Relation of coagulation parameters to patency and recurrent ischemia in the Thrombolysis in Myocardial Infarction (TIMI) Phase II Trial

Relation of coagulation parameters to patency and recurrent ischemia in the Thrombolysis in Myocardial Infarction (TIMI) Phase II Trial Russell P. Tracy, PhD,a,b Neal S. Kleiman, MD,c Bruce Thompson, PhD,d Christopher P. Cannon, MD,e Edwin G. Bovill, MD,a R. Greg Brown, MD,f Desire Collen, MD, PhD,g Edward Mahan, MD,h Kenneth G. Mann, PhD,b William J. Rogers, MD,h George Sopko, MD,i David C. Stump, MD,j David O. Williams, MD,k and Barry L. Zaret, MD,l for the TIMI II investigators

Current protocols for use of tissue-type plasminogen activator in acute myocardial infarction include heparin estimated by the activated partial thromboplastin time (aPTT). Recent reports indicate a risk of recurrent ischemic events with long aPTT values. Longer aPTT values in the Thrombolysis in Myocardial Infarction-II (TIMI II) Trial, obtained within the first 48 hours, were associated with patency at 18 to 48 hours and better left ventricular function at discharge (average 9.6 days), but also with emergency catheterizations within the first 48 hours and, weakly, with recurrent ischemia during the first 18 hours. A moderate decrease in fibrinogen, compared with a “small” decrease, was also associated with patency, but a “large” decrease was associated with hemorrhagic events. Patency was associated with higher fibrinogen values and higher plasminogen values at baseline. The aPTT results support frequent monitoring during the first 24 to 48 hours to ensure optimal clinical outcome. The coagulation factor results suggest that there may be an optimum window for fibrinogenolysis in this setting. (Am Heart J 1998;135:29-37.)

Although thrombolytic therapy has become the accepted therapeutic modality for acute myocardial infarction, both failure to achieve reperfusion and rethrombosis after successful thrombolysis remain significant problems. Unfortunately, these problems cannot be circumvented by simply using increased amounts of thrombolytic agents because increased doses are associated with an increased frequency of serious hemorrhage.1,2 Therefore, adjunctive therapies directed at the coagulation system have gained increased importance.

From the Departments of aPathology and bBiochemistry, University of Vermont College of Medicine; cDivision of Cardiology, Baylor College of Medicine; dMaryland Medical Research Institute; eDepartment of Medicine, Harvard Medical School; fDivision of Cardiology, University of Washington Medical Center; gDepartment of Medical Research, University of Leuven Center for Thrombosis and Vascular Research; hDepartment of Medicine, University of Alabama Medical Center; iDivision of Heart and Vascular Diseases, National Heart, Lung, and Blood Institute; jClinical Research Division, Genentech; kDivision of Cardiology, Brown University; and the lSection of Cardiology, Yale University School of Medicine. Dr. Mahan is currently with the Lloyd Noland Hospital, Fairfield, Ala. Submitted Jan. 21, 1997; accepted July 23, 1997. Supported by research grants and contracts from the National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Md. Reprint requests: Russell P. Tracy, PhD, University of Vermont, 55A South Park Dr., Colchester, VT 05446. E-mail: [email protected] Copyright © 1998 by Mosby, Inc. 0002-8703/98/$5.00 + 0 4/1/86049

The search for improved anticoagulant therapies for use with fibrin-specific plasminogen activation has centered on inhibitors of thrombin and platelet aggregation. The restriction of platelet aggregation and thrombin-mediated coagulation events are key factors in achieving and sustaining arterial patency,3-5 and clinical studies with heparin, aspirin, and platelet receptor–specific agents seem to confirm these results. At this time, heparin remains the major adjunctive agent. However, despite extensive research the use of heparin remains controversial and the optimal dose to be administered is unclear. The generation of relatively large amounts of plasmin during thrombolytic therapy also has an anticoagulant effect because plasmin is known to degrade key procoagulant cofactors such as fibrinogen6 and factor V and factor VIII7,8 (Tracy et al., unpublished study). The degree of anticoagulation achieved at any point in time is usually assessed with the activated partial thromboplastin time (aPTT). We have made a preliminary report that long aPTT values in the Thrombolysis in Myocardial Infarction Phase II (TIMI II) study were associated not only with bleeding events, as might be expected, but also with recurrent ischemia.9 Confirming this, the investigators of the Global Utilization of Streptokinase and t-PA for Occluded Coronary Arteries (GUSTO) trial reported an association of longer aPTT

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Table I. Relation of coagulation parameters to patency at 18 to 48 hours Group without 18-48 hour catheterization (reasons for lack of data) Measurement aPTT First aPTT (sec) Pts with first aPTT >90 sec (%) aPTT index† Fibrinogen (mg/dl) Before tPA 50 min 300 min 480 min Fibrinogen change (mg/dl)** At 50 min At 300 min At 480 min FDP (µg/dl) Before tPA 50 min 300 min 480 min Plasminogen (%) Before tPA 50 min 300 min 480 min tPA, (ng/ml) 50 min

