A randomized trial of intravenous heparin in conjunction with anistreplase (anisoylated plasminogen streptokinase activator complex) in acute myocardial infarction: The Duke University clinical cardiology study (DUCCS) 1

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A Randomized Trial of Intravenous Heparin in 12 J 11action With (Anisoylated Plasminogen Streptokinas Activator Complex) in Nuae Myocardial Infarction : The Duke University Clinical Cardiology Study (_1J_CCS) I CHRISTOPHER M . O'CONNOR, MD, FACC, RODERICK MEESE, MD, FACC, ROBERT CARNEY, MD, FACC, JACK SMITH, MD, FACC, ERIC CONN, MD, FACC, JOHN BURKS, MD, FACC, CARL HARTMAN, MD, FACC, STEVE ROARK, MD, FACC, NEAL SHADOFF, MD, FACC, MAURICE HEARD III, MD, FACC, BRANT LITTLER, MD, GARY COLLINS, MD, FACC, FRANK NAVETTA, MD, FACC, JEFF LEIMBERGER, PHD, KERRY LEE, PHD, ROBERT M . CALIFF, MD, FACC, FOR THE DUCCS GROUP* Durham, North Carolina

Objectives . We designed a randomized trial to evaluate the effects of heparin administration in conjunction with anistreplase (anisoylated plasminogen streptokinase activator complex [AFSACD on arterial patency and clinical end points . Background. The role of conjunctive intravenous heparin therapy with APSAC has not been tested despite the recommendations that intravenous heparin should be used . Methods Four hours after APSAC administration, 2,50 patients with acute myocardial infarction were randomly assigned to receive 325 mg of either aspirin alone or aspirin and a continuous infusion of hemdn (15 IU&g boody weight per h) . Clinical ischemic events and bleeding complications were monitored . On hospital day 5, coronary arteriography and left ventriculography were performed. Results . The primary end point of the trial (the combined outcome of death, reinfarction, recurrent ischemia and occlusion of the infarct-related artery) occurred in 42% of the heparin-treated group versus 43% of the group treated without heparin (p = 0 .94).

A patent artery was present in 80% of the patients treated with heparin and in 73% of those treated without heparin (p = 0.26) . Left ventricular function, as measured by ejection fraction, was well preserved in both groups (52% vs . 50.5%, respectively, p = 0.29) . The overall bleeding rate was higher in patients with (32%) than without (17 .2%) heparin (p = 0.006) . Conclusions. Weight-adjusted intravenous heparin therapy after APSAC in acute myocardial infarction does not reduce the combined incidence of death, reinfarction, recurrent ischemia and xcluslon of the infarct-related artery . Furthermore, withholding intravenous heparin therapy is associated with a 46% reduction in bleeding complications . Our findings do not support the addition of intravenous heparin after APSAC therapy, as currently recommended, and suggest that a strategy of withholding heparin is simpler and safer and does not place the patient at increased risk for ischemic complications after myocardial infarction . (J Am Coll Cardiol 1994,23 :11-8)

Cardiologists in the United States routinely use heparin as conjunctive therapy after thrombolysis in the setting of acute myocardial infarction (1). Three lines of evidence support

this pract,,ce . 1) Subcutaneous heparin reduces the risk of in-hospital death, reinfarction and other thromboembolic events when given with streptokinase and recombinant tissue-type plasminogen activator (rt-PA) (2-6) . 2) Arterial patency is maintained more completely when intravenous heparin is administered with rt-PA (7-9) . Unfortunately, there is no convincing evidence for better clinical outcome, although ongoing studies are addressing this issue (10-14) . 3) Heparin suppresses markers of ongoing thrombosis that are increased early after thrombolytic therapy regardless of the agent used (15) . APSAC (anisoylated plasminogen streptokinase activator complex), or anistreplase, is a thrombolytic agent with a marked effect on the coagulation system, as evidenced by profound fibrinogen depletion and increased fibrinogen degradation products, with their associated antiplatelet and

From the Division of Cardiology, Department of Medicine and Division of Biometry, Department of Community and Family Medicine, Duke University Medical Center . Durham, North Carolina . This study was supported by Research Grants HS-05635 and HS-06503 from the Agency for Health Care Policy and Research . Rockville . Maryland and grams from the Robert Wood Johnson Foundation, Princeton, New Jersey ; the DUCCS Reseal Foundation, Durham, North Carolina ; and Upjohn/Smithkfine Beecham Pharmaceuticals, Philadelphia, Pennsylvania . *See Appendix for a complete list of the investigators and personnel for DUCCS . Manuscript received January 25, 1993 ; revised manuscript received August 2, 1993, accepted August 4, 1993 . Address for correspondence: Dr. Christopher M . O'Connor, Duke University Medical Center, Box 3356, Durham, North Carolina 27710 . 01994 by the American College of Cardiology

0735-1097194IS6 .00



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O'CONNOR ET AL . HEPARIN AFTER APSAC IN MYOCARDIAL INFARCTION

antithrombin effects (16-25) . Initial studies, including a large mortality trial that proved the clinical benefits of anistreplase, the APSAC Intervention Mortality Study (AIMS) (26,27), used intravenous heparin starting 6 h after the administration of APSAC despite a lack of evidence that heparin either improved clinical outcome or decreased coronary artery reocclusion . Moreover, the risk of bleeding secondary to heparin was not assessed carefully . Because the profound systemic lytic state might make heparin use with its attendant risks and complexity of administration unnecessary, we designed a randomized trial to evaluate the effects of heparin in conjunction with APSAC on arterial patency and clinical end points.

