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JACC Vol. 31, No. 7 1493 June 1998:1493–8

Randomized Comparison of Direct Thrombin Inhibition Versus Heparin in Conjunction With Fibrinolytic Therapy for Acute Myocardial Infarction: Results From the GUSTO-IIb Trial

BRIAN K. METZ, MD, HARVEY D. WHITE, DSC,* CHRISTOPHER B. GRANGER, MD,† R. JOHN SIMES, MD,‡ PAUL W. ARMSTRONG, MD,§ JACK HIRSH, MD,࿣ VALENTIN FUSTER, MD, PHD, FACC,¶ CYNTHIA M. MACAULAY, MS,† ROBERT M. CALIFF, MD, FACC,† ERIC J. TOPOL, MD, FACC, FOR THE GLOBAL USE OF STRATEGIES TO OPEN OCCLUDED CORONARY ARTERIES IN ACUTE CORONARY SYNDROMES (GUSTO-IIb) INVESTIGATORS Cleveland, Ohio; Auckland, New Zealand; Durham, North Carolina; Sydney, Australia; Edmonton, Alberta and Hamilton, Ontario, Canada; and New York, New York

Among .(0.004 ؍ Objectives. We sought to show that hirudin might interact 95% confidence interval [CI] 1.20 to 2.66, p differently with streptokinase (SK) and tissue-type plasminogen t-PA–treated patients, the rates were 10.9% with heparin and for ;0.68 ؍ activator (t-PA), which could reduce the incidence of death or 10.3% with hirudin (OR 1.06, 95% CI 0.81 to 1.38, p reinfarction at 30 days. treatment heterogeneity: chi-square 4.20, degrees of freedom [df] After adjustment for baseline differences between .(0.04 ؍ Background. In a large-scale trial of patients with acute coro- 1, p nary syndromes, hirudin provided modest benefit compared with thrombolytic groups, the rates were 9.1% for SK with hirudin, heparin. However, the interaction with thrombolytic agents was 10.3% for t-PA with hirudin, 10.5% for t-PA with heparin and not specifically assessed. 14.9% for SK with heparin (for treatment heterogeneity: chi- -suggesting that the beneficial treat ,(0.03 ؍ Methods. Patients with symptoms of acute myocardial infarc- square 4.5, df 1, p tion and electrocardiographic ST segment elevation were treated ment effect of hirudin was limited to the SK-treated patients. with thrombolytic therapy and randomly assigned to receive Conclusions. Hirudin interacts favorably with SK but not t-PA, hirudin or heparin. highlighting the importance of thrombin activity after SK therapy Results. A total of 2,274 patients received t-PA, and 1,015 and the potential for simulating the effects of a more potent received SK. Baseline characteristics were balanced by antithrom- fibrinolytic agent through direct antithrombin therapy. bin assignment. Among SK-treated patients, death or reinfarction (J Am Coll Cardiol 1998;31:1493–8) at 30 days occurred more often in those treated with adjunctive ©1998 by the American College of Cardiology heparin (14.4%) rather than hirudin (8.6%, odds ratio [OR] 1.78,

Since the results of the Global Utilization of Streptokinase and United States. This regimen provided a 15% relative reduction Tissue Plasminogen Activator [tissue-type plasminogen activa- in 30-day mortality compared with streptokinase (SK) and tor] (t-PA) for Occluded Coronary Arteries (GUSTO-I) trial either intravenous or subcutaneous heparin (2). No other were published in 1993 (1), accelerated t-PA combined with combination of a thrombolytic agent and an antithrombin intravenous heparin has become the thrombolytic regimen agent has since yielded an incremental survival benefit as great. used most often to treat myocardial infarction (MI) in the The major limitations of heparin, the standard antithrom- bin therapy, are that it works indirectly, requires antithrombin III as a cofactor and is ineffective against clot-bound thrombin From the Cleveland Clinic Foundation, Cleveland, Ohio; *Green Lane (3). Newer antithrombotic agents, such as hirudin (the proto- Hospital, Auckland, New Zealand; †Duke Clinical Research Institute, Durham, typic direct thrombin inhibitor), act against both free and North Carolina; ‡National Health and Medical Research Council Clinical Trials Centre, University of Sydney, Sydney, Australia; §University of Alberta, Ed- clot-bound thrombin and lack most of the qualities that can monton, Alberta and ࿣Research Centre, McMaster University, Hamilton, On- interfere with the action of heparin. The advent of these drugs tario, Canada; and ¶Cardiovascular Institute, Mount