Megan L. Neely

Platelet Function During Extended Prasugrel and Clopidogrel Therapy for Patients With ACS Treated Without Revascularization: The TRILOGY ACS Platelet Function Substudy

CONTEXT The relationship of platelet function testing measurements with outcomes in patients with acute coronary syndromes (ACS) initially managed medically without revascularization is unknown. OBJECTIVE To characterize the differences and evaluate clinical outcomes associated with platelet reactivity among patients with ACS treated with clopidogrel or prasugrel. DESIGN, SETTING, AND PATIENTS Patients with medically managed unstable angina or non-ST-segment elevation myocardial infarction were enrolled in the TRILOGY ACS trial (2008 to 2011) comparing clopidogrel vs prasugrel. Of 9326 participants, 27.5% were included in a platelet function substudy: 1286 treated with prasugrel and 1278 treated with clopidogrel. INTERVENTIONS Aspirin with either prasugrel (10 or 5 mg/d) or clopidogrel (75 mg/d); those 75 years or older and younger than 75 years but who weighed less than 60 kg received a 5-mg prasugrel maintenance dose. MAIN OUTCOME MEASURES Platelet reactivity, measured in P2Y12 reaction units (PRUs), was performed at baseline, at 2 hours, and at 1, 3, 6, 12, 18, 24, and 30 months after randomization. The primary efficacy end point was a composite of cardiovascular death, myocardial infarction, or stroke through 30 months. RESULTS Among participants younger than 75 years and weighing 60 kg or more, the median PRU values at 30 days were 64 (interquartile range [IQR], 33-128) in the prasugrel group vs 200 (IQR, 141-260) in the clopidogrel group (P < .001), a difference that persisted through all subsequent time points. For participants younger than 75 years and weighing less than 60 kg, the median 30-day PRU values were 139 (IQR, 86-203) for the prasugrel group vs 209 (IQR, 148-283) for the clopidogrel group (P < .001), and for participants 75 years or older, the median PRU values were 164 (IQR, 105-216) for the prasugrel group vs 222 (IQR, 148-268) for the clopidogrel group (P < .001). At 30 months the rate of the primary efficacy end point was 17.2% (160 events) in the prasugrel group vs 18.9% (180 events) in the clopidogrel group (P = .29). There were no significant differences in the continuous distributions of 30-day PRU values for participants with a primary efficacy end point event after 30 days (n = 214) compared with participants without an event (n = 1794; P = .07) and no significant relationship between the occurence of the primary efficacy end point and continuous PRU values (adjusted hazard ratio [HR] for increase of 60 PRUs, 1.03; 95% CI, 0.96-1.11; P = .44). Similar findings were observed with 30-day PRU cut points used to define high on-treatment platelet reactivity-PRU more than 208 (adjusted HR, 1.16; 95% CI, 0.89-1.52, P = .28) and PRU more than 230 (adjusted HR, 1.20; 95% CI, 0.90-1.61; P = .21). CONCLUSIONS Among patients with ACS without ST-segment elevation and initially managed without revascularization, prasugrel was associated with lower platelet reactivity than clopidogrel, irrespective of age, weight, and dose. Among those in the platelet substudy, no significant differences existed between prasugrel vs clopidogrel in the occurence of the primary efficacy end point through 30 months and no significant association existed between platelet reactivity and occurrence of ischemic outcomes. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00699998.

Outcomes in patients with heart failure with preserved, borderline, and reduced ejection fraction in the Medicare population

