Prasugrel Versus Clopidogrel in Patients With ST-Segment Elevation Myocardial Infarction According to Timing of Percutaneous Coronary Intervention A TRITON–TIMI 38 Subgroup Analysis (Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel–Thrombolysis In Myocardial Infarction 38)

ObjectivesThis study sought to evaluate the efficacy of prasugrel versus clopidogrel in ST-segment elevation myocardial infarction (STEMI) by the timing of percutaneous coronary intervention (PCI).BackgroundTreatment strategies and outcomes for patients with STEMI may differ when treated with primary compared with secondary PCI.MethodsSTEMI patients in the TRITON–TIMI 38 (Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel–Thrombolysis In Myocardial Infarction 38) were randomized to prasugrel or clopidogrel on presentation if primary PCI was intended or later during secondary PCI. Primary PCI was defined as within 12 h of symptom onset. The primary endpoint was cardiovascular death, myocardial infarction (MI), or stroke. Because periprocedural MI is difficult to assess in the setting of STEMI, we performed analyses excluding these events.ResultsReductions in the primary endpoint with prasugrel versus clopidogrel (hazard ratio [HR]: 0.79; 95% confidence interval [CI]: 0.65 to 0.97; p = 0.022) were consistent between primary and secondary PCI patients at 15 months (HR: 0.89; 95% CI: 0.69 to 1.13 vs. HR: 0.65; 95% CI: 0.46 to 0.93; p interaction = 0.15). However, a tendency toward a difference in treatment effect at 30 days (HR: 0.68; 95% CI: 0.54 to 0.87; p = 0.002) was observed between primary and secondary PCI patients (HR: 0.81; 95% CI: 0.60 to 1.09 vs. HR: 0.51; 95% CI: 0.34 to 0.76; p interaction = 0.06). When periprocedural MI was excluded, the efficacy of prasugrel remained consistent among primary and secondary PCI patients at 30 days (HR: 0.53; 95% CI: 0.34 to 0.81 vs. HR: 0.44; 95% CI: 0.22 to 0.88; p interaction = 0.68) and 15 months (HR: 0.76; 95% CI: 0.56 to 1.03 vs. HR: 0.75; 95% CI: 0.46 to 1.21; p interaction = 0.96).ConclusionsThe efficacy of prasugrel versus clopidogrel was consistent irrespective of the timing of PCI, particularly in preventing nonprocedural events. (Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial Infarction 38; NCT00097591

Prospective Evaluation of the Prognostic Implications of Improved Assay Performance With a Sensitive Assay for Cardiac Troponin I

ObjectivesThe purpose of this study was to investigate the prognostic implications of low-level increases in cardiac troponin I (cTnI) using a current-generation sensitive assay in patients with suspected acute coronary syndrome (ACS).BackgroundRecent enhancements in troponin assays have enabled resolution of the 99th percentile reference limit at progressively lower concentrations. However, the clinical significance of low-level increases with sensitive assays is still debated.MethodsWe measured cTnI using a sensitive assay (TnI-Ultra, Siemens Healthcare Diagnostics, Deerfield, Illinois) at baseline in 4,513 patients with non–ST-segment elevation ACS randomly assigned to ranolazine or placebo. We applied decision limits at the 99th percentile reference limit (0.04 μg/l), the cut point of the predecessor assay (0.1 μg/l), and 1 equivalent to elevation of creatine kinase–myocardial band (1.5 ng/ml).ResultsPatients with baseline cTnI ≥0.04 μg/l (n = 2,924) were at higher risk of death/myocardial infarction (MI) at 30 days than were patients with a negative cTnI (6.1% vs. 2.0%, p < 0.001). After adjusting for the TIMI (Thrombolysis In Myocardial Infarction) risk score, cTnI ≥0.04 μg/l was associated with a 3-fold (95% confidence interval: 2.0 to 4.4, p < 0.001) higher risk of death/MI at 30 days. Moreover, patients with low-level increases (0.04 μg/l to <0.1 μg/l), were at significantly higher risk of death/MI at 30 days (5.0% vs. 2.0%, p = 0.001) and death at 12 months (6.4% vs. 2.4%, p = 0.005) than were patients with cTnI <0.04 μg/l.ConclusionsLow-level increases in cTnI using a sensitive assay identify patients at higher risk of death or MI. These findings support current American College of Cardiology/American Heart Association recommendations defining MI, and the incremental value of newer, more sensitive assays in identifying high-risk patients with ACS