Sinai Medical Center, New raised the hope that their concomitant use would improve the York, New York. This study was supported by Ciba-Geigy, Summit, New Jersey and Boehringer Mannheim, Gaithersburg, Maryland. efficacy of SK (4–7). However, neither heparin nor any other Manuscript received September 26, 1997; revised manuscript received antithrombin agent has been shown, when combined with SK, February 17, 1998, accepted February 25, 1998. to improve 30-day survival (8,9). Address for correspondence: Dr. Eric J. Topol, The Cleveland Clinic Foundation, Department of Cardiology, Desk F-25, 9500 Euclid Avenue, SK remains the least expensive thrombolytic agent, and Cleveland, Ohio 44195. E-mail: [email protected]. enhancing its efficacy with adjuvant therapy would have signif-

©1998 by the American College of Cardiology 0735-1097/98/$19.00 Published by Elsevier Science Inc. PII S0735-1097(98)00138-7 1494 METZ ET AL. JACC Vol. 31, No. 7 ANTITHROMBIN AND THROMBOLYTIC COMBINATIONS June 1998:1493–8

patients were randomized to undergo coronary angioplasty or Abbreviations and Acronyms receive accelerated t-PA as in the GUSTO-I trial (2). AMI ϭ acute myocardial infarction The study medication (hirudin or heparin) was to be aPTT ϭ activated partial thromboplastin time infused for 3 to 5 days. The heparin doses were those used in ϭ CI confidence interval GUSTO-I (2): a 5,000-U intravenous bolus followed by an df ϭ degrees of freedom GUSTO ϭ Global Use of Strategies to Open Occluded Coronary infusion of 1,000 U/h, with no increase in infusion rate for Arteries in Acute Coronary Syndromes heavier patients. The hirudin dose was a bolus of 0.1 mg/kg MI ϭ myocardial infarction body weight followed by an infusion of 0.1 mg/kg per hour. The ϭ OR odds ratio activated partial thromboplastin time (aPTT) was measured SK ϭ streptokinase TIMI ϭ Thrombolysis in Myocardial Infarction before administration of study drug; at 6, 12 and 24 h and at t-PA ϭ tissue-type plasminogen activator least daily for the duration of the infusion. The study drug infusion rate was adjusted by use of a standard nomogram to maintain the aPTT between 60 and 85 s. Study drug infusion rates could be decreased (but not increased) in response to the icant public health and economic effects. The primary hypoth- measures at 6 and 12 h. esis of the current study was that hirudin might interact All patients were given chewable aspirin (160 mg) on differently with SK and t-PA, which could reduce the incidence presentation, followed by up to 325 mg of oral aspirin daily. of death or reinfarction at 30 days for one of these agents. This The use of all other medications and interventions was at the substudy was a prospective secondary analysis of the Global discretion of the attending physician. Use of Strategies to Open Occluded Coronary Arteries in End points. The primary end point was the composite Acute Coronary Syndromes (GUSTO-IIb) trial (10). incidence of death or nonfatal reinfarction within 30 days of enrollment. The 30-day rates of mortality, nonfatal reinfarc- Methods tion and a composite of death or reinfarction in the subgroup of patients with ST segment elevation were prospectively Patient population. The GUSTO-IIb trial enrolled 12,142 defined secondary end points of the GUSTO-IIb trial (10). patients with acute coronary syndromes, of whom 3,457 These end points also were assessed at 24 h because they would (28.5%) received thrombolytic therapy, either at the discretion reflect differences in outcomes between groups during infusion of the attending physician or within a randomized substudy of the study drug. In-hospital bleeding and selected 30-day (10,11). When patients were randomized to hirudin or heparin treatment, they were stratified by the presence of ST segment clinical outcomes were also assessed. elevation Ն1 mm in at least two contiguous leads associated Severe or life-threatening bleeding was defined as intracranial with chest discomfort within the previous 12 h. Of the 3,457 hemorrhage or bleeding that caused hemodynamic compro- patients who received thrombolytic agents, 3,052 were consid- mise requiring intervention. Moderate bleeding was defined as