External Control Arms in Idiopathic Pulmonary Fibrosis Using Clinical Trial and Real-World Data Sources.

Rationale: Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease for which novel therapies are needed. External controls (ECs) could enhance IPF trial efficiency, but the direct comparability of ECs versus concurrent controls is unknown. Objectives: To develop IPF ECs by fit-for-purpose data standards to historical randomized clinical trial (RCT), multicenter registry (Pulmonary Fibrosis Foundation Patient Registry), and electronic health record (EHR) data and to evaluate endpoint comparability among ECs and the phase II RCT of BMS-986020. Methods: After data curation, the rate of change in FVC from baseline to 26 weeks among participants receiving BMS-986020 600 mg twice daily was compared with the BMS-placebo arm and ECs using mixed-effects models with inverse probability weights. Measurements and Main Results: At 26 weeks, the rates of change in FVC were -32.71 ml for BMS-986020 and -130.09 ml for BMS-placebo (difference, 97.4 ml; 95% confidence interval [CI], 24.6-170.2), replicating the original BMS-986020 RCT. RCT ECs showed treatment effect point estimates within the 95% CI of the original BMS-986020 RCT. Pulmonary Fibrosis Foundation Patient Registry ECs and EHR ECs experienced a slower rate of FVC decline compared with the BMS-placebo arm, resulting in treatment-effect point estimates outside of the 95% CI of the original BMS-986020 RCT. Conclusions: IPF ECs generated from historical RCT placebo arms result in comparable primary treatment effects to that of the original clinical trial, whereas ECs from real-world data sources, including registry or EHR data, do not. RCT ECs may serve as a potentially useful supplement to future IPF RCTs.

Time-dependent event accumulation in a cardiovascular outcome trial of patients with type 2 diabetes and established atherosclerotic cardiovascular disease.

BACKGROUND: Estimating cardiovascular (CV) event accrual is important for outcome trial planning. Limited data exist describing event accrual patterns in patients with type 2 diabetes (T2D). We compared apparent CV event accrual patterns with true event rates in the Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS). METHODS: Centrally adjudicated event dates and accrual rates for a 4-point major adverse CV event composite (MACE-4; includes CV death, nonfatal myocardial infarction, nonfatal stroke, or unstable angina hospitalization), MACE-4 components, all-cause mortality (ACM), and heart failure hospitalization were compiled. We used three graphical methods (Weibull probability plot, plot of negative log of the Kaplan-Meier survival distribution estimate, and the Epanechnikov kernel-smoothed estimate of the hazard rate) to examine hazard rate morphology over time for the 7 outcomes. RESULTS: Plots for all outcomes showed real-time constant event hazard rates for the duration of the follow-up, confirmed by Weibull shape parameters. The Weibull shape parameters for ACM (1.14, 95% CI 1.08-1.21) and CV death (1.08, 95% CI 1.01-1.16) were not sufficiently > 1 as to require non-constant hazard rate models to accurately depict the data. The time lag between event occurrence and event adjudication being completed, the adjudication gap, improved over the course of the trial. CONCLUSIONS: In TECOS, the nonfatal event hazard rates were constant over time. Small increases over time in the hazard rate for fatal events would not require complex modelling to predict event accrual, providing confidence in traditional modelling methods for predicting CV outcome trial event rates in this population. The adjudication gap provides a useful metric to monitor within-trial event accrual patterns. CLINICAL TRIAL REGISTRATION: Clinicaltrials.gov NCT00790205.

Development and validation of a model to predict cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke in patients with type 2 diabetes mellitus and established atherosclerotic cardiovascular disease.