Association among plasma levels of monocyte chemoattractant protein-1, traditional cardiovascular risk factors, and subclinical atherosclerosis

ObjectivesWe sought to evaluate the association between plasma levels of monocyte chemoattractant protein (MCP)-1 and the risk for subclinical atherosclerosis.BackgroundMonocyte chemoattractant protein is a chemokine that recruits monocytes into the developing atheroma and may contribute to atherosclerotic disease development and progression. Plasma levels of MCP-1 are independently associated with prognosis in patients with acute coronary syndromes, but few population-based data are available from subjects in earlier stages of atherosclerosis.MethodsIn the Dallas Heart Study, a population-based probability sample of adults in Dallas County ≤65 years old, plasma levels of MCP-1 were measured in 3,499 subjects and correlated with traditional cardiovascular risk factors, high-sensitivityC-reactive protein (hs-CRP), and coronary artery calcium (CAC) measured by electron beam computed tomography.ResultsHigher MCP-1 levels were associated with older age, white race, family history of premature coronary disease, smoking, hypertension, diabetes, hypercholesterolemia, and higher levels of hs-CRP (p &lt; 0.01 for each). Similar associations were observed between MCP-1 and risk factors in the subgroup of participants without detectable CAC. Compared with the subjects in the lowest quartile of MCP-1, the odds of prevalent CAC (CAC score ≥10) for subjects in the second, third, and fourth quartiles were 1.30 (95% confidence interval [CI] 0.99 to 1.73), 1.60 (95% CI 1.22 to 2.11), and 2.02 (95% CI 1.54 to 2.63), respectively. The association between MCP-1 and CAC remained significant when adjusted for traditional cardiovascular risk factors, but not when further adjusted for age.ConclusionsIn a large population-based sample, plasma levels of MCP-1 were associated with traditional risk factors for atherosclerosis, supporting the hypothesis that MCP-1 may mediate some of the atherogenic effects of these risk factors. These findings support the potential role of MCP-1 as a biomarker target for drug development

Reduction in Recurrent Cardiovascular Events with Prasugrel Compared with Clopidogrel in Patients with Acute Coronary Syndromes from the TRITON-TIMI 38 Trial

Aims: In the TRITON-TIMI 38 trial, greater platelet inhibition with prasugrel reduced the first occurrence of the primary endpoint (cardiovascular death, MI, or stroke) compared with clopidogrel in patients with an acute coronary syndrome (ACS) undergoing planned percutaneous coronary intervention. We hypothesized that prasugrel would reduce not only first events but also recurrent primary endpoint events and therefore total events compared with clopidogrel. Methods and results: Poisson regression analysis was performed to compare the number of occurrences of the primary endpoint between prasugrel and clopidogrel in TRITON-TIMI 38. Landmark analytic methods were used to evaluate the risk of a recurrent primary endpoint event following an initial non-fatal endpoint event. Among patients with an initial non-fatal event, second events were significantly reduced with prasugrel compared to clopidogrel (10.8 vs. 15.4%, HR 0.65, 95% CI 0.46–0.92; P = 0.016), as was CV death following the non-fatal event (3.7 vs. 7.1%, HR 0.46, 95% CI 0.25–0.82; P = 0.008). Overall there was a reduction of 195 total primary efficacy events with prasugrel vs. clopidogrel (rate ratio 0.79, 95% CI 0.71–0.87; P < 0.001). Recurrent bleeding events occurred infrequently (TIMI major non-CABG bleeds: four with prasugrel and two with clopidogrel). Study drug discontinuation was frequent following the initial major bleeding event (42% of patients discontinued study drug). Conclusion: While standard statistical analytic techniques for clinical trials censor patients who experience a component of the primary composite endpoint, total cardiovascular events remain important to both patients and clinicians. Prasugrel, a more potent anti-platelet agent, reduced both first and subsequent cardiovascular events compared with clopidogrel in patients with ACS

Osteoprotegerin and cardiovascular mortality in patients with non-ST elevation acute coronary syndromes

