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170 Racial Differences in Responses to Thrombolytic Therapy With Recombinant Tissue-Type Plasminogen Activator Increased Fibrin(ogen)olysis in Blacks Downloaded from http://circ.ahajournals.org/ by guest on June 16, 2017 David C. Sane, MD; David C. Stump, MD; Eric J. Topol, MD; Kristina N. Sigmon, MA; Walter K. Clair, MD; Dean J. Kereiakes, MD; Barry S. George, MD; Marcus F. Stoddard MD; Eric R. Bates, MD; Richard S. Stack, MD; Robert M. Califf, MD; and The Thrombolysis and Angioplasty in Myocardial Infarction Study Group To determine whether there are differences in responses to thrombolytic therapy in certain populations, the data for the Thrombolysis and Angioplasty in Myocardial Infarction (phase 1) study were analyzed for black and white patients. Baseline variables including risk factors and extent of coronary artery disease were similar in the 352 white and 24 black patients. The time from onset of chest pain to recombinant tissue-type plasminogen activator (rt-PA) therapy and rt-PA dosing regimens were the same in the two groups. The patency rate of the infarct-related artery at 90 minutes was 91% for blacks and was 72% for whites (p=0.051). Blacks displayed significantly lower nadir fibrinogen levels (0.57±+0.62 versus 1.3+±0.76 g/l,p<0.0001), greater A fibrinogen (baseline-nadir) (2.7±+1.1 versus 1.7±1.1 g/l,p<0.0001), and increased peak levels of fibrin(ogen) degradation products (837+±865 versus 245±475 ,ug/ml, p<0.0001). rt-PA antigen levels tended to be higher in blacks than in whites (2.8+±2.2 versus 2.2±3.2 ug/ml [p=0.10] at the peakand 1.6±+1.3 versus 0.99±+1.4 ,g/ml [p=0.06] at the end of the maintenance infusion). Major clinical outcomes including survival until time of hospital discharge (92% black versus 93% white, p =0.68) were not significantly different. However, despite undergoing fewer angioplasty procedures (25% versus 46.3%, p=O0.047), blacks received more transfusions (58.8% versus 19.5% were administered >2 units packed erythrocytes, p=0.001). In conclusion, black patients have an apparent enhanced sensitivity to rt-PA, which is manifested by increased thrombolytic efficacy, a more pronounced systemic fibrinogen breakdown, and increased transfusions. (Circulation 1991;83:170-175) C oronary artery disease is the leading cause of death among black Americans.' Due in part to a higher prevalence of baseline risk factors including hypertension and diabetes mellitus,2 blacks exhibit a poorer prognosis after a myocardial infarction.2-4 It is, therefore, important to consider the differences that may exist in the responses to medical and surgical therapy between racial groups. Blacks appear to have a similar reduction in mortality to whites while receiving propranolol after a myocar- dial infarction4 and a similar survival rate after coronary artery bypass grafting.5 However, the treatment of acute myocardial infarction with thrombolytic agents has not previously been examined for race-dependent differences in response. During the data analysis of the Thrombolysis and Angioplasty in Myocardial Infarction (phase 1) (TAMI-1) study, differences in certain clinical and laboratory parameters between blacks and whites became apparent. From the Division of Cardiology, Department of Medicine, Duke University, Durham, N.C. (D.C.S., K.N.S., W.K.C., R.S.S., R.M.C.); the Departments of Medicine and Biochemistry, University of Vermont, Burlington, Vt. (D.C.S.); the Division of Cardiology, Department of Internal Medicine, University of Michigan, Ann Arbor, Mich. (E.J.T., E.R.B.); Christ Hospital, Cincinnati, Ohio (D.J.K.); the Riverside Methodist Hospital, Columbus, Ohio (B.S.G.); and the Division of Cardiology, Department of Medicine, University of Louisville, Louisville, Ky. (M.F.S.). Presented in part at the Annual Scientific Sessions of the American Heart Association, November 1988, Washingon, D.C. Supported in part by research grant HL-35058 from the National