ered to meet the criteria for ST segment elevation and 405 spontaneous gross hematuria, hematemesis or a decline in Ͼ were not. Of these 405 patients who did not have initial ST hemoglobin 3 g/d if associated with observed blood loss or Ͼ elevation Ն1 mm, we included in our analysis those who had 4 g/dl if no bleeding site was identified. ST segment elevation Ն0.5 mm who received thrombolytic Statistical analysis. Statistical analyses included all ran- therapy within 6 h after enrollment. We excluded only 14 domized patients who met the criteria for inclusion in our patients who received both SK and t-PA from analysis. The substudy, according to the intention to treat principle. Com- resulting cohort used for all analyses therefore included 3,289 parisons of the treatment groups with regard to the primary patients, of whom 3,041 were stratified in the ST segment and discrete secondary end points were performed using the Ͻ elevation group and 248 were not. conventional chi-square test. All p values are two-tailed; p Patients were excluded from the GUSTO-IIb trial for active 0.05 was considered statistically significant. bleeding, a history of stroke, contraindication to heparin, renal A multivariable logistic regression model was used to assess insufficiency (serum creatinine concentration Ͼ2.0 mg/dl [177 the possibility of a specific thrombolytic–antithrombin interac- ␮mol/liter]), systolic blood pressure Ͼ200 mm Hg or diastolic tion after adjusting for baseline differences and, if found, to blood pressure Ͼ110 mm Hg, warfarin use at enrollment or investigate its effect on the composite of death or nonfatal childbearing potential. If a patient was enrolled and it was later reinfarction at 30 days. Variables included in this model were determined that the serum creatinine at enrollment had ex- age, gender, race, smoking status, hyperlipidemia, hyperten- ceeded 2.0 mg/dl, the study drug was discontinued. sion, diabetes, peripheral vascular disease, family history of In patients with ST segment elevation, after they were coronary artery disease, site of enrollment (inside or outside randomly assigned to hirudin or heparin therapy, the decision the United States), cardiac history, recent history of malig- to use thrombolytic therapy was made by the attending physi- nancy, height, weight, systolic and diastolic blood pressures, cian, as was the choice between an accelerated t-PA regimen or heart rate and Killip class (Table 1). Because this model was SK. A subset of patients eligible for thrombolysis was enrolled developed to adjust for baseline imbalances between the t-PA in the GUSTO-IIb direct angioplasty substudy (11), in which and SK groups, it also allowed us to compare t-PA and SK JACC Vol. 31, No. 7 METZ ET AL. 1495 June 1998:1493–8 ANTITHROMBIN AND THROMBOLYTIC COMBINATIONS

Table 1. Baseline Characteristics of Patients With ST Segment Elevation Myocardial Infarction According to Thrombolytic and Antithrombin Therapy t-PA Streptokinase Hirudin Heparin Hirudin Heparin (n ϭ 1,151) (n ϭ 1,123) (n ϭ 500) (n ϭ 515) Median age (yr) 61 62 65 64 Male gender 79% 79% 76% 73% White 94% 95% 97% 96% Current smoker 43% 43% 39% 41% Hypercholesterolemia 38% 39% 32% 34% Hypertension 39% 40% 34% 38% Diabetes 14% 17% 13% 17% PVD 6% 7% 8% 7% Family history of 40% 38% 37% 36% Figure 1. Odds ratios and 95% confidence intervals for the unadjusted CAD risk of death, reinfarction or death or reinfarction at 30 days with U.S. enrollment 44% 44% 10% 11% hirudin versus heparin treatment with SK (top) or accelerated t-PA Previous MI 16% 17% 16% 17% (bottom). Previous angina 48% 48% 43% 45% Previous CABG 5% 5% 4% 5% Previous CHF 2% 2% 2% 3% differ significantly at baseline (Table 1). However, patients Previous CVD 2% 2% 2% 1% Cancer diagnosed or 3% 2% 3% 3% treated with t-PA were younger and more often male, smokers treated within last or hypercholesterolemic than those treated with SK. Patients 5yr treated with t-PA also had more previous angina, and their Mean SBP (mm Hg) 130 130 130 130 Killip classification was less severe. Mean DBP 80 80 80 80 Within the SK group, hirudin treatment was associated with (mm Hg) a 34% relative reduction in 30-day mortality