TIMI risk score for ST-elevation myocardial infarction: A convenient, bedside, clinical score for risk assessment at presentation: An intravenous nPA for treatment of infarcting myocardium early II trial substudy.

BACKGROUND: Considerable variability in mortality risk exists among patients with ST-elevation myocardial infarction (STEMI). Complex multivariable models identify independent predictors and quantify their relative contribution to mortality risk but are too cumbersome to be readily applied in clinical practice. METHODS AND RESULTS: We developed and evaluated a convenient bedside clinical risk score for predicting 30-day mortality at presentation of fibrinolytic-eligible patients with STEMI. The Thrombolysis in Myocardial Infarction (TIMI) risk score for STEMI was created as the simple arithmetic sum of independent predictors of mortality weighted according to the adjusted odds ratios from logistic regression analysis in the Intravenous nPA for Treatment of Infarcting Myocardium Early II trial (n=14 114). Mean 30-day mortality was 6.7%. Ten baseline variables, accounting for 97% of the predictive capacity of the multivariate model, constituted the TIMI risk score. The risk score showed a >40-fold graded increase in mortality, with scores ranging from 0 to >8 (P:<0.0001); mortality was <1% among patients with a score of 0. The prognostic discriminatory capacity of the TIMI risk score was comparable to the full multivariable model (c statistic 0. 779 versus 0.784). The prognostic performance of the risk score was stable over multiple time points (1 to 365 days). External validation in the TIMI 9 trial showed similar prognostic capacity (c statistic 0.746). CONCLUSIONS: The TIMI risk score for STEMI captures the majority of prognostic information offered by a full logistic regression model but is more readily used at the bedside. This risk assessment tool is likely to be clinically useful in the triage and management of fibrinolytic-eligible patients with STEMI.

Combination therapy with abciximab reduces angiographically evident thrombus in acute myocardial infarction: a TIMI 14 substudy.

BACKGROUND: Use of abciximab in combination with administration of thrombolytics has been shown to improve epicardial and microvascular coronary blood flow in acute myocardial infarction (AMI). As a potential mechanism, we hypothesized that combination therapy would reduce angiographically evident thrombus (AET) and would increase lumen diameter compared with thrombolytic monotherapy. METHODS AND RESULTS: Patients who received combination therapy in TIMI 14 (low-dose thrombolytic plus abciximab, n=732) were compared with patients who received thrombolytic monotherapy without abciximab in the TIMI 4, 10A, 10B, and 14 trials (n=1662). Thrombus burden was assessed 90 minutes after treatment, and quantitative angiography was performed in an angiographic core laboratory by investigators blinded to treatment assignment. The frequency of AET was reduced in patients who received abciximab combination therapy compared with thrombolytic monotherapy (26.6% versus 35.4%, P<0.001). Similar findings were observed when the analysis was restricted to patients with patent arteries (14.7% versus 20.8%, P=0.001). Residual percent diameter stenosis at 90 minutes was also improved in the abciximab therapy group both in patent arteries (64.6+/-16.6 versus 68.3+/-14.8, P<0.001) and between patent and occluded arteries (69.3+/-19.5 versus 73.8+/-17.9, P<0.001). The absence of AET was associated with an increased frequency of >70% ST-segment resolution by 90 minutes (37.2%, 110/296 versus 18.9%, 54/286, P<0.001). CONCLUSIONS: Compared with thrombolytic monotherapy, combination therapy with abciximab reduces AET, which in turn is associated with reduced residual stenosis and improved ST-segment resolution in AMI. These data provide a pathophysiological link between platelet inhibition, reduced thrombus, and improvements in both epicardial and microvascular perfusion in AMI.

Relationship of TIMI myocardial perfusion grade to mortality after administration of thrombolytic drugs.