BACKGROUND Studies on outcomes among patients with heart failure (HF) with preserved left ventricular ejection fraction (HFpEF), borderline left ventricular ejection fraction (HFbEF), and reduced left ventricular ejection fraction (HFrEF) remain limited. We sought to characterize mortality and readmission in patients with HF in the contemporary era. METHODS Get With The Guidelines-HF was linked to Medicare data for longitudinal follow-up. Patients were grouped into HFpEF (left ventricular ejection fraction [EF] ≥ 50%), HFbEF (40% ≤ EF < 50%), and HFrEF (EF < 40%). Multivariable models were constructed to examine the relationship between EF and outcomes at 30 days and 1 year and to study trends over time. RESULTS A total of 40,239 patients from 220 hospitals between 2005 and 2011 were included in the study: 18,897 (47%) had HFpEF, 5,626 (14%) had HFbEF, and 15,716 (39%) had HFrEF. In crude survival analysis, patients with HFrEF had slightly increased mortality compared with HFbEF and HFpEF. After risk adjustment, mortality at 1 year was not significantly different for HFrEF, HFbEF, and HFpEF (HFrEF vs HFpEF, hazard ratio [HR] 1.040 [95% CI 0.998-1.084], and HFbEF vs HFpEF, HR 0.967 [95% CI 0.917-1.020]). Patients with HFpEF had increased risk of all-cause readmission compared with HFrEF. Conversely, risk of cardiovascular and HF readmissions were higher in HFrEF and HFbEF compared with HFpEF. CONCLUSIONS Among patients hospitalized with HF, patients with HFpEF and HFbEF had slightly lower mortality and higher all-cause readmission risk than patients with HFrEF, although the mortality differences did not persist after risk adjustment. Irrespective of EF, these patients experience substantial mortality and readmission highlighting the need for new therapeutic strategies.

The Learning Curve for Transradial Percutaneous Coronary Intervention Among Operators in the United States A Study From the National Cardiovascular Data Registry

Background— Adoption of transradial percutaneous coronary intervention (TRI) in the United States is low and may be related to challenges learning the technique. We examined the relationships between operator TRI volume and procedural metrics and outcomes. Methods and Results— We used CathPCI Registry data from July 2009 to December 2012 to identify new radial operators, defined by an exclusively femoral percutaneous coronary intervention approach for 6 months after their first percutaneous coronary intervention in the database and ≥15 total TRIs thereafter. Primary outcomes of fluoroscopy time, contrast volume, and procedure success were chosen as markers of technical proficiency. Secondary outcomes included in-hospital mortality, bleeding, and vascular complications. Adjusted outcomes were analyzed by using operator TRI experience as a continuous variable with generalized linear mixed models. Among 54 561 TRI procedures performed at 704 sites, 942 operators performed 1 to 10 procedures, 942 operators performed 11 to 50 procedures, 375 operators performed 51 to 100 procedures, and 148 operators performed 101 to 200 procedures. As radial caseload increased, more TRIs were performed in women, in patients presenting with ST-segment elevation myocardial infarction, and for emergency indications. Decreased fluoroscopy time and contrast use were nonlinearly associated with greater operator TRI experience, with faster reductions observed for newer (<30–50 cases) compared with more experienced (>30–50 cases) operators. Procedure success was high, whereas mortality, bleeding, and vascular complications remained low across TRI volumes. Conclusions— As operator TRI volume increases, higher-risk patients are chosen for TRI. Despite this, operator proficiency improves with greater TRI experience, and safety is maintained. The threshold to overcome the learning curve appears to be approximately 30 to 50 cases.

Soluble ST2 in Ambulatory Patients with Heart Failure: Association with Functional Capacity and Long-Term Outcomes

