Determinants of improvement in epicardial flow and myocardial perfusion for ST elevation myocardial infarction; insights from TIMI 14 and InTIME-II.

BACKGROUND: When evaluating new reperfusion regimens for ST elevation MI, it is important to adjust for factors that influence the likelihood of achieving normal epicardial flow and complete ST resolution. METHODS AND RESULTS: A total of 610 patients from TIMI 14 contributed to the angiographic analyses. The electrocardiographic analyses were based on 544 patients from TIMI 14 and 763 patients from InTIME-II. For each hour from onset of symptoms to initiation of pharmacological reperfusion, the odds of achieving TIMI 3 flow at 90 min or complete ST resolution at 60-90 min decreased significantly (P=0.03). Anterior location of infarction was associated with a reduction in the odds of achieving TIMI 3 flow or complete ST resolution. The use of abciximab as part of the reperfusion regimen significantly increased the odds of TIMI 3 flow (P=0.01) and ST resolution (P<0.001). The fibrinolytic administered (alteplase, reteplase, lanoteplase) did not influence the odds of TIMI 3 flow or ST resolution after adjusting for time to treatment, infarct location, and use of abciximab. CONCLUSIONS: The influence of time from symptoms on epicardial flow and STRES reinforces the need for increased efforts to reduce treatment delays in patients with ST elevation MI. The significant benefits of abciximab with respect to facilitation of epicardial and myocardial reperfusion are evident even after adjusting for time to treatment and infarct location. To adjust for determinants of success of reperfusion regimens, phase II trials evaluating new drug combinations should consider using a randomization scheme that stratifies patients based on infarct location and time from symptoms.

An integrated clinical approach to predicting the benefit of tirofiban in non-ST elevation acute coronary syndromes. Application of the TIMI Risk Score for UA/NSTEMI in PRISM-PLUS.

AIMS: We evaluated the TIMI Risk Score for Unstable Angina and Non-ST Elevation Myocardial Infarction for predicting clinical outcomes and the efficacy of tirofiban in non-ST elevation acute coronary syndromes. METHODS AND RESULTS: Developed in TIMI 11B, the risk score is calculated as the sum of seven presenting characteristics (age > or =65 years, > or =3 cardiac risk factors, documented coronary disease, recent severe angina, ST deviation > or =0.5 mm, elevated cardiac markers, prior aspirin use). The risk score was validated in the PRISM-PLUS database (n=1915) and tested for interaction with the efficacy of tirofiban+heparin vs heparin alone. The risk score revealed an increasing gradient of risk for death, myocardial infarction or recurrent ischaemia at 14 days ranging from 7.7-30.5% (P<0.001). Dichotomized at the median, patients with a score > or =4 derived a greater relative risk reduction with tirofiban (P((Interaction))=0.025). Among patients with normal creatine kinase myocardial bands, the risk score showed a 3.5-fold gradient of risk (P<0.001) and identified a population that derived significant benefit from tirofiban (RR 0.73, P=0.027). CONCLUSION: The TIMI Risk Score is a simple clinical tool for risk assessment that may aid in the early identification of patients who should be considered for treatment with potent antiplatelet therapy.

Availability of on-site catheterization and clinical outcomes in patients receiving fibrinolysis for ST-elevation myocardial infarction.

AIMS: To compare management and clinical outcomes in hospitals stratified by the availability of on-site catheterization in InTIME-II, a multicentre trial comparing alteplase with lanoteplase for acute myocardial infarction. METHODS AND RESULTS: We studied 15,078 patients enrolled in 35 countries and 855 hospitals. Thirty-one percent of hospitals had 24-h, 25% day-only, and 44% no on-site catheterization facilities. Rates of cardiac angiography (57%, 38%, 26%) and revascularization (37%, 21%, 17%) were higher in hospitals with increasing access to on-site facilities(P<0.0001). The presence of a 24-h on-site facility was the strongest predictor of angiography during the index admission (odds ratio 4.17, 95% CI 3.85-4.54). There were no major differences in patient outcomes at 30 days when hospitals were stratified by availability of on-site catheterization. Adjusted 1-year mortality was similar between groups of hospitals (odds ratio for day-only 0.94 [0.80-1.09] and odds ratio for no availability 0.95 [0.83-1.10] compared to hospitals with 24-h facilities). CONCLUSIONS: There is a marked variation in procedure use by the availability of on-site catheterization with no major differences in patient outcomes. There is a need for additional randomized trials in the current era to address both the appropriate selection of patients and timing of invasive procedures in ST-elevation acute myocardial infarction.