Institutes of Health and a grant from Genentech, Inc., South San Francisco, Calif. D.C.St. was an Established Investigator of the American Heart Association and of Genentech, Inc., during this work. Address for reprints: David C. Sane, MD, P.O. Box 3360, Duke University Medical Center, Durham, NC 27710. Received March 13, 1990; revision accepted September 4, 1990. Sane et al Racial Differences in Thrombolytic Therapy Methods Downloaded from http://circ.ahajournals.org/ by guest on June 16, 2017 Patient Population A total of 386 patients (24 black, 352 white, 10 other race), enrolled in the TAMI-1 trial from five participating centers, were analyzed for race-specific differences in response to thrombolytic therapy. The patients enrolled in this study have been described in detail in previous reports.6,7 Criteria for inclusion in the study were acute myocardial infarction of 30 minutes to 6 hours in duration and ST-segment elevation of at least 0.1 mV in at least two contiguous leads of the standard 12-lead electrocardiogram. Exclusionary criteria for entry into the protocol were recent (<6 months) trauma, major surgery within 2 weeks, recent active internal bleeding (gastrointestinal or genitourinary), brain tumors or arteriovenous malformations, stroke within 6 months, uncontrolled hypertension (diastolic blood pressure > 120 mm Hg by several measurements), prolonged cardiopulmonary resuscitation within 2 weeks, and serious advanced illnesses such as cancer. Patients older than 75 years of age, those with previous coronary artery bypass surgery, and those in cardiogenic shock upon admittance to the hospital were also excluded. rt-PA Administration All patients were treated with an infusion of a predominantly single-chain form of recombinant tissue-type plasminogen activator (rt-PA) (preparation G11044), supplied by Genentech, Inc., South San Francisco, Calif. In the first 176 patients, 60 mg was administered intravenously during the first hour, followed by 20 mg/hr for 2 hours, then 10 mg/hr for the next 5 hours (dose 1). A weight-adjusted dose was used in the final 210 patients, with 1 mg/kg given during the first hour (maximum 90 mg), followed by the remainder of a total dose of 150 mg for the next 5 hours (dose 2). A bolus of 10% of the first-hour dose was given throughout the study. The weight-adjusted dose was associated with less bleeding, whereas patency rates between the two regimens were similar.8 Angiography and Angioplasty At 90 minutes after initiation of rt-PA infusion, coronary arteriography and left ventriculography were performed in all patients. Patients were then assigned to one of several treatment groups based on the patency of the infarct-related artery as classified by the Thrombolysis in Myocardial Infarction Trial (TIMI).9 Patients who had persistent occlusion (TIMI grade 0 or 1) were not included in the randomization. These patients all underwent angioplasty unless the vessel was not suitable or the area of infarction was judged to be small. Patients with patent vessels but with more than 50% stenosis of the left main coronary artery, severe diffuse disease, cardiogenic shock, an unidentifiable infarct-related artery, or residual stenosis less than 50% were also excluded. Patients with patent infarct vessels with 50% or greater residual stenosis and TIMI grade 2 or 3 flow were randomized to 171 receive either immediate angioplasty or delayed angioplasty 1 week later. Angioplasty was performed sooner if clinically significant ischemia recurred. A successful angioplasty was defined by residual stenosis of 50% or less with TIMI grade 3 flow. After leaving the interventional cardiac catheterization laboratory, all patients received heparin for a minimum of 24 hours to maintain the activated partial thromboplastin time 1.5-2.0 times the control level. Aspirin 325 mg/day, dipyridamole 75 mg three times each day, and diltiazem 30-90 mg four times each day were administered throughout the