Faculty Bibliography

BACKGROUND: Left ventricular end-diastolic pressure (LVEDP) is frequently measured during primary percutaneous coronary intervention (PCI). However, little is known of this measurement's utility in predicting outcomes or informing treatment decisions. We sought to determine the prognostic value of LVEDP measured during primary PCI for ST-segment elevation myocardial infarction (STEMI). METHODS: We studied 1,909 (33.2%) of 5,745 STEMI patients in whom LVEDP was measured during primary PCI in the APEX-AMI trial. Cox regression analysis was used to evaluate whether LVEDP was an independent predictor of mortality and the composite of death, cardiogenic shock, or congestive heart failure (CHF) at 90 days. RESULTS: The median (25th, 75th percentiles) LVEDP level was 22 mm Hg (16, 29); compared with patients with LVEDP 22 mm Hg had higher rates of CHF (7.3% vs 3.1%, P < .001), cardiogenic shock (4.6% vs 1.7%, P < .001), and death (4.1% vs 2.2%, P = .014) at 90 days. After multivariable adjustment, LVEDP was associated with increased risk of mortality through 90 days (adjusted hazard ratio 1.22, 95% CI 1.02-1.46, per 5-mmHg increase, P = .044) and the composite of death, cardiogenic shock, or CHF within the first 2 days (adjusted hazard ratio 1.40, 95% CI 1.23-1.59, per 5-mm Hg increase, P < .001), but not from day 3 to 90 (P = .25). CONCLUSIONS: Left ventricular end-diastolic pressure measured during primary PCI for STEMI is an independent predictor of inhospital and longer term cardiovascular outcomes. Measuring LVEDP may be useful to stratify patient risk and guide postinfarct treatment.

BACKGROUND: The purpose of the Occluded Artery Trial (OAT) Biomarker substudy was to evaluate the impact of infarct related artery (IRA) revascularization on serial levels of N-terminal prohormone of brain natriuretic peptide (NT-proBNP) and dynamics of other biomarkers related to left ventricular remodeling, fibrosis and angiogenesis. METHODS: Patients were eligible for OAT-Biomarker based on the main OAT criteria. Of 70 patients (age 60.8 +/- 8.8, 25% women) enrolled in the substudy, 37 were randomized to percutaneous coronary intervention (PCI) and 33 to optimal medical therapy alone. Baseline serum samples were obtained prior to OAT randomization with follow up samples taken at one year. The primary outcome was percent change of NT-proBNP from baseline to 1 year. The secondary outcomes were respective changes of matrix metalloproteinases (MMP) 2 and 9, tissue inhibitor of matrix metalloproteinase 2 (TIMP-2), Vascular Endothelial Growth Factor (VEGF), and Galectin-3. RESULTS: Paired (baseline and one-year) serum samples were obtained in 62 subjects. Baseline median NT-proBNP level was 944.8 (455.3, 1533) ng/L and decreased by 69% during follow-up (p < 0.0001). Baseline MMP-2 and TIMP-2 levels increased significantly from baseline to follow-up (p = 0.034, and p = 0.027 respectively), while MMP-9 level decreased from baseline (p = 0.038). Levels of VEGF and Galectin-3 remained stable at one year (p = NS for both). No impact of IRA revascularization on any biomarker dynamics were noted. CONCLUSIONS: There were significant changes in measured biomarkers related to LV remodeling, stress, and fibrosis following MI between 0 and 12 month. Establishing infarct vessel patency utilizing stenting 24 hours-28 days post MI did not however influence the biomarkers' release.

BACKGROUND: Percutaneous coronary intervention (PCI) of a persistently totally occluded infarct-related artery (IRA) in stable high-risk patients >24h after myocardial infarction (MI) does not reduce the occurrence of death, re-infarction, or heart failure. Diabetic patients are at higher risk for cardiovascular events; we examined their outcomes overall with PCI and optimal medical therapy alone (MED). METHODS: The long-term (7-year) outcomes of 454 diabetic patients (20.6%) randomized to PCI or MED in the Occluded Artery Trial (OAT) were assessed for the composite primary endpoint of death, re-MI, or New York Heart Association class IV heart failure. Diabetics and non-diabetics were compared and outcomes assessed by treatment strategy. RESULTS: The 7-year cumulative primary event rate for diabetic patients was 35.0% vs. 19.4% in the non-diabetic cohort (p<0.001). Multivariable analyses revealed diabetes to be an independent predictor (p<0.01) for the primary outcome, fatal or nonfatal recurrent MI, Class IV Heart Failure (HF), and death. The 7-year cumulative primary event rates were 35.3% in the PCI group vs. 34.5% in the medical therapy group in diabetic patients (p=0.19) and 19.3% in the PCI group vs. 19.5% in the medical therapy group in patients without diabetes (p=0.60). CONCLUSIONS: Despite the higher overall risk conferred by the presence of diabetes, PCI did not improve clinical outcomes in this subpopulation, and is not indicated in otherwise stable patients with a totally occluded infarct-related artery in the sub-acute phase after MI.