Occluded group 254, 70 (2) 254, 30 254, 1.80 (0.02)

Patent group

Early hemorrhage

1161, 77 (1)* 1161, 37* 1161, 1.93 (0.01)‡

17, 81 (11) N/A 19, 1.5 (0.10)

Emergency cath 33, 99 (7) N/A 37, 2.0 (0.08)#

Cause unknown 50, 73 (6) N/A 59, 1.7 (0.06)

152, 295 (8) 153, 246 (7) 156, 208 (8) 147, 198 (7)

673, 306 (3)ll 650, 246 (3) 727, 185 (3)ll 666, 183 (3)

7, 366 (29) 8, 237 (46) 9, 154 (33) 9, 145 (31)

20, 300 (10)¶ 17, 261 (13) 23, 202 (17) 26, 180 (16)

33, 323 (18) 33, 237 (19) 29, 191 (16) 27, 186 (14)

125,–48 (7) 125,–89 (8) 119,–85 (8)

550,–62 (4) 595,–122 (5)§ 544,–122 (5)§

7,–140 (64) 7,–229 (58) 6,–288 (42)

15,–46 (15) 15,–104 (20)¶ 17,–121 (19)‡

29–78 (22) 26,–130 (29) 22,–120 (30)

150, 28 (15) 149, 229 (75) 155, 343 (91) 144, 316 (93)

679, 14 (1) 639, 203 (21)ll 718, 351 (27) 656, 283 (24)

20, 15 (3) 17, 97 (33) 23, 348 (118) 25, 364 (109)

30, 14 (4) 32, 600 (234) 26, 451 (195) 27, 558 (330)

121, 100 (2) 133, 66 (2) 137, 60 (1) 132, 58 (1)

503, 104 (1)* 553, 68 (1) 656, 56 (1) 601, 57 (1)

7, 113 (4) 8, 62 (7) 9, 59 (6) 9, 61 (6)

12, 102 (3) 14, 71 (4) 21, 54 (3) 24, 47 (3)

25, 110 (3) 27, 69 (4) 21, 56 (3) 22, 59 (3)

151, 1681 (109)

622, 1747 (47)

8, 2335 (683)

18, 1344 (168)

29, 1801 (146)

5, 10 (2) 6, 786 (722) 7, 739 (611) 7, 714 (615)

Data presented as n, mean (SEM). Cath, Catheter. *p ≤ 0.01 for open vs closed groups. †aPTT index calculated as described in Methods section. ‡p ≤ 0.0001 for open vs closed groups. §p ≤ 0.001 for open vs closed groups. llp ≤ 0.05 for open vs closed groups. ¶p ≤ 0.05 for hemorrhagic vs emergency groups. #p ≤ 0.001 for hemorrhagic vs emergency groups. **Fibrinogen change calculated from the pre-tPA value for each time point.

values with reinfarction, as well as bleeding, stroke, and mortality.10 We now report an analysis of the TIMI II aPTT data, including an examination of the effect of thrombolytic therapy on key coagulation parameters.

Methods Patients Data were obtained from patients entered into the TIMI II between April 1986 and June 1988.11 A total of 3232 of the 3339 TIMI II patients are described in this report. The TIMI II trial included two major arms. In the TIMI II-A study (n = 586), patients were randomized to one of three treatment strategies: (1) catheterization and percutaneous transluminal coronary angioplasty (PTCA) (if feasible) within 2 hours (immediate invasive, n = 195); (2) catheterization and PTCA between 18 and 48 hours (delayed invasive, n = 194); and (3) catheterization at 7 days, with PTCA performed if clinically indicated (conservative, n = 197). In the larger TIMI II-B

study (n = 2948), patients were randomized between the invasive (catheterization with revascularization at 18 to 48 hours after infusion) and conservative strategies (catheterization with revascularization if clinically indicated). The major inclusion criteria for TIMI II include age <76 years, symptoms of ischemic chest pain of >30 minutes duration, and treatment possible within 4 hours of the onset of symptoms. The complete list of inclusion and exclusion criteria has been published, as have reports that detail results concerning treatment strategies.11,12 The initial dose of rt-PA used in TIMI II was 150 mg. This dose was altered to 100 mg early in the study because of the occurrence of an unacceptable number of intracerebral hemorrhages.13 This report includes individuals receiving both doses.

Treatment The rt-PA used in this study was Activase supplied by Genentech, Inc., South San Francisco, California. For the first 520 patients, the dose was 150 mg, given as a 10 mg bolus,

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followed by 90 mg over the first hour, 20 mg in the second hour, and 10 mg/hour for the next 4 hours. After the dose change, the remaining 2819 patients received a total of 100 mg, given as a 6 mg bolus, followed by 54 mg in the first hour, 20 mg in the second hour, and 5 mg/hour for the remaining 4 hours. Adjunctive therapy included aspirin (80 mg/day increased to 325 mg/day on day 6). Heparin was also administered, with a 5000-unit bolus given within 1 hour of the start of rt-PA treatment. Heparin was subsequently infused at 1000 units/hr, adjusted as needed to maintain the aPTT at 1.5 to 2.0-fold, the laboratory control value. Starting on day 5, intravenous heparin was discontinued and subcutaneous heparin was started at 10,000 U every 12 hours until the patient was discharged.

