Reexamination of the Thrombin Hypothesis: What We Have Learned from TIMI 9B and GUSTO IIb.
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Journal Article↗
Biomedical subjects
E Braunwald
Publications and source records attributed to E Braunwald.
A new treatment for hypertrophic cardiomyopathy?
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Cardiomyopathy, Hypertrophic↗
Ischemic cerebral infarction after rt-PA and heparin therapy for acute myocardial infarction. The TIMI-II pilot and randomized clinical trial combined experience.
BACKGROUND AND PURPOSE: Ischemic cerebral infarction (CI) is a serious complication of acute myocardial infarction (MI). Little information exists on CI after thrombolytic therapy for MI. METHODS: Of 3924 MI patients treated with recombinant tissue plasminogen activator (rt-PA) and heparin, 29 (0.7%) developed CI after treatment. All CI patients had detailed neurological evaluations, and 27 (93%) had CT scans centrally reviewed. RESULTS: Age range was 40 to 74 years (mean, 60 years); 25 patients (86%) were men, and 22 (76%) were white. The electrocardiographic location of MI was anterior in 22 (76%) and nonanterior in 7 (24%). Five CIs occurred within 6 hours, 4 between 6 to 24 hours, 8 during the remainder of the first week, 10 during the second week, and 2 others distributed over the 4 weeks after study entry. Six of 29 CIs did not involve the cerebral cortex; 9 patients (31%) had multiple CIs. Of 28 CIs thought to be embolic in origin, 17 showed strong evidence for at least one cardiac abnormality (mural clot, wall-motion abnormality, aneurysm, or atrial fibrillation) known to be associated more specifically with embolism than MI. Eight of 27 CIs (30%) with CT scans had hemorrhagic transformation of varying degrees; 5 were symptomatic. CONCLUSIONS: The time of occurrence and sites of CI after rt-PA and heparin therapy for acute MI are similar to those reported during the prethrombolytic era.
Adult↗
Results of percutaneous transluminal coronary angioplasty in unstable angina and non-Q-wave myocardial infarction. Observations from the TIMI IIIB Trial.
BACKGROUND: This report describes the results of percutaneous transluminal coronary angioplasty (PTCA) in the Thrombolysis in Myocardial Ischemia (TIMI) IIIB Investigation. METHODS AND RESULTS: PTCA was performed before hospital discharge in 444 of 1473 patients with either unstable angina pectoris or non-Q-wave myocardial infarction (NQWMI) enrolled in TIMI IIIB. Angiographic success was observed in 96.1% of patients. For the entire cohort, the cumulative incidences of death and infarction at 1 year were 2.0% and 8.2%, respectively. The periprocedural incidence of myocardial infarction was 2.7%; emergency coronary bypass surgery, 1.4%; and death, 0.5%. By 1 year of follow-up, 122 patients (28.0%, Kaplan-Meier) had an additional revascularization procedure, 75 (61.5%) had PTCA only, 30 (24.6%) had coronary bypass surgery only, and 17 (13.9%) had both procedures. The results of PTCA were not improved by routine pretreatment with intravenous tissue plasminogen activator (TPA). Periprocedural myocardial infarction was more common among patients receiving TPA than placebo (odds ratio [OR], 2.19; P = .03) and among those with unstable angina than those with NQWMI (OR, 15.5; P = .007). No difference in outcome was observed when patients were analyzed according to age (OR, 1.06; P = .092) or sex (OR, 1.54; P = .51). Variables predictive of poor outcome were PTCA within the first 24 hours of enrollment, PTCA site being the left anterior descending coronary artery, and unsuccessful angiography. CONCLUSIONS: In TIMI IIIB, PTCA was performed for patients with unstable angina and NQWMI with a very high rate of angiographic success and a low incidence of complications. By 1 year, repeat revascularization was performed in 28.0% of patients. Routine pretreatment with thrombolysis did not enhance outcome.
Aged↗
Cardiac-specific troponin I levels to predict the risk of mortality in patients with acute coronary syndromes.