Methods Study patients . Between August 1990 and duly 1991, 250 patients presenting within 12 h of the onset of symptoms suggestive of an acute myocardial infarction were enrolled in this randomized trial . Patients <86 years of age were considered eligible if there was ST segment elevation of at least 0.1 mV in two or more contiguous electrocardiographic (ECG) leads . The inclusion of elderly patients and patients presenting relatively late after symptom onset was based on recent data indicating the benefit of thrombolysis in these patients (28) . Patients were excluded for the following reasons: need for heparin or long-term warfarin therapy ; contraindication to heparin therapy ; history of significant bleeding diathesis ; history of gastrointestinal and genitourinary bleeding within the previous 4 weeks ; history of cerebrovascular disease ; major surgery or biopsy within the previous 14 days ; cardiopulmonary resuscitation lasting >10 min within the previous 2 weeks ; severe trauma within the previous 6 months ; intracranial lesions ; uncontrolled hypertension, with a diastolic blood pressure >110 mm Hg or a systolic blood pressure > 180 mm Hg after treatment for pain and confirmed by two repeated measurements ; cardiogenic shock ; comorbid illness likely to limit life expectancy within the next 2 years ; previous treatment with streptokinase or APSAC ; diabetic hemorrhagic retinopathy ; pregnancy or childbearing potential ; inability to give informed consent . The expanded criteria of advanced age up to 85 years, presentation within 12 h, previous coronary artery bypass surgery, cardiopulmonary resuscitation lasting <10 min within the previous 2 weeks or mild to moderate hypertension allowed the inclusion of patients traditionally excluded in trials of thrombolytic therapy. All patients provided written informed consent. Institutional Review Board approval was required before initiation of the protocol . Study design. Patients who met criteria for entry into the protocol were randomized by telephone to receive heparin or no heparin . Permuted block randomization was used with a block size of eight . Because of concern about the efficacy of heparin in late-presenting patients, two strata were defined at the time of randomization : presentation within 6 h

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and between 6 and 12 h . Patients received 30 U of intravenous APSAC (anistreplase [Eminasel) for 2 to 5 min . All patients received 325 mg of aspirin orally (first dose preferably chewed) on presentation and daily thereafter . Concurrent beta-adrenergic blocking agent and nitrate therapy were encouraged . Patients randomized to heparin therapy received an infusion until 18 to 24 h before the elective cardiac catheterization on day 5 . The hospital course was monitored carefully for clinical outcome and bleeding complications . Coronary angiography was performed earlier than the 5th hospital day if clinically indicated because of recurrent isehemia or reinfarction . Cardiac catheter° lion . On achieving vascular access, a 3,000-U heparin bolus was administered to all patients . Biplane left ventriculography was performed first, followed by angiography of the noninfarct-related arteries with paired orthogonal views . Next, the infarct-related artery was injected, and the Thrombolysis in Myocardial Infarction (TIMI) flow grade was scored on the initial injection (29) . Management of the patient after the initial injection into the infarct-related artery was left to the discretion of the investigator . All cardiac catheterization angiograms were reviewed and analyzed at the angiographic core laboratory . Angiograms were interpreted without knowledge of the treatment assignment . The primary angiographic end point was the assessment of patency of the infarct-related coronary artery . Patency was defined as TIMI flow grade 2 or 3, and occlusion was defined as TIMI flow grade 0 or 1 (29) . Angiographic core laboratory readings were used in the final analysis . The variables interpreted visually included percent lumen diameter narrowing at the infarct lesion location and TIM[ flow grade into the coronary bed distal to the irfarct site. The infarct-related artery segments remote to the infarct lesion and noninfarct-related arteries were graded visually as to the presence or absence of significant stenusis . The aforementioned assessments were repeated after any mechanical intervention at the infarct site . Global left ventricular ejection fraction and regional wall motion were determined using the centerline regional wall motion analysis method (30,31) . And coagulation . For patients who were randomized to receive heparin (CUSP, heparin, Upjohn Company), an infusion of 15 lUIkg body weight per h of heparin was started 4 h after the administration of APSAC and continued for 24 h . Adjustments were allowed in the 1st 24 h only if the activated partial thromboplastin time (aPTT) was <50 s . After the 1st 24 h of heparin administration, heparin was monitored by the aPTI' and adjusted to maintain anticoagulation between 50 and 90 s using weight-adjusted methods . Heparin was discontinued 18 to 24 h before day 5 of cardiac catheterization to minimize access site bleeding complications . To carefully monitor the degree of anticoagulation, the WIT was measured every 6 h for the 1st 24 h, then every 12 h.



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Management of bleeding complications. Recommendations for the management of bleeding complications were standardized but ultimately left to the discretion of the investigator. Transfusion with packed red blood cells was withheld unless the following conditions were met, 1) documented hematocrit !525% in a patient who was stable hemodynamically, and 2) hemodynamic instability not responsive to crystalloid infusion, with clinical evidence of significant blood loss regardless of measured hematocrit . If significant hemorrhage occurred within 24 to 48 h after administration of thrombolytic therapy, the standardized strategy, as described previously by Sane et al . (32), was instituted . Definitions . Important clinical outcomes were prospectively defined . Stroke was defined as an acute neurologic deficit resulting in death or lasting >24 h, which was confirmed by a neurologist and a computed tomographic scan of the head, nuclear magnetic resonance imaging or autopsy . Reinfarction was defined as a second elevation in serum cardiac enzyme. levels more than two times the previous trough level after the 16th hour sample . If enzyme levels were not available, typical symptoms and ECC changes were required . Congestive heart failure was defined as pulmonary edema on chest radiograph, rales more than basilar or an S3 gallop with the requirement of additional diuretic therapy over pretreatment requirements . Recurrent ischemia was symptomatic (chest, neck or arm ischemic pain), with new ST segment changes, a deep T wave inversion on the ECG, new hypotension, pulmonary edema or a holosystolic murmur with symptoms of ischemia . Bleeding complications were assessed using the Thrombolysis and Angioplasty in Myocardial Infarction (TAW) bleeding criteria (33) . Life-threatening bleeding was defined as an intracranial hemorrhage or internal bleeding (gastrointestinal, genitourinary, retroperitoneal or perivascular) that catsed sustained hypotension (systolic blood pressure <90 mm Hg for >1 h). Severe bleeding wa.- defined as gastrointestinal, genitourinary, retroperitoneal or perivascular bleeding with >500 ml of observed blood loss requiring blood transfusion to improve the clinical condition . Moderate bleeding was defined as superficial gastrointestinal, genitourinary, retroperitoneal or perivascular bleeding with an observed blood loss of 250 to 500 ml without the requirement for blood transfusion other than to augment the hema tocrit. Mild bleeding was defined as bleeding of no clinical consequence, not requiring a transfusion and with <250 ml of observed blood loss . End points. The primary end point of the study was a composite angiographic clinical assessment of coronary occlusionlischemia . The patient's treatment was recorded as a failure when angiographic coronary artery occlusion (TIM] flow grade 0 or 1) (30), reinfarction, recurrent ischemia or death occurred . Three important secondary end points were defined before the trial began: 1) a composite clinical morbidity end point that scored recurrent ischemia, congestive heart failure, reinfarction, stroke and death in rank order (12) ;

