Edoxaban vs. warfarin in patients with atrial fibrillation on amiodarone: a subgroup analysis of the ENGAGE AF-TIMI 48 trial.

BACKGROUND: In the ENGAGE AF-TIMI 48 trial, the higher-dose edoxaban (HDE) regimen had a similar incidence of ischaemic stroke compared with warfarin, whereas a higher incidence was observed with the lower-dose regimen (LDE). Amiodarone increases edoxaban plasma levels via P-glycoprotein inhibition. The current pre-specified exploratory analysis was performed to determine the effect of amiodarone on the relative efficacy and safety profile of edoxaban. METHODS AND RESULTS: At randomization, 2492 patients (11.8%) were receiving amiodarone. The primary efficacy endpoint of stroke or systemic embolic event was significantly lower with LDE compared with warfarin in amiodarone treated patients vs. patients not on amiodarone (hazard ratio [HR] 0.60, 95% confidence intervals [CIs] 0.36-0.99 and HR 1.20, 95% CI 1.03-1.40, respectively; P interaction <0.01). In patients randomized to HDE, no such interaction for efficacy was observed (HR 0.73, 95% CI 0.46-1.17 vs. HR 0.89, 95% CI 0.75-1.05, P interaction = 0.446). Major bleeding was similar in patients on LDE (HR 0.35, 95% CI 0.21-0.59 vs. HR 0.53, 95% CI 0.46-0.61, P interaction = 0.131) and HDE (HR 0.94, 95% CI 0.65-1.38 vs. HR 0.79, 95% CI 0.69-0.90, P interaction = 0.392) when compared with warfarin, independent of amiodarone use. CONCLUSIONS: Patients randomized to the LDE treated with amiodarone at the time of randomization demonstrated a significant reduction in ischaemic events vs. warfarin when compared with those not on amiodarone, while preserving a favourable bleeding profile. In contrast, amiodarone had no effect on the relative efficacy and safety of HDE.

Assessment of the treatment effect of enoxaparin for unstable angina/non-Q-wave myocardial infarction. TIMI 11B-ESSENCE meta-analysis.

BACKGROUND: Two phase III trials of enoxaparin for unstable angina/non-Q-wave myocardial infarction have shown it to be superior to unfractionated heparin for preventing a composite of death and cardiac ischemic events. A prospectively planned meta-analysis was performed to provide a more precise estimate of the effects of enoxaparin on multiple end points. METHODS AND RESULTS: Event rates for death, the composite end points of death/nonfatal myocardial infarction and death/nonfatal myocardial infarction/urgent revascularization, and major hemorrhage were extracted from the TIMI 11B and ESSENCE databases. Treatment effects at days 2, 8, 14, and 43 were expressed as the OR (and 95% CI) for enoxaparin versus unfractionated heparin. All heterogeneity tests for efficacy end points were negative, which suggests comparability of the findings in TIMI 11B and ESSENCE. Enoxaparin was associated with a 20% reduction in death and serious cardiac ischemic events that appeared within the first few days of treatment, and this benefit was sustained through 43 days. Enoxaparin's treatment benefit was not associated with an increase in major hemorrhage during the acute phase of therapy, but there was an increase in the rate of minor hemorrhage. CONCLUSIONS: The accumulated evidence, coupled with the simplicity of subcutaneous administration and elimination of the need for anticoagulation monitoring, indicates that enoxaparin should be considered as a replacement for unfractionated heparin as the antithrombin for the acute phase of management of patients with high-risk unstable angina/non-Q-wave myocardial infarction.

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.

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.

High levels of platelet inhibition with abciximab despite heightened platelet activation and aggregation during thrombolysis for acute myocardial infarction: results from TIMI (thrombolysis in myocardial infarction) 14.

BACKGROUND: We evaluated platelet activation and aggregation in patients with acute myocardial infarction (AMI) treated with thrombolytic therapy alone or with reduced-dose thrombolysis and concomitant abciximab. METHODS AND RESULTS: The study was performed in 20 control subjects and 51 patients with AMI before and after reperfusion with either alteplase or reteplase or reduced doses of these agents with concomitant abciximab. Platelet activation was assayed by platelet surface expression of P-selectin. Turbidometric platelet aggregation in response to ADP was measured in patients before thrombolytic therapy and 90 minutes and 24 hours after the beginning of thrombolytic therapy. P-selectin expression was greater at baseline in patients than normal control subjects (30.4% versus 9. 8%, P<0.0001) but was identical between the 2 groups after stimulation with ADP (64.4% versus 69.3%, P=0.37). However, at 24 hours, basal P-selectin expression declined in patients (P=0.0025 versus baseline), whereas ADP-stimulated P-selectin expression was lower in patients than in control subjects (48% versus 69%, P=0. 0004). When combined with reduced doses of either alteplase or reteplase, abciximab achieved 91% and 83% inhibition of 5 and 20 micromol/L ADP-induced platelet aggregation, which decreased to 46% and 40%, respectively, at 24 hours. No appreciable difference in the platelet inhibition profile of abciximab was observed between the 2 thrombolytics. CONCLUSIONS: Platelet activation and aggregation are heightened in the setting of thrombolysis for AMI. Despite this enhanced level of platelet activation, abciximab, combined with a reduced-dose thrombolytic, inhibited platelet aggregation similarly to the level reported in elective settings.