BACKGROUND: Although improved epicardial blood flow (as assessed with either TIMI flow grades or TIMI frame count) has been related to reduced mortality after administration of thrombolytic drugs, the relationship of myocardial perfusion (as assessed on the coronary arteriogram) to mortality has not been examined. METHODS AND RESULTS: A new, simple angiographic method, the TIMI myocardial perfusion (TMP) grade, was used to assess the filling and clearance of contrast in the myocardium in 762 patients in the TIMI (Thrombolysis In Myocardial Infarction) 10B trial, and its relationship to mortality was examined. TMP grade 0 was defined as no apparent tissue-level perfusion (no ground-glass appearance of blush or opacification of the myocardium) in the distribution of the culprit artery; TMP grade 1 indicates presence of myocardial blush but no clearance from the microvasculature (blush or a stain was present on the next injection); TMP grade 2 blush clears slowly (blush is strongly persistent and diminishes minimally or not at all during 3 cardiac cycles of the washout phase); and TMP grade 3 indicates that blush begins to clear during washout (blush is minimally persistent after 3 cardiac cycles of washout). There was a mortality gradient across the TMP grades, with mortality lowest in those patients with TMP grade 3 (2.0%), intermediate in TMP grade 2 (4.4%), and highest in TMP grades 0 and 1 (6.0%; 3-way P=0.05). Even among patients with TIMI grade 3 flow in the epicardial artery, the TMP grades allowed further risk stratification of 30-day mortality: 0.73% for TMP grade 3; 2.9% for TMP grade 2; 5.0% for TMP grade 0 or 1 (P=0.03 for TMP grade 3 versus grades 0, 1, and 2; 3-way P=0.066). TMP grade 3 flow was a multivariate correlate of 30-day mortality (OR 0.35, 95% CI 0.12 to 1.02, P=0.054) in a multivariate model that adjusted for the presence of TIMI 3 flow (P=NS), the corrected TIMI frame count (OR 1.02, P=0.06), the presence of an anterior myocardial infarction (OR 2.3, P=0.03), pulse rate on admission (P=NS), female sex (P=NS), and age (OR 1.1, P<0.001). CONCLUSIONS: Impaired perfusion of the myocardium on coronary arteriography by use of the TMP grade is related to a higher risk of mortality after administration of thrombolytic drugs that is independent of flow in the epicardial artery. Patients with both normal epicardial flow (TIMI grade 3 flow) and normal tissue level perfusion (TMP grade 3) have an extremely low risk of mortality.

Relationship between TIMI frame count and clinical outcomes after thrombolytic administration. Thrombolysis In Myocardial Infarction (TIMI) Study Group.

BACKGROUND: The corrected TIMI frame count (CTFC) is the number of cine frames required for dye to first reach standardized distal coronary landmarks, and it is an objective and quantitative index of coronary blood flow. METHODS AND RESULTS: The CTFC was measured in 1248 patients in the TIMI 4, 10A, and 10B trials, and its relationship to clinical outcomes was examined. Patients who died in the hospital had a higher CTFC (ie, slower flow) than survivors (69. 6+/-35.4 [n=53] versus 49.5+/-32.3 [n=1195]; P=0.0003). Likewise, patients who died by 30 to 42 days had higher CTFCs than survivors (66.2+/-36.4 [n=57] versus 49.9+/-32.1 [n=1059]; P=0.006). In a multivariate model that excluded TIMI flow grades, the 90-minute CTFC was an independent predictor of in-hospital mortality (OR=1.21 per 10-frame rise [95% CI, 1.1 to 1.3], an approximately 0.7% increase in absolute mortality for every 10-frame rise; P<0.001) even when other significant correlates of mortality (age, heart rate, anterior myocardial infarction, and female sex) were adjusted for in the model. The CTFC identified a subgroup of patients with TIMI grade 3 flow who were at a particularly low risk of adverse outcomes. The risk of in-hospital mortality increased in a stepwise fashion from 0.0% (n=41) in patients with a 90-minute CTFC that was faster than the 95% CI for normal flow (0 to 13 frames, hyperemia, TIMI grade 4 flow), to 2.7% (n=18 of 658 patients) in patients with a CTFC of 14 to 40 (a CTFC of 40 has previously been identified as the cutpoint for distinguishing TIMI grade 3 flow), to 6.4% (35/549) in patients with a CTFC >40 (P=0.003). Although the risk of death, recurrent myocardial infarction, shock, congestive heart failure, or left ventricular ejection fraction 20 to

Oral glycoprotein IIb/IIIa inhibition with orbofiban in patients with unstable coronary syndromes (OPUS-TIMI 16) trial.