Clinical outcome variables Patency of the infarct-related artery was assessed by angiography at 18 to 48 hours in patients assigned to the delayed-invasive strategy of TIMI IIA and the invasive strategy of TIMI IIB, using the TIMI flow grade system.14 Angiography quality was determined by the Angiographic Core Laboratory, and all angiographic data in this report were based on Core Laboratory analyses. For patients dying within 2 days (precluding catheterization), the infarct-related artery was assumed to be occluded. Early recurrent ischemia, within 18 hours of the start of infusion, was determined by clinical evidence including chest pain, electrocardiography (ECG) changes, and cardiac enzyme changes.12 Definite recurrent myocardial infarction and death were included in this category as well. Recurrent ischemia beyond the first 18 hours is not examined in this report. Global left ventricular ejection fraction (LVEF) was assessed by resting radionuclide ventriculography performed before hospital discharge by use of the left anterior oblique position, as described in detail elsewhere.15,16 LVEF greater than 55 was used to classify patients with a favorable result; all other values were considered unfavorable. Fig. 1 is a time line indicating the relative timing of the administration of therapies and blood collection and the outcome variables.

Blood collection and coagulation measurements As previously described, blood was most commonly collected by piercing the end piece of an indwelling catheter with a syringe and withdrawing a sample.2 The syringe was then used to pierce evacuated collection tubes containing anticoagulants. Infrequently, direct venipuncture was done. An anticoagulant mixture used to ensure minimal artifact included citrate plus 50 µM D-Phe-Pro-Arg Chloromethyl Ketone (PPACK), a potent thrombin inhibitor.17 A small amount of blood was withdrawn and discarded to ensure a clean sample. After the plasma was prepared by centrifugation, it was frozen at the clinical centers and shipped to the University of Vermont on dry ice for analysis in the Coagulation Core Laboratory. Blood was collected before the initiation of rt-PA infusion; at 50 minutes, which corresponds to the peak of infusion; at 5 hours, which is toward the end

Table II. Relation of coagulation parameters to recurrent ischemia within 18 hours of the start of treatment with rt-PA Measurement

Ischemia present

aPTT First aPTT (sec) 259, 83 (3) Patients with first aPTT > 90 sec (%) 259, 43 aPTT index† 248, 1.91 (0.02) Fibrinogen (mg/dl) Before tPA 171, 315 (8) 50 min 155, 256 (8) 300 min 162, 206 (7) 480 min 151, 193 (6) Fibrinogen change (mg/dl)§ At 50 min 133, –62 (9) At 300 min 125, –112 (10) At 480 min 114, –117 (11) FDP (mg/dl) Before tPA 170, 14 (1) 50 min 156, 220 (68) 300 min 162, 328 (70) 480 min 150, 281 (53) Plasminogen (%) Before tPA 115, 101 (1) 50 min 135, 66 (1) 300 min 145, 58 (1) 480 min 138, 55 (1) t-PA (ng/ml) 50 min 160, 1790 (91)

Ischemia absent 2973, 77 (1)* 2973, 37* 2984, 1.89 (0.01) 1670, 306 (2) 1644, 248 (2) 1799, 189 (2)‡ 1649, 184 (2) 1381, –59 (2) 1464, –117 (3) 1341, –121 (3) 1667, 16 (1) 1617, 200 (14) 1762, 326 (16) 1621, 296 (17) 1253, 104 (1) 1433, 68 (1) 1605, 57 (1) 1495, 57 (1) 1586, 1738 (29)

Data presented as n, mean (SEM). *p ≤ 0.05. †aPTT index calculated as described in Methods. ‡p ≤ 0.01. §Fibrinogen change calculated from the pre-tPA value for each time point.

of infusion; and at 8 hours, which is approximately 2 hours after the end of infusion. The measurements of fibrinogen, plasminogen, fibrin(ogen) degradation products (FDPs), and rt-PA were done in TIMI II participants, nominally at four time points per patient: before rt-PA infusion (the “pre” sample), at 50 minutes (peak infusion), and at 5 and 8 hours. Not infrequently, however, samples from one or more time points were missing for a given patient. Fibrinogen, FDPs, and rt-PA were measured as described.2 Plasminogen was measured with a chromogenic substrate, Spectrozyme PL (American Diagnostica, New York, NY). The residual PPACK was removed by preincubation as described. Each sample was analyzed in duplicate, with a blank to correct for any endogenous color. The coefficient of variation (CV) for the plasminogen assay was 7.3%. Activated partial thromboplastin times (aPTTs) were performed at the clinical laboratory of each clinical site and used to adjust the heparin infusion rates. The first aPTT was performed at an average of 8 hours after the initiation of heparin (range 4.8 to 12 hours). Analytical emphasis was placed on the first aPTT value because subsequent values

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Figure 1

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groups being compared in Tables I, II, and III were sufficient to detect a difference of at least 0.3 standard deviations between the two population means with at least 80% power. For comparing the proportion of patients with the first aPTT >90 seconds, the sample sizes in each of the groups being compared were sufficient to detect a twofold difference in the proportions with at least 80% power.