Background—ST2 is involved in cardioprotective signaling in the myocardium and has been identified as a potentially promising biomarker in heart failure (HF). We evaluated ST2 levels and their association with functional capacity and long-term clinical outcomes in a cohort of ambulatory patients with HF enrolled in the Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training (HF-ACTION) study—a multicenter, randomized study of exercise training in HF. Methods and Results—HF-ACTION randomized 2331 patients with left ventricular ejection fraction <0.35 and New York Heart Association class II to IV HF to either exercise training or usual care. ST2 was analyzed in a subset of 910 patients with evaluable plasma samples. Correlations and Cox models were used to assess the relationship among ST2, functional capacity, and long-term outcomes. The median baseline ST2 level was 23.7 ng/mL (interquartile range, 18.6–31.8). ST2 was modestly associated with measures of functional capacity. In univariable analysis, ST2 was significantly associated with death or hospitalization (hazard ratio, 1.48; P<0.0001), cardiovascular death or HF hospitalization (hazard ratio, 2.14; P<0.0001), and all-cause mortality (hazard ratio, 2.33; P<0.0001; all hazard ratios for log2 ng/mL). In multivariable models, ST2 remained independently associated with outcomes after adjustment for clinical variables and amino-terminal pro-B-type natriuretic peptide. However, ST2 did not add significantly to reclassification of risk as assessed by changes in the C statistic, net reclassification improvement, and integrated discrimination improvement. Conclusions—ST2 was modestly associated with functional capacity and was significantly associated with outcomes in a well-treated cohort of ambulatory patients with HF although it did not significantly affect reclassification of risk. Clinical Trial Information—URL: http://www.clinicaltrials.gov. Unique identifier: NCT00047437.Background— ST2 is involved in cardioprotective signaling in the myocardium and has been identified as a potentially promising biomarker in heart failure (HF). We evaluated ST2 levels and their association with functional capacity and long-term clinical outcomes in a cohort of ambulatory patients with HF enrolled in the Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training (HF-ACTION) study—a multicenter, randomized study of exercise training in HF. Methods and Results— HF-ACTION randomized 2331 patients with left ventricular ejection fraction <0.35 and New York Heart Association class II to IV HF to either exercise training or usual care. ST2 was analyzed in a subset of 910 patients with evaluable plasma samples. Correlations and Cox models were used to assess the relationship among ST2, functional capacity, and long-term outcomes. The median baseline ST2 level was 23.7 ng/mL (interquartile range, 18.6–31.8). ST2 was modestly associated with measures of functional capacity. In univariable analysis, ST2 was significantly associated with death or hospitalization (hazard ratio, 1.48; P <0.0001), cardiovascular death or HF hospitalization (hazard ratio, 2.14; P <0.0001), and all-cause mortality (hazard ratio, 2.33; P <0.0001; all hazard ratios for log2 ng/mL). In multivariable models, ST2 remained independently associated with outcomes after adjustment for clinical variables and amino-terminal pro-B-type natriuretic peptide. However, ST2 did not add significantly to reclassification of risk as assessed by changes in the C statistic, net reclassification improvement, and integrated discrimination improvement. Conclusions— ST2 was modestly associated with functional capacity and was significantly associated with outcomes in a well-treated cohort of ambulatory patients with HF although it did not significantly affect reclassification of risk. Clinical Trial Information— URL: . Unique identifier: [NCT00047437][1]. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00047437&atom=%2Fcirchf%2F6%2F6%2F1172.atom

Gaps in referral to cardiac rehabilitation of patients undergoing percutaneous coronary intervention in the United States.

BACKGROUND Rates of referral to cardiac rehabilitation after percutaneous coronary intervention (PCI) have been historically low despite the evidence that rehabilitation is associated with lower mortality in PCI patients. OBJECTIVES This study sought to determine the prevalence of and factors associated with referral to cardiac rehabilitation in a national PCI cohort, and to assess the association between insurance status and referral patterns. METHODS Consecutive patients who underwent PCI and survived to hospital discharge in the National Cardiovascular Data Registry between July 1, 2009 and March 31, 2012 were analyzed. Cardiac rehabilitation referral rates, and patient and institutional factors associated with referral were evaluated for the total study population and for a subset of Medicare patients presenting with acute myocardial infarction. RESULTS Patients who underwent PCI (n = 1,432,399) at 1,310 participating hospitals were assessed. Cardiac rehabilitation referral rates were 59.2% and 66.0% for the overall population and the AMI/Medicare subgroup, respectively. In multivariable analyses, presentation with ST-segment elevation myocardial infarction (odds ratio 2.99; 95% confidence interval: 2.92 to 3.06) and non-ST-segment elevation myocardial infarction (odds ratio: 1.99; 95% confidence interval: 1.94 to 2.03) were associated with increased odds of referral to cardiac rehabilitation. Models adjusted for insurance status showed significant site-specific variability in referral rates, with more than one-quarter of all hospitals referring <20% of patients. CONCLUSIONS Approximately 60% of patients undergoing PCI in the United States are referred for cardiac rehabilitation. Site-specific variation in referral rates is significant and is unexplained by insurance coverage. These findings highlight the potential need for hospital-level interventions to improve cardiac rehabilitation referral rates after PCI.