BACKGROUND: Among individuals with atherosclerotic cardiovascular disease (ASCVD), type 2 diabetes mellitus (T2DM) is common and confers increased risk for morbidity and mortality. Differentiating risk is key to optimize efficiency of treatment selection. Our objective was to develop and validate a model to predict risk of major adverse cardiovascular events (MACE) comprising the first event of cardiovascular death, myocardial infarction (MI), or stroke for individuals with both T2DM and ASCVD. METHODS: Using data from the Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS), we used Cox proportional hazards models to predict MACE among participants with T2DM and ASCVD. All baseline covariates collected in the trial were considered for inclusion, although some were excluded immediately because of large missingness or collinearity. A full model was developed using stepwise selection in each of 25 imputed datasets, and comprised candidate variables selected in 20 of the 25 datasets. A parsimonious model with a maximum of 10 degrees of freedom was created using Cox models with least absolute shrinkage and selection operator (LASSO), where the adjusted R-square was used as criterion for selection. The model was then externally validated among a cohort of participants with similar criteria in the ACCORD (Action to Control Cardiovascular Risk in Diabetes) trial. Discrimination of both models was assessed using Harrell's C-index and model calibration by the Greenwood-Nam-D'Agostino statistic based on 4-year event rates. RESULTS: Overall, 1491 (10.2%) of 14,671 participants in TECOS and 130 (9.3%) in the ACCORD validation cohort (n = 1404) had MACE over 3 years' median follow-up. The final model included 9 characteristics (prior stroke, age, chronic kidney disease, prior MI, sex, heart failure, insulin use, atrial fibrillation, and microvascular complications). The model had moderate discrimination in both the internal and external validation samples (C-index = 0.65 and 0.61, respectively). The model was well calibrated across the risk spectrum-from a cumulative MACE rate of 6% at 4 years in the lowest risk quintile to 26% in the highest risk quintile. CONCLUSION: Among patients with T2DM and prevalent ASCVD, this 9-factor risk model can quantify the risk of future ASCVD complications and inform decision making for treatments and intensity.

Exploring the Possible Impact of Unbalanced Open-Label Drop-In of Glucose-Lowering Medications on EXSCEL Outcomes.

BACKGROUND: EXSCEL (Exenatide Study of Cardiovascular Event Lowering) assessed the impact of once-weekly exenatide 2 mg versus placebo in patients with type 2 diabetes mellitus, while aiming for glycemic equipoise. Consequently, greater drop-in of open-label glucose-lowering medications occurred in the placebo group. Accordingly, we explored the potential effects of their unbalanced use on major adverse cardiovascular events (MACE), defined as cardiovascular death, nonfatal myocardial infarction or nonfatal stroke, and all-cause mortality (ACM), given that some of these agents are cardioprotective. METHODS: Cox hazard models were performed by randomized treatment for drug classes where >5% open-label drop-in glucose-lowering medication occurred, and for glucagon-like peptide-1 receptor agonists (GLP-1 RAs; 3.0%) using three methodologies: drop-in visit right censoring, inverse probability for treatment weighting (IPTW), and applying drug class risk reductions. RESULTS: Baseline glucose-lowering medications for the 14 752 EXSCEL participants (73.1% with previous cardiovascular disease) did not differ between treatment groups. During median 3.2 years follow-up, open-label drop-in occurred in 33.4% of participants, more frequently with placebo than exenatide (38.1% versus 28.8%), with metformin (6.1% versus 4.9%), sulfonylurea (8.7% versus 6.9%), dipeptidyl peptidase-4 inhibitors (10.6% versus 7.5%), SGLT-2i (10.3% versus 8.1%), GLP-1 RA (3.4% versus 2.4%), and insulin (13.8% versus 9.4%). The MACE effect size was not altered meaningfully by right censoring, but the favorable HR for exenatide became nominally significant in the sulfonylurea and any glucose-lowering medication groups, while the ACM HR and p-values were essentially unchanged. IPTW decreased the MACE HR from 0.91 (P=0.061) to 0.85 (P=0.008) and the ACM HR from 0.86 (P=0.016) to 0.81 (P=0.012). Application of literature-derived risk reductions showed no meaningful changes in MACE or ACM HRs or P values, although simulations of substantially greater use of drop-in cardioprotective glucose-lowering agents demonstrated blunting of signal detection. CONCLUSIONS: EXSCEL-observed HRs for MACE and ACM remained robust after right censoring or application of literature-derived risk reductions, but the exenatide versus placebo MACE effect size and statistical significance were increased by IPTW. Effects of open-label drop-in cardioprotective medications need to be considered carefully when designing, conducting, and analyzing cardiovascular outcome trials of glucose-lowering agents under the premise of glycemic equipoise. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01144338.

Initial Invasive Versus Conservative Management of Stable Ischemic Heart Disease in Patients With a History of Heart Failure or Left Ventricular Dysfunction: Insights From the ISCHEMIA Trial.