O'CONNOR ET AL . HEPARIN AFTER APSAC IN MYOCARDIAL INFARCTION

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Table t> Baseline Characteristics DF 11T, Two TreaImena Groups

Age (yr) >75 yr Men (%) Anterior Ml ( 17o) Symptoms to treatment (h) Baseline HR (beatsimin) Systolic BP (mm Hg) Diastolic BP (mm Hg)

Heparin (a = 123)

No Heparin in =1221

62 (52-69) 9 77 36 3 .2 (2 .2-43) 73 (62-85) 132 (117-150) 80 (70-92)

61 (52-68) 11 77 4.1 3 .0 (2 .2-4.3) 76 (64-86) 128 (112-143) 80 (69-90)

Numbers in parentheses are interquartile ranges . HP = blood pressure ; HR = heart rate ; MI = myocardial infarction .

2) hemmrrhLgic events (major and minor) ; and 3) ejection fraction (global and regional) . Statistical analysis. All end points were analyzed using the intention to treat principle . Because two enrolled patients did not have confirmation of acute myocardial infarction, a secondary analysis of patency included only patients with a documented myocardial infarction and an infarctrelated artery that could be identified . Discrete baseline variables were summarized as percents, whereas continuous variables were summarized as medians with 25th and 75th percentiles unless otherwise noted . Categoric outcome variables were compared between the treatment groups using chi-square methods or the Fisher exact test with appropriate confidence intervals constructed . Continuous efficacy and safety variables were compared using the Wilcoxon ranksum test . The in-hospital morbidity index and hemorrhagic scores were examined by ordinal logistic regression analysis . Sample size . On the basis of reported studies evaluating heparin, this trial was designed to be able to detect a reduction of 20% in the primary end point (30% in the treatment group vs . 50% in the control group) . Accordingly, with an alpha level of 0 .05 and a power of 0 .8, a sample size of 103 patients in each group was required . However, to define treatment differences in both primary and secondary end points with a greater degree of precision, the chosen sample size was 250 patients .

Results One hundred twenty-eight patients were randomized to receive heparin and 122 patients to receive no heparin . Two hundred thirty (92%) of the 250 patients were enrolled in the first stratum (between 0 and 6 h of presentation) and 20 patients ia the second stratum . The baseline characteristics and demographics of the patients (Table 1) were evenly distributed between the treatment groups . In patients assigned to the weight-adjusted intravenous heparin strategy, the blood was well anticoagulated at 24 h . The median aPTT at the 24-h point in the heparin group was 67 s versus 27 s in the no-heparin (p = 0 .001) . At 24 h, 10% of the patients assigned to receive heparin had an aPTT



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O'CONNOR ET AL . HEPARIN AFTER APSAC IN MYOCARDIAL INFARCTION

Table 2 . Perfusion Grades and Left Ventricular Function at Day 5 of Diagnostic Catheterization Heparin (%) (n = 117) TIMI flow grade 0 1 2 3 Patent infarct-related artery (TIMI flow grade 2 or 3) Stratum 0-6 h to treatment LV ejection fraction (%)

No Heparin (%) (n = 114)

p Value

11(6-16) 10(5-15) 40-9) 75(67-83) 80 (73-87)

15(7-21) 12(6-18) 8(3-13) 65(57-73) 73(65-81)

0.26

79(71-87) 52(46-60)

75(60-84) 50 .5 (43-59)

0.29

Numbers in parentheses represent 95% confidence limits for the point e stimate . LV = left ventricular; TIM[ = Thrombolysis in Myocardial Infarction trial .

>114 s, and 10% had an aPTT <38 s . Only 10% of the patients with no heparin had an >44 s at 24 h. By 48 h, the majority of heparin-treated patients had aPTT measurements in the desired range (88% vs . 18%, p = 0.0001) . Thirteen (9.9%) of 122 patients randomized to receive no heparin were treated with heparin for clinical indications, the majority (9 of 13) because of recurrent ischemia or hemodynamic instability . Two hundred thirty-one (92%) of the 250 patients underwent predischarge cardiac catheterization at a median of 4 .5 days . The angiographic outcomes are displayed in Table 2 . The overall patency (TIM[ flow grade 2 or 3) at day 5 cardiac catheterization was 77% . Eighty percent of patients in the heparin group had a patent infarct-related artery versus 73% in the no-heparin (p = 0 .26) . In the first stratum (presentation within 6 h) . the ratency was 79% in the heparin group and 76% in the no-heparin group . Clinical outcome is displayed in Tables 3 and 4 . Although

Table 3 . Clinical Outcome

Death By day 14 (%) Age s75 yr (%) Age >75 yr (%) Male (%) Female (%) Stroke (%) Hemorrhagic (%) Nonhemorrhagic (%) Reinfarction (%) Recurrent ischemia (%) CHF (%) Any of the five previous outrlmes (%) Primary end point failure nary occlusion, recurrent ischemia, Ml - path)

Heparin (n = 128)

No Heparin (n = 122)

9(4-14) 7(3-11) 31 (23-39) 4(1-7) 27(.20-34) 3(0-6) 1 .6(0-3 .8) 1 .6(0-3 .8) 7(3-11) 26(18-34) 30(22-38) 52(43-61) 42(33-51)

7(2-12) 10-3) 50(41-59) 2(0-4) 18(11-25) 0.8(0-2 .4) 0 0.8(0-24) 3(0-6) 24(16-32) 33(25-41) 50(41-59) 43(34-52)

Numbers in parentheses represent 95% confidence limits for the point estimate . CHF = congestive heart failure ; M1= myocardial infarction .