Results

TIMI II: rt-PA infusion, blood sampling, and outcome measures. The duration of rt-PA infusion was 6 hours. Blood samples were collected before the start of infusion, as well as at 50 minutes, 5 hours, and 8 hours (2 hours after the end of the infusion). The first aPTT measurement was made between 4.8 and 12 hours after the start of infusion, with the average being 8 hours. Patency measurements were made between 18 and 48 hours, whereas early recurrent ischemia was estimated between the start of infusion and 18 hours. LVEF measurements were made at the time of hospital discharge, at an average of 9.6 days.

were more likely to be affected by the patient’s clinical status and the timing of aPTT measurements after the first measurement was more variable. An integrated measurement (the aPTT index) was developed, which was calculated for those patients with more than one aPTT measurement. The integration represented the average aPTT measurement in the first 2 days after administration of t-PA. aPTT measurements were coded to limit the influence of large aPTT values in the integration. Values were coded as follows: (1) aPTT <45 seconds; (2) aPTT between 45 and 90 seconds; and (3) aPTT >90 seconds. It was assumed that the patient was adequately maintained (aPTT code = 2) at the start of the infusion if the patient was receiving heparin; otherwise the patient was scored as not adequately maintained. Once coded values for heparin measurement were obtained for the 2-day period, these coded values were integrated by use of Simpson’s approximation.

Statistical analyses Dependent variables analyzed in this study were continuous or binary. To analyze continuous variables, Student’s t test was used to assess statistical significance of the difference between two means. The chi-square test without correction for continuity was used to assess the statistical significance of the difference in two proportions. To adjust for the many hypotheses being tested in this report, a p value of 0.01 or less was specified as indicating statistical significance. Power calculations were made for all of the proposed comparisons made in Tables I, II, and III. For comparing two means, the sample sizes in each of the

The major clinical results from TIMI II have been reported elsewhere.11,12 Briefly, 84.6% of the patients in the invasive strategy group had patent (TIMI grade 2 or 3 flow) infarct-related arteries at 18 to 48 hours, at a mean time to arteriography of 32.5 hours. Reinfarction or death, within 21 and 42 days, occurred in 9.9% and 10.6% of the TIMI II participants, respectively; 15.3% had a positive radionuclide ventriculography exercise test at the time of hospital discharge.

Relation of measured parameters to patency at 18 hours Table I indicates how the aPTT values and the mean coagulation values were associated with patients who are patent at 18 to 48 hours compared with those with an occluded infarct-related artery and to those for whom patency data could not be collected. Compared with patients with occluded arteries, the group with patent arteries was characterized by a 10% greater mean value for the first aPTT (p ≤ 0.01), more patients with first aPTT values >90 seconds (p ≤ 0.01), and a greater aPTT index (p ≤ 0.0001). These associations were predominantly with those in the patent group with TIMI grade 3 flow. For grade 2 and grade 3 first aPTTs, the average values were 73 seconds (n = 2261) and 79 seconds (n = 900; 77 seconds for the total group); percentage of patients with long first aPTTs was 31% and 38% (37% for the total group). However, the index values were approximately the same in the two flow groups. The mean fibrinogen value in those with patent arteries was higher at baseline and lower at 5 and 8 hours compared with those with occluded arteries. This finding was reflected in the mean values for the change in fibrinogen concentrations over time, which indicated that there was a significantly greater fibrinogen drop in the patent group at both 5 hours and 8 eight hours (p ≤ 0.001). These results indicate a decrease in fibrinogen at 5 hours of approximately 40% in the patent group compared with just over 30% in those with occlusion. There was little difference between those with TIMI grade 2 and grade 3 flow (data not shown). There was no sig-

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Table III. Relation of coagulation parameters to resting radionuclide ventriculography Measurement aPTT First aPTT (sec) Patients with first aPTT >90 sec (%) aPTT Index* Fibrinogen (mg/dl) Before tPA 50 min 300 min 480 min Fibrinogen change (mg/dl)‡ At 50 min At 300 min At 480 min FDP (mg/dl) Before tPA 50 min 300 min 480 min Plasminogen (%) Before tPA 50 min 300 min 480 min t-PA (ng/ml) 50 min

LVEF >55

All others

985, 78 (1) 985, 38 985, 1.93 (0.01)

2247, 77 (1) 2247, 37 2247, 1.88 (0.01)†

564, 305 (3) 542, 249 (3) 614, 194 (3) 555, 183 (3)

1277, 307 (2) 1257, 248 (2) 1347, 189 (2) 1245, 186 (2)

460,–55 (4) 502,–110 (5) 457,–120 (5)

1054,–61 (3) 1087,–120 (3) 998,–121 (3)