BACKGROUND: Although intravenous glycoprotein IIb/IIIa inhibitors are beneficial in patients with acute coronary syndromes, prolonged oral IIb/IIIa inhibition might provide an additional reduction in recurrent events. METHODS AND RESULTS: Investigators at 888 hospitals in 29 countries enrolled 10 288 patients with acute coronary syndromes, which was defined as ischemic pain at rest within 72 hours of randomization, associated with positive cardiac markers, electrocardiographic changes, or prior cardiovascular disease. Patients received aspirin and were randomized to receive, for the duration of the trial, (1) 50 mg of orbofiban twice daily (50/50 group), (2) 50 mg of orbofiban twice daily for 30 days followed by 30 mg of orbofiban twice daily (50/30 group), or (3) a placebo. The primary composite end point was death, myocardial infarction, recurrent ischemia requiring rehospitalization, urgent revascularization, or stroke. The trial was terminated prematurely because of an unexpected increase in 30-day mortality in the 50/30 orbofiban group. Mortality through 10 months was 3.7% for the placebo group versus 5.1% in the 50/30 group (P=0.008) and 4.5% in the 50/50 group (P=0.11). There were no differences in the primary end point (22.9%, 23.1%, and 22.8%, for the placebo, 50/30, and 50/50 groups, respectively). Major or severe bleeding (but not intracranial hemorrhage) was higher with orbofiban; it occurred in 2. 0%, 3.7% (P=0.0004), and 4.5% (P<0.0001) of patients, respectively. Exploratory subgroup analyses found that patients who underwent percutaneous coronary intervention had a lower mortality and a significant reduction in the composite end point (P=0.001) with orbofiban. CONCLUSIONS: -Fixed-dose orbofiban failed to reduce major cardiovascular events and was associated with increased mortality in this broad population of patients with acute coronary syndromes; however, a benefit was observed among patients who underwent percutaneous coronary intervention.

Enoxaparin prevents death and cardiac ischemic events in unstable angina/non-Q-wave myocardial infarction. Results of the thrombolysis in myocardial infarction (TIMI) 11B trial.

BACKGROUND: Low-molecular-weight heparins are attractive alternatives to unfractionated heparin (UFH) for management of unstable angina/non-Q-wave myocardial infarction (UA/NQMI). METHODS AND RESULTS: Patients (n=3910) with UA/NQMI were randomized to intravenous UFH for >/=3 days followed by subcutaneous placebo injections or uninterrupted antithrombin therapy with enoxaparin during both the acute phase (initial 30 mg intravenous bolus followed by injections of 1.0 mg/kg every 12 hours) and outpatient phase (injections every 12 hours of 40 mg for patients weighing <65 kg and 60 mg for those weighing >/=65 kg). The primary end point (death, myocardial infarction, or urgent revascularization) occurred by 8 days in 14.5% of patients in the UFH group and 12.4% of patients in the enoxaparin group (OR 0.83; 95% CI 0.69 to 1.00; P=0. 048) and by 43 days in 19.7% of the UFH group and 17.3% of the enoxaparin group (OR 0.85; 95% CI 0.72 to 1.00; P=0.048). During the first 72 hours and also throughout the entire initial hospitalization, there was no difference in the rate of major hemorrhage in the treatment groups. During the outpatient phase, major hemorrhage occurred in 1.5% of the group treated with placebo and 2.9% of the group treated with enoxaparin (P=0.021). CONCLUSIONS: Enoxaparin is superior to UFH for reducing a composite of death and serious cardiac ischemic events during the acute management of UA/NQMI patients without causing a significant increase in the rate of major hemorrhage. No further relative decrease in events occurred with outpatient enoxaparin treatment, but there was an increase in the rate of major hemorrhage.

Abciximab improves both epicardial flow and myocardial reperfusion in ST-elevation myocardial infarction. Observations from the TIMI 14 trial.

BACKGROUND: In the presence of ST-elevation myocardial infarction, patients with successful epicardial reperfusion (TIMI 3 flow) but persistent ST elevation on a 12-lead ECG are at high risk for subsequent death and left ventricular dysfunction. In the TIMI 14 trial, a dose-ranging angiographic study, combined therapy with abciximab plus reduced-dose tPA enhanced the speed and efficacy of epicardial reperfusion. We determined whether the combination of abciximab plus reduced-dose tPA provided additional benefit in terms of myocardial reperfusion, as evidenced by greater resolution of ST elevation. METHODS AND RESULTS: All 346 patients with interpretable baseline and 90-minute ECGs, treated with either tPA alone or abciximab plus reduced-dose tPA (combination therapy), were included. Patients receiving combination therapy (n=221) had a 59% rate of complete (>/=70%) ST resolution at 90 minutes versus 37% in those treated with tPA alone (n=125) (P<0.0001). When the analysis was limited to patients with TIMI 3 flow, patients treated with combination therapy (n=151) remained significantly more likely to achieve complete ST resolution than those receiving tPA alone (n=80) (69% versus 44%; P=0.0002). CONCLUSIONS: Combination therapy with abciximab and reduced-dose tPA improves myocardial (microvascular) reperfusion, as reflected in greater ST-segment resolution, in addition to epicardial flow. This finding may translate into improved clinical outcomes by enhancing myocardial salvage.

Abciximab facilitates the rate and extent of thrombolysis: results of the thrombolysis in myocardial infarction (TIMI) 14 trial. The TIMI 14 Investigators.