Table 4. Revascularization Procedures

CABG Emergency Urgent Elective Angioplasty Emergency Elective Any revascularization (FT . CA or CABG)

Heparin (%) (n = 128)

No Heparin (%) (n = 122)

4 4 7

4 2 7

14 18 43

14 27 54

CABG = coronary artery bypass grafting; PTCA = percutaneous transluminal coronary angioplasty .

all differences were small and not statistically significant, the trends were for fewer thromboembolic complications in the patients treated without heparin . The overall incidences of death, stroke and reinfarction were somewhat lower in this treatment group . The requirement for invasive procedures during the hospital stay was similar in both groups . Coronary artery bypass grafting was performed in 15% of patients treated with heparin and 13% of patients treated without heparin, and percutaneous transluminal coronary angioplasty was performed in 32% and 41% of patients, respectively, in the heparin and no-heparin groups (p = 0 .14) . The primary end point of the trial (the combined incidence of death, reinfarction, recurrent ischemia and occlusion of the infarct-related artery) occurred in 42% of the heparin group versus 43% in the no-heparin group (p = 0 .94) . When recurrent ischemia, the "softest" end point, was omitted from this analysis, there was still no difference between the groups (28% in the heparin vs . 30% in the no-heparin group) . No significant differences were found in the key secondary end points of composite clinical events (p = 0.46) or left ventricular function (Table 5) . Left ventricular ejection fraction was well preserved in both groups (52% vs . 50 .5%, p = 0 .29) . The overall rate of bleeding complications of greater than mild degree was higher in the heparin group (32%) than in the no-heparin group (17 .2%) (p = 0.006) (Table 6) . A sixfold reduction in life-threatening bleeding complications was observed in patients randomized to the no-heparin group (0 .8% vs . 4 .7%) . The transfusion rate was 23% in the heparin group and 16% in the no-heparin group (p = 0 .12) .

Table 5 . Composite Clinical End Point

Clinical

Rank*

Heparin (%) (n = 128)

No Heparin (%) (n = 122)

None CHF or recurrent ischemia Reinfarction Stroke Death

0 1 2 3 4

50 35 5 2 9

48 41 2 0 7

*Rank order: death, stroke, reinfarction, congestive heart failure (CHF) or new pulmonary edema or recurrent ischemia and none of these ; p = 0 .46 .



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Table 6. Bleeding Complications

Type of Bleeding Episode Moderate Severe Life-threatening Total patients with bleeding episodes (only most severe counted)

Heparin (%) W= Im 18 .8 8 .6 4 .7 32

No Heparin (n = 122)

Value

10 .7 5 .7 0.4 17 .2

0 .006

Discussion The most important finding of this study is that intravenous heparin added to a regimen of 325 mg of aspirin failed to reduce the combined incidence of recurrent ischemia, reinfarction, death and occlusion of the infarct-related artery after anistreplase therapy . Furthermore, the rate of significant bleeding was 46% lower in patients randomized to receive no heparin, and life-threatening bleeding was six times lower in this group . Baseline characteristics . The patients in this trial constituted a higher risk group than patients enrolled in previous angiographic trials evaluating the role of heparin therapy (7-11) . Patients with previous coronary artery bypass grafting and prolonged cardiopulmonary resuscitation were not excluded from the study and 10% of the patients were >75 years old, 25% were women, and 10% presented after 6 h of symptoms . The high risk composition of the patient group explains in part the high rate of bleeding and adverse clinical events in the patients who received heparin and underscores the importance of reduced bleeding in the patients with no heparin . Anticoaplation . Because subtherapeutic aPTT measurements have been associated with recurrent ischemia after administration of streptokinase and with low patency rates after treatment with rt-PA (34-38), we chose a heparin protocol that was adjusted to body weight and monitored every 12 h after the 1st 24 h. We also chose a range of anticoagulantt therapy that was higher (two to three times control) than that of previous heparin angiographic trials . The range of heparin anticoagulation most commonly desired by our investigators who were polled before the study was 50 to 90 s . Of importance, the majority of patients (88%) randomized to receive heparin had an aPTT in this range during the 1st 48 h compared with 18% of patients randomized to receive no heparin (p = 0 .0001) . All patients who underwent protocol-mandated cardiac catheterization in the absence of an urgent clinical indication had the heparin administration stopped 18 to 24 h before cardiac catheterization to avoid excessive access site bleeding . The frequency of events in this time period was small and not significantly different between the heparin (2 .41%) and the no-heparin (2 .3%) groups . These findings are similar to the results of the National Heart Foundation of Australia trial (11), in which there were no increased ischemic events

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after stopping heparin 24 h after the infusion of intravenous rt-PA . Paicacy . We found no significant difference in patency between the two study groups, and the difference in patency among those treated within 6 h of symptom onset was even smaller (79% vs . 75%) . Similarly, in patients treated with APSAC and intravenous heparin, Meinertz et al . ported a late (2-week) patency rate of 75%, and the patency rate in the Angiographic Patency Study in Myocardial Infarction (APSIM) study (38) at a median of 4 days was 77% . Early angiographic data suggest patency rates of 60% to 75% at 90 min and up to 907o at 24 to 48 h (39-41) . Clinical events . The 14-day mortality rate of 8% compares favorably with previously reported mortality rates of APSAC-treated patients (41,42) and with that of the heparin randomized mortality trials (2-4) . The mortality rate in this trial is due at least in part to the higher risk patients in our study: 10% of the patients were >75 years old, and they had an associated 40% mortality rate compared with 4% in younger patients . Elderly patients are known to have a higher baseline risk of death, partly because of the greater extent of their coronary artery disease and their propensity to experience mechanical and bleeding complications (43). The total stroke rate was 2% in this trial, which is comparable to that of previous studies with careful follow-up (44,45) . The rates of reinfarction and recurrent ischemia tended to be higher in the heparin group but overall rates were similar, as in previous studies (46) . There are several potential reasons for these findings . 1) Statistical chance must be considered given the small size of our study . 2) Patients randomized to receive heparin may experience intraplaque hemorrhage, causing further instability of the reperfused infarct-related artery and thus causing recurrent ischemia and reinfarction . 3) Patients randomized to receive heparin may actually have had a higher early patency rate and thus a greater risk for experiencing reinfarction and recurrent ischemia. This trend has been observed in several other studies (7,8) (Coe J, personal communication, November 1992) . 4) The procoagulant effects of heparin may become important in the postthrombolytic setting . 5) Heparin may cause thrombocytopenia, which enhances platelet agglutination . Bleeding complications and left ventricular function . Bleeding complications were carefully monitored and scored using the previously discussed TAMI criteria (33) . Although 50% of the patients in the trial experienced a bleeding complication, most cases were classified as mild . The overall rate of bleeding events was similar to those in previous thrombolytic trials with protocol angiography (7-11,33, 39,40,46-48) . The Heparin-Aspirin Reperfusion Trial study investigators (7) reported a lower rate of bleeding (12%) . However, Bleich et al . (8) reported a similar bleeding rate . The most common site of bleeding was at the access site in the femoral region . Genitourinary (17%) and gastrointestinal (5%) bleeding were also not infreque at . ir.iracranial hemorrhage occurred in two patients (1 .6%), both of whom