hospitalization. ,-Blockers were withheld unless there was a strong indication for their use. Lidocaine was administered intravenously for 24 hours as prophylaxis against ventricular arrhythmias. Recurrent ischemia was defined as more than 20 minutes of angina accompanied by ST segment elevation in the infarcted territory that was unresponsive to nitrates. Reocclusion was defined as total occlusion of a reperfused infarct-related artery at any time after the patient left the cardiac catheterization laboratory. Coronary angiography with multiple views of the infarct vessel and left ventriculography were performed at 7-10 days in all patients who gave informed consent. Assessment of Bleeding Complications The performance of coronary artery bypass grafting was the variable most strongly associated with bleeding in the TAMI-1 study.10 To examine the effects of thrombolytic therapy without the additional hemostatic defects induced by cardiopulmonary bypass, only nonsurgical patients were analyzed for hemorrhagic complications. Serial hematocrit levels were obtained during the hospital course. Emesis and stool were checked for occult blood. An estimate of blood loss was calculated by adding the number of transfused units of packed red blood cells to the admission minus the nadir hematocrit level (A hematocrit) divided by three.10"11 The decision to transfuse was made by the attending physician. Coagulation Parameters rt-PA antigen, fibrinogen, fibrin(ogen) degradation products, and fragment D-dimer were assayed at baseline and at 3, 5, 8, and 12 hours after the initiation of rt-PA therapy. In vitro assay artifacts were avoided by collecting samples in 10 mM citrate containing 1 ,uM D-Phe-Pro-Arg-chloromethyl ketone (PPACK) as previously described.12 Cell-free plasma was prepared by centrifugation within 1 hour of sample collection, and the plasma was stored at -70°C until assayed. Fibrinogen levels were measured by the coagulation rate assay of Clauss13 as modified by Vermylen et al.14 Heparin levels in the therapeutic range do not interfere with the Clauss method.'2 An enzyme-linked immunosorbent assay (ELISA) based on three monoclonal antibodies was used for calculating rt-PA antigen levels.15 Fragment D-dimer was measured using an ELISA (American 172 Circulation Vol 83, No 1, January 1991 Downloaded from http://circ.ahajournals.org/ by guest on June 16, 2017 TABLE 1. Clinical Characteristics of Patient Groups Black Characteristic (n =24) Age (yr) 57+10 Sex (% male) 67 Body weight (kg) 78+15 Infarct-related artery (% of patients) Left main 0 Left anterior descending 55 Left circumflex 9 Right 36 Time from onset of chest pain to rt-PA therapy (hr) 3.1+ 1.1 Multivessel disease (% of patients) Two vessel 33 Three vessel 4 144±18 Systolic blood pressure (mm Hg) Heart rate (beats/min) 83+22 51±+12 Ejection fraction (%) History of diabetes (%) 21 71 History of smoking (%) Dose 1 vs. dose 2 (% Dose 1) 46 White TABLE 2. Effect of Race on Infarct Vessel Patency Black White (n=352) 56+11 79 82+14 0.3 40 13 47 2.9+1.1 29 1 135-+26 79+18 52+11 13 67 46 rt-PA, recombinant tissue-type plasminogen activator. Diagnostica) and was corrected for the generation of D-dimerlike epitopes in rt-PA-treated normal plasma. Fibrin(ogen) degradation products were calculated with a hemagglutination inhibition immunoassay16 performed on sera prepared by incubating plasma with thrombin (final concentration, 65 units/ ml) and aprotinin (final concentration, 1,500 KIU/ ml) for 2 hours at 37°C. Plasminogen activator inhibitor activity was measured only on baseline samples not containing PPACK by determining residual rt-PA activity after adding exogenous rt-PA.17 Statistical Methods Values are reported as mean± 1 SD. Clinical outcomes were compared by the x2 or Fisher's exact test for discrete variables and Wilcoxon's ranked-sum test for continuous variables. All reported probability values are two tailed. Clinical end points were assessed with use of the intention-to-treat