BACKGROUND: The TIMI 14 trial tested the hypothesis that abciximab, the Fab fragment of a monoclonal antibody directed to the platelet glycoprotein (GP) IIb/IIIa receptor, is a potent and safe addition to reduced-dose thrombolytic regimens for ST-segment elevation MI. METHODS AND RESULTS: Patients (n=888) with ST-elevation MI presenting <12 hours from onset of symptoms were treated with aspirin and randomized initially to either 100 mg of accelerated-dose alteplase (control) or abciximab (bolus 0.25 mg/kg and 12-hour infusion of 0.125 microg. kg-1. min-1) alone or in combination with reduced doses of alteplase (20 to 65 mg) or streptokinase (500 000 U to 1.5 MU). Control patients received standard weight-adjusted heparin (70-U/kg bolus; infusion of 15 U. kg-1. h-1), whereas those treated with a regimen including abciximab received low-dose heparin (60-U/kg bolus; infusion of 7 U. kg-1. h-1). The rate of TIMI 3 flow at 90 minutes for patients treated with accelerated alteplase alone was 57% compared with 32% for abciximab alone and 34% to 46% for doses of streptokinase between 500 000 U and 1.25 MU with abciximab. Higher rates of TIMI 3 flow at both 60 and 90 minutes were observed with increasing duration of administration of alteplase, progressing from a bolus alone to a bolus followed by either a 30- or 60-minute infusion (P<0.02). The most promising regimen was 50 mg of alteplase (15-mg bolus; infusion of 35 mg over 60 minutes), which produced a 76% rate of TIMI 3 flow at 90 minutes and was tested subsequently in conjunction with either low-dose or very-low-dose (30-U/kg bolus; infusion of 4 U. kg-1. h-1) heparin. TIMI 3 flow rates were significantly higher in the 50-mg alteplase plus abciximab group versus the alteplase-only group at both 60 minutes (72% versus 43%; P=0.0009) and 90 minutes (77% versus 62%; P=0.02). The rates of major hemorrhage were 6% in patients receiving alteplase alone (n=235), 3% with abciximab alone (n=32), 10% with streptokinase plus abciximab (n=143), 7% with 50 mg of alteplase plus abciximab and low-dose heparin (n=103), and 1% with 50 mg of alteplase plus abciximab with very-low-dose heparin (n=70). CONCLUSIONS: Abciximab facilitates the rate and extent of thrombolysis, producing early, marked increases in TIMI 3 flow when combined with half the usual dose of alteplase. This improvement in reperfusion with alteplase occurred without an increase in the risk of major bleeding. Substantial reductions in heparin dosing may reduce the risk of bleeding even further. Modest improvements in TIMI 3 flow were seen when abciximab was combined with streptokinase, but there was an increased risk of bleeding.

Time to positivity of a rapid bedside assay for cardiac-specific troponin T predicts prognosis in acute coronary syndromes: a Thrombolysis in Myocardial Infarction (TIMI) 11A substudy.

OBJECTIVES: We sought to determine whether the rapid bedside assay for troponin T identified patients at risk for a more complicated hospital stay and a higher rate of adverse clinical events. BACKGROUND: In patients with an acute coronary syndrome, the amount of cardiac-specific troponin T released bears a stoichiometric relation to the extent of myocardial damage. METHODS: In 597 patients with unstable angina or non-Q wave myocardial infarction participating in the Thrombolysis in Myocardial Infarction (TIMI) 11A substudy, a rapid bedside assay and simultaneous quantitative serum measurement for troponin T were obtained at enrollment. RESULTS: The composite end point of the sum of death, nonfatal myocardial infarction or recurrent ischemia through day 14 occurred in 33.6% of patients with a positive assay compared with only 22.5% of patients with a negative assay (p = 0.01). Those patients in whom the rapid assay became positive in < or = 10 min had the highest mortality rate of 4.2% through day 14 compared with 1.1% in those patients who had either a late-appearing positive assay (> 10 min) or a negative assay. The duration of hospital stay in the 116 patients (19%) with a positive rapid assay at enrollment was a median of 5 days compared with only 3 days in the 481 patients (81%) with a negative rapid assay at enrollment (p = 0.002). CONCLUSIONS: A positive rapid assay for troponin T at presentation identifies those patients at risk for higher rates of adverse clinical events and longer, more complicated hospital stays. Stratification of patients by time to development of a positive rapid assay identifies those patients at highest mortality risk.

Comparison of coronary artery bypass surgery and medical therapy in patients with exercised-induced silent myocardial ischemia: a report from the Coronary Artery Surgery Study (CASS) registry.