A simple risk index for rapid initial triage of patients with ST-elevation myocardial infarction: an InTIME II substudy.

BACKGROUND: Rapid, effective triage is integral to emergency cardiac care of patients with ST-elevation myocardial infarction (STEMI). Available models for predicting mortality in STEMI include up to 45 variables, but have consistently shown advanced age, increased heart rate, and decreased blood pressure to be among the strongest predictors. METHODS: On the basis of observed risk relations among 13,253 patients with STEMI from the InTIME II trial, we developed and assessed a simple risk index using age, heart rate, and systolic blood pressure (SBP) for predicting mortality over 30 days: (heart rate x [age/10](2))/SBP. FINDINGS: The risk index was a strong (c statistic=0.78) and independent predictor of mortality risk (p<0.0001). When the risk index was categorised into quintiles for convenient clinical use, it revealed a more than 20-fold gradient of increasing mortality from 0.8 to 17.4%, p<0.0001. The risk index was also a robust predictor of very early events, including death by 24 h (c statistic=0.81). External validation in patients with STEMI from the TIMI 9 trials (n=3659) showed both a high discriminatory capacity (c statistic=0.79), and excellent concordance between the observed 30-day mortality in each of the five risk groups and the predictions based on InTIME II (goodness-of-fit, p=0.7). INTERPRETATION: A simple risk index based on characteristics easily assessed by any paramedical or clinical personnel captures most of the information from more complex tools, and is likely to be useful in the rapid triage of patients with STEMI outside hospital or on first arrival in the hospital.

The prognostic value of B-type natriuretic peptide in patients with acute coronary syndromes.

BACKGROUND: Brain (B-type) natriuretic peptide is a neurohormone synthesized predominantly in ventricular myocardium. Although the circulating level of this neurohormone has been shown to provide independent prognostic information in patients with transmural myocardial infarction, few data are available for patients with acute coronary syndromes in the absence of ST-segment elevation. METHODS: We measured B-type natriuretic peptide in plasma specimens obtained a mean (+/-SD) of 40+/-20 hours after the onset of ischemic symptoms in 2525 patients from the Orbofiban in Patients with Unstable Coronary Syndromes-Thrombolysis in Myocardial Infarction 16 study. RESULTS: The base-line level of B-type natriuretic peptide was correlated with the risk of death, heart failure, and myocardial infarction at 30 days and 10 months. The unadjusted rate of death increased in a stepwise fashion among patients in increasing quartiles of base-line B-type natriuretic peptide levels (P< 0.001). This association remained significant in subgroups of patients who had myocardial infarction with ST-segment elevation (P=0.02), patients who had myocardial infarction without ST-segment elevation (P<0.001), and patients who had unstable angina (P<0.001). After adjustment for independent predictors of the long-term risk of death, the odds ratios for death at 10 months in the second, third, and fourth quartiles of B-type natriuretic peptide were 3.8 (95 percent confidence interval, 1.1 to 13.3), 4.0 (95 percent confidence interval, 1.2 to 13.7), and 5.8 (95 percent confidence interval, 1.7 to 19.7). The level of B-type natriuretic peptide was also associated with the risk of new or recurrent myocardial infarction (P=0.01) and new or worsening heart failure (P<0.001) at 10 months. CONCLUSIONS: A single measurement of B-type natriuretic peptide, obtained in the first few days after the onset of ischemic symptoms, provides powerful information for use in risk stratification across the spectrum of acute coronary syndromes. This finding suggests that cardiac neurohormonal activation may be a unifying feature among patients at high risk for death after acute coronary syndromes.

Application of the TIMI risk score for ST-elevation MI in the National Registry of Myocardial Infarction 3.