principle. Caution must be used in interpretation of the probability values because of the retrospective nature of the comparisons and the multiple statistical tests.18 Results The baseline characteristics of the patients grouped by race are shown in Table 1. Black and white patients were very similar in major clinical variables including risk factors, extent of coronary artery disease, and left ventricular function. The time from onset of chest pain to thrombolytic therapy and the distribution of the two dosing regimens were also quite similar. Clinical End Points The infarct artery patency rate after 90 minutes of rt-PA infusion was 91% for black patients versus 72% Patency at 90 minutes (%) Residual stenosis at 90 minutes (%) Reocclusion at 7-10 days (%) (n=24) (n=352) 91 72 p 0.051 86+21 4.4 89+16 15 0.089 0.222 for white patients (p=0.051) (Table 2). Patients who underwent reperfusion had similar degrees of residual stenosis and rates of reocclusion during the 7- to 10-day follow-up period. The relation between race and other major clinical outcomes is shown in Table 3. Survival to discharge was the same for the two groups. Blacks and whites were equally likely to undergo coronary artery bypass grafting during the hospital period. However, white patients more frequently underwent coronary angioplasty, especially during the acute period because the 90-minute patency rate was lower in whites and the protocol mandated angioplasty of totally occluded vessels.6 During the posthospitalization follow-up period, survival rates at 6 and 12 months were similar, but the number of deaths were too few to allow valid statistical comparisons (Table 3). Coagulation Parameters Peak rt-PA antigen levels did not differ significantly between blacks and whites (Table 4). However, there was a trend toward higher rt-PA levels in blacks during and at the end of the rt-PA infusion. Baseline fibrinogen levels were similar, but nadir fibrinogen levels were markedly lower for blacks (0.57±+0.62 g/l) than for whites (1.3+0.76 g/l). The A fibrinogen (baseline -nadir) was also much greater for blacks than whites. When examined by the percentage of patients with nadir fibrinogen levels less than 0.5 g/l and less than 1.0 g/l, a striking difference was seen. More than 50% of blacks had nadir fibrinogen levels less than 0.5 g/l and more than 80% had nadir levels less than 1.0 g/l. Whites were generally resistant to severe fibrinogen depletion, and more than 60% had nadir fibrinogen levels greater than 1.0 g/l. Commensurate with greater fibrinogen depletion, the black population also had significantly greater peak fibrin(ogen) degradation product levels. Peak D-dimer levels were similar in blacks and whites. Baseline plasminogen activator inhibitor levels were also similar between the two groups. Hemorrhagic Complications Major overt clinical bleeding including intracranial and gastrointestinal hemorrhage did not differ significantly between the two groups of nonsurgical patients (Table 5). Moreover, the nadir hematocrit level and A hematocrit were similar in blacks and whites. Transfusion of 2 units or more of packed erythrocytes was required more frequently in blacks. Quantitative Sane et al Racial Differences in Thrombolytic Therapy Downloaded from http://circ.ahajournals.org/ by guest on June 16, 2017 TABLE 3. Effect of Race on Major Clinical Outcomes White Black p (n=24) (n=352) Outcome During hospitalization 92 93 0.677 Survival to discharge 6.3 8.3 Emergency CABG 0 3.7 0.444* Urgent CABG 21 12 Elective CABG 25.0 46.3 Acute PTCA 4.2 6.8 0.047* Emergency PTCA 13 11 Late PTCA Postdischarget Survival 95.5 98.8 6 Mo 98.2 12 Mo 95.5 Nonfatal MI 0 3.5 6 Mo 4.8 4.8 12 Mo PTCA 0 5.2 6 Mo 10.0 7.3 12 Mo CABG 0 1.6 6Mo 0 4.1 12 Mo CABG, coronary artery bypass graft; PTCA, percutaneous transluminal coronary angioplasty; MI, myocardial infarction. *Test of having the procedure at any time versus having no procedure. tPostdischarge values are cumulative