563, 18 (4) 529, (25, 180) 602, 295 (27) 544, 261 (23)

1274, 14 (1) 1244, 211 (17) 1322, 340 (20) 1227, 310 (21)

427, 104 (1) 475, 69 (1) 556, 57 (1) 508, 56 (1)

941, 103 (1) 1093, 67 (1) 1194, 56 (0) 1125, 58 (1)

529, 1659 (46)

1217, 1779 (35)§

Data presented as n, mean (SEM). *aPTT index calculated as described in Methods section. †p ≤ 0.001. ‡Fibrinogen change calculated from the pre-tPA value for each time point. §p ≤ 0.05.

nificant association between the amount of fibrinogen loss at 5 hours and the aPTT index (r = –0.02, p = 0.32). The patent group had a slightly (but significantly) higher mean plasminogen level at baseline but no clear indication of greater plasminogen loss over time. The patent group had a slightly higher value for the peak rt-PA concentration (4% higher than those with occlusion), but this difference was not statistically significant, with no significant difference between those with TIMI grade 2 and grade 3 flow: 1729 ng/ml and 1751 ng/ml, respectively. Protocol catheterizations at 18 to 48 hours were not performed in 116 of the 1161 patients assigned to the conservative strategy in TIMI IIB. The reasons included hemorrhagic complications in 19 patients and emergency catheterization within the first 18 hours in 60 patients. In the remainder, the reasons were not readily apparent. The coagulation results for these individuals are listed in Table I. The group with hemorrhagic complications had a high mean baseline fibrinogen value and exhibited extensive fibrinogen loss. Elevated FDP values in this group are consistent with extensive fibrinogenolysis.

The hemorrhagic group was also characterized by having a significantly higher baseline plasminogen level and, although not statistically significant, an elevated rt-PA peak level. The average first aPTT value was greater (not significant) and the aPTT Index higher (p ≤ 0.001) in those individuals with emergency catheterizations compared with those with hemorrhagic events.

Relation of measured parameters to recurrent ischemia Table II indicates the aPTT values and the mean coagulation values, comparing the group with recurrent ischemia within 18 hours of the start of rt-PA infusion to the group free of ischemia during this period. Patients with ischemia were characterized by a greater mean value for the first aPTTs (p ≤ 0.05), a larger percentage of patients with a first aPTT longer than 90 seconds (p ≤ 0.05), and a greater aPTT index. Although none of these findings reached our a priori statistical significance level of p ≤ 0.01, taken together they suggest an association of longer aPTT values with increased risk of recurrent ischemia. None of the coagulation measurements were associated with recurrent ischemia.

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Table IV. Reinfarction and recurrent ischemia in trials of rt-PA with and without intravenous heparin Incidence Study TAMI-3* Recurrent ischemia Reocclusion ECSG-6† (recurrent chest pain) <120 hours >120 hours ECSG-6 subgroup† (recurrent ischemia) Angiography <48-120 hr Angiography >48-120 hr HART‡ Recurrent ischemia Reocclusion (by 7 days) Australian HF§ Reinfarction

Heparin ratio (%)

No heparin ratio (%)

22/64 (34) 11/64 (17)

23/70 (33) 5/70 (7)

30/324 (9) 31/324 (10)

37/320 (12) 30/320 (9)

17/149 (11) 14/132 (11)

20/132 (15) 17/149 (11)

8/106 (8) 7/60 (12)

2/99 (2) 2/38 (5)

5/99 (5)

2/103 (2)

*In TAMI-3 the no heparin group received no adjunctive therapy; after angiography (and possibly rescue angioplasty) at 90 minutes, all patients received heparin and aspirin.21 †In ECSG-6 all patients received intravenous aspirin as adjunctive therapy; the no-heparin group received an albumin placebo. Subgroup indicates the group of ECSG patients that had samples drawn for coagulation assays.19 ‡In HART, patients were randomized between intravenous heparin and oral aspirin.3 §The data from the Australian Heart Foundation were reported in reference 5 as unpublished studies.

Relation of measured parameters to resting radionuclide ventriculography There were no differences in mean first aPTT values or percentage of patients with long aPTTs, but there was a highly significant difference in aPTT index, with those with LVEF >55 being characterized by a greater index value (p ≤ 0.001).There were no significant differences between mean values for fibrinogen, fibrinogen loss, FDP, or plasminogen when the group with good LVEF was compared with all others. However, the group with LVEF of >55 was characterized by a slightly higher mean peak rt-PA value.

Discussion The purpose of this analysis was to examine the relations of angiographic and clinical outcomes in TIMI II to the following: (1) the degree of anticoagulation (as reflected in the aPTT), and (2) the baseline values and changes in coagulation parameters. Our major findings are as follows: (1) concerning the aPTT, longer values were associated with increased patency at 18 to 48 hours and better LVEF, but also with recurrent ischemia and emergency catheterizations, (2) patency at 18 to 48 hours was associated with higher baseline fibrinogen and higher plasminogen values, and (3) a “moderate” decrease in fibrinogen, compared with a “small” decrease, was associated with patency, but a “large” decrease was associated with hemorrhagic events (see also reference 2).