compared with Mean HR 74 74 72 73 ϭ (beats/min) heparin treatment (p 0.092) (Fig. 1). There was also a Mean height (cm) 171 171 170 170 relative reduction of 50% (p ϭ 0.007) in the rate of reinfarc- Mean weight (kg) 79 80 77 77 tion at 30 days with hirudin and a relative reduction of 40% in Killip class the incidence of the composite 30-day end point of death or I 90% 88% 87% 84% nonfatal reinfarction (p ϭ 0.004). Within the t-PA group, II 9% 11% 11% 14% treatment groups did not differ significantly at 30 days with III 1% 0.9% 1% 2% IV 0.4% 0.4% 0.4% 0.2% regard to rates of death, nonfatal reinfarction or the two combined. The test for an interaction between the thrombo- Data presented are percent of patients, unless otherwise indicated. CABG ϭ ϭ ϭ lytic and antithrombin agents yielded an unadjusted chi-square coronary artery bypass graft surgery; CAD coronary artery disease; CHF ϭ congestive heart failure; CVD ϭ cerebrovascular disease; DBP ϭ diastolic blood value of 4.20 (degrees of freedom [df] 1, p 0.04); that is, the pressure; HR ϭ heart rate; MI ϭ myocardial infarction; PVD ϭ peripheral treatment effect of hirudin was statistically different for the SK vascular disease; SBP ϭ systolic blood pressure; t-PA ϭ tissue-type plasminogen and t-PA groups. activator. At 24 h, patients fared better if they had received SK and hirudin than heparin (Fig. 2). There was a 49% relative reduction in mortality with hirudin (p ϭ 0.093). Hirudin was (with either hirudin or heparin) with regard to the composite also associated with an 89% relative reduction in the incidence end point. of reinfarction (p ϭ 0.013), but there were very few events. Similarly, hirudin was associated with a relative reduction of 61% (p ϭ 0.009) in the incidence of the composite end point Results of death or nonfatal reinfarction at 24 h. Within the t-PA Patient treatment groups. Of the 2,274 patients treated group, patients treated with heparin or hirudin did not differ with t-PA, 1,919 received t-PA rather than SK at the discretion significantly with regard to the 24-h end points. of their physicians, and another 355 patients were randomized Moderate bleeding occurred more often with t-PA than to receive t-PA as part of the direct angioplasty substudy. Of with SK treatment and least often in patients who received these 2,274 patients, 1,151 had been randomized to receive SK and heparin (Table 2). However, patients treated with SK hirudin and 1,123 to receive heparin. Of the 1,015 patients with heparin were the most likely, and those treated with treated with SK, 500 had been randomized to receive hirudin SK with hirudin were the least likely, to have severe bleeding. and 515 to receive heparin. With either antithrombin agent, SK yielded a lower rate for the Within either thrombolytic group, patients assigned to combination of moderate or severe bleeding than did t-PA. In receive heparin and those assigned to receive hirudin did not the SK group, fewer hemorrhagic strokes were seen in patients 1496 METZ ET AL. JACC Vol. 31, No. 7 ANTITHROMBIN AND THROMBOLYTIC COMBINATIONS June 1998:1493–8

Figure 3. aPTT time at 6, 12 and 24 h after enrollment in patients who Figure 2. Odds ratios and 95% confidence intervals for the unadjusted received (from left to right) t-PA and hirudin; t-PA and heparin; SK ϭ risk of death, reinfarction or death or reinfarction at 24 h with hirudin and hirudin; or SK and heparin. Box plots: top horizontal lines 75th ϭ ϭ versus heparin treatment with SK (top) or accelerated t-PA (bottom). percentiles; intermediate horizontal lines medians; bottom lines 25th percentiles; vertical lines above and below boxes ϭ 95% confi- dence interval. treated with heparin than in those given hirudin (although event rates were very low). Differences among the four groups patients treated with hirudin (1.6% vs. 0.6%, p ϭ 0.12). Among in bleeding complications were not statistically significant, nor patients receiving t-PA, there were no significant differences were differences in bleeding outcomes by antithrombin agent between treatment groups with regard to any of these out- within each thrombolytic group. comes. The incidence of congestive heart failure did