percentages of patients who survived the initial hospitalization. Numbers in this group were too small to assign p values. TABLE 5. Effect of Race on Hemorrhagic Complications in Nonsurgical Patients White Black p (n= 17) (n=276) Complication Transfusion .2 units packed 19.5 0.001 RBC (%) 58.8 0.7 1.00 0.0 Intracranial bleeding (%) (%) 9.1 1.00 Gastrointestinal bleeding 5.9 30.6+5.6 32.5±5.4 0.146 Nadir hematocrit A Hematocrit 11.8±5.6 11.2±5.2 0.478 Units transfused + A hematocrit/3 5.4±2.8 4.5±3.4 0.072 RBC, red blood cells. blood loss estimated by the formula of units transfused + A hematocrit/311 also tended to be greater in blacks. Discussion Results from the TAMI-1 study were examined to determine whether there are differences in the response to thrombolytic therapy with rt-PA between blacks and whites. Our patient populations were quite similar in relevant demographic and baseline characteristics. Surprising differences in therapeutic and hematologic responses were found that may affect both the success and the complications of fibrinolytic therapy with rt-PA in the black population. Increased Patency of the Infarct Vessel A trend toward higher patency at the 90-minute angiographic end point was observed in blacks. The 91% patency rate in blacks exceeds that in whites (72%, p=0.051) and is greater than that observed TABLE 4. Effect of Race on Hematologic Parameters Black Parameter 2.8±2.2 Peak rt-PA antigen (,g/ml) White 2.2±3.2 (0.02/0.90/1.4/2.8/50) p 0.101 1.6±1.3 0.99±1.4 0.058 (0.06/0.29/1.20/2.66/4.49) (0.02/0.27/0.73/1.12/18.9) (0.06/0.90/3.0/3.9/8.8) End maintenance infusion rt-PA antigen (,ug/ml) Fibrinogen (g/l) Baseline Nadir A Fibrinogen Peak fibrin(ogen) degradation products (1g/ml) Peak D-dimer corrected (ng/ml) Baseline plasminogen activator inhibitor activity (units/ml) 173 3.31±0.90 2.99±0.92 (1.70/2.60/3.40/3.87/5.20) (0.080/2.37/2.80/3.60/6.90) 0.57±0.62 1.3±0.76 (0.08/0.08/0.44/0.70/2.70) (0.08/0.83/1.30/1.72/6.90) 2.7± 1.1 1.7± 1.1 (0/2.0/2.8/3.6/4.7) (0/0.90/1.5/2.3/4.9) 0.120 <0.0001 <0.0001 837±865 245 475 <0.0001 (5/135/400/1430/2660) 0.654 (0.01/0.30/1.72/2.45/16.2) (5/15/60/210/2660) 2.26±3.74 (0.01/0.85/1.36/2.19/40.3) 24±31 19±20 0.816 3.06±4.74 (3/7/12/19/118) (5/5/10/26/112) in distributions in Values parentheses represent percentiles: Oth/25th/50th/75th/100th. rt-PA, recombinant tissue-type plasminogen activator. 174 Circulation Vol 83, No 1, January 1991 Downloaded from http://circ.ahajournals.org/ by guest on June 16, 2017 with any thrombolytic agent used alone or in combination, with the possible exception of rt-PA infused at a rapid rate.19 Factors that may be expected to increase the rate of reperfusion include the time from onset of chest pain to rt-PA therapy and the dose administered. However, these factors were essentially identical in the two groups (Table 1). After reperfusion, the infarct-related vessel in blacks and whites had similar degrees of residual stenosis and reocclusion rates (Table 2). The higher patency rates in blacks suggest altered pharmacology of rt-PA or an increased sensitivity to fibrinolysis at equivalent rt-PA levels. Tissue plasminogen activator antigen levels in both groups were widely variable and not significantly different (Table 4), which is consistent with equivalent dosing regimens and volumes of distribution. There was a trend, however, toward higher rt-PA antigen levels in black patients at both peak and end of maintenance infusion time points. Tissue plasminogen activator is cleared predominantly by the liver,20,21 but hepatic blood flow must be reduced to less than 10% of normal to affect the pharmacodynamics of rt-PA.22 Because none of these patients was in cardiogenic shock at hospital admission, a reduction of blood flow to that extent probably did not occur. Thus, intrinsic differences may exist in the hepatic clearance of rt-PA between blacks and whites, but more detailed pharmacological studies will be necessary to evaluate this