BACKGROUND: In patients with acute coronary syndromes, it is desirable to identify a sensitive serum marker that is closely related to the degree of myocardial damage, provides prognostic information, and can be measured rapidly. We studied the prognostic value of cardiac troponin I levels in patients with unstable angina or non-Q-wave myocardial infarction. METHODS: In a multicenter study, blood specimens from 1404 symptomatic patients were analyzed for cardiac troponin I, a serum marker not detected in the blood of healthy persons. The relation between mortality at 42 days and the level of cardiac troponin I in the specimen obtained on enrollment was determined both before and after adjustment for baseline characteristics. RESULTS: The mortality rate at 42 days was significantly higher in the 573 patients with cardiac troponin I levels of at least 0.4 ng per milliliter (21 deaths, or 3.7 percent) than in the 831 patients with cardiac troponin I levels below 0.4 ng per milliliter (8 deaths, or 1.0 percent; P < 0.001). There were statistically significant increases in mortality with increasing levels of cardiac troponin I (P < 0.001). Each increase of 1 ng per milliliter in the cardiac troponin I level was associated with a significant increase (P = 0.03) in the risk ratio for death after adjustment for the base-line characteristics that were independently predictive of mortality (ST-segment depression and age > or = 65 years). CONCLUSIONS: In patients with acute coronary syndromes, cardiac troponin I levels provide useful prognostic information and permit the early identification of patients with an increased risk of death.
Acute Disease↗
The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. Cholesterol and Recurrent Events Trial investigators.
BACKGROUND: In patients with high cholesterol levels, lowering the cholesterol level reduces the risk of coronary events, but the effect of lowering cholesterol levels in the majority of patients with coronary disease, who have average levels, is less clear. METHODS: In a double-blind trial lasting five years we administered either 40 mg of pravastatin per day or placebo to 4159 patients (3583 men and 576 women) with myocardial infarction who had plasma total cholesterol levels below 240 mg per deciliter (mean, 209) and low-density lipoprotein (LDL) cholesterol levels of 115 to 174 mg per deciliter (mean, 139). The primary end point was a fatal coronary event or a nonfatal myocardial infarction. RESULTS: The frequency of the primary end point was 10.2 percent in the pravastatin group and 13.2 percent in the placebo group, an absolute difference of 3 percentage points and a 24 percent reduction in risk (95 percent confidence interval, 9 to 36 percent; P = 0.003). Coronary bypass surgery was needed in 7.5 percent of the patients in the pravastatin group and 10 percent of those in the placebo group, a 26 percent reduction (P=0.005), and coronary angioplasty was needed in 8.3 percent of the pravastatin group and 10.5 percent of the placebo group, a 23 percent reduction (P=0.01). The frequency of stroke was reduced by 31 percent (P=0.03). There were no significant differences in overall mortality or mortality from noncardiovascular causes. Pravastatin lowered the rate of coronary events more among women than among men. The reduction in coronary events was also greater in patients with higher pretreatment levels of LDL cholesterol. CONCLUSIONS: These results demonstrate that the benefit of cholesterol-lowering therapy extends to the majority of patients with coronary disease who have average cholesterol levels.
Adult↗
Usefulness of fibrinogenolytic and procoagulant markers during thrombolytic therapy in predicting clinical outcomes in acute myocardial infarction. TIMI-5 Investigators. Thrombolysis in Myocardial Infarction.