CONTEXT: The Thrombolysis in Myocardial Infarction (TIMI) risk score for ST-elevation myocardial infarction (STEMI) is a simple integer score for bedside risk assessment of patients with STEMI. Developed and validated in multiple clinical trials of fibrinolysis, the risk score has not been validated in a community-based population. OBJECTIVE: To validate the TIMI risk score in a population of STEMI patients reflective of contemporary practice. DESIGN, SETTING, AND PARTICIPANTS: The risk score was evaluated among 84 029 patients with STEMI from the National Registry of Myocardial Infarction 3 (NRMI 3), which collected data on consecutive patients with myocardial infarction (MI) from 1529 US hospitals between April 1998 and June 2000. MAIN OUTCOME MEASURES: Ability of the TIMI risk score to correctly predict risk of death in terms of model discrimination (c statistic) and calibration (agreement of predicted and observed death rates). RESULTS: Patients in NRMI 3 tended to be older, to be more often female, and to have a history of coronary disease more often than those in the derivation set. Forty-eight percent received reperfusion therapy. The TIMI risk score revealed a significant graded increase in mortality with rising score (range, 1.1%-30.0%; P<.001 for trend). The risk score showed strong prognostic capacity overall (c = 0.74 vs 0.78 in derivation set) and among patients receiving acute reperfusion therapy (c = 0.79). Predictive behavior of the risk score was similar between fibrinolytic-treated patients (n = 23 960; c = 0.79) and primary percutaneous coronary intervention patients (n = 15 348; c = 0.80). In contrast, among patients not receiving reperfusion therapy, the risk score underestimated death rates and offered lower discriminatory capacity (c = 0.65). CONCLUSIONS: Sufficiently simple to be practical at the bedside and effective for risk assessment across a spectrum of patients, the TIMI risk score may be useful in triage and treatment of patients with STEMI who are treated with reperfusion therapy.

Early noninvasive detection of failed epicardial reperfusion after fibrinolytic therapy.

Available noninvasive techniques for identifying patients with failed epicardial reperfusion after fibrinolytic therapy are limited by poor accuracy. It is unknown whether combining multiple noninvasive predictors would improve diagnostic accuracy and facilitate identification of candidates for rescue percutaneous coronary intervention. In the Thrombolysis In Myocardial Infarction (TIMI) 14 trial, we evaluated the ability of ST-segment resolution (n = 606), chest pain resolution (n = 859), and the ratio of 60-minute/baseline serum myoglobin (n = 308) to identify patients with angiographic evidence of failed reperfusion 90 minutes after fibrinolysis. Three criteria were prospectively defined: <50% ST resolution at 90 minutes, presence of chest pain at the time of angiography, and myoglobin ratio <4. Patients who met any individual criterion were more likely to have less than TIMI 3 flow and an occluded infarct-related artery (TIMI 0/1 flow) than those who did not meet the criterion (p <0.005 for each). When the 3 criteria were used together (n = 169), patients who satisfied 0 (n = 29), 1 (n = 68), 2 (n = 51), or 3 (n = 21) of the criteria had a 17%, 24%, 35%, and 76% probability of failing to achieve TIMI 3 flow (p <0.0001 for trend), a 0%, 6%, 18%, and 57% probability of an occluded infarct-related artery (p <0.0001 for trend), and a 0%, 1.5%, 2.0%, and 9.5% rate of 30-day mortality (p = 0.05 for trend), respectively. Use of the criteria in combination increased positive predictive values without decreasing negative predictive values. In conclusion, ST-segment resolution, chest pain resolution, and early washout of serum myoglobin can be used in combination to aid in the early noninvasive identification of candidates for rescue percutaneous coronary intervention.

Geographic variation in patient and hospital characteristics, management, and clinical outcomes in ST-elevation myocardial infarction treated with fibrinolysis. Results from InTIME-II.