not differ At 6 h after thrombolytic therapy began, within each by antithrombin agent within the thrombolytic groups. thrombolytic group the median aPTT was significantly longer Analysis. A multivariable regression model was applied to for those treated with heparin than for those treated with adjust for known imbalances in baseline characteristics be- hirudin (Fig. 3). However, within each thrombolytic group the tween the t-PA and SK groups. After adjustment, the risk of median values at 12 and 24 h were shorter for those treated the composite 30-day end point of death or nonfatal reinfarc- with heparin than with hirudin. Over the first 24 h, aPTT values tion was similar in three groups: patients treated with SK and varied less overall in patients treated with hirudin. For hirudin, hirudin (9.1%), those treated with t-PA and hirudin (10.3%) there was considerably less variability from the 25th and 75th and those treated with t-PA and heparin (10.5%). However, percentiles at 6, 12 and 24 h, as shown in Figure 3. Ninety-four the risk was significantly lower in patients treated with SK and percent of patients in this substudy did have an MI by cardiac hirudin than with SK and heparin (9.1% vs. 14.9%, odds ratio enzyme levels. All patients classified as having reinfarction did [OR] 0.57, 95% confidence interval [CI] 0.38 to 0.87, p ϭ have an MI by measurement of enzyme levels on presentation. 0.009, a relative reduction of 39%). The adjusted 30-day rate of Among patients treated with SK, cardiogenic shock oc- death or nonfatal reinfarction for t-PA and hirudin treatment curred less often with hirudin than with heparin treatment (10.3%) was similar to that for t-PA and heparin treatment (4.8% vs. 7.2%, p ϭ 0.11) (Table 3). Similarly, recurrent (10.5%, p ϭ 0.91, OR 0.98, 95% CI 0.74 to 1.30). The ischemia occurred less often in patients treated with hirudin (21.2% vs. 25.4%, p ϭ 0.11), as did refractory ischemia (7.2% vs. 10.9%, p ϭ 0.04). However, stroke occurred more often in Table 3. Clinical Outcomes at 30 Days in Patients With ST Segment Elevation Myocardial Infarction According to Thrombolytic and Antithrombin Therapy* Table 2. In-Hospital Bleeding Complications of Patients With ST t-PA Streptokinase Segment Elevation Myocardial Infarction According to Thrombolytic and Antithrombin Therapy* Hirudin Heparin Hirudin Heparin (n ϭ 1,151) (n ϭ 1,123) (n ϭ 500) (n ϭ 515) t-PA Streptokinase Cardiogenic shock 4.9% 5.0% 4.8% 7.2% Hirudin Heparin Hirudin Heparin Stroke 1.4% 1.3% 1.6% 0.6% (n ϭ 1,151) (n ϭ 1,123) (n ϭ 500) (n ϭ 515) CHF 9.4% 8.7% 10.1% 9.3% Moderate bleeding 9.0% 9.1% 7.6% 6.2% Recurrent ischemia 24.1% 24.3% 21.2% 25.4% Severe bleeding 1.4% 0.8% 0.6% 1.6% Refractory 8.7% 8.9% 7.2% 10.9% Moderate or severe 10.3% 9.7% 8.0% 7.6% ischemia bleeding *Data not complete for European patients; the denominators for this Hemorrhagic 0.7% 0.7% 0.6% 0.2% outcome are 628, 608, 198 and 225 for tissue-type plasminogen activator stroke (t-PA)–hirudin, t-PA–heparin, streptokinase–hirudin and streptokinase– *p ϭ NS for all comparisons. Data presented are percent of patients. t-PA ϭ heparin, respectively. Data presented are percent of patients. CHF ϭ congestive tissue-type plasminogen activator. heart failure. JACC Vol. 31, No. 7 METZ ET AL. 1497 June 1998:1493–8 ANTITHROMBIN AND THROMBOLYTIC COMBINATIONS interaction between antithrombin treatment and thrombolytic generation more than t-PA, and thrombin generation was agent was significant (chi-square 4.5, df 1, p ϭ 0.03). completely halted by the addition of hirudin to SK in the test medium. A substudy of 293 patients in the GUSTO-I trial (17) showed a greater increase in thrombin–antithrombin com- Discussion plexes after SK than t-PA, consistent with the hypothesis that Subgroup analysis. The present subgroup analysis of pa- SK exposes more thrombin than t-PA. These data, which show tients treated with thrombolytic therapy for acute myocardial greater amounts and activity levels of thrombin after SK than infarction (AMI) in the GUSTO-IIb trial reveals a beneficial t-PA, provide a pathophysiologic rationale for our findings. effect of hirudin with SK but not t-PA. As an adjunct to SK, Of