To determine whether coronary artery bypass surgery would prolong survival in patients with silent myocardial ischemia during exercise testing, the data on 692 such patients from the Coronary Artery Surgery Study (CASS) registry were analyzed. The patients were followed up for up to 7 years after medical (n = 424) or surgical (n = 268) therapy. Stratification of patients into subsets was based on the results of cardiac catheterization. Surgical benefit was greatest in the patients with three vessel coronary artery disease or abnormal left ventricular function. Among the 75 patients with three vessel coronary disease and left ventricular dysfunction, the 7 year survival rate was 37% for the medical group and 90% for the surgical group (p less than 0.0001). Thus, among patients with silent myocardial ischemia during exercise testing in this nonrandomized study, survival appeared to be enhanced by coronary artery bypass surgery in subsets of patients with severe coronary artery disease and abnormal left ventricular function.

Incidence and management of limb ischemia with percutaneous wire-guided intraaortic balloon catheters.

In 103 patients who underwent placement of 106 percutaneous wire-guided intraaortic balloon catheters between August 1983 and January 1986, all placements were successful and the average duration of counterpulsation was 3.4 +/- 1.6 days. During counterpulsation, 45 patients developed limb ischemia that required premature balloon removal in 29 patients. The development of limb ischemia was significantly related to the presence of diabetes (risk ratio 2.0), peripheral vascular disease (risk ratio 1.9), female gender (risk ratio 1.8) and the presence of a postinsertion ankle-brachial pressure index less than 0.8 (risk ratio 7.9). There was no association between the development of limb ischemia and age, body surface area, balloon size (10.5F/12F) or adequacy of anticoagulation. Fifteen patients underwent vascular surgery for treatment of balloon-related limb ischemia, which was associated with one operative death. Nine patients had persistent limb ischemia (seven asymptomatic, two symptomatic) at the time of hospital discharge. Improvements in wire-guided balloon technology have increased the probability of successful balloon placement over that of surgical placement and have reduced the incidence of major aortic injury, but there is no evidence that these improvements have reduced the incidence of limb ischemia or its sequelae. This should be borne in mind before proceeding with balloon insertion in patients with one or more risk factors for developing limb ischemia.

The role of exercise testing in identifying patients with improved survival after coronary artery bypass surgery.

To determine whether exercise testing can identify patients whose survival might be prolonged by coronary artery bypass surgery, the results of bypass surgery were compared with those of medical therapy alone in 5,303 nonrandomized patients from the Coronary Artery Surgery Study registry who underwent exercise testing. Patients in the two treatment groups differed substantially with regard to important baseline variables. Analysis of 32 variables by Cox's regression model for survival revealed an independent beneficial effect of bypass surgery on survival (p less than 0.00001). Patients were then stratified into subsets according to the results of exercise testing. Surgical benefit was greatest in the 789 patients who exhibited at least 1 mm of ST segment depression and who could exercise only into stage 1 or less. Among the 398 patients with three vessel coronary disease showing these characteristics, 7 year survival was 58% for the medical group and 81% for the surgical group (p less than 0.001). There was no difference in survival between the surgical and medical groups among the 1,545 patients without ischemic ST segment depression who were able to exercise into stage 3 or greater. Thus, in patients who demonstrate ischemia on exercise testing and whose exercise capacity is limited, coronary bypass surgery appears to improve survival in comparison with medical therapy alone.

Cardiac troponin I for stratification of early outcomes and the efficacy of enoxaparin in unstable angina: a TIMI-11B substudy.

OBJECTIVES: We sought to evaluate cardiac troponin I (cTnI) for predicting early clinical outcomes and the efficacy of enoxaparin among patients with non-ST segment elevation acute coronary syndrome (ACS) and negative creatine kinase, MB fraction (CK-MB) levels. BACKGROUND: Cardiac TnI identifies patients with unstable angina who are at higher risk of death or myocardial infarction (MI) by 30 days. The utility of cTnI for predicting very early clinical events, including recurrent ischemia, and the efficacy of enoxaparin are not yet established. METHODS: At baseline and 12 h to 24 h after enrollment in the Thrombolysis in Myocardial Infarction (TIMI)-11B trial, samples were collected for cTnI determination. RESULTS: Among 359 patients with negative serial CK-MB values, 50.1% had a cTnI result > or =0.1 ng/ml within the first 24 h. Patients with elevated cTnI were at higher risk of death or MI at 48 h (3.9 vs. 0%, p = 0.01) and 14 days (13.9 vs. 2.2%, p<0.0001). Elevated cTnI also correlated with higher risk of recurrent ischemia requiring urgent revascularization by 48 h (10.0 vs. 1.7%, p = 0.001) and 14 days (20.6 vs. 5.6%, p< or =0.0001). Enoxaparin had a greater benefit among patients with elevated vs. normal cTnI (p = 0.03), achieving a 47% reduction in the risk of death, MI or urgent revascularization by 14 days in cTnI-positive patients (p = 0.007). CONCLUSIONS: Elevation of cTnI among patients with non-ST segment elevation ACS and negative levels of CK-MB identifies those at higher risk for very early adverse outcomes, including severe recurrent ischemia. Treatment with enoxaparin reduces the risk associated with elevated cTnI.