question. Although population differences in the hepatic metabolism of certain drugs have been described,23 25 we are unaware of previous reports of significant race-dependent differences in rates of clearance of human recombinant proteins such as rt-PA. Extent of Fibrinogen Depletion As an indication of differences in the pharmacokinetics or pharmacodynamics of rt-PA in the two populations, blacks had significantly greater degradation of fibrinogen than did whites (Table 4). Although baseline fibrinogen levels were equivalent, nadir fibrinogen levels were significantly lower in blacks than in whites. Greater fibrinogen depletion in blacks was also reflected in the greater magnitude of the A fibrinogen (baseline - nadir). In agreement with greater fibrinogen depletion, blacks also had higher peak fibrin(ogen) degradation product levels (Table 4). Peak D-dimer levels were not significantly different in the two populations despite differences in patency rates and extent of fibrinogenolysis. Previous studies have shown that D-dimer is a poor predictor of reperfusion,26.27 and our results are consistent with this observation. Although the trend toward higher rt-PA levels in blacks at the end of the maintenance infusion may partially explain the increased fibrinogenolysis in this group, other factors should be considered. Further studies will be necessary to elucidate the exact mechanism(s) for the enhanced fibrinogenolysis during therapy with rt-PA now observed in US blacks. The differences observed in patency rates and fibrinogenolysis did not affect major clinical outcomes such as survival to discharge or the necessity for revascularization by coronary artery bypass grafting (Table 3). Blacks did have fewer angioplasty procedures, especially acute procedures, than did whites, reflecting the higher acute patency rates. In the 6-12month follow-up period, there was a trend for more angioplasties in blacks than in whites, perhaps reflecting the decreased use of angioplasty in this population during the in-hospitalization period. However, the number of patients in the postdischarge group was too small to allow more meaningful comparisons. Risk of Bleeding The major complication of thrombolytic therapy is hemorrhage. The major contributors to bleeding are invasive procedures, especially coronary artery bypass grafting during the lytic period.10 Because cardiopulmonary bypass creates an additional set of hemostatic defects, only nonsurgical patients were examined for the bleeding associated with rt-PA administration. Major overt clinical bleeding rates at intracranial and gastrointestinal sites were similar between blacks and whites (Table 5). However, blacks received more transfusions than did whites, even though the nadir hematocrit level and A hematocrit (baseline-nadir) did not differ significantly. The difference in transfusion rates may indicate that packed erythrocytes were administered to some bleeding patients early in the course of the bleeding complication, thereby avoiding an exceptionally large drop in the hematocrit level. As a measure of bleeding, the more frequent transfusion rate in blacks correlates with their greater extent of fibrinogen depletion and higher fibrin(ogen) degradation product levels. Both of these factors have been significantly but weakly correlated with bleeding risk in prior studies.102829 The excess bleeding in blacks occurred despite fewer angioplasty procedures during the acute period, providing even stronger support for the association of increased transfusion requirements with fibrinogen depletion. In conclusion, this study demonstrates differences between blacks and whites in the response to thrombolytic therapy with rt-PA. Because the black population in this study was relatively small, these findings must be viewed as preliminary, requiring confirmation by larger studies. Further investigation will also be necessary to determine whether the observed differences are due chiefly to higher rt-PA