moines, Iowa. David Gordon, MD; Dawn Stangl, RN.

Summit Medical Center, Oakland, Calif. Eden Medical Center, Castro Valley, Calif. San Leandro Hospital, San Leandro, Calif. David Anderson, MD; Les DeFacio, RN.

University of Tennessee Medical Center at Knoxville, Knoxville, Tenn. Stuart Bresee, MD; Faye Reynolds, RN.

New Britain General Hospital, New Britain, Conn. Milton Sands, MD; Pat Malone, RN.

Lincoln General Hospital, Lincoln, Neb. Sabyasachi Mahapatra, MD; Tam Mahaffey, RN; Linda Cahoon, RN.

Brotman Medical Center/University of California, LA, Culver City, Calif. Century City Hospital, Los Angeles, Calif. Westside Hospital/Cardiovascular Research Institute, Beverly Hills, Calif. Midway Medical Center, Los Angeles, Calif. Ronald P. Karlsberg, MD; Jill Stone, RN; Sonia Maccioni.

Germany
National clinical coordinating center: Klinikum Augustinum/Medizinische Klinik, Munchen, Germany. Lead investigator: Rainer vonEssen, MD.

Evangl. Krankenhaus Witten, Witten, Germany. Thomas Horacek, MD; S. Beckebaum, MD; M. Iasevoli, MD.

Stadt. Krankenhaus Munchen-Schwabing, Munchen, Germany. W. Doering, MD; F. Weißthanno.

Kreiskrankenhaus Boeblingen, Boeblingen, Germany. H. Nebelsieck, MD; Dr Wolff-Haibt.

Krankenhaus Itzehoe, Itzehoe, Germany. H.J. Schwarzkopf, MD.

Kreiskrankenhaus Rudolstadt, Rudolstadt, Germany. F. Meier, MD; S. Segel, MD.

Stadt. Krankenhaus Traunstein, Traunstein, Germany. G. Alber, MD; K. Schlotterbeck, MD.

Stadt. Krankenhaus Wolfsburg, Wolfsburg, Germany. Rolf Engberding, MD; B. Gerecke, MD.

Krankenhaus Trostberg, Trostberg, Germany. H.G. Biedermann, MD; Herbert Bruckmayer, MD.

St Franziskus-Hospital Koln, Koln, Germany. F.J. Schneider, MD; Research coordinator: S. Troost, MD.

Cartiaskrankenhaus Bad-Mergentheim, Mergentheim, Germany. H.D. Bundschu, MD.

Carl Thiem Klinikum Cohgus, Cohgus, Germany. J. Krull-Munch, MD.

Klinikum Karlsruhe, Karlsruhe, Germany. Helmut Mehmel, MD; Gerd Ringwald, MD.

Stadtisches Krankenhaus Neukolin, Berlin, Germany. Joachim Wagner, MD.

Krankenhaus Duren, Duren, Germany. Hansjorg Simon, MD.

Kreiskrankenhaus Wilhemstrasse, Hameln, Germany. Karl-Heinz Depping, MD; Wolfgang Muller, MD.

Kreisklinik Dachau, Dachau, Germany. A. Weber, MD.

Israel
National coordinating center: Tel-Aviv Sourasky University, Tel-Aviv, Israel. Lead investigator: Gabriel Barbash, MD; Hanoch Hod, MD; Yemima Nahum, RN.

Tel-Aviv Sourasky Medical Center, Tel-Aviv, Israel. Arie Roth, MD; David Sheps, MD; Tina Shamis, RN.

Beilinson Medical Center, Petach Tikva, Israel. Samuel Sclarovsky, MD; David Hasdai, MD.

Sheba Medical Center, Tel-Hashomer, Israel. Hanoch Hod, MD; Eliezer Kaplinsky, MD; Dov Freimark, MD; Zila Halevy, RN.

Western Galilee Hospital-Nahariya, Nahariya, Israel. Nathan Roguin, MD; Anatoli Krivilevich, MD.

Soroka Medical Center, Beer-Sheva, Israel. Alexander Battler, MD; Harel Gilutz, MD.

Rambam Hospital, Haifa, Israel. Haim Hammerman, MD; Eugenia Nikolsky, MD.

Assaf Harofeh Hospital, Tzrifin, Israel. Zvi Schlesinger, MD; Hedy Faibel, MD.

Carmel Medical Center, Haifa, Israel. Avraham Palant, MD; Chen Shapira, MD.

Hadassah University Hospital, Jerusalem, Israel. Yonathan Hasin, MD; Doron Zahger, MD; Deborah Ben-Zvi, RN.

Kaplan Hospital, Rehovot, Israel. Avraham Caspi, MD; Oscar Kracoff, MD.

Hillel-Yaffe Medical Center, Hadera, Israel. Benny Pelled, MD; Jamal Agbaria, MD.

Bikur Cholim Hospital, Jerusalem, Israel. Shmuel Gottlieb, MD; Andre Keren, MD.

Meir General Hospital, Kfar-Saba, Israel. Daniel David, MD; Hana Pauzner, MD.

Shaare Zedek Medical Center, Jerusalem, Israel. Dan Tzivoni, MD; Jonathan Balkin, MD.

United Kingdom
National clinical coordinating center: Royal Brompton National Heart and Lung Hospital, London, England. Lead investigator: Kim Fox, MD; Deven Patel, MD; Christine Wright.

Birmingham Heartlands Hospital, Birmingham, England. R. Gordon Murray, FRCP; S. Balaji, MRCP; J.M. Beattie, FRCP.

Royal Gwent Hospital, Gwent, England. John Davies, MD; Mohammed Jarved, MD.

St Peter's Hospital-Chertsey, Chertsey, England. Michael Joy, MD; Julie Gardner, RN.

Royal Alexandra Hospital, Paisley, Scotland. Iain Findlay, MD; Sandra McMillan, RN.

Chelsea & Westminister Hospital, London, England. Kim Fox, MD; Ben King, RN.

Hillingdon Hospital, Uxbridge, England. George Sutton, MD; Anne-Marie Ellison, RN.

Northern General Hospital, Sheffield, England. Stephen Campbell, MD; Rose Ecob, RN.

Poole Hospital, Poole, England. Principal Investigator: Andrew McLeod, MD; Brenda Howarth, MBChB.

North Middlesex Hospital, London, England. Thomas Crake, MD; Bernadette Denehy, RN.

St Mary's Hospital, Portsmouth, England. John Watkins, MD; Jane Lowe, RN.

Received May 7, 1996; revision received June 6, 1996; accepted June 19, 1996.


*    References
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 *References
 

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