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received heparin therapy . Moderate, severe and lifethreatening hemorrhages were two times higher in the heparin group than in the no-heparin group, which is consistent with data from the Third International Study of Infarct Survival (4) and Gruppo Italiano per to Studio della Sopravvivenza nell'Infarto Miocardico (2) studies . The blood transfusion rate paralleled the bleeding rate and tended to be lower in the no-heparin group . Study limitations . Several design limitations of this study should be considered . 1) Most important, the size of the trial was not sufficient to detect small differences in perfusion or clinical event rates . Before the study we believed that 200 patients would be adequate to detect a significant reduction in recurrent ischemic events and infarct-related artery occlusion on the basis of differences found in published reports evaluating conjunctive heparin therapy with rt-PA (7-11) . To have adequate power to detect a difference of the magnitude that we observed (Table 2), > 1,500 patients with angiograms would have L-en required . 2) Neither the patients nor the medical staff members were unaware of the study treatment . All efforts were made to reduce bias by keeping the angiographic core laboratory unaware of the study treatment and by having the clinical monitors assess the hospital course and adverse events independently of the nurses and physicians conducting the study . The route and timing of heparin administration chosen for this protocol could be questioned . The heparin protocol was based on its nearly universal adaptation for clinical use, largely because the combination of APSAC and heparin successfully reduced mortality compared with conservative care in the AIMS trial and because it was adopted in all other clinical trials evaluating APSAC (26,27,39-41) . Alternative heparin regimens could have ranged from immediate intravenous heparin with a bolus to delayed subcutaneous heparin . Recent preliminary data suggest that reperfusion may be hastened with a bolus of heparin with streptokinase, but within 2 to 3 h an effect on patency is not detectable (Coe J, personal communication, November 1992) . Although antithrombin therapy is important in preventing recurrent thrombotic occlusions after myocardial infarction, heparin as a specific agent has several limitations . Of most importance, the residual thrombus contains active thrombin bound to fibrin, which is not easily accessible to the large heparin antithrombin III complex . Furthermore, the platelet-rich arterial thrombus releases platelet factor 4 . Both platelet factor 4 and the fibrin II monomer, which is formed by the action of thrombin on fibrinogen, inhibit heparin (49-51) . Thus, different antithrombin agents used after APSAC may have resulted in different outcomes . In addition, the aPTT measurements were not performed at a core laboratory ; thus, these measurements may reflect site to site variability . Another limitation was the timing of the angiogram . We chose predischarge angiography because of our belief that sustained infarct-related artery patency is the critical issue (52) . If important differences in early patency were not detected because of the timing of angiography, they should

have been reflected by either better early clinical outcome or improved left ventricular function . We found evidence for neither in this study in the group assigned to routine administration of heparin . Finally, there may be select subsets of patients who could benefit from heparin therapy (i .e ., patients with mobile left ventricular thrombi or previous embolic events), which was not demonstrated in our study because of limited power. Conclusions . The current study provides evidence that the administration of intravenous heparin after APSAC therapy should not be routinely recommended . The longer half-life, systemic fibrinolytic activity, antiplatelet properties, as well as the viscosity-reducing properties of APSAC compared with other thrombolytic regimens, may protect the patient from reocclusion, particularly in the Ist 24 h after thrombolysis . thus making heparin administration unnecessary . Ohman et al . (53) found that most reocclusions after thrombolytic therapy occur within the I st 12 to 24 h (53) . and the results of the National Heart Foundation of Australia trial (11) suggest that the most important window for an antithrombotic effect to prevent reocclusion is within the 1st 24 h, when the primary effects of APSAC persist (11) . Given that heparin did not reduce ischemia or the presence of angiographic patency and was associated with higher bleeding and transfusion rates, there is little evidence from our trial to support its use after APSAC . Thus, our findings suggest that the routine addition of heparin to a regimen of 325 mg of aspirin after APSAC therapy, as currently recommended, may not be warranted . We thank Galen Wagner . MD . Gary Stiles, MD. Joseph C . Greenfteld, Jr., MD. and Eugene A. Stead. Jr ., MD for their full support and vision of the Duke University Clinical Cardiology Study Organization, and we dedicate this manuscript to the late Peter Maroko, MD for his lifetime commitment to the basic and clinical investigation of acute myocardial infarction . Without his strength and insight, this project would never have been completed . We also thank Renee Story for manuscript preparation .

Appendix

Investigators and Personnel for the Duke University Clinical Cardiology Study (DUCCS) Principal investigator: Roderick Meese . MD . Coinvestigators: Robert J . Carney, MD, Frank I . Navetla. MD, C . F. Sanford, MD. David M . Dick, MD. Randy Randall . MD. Kenneth Kummerfeld, MD . Research coordinator : Greg Murphy . RPh . Research assistants: Renee LeBoeuf, RPh . Shannon Spencer. CCRN . Principal investigator . Jack E . Smith, MD . Coinvestigators: James MacKrell, MD, Gordon P. Anderson, MD . Thomas M . Dugan, MD, Jeffrey A . Buetkofer. MD, Richard H . Heibel . MD, Joseph R . McClellan, MD, Jeffrey I . Blake, MD. Research coordinator: Patty (Pat) Henry . Principal investigator: Eric Conn . MD . Coinvestigators : Robert K . Berglund, MD . Noel C . Hunt 111, MD, Kinsman Wright, Jr., MD . Samuel Parker Ill . MD, James W . Hoback . Jr., MD . Research coordinator: Carol McWilliams, RN . Principal investigator: John Burks, MD . Coinvestigators: Joseph R . Calder, MD, Edward C . Keating, MD . Research coordinator: Jan Kirby, RN . Principal investigator: Carl W . Hartman . MD. Coinvestigators : Charles C . Ashby, MD . W. Andrew Dickinson. MD, Alan G . Barrel, MD, Thomas D .