Thrombin activity is increased in the setting of acute myocardial infarction (AMI) and has been shown to increase further after the administration of thrombolytic therapy for acute infarction. This increase in thrombin activity may play an important role in the 15% to 25% rate of failure to achieve initial reperfusion and in the 5% to 15% rate of early reocclusion after initially successful thrombolysis. To investigate potential mechanisms of thrombin formation in vivo, to understand better the balance of coagulation and fibrinolysis during treatment with recombinant tissue-type plasminogen activator (rt-PA), and to investigate the role of hemostatic markers as predictors of clinical events, we measured 3 markers of procoagulant activity: fibrinopeptide A (FPA), thrombin-antithrombin III complexes (TAT), and prothrombin fragment 1.2 (F1.2), and a marker of fibrinogenolytic activity (B beta 1-42) in patients enrolled in the Thrombolysis in Myocardial Infarction (TIMI)-5 study. This trial was a randomized, dose-ranging, pilot trial of hirudin versus heparin as adjunctive antithrombotic therapy with rt-PA administered to patients with AMI. Correlation of markers at 1 hour with clinical outcomes revealed that increased FPA and TAT levels were associated with increased mortality and TIMI grades 0, 1, or 2 flow at 90 minutes; increased F1.2 levels were associated with TIMI grade 0 or 1 flow at 90 minutes; and increased levels of all 3 procoagulant markers were associated with hemorrhagic events. Late (12 to 24 hours) increases in F1.2, TAT, and B beta 1-42 may be predictive of recurrent ischemia. These results suggest that selected markers of procoagulant and fibrinogenolytic activity may be useful in predicting clinical outcomes in patients treated with thrombolytic therapy for AMI.
Antithrombin III↗
Distortion of the terminal portion of the QRS on the admission electrocardiogram in acute myocardial infarction and correlation with infarct size and long-term prognosis (Thrombolysis in Myocardial Infarction 4 Trial).
Previous studies have shown an association between distortion of the terminal portion of the QRS (QRS[+] pattern: emergence of the J point > or = 50%. of the R wave in leads with qR configuration or disappearance of the S wave in leads with an Rs configuration) on admission and in-hospital mortality in acute myocardial infarction (AMI). However, the mechanism for this association is not known. We assessed the relation between QRS(+) pattern and coronary angiographic findings, infarct size, and long-term prognosis in the Thrombolysis In Myocardial Infarction 4 trial. Patients were allocated into 2 groups based on the presence (QRS[+], n = 85) or absence (QRS[-], n = 293) of QRS distortion. The QRS(+) patients were older (mean +/- SD: 61.1 +/- 10.6 vs 57.5 +/- 10.6 years, p = 0.004), had more anterior AMI (49% vs 37%, p = 0.04), and less previous angina (42% vs 54%, p = 0.05). QRS(+) patients had larger infarct size as assessed by creatine kinase release over 24 hours (209 +/- 147 vs 155 +/- 129, p = 0.003), and predischarge sestamibi (MIBI) defect (17.9 +/- 15.9% vs 11.2 +/- 13.4%, p <0.001). When adjusting for difference in baseline characteristics, p values for the differences in 24-hour creatine kinase release were 0.03 and 0.64 for anterior and nonanterior AMI, respectively, and for MIBI defect size 0.03 and 0.02, respectively. One-year mortality (18% vs 6%, p = 0.03) was higher and the weighted end point of death, reinfarction, heart failure, or left ventricular ejection fraction <40% (0.33 +/- 0.37 vs 0.24 +/- 0.32, p = 0. 13), tended to be higher in the anterior AMI patients with QRS(+). No difference in clinical outcome was found in patients with non-anterior AMI. These findings suggest that this simple electrocardiographic definition of presence of QRS(+) pattern on admission may provide an early estimation of infarct size and long-term prognosis, especially in anterior AMI.
Adult↗
Influence of race, sex, and age on management of unstable angina and non-Q-wave myocardial infarction: The TIMI III registry.