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.

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.

Use of an ultrashort-acting beta-receptor blocker (esmolol) in patients with acute myocardial ischemia and relative contraindications to beta-blockade therapy.

The hemodynamic responses to esmolol, an ultrashort-acting (t1/2 = 9 min) beta 1-adrenergic receptor antagonist, were examined in 16 patients with myocardial ischemia and compromised left ventricular function as evidenced by a mean pulmonary capillary wedge pressure of 15 to 25 mm Hg. Esmolol was infused intravenously to a maximal dose of 300 micrograms/kg body weight per min for less than or equal to 48 h in 16 patients: 9 with acute myocardial infarction, 6 with periinfarction angina and 1 with acute unstable angina. The sinus rate and systolic arterial pressure declined rapidly in all patients from baseline values of 99 +/- 12 beats/min and 126 +/- 19 mm Hg to 80 +/- 14 beats/min (p less than 0.05) and 107 +/- 20 mm Hg (p less than or equal to 0.05) during esmolol treatment. Rate-pressure product decreased by 33% and cardiac index by 14% during esmolol treatment, but pulmonary capillary wedge pressure was not significantly altered by drug infusion (19 +/- 3 mm Hg at baseline versus 19 +/- 5 during treatment, p = NS). In all patients there was a rapid return toward baseline hemodynamic measurements within 15 min of stopping administration of esmolol, and virtually complete resolution of drug effect was evident within approximately 30 min. During infusion of esmolol, four of nine patients receiving intravenous nitroglycerin required downward adjustment of nitroglycerin infusion rate to maintain systolic blood pressure greater than 90 mm Hg.(ABSTRACT TRUNCATED AT 250 WORDS)

Detailed analysis of 24 hour ambulatory electrocardiographic recordings during ventricular fibrillation or torsade de pointes.

Although the terminal cardiac rhythm is often well documented in many cases of sudden cardiac death, the antecedent or premonitory arrhythmias are usually not retrievable. The ambulatory electrocardiographic recordings of 12 patients who sustained ventricular fibrillation or torsade de pointes while wearing a long-term electrocardiographic monitor were analyzed in detail. A printout of the entire electrocardiographic recording was made and hand counts of ventricular arrhythmias were correlated with heart rate, QTc interval, RR interval preceding ventricular fibrillation or torsade de pointes and (RR')/QT initiating ventricular fibrillation or torsade de pointes. Common ambulatory electrocardiographic features in these 12 patients experiencing ventricular fibrillation or torsade de pointes included: 1) a period of high density of increasingly frequent or complex ventricular arrhythmias, or both, preceding ventricular fibrillation or torsade de pointes (11 patients); 2) R on T beats frequently initiating ventricular fibrillation or torsade de pointes (9 patients); and 3) repolarization abnormalities present for several hours before ventricular fibrillation or torsade de pointes (7 patients). No consistent relation between the RR and RR' interval initiating ventricular fibrillation or torsade de pointes was found; no consistent alteration in heart rate occurred before ventricular fibrillation or torsade de pointes. Thus, ventricular arrhythmias leading to sudden death in an ambulatory population do not occur in isolation but are preceded by a period of increased ventricular ectopic activity. Future guidelines for assessment of antiarrhythmic drug efficacy should include an evaluation of a drug's impact not only on ectopic beat frequency but also on arrhythmia density.

Efficacy of propafenone in Wolff-Parkinson-White syndrome: electrophysiologic findings and long-term follow-up.