Short- and Long-term Rehospitalization and Mortality for Heart Failure in 4 Racial/Ethnic Populations

Background The degree to which outcomes following hospitalization for acute heart failure (HF) vary by racial and ethnic groups is poorly characterized. We sought to compare 30‐day and 1‐year rehospitalization and mortality rates for HF among 4 race/ethnic groups. Methods and Results Using the Get With The Guidelines–HF registry linked with Medicare data, we compared 30‐day and 1‐year outcomes between racial/ethnic groups by using a multivariable Cox proportional hazards model adjusting for clinical, hospital, and socioeconomic status characteristics. We analyzed 47 149 Medicare patients aged ≥65 years who had been discharged for HF between 2005 and 2011: there were 39 213 whites (83.2%), 4946 blacks (10.5%), 2347 Hispanics (5.0%), and 643 Asians/Pacific Islanders (1.4%). Relative to whites, blacks and Hispanics had higher 30‐day and 1‐year unadjusted readmission rates but lower 30‐day and 1‐year mortality; Asians had similar 30‐day readmission rates but lower 1‐year mortality. After risk adjustment, blacks had higher 30‐day and 1‐year CV readmission than whites but modestly lower short‐ and long‐term mortality; Hispanics had higher 30‐day and 1‐year readmission rates and similar 1‐year mortality than whites, while Asians had similar outcomes. When socioeconomic status data were added to the model, the majority of associations persisted, but the difference in 30‐day and 1‐year readmission rates between white and Hispanic patients became nonsignificant. Conclusions Among Medicare patients hospitalized with HF, short‐ and long‐term readmission rates and mortality differed among the 4 major racial/ethnic populations and persisted even after controlling for clinical, hospital, and socioeconomic status variables.

The effects of exercise on cardiovascular biomarkers in patients with chronic heart failure

BACKGROUND Exercise training is recommended for chronic heart failure (HF) patients to improve functional status and reduce risk of adverse outcomes. Elevated plasma levels of amino-terminal pro-brain natriuretic peptide (NT-proBNP), high-sensitivity C-reactive protein (hs-CRP), and cardiac troponin T (cTnT) are associated with increased risk of adverse outcomes in this patient population. Whether exercise training leads to improvements in biomarkers and how such improvements relate to clinical outcomes are unclear. METHODS AND RESULTS Amino-terminal pro-brain natriuretic peptide, hs-CRP, and cTnT levels were assessed at baseline and 3 months in a cohort of 928 subjects from the HF-ACTION study, a randomized clinical trial of exercise training versus usual care in chronic HF patients with reduced left ventricular ejection fraction (<35%). Linear and logistic regressions were used to assess 3-month biomarker levels as a function of baseline value, treatment assignment (exercise training vs usual care), and volume of exercise. Linear regression and Cox proportional hazard modeling were used to evaluate the relations between changes in biomarker levels and clinical outcomes of interest that included change in peak oxygen consumption (peak VO2), hospitalizations, and mortality. Exercise training was not associated with significant changes in levels of NT-proBNP (P = .10), hs-CRP (P = .80), or detectable cTnT levels (P = .83) at 3 months. Controlling for baseline biomarker levels or volume of exercise did not alter these findings. Decreases in plasma concentrations of NT-proBNP, but not hs-CRP or cTnT, were associated with increases in peak VO2 (P < .001) at 3 months and decreased risk of hospitalizations or mortality (P ≤ .04), even after adjustment for a comprehensive set of known predictors. CONCLUSIONS Exercise training did not lead to meaningful changes in biomarkers of myocardial stress, inflammation, or necrosis in patients with chronic HF. Only improvements in NT-proBNP translated to reductions in peak VO2 and reduced risk of clinical events.