Clinical outcome and anticoagulation Heparin use has an intimate and complex association with the thrombolytic process. Hsia et al.18 and Arnout et al.19 have reported that anticoagulation, as reflected in the aPTT, is associated with increased patency with rt-PA. Granger et al.10 have recently reported on the associations of the aPTT with outcome events in GUSTO-I. The major finding of their analysis was a strong association of optimal outcome with a “window” of aPTT values, with both short and long aPTT values being associated with adverse events.

aPTT and recurrent ischemia The measures of anticoagulation we have chosen (i.e., the average first aPTT value, the percentage of patients with an aPTT >90 seconds, and the aPTT index, were all positively associated with patency at 18 to 48 hours in the patency subgroup analysis (n = 1415). This result confirms the finding described by Hsia et al.18 in a study of 94 patients in the Heparin Aspirin Reperfusion Trial (HART), where patency was assessed at 18 hours; the mean aPTT values at 8, 12, and 23 hours were greater in the patients with patent arteries when compared with those with occluded arteries, with statistical significance at the 8-hour time point.18 Several other studies have demonstrated that heparin, as adjunctive therapy with rtPA, is associated with improved patency rates in the 18 to 72 hour range,3,4,19,20 but not with very early mea-

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sures of patency such as 90 minutes.21 Prins and Hirsh5 have suggested that after the initial rt-PA–dependent reperfusion, heparin is effective for the first few days but not particularly so thereafter. Arnout et al.19 have reported an association of heparin and patency in the 281 patients of the ECSG-6 heparin substudy. Patency was assessed between 2 and 5 days after thrombolytic therapy in a heparin group and a placebo group. The patency rate was higher in those receiving heparin compared with those in the placebo group and correlated with extent of anticoagulation in the heparin group. These findings, taken together with our result that there was a positive relation between aPTT index and left ventricular function measured at hospital discharge (mean time 9.6 days), suggest that heparin effectiveness may extend further than the first few days after infarction. Our results indicating that longer aPTT measures were associated, albeit weakly, with early recurrent ischemia were unexpected. The subgroup missing 18 to 48 hour catheterization data due to emergency catheterization also exhibited longer aPTT measures. In the literature, the relation of heparin to recurrent ischemic events is unclear. In both the full cohort4 and subgroup analyses19 done by the ECSG, the heparin arm of the trial compared with the nonheparin arm appeared to have slightly fewer recurrent ischemic events before 120 hours after infusion, and slightly more events after 120 hours. In TAMI-3,21 the HART study,3 and the Australian Heart Foundation study,5 there were more recurrent events in the heparin arms than in the nonheparin arms (Table IV). The aPTT has been widely accepted as an estimate of heparin-induced anticoagulation, and in the absence of other factors this is true. In the setting of plasminogen activation, the aPTT may also measure anticoagulation caused by the effect of plasmin on coagulation cofactors such as factors V and VIII. It is clear that factor V is transiently activated and then irreversibly inactivated by plasmin, and we have reported the plasmin-mediated degradation of factor V in the setting of disseminated intravascular coagulation.22 In a subset of TIMI II and GUSTO-I patients, we have identified a dramatic degradation of factor V during rt-PA infusion, followed by an increase in the plasma concentration of intact factor V after the rt-PA infusion is finished (Tracy RP et al., unpublished manuscript). There was at least some factor V loss in every patient receiving thrombolytic therapy that we examined.

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Therefore, at least in some cases, it seems likely that the first aPTT measurement reflects both heparin infusion and loss of factors V and VIII. Any adjustment made to the heparin infusion rate at that time would be appropriate only so long as the factor V and factor VIII concentrations remained low. As the plasma levels of these factors increase after the cessation of rt-PA infusion, heparinization may prove inadequate unless frequent aPTT measurements in this interval are used for accurate estimation of the total anticoagulation. Because the longer first aPTT values may be associated with greater degradation of factors V and VIII, we hypothesize that there is a greater potential for inadequate thrombin inhibition by heparin in these individuals, yielding the apparent association of heparin with recurrent ischemic events. This hypothesis implies that there is a time after cessation of infusion during which frequent aPTT monitoring is advisable. Alternatively, because “recurrent” ischemia requires the presence of a patent infarct-related artery, and heparin improves patency, this might explain a greater recurrent ischemic rate in the group with greater heparinization. It is also possible that in some cases patients clinically judged to be particularly at risk may receive more attention and more aggressive heparinization. If such high-risk patients have a greater incidence of recurrent ischemia, this may also contribute to an association between heparinization and recurrent ischemic events.

