Faculty Bibliography

BACKGROUND: Dual antiplatelet therapy in older versus younger patients with acute coronary syndromes is understudied. Low-dose prasugrel (5 mg/d) is recommended for younger, lower-body-weight patients and elderly patients with acute coronary syndromes to mitigate the bleeding risk of standard-dose prasugrel (10 mg/d). METHODS AND RESULTS: A total of 9326 medically managed patients with acute coronary syndromes from the Targeted Platelet Inhibition to Clarify the Optimal Strategy to Medically Manage Acute Coronary Syndromes (TRILOGY ACS) trial (<75 years of age, n=7243; >/=75 years of age, n=2083) were randomized to prasugrel (10 mg/d; 5 mg/d for those >/=75 or <75 years of age and <60 kg in weight) or clopidogrel (75 mg/d) plus aspirin for /=75 years of age (25% of total elderly population) had serial platelet reactivity unit measurements in a platelet-function substudy. Cumulative risks of the primary end point (cardiovascular death/myocardial infarction/stroke) and Thrombolysis in Myocardial Infarction (TIMI) major bleeding increased progressively with age and were >/=2-fold higher in older participants. Among those >/=75 years of age, TIMI major bleeding (4.1% versus 3.4%; hazard ratio, 1.09; 95% confidence interval, 0.57-2.08) and the primary end point rates were similar with reduced-dose prasugrel and clopidogrel. Despite a correlation between lower 30-day on-treatment platelet reactivity unit values and lower weight only in the prasugrel group, there was a nonsignificant treatment-by-weight interaction for platelet reactivity unit values among participants >/=75 years of age in the platelet-function substudy (P=0.06). No differences in weight were seen in all participants >/=75 years of age with versus without TIMI major/minor bleeding in both treatment groups. CONCLUSIONS: Older age is associated with substantially increased long-term cardiovascular risk and bleeding among patients with medically managed acute coronary syndromes, with no differences in ischemic or bleeding outcomes with reduced-dose prasugrel compared with clopidogrel in elderly patients. No significant interactions among weight, pharmacodynamic response, and bleeding risk were observed between reduced-dose prasugrel and clopidogrel in elderly patients. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov/ct2/home. Unique identifier: NCT0069999.

BACKGROUND: Cardiogenic shock complicating acute myocardial infarction (MI) in older patients is associated with a high risk of inhospital mortality; however, the long-term prognosis among these patients who survive the index hospitalization is uncertain. METHODS: We evaluated 42,656 patients 65 years or older with non-ST-segment elevation MI from the CRUSADE Registry treated at 448 hospitals in the United States from 2003 to 2006 and linked to Medicare longitudinal claims data. Among patients who survived to hospital discharge, Cox proportional hazards modeling was used to compare survival between patients with and without inhospital shock. The secondary outcome of "percent days alive and out of hospital" (%DAOH) was also compared between the 2 groups. RESULTS: Overall, 2,001 (4.7%) patients had shock on presentation and/or developed shock during the index hospitalization. Inhospital mortality rates among those with and without shock were 39.1% versus 4.5% (P < .001). Among the 40,036 index hospital survivors, postdischarge survival curves diverged early with lower survival (48.1% [95% CI 45.0-51.2] vs 56.5% [95% CI 56.0-57.1], P < .001) and lower %DAOH (65.5% +/- 40.6% and 73.4% +/- 36.8 %, P < .001) among patients with shock through 4 years. Based on the observation of parallel survival curves starting 6 months postdischarge, we performed landmark analyses and found no difference in mortality (hazard ratio 1.02, 95% CI 0.91-1.14) or %DAOH (79.7% +/- 32.0% vs 81.3% +/- 31.0%, P = .17) beyond 6 months between those with and without shock. CONCLUSIONS: Our results highlight the time-dependent hazard of risk during the early postdischarge period for older patients with non-ST-segment elevation MI and cardiogenic shock that appears to be mitigated after 6 months, thereby lending support for the examination of new therapies designed to ameliorate this early risk.

BACKGROUND:Larger infarct size measured by creatine kinase (CK)-MB release is associated with higher mortality and has been used as an important surrogate endpoint in the evaluation of new treatments for ST-segment elevation myocardial infarction (STEMI). Traditional approaches to quantify infarct size include the observed CK-MB peak and calculated CK-MB area under the curve (AUC). We evaluated alternative approaches to quantifying infarct size using CK-MB values, and the relationship between infarct size and clinical outcomes. METHODS:Of 1,850 STEMI patients treated with reperfusion therapy in the COMplement inhibition in Myocardial infarction treated with Angioplasty (COMMA) (percutaneous coronary intervention (PCI)-treated) and the COMPlement inhibition in myocardial infarction treated with thromboLYtics (COMPLY) (fibrinolytic-treated) trials, 1,718 (92.9%) (COMMA, n = 868; COMPLY, n = 850) had at least five of nine protocol-required CK-MB measures. In addition to traditional methods, curve-fitting techniques were used to determine CK-MB AUC and estimated peak CK-MB. Cox proportional hazards modeling assessed the univariable associations between infarct size and mortality, and the composite of death, heart failure, shock and stroke at 90 days. RESULTS:In COMPLY, CK-MB measures by all methods were significantly associated with higher mortality (hazard ratio range per 1,000 units increase: 1.09 to 1.13; hazard ratio range per 1 standard deviation increase: 1.41 to 1.62; P <0.01 for all analyses). In COMMA, the associations were similar but did not reach statistical significance. For the composite outcome of 90-day death, heart failure, shock and stroke, the associations with all CK-MB measures were statistically significant in both the COMMA and COMPLY trials. CONCLUSIONS:Sophisticated curve modeling is an alternative to infarct-size quantification in STEMI patients, but it provides information similar to that of more traditional methods. Future studies will determine whether the same conclusion applies in circumstances other than STEMI, or to studies with different frequencies and patterns of CK-MB data collection.

We hypothesized that the insensitivity of the electrocardiogram in identifying acute circumflex occlusion would result in differences in the distribution of the infarct-related artery (IRA) between patients with non-ST-segment elevation myocardial infarction (NSTEMI) and STEMI enrolled in the Occluded Artery Trial. We also sought to evaluate the effect of percutaneous coronary intervention to the IRA on the clinical outcomes for patients with NSTEMI. Overall, those with NSTEMI constituted 13% (n = 283) of the trial population. The circumflex IRA was overrepresented in the NSTEMI group compared to the STEMI group (42.5 vs 11.2%; p <0.0001). The 7-year clinical outcomes for the patients with NSTEMI randomized to percutaneous coronary intervention and optimal medical therapy versus optimal medical therapy alone were similar for the primary composite of death, myocardial infarction, and class IV congestive heart failure (22.3% vs 20.2%, hazard ratio 1.20, 99% confidence interval 0.60 to 2.40; p = 0.51) and the individual end points of death (13.8% vs 17.0%, hazard ratio 0.82, 99% confidence interval 0.37 to 1.84; p = 0.53), myocardial infarction (6.1 vs 5.1%, hazard ratio 1.11, 99% confidence interval 0.28 to 4.41; p = 0.84), and class IV congestive heart failure (6.7% vs 6.0%, hazard ratio 1.50, 99% confidence interval 0.37 to 6.02; p = 0.45). No interaction was seen between the electrocardiographically determined myocardial infarction type and treatment effect (p = NS). In conclusion, the occluded circumflex IRA is overrepresented in the NSTEMI population. Consistent with the overall trial results, stable patients with NSTEMI and a totally occluded IRA did not benefit from randomization to percutaneous coronary intervention.