AIMS: We examined the geographic variations in InTIME-II, a randomized double-blind trial comparing alteplase with lanoteplase for myocardial infarction. METHODS AND RESULTS: We compared baseline characteristics, management, and outcomes in four regions (Western Europe, Eastern Europe, North America, and Latin America) and in countries with historically different management approaches (Germany vs the U.K., the U.S. vs Canada). Thirty-day mortality in Western Europe, Eastern Europe, North America and Latin America was 6.7%, 7.3%, 5.7%, 10.1%, P<0.0001. Adjusted mortality for Europe was intermediate between North America and Latin America (odds ratios (OR) [95% confidence intervals (CI)] compared to Western Europe: North America 0.84 [0.67-1.0], Eastern Europe 1.2 [1.0-1.4], and Latin America 1.8 [1.3-2.7]). Revascularization rates varied 10-fold but did not explain regional mortality differences. Germany and the U.K. had similar adjusted 1-year mortality (OR for the U.K. 1.16 [0.92-1.5]), although invasive procedures were four- to 10-fold more common in Germany. Similarly the U.S. and Canada had equal adjusted 1-year mortality (OR for Canada 0.85 [0.61-1.17]) despite three-fold higher use of invasive procedures in the U.S. CONCLUSIONS: Significant geographic variations in practice and adjusted mortality following fibrinolysis persist despite recent guidelines. These findings have important implications in the design and interpretation of international studies, identify under- and over-utilized therapies, and support further study of treatments with marked worldwide variations.

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.

Lower-dose heparin with fibrinolysis is associated with lower rates of intracranial hemorrhage.

BACKGROUND: The optimal heparin dose as an adjunct to fibrinolysis and its role in causing intracranial hemorrhage (ICH) is unclear. METHODS: We reviewed the heparin regimens and rates of ICH in 3 sets of recent fibrinolytic trials: (1) studies with accelerated recombinant tissue plasminogen activator (TPA, alteplase) plus intravenous heparin, in which the heparin regimen was changed during the course of the trial; (2) phase III trials with accelerated TPA plus intravenous heparin; and (3) trials of new single-bolus fibrinolytic agents. RESULTS: Lower rates of ICH were observed among studies of accelerated TPA that reduced the heparin dose mid-trial (TIMI 9A --> 9B: 1.87% --> 1.07%, GUSTO-IIa --> IIb: 0.92% --> 0.71%, TIMI 10B: 2.80% --> 1.16%). Rates of ICH with accelerated TPA gradually increased from GUSTO-I (0.72%) in 1990 to 1993 to ASSENT-2 (0.94%) in 1997 to 1998. However, this trend was reversed in InTIME-II, which used the lowest heparin dose and most aggressive activated partial thromboplastin time monitoring and observed an ICH rate of 0.64% with accelerated TPA. Lower ICH rates were also observed when the heparin dose was reduced with single-bolus tenecteplase (TNK-TPA) and lanoteplase. CONCLUSIONS: Nonrandomized comparisons with accelerated TPA suggest that lower doses of intravenous heparin are associated with lower rates of ICH. This observation also appears to apply to single-bolus TNK-TPA and novel plasminogen activator. A lower-dose, weight-adjusted heparin regimen (60 U/kg bolus; maximum, 4000 U; 12 U/kg per hour infusion; maximum, 1000 U/h) with earlier monitoring of activated partial thromboplastin time is currently recommended in the revised American College of Cardiology/American Heart Association myocardial infarction guidelines and should be used in clinical practice.

Prior aspirin users with acute non-ST-elevation coronary syndromes are at increased risk of cardiac events and benefit from enoxaparin.

BACKGROUND: The aim of this article was to investigate whether prior aspirin use in patients with acute coronary syndromes affects clinical outcome. The Efficacy Safety Subcutaneous Enoxaparin in Non-Q-Wave Coronary Events Study (ESSENCE) and Thrombolysis in Myocardial Infarction (TIMI) 11B trials have shown superiority of enoxaparin over unfractionated heparin (UFH) in patients with unstable angina and non-ST-segment elevation myocardial infarction (UA/NSTEMI). However, the treatment effect of enoxaparin in the subset of patients reporting prior aspirin use has not been determined. METHODS: The rate of death, myocardial infarction, and urgent revascularization at days 8 and 43 after randomization was compared among patients who received aspirin within the week before randomization with those who did not receive aspirin in the TIMI 11B trial. A total of 3275 patients (84%) were prior aspirin users. RESULTS: The admission diagnosis was similar for prior and nonprior aspirin users. At both day 8 and day 43 the event rate was higher for prior aspirin users than for nonprior aspirin users (odds ratio 1.6 [1.24-2.08], P =.0004 at day 43), even after correction for baseline characteristics. Compared with those prior aspirin users taking UFH, enoxaparin-treated prior aspirin users had a reduced rate of the composite end point of death, myocardial infarction, and urgent revascularization at day 8 (odds ratio 0.82 [0.67-1.00], P =.046) and day 43 (odds ratio 0.83 [0.70-0.98], P =.032). CONCLUSION: Patients with UA/NSTEMI and prior aspirin use had a 60% higher risk of death and cardiac ischemic events compared with nonprior aspirin users. On the basis of this subanalysis, enoxaparin is superior to UFH in all patients. In prior aspirin users the benefit is more clearly demonstrated.