Objective: To assess the relationship between osteoprotegerin (OPG) and cardiovascular death, and the pathobiological mechanisms contributing to the association, in acute coronary syndromes (ACS). Design: Prospective observational. Setting: Biomarker substudy of MERLIN-TIMI 36, a randomised, placebo controlled trial of ranolazine in non-ST elevation (NSTE)-ACS. Patients: 4463 patients with NSTE-ACS. Interventions: Ranolazine or placebo. Main outcome measures: Incidence of cardiovascular death (CV death); additionally, heart failure (HF), cardiac arrhythmias, inhospital ischaemia, severe recurrent ischaemia or recurrent myocardial infarction (MI). Results: During a median follow-up of 341 days, 208 patients died of cardiovascular causes. The OPG baseline concentration was strongly associated with both 30 day and 1 year incidence of CV death. After adjustment for conventional risk markers, OPG concentrations (log transformed) remained a significant predictor of CV death by 30 days (HR (95% CI) 2.32 (1.30 to 4.17); p¼0.005) and by 1 year (HR 1.85 (1.33 to 2.59); p<0.001). Baseline levels of OPG were also an independent predictor of new or worsening HF at 30 days (HR 2.25 (1.38 to 3.69); p¼0.001) and 1 year (HR 1.81 (1.26 to 2.58) p¼0.001). By univariable analysis, higher OPG was associated with both early ischaemic and arrhythmic events. Although OPG levels were associated with recurrent MI within 12 months, this association was attenuated and no longer significant after multivariable adjustment. Conclusions: OPG is independently associated with 30 day and 1 year risk of cardiovascular mortality and HF development after NSTE-ACS. As no independent relationship between OPG levels and recurrent ischaemia or MI was observed, myocardial dysfunction may be a more important stimulus for OPG production than ischaemia in ACS

Prospective Evaluation of Pregnancy-Associated Plasma Protein-A and Outcomes in Patients With Acute Coronary Syndromes

ObjectivesThis study sought to investigate whether pregnancy-associated plasma protein-A (PAPP-A) is useful for risk assessment in non–ST-segment elevation acute coronary syndrome (NSTE-ACS).BackgroundPAPP-A is a high molecular weight, zinc-binding metalloproteinase that is associated with vulnerable plaque and may be a predictor of cardiovascular disease and mortality.MethodsWe measured PAPP-A at baseline in 3,782 patients with non NSTE-ACS randomized to ranolazine or placebo in the MERLIN–TIMI 36 (Metabolic Efficiency With Ranolazine for Less Ischemia in Non-ST Elevation Acute Coronary Syndromes) trial and followed for an average of 1 year. A cut point of 6.0 μIU/ml was chosen from pilot work in this cohort.ResultsPAPP-A >6.0 μIU/ml at presentation was associated with higher rates of cardiovascular death (CVD) or myocardial infarction (MI) at 30 days (7.4% vs. 3.7%, hazard ratio [HR]: 2.01; 95% confidence interval [CI]: 1.43 to 2.82; p < 0.001) and at 1 year (14.9% vs. 9.7%, HR: 1.63; 95% CI: 1.29 to 2.05; p < 0.001). PAPP-A was also associated with higher rates of CVD (HR: 1.94; 95% CI: 1.07 to 3.52, p = 0.027) and myocardial infarction (HR: 1.82; 95% CI: 1.22 to 2.71, p = 0.003) individually at 30 days. There was no difference in the risk associated with PAPP-A stratified by baseline cardiac troponin I [Accu-TnI >0.04 μg/l], p interaction = 0.87). After adjustment for cardiac troponin I, ST-segment deviation, age, sex, diabetes, smoking, hypertension, and coronary artery disease, PAPP-A was independently associated with CVD/myocardial infarction at 30 days (adjusted HR: 1.62, 95% CI: 1.15 to 2.29; p = 0.006) and 1 year (adjusted HR: 1.35, 95% CI: 1.07 to 1.71; p = 0.012). PAPP-A also improved the net reclassification for CVD/MI (p = 0.003). There was no significant interaction with ranolazine.ConclusionsPAPP-A was independently associated with recurrent cardiovascular events in patients with NSTE-ACS. This finding supports PAPP-A as a candidate prognostic marker in patients with ACS and supports investigation of its therapeutic implications