The efficacy and safety of intravenous propafenone was studied in 10 patients with Wolff-Parkinson-White syndrome and in 2 patients with a concealed accessory pathway. During electrophysiologic study, the effect of propafenone on the effective refractory period of the accessory pathway was determined, as well as its effect during orthodromic atrioventricular (AV) reentrant tachycardia and atrial fibrillation. Propafenone caused significant increases in the accessory pathway refractory period, both in the anterograde direction (290 +/- 19 versus 474 +/- 50 ms, p less than 0.05) and in the retrograde direction (238 +/- 15 versus 408 +/- 44 ms, p less than 0.05). Complete anterograde accessory pathway conduction block occurred in four patients. Sustained AV reentrant tachycardia was inducible in 11 patients before administration of propafenone. Drug infusion during AV reentrant tachycardia promptly terminated arrhythmia in 10 of these 11 patients and caused slowing of AV reentrant tachycardia in the remaining patient. Before propafenone, sustained atrial fibrillation was inducible in six patients and nonsustained atrial fibrillation in four patients. After propafenone, no patient had inducible sustained atrial fibrillation. Furthermore, propafenone caused a marked decrease in peak ventricular rate during atrial fibrillation. Eight patients have been treated with oral propafenone and followed up for 12 +/- 2 months. All have remained virtually free of recurrent arrhythmia and none has developed significant side effects. Propafenone is a very promising agent for emergency intravenous therapy as well as long-term oral therapy in patients with Wolff-Parkinson-White syndrome.

Myocardial infarction redefined--a consensus document of The Joint European Society of Cardiology/American College of Cardiology Committee for the redefinition of myocardial infarction.

Definition of MI. Criteria for acute, evolving or recent MI. Either one of the following criteria satisfies the diagnosis for an acute, evolving or recent MI: 1) Typical rise and gradual fall (troponin) or more rapid rise and fall (CK-MB) of biochemical markers of myocardial necrosis with at least one of the following: a) ischemic symptoms; b) development of pathologic Qwaves on the ECG; c) ECG changes indicative of ischemia (ST segment elevation or depression); or d) coronary artery intervention (e.g., coronary angioplasty). 2) Pathologic findings of an acute MI. Criteria for established MI. Any one of the following criteria satisfies the diagnosis for established MI: 1) Development of new pathologic Q waves on serial ECGs. The patient may or may not remember previous symptoms. Biochemical markers of myocardial necrosis may have normalized, depending on the length of time that has passed since the infarct developed. 2) Pathologic findings of a healed or healing MI.

Long-term oral propafenone therapy for suppression of refractory symptomatic atrial fibrillation and atrial flutter.

Sixty patients who had recurrent episodes of symptomatic atrial fibrillation or flutter, or both, and who had failed one to five prior drug trials were treated with open label oral propafenone hydrochloride. On a mean maximal tolerated dose of 795 +/- 180 mg/day, actuarial estimates of the percent of individuals free of recurrences of symptomatic atrial fibrillation/flutter during propafenone treatment were: 1 month, 54%; 3 months, 44% and 6 months, 40%. No individual baseline characteristic achieved statistical significance as a correlate of poor response to propafenone. Drug-related adverse reactions were reported in 22% of patients but were severe enough to require termination of propafenone in only 5%. Thus, oral propafenone is a useful and well tolerated drug for long-term suppression of symptomatic recurrences of atrial fibrillation/flutter despite a history of unresponsiveness to prior antiarrhythmic drug treatment.

Therapy of refractory symptomatic atrial fibrillation and atrial flutter: a staged care approach with new antiarrhythmic drugs.

One hundred nine patients with recurrent episodes of symptomatic atrial fibrillation or flutter, or both, who had failed one to five previous antiarrhythmic drug trials were treated with propafenone and, subsequently, sotalol if atrial fibrillation recurred. The clinical profile of the study group was as follows: age 63 +/- 13 years, left atrial anteroposterior dimension 4.4 +/- 0.9 cm and left ventricular ejection fraction 57 +/- 14%. Paroxysmal atrial fibrillation occurred in 56 patients (51%) and chronic atrial fibrillation occurred in 53 patients (49%). After loading and dose titration phases were completed, the maintenance doses of drugs were 450 to 900 mg/day for propafenone and 160 to 960 mg/day for sotalol. Life table estimates of the duration of freedom from atrial fibrillation were constructed for each drug trial. The percent of patients free of recurrent symptomatic arrhythmia at 6 months was 39% for propafenone and 50% for sotalol. The cumulative proportion of patients successfully treated with propafenone or sotalol, or both, by 6 months was 55% and remained relatively constant beyond that point. The incidence of intolerable side effects necessitating discontinuation of therapy ranged from 7% to 8%. Thus, despite previous unsuccessful drug trials, a substantial proportion of patients with recurrent symptomatic atrial fibrillation refractory to conventional therapy can be treated successfully and safely with newer antiarrhythmic drugs. Treatment failures tend to occur early in the course of follow-up, permitting easy identification of candidates for alternative therapeutic approaches.

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.

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.

Myoglobin, creatine-kinase-MB and cardiac troponin-I 60-minute ratios predict infarct-related artery patency after thrombolysis for acute myocardial infarction: results from the Thrombolysis in Myocardial Infarction study (TIMI) 10B.

