Phillip J. Schulte

Association between change in daily ambulatory activity and cardiovascular events in people with impaired glucose tolerance (NAVIGATOR trial): a cohort analysis

BACKGROUND The extent to which change in physical activity can modify the risk of cardiovascular disease in individuals at high cardiovascular risk is uncertain. We investigated whether baseline and change in objectively-assessed ambulatory activity is associated with the risk of a cardiovascular event in individuals at high cardiovascular risk with impaired glucose tolerance. METHODS We assessed prospective data from the NAVIGATOR trial involving 9306 individuals with impaired glucose tolerance who were recruited in 40 countries between January, 2002, and January, 2004. Participants also either had existing cardiovascular disease (if age ≥50 years) or at least one additional cardiovascular risk factor (if age ≥55 years). Participants were followed-up for cardiovascular events (defined as cardiovascular mortality, non-fatal stroke, or myocardial infarction) for 6 years on average and had ambulatory activity assessed by pedometer at baseline and 12 months. Adjusted Cox proportional hazard models quantified the association of baseline and change in ambulatory activity (from baseline to 12 months) with the risk of a subsequent cardiovascular event, after adjustment for each other and potential confounding variables. This study is registered with ClinicalTrials.govNCT00097786. FINDINGS During 45,211 person-years follow-up, 531 cardiovascular events occurred. Baseline ambulatory activity (hazard ratio [HR] per 2000 steps per day 0·90, 95% CI 0·84-0·96) and change in ambulatory activity (0·92, 0·86-0·99) were inversely associated with the risk of a cardiovascular event. Results for change in ambulatory activity were unaffected when also adjusted for changes in body-mass index and other potential confounding variables at 12 months. INTERPRETATION In individuals at high cardiovascular risk with impaired glucose tolerance, both baseline levels of daily ambulatory activity and change in ambulatory activity display a graded inverse association with the subsequent risk of a cardiovascular event. FUNDING Novartis Pharmaceuticals.

Apixaban in Comparison With Warfarin in Patients With Atrial Fibrillation and Valvular Heart Disease: Findings From the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) Trial.

Background— Apixaban is approved for the prevention of stroke and systemic embolism in patients with nonvalvular atrial fibrillation. However, the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial included a substantial number of patients with valvular heart disease and only excluded patients with clinically significant mitral stenosis or mechanical prosthetic heart valves. Methods and Results— We compared the effect of apixaban and warfarin on rates of stroke or systemic embolism, major bleeding, and death in patients with and without moderate or severe valvular heart disease using Cox proportional hazards modeling. Of the 18 201 patients enrolled in ARISTOTLE, 4808 (26.4%) had a history of moderate or severe valvular heart disease or previous valve surgery. Patients with valvular heart disease had higher rates of stroke or systemic embolism and bleeding than patients without valvular heart disease. There was no evidence of a differential effect of apixaban over warfarin in patients with and without valvular heart disease in reducing stroke and systemic embolism (hazard ratio [HR], 0.70; 95% confidence interval [CI], 0.51–0.97 and HR, 0.84; 95%, CI 0.67–1.04; interaction P=0.38), causing less major bleeding (HR, 0.79; 95% CI, 0.61–1.04 and HR, 0.65; 95% CI, 0.55–0.77; interaction P=0.23), and reducing mortality (HR, 1.01; 95% CI, 0.84–1.22 and HR, 0.84; 95% CI, 0.73–0.96; interaction P=0.10). Conclusions— More than a quarter of the patients in ARISTOTLE with nonvalvular atrial fibrillation had moderate or severe valvular heart disease. There was no evidence of a differential effect of apixaban over warfarin in reducing stroke or systemic embolism, causing less bleeding, and reducing death in patients with and without valvular heart disease. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00412984.

Extent, location, and clinical significance of non-infarct-related coronary artery disease among patients with ST-elevation myocardial infarction