Association of white blood cell count with increased mortality in acute myocardial infarction and unstable angina pectoris. OPUS-TIMI 16 Investigators.

We observed in a study of 7,651 patients with acute coronary syndromes that a white blood cell (WBC) count of > 10,000 was associated with increased 30-day and 10-month mortality (6.2% vs 3.2% to 3.6% for WBC count < 10,000; p < 0.000). With its simplicity and widespread availability, WBC count could serve as a simple, inexpensive, new tool for risk stratification in acute coronary syndromes.

Can we replace the 90-minute thrombolysis in myocardial infarction (TIMI) flow grades with those at 60 minutes as a primary end point in thrombolytic trials? TIMI Study Group.

The establishment of patency (Thrombolysis In Myocardial Infarction [TIMI] grade 2 or 3 flow) and/or TIMI grade 3 flow at 60 minutes after thrombolytic administration is both a univariate and multivariate predictor of in-hospital and 30-day mortality, and the odds ratios for mortality are nearly identical for TIMI grade 3 flow at 60 and 90 minutes. Thus, the 60-minute angiographic end point appears to be a valid alternative to that at 90 minutes and may permit earlier decisions regarding post-thrombolytic intervention.

ST-segment resolution and infarct-related artery patency and flow after thrombolytic therapy. Thrombolysis in Myocardial Infarction (TIMI) 14 investigators.

Because patients who fail to achieve reperfusion after thrombolytic therapy remain at high risk for morbidity and mortality, noninvasive measures of infarct-related artery (IRA) patency are needed to identify candidates for rescue interventions. We prospectively studied 444 patients from the Thrombolysis In Myocardial Infarction (TIMI) 14 trial with interpretable baseline and 90 minute 12-lead electrocardiograms. The percent resolution of ST-segment deviation from baseline to 90 minutes was compared with 90-minute IRA TIMI flow grade, as determined in an angiographic core laboratory. Patients with complete (> or = 70%) ST resolution (n = 208; 47%) had a patency (TIMI 2 or 3 flow) rate of 94%, a TIMI 3 flow rate of 79%, and a 30-day mortality rate of 1.0%. Patients with partial (30% to 70%) or no (< or = 30%) ST resolution had significantly lower rates of patency (72% and 68%; p < 0.0001 vs complete ST resolution) and TIMI 3 flow (50% and 44%; p < 0.0001 vs complete ST resolution), and higher 30-day mortality (4.2% and 5.9%; p = 0.01 vs complete ST resolution). With use of electrocardiographic criteria alone, approximately 50% of patients can be classified as having a high (94%) probability of IRA patency and a very low risk for mortality. Angiography to determine patency of the IRA may be unnecessary in these patients. In patients without complete (> or = 70%) ST resolution, the IRA is still likely to be patent, and additional information from clinical variables or serum markers may help to identify candidates for coronary angiography. Patients with persistent ST elevation despite a patent IRA are at increased risk for mortality, likely due to extensive microvascular and tissue injury.

Combination reperfusion therapy with abciximab and reduced dose reteplase: results from TIMI 14. The Thrombolysis in Myocardial Infarction (TIMI) 14 Investigators.