BACKGROUND: Whether an initial invasive strategy in patients with stable ischemic heart disease and at least moderate ischemia improves outcomes in the setting of a history of heart failure (HF) or left ventricular dysfunction (LVD) when ejection fraction is ≥35% but <45% is unknown. METHODS: Among 5179 participants randomized into ISCHEMIA (International Study of Comparative Health Effectiveness With Medical and Invasive Approaches), all of whom had left ventricular ejection fraction (LVEF) ≥35%, we compared cardiovascular outcomes by treatment strategy in participants with a history of HF/LVD at baseline versus those without HF/LVD. Median follow-up was 3.2 years. RESULTS: There were 398 (7.7%) participants with HF/LVD at baseline, of whom 177 had HF/LVEF >45%, 28 HF/LVEF 35% to 45%, and 193 LVEF 35% to 45% but no history of HF. HF/LVD was associated with more comorbidities at baseline, particularly previous myocardial infarction, stroke, and hypertension. Compared with patients without HF/LVD, participants with HF/LVD were more likely to experience a primary outcome composite of cardiovascular death, nonfatal myocardial infarction, or hospitalization for unstable angina, HF, or resuscitated cardiac arrest (4-year cumulative incidence rate, 22.7% versus 13.8%; cardiovascular death or myocardial infarction, 19.7% versus 12.3%; and all-cause death or HF, 15.0% versus 6.9%). Participants with HF/LVD randomized to the invasive versus conservative strategy had a lower rate of the primary outcome (17.2% versus 29.3%; difference in 4-year event rate, -12.1% [95% CI, -22.6 to -1.6%]), whereas those without HF/LVD did not (13.0% versus 14.6%; difference in 4-year event rate, -1.6% [95% CI, -3.8% to 0.7%]; P interaction = 0.055). A similar differential effect was seen for the primary outcome, all-cause mortality, and cardiovascular mortality when invasive versus conservative strategy-associated outcomes were analyzed with LVEF as a continuous variable for patients with and without previous HF. CONCLUSIONS: ISCHEMIA participants with stable ischemic heart disease and at least moderate ischemia with a history of HF or LVD were at increased risk for the primary outcome. In the small, high-risk subgroup with HF and LVEF 35% to 45%, an initial invasive approach was associated with better event-free survival. This result should be considered hypothesis-generating. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01471522.

Low-density lipoprotein cholesterol treatment and outcomes in patients with type 2 diabetes and established cardiovascular disease: Insights from TECOS.

BACKGROUND: Type 2 diabetes (T2D) patients are at increased risk for cardiovascular (CV) events. Most guidelines recommend treating low-density lipoprotein cholesterol (LDL-C) levels to ≤70 mg/dL (1.8 mM) for patients with T2D and established atherosclerotic CV disease, and some a more aggressive target of ≤55 mg/dL (1.4 mM). Our objective was to assess the degree to which these LDL-C targets are achieved in routine practice. METHODS: Using data from TECOS, an international pragmatic CV outcomes trial of sitagliptin vs placebo, we assessed lipid-lowering treatment among patients with T2D and CV disease, baseline lipid values, and the association between baseline LDL-C and 5-year risk for major adverse cardiac events (MACE; ie, CV death, nonfatal myocardial infarction, or nonfatal stroke). RESULTS: Overall, 11,066 of 14,671 TECOS participants (75.4%) had LDL-C measured at baseline. Median age was 65 years, 72% were male, and median T2D duration was 10 years. Overall, 82.5% of patients were on statins; only 5.8% were on ezetimibe. At baseline, 14.3% had LDL-C ≤55 mg/dL, 18.4% between 55.1 and 70 mg/dL, 35% between 70.1 and 100 mg/dL, and 32.3% >100 mg/dL. Each 10 mg/dL higher LDL-C value was associated with a higher risk of MACE (HR 1.05, 95% CI 1.03-1.07) or CV death (HR 1.06, 95% CI 1.04-1.09). CONCLUSIONS: Although most high-risk patients with T2D and CV disease were on lipid-lowering therapy, only 1:3 had LDL-C <70 mg/dL and 1:6 had LDL-C <55 mg/dL. Each 10 mg/dL higher LDL-C value was associated with a 5% and 6% higher 5-year incidence of MACE and CV death, respectively. (TECOS, NCT00790205).