IMPORTANCE Little information exists about the anatomical characteristics and clinical relevance of non-infarct-related artery (IRA) disease among patients with ST-segment elevation myocardial infarction (STEMI). OBJECTIVES To investigate the incidence, extent, and location of obstructive non-IRA disease and compare 30-day mortality according to the presence of non-IRA disease in patients with STEMI. DESIGN, SETTING, AND PARTICIPANTS Retrospective study of patients pooled from a convenience sample of 8 independent, international, randomized STEMI clinical trials published between 1993 and 2007. Follow-up varied from 1 month to 1 year. Among 68,765 patients enrolled in the trials, 28,282 patients with valid angiographic information were included in this analysis. Obstructive coronary artery disease was defined as stenosis of 50% or more of the diameter of a major epicardial artery. To assess the generalizability of trial-based results, external validation was performed using observational data for patients with STEMI from the Korea Acute Myocardial Infarction Registry (KAMIR) (between November 1, 2005, and December 31, 2013; n = 18,217) and the Duke Cardiovascular Databank (between January 1, 2005, and December 31, 2012; n = 1812). MAIN OUTCOMES AND MEASURES Thirty-day mortality following STEMI. RESULTS Overall, 52.8% (14,929 patients) had obstructive non-IRA disease; 29.6% involved 1 vessel and 18.8% involved 2 vessels. There was no substantial difference in the extent and distribution of non-IRA disease according to the IRA territory. Unadjusted and adjusted rates of 30-day mortality were significantly higher in patients with non-IRA disease than in those without non-IRA disease (unadjusted, 4.3% vs 1.7%, respectively; risk difference, 2.7% [95% CI, 2.3% to 3.0%], P < .001; and adjusted, 3.3% vs 1.9%, respectively; risk difference, 1.4% [95% CI, 1.0% to 1.8%], P < .001). The overall prevalence and association of non-IRA disease with 30-day mortality was consistent with findings from the KAMIR registry (adjusted, 3.6% for patients with non-IRA disease vs 2.5% in those without it; risk difference, 1.1% [95% CI, 0.6% to 1.7%]; P < .001), but not with the Duke database (adjusted, 4.7% with non-IRA disease vs 4.3% without it; risk difference, 0.4% [95% CI, -1.4% to 2.2%], P = .65). CONCLUSIONS AND RELEVANCE In a retrospective pooled analysis of 8 clinical trials, obstructive non-IRA disease was common among patients presenting with STEMI, and was associated with a modest statistically significant increase in 30-day mortality. These findings require confirmation in prospectively designed studies, but raise questions about the appropriateness and timing of non-IRA revascularization in patients with STEMI.

Apixaban Compared with Warfarin in Patients With Atrial Fibrillation and Valvular Heart Disease: Findings From the ARISTOTLE Trial

Background— Apixaban is approved for the prevention of stroke and systemic embolism in patients with nonvalvular atrial fibrillation. However, the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial included a substantial number of patients with valvular heart disease and only excluded patients with clinically significant mitral stenosis or mechanical prosthetic heart valves. Methods and Results— We compared the effect of apixaban and warfarin on rates of stroke or systemic embolism, major bleeding, and death in patients with and without moderate or severe valvular heart disease using Cox proportional hazards modeling. Of the 18 201 patients enrolled in ARISTOTLE, 4808 (26.4%) had a history of moderate or severe valvular heart disease or previous valve surgery. Patients with valvular heart disease had higher rates of stroke or systemic embolism and bleeding than patients without valvular heart disease. There was no evidence of a differential effect of apixaban over warfarin in patients with and without valvular heart disease in reducing stroke and systemic embolism (hazard ratio [HR], 0.70; 95% confidence interval [CI], 0.51–0.97 and HR, 0.84; 95%, CI 0.67–1.04; interaction P=0.38), causing less major bleeding (HR, 0.79; 95% CI, 0.61–1.04 and HR, 0.65; 95% CI, 0.55–0.77; interaction P=0.23), and reducing mortality (HR, 1.01; 95% CI, 0.84–1.22 and HR, 0.84; 95% CI, 0.73–0.96; interaction P=0.10). Conclusions— More than a quarter of the patients in ARISTOTLE with nonvalvular atrial fibrillation had moderate or severe valvular heart disease. There was no evidence of a differential effect of apixaban over warfarin in reducing stroke or systemic embolism, causing less bleeding, and reducing death in patients with and without valvular heart disease. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00412984.

Q- and A-learning Methods for Estimating Optimal Dynamic Treatment Regimes.

In clinical practice, physicians make a series of treatment decisions over the course of a patients disease based on his/her baseline and evolving characteristics. A dynamic treatment regime is a set of sequential decision rules that operationalizes this process. Each rule corresponds to a decision point and dictates the next treatment action based on the accrued information. Using existing data, a key goal is estimating the optimal regime, that, if followed by the patient population, would yield the most favorable outcome on average. Q- and A-learning are two main approaches for this purpose. We provide a detailed account of these methods, study their performance, and illustrate them using data from a depression study.