OBJECTIVE: To investigate the natural history and response to treatment of patients with unstable angina or non-Q-wave myocardial infarction (MI). DESIGN: Inception cohort. SETTING: Patients in general community, primary care, or referral hospitals. PATIENTS: All patients with an episode of unstable exertional chest pain or chest pain at rest presumed to be ischemic in origin lasting 5 minutes or more but without persisting ST-segment elevation greater than 30 minutes or the development of Q-waves were identified and enumerated in 18 participating hospitals. A subset of enumerated patients was selected to be followed prospectively using specific sampling strategies that would provide adequate numbers of black, women, and elderly (aged > or = 75 years) patients for comparison with their respective counterparts. MAIN OUTCOME MEASURES: The primary analysis compared the incidence of death or MI at 42 days after entry into the prospective study according to race, sex, and age. Other outcomes considered were recurrent ischemia and the combined outcomes of death, MI, or recurrent ischemia by 42 days after entry. RESULTS: A total of 8676 admissions with unstable angina or non-Q-wave MI were enumerated and, of these, 3318 patients were selected for the prospective study. The direct adjusted mean age of 3318 patients was 63.8 years. There were 943 blacks and 2375 nonblacks. Compared with nonblacks, blacks were less likely to be treated with intensive anti-ischemic therapy for their qualifying anginal episode and less likely to undergo invasive procedures (risk ratio [RR], 0.65%; 95% confidence interval [CI], 0.58 to 0.72; P<.001). However, of those who underwent angiography (45% of blacks and 61% of nonblacks), blacks had less extensive and severe coronary stenoses than nonblacks. The incidence of death and MI was similar for blacks and nonblacks, but blacks had a lower incidence of recurrent ischemia. There were 1678 men and 1640 women. Women were less likely than men to receive intensive anti-ischemic therapy and less likely to undergo coronary angiography (RR, 0.71; 95% CI, 0.65 to 0.78; P<.001). Women had less severe and extensive coronary disease and were less likely to undergo revascularization, yet had a similar risk of experiencing an adverse cardiac event by 6 weeks. There were 2490 patients aged 75 years or less and 828 patients aged more than 75 years. Elderly patients received less aggressive anti-ischemic therapy and were less likely to undergo coronary angiography than their younger counterparts. Elderly patients had more severe and extensive coronary disease but fewer revascularization procedures than younger patients and experienced a much higher incidence of adverse cardiac events both in hospital and by 6 weeks. CONCLUSIONS: Among patients presenting with acute ischemic chest pain without persistent ST-segment elevation, blacks appeared to have less severe coronary disease, received revascularization less frequently, and had less recurrent ischemia compared with nonblacks. Women were also found to have less severe coronary disease and were treated less intensely than men, but experienced similar outcomes. Elderly patients had more severe coronary disease than younger patients on coronary angiography, but were more likely to be treated medically, and they experienced far more adverse outcomes. These data suggest that more aggressive strategies should be directed to those patients with the greatest likelihood of adverse outcomes.
Age Factors↗
TIMI frame count: a quantitative method of assessing coronary artery flow.
BACKGROUND: Although the Thrombolysis in Myocardial Infarction (TIMI) flow grade is valuable and widely used qualitative measure in angiographic trials, it is limited by its subjective and categorical nature. METHODS AND RESULTS: In normal patients and patients with acute myocardial infarction (MI) (TIMI 4), the number of cineframes needed for dye to reach standardized distal landmarks was counted to objectively assess an index of coronary blood flow as a continuous variable. The TIMI frame-counting method was reproducible (mean absolute difference between two injections, 4.7 +/- 3.9 frames, n=85). In 78 consecutive normal arteries, the left anterior descending coronary artery (LAD) TIMI frame count (36.2 +/- 2.6 frames) was 1.7 times longer than the mean of the right coronary artery (20.4 +/- 3.0) and circumflex counts (22.2 +/- 4.1, P < .001 for either versus LAD). Therefore, the longer LAD frame counts were corrected by dividing by 1.7 to derive the corrected TIMI frame count (CTFC). The mean CTFC in culprit arteries 90 minutes after thrombolytic administration followed a continuous unimodal distribution (there were not subpopulations of slow and fast flow) with a mean value of 39.2 +/- 20.0 frames, which improved to 31.7 +/- 12.9 frames by 18 to 36 hours (P < .001). No correlation existed between improvements in CTFCs and changes in minimum lumen diameter (r=-.05, P=.59). The mean 90-minute CTFC among nonculprit arteries (25.5 +/- 9.8) was significantly higher (flow was slower) compared with arteries with normal flow in the absence of acute MI (21.0 +/- 3.1, P < .001) but improved to that of normal arteries by 1 day after thrombolysis (21.7 +/- 7.1, P=NS). CONCLUSIONS: The CTFC is a simple, reproducible, objective and quantitative index of coronary flow that allows standardization of TIMI flow grades and facilitates comparisons of angiographic end points between trials. Disordered resistance vessel function may account in part for reductions in flow in the early hours after thrombolysis.