A novel approach to systematically implement the universal definition of myocardial infarction: insights from the CHAMPION PLATFORM trial

Objective To reassess the efficacy of cangrelor efficacy using the universal definition of myocardial infarction (MI). Design We adopted a novel approach to systematically implement the universal definition of MI. Two physicians blinded to treatment allocation reviewed plots of CK-MB and troponin values in relation to time of randomisation and percutaneous coronary intervention (PCI) to identify patients with stable or falling biomarkers pre-PCI (ie, primary cohort), and those with post-PCI CK-MB elevations. Setting The CHAMPION PLATFORM trial. Patients Non-ST-elevation acute coronary syndromes (95%) and stable angina patients (5%). Interventions Cangrelor versus placebo. Main outcome measures The efficacy of cangrelor compared with placebo using the reclassified events (type 4a MI) and the original clinical events committee-adjudicated (CEC PCI-MI) results was investigated. Results Of 5295 patients, 3406 (64.4%) were in the primary cohort. Type 4a MI occurred in 4.3% (226 events/5295 patients) while original CEC PCI-MI occurred in 6.5% (344 events/5295 patients), a significant difference (p<0.0001). Using the reclassified MI events, the primary composite endpoint of death, MI, or ischaemia-driven revascularisation through 48 h occurred in 5.4% of patients (4.9% cangrelor, 6.0% placebo; OR 0.80; 95% CI 0.63 to 1.02) as opposed to 7.5% of the primary analyses (7.0% cangrelor, 8.0% placebo; OR 0.87; 95% CI 0.71 to 1.07). Conclusions Systematic, strict implementation of the universal MI definition with emphasis on baseline assessment may enhance discrimination in detecting PCI-MI and may allow for more rigorous assessment of interventions in patients undergoing early PCI.

Association between adrenergic receptor genotypes and beta‐blocker dose in heart failure patients: analysis from the HF‐ACTION DNA substudy

Beta‐blockers reduce morbidity and mortality in chronic heart failure (HF) patients with reduced ejection fraction. However, there is heterogeneity in the response to these drugs, perhaps due to genetic variations in the β1‐adrenergic receptor (ADRβ1). We examined whether the Arg389Gly polymorphism in ADRβ1 interacts with the dose requirements of beta‐blockers in patients with systolic HF.

Comparison of the Prognosis of Spontaneous and Percutaneous Coronary Intervention Related-Myocardial Infarction

OBJECTIVES This study compared prognoses of myocardial infarction related to percutaneous coronary intervention (PCI, procedural MI) using increasing creatine kinase-myocardial band (CK-MB) thresholds with spontaneous MI. BACKGROUND Procedural MI usually is defined by a CK-MB elevation of more than 3 times the upper limit of normal (ULN), but higher thresholds have been proposed. METHODS Patients from the EARLY-ACS (Early Glycoprotein IIb/IIIa Inhibition in Non-ST-Segment Elevation Acute Coronary Syndrome) study and the SYNERGY (Superior Yield of the New strategy of Enoxaparin, Revascularization and GlYcoprotein IIb/IIIa inhibitors) study treated with PCI were included. The primary end point was 1-year all-cause mortality from 24 h after PCI. To determine an enzymatic threshold for procedural MI with a prognosis similar to that of spontaneous MI, we redefined procedural MI using increasing CK-MB thresholds and compared corresponding hazard ratios with those of spontaneous MI (CK-MB more than twice the ULN). Hazard ratios for mortality for procedural and spontaneous MI were calculated using Cox proportional hazards regression and Global Registry of Acute Cardiac Events covariates for risk adjustment. RESULTS Nine thousand eighty-seven patients who underwent PCI (46.8%) were included; 773 procedural MI and 239 spontaneous MI occurred within 30 days. Adjusted hazard ratios for 1-year death were 1.39 (95% confidence interval [CI]: 1.01 to 1.89) for procedural MI and 5.37 (95% CI: 3.90 to 7.38) for spontaneous MI. The CK-MB threshold for procedural MI that achieved the same prognosis as spontaneous MI was 27.7 times the ULN (95% CI: 13.9 to 58.4), but this differed between the SYNERGY study (57.9 times the ULN, 95% CI: 17.9 to 63.6) and the EARLY-ACS study (20.4 times the ULN, 95% CI: 5.16 to 24.2). Of all procedural MI, 49 (6%) had CK-MB elevations of 27.7 or more times the ULN. CONCLUSIONS The current enzymatic definition of procedural MI (CK-MB more than 3 times the ULN) used in clinical trials is less strongly associated with death than that of spontaneous MI. Procedural MI achieves similar prognosis for 1-year mortality when much higher CK-MB thresholds are applied.