Clinical characteristics, response to exercise training, and outcomes in patients with heart failure and chronic obstructive pulmonary disease: Findings from Heart Failure and A Controlled Trial Investigating Outcomes of Exercise TraiNing (HF-ACTION)

BACKGROUND The aim of this study was to investigate the clinical characteristics, exercise training response, β-blocker selectivity, and outcomes in patients with heart failure (HF) and chronic obstructive pulmonary disease (COPD). METHODS We performed an analysis of HF-ACTION, which randomized 2,331 patients with HF having an ejection fraction of ≤35% to usual care with or without aerobic exercise training. We examined clinical characteristics and outcomes (mortality/hospitalization, mortality, cardiovascular [CV] mortality/CV hospitalization, and CV mortality/HF hospitalization) by physician-reported COPD status using adjusted Cox models and explored an interaction with exercise training. The interaction between β-blocker cardioselectivity and outcomes was investigated. RESULTS Of patients with COPD status documented (n = 2311), 11% (n = 249) had COPD. Patients with COPD were older, had more comorbidities, and had lower use of β-blockers compared with those without COPD. At baseline, patients with COPD had lower peak oxygen consumption and higher V(E)/V(CO)(2) slope. During a median follow-up of 2.5 years, COPD was associated with increased mortality/hospitalization, mortality, and CV mortality/HF hospitalization. After multivariable adjustment, the risk of CV mortality/HF hospitalization remained increased (hazard ratio [HR] 1.46, 95% CI 1.14-1.87), whereas mortality/hospitalization (HR 1.15, 95% CI 0.96-1.37) and mortality (HR 1.33, 95% CI 0.99-1.76) were not significantly increased. There was no interaction between COPD and exercise training on outcomes or between COPD and β-blocker selectivity on mortality/hospitalization (all P > .1). CONCLUSIONS Chronic obstructive pulmonary disease in patients with HF was associated with older age, more comorbidities, reduced exercise capacity, and increased CV mortality/HF hospitalization, but not a differential response to exercise training. β-Blocker selectivity was not associated with differences in outcome for patients with vs without COPD.

Diuretic response in acute heart failure-an analysis from ASCEND-HF

BACKGROUND Diuretic unresponsiveness often occurs during hospital admission for acute heart failure (AHF) and is associated with adverse outcome. This study aims to investigate determinants, clinical outcome, and the effects of nesiritide on diuretic response early after admission for AHF. METHODS Diuretic response, defined as weight loss per 40 mg of furosemide or equivalent, was examined from hospital admission to 48 hours in 4,379 patients from the ASCEND-HF trial. As an additional analysis, a urinary diuretic response metric was investigated in 5,268 patients using urine volume from hospital admission to 24 hours per 40 mg of furosemide or equivalent. RESULTS Mean diuretic response was -0.42 kg/40 mg of furosemide (interquartile range -1.0, -0.05). Poor responders had lower blood pressure, more frequent diabetes, long-term use of loop diuretics, poorer baseline renal function, and lower urine output (all P < .01). Randomized nesiritide treatment was not associated with diuretic response (P = .987). Good diuretic response was independently associated with a significantly decreased risk of 30-day all-cause mortality or heart failure rehospitalization (odds ratio 0.44, 95% CI 0.29-0.65, highest vs lowest quintile, P < .001). Diuretic response based on urine output per 40 mg of furosemide showed similar results in terms of clinical predictors, association with outcome, and the absence of an effect of nesiritide. CONCLUSIONS Poor diuretic response early after hospital admission for AHF is associated with low blood pressure, renal impairment, low urine output, and an increased risk of death or rehospitalization early after discharge. Nesiritide had a neutral effect on diuretic response.

Heart Rate at Hospital Discharge in Patients With Heart Failure Is Associated With Mortality and Rehospitalization

Background Whether heart rate upon discharge following hospitalization for heart failure is associated with long‐term adverse outcomes and whether this association differs between patients with sinus rhythm (SR) and atrial fibrillation (AF) have not been well studied. Methods and Results We conducted a retrospective cohort study from clinical registry data linked to Medicare claims for 46 217 patients participating in Get With The Guidelines®–Heart Failure. Cox proportional‐hazards models were used to estimate the association between discharge heart rate and all‐cause mortality, all‐cause readmission, and the composite outcome of mortality/readmission through 1 year. For SR and AF patients with heart rate ≥75, the association between heart rate and mortality (expressed as hazard ratio [HR] per 10 beats‐per‐minute increment) was significant at 0 to 30 days (SR: HR 1.30, 95% CI 1.22 to 1.39; AF: HR 1.23, 95% CI 1.16 to 1.29) and 31 to 365 days (SR: HR 1.15, 95% CI 1.12 to 1.20; AF: HR 1.05, 95% CI 1.01 to 1.08). Similar associations between heart rate and all‐cause readmission and the composite outcome were obtained for SR and AF patients from 0 to 30 days but only in the composite outcome for SR patients over the longer term. The HR from 0 to 30 days exceeded that from 31 to 365 days for both SR and AF patients. At heart rates <75, an association was significant for mortality only for both SR and AF patients. Conclusions Among older patients hospitalized with heart failure, higher discharge heart rate was associated with increased risks of death and rehospitalization, with higher risk in the first 30 days and for SR compared with AF.