Relation of patency and coagulation measurements Rao et al.23 and Bovill et al.2 reported the results of TIMI I and TIMI II, respectively, concerning coagulation factors and hemorrhagic events. Stump et al.24 reported results from the Thrombolysis and Angioplasty in Myocardial Infarction Phase I trial (TAMI-1) in a total of 386 patients that indicated that there were no significant associations between fibrinogen, FDPs, or rt-PA values and patency at 90 minutes. However, they did report that a greater loss in fibrinogen (or a higher baseline fibrinogen value) was associated with a lower reocclusion rate at 7 to 10 days. In our study, patency at 18 to 48 hours was associated with both a higher baseline fibrinogen value and a greater loss of fibrinogen, supporting the TAMI-1 finding in a larger group. The mechanism for the relation of recurrent ischemia and patency with baseline fibrinogen, and fibrinogen loss, is unclear. It is possible that greater fibrinogen at baseline identifies those patients with greater thrombotic risk and, conceivably, less atherosclerotic risk; these patients might be more likely to respond well to rt-PA.

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As a marker of plasmin activity, the loss of fibrinogen might simply reflect effective plasminogen activation. Such a mechanism has been proposed to explain improved patency after thrombolysis in smokers.25,26 However, this would not explain the association of patency with baseline fibrinogen. It seems likely that the loss of fibrinogen might itself be important, inasmuch as compromised coagulation could lead to decreased thrombosis. Alternatively, fibrinogenolysis might lead to the release of fibrinogen fragments that could, in turn, disrupt fibrin assembly, increase rt-PA activity as an active cofactor, or decrease platelet cross-linking by blocking fibrinogen binding sites.6 However, it remains unclear whether or not FDP concentration in plasma is mechanistically related to lack of reocclusion. Whatever the mechanism, this study provides additional evidence that fibrinogen loss is associated with effective thrombolytic therapy and that extreme fibrinogenolysis is associated with hemorrhagic risk. Our data support the hypothesis that there is most likely an optimal therapeutic window for each individual within which the advantages of effective plasmin generation are balanced with the potential hazards of unwanted fibrinolysis or compromised coagulation. This is the first large study to report on plasminogen values and clinical outcome. Although no association was found between plasminogen and early recurrent ischemia or left ventricular function at discharge, an association was noted between baseline plasminogen values and patency at 18 to 48 hours. Although the mechanism is not defined, one might speculate that a higher plasminogen value (as substrate for rt-PA) could lead to increased plasmin production and thus more effective fibrinolysis. This concept has been examined as part of “plasminogen steal,” in which increased plasminogen leads to increased clot lysis.27 As has been the case for other studies in which peak rt-PA values and hemorrhagic events were examined,2,24,28,29 we found little association between peak rt-PA values and outcomes. The only exception was a weak negative association with left ventricular function and a trend towards high t-PA values in the subgroup without 18- to 48-hour catheterization data because of bleeding. In conclusion, our results suggest that frequent aPTT monitoring during the first 24 to 48 hours may be required to ensure not only optimal patency rates but also optimal protection from recurrent ischemia and

American Heart Journal January 1998

hemorrhagic events. It also appears likely that increased fibrinogenolysis is associated with improved patency, suggesting that there may be an optimum window for fibrinogenolysis, as a process separate from fibrinolysis, in this setting. We thank Elaine Cornell, Florence Keating, and Ray Losito for their technical assistance, and Drs. Richard Becker and Eugene Braunwald for helpful discussions.

References 1. Gore J, Sloan M, Price T, Young-Randall A, Bovill E, Collen D, et al. Intracerebral hemorrhage, cerebral infarction, and subdural hematoma after acute myocardial infarction and thrombolytic therapy in the Thrombolysis In Myocardial Infarction study: Thrombolysis In Myocardial Infarction, phase II, pilot and clinical trial. Circulation 1991;83:448-59. 2. Bovill E, Terrin M, Stump D, Berke A, Frederick M, Collen D, et al. Hemorrhagic events during therapy with recombinant tissue-type plasminogen activator, heparin, and aspirin for acute myocardial infarction: results of the Thrombolysis in Myocardial Infarction (TIMI), phase II trial. Ann Intern Med 1991;115:256-65. 3. Hsia J, Hamilton W, Kleiman N, Roberts R, Chaitman B, Ross A, et al. 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. 4. de Bono D, Simoons M, Tijssen J, Arnold A, Betriu A, Burgersdijk C, et al. Effect of early intravenous heparin on coronary patency, infarct size, and bleeding complications after alteplase thrombolysis: results of a randomized double-blind European Cooperative Study Group trial. Br Heart J 1992;67:122-8. 5. Prins M, Hirsh J. Heparin as an adjunctive treatment after thrombolytic therapy for acute myocardial infarction.Am J Cardiol 1991; 67:3A-11A. 6. Tracy R, Mann K, Bovill E. Mechanisms of thrombolysis. In: Ezekowitz M, editor. Cardiac sources of systemic embolization. New York: Marcel Dekker; 1994. p. 55-70. 7. Lee C, Mann K. Activation/inactivation of human factor V by plasmin. Blood 1989;73:185-90. 8. Omar M, Mann K. Inactivation of factor Va by plasmin. J Biol Chem 1987;262:9750-5. 9. Tracy R, Kleiman N, Thompson B, Bovill E, Braunwald E, Brown B, et al. Relationship of coagulation parameters to patency at 18-48 hours in the Thrombolysis in Myocardial Infarction phase II trial [abstract]. Clin Res 1991;39:239A. 10. Granger C, Hirsh J, Califf R, Col J, White H, Betriu A, et al. Activated partial thromboplastin time and outcome after thrombolytic therapy for acute myocardial infarction: results from the GUSTO-I trial. Circulation 1996;93:870-8. 11. The TIMI Research Group. Immediate vs. delayed catheterization and angioplasty following thrombolytic therapy for acute myocardial infarction. JAMA 1988;260:2849-58. 12. The TIMI Study Group. Comparison of invasive and conservative strategies after treatment with intravenous tissue plasminogen activator in acute myocardial infarction. N Engl J Med 1989;320:618-27. 13. The TIMI Operations Committee, Braunwald E, Knatterud G, Passamani E, Robertson T, Solomon R. Update from the Thrombolysis in Myocardial Infarction Trial [letter]. J Am Coll Cardiol 1987;10:970.