Determinants of Diuretic Responsiveness and Associated Outcomes During Acute Heart Failure Hospitalization: An Analysis From the NHLBI Heart Failure Network Clinical Trials.

BACKGROUND: Poor response to loop diuretic therapy is a marker of risk during heart failure hospitalization. We sought to describe baseline determinants of diuretic response and to further explore the relationship between this response and clinical outcomes. METHODS AND RESULTS: Patient data from the National Heart, Lung, and Blood Institute Heart Failure Network ROSE-AHF and CARRESS-HF clinical trials were analyzed to determine baseline determinants of diuretic response. Diuretic efficiency (DE) was defined as total 72-hour fluid output per total equivalent loop diuretic dose. Data from DOSE-AHF was then used to determine if these predictors of DE correlated with response to a high- versus low-dose diuretic strategy. At 72 hours, the high-DE group had median fluid output of 9071 ml (interquartile range: 7240-11775) with median furosemide dose of 320 mg (220-480) compared with 8030 ml (6300-9915) and 840 mg (600-1215) respectively for the low DE group. Cystatin C was independently associated with DE (odds ratio 0.36 per 1mg/L increase; 95% confidence interval: 0.24-0.56; P < 0.001). Independently from baseline characteristics, reduced fluid output, weight loss and DE were each associated with increased 60 day mortality. Among patients with estimated glomerular filtration rate below the median, those randomized to a high-dose strategy had improved symptoms compared with those randomized to a low-dose strategy. CONCLUSIONS: Elevated baseline cystatin C, as a biomarker of renal dysfunction, is associated with reduced diuretic response during heart failure hospitalization. Higher loop diuretic doses are required for therapeutic decongestion in patients with renal insufficiency. Poor response identifies a high-risk population.

Clinical Significance of Early Fluid and Weight Change During Acute Heart Failure Hospitalization.

AIMS: To explore the association of changes in weight and fluid during treatment for acute heart failure (AHF) with clinical endpoints. METHODS AND RESULTS: Weight and net fluid changes recorded at 72-96 hours in 708 AHF patients enrolled in Diuretic Optimization Strategy Evaluation in Acute Decompensated Heart Failure, Cardiorenal Rescue Study in Acute Decompensated Heart Failure, and Renal Optimization Strategies Evaluation in Acute Heart Failure studies were compared with freedom from congestion at 72-96 hours and a composite endpoint of death, rehospitalization, and unplanned hospital visit at 60 days. Weight loss was concordant with net fluid loss in 55%, discordant and less than expected for fluid loss in 34%, and paradoxically discordant or more than expected for fluid loss in 11% of patients. Weight loss, but not fluid loss, was associated with freedom from congestion (odds ratio per 1-kg weight loss = 1.11 [1.03-1.19]) and a nominal reduction in the composite endpoint (hazard ratio per 1-kg weight loss = 0.98 [0.95-1.00]). Outcomes were similar in patients with concordant and discordant weight-fluid loss. CONCLUSION: During treatment for AHF, early changes in weight may be more useful for identifying response to therapy and for predicting outcomes than net fluid output. Nearly one-half of patients receiving decongestive therapies demonstrate discordant changes in weight and fluid; however, discordance was not associated with outcomes.

Sex differences in management and outcomes of patients with type 2 diabetes and cardiovascular disease: A report from TECOS.

AIM: To examine sex differences in baseline characteristics and outcomes in patients with type 2 diabetes and atherosclerotic vascular disease. MATERIALS AND METHODS: Cox models were used to analyse the association between sex and outcomes in the Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS), a randomized, placebo-controlled trial assessing the impact of sitagliptin on cardiovascular (CV) outcomes in patients with type 2 diabetes and atherosclerotic vascular disease. RESULTS: A total of 4297 women and 10 374 men were followed for a median of 3.0 years. Women were slightly older and more often had cerebrovascular disease and peripheral arterial disease but less often coronary heart disease than men. At baseline, women were less likely to use aspirin or statins. The primary composite outcome of CV death, myocardial infarction, stroke, or hospitalization for unstable angina occurred in 418 women (9.7%) and 1272 men (12.3%; 3.48 vs 4.38 events/100 participant-years, crude hazard ratio [HR] 0.79, 95% confidence interval [CI] 0.71-0.89, adjusted HR 0.64, 95% CI 0.55-0.74; P < .0001). Women also had a significantly lower risk of secondary CV outcomes and all-cause death. CONCLUSIONS: In this large prospective study of people with type 2 diabetes and CV disease, women had different CV disease burden, worse CV risk factor profiles, and less use of indicated medications than men. Despite this, women had significantly lower risk of CV events, suggesting that the cardioprotective effects of female sex extend to populations with type 2 diabetes.