BACKGROUND: Plaque rupture, acute ischemia, and necrosis in acute coronary syndromes are accompanied by concurrent pro- and anti-inflammatory cascades. Whether STEMI clinical prediction models can be improved with the addition of baseline inflammatory biomarkers remains unknown. METHODS: In an APEX-AMI trial substudy, 772 patients had a panel of 9 inflammatory serum biomarkers, high sensitivity C reactive protein (hsCRP), and N-terminal pro-B-type natriuretic peptide (NT-proBNP) measured at baseline after randomization. Baseline biomarkers were incorporated into a clinical prediction model for a composite of 90-day death, shock, or heart failure. Incremental prognostic value was assessed using Net Reclassification Improvement (NRI) and Integrated Discrimination Improvement (IDI). RESULTS: Individually, several biomarkers were independent predictors of clinical outcome: hsCRP (hazard ratio [HR] 1.12; 95% confidence interval [CI], 1.03-1.21; p=0.007, per doubling), NT-proBNP (HR 1.14; 95% CI, 1.06-1.23; p<0.001, per doubling), interleukin (IL)-6 (HR 1.26; 95% CI, 1.12-1.41;p<0.001, per doubling), and inducible protein-10 (IP-10) (HR 0.86; 95% CI, 0.76-0.98; p<0.025, per doubling). The addition of baseline NT-proBNP (NRI 8.6%, p=0.028; IDI 0.030, p<0.001) and IL-6 (NRI 8.8%, p=0.012; IDI 0.036, p<0.001) improved the clinical risk prediction model and the addition of hsCRP (NRI 6.5%, p=0.069; IDI 0.018, p=0.004) yielded minimal improvement. After incorporating NT-proBNP into the model, the remaining biomarkers added little additional predictive value. CONCLUSIONS: Multiple inflammatory biomarkers independently predicted 90-day death, shock or heart failure; however, they added little value to a clinical prediction model that included NT-proBNP. Future studies of inflammatory biomarkers in STEMI should report incremental value in a prediction model that includes NT-proBNP.

BACKGROUND: Female sex is an established risk factor for bleeding, which is an important safety end point in patients presenting with non-ST-segment elevation acute coronary syndromes (NSTE ACS). However, it is unknown whether the association between bleeding and mortality is modulated by sex in this patient population. METHODS: We examined the interaction between sex and bleeding and 30-day mortality outcomes among 2,975 women and 6,431 men with high-risk NSTE ACS enrolled in the EARLY ACS trial. The Global Utilization of Strategies to Open Occluded Arteries (GUSTO) criteria were used to identify moderate or severe bleeds. RESULTS: Women were older and had more comorbid disease compared with men. Bleeding rates were higher among women (8.2%) than among men (5.5%; P < .01). However, the association of bleeding and 30-day mortality was stronger among men (odds ratio 5.8, 95% CI 3.9-8.8) than among women (odds ratio 1.5, 95% CI 0.8-2.9; sex * bleeding interaction P < .01). Sex differences in the association of bleeding and mortality persisted in a landmark analysis of 120-hour survivors. CONCLUSIONS: In a contemporary high-risk NSTE ACS cohort, women had higher bleeding rates than did men. Paradoxically, the association between bleeding and mortality was worse among men than among women.