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Call, MD, John G . Kenerson, MD, Joseph A . Robbins, MD, Jesse W . St . Clair, MD . John G. Griffin, MD, Edward C . Miller, MD, Wayne D . Old. MD . Research coordinator : Kaye Comninaki, Principal investigator: Steven Roark. MD . Coinvestigators : Gary R . Cooper. MD, Burton V . Silverstein, MD . Michael G . Dillon, MD . Research coordinator : Nancy Marquis, RN . Principal investigator : Neal Shadoff, MD . Coim estigalors : Barry Ramo, MD, Jerome E . Goss, MD, Gilbert L . Raff, MD . George F . L+atherman . MD . Kathleen Blake, MD . Research coordinators : Kelli Heimgartner, Ann Brown . Co-Principal investigators . Eric B . Carlson, MD, Maurice E . Heard Ill, MD, Garrett Rogers. MD . Coinvestigators : Douglas C . Privette, MD, Allen Oseroff, MD . Research coordinators : Susan Denton . RN . Pat Brewer, RN, Monica McKowan . Principal investigator : Brant Mittler, MD . Research coordinators : Kelly Warren, RN, Craig Horton, RN . Principal investigator : Gary J . Collins, MD . Coinvestigators : George M, Broderick, MD, Edmund Coyne, MD, Barry Feldman, MD, Howard Zeman . MD . Research coordinator : Dana Lowry, RN . Clinical investigations coordinator : Cherie Miller. Principal investigator: Kenneth Hanger, MD. Coinvestigator.• Joseph M . Kmonicek . Research coordinators: Martha Griebel. RN, Betsy Williams, RN, Principal investigator: Bruce Hettleman, MD . Subinvestigators : Bruce Friedman, MD, Mark Greenberg, MD, Ellis Rolett, MD, John Robb . MD, Edward Catherwood, MD . Robert Rokowski, MD, Carol Duffy, MD, Andrew Torkelsun, MD, Nathaniel Niles, MD, Jonathan Plehn, MD, Douglas James, MD, Peter Holzberger . Research coordinators : Cheryl Carlson . RN . Carol Moriarity, RN . Coinvestigators: Constantine Hassapoyannes, MD, William Nelson, MD . Coinvestigators : Donald E . Saunders, MD, Christie B . Hopkins, MD, Norma Khoury, MD. Alberta Saenz, MD, William Nelson, MD, Leon Khoury, MD, Joseph Henderson, MD, Floyd Burke, MD, John Hicks, MD . Research coordinators: Mya Kline, Michael Berbin . Coinvestigator: Jose Perez, MD. Coinvestigator: Hector VillaSenor, MD, Jesus G . Garcia . Research coordinator: Andrea Garca . Principal investigator : Donald Lilly, MD . Coinvestigators : William Carer, MD, Stafford Warren, MD, N . Andrew Vaughan, MD, Ronald McCowan, MD, Stephen McCormick, MD . Research coordinator : Susan Nolan, RN . Principal investigator : G . Ramon Aycock, MD . Coinvestigators : William S . Pickens, MD . W. Daniel Doty, MD, Edwin W . Rogers, MD, J . L . Trantham, MD, Charles P . Riley, MD. Research coordinator: Terri Wilcox . RN . Principal investigator : Thomas Trahey, MD . Research coordinator: Judy Taylor. RN . Principal investigator : Ricky Schneider . MD . Coinvestigators : Luis Orihuela, MD, Stanley E . Richter . MD . Research coordinators : Tricia Martin, RN, Karen Goetz, RN, Rena Eatherton, RPh . Principal investigator : Greg San, MD . Coin vestigator: Wiliam 1V . Pryor, MD. Research coordinator: Joan Keller, RN . Principal investigator: Allen A . Ciuffo, MD . Coinvestigators : Jack B . Taylor, MD, Glenn C . Nye, MD, John P. Parker, MD, Donald J . Lipskis, MD, Ronald A . Stine, MD, Martin J . Goldberg, MD . Thomas Klevan, MD, John M . Herre, MD . Robert Bernstein . MD . Research coordinators : Becky Danielson, Bill Wagner, Belinda Williams . Principal investigator: Dean Bramlet, MD. Coin vestigators : John Hoche, MD, Michael E . McIvor . M D . Research coordinator: Cheryl Heck-Martinez, PA-C. Coinvestigators : Paul Gurbel, MD, Arthur Perpall, MD . Coin vestiga tors : Andrew Ziskind, MD, J. Lawrence Stafford, MD . Research coordinators : Pat Colegrove, RN, Cindi Lemon, RN . Coinvestigators : Franklin C . Wefald, MD, Mark L . Smucker, MD . Coinvestigators : Paul Howard, MD, William Sarnet, MD, Daniel Scherb, MD . Research coordinator: Dianne Kil, RN . The DIJCCS Coordinating Center, Durham, North Carolina : Co-Principal Investigators : Christopher M. O'Connor, MD. Robert M . Califf, MD. Coordinators: Lisa Berdan, PA-C, Dave Rendall, PA-C . Monitors : Tammy Allen, RN, Kathi D . Lucas . Core ongiography laboratory : Jimmy Teheng, MD . Core electrocardiography laboratory : Galen Wagner, MD . Chief statistician : Kerry Lee. PhD, Statisticians : Lynn Woodlief, Jeff Leimberger . Assistant statistician : Gerri Roberts . Coordinating center administrator: Sharon Karnash . Financial officer: Jimmy Melton . The Upjohn Company : Garnett S. Huguley, BS, MT. Data Safety Monitoring Committee : Daniel B . Mark, MD, Chairman, Christopher Granger, MD, E . Magnus Ohman, MD, Robert M. Califf, MD,

O'CONNOR ET AL . HEPARIN AFTER APSAC IN MYOCARDIAL INFARCTION

17

Kerry L . Lee, PhD, Peter Maroko, MD, Robert Daly, PhD, Marcus Saltzman . MD.