Antiarrhythmic Drug Therapy for Sustained Ventricular Arrhythmias Complicating Acute Myocardial Infarction

Objective:Few data exist to guide antiarrhythmic drug therapy for sustained ventricular tachycardia/ventricular fibrillation after acute myocardial infarction. The objective of this analysis was to describe the survival of patients with sustained ventricular tachycardia/ventricular fibrillation after myocardial infarction according to antiarrhythmic drug treatment. Design and Setting:We conducted a retrospective analysis of ST-segment elevation myocardial infarction patients with sustained ventricular tachycardia/ventricular fibrillation in Global Use of Strategies to Open Occluded Coronary Arteries in Acute Coronary Syndromes (GUSTO) IIB and GUSTO III and compared all-cause death in patients receiving amiodarone, lidocaine, or no antiarrhythmic. We used Cox proportional-hazards modeling and inverse weighted estimators to adjust for baseline characteristics, &bgr;-blocker use, and propensity to receive antiarrhythmics. Due to nonproportional hazards for death in early follow-up (0–3 hrs after sustained ventricular tachycardia/ventricular fibrillation) compared with later follow-up (>3 hrs), we analyzed all-cause mortality using time-specific hazards. Patients and Interventions:Among 19,190 acute myocardial infarction patients, 1,126 (5.9%) developed sustained ventricular tachycardia/ventricular fibrillation and met the inclusion criteria. Patients received lidocaine (n = 664, 59.0%), amiodarone (n = 50, 4.4%), both (n = 110, 9.8%), or no antiarrhythmic (n = 302, 26.8%). Results:In the first 3 hrs after ventricular tachycardia/ventricular fibrillation, amiodarone (adjusted hazard ratio 0.39, 95% confidence interval 0.21–0.71) and lidocaine (adjusted hazard ratio 0.72, 95% confidence interval 0.53–0.96) were associated with a lower hazard of death—likely evidence of survivor bias. Among patients who survived 3 hrs, amiodarone was associated with increased mortality at 30 days (adjusted hazard ratio 1.71, 95% confidence interval 1.02–2.86) and 6 months (adjusted hazard ratio 1.96, 95% confidence interval 1.21–3.16), but lidocaine was not at 30 days (adjusted hazard ratio 1.19, 95% confidence interval 0.77–1.82) or 6 months (adjusted hazard ratio 1.10, 95% confidence interval 0.73–1.66). Conclusion:Among patients with acute myocardial infarction complicated by sustained ventricular tachycardia/ventricular fibrillation who survive 3 hrs, amiodarone, but not lidocaine, is associated with an increased risk of death, reinforcing the need for randomized trials in this population.

Association of spontaneous and procedure-related bleeds with short- and long-term mortality after acute coronary syndromes: an analysis from the PLATO trial

AIMS We sought to describe the differential effect of bleeding events in acute coronary syndromes (ACS) on short- and long-term mortality according to their type and severity. METHODS AND RESULTS The PLATO trial randomised 18,624 ACS patients to clopidogrel or ticagrelor. Post-randomisation bleeding events were captured according to bleeding type (spontaneous or procedure-related), with PLATO, TIMI, and GUSTO definitions. The association of bleeding events with subsequent short-term (<30 days) and long-term (>30 days) all-cause mortality was assessed using time-dependent Cox proportional hazard models. A model was fitted to compare major and minor bleeding for mortality prediction. Of 18,624 patients, 2,189 (11.8%) had at least one PLATO major bleed (mean follow-up 272.2±123.5 days). Major bleeding was associated with higher short-term mortality (adjusted hazard ratio [HR] 9.28; 95% confidence interval [CI]: 7.50-11.48) but not with long-term mortality (adjusted HR 1.28; 95% CI: 0.93-1.75). Spontaneous bleeding was associated with short-term (adjusted HR 14.59; 95% CI: 11.14-19.11) and long-term (adjusted HR 3.38; 95% CI: 2.26-5.05) mortality. Procedure-related bleeding was associated with short-term mortality (adjusted HR 5.29; 95% CI: 4.06-6.87): CABG-related and non-coronary-procedure-related bleeding were associated with a higher short-term mortality, whereas PCI or angiography-related bleeding was not associated with either short- or long-term mortality. Similar results were obtained using the GUSTO and TIMI bleeding definitions. CONCLUSIONS Major bleeding is associated with high subsequent mortality in ACS. However, this association is much stronger in the first 30 days and is strongest for spontaneous (vs. procedure-related) bleeding.