Impact of Intubation Time on Survival following Coronary Artery Bypass Grafting: Insights from the Surgical Treatment for Ischemic Heart Failure (STICH) Trial.

OBJECTIVE: The authors aimed to assess determinants of intubation time and evaluate its impact on 30-day and 1-year postoperative survival in Surgical Treatment for Ischemic Heart Failure (STICH) trial patients. DESIGN, SETTING, PARTICIPANTS, AND INTERVENTIONS: A multivariable Cox proportional hazards model was used among the 1,446 surgical patients from the STICH trial who survived 36 hours after operation, in order to identify perioperative factors associated with 30-day and 1-year postoperative mortality. A multivariable logistic regression model was used to determine risk factors associated with intubation time. MEASUREMENTS AND MAIN RESULTS: At 36 hours post-operation, 1,298 (out of 1,446) were extubated and 148 (10.2%) still intubated. Median postoperative intubation time was 11.4 hours. Among patients surviving 36 hours, a multivariable model was developed to predict 30-day (c-index = 0.88) and 1-year (c-index = 0.78) mortality. Intubation time was the strongest independent predictor of 30-day (hazard ratio [HR] 5.50) and 1-year mortality (HR 3.69). Predictors of intubation time >36 hours included mitral valve procedure, New York Heart Association class, left ventricular systolic volume index, creatinine, previous coronary artery bypass grafting (CABG), and age. Results were similar in patients surviving 24 hours post-operation, where intubation time was also the strongest predictor of 30-day (HR 4.18, c-index 0.87) and 1-year (HR 2.81, c-index 0.78) mortality. CONCLUSIONS: Intubation time is the strongest predictor of 30-day and 1-year mortality among patients with ischemic heart failure undergoing CABG. Combining intubation time with other mortality risk factors may allow the identification of patients at the highest risk for whom the development of specific strategies may improve outcomes.

Predicting risk of cardiac events among ST-segment elevation myocardial infarction patients with conservatively managed non-infarct-related artery coronary artery disease: An analysis of the Duke Databank for Cardiovascular Disease.

BACKGROUND: Recent randomized evidence has demonstrated benefit with complete revascularization during the index hospitalization for multivessel coronary artery disease ST-segment elevation myocardial infarction (STEMI) patients; however, this benefit likely depends on the risk of future major adverse cardiovascular events (MACE). METHODS: Using data from Duke University Medical Center (2003-2012), we identified those at high risk for 1-year MACE among 664 STEMI patients with conservatively managed non-infarct-related artery (non-IRA) lesions. Using multivariable logistic regression, we identified clinical and angiographic characteristics associated with MACE (death, myocardial infarction, urgent revascularization) to 1 year and developed an integer-based risk prediction model for clinical use. RESULTS: In this cohort (median age 60 years, 30% female), the unadjusted Kaplan-Meier rates for MACE at 30 days and 1 year were 10% and 28%, respectively. Characteristics associated with MACE at 1 year included reduced left ventricular ejection fraction, hypertension, heart failure, higher-risk non-IRA vessels (left main), renal insufficiency, and greater % stenosis of non-IRA lesions. A 15-point risk score including these variables had modest discrimination (C-index 0.67) across a spectrum of subsequent risk (4%-88%) for 1-year MACE. CONCLUSIONS: There is a wide spectrum of risk following primary percutaneous coronary intervention for STEMI patients with multivessel disease. Using readily available clinical characteristics, the expected incidence of MACE by 1 year can be calculated with a simplified risk score, facilitating a tailored approach to clinical care.

Safety of sitagliptin in patients with type 2 diabetes and chronic kidney disease: outcomes from TECOS.