Aims Abciximab has previously been shown to enhance thrombolysis and improve myocardial perfusion when combined with reduced doses of alteplase. The purpose of the reteplase phase of TIMI 14 was to evaluate the effects of abciximab when used in combination with a reduced dose of reteplase for ST-elevation myocardial infarction. Methods and Results Patients (n=299) with ST-elevation myocardial infarction were treated with aspirin and randomized to a control arm with standard dose reteplase (10+10 U given 30 min apart) or abciximab (bolus of 0.25 mg. kg(-1)and 12-h infusion of 0.125 microg. kg(-1). min(-1)) in combination with reduced doses of reteplase (5+5 U or 10+5 U). Control patients received standard weight-adjusted heparin (bolus of 70 U. kg(-1); infusion of 15 U. kg(-1). h(-1)), while each of the combination arms with abciximab and reduced dose reteplase received either low dose heparin (bolus of 60 U. kg(-1); infusion of 7 U. kg(-1). h(-1)) or very low dose heparin (bolus of 30 U. kg(-1); infusion of 4 U. kg(-1). h(-1)). The rate of TIMI 3 flow at 90 min was 70% for patients treated with 10+10 U of reteplase alone (n=87), 73% for those treated with 5+5 U of reteplase with abciximab (n=88), and 77% for those treated with 10+5 U of reteplase with abciximab (n=75). Complete (>/=70%) ST resolution at 90 min was seen in 56% of patients receiving a reduced dose of reteplase in combination with abciximab compared with 48% of patients receiving reteplase alone. Conclusions Reduced doses of reteplase when administered in combination with abciximab were associated with higher TIMI 3 flow rates than reported previously for reduced doses of reteplase without abciximab and were at least as high as for full dose reteplase alone

Comparison of a 60- versus 90-minute determination of ST-segment resolution after thrombolytic therapy for acute myocardial infarction. In TIME-II Investigators. Intravenous nPA for Treatment of Infarcting Myocardium Early-II.

Determination of ST-segment resolution 60 minutes after the administration of thrombolytic therapy allows accurate risk stratification for mortality and congestive heart failure. Patients with complete ST resolution at 60 minutes tended to be at lower risk for 30-day mortality than patients with complete ST resolution at 90 minutes.

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.

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.

Superiority of enoxaparin versus unfractionated heparin for unstable angina/non-Q-wave myocardial infarction regardless of activated partial thromboplastin time.

BACKGROUND: Whether the clinical superiority of enoxaparin versus unfractionated heparin (UFH) depends on a more stable antithrombotic effect or the proportion of patients not reaching the therapeutic level with UFH has not been addressed. METHODS: All patients participating in the Thrombolysis In Myocardial Infarction 11B trial who received UFH and had sufficient activated partial thromboplastin time (aPTT) data (n = 1893) were compared with patients who received enoxaparin (n = 1938). Patients receiving UFH were divided into 3 categories depending on mean aPTT values throughout 48 hours: subtherapeutic, for those in whom the average aPTT fell below 55 seconds; therapeutic, between 55 and 85 seconds; and supratherapeutic, longer than 85 seconds. Events and bleeding rates were determined at 48 hours. RESULTS: A small portion of patients (6. 7%) had a subtherapeutic average aPTT value (n = 127). Forty-seven percent of patients (n = 891) fell within the therapeutic range, and 46% were in the supratherapeutic level (n = 875). Event rates were 7. 0% in the UFH group versus 5.4% with enoxaparin (P =.039). Events rates were higher in every aPTT strata compared with enoxaparin and statistically significant in the supratherapeutic group (odds ratio 0.65; 95% confidence interval, 0.47-0.89). Major bleeding rates were 0%, 0.6%, and 0.9% for the subtherapeutic, target, and supratherapeutic strata, respectively, and 0.8% with enoxaparin. Minor hemorrhages occurred in 5.1% of patients receiving enoxaparin versus 3.9%, 2%, and 2.3%, respectively, for the UFH subgroups (P <. 001 for all UFH groups vs enoxaparin). CONCLUSIONS: Enoxaparin showed a better clinical profile compared with every level of anticoagulation with UFH. Potential mechanisms for enoxaparin superiority are stable antithrombotic activity, lack of rebound thrombosis, and intrinsic superiority.