levels in blacks or to other factors. The increased 90-minute patency rate after treatment of blacks with rt-PA, if confirmed, may compensate for the reported worse prognosis of myocardial infarction in this population. However, this potential benefit should be weighed against the increased transfusion requirement. Furthermore, these findings raise the possibility that the rt-PA dosing regimen may need to be adjusted for blacks and other nonwhite races to achieve a maximal benefit to risk ratio. It is also important to recognize Sane et al Racial Differences in Thrombolytic Therapy that large, randomized studies may not allow for accurate determination of race-dependent benefits and risks of therapy if disproportionately composed of restricted populations or if reported for the population as a whole. Acknowledgments We are grateful to Dagnija Thornton and Elizabeth Macy for expert technical assistance. Although Dr. Stump had no financial interest in Genentech, Inc., during the conduct of this study, he has since become its employee. References 1. Gillum RF, Liu KC: Coronary heart disease mortality in United States blacks: 1940-1978: Trends and unanswered questions. Am Heart J 1984;108:728-732 Downloaded from http://circ.ahajournals.org/ by guest on June 16, 2017 2. Tofler GH, Stone PH, Muller JE, Willich SN, Davis VG, Poole WK, Strauss HW, Willerson JT, Jaffe AS, Robertson T, Passamani E, Braunwald E, and the MILIS Study Group: Effects of gender and race on prognosis after myocardial infarction: Adverse prognosis for women, particularly black women. J Am Coll Cardiol 1987;9:473-482 3. Castaner A, Simmons BE, Mar M, Cooper R: Myocardial infarction among black patients: Poor prognosis after hospital discharge. Ann Intem Med 1988;109:33-35 4. Haywood LJ: Coronary heart disease mortality/morbidity and risk in blacks: I. Clinical manifestations and diagnostic criteria: The experience with the Beta Blocker Heart Attack Trial. Am Heart J 1984;108:787-793 5. Oberman A, Cutter G: Issues in the natural history and treatment of coronary heart disease in black populations: Surgical treatment. Am Heart J 1984;108:688-694 6. Topol EJ, Califf RM, George BS, Kereiakes DJ, Abbottsmith CW, Candela RJ, Lee KL, Pitt B, Stack RS, O'Neill WW, and the TAMI Study Group: A multicenter randomized trial of intravenous recombinant tissue plasminogen activator and immediate versus deferred angioplasty in acute myocardial infarction. N Engl J Med 1987;317:581-588 7. Topol EJ, Califf RM, Kereiakes DJ, George BS: Thrombolysis and Angioplasty in Myocardial Infarction (TAMI) Trial. JAm Coll Cardiol 1987;10:65B-74B 8. Topol EJ, George BS, Kereiakes DJ, Candela RJ, Abbottsmith CW, Stump DC, Boswick JM, Stack RS, Califf RM, and the TAMI Study Group: Comparison of two dose regimens of intravenous tissue plasminogen activator for acute myocardial infarction. Am J Cardiol 1988;61:723-728 9. TIMI Study Group: The Thrombolysis in Myocardial Infarction trial: Phase I findings. N Engl J Med 1985;312:932-936 10. Califf RM, Topol EJ, George BS, Boswick JM, Abbottsmith C, Sigmon KN, Candela R, Masek R, Kereiakes D, O'Neil WW, Stack RS, Stump D: Hemorrhagic complications associated with the use of intravenous tissue plasminogen activator in treatment of acute myocardial infarction. Am J Med 1988;85: 353-359 11. Landefeld CS, Cook EF, Hatley M, Weisberg M, Goldman L: Identification and preliminary validation of predictors of major bleeding in hospitalized patients starting anticoagulant therapy. Am J Med 1987;82:703-713 12. Stump DC, Topol EJ, Chen AB, Hopkins A, Collen D: Monitoring of hemostasis parameters during coronary thrombolysis with recombinant tissue-type plasminogen activator. Thromb Haemost 1988;59:133-137 175 13. Clauss A: Gerinnungsphysiologische Schnellmethode zur Bestimmung des Fibrinogens. Acta Haematol 1957;37:237-246 14. Vermylen C, DeVreker RA, Verstraete M: A rapid enzymatic method for assay of fibrinogen fibrin polymerization time (FPT-test). Clin