Graham C. Wong

Elevations in Troponin T and I Are Associated With Abnormal Tissue Level Perfusion A TACTICS-TIMI 18 Substudy

Background—Cardiac troponin T (cTnT) and I elevations are associated with a higher risk of adverse events, a higher incidence of multivessel disease, complex lesions, and visible thrombus in the setting of non-ST elevation (NSTE) acute coronary syndromes (ACS). Other pathophysiological mechanisms underlying troponin elevation remain unclear. Methods and Results—We evaluated the relationship between troponin elevation and tissue level perfusion using the TIMI myocardial perfusion grade (TMPG) in 310 patients with NSTE-ACS in the Treat Angina with Aggrastat and Determine Cost of Therapy with an Invasive or Conservative Strategy-Thrombolysis in Myocardial Infarction (TACTICS-TIMI) 18 trial. TMPG 0/1 (“closed” microvasculature) was observed more frequently in cTnT-positive patients both before (58.1% versus 42.1%;P =0.007) and after percutaneous coronary intervention (55.4% versus 35.6%;P =0.004). cTnT levels were higher among patients with TMPG 0/1 versus patients with TMPG 2/3 (0.50 versus 0.31 ng/mL;P =0.006). cTnT-positive patients were more likely to have thrombus (42.5% versus 29.3%), tighter stenoses (72.0% versus 64.8%), and higher rates of TIMI flow grade 0/1 (15.6% versus 7.0%; all P <0.05). TMPG 0/1 remained independently associated with cTnT elevation (odds ratio, 1.81;P =0.02), even after adjusting for epicardial TIMI flow grade, presence of thrombus, and prior myocardial infarction. TMPG 0/1 flow both before and after intervention was associated with increased risk of death or myocardial infarction at 6 months. Conclusions—Similar to what has been observed in the setting of ST-elevation myocardial infarction, abnormal tissue level perfusion is also associated with adverse outcomes in the NSTE-ACS setting. Independent of the presence of thrombus and abnormal flow in the epicardial artery, impaired tissue level perfusion is associated with a 1.8-fold increased risk of cTnT elevation.

Time for contrast material to traverse the epicardial artery and the myocardium in ST-Segment elevation acute myocardial infarction versus unstable angina pectoris/non–ST-elevation acute myocardial infarction☆

Although the time for contrast material to fill the epicardial artery in the setting of acute coronary syndromes has been studied extensively, the time for contrast material to fill the myocardium has not been evaluated. We compared differences in myocardial contrast material transit among patients with unstable angina pectoris/non-ST-elevation acute myocardial infarction (UAP/NSTEAMI) with patients with ST-elevation acute myocardial infarction (STEAMI). The time it took for contrast material to first appear and to arrive at peak intensity in the myocardium was compared in 224 patients with STEAMI enrolled in the LIMIT-AMI study versus 430 patients with UAP/NSTEAMI enrolled in the TACTICS-TIMI 18 trial. In patients with STEAMI, there was a delay in both the time for contrast material to first enter the myocardium (5,619 +/- 1,789 vs 4,663 +/- 1,626 ms, p <0.0001) and the time from entrance to peak blush intensity (2,387 +/- 1,359 vs 1,959 +/- 1,244 ms, p = 0.003) compared with patients with UAP/NSTEAMI. STEAMI remained significantly associated with impaired entrance of contrast material into the myocardium (p <0.0001) in a multivariate model controlling for known correlates of impaired epicardial flow (presence of thrombus, percent diameter stenosis, left anterior descending artery location, and contrast material inflow in the epicardial artery [corrected TIMI frame count]). The time for contrast material to enter the myocardium is impaired to a greater degree in STEAMI compared with UAP/NSTEAMI, even after adjusting for other variables known to delay flow in the epicardial artery. These data provide insight into potential mechanistic differences between these 2 clinical syndromes.