five previous studies of SK and direct thrombin inhibi- hirudin resulted in a lower combined incidence of death and tion (4–7,18), only one did not show improvement in rates of nonfatal reinfarction than did heparin, both at 24 h and at 30 death and reinfarction with direct thrombin inhibitors. In that days. However, as an adjunct to t-PA hirudin did not differ trial, the Thrombolysis and Thrombin Inhibition in Myocardial significantly from heparin in its effects on these composite end Infarction (TIMI-9B) study (18), 1,496 patients were randomly points. The interaction between the antithrombin and throm- assigned to receive heparin and 1,506 hirudin, at dosages bolytic agents with regard to the prevention of death and similar to those used in GUSTO-IIb. These patients also reinfarction at 30 days remained significant after adjustment received either t-PA or SK at the discretion of their physicians. for independent variables. The combination of SK and hirudin The incidence of the composite end point of death or nonfatal had the lowest adjusted 30-day rate of the composite end point reinfarction did not differ significantly by thrombolytic or of the four strategies (9.1%, an absolute reduction of 5.8% antithrombin agent. Analysis of the timing of study drug from the 14.9% rate with SK and heparin treatment). administration after thrombolysis suggests a reason for the Previous studies. Although potential mechanisms for im- significant benefits observed in GUSTO-IIb but not in TIMI- proved outcomes with hirudin as an adjunct to SK remain 9B. The study drug was given a mean of 35 min after uncertain, the results of an angiographic infarct-related vessel thrombolysis in GUSTO-IIb, and systemic thrombin activity patency trial with another direct thrombin inhibitor, hirulog has been shown (19) to peak 30 min after administration of SK (the Hirulog Early Reperfusion Occlusion [HERO] trial [6]) in patients with an AMI. The median time from randomization showed a significant increase in early (90 min) infarct-related to institution of study drug was 44 min in TIMI-9B, possibly vessel patency with hirulog compared with heparin among explaining why the additive benefit of hirudin with SK was not patients treated with SK. These data were corroborated by observed in that study. The patients in TIMI-9B who were another patency trial of hirulog in patients with an AMI (7). In treated with hirudin rather than heparin within 30 min of fact, the patency rates in both trials for SK with hirulog randomization did show a strong trend toward a lower rate of approximated that seen with accelerated t-PA with heparin in death or reinfarction than patients treated with either drug the GUSTO-I angiographic substudy (12). Two other random- after 30 min (20). This finding emphasizes that early treatment ized trials of SK and hirudin also have shown favorable results with hirudin or hirulog may be important to obtain maximal for this combination with respect to early infarct-related vessel benefit from these potent thrombin inhibitors (21). patency (5) and clinical end points (4). The direct thrombin inhibitors are the first antithrombin An angiographic substudy was not included in the GUSTO- agents to improve the outcomes of patients treated with SK. IIb trial, but the aforementioned trials suggest that improved Delayed subcutaneous heparin did not improve survival when early infarct-related vessel patency is the likely mechanism for used with either conventional t-PA or SK in the combined data improved outcomes in the patients treated with SK and from the Gruppo Italiano per lo Studio della Sopravvivenza hirudin. Additionally, the reduced rates of refractory ischemia, nell’Infarto Miocardico (GISSI-2) and the Third International recurrent ischemia and cardiogenic shock in patients so Study of Infarct Survival (ISIS-3) trials, which together in- treated, consistent with the reduced rate of the composite end cluded 62,000 patients treated for AMI. With the addition of point of death or nonfatal reinfarction, suggest improved blood subcutaneous heparin, there was no significant survival benefit flow in the infarct-related artery. Although the incidence of at 30 