Blood Flow Velocity↗
Acute myocardial infarction--the value of being prepared.
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Angina, Unstable↗
Time to Reperfusion: The Critical Modulator in Thrombolysis and Primary Angioplasty.
Rapid achievement of reperfusion with thrombolytic therapy or primary angioplasty has made a dramatic impact an improving the survival of patients with acute myocardial infarction (MI). Restoring infarct-related artery patency early after the onset of MI minimizes infarct size, reduces the degree of left ventricular dysfunction, and improves survival. Several recent studies have confirmed the benefit of reducing time to treatment with thrombolysis (between the onset of pain to initiation of thrombolysis), and that of more rapid drug reperfusion time with more aggressive thrombolytic regimens (between initiation of thrombolytic therapy and actual achievement of reperfusion). Furthermore, these effects are additive, confirming the benefit of rapid reperfusion. For primary angioplasty, the same relationship has been observed-more rapid treatment appears to be associated with improved outcome. The "door-to-balloon" time is a major determinant of overall time to reperfusion, and as such is a crucial component of the overall strategy. Integrating the experience in trials of thrombolytic therapy and primary angioplasty, a clear relationship exists between higher rates of early reperfusion and lower mortality. Thus, time to reperfusion appears to be the critical modulator in both thrombolysis and primary angioplasty.
Journal Article↗
Non-Q wave and ST segment depression myocardial infarction: is there a role for thrombolytic therapy?
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Electrocardiography↗
Relation between systemic anticoagulation as determined by activated partial thromboplastin time and heparin measurements and in-hospital clinical events in unstable angina and non-Q wave myocardiaL infarction. Thrombolysis in Myocardial Ischemia III B Investigators.
Although coronary thrombosis is thought to play a pivotal role in the pathogenesis of unstable angina and non-Q wave myocardial infarction and antithrombotic therapy is a mainstay in the early management of these patients, the relation between measures of systemic anticoagulation and clinical events has not been defined clearly. In the Thrombolysis in Myocardial Ischemia III trial, 1473 patients with ischemic chest pain at rest evaluated within 24 hours of symptom onset were randomized to (1) tissue plasminogen activator (TPA) or placebo and (2) an early invasive or an early conservative strategy. All patients received a full complement of anti-ischemic medication, aspirin, and continuous intravenous heparin titrated to an activated partial thromboplastin time (aPTT) of 1.5 to 2.0 times control for 72 to 96 hours. The median aPTT in all study groups exceeded the minimum threshold (45 seconds) by 24 hours and remained within the designated range during the protocol-directed heparin infusion. No differences in median aPTT values for the 72- to 96-hour study period were observed between groups (p=not significant). Median 12-hour heparin concentrations were >0.2 U/ml in all groups; however, values <0.2 U/ml were common thereafter, particularly in TPA-treated patients. Time-dependent covariate analyses failed to identify statistically significant differences in either aPTT or heparin levels between patients with in-hospital clinical events (spontaneous ischemia, myocardial infarction, or death) and those without events (p=0.27). Furthermore, early clinical events occurred in a similar percentage of patients with optimal anticoagulation (all aPTTs >60 seconds, all heparin levels>0.2 U/ml), and those with aPTTs or heparin levels below these thresholds. Aggressive (high-intensity) anticoagulation with heparin to achieve aPTTs >2.0 times control does not appear to offer additional clinical benefit to lower levels (1.5 to 2.0 times control) among patients with unstable angina and non-Q wave myocardial infarction receiving intravenous heparin and oral aspirin. Therefore, the optimal level of anticoagulation in this common clinical setting is between 45 and 60 seconds when heparin is included in the treatment strategy. Direct plasma heparin measurement does not offer an advantage to routine aPTT monitoring. The occurrence of spontaneous ischemia, myocardial infarction, and death in spite of antischemic therapy and optimal anticoagulation (as it is currently defined) with heparin supports ongoing efforts to develop more effective antithrombotic agents.