Outcome and profile of women and men presenting with acute coronary syndromes: a report from TIMI IIIB. TIMI Investigators. Thrombolysis in Myocardial Infarction.

OBJECTIVES: Women and men enrolled in the Thrombolysis in Myocardial Infarction (TIMI) IIIB trial of unstable angina and non-Q wave myocardial infarction (MI) were evaluated to determine gender differences in characteristics and outcome. BACKGROUND: Coronary heart disease is the leading cause of death for women and men. However, the characteristics and outcome of women compared with men with unstable angina and non-Q wave MI have not been extensively studied. METHODS: The characteristics, outcomes and proportion of 497 women and 976 men with unstable angina and non-Q wave MI at the time of enrollment were compared. When these proportions were noted to be significantly different, we compared them with the 7,731-patient TIMI IIIB Registry, which represents the non-trial, screened population with these syndromes at these centers. RESULTS: For both coronary syndromes, women were older, were less frequently white, had a higher incidence of diabetes and hypertension and were receiving more cardiac medications. The 42-day rate of death and MI in TIMI IIIB was similar for women and men (7.4% vs. 7.5%). Coronary angiography revealed less severe coronary artery disease for women than for men, with absence of critical obstructions in 25% versus 16% and mean ejection fractions 62 +/- 12% versus 57 +/- 13% for women versus men (p < 0.01). Medical management failed in women as often as in men, and rates of cardiac catheterization and percutaneous transluminal coronary angioplasty or coronary artery bypass graft surgery were similar for women and men in the conservative strategy arm as well as in the invasive strategy arm. Women in the TIMI IIIB trial had proportionately more unstable angina than did men. The proportion of unstable angina and non-Q wave MI for women was similar in the trial and Registry. However, proportionately more men in the trial had non-Q wave MI than men in the Registry. CONCLUSIONS: 1) Women with each acute coronary syndrome are older than men and have more comorbidity. 2) The outcome with unstable angina and non-Q wave MI is related to severity of illness and not gender. 3) Mortality associated with revascularization for unstable angina and non-Q wave MI was similar for women and men. 4) The proportion of women and men enrolled with each acute coronary syndrome is different. These rates reflect both the prevalence of disease and selection bias owing to trial eligibility criteria and other identified factors.

Serum amyloid A predicts early mortality in acute coronary syndromes: A TIMI 11A substudy.

OBJECTIVES: We evaluated the ability of serum amyloid A (SAA), alone and in combination with a rapid qualitative assay for cardiac-specific troponin T (cTnT), to predict 14-day mortality in patients with unstable angina or non-Q wave myocardial infarction (NQMI). BACKGROUND: Elevated C-reactive protein (CRP) has been associated with adverse outcomes in unstable coronary syndromes but data regarding its acute phase counterpart, SAA, are conflicting. METHODS: Serum amyloid A measurement and a rapid cTnT assay were performed on blood obtained at enrollment into Thrombolysis in Myocardial Infarction 11A, a dose-ranging trial of enoxaparin for unstable angina and NQMI. RESULTS: Serum amyloid A was higher in patients who died compared with survivors (6.28 vs. 0.75 mg/dL, p = 0.002). Among patients with a negative rapid cTnT, mortality was higher for those in the top quintile of SAA (6.1 vs. 0.7%, p = 0.003). Patients with both an early positive rapid cTnT (< or =10 min until assay positive) and SAA in the fifth quintile had the highest mortality followed by those with either markedly elevated SAA or an early positive rapid cTnT, while patients with both a negative rapid cTnT and SAA in quintiles 1-4 were at very low risk, (9.1 vs. 3.6 vs. 0.7%, p <0.002). CONCLUSIONS: Similar to CRP, baseline elevation of SAA identifies patients hospitalized with unstable angina and NQMI at higher risk for early mortality, even among those with a negative rapid assay for cTnT. These data support further investigation of inflammatory markers used alone and in combination with cardiac troponins for risk assessment in unstable coronary syndromes.