to 35 days, and there was an excess incidence of major bleeding complications did not differ significantly between bleeding, including an excess of about one cerebral hemor- hirudin and heparin, the slightly greater incidence of intracra- rhage per 1,000 patients treated (22–25). Similarly in the nial hemorrhage with hirudin (0.6% SK/hirudin vs. 0.2% GUSTO-I trial, no incremental benefit was shown for intrave- SK/heparin) is noteworthy and is consistent with more exten- nous than for subcutaneous heparin with SK; the mortality rate sive clot lysis. This hemorrhage rate is similar to that with t-PA in both groups was nearly identical at 30 days (2). Thus, the (0.7% for both hirudin and heparin) and improved when role for intravenous heparin as an adjunct to SK in AMI compared with the results of previous trials that used higher remains controversial (26). Although a recent meta-analysis doses of antithrombin agents (13–15). (27,28) of 26 randomized trials of anticoagulant therapy versus Thrombolytic therapy induces both thrombin generation control in suspected AMI has questioned the need to add (measured by prothrombin fragment 1.2) and thrombin activity heparin to a regimen of aspirin and any thrombolytic agent, (measured by fibrinopeptide A). A laboratory study by Brom- including t-PA, published guidelines (29) continue to recom- mer and Meijer (16) has shown that SK accelerates thrombin mend that heparin be used an adjunct to t-PA. 1498 METZ ET AL. JACC Vol. 31, No. 7 ANTITHROMBIN AND THROMBOLYTIC COMBINATIONS June 1998:1493–8

Study limitations. The limitations of the present study 10. The GUSTO IIb Investigators. A comparison of recombinant hirudin with heparin for the treatment of acute coronary syndromes. N Engl J Med relate to the use of a subgroup of patients for analysis (27.1% 1996;335:775–82. of the total enrollment of GUSTO-IIb), even though the 11. The GUSTO-II Angioplasty Substudy Investigators. A clinical trial compar- subgroup was specified in advance. The GUSTO-IIb trial was ing primary coronary angioplasty with tissue plasminogen activator for acute powered to detect a significant difference between the hirudin myocardial infarction. N Engl J Med 1997;336:1621–8. and heparin groups for the entire patient population, including 12. GUSTO Angiographic Investigators. The effects of tissue plasminogen activator, streptokinase, or both on coronary-artery patency, ventricular those with and without ST segment elevation MI. Because function, and survival after acute myocardial infarction. N Engl J Med patients were not randomized to receive t-PA or SK, com- 1993;329:1615–22. parisons between these thrombolytic agents must adjust for 13. GUSTO IIa Investigators. Randomized trial of intravenous heparin versus recombinant hirudin for acute coronary syndromes. Circulation 1994;90: differences in baseline characteristics. Although we used a 1631–7. multivariate logistic regression model to perform such adjust- 14. Antman EM. Hirudin in acute myocardial infarction: safety report from the ments, the comparison of the thrombolytic agents should be Thrombolysis and Thrombin Inhibition in Myocardial Infarction (TIMI) 9A regarded as exploratory. trial. Circulation 1994;90:1624–30. 15. Neuhaus K-L, van Essen R, Tebbe U, et al. Safety observations from the Conclusions. The results of the present analysis support pilot phase of the randomized r-Hirudin for Improvement of Thrombolysis the combination of the direct thrombin inhibitor hirudin and (HIT-III) study: a study of the Arbeitsgemeinschaft Leitender Kardiologis- SK as a promising alternative to the current standard therapy cher Krankenhausarzte (ALKK). Circulation 1994;90:1638–42. of t-PA with heparin. The more potent, direct thrombin 16. Brommer EJP, Meijer P. Thrombin generation induced by the intrinsic or extrinsic coagulation pathway is accelerated by streptokinase, independently inhibitors may improve clinical outcomes with SK, a less of plasminogen. Thromb Haemostas 1993;70:995–7. effective agent than t-PA when used with intravenous heparin 17. Granger CB, Becker R, Tracy RP, et al. Thrombin generation, inhibition, (2). 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