OBJECTIVES:: To assess whether systemic inflammatory response syndrome is associated with morbidity and mortality in ST-elevation myocardial infarction. DESIGN AND SETTING:: Secondary analysis of multicenter randomized controlled trials. PATIENTS:: Complement and reduction of infarct size after angioplasty or lytics project patients (n = 1,903) with ST-elevation myocardial infarction undergoing fibrinolysis or mechanical reperfusion. INTERVENTIONS:: None MEASUREMENTS AND MAIN RESULTS:: The prevalence of systemic inflammatory response syndrome was described in the 1,186 patients (64.4%) with data available for all systemic inflammatory response syndrome criteria. Using multiple imputations for the 1,843 patients (96.8%) with available endpoints, we compared the 90-day prevalence of death, shock, heart failure, or stroke between patients with and without systemic inflammatory response syndrome at presentation and at 24 hours post admission. Systemic inflammatory response syndrome was defined as >/= 2 of 1) heart rate > 90 beats/min, 2) respiratory rate > 20 breaths/min, 3) body temperature > 38 or < 36 degrees C, or 4) leukocyte count > 12 or < 4 x 10/L. At presentation, 25.0% of patients met systemic inflammatory response syndrome criteria; at 24 hours, 8.1% of patients met systemic inflammatory response syndrome criteria. The primary outcome was more frequent among patients with systemic inflammatory response syndrome at presentation (31.0% vs 16.7%; adjusted hazard ratio, 1.78 [95% CI, 1.35-2.34]; p < 0.001) and at 24 hours (36.7% vs 11.1%; adjusted hazard ratio, 2.84 [95% CI, 2.03-3.97]; p < 0.001). Mortality at 90 days was also higher among patients with systemic inflammatory response syndrome at either time point. Each additional systemic inflammatory response syndrome criterion was independently associated with 90-day outcomes at the time of presentation (adjusted hazard ratio, 1.41 per systemic inflammatory response syndrome criteria [95% CI, 1.24-1.61]; p < 0.001) and at 24 hours (adjusted hazard ratio, 1.72 per systemic inflammatory response syndrome criteria [95% CI, 1.47-2.01]; p < 0.001). CONCLUSION:: The diagnosis of systemic inflammatory response syndrome and the cumulative number of systemic inflammatory response syndrome criteria were independently associated with 90-day clinical outcomes in a population of patients with ST-elevation myocardial infarction. The independent association of this simple composite measure of the inflammatory response with outcomes underscores the importance of the clinical inflammatory response in ST-elevation myocardial infarction.

BACKGROUND: The precise relationship between risk factor burden and prevalence of peripheral artery disease (PAD) in different vascular territories (PAD, carotid artery stenosis [CAS], and abdominal aortic aneurysms [AAAs]) is unclear. METHODS: We investigated the association of modifiable risk factors (hypertension, hypercholesterolemia, smoking, diabetes, and sedentary lifestyle) with any and type-specific peripheral vascular disease (PVD) among 3.3 million patients in the U.S., aged 40 to 99, who underwent screening bilateral ankle brachial indices, carotid duplex ultrasound, and abdominal aortic ultrasound in the Life Line Screening program between 2004 and 2008. Multivariate logistic regression analysis was used to estimate the odds of disease in different risk factor categories. Population-attributable risk was calculated to estimate the proportion of disease that could be potentially ascribed to modifiable risk factors. RESULTS: Among 3,319,993 participants, prevalence of any PVD was 7.51% (95% confidence interval [CI], 7.50%-7.53%). PAD was present in 3.56% (95% CI, 3.54%-3.58%), CAS in 3.94% (95% CI, 3.92%-3.96%), and AAAs in 0.88% (95% CI, 0.86%-0.89%). The multivariate-adjusted prevalence with the presence of 0, 1, 2, 3, 4, and 5 modifiable risk factors was 2.76, 4.63, 7.12, 10.73, 16.00, and 22.08 (P < .0001 for trend) for any PVD; 1.18, 2.09, 3.28, 5.14, 8.32, and 12.43 (P < .0001 for trend) for PAD; 1.41, 2.36, 3.72, 5.73, 8.48, and 11.58 (P < .0001 for trend) for CAS; and 0.31, 0.54, 0.85, 1.28, 1.82, and 2.39 (P < .0001 for trend) for AAAs, respectively. These associations were similar for men and women. For every additional modifiable risk factor that was present, the multivariate-adjusted odds of having vascular disease increased significantly (any PVD [odds ratio (OR), 1.58; 95% CI, 1.58-1.59]; PAD [OR, 1.62; 95% CI, 1.62-1.63]; CAS [OR, 1.57; 95% CI, 1.56-1.57]; and AAA [OR, 1.51; 95% CI, 1.50-1.53]). CONCLUSION: This very large contemporary database demonstrates that risk factor burden is associated with an increased prevalence of PVD, and there is a graded association between the number of risk factors present and the prevalence of PAD, CAS, and AAAs.

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.