OBJECTIVES: We examined the diagnostic performance of serum myoglobin, creatine-kinase-MB (CK-MB) and cardiac troponin-I (cTnI) for predicting the infarct-related artery (IRA) patency in patients receiving TNK-tissue plasminogen activator (TNK-tPA) therapy for acute myocardial infarction (AMI) in the Thrombolysis in Myocardial Infarction (TIMI) 10B trial. BACKGROUND: A reliable noninvasive serum marker of IRA patency is desired to permit early identification of patients with a patent IRA after thrombolysis. METHODS: We measured myoglobin, CK-MB and cTnI concentrations in sera obtained just before thrombolysis (T0) and 60 min later (T60) in 442 patients given TNK-tPA and who underwent coronary angiography at 60 min. RESULTS: Angiography at 60 min showed a patent IRA (TIMI flow grade 2, 3) in 344 and occluded IRA (TIMI flow grade 0, 1) in 98 patients. The median serum T60 concentration, the ratio of the T60 and T0 serum concentration (60-min ratio) and the slope of increase over 60 min for each serum marker were significantly higher in patients with patent arteries compared with patients with occluded arteries. The area under the receiver-operating characteristic (ROC) curve for diagnosis of occlusion was 0.71, 0.70 and 0.71 for the 60-min ratio of myoglobin, cTnI and CKMB, respectively. The 60-min ratios of > or =4.0 for myoglobin, > or =3.3 for CK-MB and > or =2.0 for cTnI yielded a probability of patency of 90%, 88% and 87%, respectively. CONCLUSIONS: The diagnostic performance of serum myoglobin, CK-MB and cardiac troponin-I (cTnI) 60-min ratios was similar. The probability of a patent IRA was very high (90%) in patients with 60-min myoglobin ratio > or =4.0, and early invasive interventions to establish IRA patency may not be necessary in this group. Serum marker determinations at baseline and 60-min after thrombolysis may permit rapid triage of patients receiving thrombolytic therapy by ruling out IRA occlusion.

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.

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.

Impaired coronary blood flow in nonculprit arteries in the setting of acute myocardial infarction. The TIMI Study Group. Thrombolysis in myocardial infarction.

OBJECTIVES AND BACKGROUND: While attention has focused on coronary blood flow in the culprit artery in acute myocardia infarction (MI), flow in the nonculprit artery has not been studied widely, in part because it has been assumed to be normal. We hypothesized that slower flow in culprit arteries, larger territories infarcted and hemodynamic perturbations may be associated with slow flow in nonculprit arteries. METHODS: The number of frames for dye to first reach distal landmarks (corrected TIMI [Thrombolysis in Acute Myocardial Infarction] frame count [CTFC]) were counted in 1,817 nonculprit arteries from the TIMI 4, 10A, 10B and 14 thrombolytic trials. RESULTS: Nonculprit artery flow was slowed to 30.9 +/- 15.0 frames at 90 min after thrombolytic administration, which is 45% slower than normal flow in the absence of acute MI (21 +/- 3.1, p < 0.0001). Patients with TIMI grade 3 flow in the culprit artery had faster nonculprit artery CTFCs than those patients with TIMI grades 0, 1 or 2 flow (29.1 +/- 13.7, n = 1,050 vs. 33.3 +/- 16.1, n = 752, p < 0.0001). The nonculprit artery CTFC improved between 60 and 90 min (3.3 +/- 17.9 frames, n = 432, p = 0.0001), and improvements were related to improved culprit artery flow (p = 0.0005). Correlates of slower nonculprit artery flow included a pulsatile flow pattern (i.e., systolic flow reversal) in the nonculprit artery (p < 0.0001) and in the culprit artery (p = 0.01), a left anterior descending artery culprit artery location (p < 0.0001), a decreased systolic blood pressure (p = 0.01), a decreased ventriculographic cardiac output (p = 0.02), a decreased double product (p = 0.0002), a greater percent diameter stenosis of the nonculprit artery (p = 0.01) and a greater percent of the culprit artery bed lying distal to the stenosis (p = 0.04). Adjunctive percutaneous transluminal coronary angioplasty (PTCA) of the culprit artery restored a culprit artery CTFC (30.4 +/- 22.2) that was similar to that in the nonculprit artery at 90 min (30.2 +/- 13.5), but both were slower than normal CTFCs (21 +/- 3.1, p < 0.0005 for both). If flow in the nonculprit artery was abnormal (CTFC > or = 28 frames) then the CTFC after PTCA in the culprit artery was 17% slower (p = 0.01). Patients who died had slower global CTFCs (mean CTFC for the three arteries) than patients who survived (46.8 +/- 21.3, n = 47 vs. 39.4 +/- 16.7, n = 1,055, p = 0.02). CONCLUSIONS: Acute MI slows flow globally, and slower global flow is associated with adverse outcomes. Relief of the culprit artery stenosis by PTCA restored culprit artery flow to that in the nonculprit artery, but both were 45% slower than normal flow.