One-year results of the Thrombolysis in Myocardial Infarction (TIMI) IIIB clinical trial. A randomized comparison of tissue-type plasminogen activator versus placebo and early invasive versus early conservative strategies in unstable angina and non-Q wave myocardial infarction.

OBJECTIVES: We report mortality, infarction, revascularization and repeat hospital admission events for 1 year after enrollment and randomization in the Thrombolysis in Myocardial Ischemia (TIMI) IIIB clinical trial. BACKGROUND: The purpose of this trial was to investigate the role of a thrombolytic agent added to conventional medical therapies and to compare an early invasive management strategy to a more conservative early strategy in patients with unstable angina and non-Q wave myocardial infarction. METHODS: There were 1,473 patients enrolled, and they received conventional anti-ischemic medical therapies. They were randomized to therapy with either tissue-type plasminogen activator (t-PA) or placebo and also to an early invasive management strategy with coronary arteriography at 18 to 48 h, followed by revascularization as soon as possible if appropriate, or, alternatively, to an early conservative strategy with arteriography and revascularization reserved for failure of initial therapy to prevent recurrent ischemia. The primary end point was a composite outcome variable and was assessed at 42 days. Patients were then managed entirely at the discretion of their treating physician. Follow-up contacts were made at 1 year. RESULTS: The incidence of death or nonfatal infarction for the t-PA- and placebo-treated groups was similar after 1 year (12.4% vs. 10.6%, p = 0.24). The incidence of death or nonfatal infarction was also similar after 1 year for the early invasive and early conservative strategies (10.8% vs. 12.2%, p = 0.42). A trial of this size should be able to detect differences in relative risk for death or infarction > or = 1.81 with a power of 80% at a significance level (alpha) of 0.01. Revascularization by 1 year was common, but was slightly more common with the early invasive than the early conservative strategy (64% vs. 58%, p < 0.001). This result was related entirely to a small difference in angioplasty rates (39% vs. 32%, p < 0.001) inasmuch as rates of bypass grafting by 1 year were equivalent (30% in each group, p = 0.50). The high rate of revascularization in both strategies was accompanied by comparable clinical status at the 1-year follow-up contact. CONCLUSIONS: In this large study of unstable angina and non-Q wave myocardial infarction, the incidence of death and nonfatal infarction or reinfarction was low but not trivial after 1 year (4.3% mortality, 8.8% nonfatal infarction). An early invasive management strategy was associated with slightly more coronary angioplasty procedures but equivalent numbers of bypass surgery procedures than a more conservative early strategy of catheterization and revascularization only for signs of recurrent ischemia. The incidence of death or nonfatal infarction, or both, did not differ after 1 year by strategy assignment, but fewer patients in the early invasive strategy group underwent later repeat hospital admission (26% vs. 33%, p < 0.001). Either strategy is appropriate for patient management; differences in hospital admissions and revascularization procedures, with their attendant costs, are likely to be minimal.

Angiographic predictors of reocclusion after thrombolysis: results from the Thrombolysis in Myocardial Infarction (TIMI) 4 trial.

OBJECTIVES: This study attempted to determine which lesion characteristics are associated with reocclusion by 18 to 36 h. BACKGROUND: Reocclusion of the infarct-related artery after successful reperfusion is associated with significant morbidity and up to a threefold increase in mortality. METHODS: Two hundred seventy-eight patients with acute myocardial infarction were randomized to receive either anisoylated plasminogen streptokinase activator complex (APSAC) or recombinant tissue-type plasminogen activator (rt-PA) or their combination. Culprit arteries were assessed for Thrombolysis in Myocardial Infarction (TIMI) flow grade, lesion ulceration, thrombus, collateral circulation and eccentricity. Minimal lumen diameter, percent diameter stenosis and lesion irregularity (power) were calculated using quantitative angiography. RESULTS: Reocclusion was observed more frequently in arteries with TIMI 2 versus TIMI 3 flow (10.4% vs. 2.2%, p = 0.003), in ulcerated lesions (10.7% vs. 3.0%, p = 0.009) and in the presence of collateral vessels (18.2% vs. 5.6%, p = 0.03). Similar trends were observed for eccentric (7.3% vs. 2.3%, p = 0.06) and thrombotic (8.4% vs. 3.3%, p = 0.06) lesions. Reocclusion was associated with more severe mean percent stenosis (77.9% vs. 73.9%, p = 0.04). Lesion length, reference segment diameter and Fourier measures of lesion irregularity were not associated with reocclusion. CONCLUSIONS: Several simply assessed angiographic variables, such as the presence of TIMI grade 2 flow, ulceration, collateral vessels and greater percent diameter stenosis at 90 min after thrombolytic therapy, are associated with significantly higher rates of infarct-related artery reocclusion by 18 to 36 h and may aid in identifying the subset of patients who are at significantly higher risk of early reocclusion and who potentially warrant further early pharmacologic or mechanical intervention.