Aged↗
Trials and tribulations of thrombin inhibition.
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Clinical Trials as Topic↗
Value of rescue percutaneous transluminal coronary angioplasty following unsuccessful thrombolytic therapy in patients with acute myocardial infarction. Thrombolysis in Myocardial Infarction Investigators.
Rescue percutaneous transluminal coronary angioplasty (PTCA) has been advocated as a mechanical method to achieve reperfusion in instances where the myocardial infarct artery remains occluded after thrombolytic therapy. Most prior reports of rescue PTCA have been observational and analyses of value have been inconclusive. To evaluate the benefit of rescue PTCA, we studied 133 patients enrolled in the Thrombolysis in Myocardial Infarction Phase I Open Label and Phase II trials who had an occluded infarct-related artery after thrombolytic therapy. According to protocol, 100 consecutive patients had no rescue PTCA performed (no rescue group), and 33 consecutive patients underwent protocol-directed rescue PTCA (rescue group). The 2 cohorts were compared for clinical and angiographic outcome. Baseline characteristics of the 2 groups were similar. Rescue PTCA was attempted in each rescue group patient and was successful in 82%. At 21 days the mortality rate was 12% in the rescue group and 7% in the no rescue group (p = NS). Failed rescue PTCA was associated with a mortality of 33%. Reinfarction occurred in 6% of patients in the rescue group, and in 5% of those in the no rescue group (p = NS). At 21 days, mean left ventricular ejection fraction was 51 +/- 13% in the rescue group and 48 +/- 12% in the no rescue group (p = NS). We conclude that the routine use of rescue PTCA does not appear to offer significant benefit beyond that of contemporary medical therapy after thrombolytic failure.
Angioplasty, Balloon, Coronary↗
Prognostic value of N-terminal proatrial natriuretic factor plasma levels measured within the first 12 hours after myocardial infarction. Thrombolysis in Myocardial Infarction (TIMI) II Investigators.
OBJECTIVES: The aim of the present study was to examine the relation between the plasma levels of the atrial peptide N-terminal proatrial natriuretic factor (proANF) measured during the 1st 12 h after myocardial infarction and 1-year mortality. BACKGROUND: The atrial peptides atrial natriuretic factor and N-terminal proANF are released from cardiac atria secondary to increased atrial pressures. The plasma levels of both peptides have been found to be related to long-term prognosis when measured in the subacute phase of myocardial infarction. METHODS: The study was of a retrospective case-control design studying patients enrolled in the Thrombolysis in Myocardial Infarction (TIMI) II trial. Seventy-six patients who died within the 1st year of enrollment in the trial were matched with another 76 patients who survived. N-terminal proANF was analyzed by radioimmunoassay at enrollment (no later than 4 h after the start of chest pain) and at 50 min, 5 h and 8 h after enrollment. RESULTS: At all studied time points the peptide levels were significantly higher in the case group than in the control group. At 8 h after enrollment, an N-terminal proANF value above a cutoff point of 1,500 pmol/liter was associated with an odds ratio for death of 3.9. CONCLUSIONS: The plasma level of N-terminal proANF, when measured during the 1st 12 h after the onset of chest pain, is related to 1-year mortality after myocardial infarction. Together with previous findings, these results suggest that N-terminal proANF measurements represent a valuable supplement to currently used prognostic indicators after myocardial infarction.
Aged↗