Chem Acta 1963;8:418-424 15. Holvoet P, Cleemput H, Collen D: Assay of human tissue-type plasminogen activator (t-PA) with an enzyme-linked immunosorbent assay (ELISA) based on three murine monoclonal antibodies to t-PA. Thromb Haemost 1985;54:684-687 16. Merskey C, Lalezari P, Johnson AJ: A rapid, simple, sensitive method for measuring fibrinolytic split products in human serum. Proc Soc Exp Biol Med 1969;131:871-875 17. Verheijen JH, Chang GTG, Kluft C: Evidence for the occurrence of fast acting inhibitor for tissue-type plasminogen activator in human plasma. Thromb Haemost 1984;5 11: 392-395 18. Browner WS, Newman TH: Are all significant p values created equal? The analogy between diagnostic tests and clinical research. JAMA 1987;257:2459-2463 19. Neuhaus KL, Feuerer W, Jeep-Tebbe S, Niederer Vogt A, Tebbe U: Improved thrombolysis with a modified dose regimen of recombinant tissue type plasminogen activator. J Am Coll Cardiol 1989;14:1566-1569 20. Korninger C, Stassen JM, Collen D: Turnover of human extrinsic (tissue-type) plasminogen activator in rabbits. Thromb Haemost 1981;46:658-661 21. Dzik WH, Arkin CF, Jenkins RL, Stump DC: Fibrinolysis during liver transplantation in humans: Role of tissue-type plasminogen activator. Blood 1988;71:1090-1095 22. Bounameaux H, Stassen JM, Seghers C, Collen D: Influence of fibrin and liver blood flow on the turnover and the systemic fibrinogenolytic effects of recombinant tissue-type plasminogen activator in rabbits. Blood 1986;67:1493-1497 23. Clark DW: Genetically determined variability in acetylation and oxidation: Therapeutic implications. Drugs 1985;29: 342-375 24. Jacqz R, Hall SD, Branch RA: Genetically determined polymorphisms in drug oxidation. Hepatology 1986;6:1020-1032 25. Zhou H-H, Koshakji RP, Silberstein DJ, Wilkinson GP, Wood AJJ: Racial differences in drug response: Altered sensitivity to and clearance of propanolol in men of Chinese descent as compared with American whites. N Engl J Med 1989;320: 565-570 26. Francis CW, Connaghan G, Marder VJ: Assessment of fibrin degradation products during fibrinolytic therapy for acute myocardial infarction. Circulation 1986;74:1027-1036 27. Brenner B, Francis CW, Fitzpatrick PG, Rothbard RL, Cox C, Hackworthy RA, Anderson JL, Sorensen SG, Marder VJ: Relation of plasma D-dimer concentrations to coronary artery reperfusion before and after thrombolytic treatment in patients with acute myocardial infarction. Am J Cardiol 1989; 63:1179-1184 28. Rao AK, Pratt C, Berke A, Jaffe A, Ockene I, Schreiber TL, Bell WR, Knatterud G, Robertson TL, Terrin ML for the TIMI Investigators: Thrombolysis in Myocardial Infarction Trial. Phase I: Hemorrhagic manifestations and changes in plasma fibrinogen and the fibrinolytic system in patients treated with recombinant tissue plasminogen activator and streptokinase. JAm Coll Cardiol 1988;11:1-11 29. Stump DC, Califf RM, Topol EJ, Sigmon K, Thornton D, Masek R, Anderson L, Collen D, and the TAMI Study Group: Pharmacodynamics of thrombolysis with recombinant tissuetype plasminogen activator: Correlation with characteristics of and clinical outcomes in patients with acute myocardial infarction. Circulation 1989;80:1222-1230 KEY WORDS * TAMI-1 fibrinolytic therapy * hemorrhagic complications plasminogen activator * racial stocks Racial differences in responses to thrombolytic therapy with recombinant tissue-type plasminogen activator. Increased fibrin(ogen)olysis in blacks. The Thrombolysis and Angioplasty in Myocardial Infarction Study Group. D C Sane, D C Stump, E J Topol, K N Sigmon, W K Clair, D J Kereiakes, B S George, M F Stoddard, E R Bates and R S Stack Downloaded from http://circ.ahajournals.org/ by guest on June 16, 2017 Circulation. 1991;83:170-175 doi: 10.1161/01.CIR.83.1.170 Circulation is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231 Copyright © 1991 American Heart Association, Inc. All rights reserved. Print ISSN: 0009-7322. 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