References I . Gunnar RM, Bourdillon PDV . Dixon OW, et al . Guidelines for the early management of patients with acute myocardial infarction . A report of the American College of CardiologylAmerican Heart Association Task Force on assessment of diagnostic and therapeutic cardiovascular procedures (subcommittee to develop guidelines for the early management of patients with acute myocardial infarction) . . Am Coll Cardiol 1990 ;16 :249-92 . 2 . Gruppo Italian per to 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 19 ;336:65-70 . 3 . The International Study Group . In-hospital mortality and clinical course of 20,891 patients with suspected acute myocardial infarction randomized between alteplase and streptokinase with or without heparin . Lancet 1990 ;336 :71-5 . 4 . ISIS 3 4hird 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 1992:339:713-70 . 5 . The SCAT. (Studio sully Calciparina nell'Angina e nella Thrombosi Ventriculare nell'lnfarto) group . Randomised controlled trial of subcutaneous calcium-heparin in acute myocardial infarction . Lancet 1989 ;2: 182-6. 6 . Turpie AGG . Robinson JG, Doyle DJ, et al . Comparison of high-dose with low-dose subcutaneous heparin to prevent left ventricular mural thrombosis in patients with acute transmural anterior myocardial infarction . N Engl J Med 1989;320:352-7 . 7. Hsia J, Hamilton WP, Kleiman N, Roberts R, Chairman BR, Ross AM . A comparison between heparin and low-dose aspirin as adjunctive therapy with tissue plasminogen activator for acute myocardial infarction . N Engl J Med 1990 ;323 :1433-7. 8. Bleich SD . Nichols TC, Schumacher RR, Cooke DH . Tate DA, Teichman SL . Effect of heparin on coronary arterial patency after thrombolysis with tissue plasminogen activator in acute myocardial infarction . Am J Cardiol 1990 :66 :1412-7 . 9. de Bono DP . Simoons ML, Tijssen J, et al ., for the European Cooperative Study Group (ECSG) . Effect of early intravenous heparin on coronary patency, infarct size and bleeding complications after alteplase thrombolysis : results of a randomised double blind European Cooperative Study Group trial . Br Heart J 1992 :67 :122-8 . 10. Topol EJ, George BS, Kerciakes DJ . Stump DC . Candela RJ, Abbottsmith CW, and the TAMI 7 Group . A randomized controlled trial of intravenous tissue plasminogen activator and early intravenous heparin in acute myocardial infarction . Circulation 1989 ;79 :281-6 . 11 . Thompson PL, Aylward PE . Federman J, et al ., for the National Heart Foundation of Australia Coronary Thrombolysis Group. A randomized comparison of intravenous heparin with oral aspirin and dipyridamole 24 hours after recombinant tissue-type plasminogen activator for acute myocardial infarction . Circulation 1991 ;83 :1534-42 . 12. Cafiff RM, Harreison- oodlief L, Topol El . Left ventricular ejection fraction may not be useful as an end point of thrombolytic therapy comparative trials . Circulation 1990;82:1847-53 . 13 . Van de Werf F . Discrepancies between the effects of coronary reperfan sion on survival and left ventricular function . Lancet 1989:1 :1367-9 . 14. Topol F.J . Which thrombolytic agent should one choose'' Frog Cardiovasc Dis 199134:165-78 . 15 . Eisenberg PR . Miletich JP . Sobel BE, Jaffe AS . Differential effects of activation of prothrombin by streptokinase compared with urokinase and tissue-type plasminogen activator (t-PAL . Thromb Res 1988 :50 :707-17. 16. Monnasier JP (on behalf of the IRS Il Study Group), Hanssen M . Haematological effects of anisoylated plasminogen streptokinase activator complex and streptokinase in patients with acute myocardial infarction, interim report of the IRS II Study . Drugs 1997 ;33 Suppl 3 :247-52 . 17 . Smith RAG, Dupe RJ, English PD, Green J . Fibrinolysis with acylenzymes : a new approach to thrombolytic therapy . Nature 1981 :290: 505-8.



19

O'CONNOR ET AL . HEPARIN AFTER APSAC IN MYOCARDIAL INFARCTION

18 . Hulls WS, Hornung RS, Dunn FG . Coronary repetfusion following single

dose intravenous BRL .26921 . Br Heart J 1985 ;53 :178 . 19 . Bonnier HJRM, Visser RF, Klomps HC, Hoffmann H!ML, and the Dutch Invasive Reperfusion Study Group . Comparison of intravenous anisoylated plasminogen streptokinase activator complex and intracoronary ;62 :25-30. streptokinase in acute myocardial infarction . Am J Cardiol 1 . Anisoylated plasminogen streptokinase activator 20. Monk JP, Heel RC complex (APSAC). A review of its mechanism of action, clinical pharmacology and therapeutic use in acute myocardial infarction . Drugs 1 7; 34 :25-49. 21 . Been M, de Bono DP, Muir AL, et al . Clinical effects and kinetic properties of intravenous APSAC-anisoylated plasminogen--streptokiu se activator complex (BRL 26921) in acute myocardial infarction . Int 1 Cardiol 1986 ;11 :53-61 . 22. Hoffman JJML, Bonnier JJRM, de Swart JBRM, Custers P, Vijgen M . Systemic effects of anisoylated plasminogen streptokinase activator complex and streptokinase therapy in acute myocardial infarction . Drugs 1987 ;33 Suppl 3 :242-6 . 23. Brochier ML. Quillet L, Kulbertus H, et al . Intravenous anisoylated plasminogen streptokinase activator complex versus intravenous streptokinase in evolving myocardial infarction . Preliminary data from a randomised multicentre study . Drugs 1987 ;33 Suppl 3 :140-5. 24. Meinertz T . Kasper W, Schumacher M, Just H, for the APSAC Multicenter Trial Group . The German multicenter trial off anisoylated plasminogen streptokinase activator complex versus heparin for acute myocardial infarction . Am J Cardiol 1988 ;62 :347-51 . 25 . Hogg KJ, Gemmill JD, Bums JMA, et al . Angiographic patency study of anistreplase versus streptokinase in acute myocardial infarction . Lancet 1990 ;335:254-8. 26 . AIMS Trial Study Group . Effect of intravenous APSAC on mortality after acute myocardial infarction : preliminary report of a placebo-controlled clinical trial . Lancet 1 ;1 :545-9. 27. AIMS Trial Study Group . Long-term effects of intravenous anistreplase in acute myocardial infarction : final report of the AIMS Study . Lancet 1990;335 :427-31 . 28 . Grins CL, DeMaria AN . Optimal utilization of thrombolytic therapy for acute myocardial infarction : concepts and controversies . J Am Coll Cardiol 1990;16 :223-31 . 29. TIMI Study Group. The thrombolysis in myocardial infarction (TIMI) trial . Phase I findings. N Engi J Med 1985:312:932-6. 30. Sheehan FH, Dodge HT, Bolson EL . Hok-Wai W, Caputo GR, Stewart DK . Value of partial ejection fraction, volume increment, and regional wall motion in identifying patients with clinically significant coronary artery disease . Circulation 1 3;68 :756-62. 31 . Sheehan FH, Stewart DK, Dodge HT, Mitten S, Bolson EL, Brown G . Variability in the measurement of regional left ventricular wall motion from contrast angiograms . Circulation 1983,68:550-9. 32. Sane DC, Califf RM, Topol EJ, Stump DC, Mark DB, Greenberg CS . Bleeding during thrombolysic therapy for acute myocardial infarction : mechanisms and management . Ann Intern Med 1989 ;111 :1010-22 . 33. Califf RM, Topol EJ, George BS, et al. Hemorrhagic complications associated with the use of intravenous tissue plasminogen activator in treatment of acute myocardial infarction . Am J Med 1988 ;85 :353-9. 34. Kander NH, Holland K1, Pitt B . Topol EJ . A randomized pilot trial of brief versus prolonged heparin after successful reperfusion in acute myocardial infarction . Am ! Cardiol 1990 ;65 :139-42 . 35 . Mahan EF, Chandler JW, Rogers WJ . et al. Heparin and infarct coronary artery latency after streptokinase in acute myocardial infarction . Am 1 Cardiol 1990;65 :9667-72. 36 . Hull RD, Raskob GE, Hirsh J, et al. Continuous intravenous heparin compared with intermittent subcutaneous heparin in the initial treatment of proximal-vein thrombosis . N EngI 1 Med 1986 ;315 :1109-4 . 37 . Hsia J . Kleiman N, Aguirre F, Chaitman BR, Roberts R . Ross AM . Heparin induced partial thromboplastin time after thrombolysis : prolongation magnitude determines coronary patency [abstract] . Circulation 191 ;84 Suppl 1111-116.