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14. The TIMI Research Group. The Thrombolysis in Myocardial Infarction (TIMI) trial: phase I findings. N Engl J Med 1985;312:932-6. 15. Zaret B, Wackers F, Terrin M, Ross R, Weiss M, Slater J, et al. Assessment of global and regional left ventricular performance at rest and during exercise after thrombolytic therapy for acute myocardial infarction: results of the Thrombolysis in Myocardial Infarction (TIMI) II Study. Am J Cardiol 1992;69:1-9. 16. Zaret B, Wackers F, Terrin M, Forman S, Williams D, Knatterud G, et al. Value of radionuclide rest and exercise left ventricular ejection fraction in assessing survival of patients after thrombolytic therapy for acute myocardial infarction: results of Thrombolysis In Myocardial Infarction (TIM1) phase II study. J Am Coll Cardiol 1995;26:73-9. 17. Tracy R, Bovill E, Stump D, Lin T, Gomol T, Collen D, et al. Reduction of in vitro artifact during blood collection in TIMI II [abstract]. Blood 1988; 78(suppl 1):376. 18. Hsia J, Kleiman N, Aguirre F, Chaitman B, Roberts R, Ross A, et al. Heparin-induced prolongation of partial thromboplastin time after thrombolysis: relation to coronary artery patency. J Am Coll Cardiol 1992;20:31-5. 19. Arnout J, Simoons M, de Bono D, Rapold H, Collen D, Verstraete M. Correlation between level of heparinization and patency of the infarctrelated coronary artery after treatment of acute myocardial infarction with alteplase (rt-PA). J Am Coll Cardiol 1992;20:513-9. 20. Bleich S, Nichols T, Schumacher R, Cooke D, Tate D, Teichman S. Effect of heparin on coronary arterial patency after thrombolysis with tissue plasminogen activator in acute myocardial infarction. Am J Cardiol 1990;66:1412-7. 21. Topol E, George B, Kereiakes D, Stump D, Candela R, Abbottsmith C, et al. A randomized controlled trial of intravenous tissue plasminogen activator and early intravenous heparin in acute myocardial infarction. Circulation 1989;79:281-6.

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22. Rubin D, Tracy R, Mann K, Tracy P. Western blotting of human factors V and Va in patients with disseminated intravascular coagulation (DIC) and in patients with exercise-induced angina pectoris [abstract]. Circulation 1986;74(suppl II):II-411. 23. Rao A, Pratt C, Berke A, Jaffe A, Ockene I, Schreiber T, et al. Thrombolysis In Myocardial Infarction (TIMI) Trial—phase I: hemorrhagic manifestations and changes in plasma fibrinogen and the fibrinolytic system in patients treated with recombinant tissue plasminogen activator and streptokinase [abstract]. J Am Coll Cardiol 1988; 11:1-11. 24. Stump D, Topol E, Chen A, Hopkins A, Collen D. Monitoring of hemostasis parameters during coronary thrombolysis with recombinant tissue-type plasminogen activator. Thromb Haemost 1988; 59:133-7. 25. Grines C, Topol E, O’Neill W, George B, Kereiakes D, Phillips H, et al. Effect of cigarette smoking on outcome after thrombolytic therapy for myocardial infarction. Circulation 1995;91:298-303. 26. Zahger D, Cercek B, Cannon C, Jordan M, Davis V, Braunwald E, et al. How do smokers differ from nonsmokers in their response to thrombolysis? (the TIMI-4 trial). Am J Cardiol 1995;75:232-6. 27. Torr S, Machowiak D, Fujii S, Sobel B. “Plasminogen steal” and clot lysis. J Am Coll Cardiol 1992;19:1085-90. 28. Califf R, Topol E, George B, Boswick J, Abbottsmith C, Sigmon K, 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. 29. Stump D, Califf R, Topol E, Sigmon K, Thornton D, Masek R, et al. Pharmacodynamics of thrombolysis with recombinant tissue-type plasminogen activator: correlation with characteristics of and clinical outcomes in patients with acute myocardial infarction. Circulation 1989; 80:1222-30.

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