Efficacy and safety of incremental doses of diltiazem for the treatment of stable angina pectoris.

The safety and efficacy of incremental doses of diltiazem in treating angina pectoris were assessed in 20 patients with functional class II to III exertional angina. During an initial single-blind dose titration phase, dilitiazem produced a dose-related improvement in anginal frequency and exercise capacity. Weekly anginal attacks were reduced to 7.5 +/- 8.9, 5.6 +/- 7.8 and 4.9 +/- 7.3 on diltiazem, 120, 240 and 360 mg per day, respectively, as compared with 11.9 +/- 8.7 on placebo (all p less than 0.001). Treadmill time was significantly enhanced by high dose (360 mg per day) as compared with moderate dose (240 mg per day) diltiazem: 473 +/- 149 versus 424 +/- 146 seconds (p less than 0.05). Time to ischemic ST segment depression was similarly changed: 344 +/- 132 versus 298 +/- 142 seconds (p less than 0.05) by high dose as compared with moderate dose diltiazem. During a subsequent double-blind phase, high dose diltiazem significantly reduced weekly anginal frequency when compared with placebo: 3.1 +/- 3.0 versus 9.3 +/- 7.1 (p less than 0.001); and increased treadmill exercise time: 508 +/- 158 versus 418 +/- 172 seconds on placebo (p less than 0.05). Subjective and objective benefits of high dose diltiazem were sustained during a follow-up period of 6 months without major drug side effects.

Prognostic importance of a clinical profile and exercise test in medically treated patients with coronary artery disease.

To identify predictors of mortality in medically treated patients with symptomatic coronary artery disease, 30 variables were analyzed in 4,083 patients. Regression analysis demonstrated that seven variables were independent predictors of survival. A high risk subgroup (annual mortality rate above 5%) was identified, consisting of patients with either a congestive heart failure score of 3 to 4 or 1 mm or greater ST segment depression and final exercise stage of 1 or less. When all 30 variables were analyzed conjointly, the left ventricular contraction pattern (p less than 0.0001) and the number of diseased coronary vessels (p less than 0.003) proved to be the most important predictors of survival. In a subgroup of 572 patients with three vessel coronary disease and preserved left ventricular function, the probability of survival at 4 years ranged from 53% for patients only able to achieve stage 1/2 of exercise to 100% for patients able to exercise into stage 5 (p less than 0.004). Thus, in patients with defined coronary pathoanatomy, clinical and exercise variables primarily relating to the functional state of the left ventricle are helpful in assessing prognosis.

C-reactive protein is a potent predictor of mortality independently of and in combination with troponin T in acute coronary syndromes: a TIMI 11A substudy. Thrombolysis in Myocardial Infarction.

OBJECTIVES: We evaluated C-reactive protein (CRP) alone and in conjunction with a rapid qualitative assay for cardiac-specific troponin T (cTnT) for predicting 14-day mortality in patients with unstable angina or non-Q wave myocardial infarction (NQMI). BACKGROUND: Elevated CRP has been found to correlate with higher risk for cardiac events in patients with coronary disease. METHODS: At enrollment into the Thrombolysis in Myocardial Infarction (TIMI) 11A trial, a dose-ranging trial of enoxaparin for unstable angina and NQMI, serum was obtained for CRP measurement and rapid cTnT assay. RESULTS: Quantitative CRP and rapid cTnT assays were performed in all patients. CRP was higher among patients who died than in survivors (7.2 vs. 13 mg/dl, p = 0.0038). The probability of a positive rapid cTnT assay rose with increasing CRP concentration (p < 0.0001). Among patients with a negative rapid cTnT assay, the mortality rate was higher among patients with CRP > or = 1.55 mg/dl (5.80% vs. 0.36%, p = 0.006). Patients with both an early positive rapid cTnT assay (< or = 10 min until assay positive) and CRP > or = 1.55 mg/dl had the highest mortality, followed by those with either CRP > or = 1.55 mg/dl or an early positive rapid cTnT assay, whereas patients with both a negative rapid cTnT assay and CRP < 1.55 mg/dl were at very low risk (9.10% vs. 4.65% vs. 0.36%, p = 0.0003). CONCLUSIONS: Elevated CRP at presentation in patients with unstable angina or NQMI is correlated with increased 14-day mortality, even in patients with a negative rapid cTnT assay. Quantitative CRP and a rapid cTnT assay provide complementary information for stratifying patients with regard to mortality risk.