861-3 A phase I open-label dose escalation trial of a monoclonal antibody against tissue factor (sunol cH36) in stable coronary artery disease: Results of the PROXIMATE-TIMI 27 trial

Tissue factor (TF) is a critical participant in the genesis of acute coronary syndromes. Sunol cH36 is a chimeric monoclonal antibody to TF that blocks binding of factor X to TF:VIIa. This novel anticoagulant had not yet been tested in humans. METHODS: We assessed the safety & pharmacokinetics of cH36 in pts with stable CAD receiving aspirin. The safety analysis included all adverse events (AEs) with a focus on bleeding during 7 weeks post-dose. RESULTS: Five doses of cH36 were given IV x1 among 26 subjects (3-8 per dose tier). Preliminary results show no major bleeding (>2 g/dL fall in Hgb). Spontaneous minor bleeding exhibited a dose-related pattern (Table). Notably, most bleeding events were clinically consistent with platelet-mediated bleeding (eg. gum/ tongue). Through expected interaction with a human tissue-factor based assay, cH36 exhibited a dose-related prolongation of the prothrombin time. There were no other lab abnormalities or rx-related AEs. Human anti-chimeric antibody was not elevated at 7 wks. PK data will also be presented with the final study results. CONCLUSION: In this initial experience in humans, cH36 exhibited dose-related anticoagulant effects manifest with minor bleeding. These data support additional study at doses <0.1 mg/kg. We postulate that the platelet-mediated bleeding observed with this potent inhibitor of thrombin generation reflects important networking between thrombin & platelet pathways that may prove clinically relevant with this novel class of anticoagulants.

Association of major bleeding with adverse clinical outcomes and length of stay: A TACTICS TIMI 18 substudy

Mark K. Jordan, David E. Cohen, Graham C. Wang, Christopher P. Cannon, Eugene Braunwald, C. Michael Gibson, The TIMI Study Group, Brigham & Women’s Hospital, Boston, MA John K. French, John J. Edmond, Philip E. Aylward, Cheuk-Kit Wang, Ralph A. Stewart, Barbara F. Williams, lvor L. Gerber, Carmine DePasquale, Rachel O’Connell, John Simes, Harvey D. White, for the HERO-2 Investigators, Green Lane Hospital, Auckland, New Zealand, Flinders Medical Centre, Adelaide, Australia

Is recurrent myocardial infarction following thrombolytic administration associated with long-term mortality?

Background: While early recurrent MI (re MI) after thrombolytic therapy has been associated with higher short-term mortality in acute MI, its relationship to long-term mortality has not been explored. We hypothesized that re MI would be associated with higher mortality at both 30 days and 2 years due to the association of reMI with lower EF, more CHF, and more SCD/CHF death, Methods: 30 day mortality was ascertained in the InTIME-II trial and the TIMI 4, 9A, 9B, and 10B acute MI triels. 5122 patients had followup <1 yr, 14379 patients had data from 1 yr to <2 years, and 598 had >=2 years, but all data after 2 yrs was censored at 2 yrs. Results: The frequency of re MI dudng the index hospitalization was 4.16% (836/20101) in the five trials. Mortality by 30 days was increased in patients who experienced re MI during the index hospitalization (16.4%, 137/836 vs 6.17%, 1188/19260, p<0.001). Long-term mortality remained higher in patients sustaining re MI, even after adjusting for age, anterior MI, pulse on admission, and gender (Hazard ratio=2.07, p<0.001, Figure). However, in an analysis restricted to patients who survived the index hospitalization, long-term mortality was not significantly higher in patients who had an early reinfarction (4.38%, 31/707 vs 3.76%, 685/18206, p=NS). Conclusion: Early re MI is associated with increased mortality at 2 years. However, most deaths occur early, and the dsk of additional deaths between the index hospitalization and 2 years did not appear to be increased.

Patterns of use of targeted temperature management for acute myocardial infarction patients following out-of-hospital cardiac arrest: Insights from the National Cardiovascular Data Registry

&NA; Contemporary utilization patterns for targeted temperature management (TTM) among patients with acute myocardial infarction (MI) and out‐of‐hospital cardiac arrest (OHCA) have not been well characterized in the United States. In this nationwide evaluation of MI patients with OHCA (01/2015–03/2016; 691 hospitals), 34.1% (1792/5260) of OHCA patients received TTM. Patients who were treated with TTM had higher risk clinical features. A wide inter‐hospital variation (ranging from 0% to 82%) in TTM use observed despite few differences in case mix.