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38 . Bassand JP, Machecourt J, Cassagnes 1, et al ., for the APSIM Study Investigators . Multicenter trial of intravenous anisoylated plasminogen streptokinase activator complex (APSAC) in acute myocardial infarction : effects on irfatct size and left ventricular function . J Am Coll Cardiol 1989 ;11988-'7 . 39. Anderson IL, :3orensen SG. Moreno FL, el al ., and the Team 2 Study Investigators . Multicenter patency trial of intravenous anistreplase compared with streptokinase in acute myocardial infarction . Circulation 1991 ;83 :126-39 . 40. Anderson JL, Sorensen $G, Karagounis L, et al ., for the TEAM-3 Investigators . A double-blind, randomized comparison of anistreplase and alteplase in acute myocardial infarction : coronary patency results from the TEAM-3 study [abstract]. J Am Coll Cardiol l99l ;17:152A. 41 . von Essen R, Vogt A, Roth M, Reiss M, Tebbe U . Neuhaus KL, for the TAPS Study Group . Early patency of infarct-related vessel after accelerated infusion of 100 mg rt-PA as compared to 30 mg APSAC : results of the TAPS Study (abstract[ . Eur Heart J 1991 ;12 Suppl:3l1. 42. Hassand JP, Cassagnes J, Machecourt J, et al . Comparative effects of APSAC and rt-PA on infarct size and left ventricular function in acute myocardial infarction. A multicenter randomized study . Circulation 1991 ; 84:1107-17 . 43 . O'Connor CM, Aronson L . Kitzman DW, Mark DB, Califf RM . Aggressive therapy of acute myocardial infarction in the elderly (abstract] . J Am Coll Cardiol 1990 ;15 :34A . 44 . O'Connor CM, CaliO' RM, Massey EW, et al . Stroke and acute myocardial infarction in the thrombolytic era : clinical correlates and long-term prognosis. J Am Coll Cardiol 1990 ;16:533-40. 45 . Gore JM, Sloan M, Price TR, Randall AMY, Bovill E, Collen D, and the TIMI Investigators. Intracerebral hemorrhage, cerebral infarction, and subdurat hematoma following acute myocardial infarction and thrmmbolytic therapy in the Thrombolysis in Myocardial Infarction (TIME) study . Thromboiysis in Myocardial Infarction, Phase II pilot and clinical trial . Circulation 1991 ;83 :448-59. 46. Califf RM, Topol i:J, Stack RS, el al., for the TAMI Study Group . Evaluation of combination thrombolytic therapy and timing of cardiac catheterization in acute myocardial infarction . Results of thrombolysis and angioplasty in myocardial infarction-Phase 5 randomized trial . Circulation 1991 ;83 :1543-56 . 47 . Rao AK, Pratt C, Berke A, Jaffe A, Ockene 1, Schreiber TL, for the TIMI Investigators . Thrombolysis in Myocardial Infarction (TIMI) trial-Phase 1 : hemorrhagic manifestations and changes in plasma fibrinogen and the fibs-''olytic system in patients treated with recombinant tissue plasminogen activator and streptokinase . J Am Cob Cardiol 1988 ;11 :1-11 . 48 . Bovill EG, Terrin ML, Stump DC . Hemorrhagic events during therapy with recombinant tissue-type plasminogen activator, heparin, and aspirin for acute myocardial infarction (TIMI), Phase II trial . Ann Intern Mcd 1991 :115 :256-65 . 49. Gallino A, Haeberli A, Hess T . Mombelli G, Straub PW . Fibrin formation and platelet aggregation in patients with acute myocardial infarction : effects of intravenous and subcutaneous low-dose heparin . Am Heart J 1986312 :285-90. 50. Bonnier H, Hoffman H, Melman P . Bartholomeus 1 . Is there an effect of APSAC on blood viscosity and platelet function in patients with acute myocardial infarction treated with APSAC? (abstract[ . Circulation 1991 ;84 Suppl 11:11-542. 51 . Fuster V, Stein B, Badimon L, Chesebro JH . Antithrombotic therapy after myocardial reperfusion in acute myocardial infarction . I Am Coll Cardiol 1988 :12 Suppi A :78A-84A . 52 . Fortin DF, Calif RM . Long-term survival from acute myocardial infarction : salutary effect of an open coronary vessel . Am J Med 1990 ; :I-9N15N. 53 . Ohman EM, Califf RM, Topol EJ, Candela R, Abbottsmith C . Ellis S . and the TAMI Study Group . Consequences of reocclusion after successful repetfusion therapy in acute myocardial infarction . Circulation 1990 ;82 : 781-91 .