AIMS: To characterize the incidence of diabetes-associated complications and assess the safety of sitagliptin in participants with chronic kidney disease (CKD) in the Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS). MATERIALS AND METHODS: For participants with baseline eGFR measurements (n = 14 528), baseline characteristics and safety outcomes were compared for the CKD cohort (eGFR < 60 mL/min per 1.73 m2 ) vs those without CKD. Within the CKD cohort, the same analyses were performed, comparing sitagliptin- and placebo-assigned participants. Baseline characteristics were summarized for all participants, and serious adverse events were analysed in those who received at least 1 dose of study medication. Adverse events of interest and diabetes complications were summarized for the intention-to-treat population. RESULTS: CKD was present in 3324 (23%) participants at entry into TECOS. The mean (SD) age for this CKD cohort was 68.8 (7.9) years, mean diabetes duration was 13.7 (9.0) years, and 62% were men. Incidences of serious adverse events, malignancy, bone fracture, severe hypoglycaemia and most categories of diabetes complications were higher in the CKD cohort compared with those without CKD. Over ~2.8 median years of follow-up, CKD participants assigned to sitagliptin had rates of diabetic eye disease, diabetic neuropathy, renal failure, malignancy, bone fracture, pancreatitis and severe hypoglycaemia similar to those of placebo-assigned participants. CONCLUSIONS: Participants in TECOS with CKD had higher incidences of serious adverse events and diabetes complications than those without CKD. Treatment with sitagliptin was generally well tolerated, with no meaningful differences in safety outcomes observed between those with CKD assigned to sitagliptin or placebo.

Influence of Baseline Characteristics, Operative Conduct, and Postoperative Course on 30-Day Outcomes of Coronary Artery Bypass Grafting Among Patients With Left Ventricular Dysfunction: Results From the Surgical Treatment for Ischemic Heart Failure (STICH) Trial.

BACKGROUND: Patients with severe left ventricular dysfunction, ischemic heart failure, and coronary artery disease suitable for coronary artery bypass grafting (CABG) are at higher risk for surgical morbidity and mortality. Paradoxically, those patients with the most severe coronary artery disease and ventricular dysfunction who derive the greatest clinical benefit from CABG are also at the greatest operative risk, which makes decision making regarding whether to proceed to surgery difficult in such patients. To better inform such decision making, we analyzed the Surgical Treatment for Ischemic Heart Failure (STICH) CABG population for detailed information on perioperative risk and outcomes. METHODS AND RESULTS: In both STICH trials (hypotheses), 2136 patients with a left ventricular ejection fraction of ≤35% and coronary artery disease were allocated to medical therapy, CABG plus medical therapy, or CABG with surgical ventricular reconstruction. Relationships of baseline characteristics and operative conduct with morbidity and mortality at 30 days were evaluated. There were a total of 1460 patients randomized to and receiving surgery, and 346 (≈25%) of these high-risk patients developed a severe complication within 30 days. Worsening renal insufficiency, cardiac arrest with cardiopulmonary resuscitation, and ventricular arrhythmias were the most frequent complications and those most commonly associated with death. Mortality at 30 days was 5.1% and was generally preceded by a serious complication (65 of 74 deaths). Left ventricular size, renal dysfunction, advanced age, and atrial fibrillation/flutter were significant preoperative predictors of mortality within 30 days. Cardiopulmonary bypass time was the only independent surgical variable predictive of 30-day mortality. CONCLUSIONS: CABG can be performed with relatively low 30-day mortality in patients with left ventricular dysfunction. Serious postoperative complications occurred in nearly 1 in 4 patients and were associated with mortality. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00023595.

Digoxin use in patients with atrial fibrillation and adverse cardiovascular outcomes: a retrospective analysis of the Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF).

BACKGROUND: Digoxin is a widely used drug for ventricular rate control in patients with atrial fibrillation (AF), despite a scarcity of randomised trial data. We studied the use and outcomes of digoxin in patients in the Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF). METHODS: For this retrospective analysis, we included and classified patients from ROCKET AF on the basis of digoxin use at baseline and during the study. Patients in ROCKET AF were recruited from 45 countries and had AF and risk factors putting them at moderate-to-high risk of stroke, with or without heart failure. We used Cox proportional hazards regression models adjusted for baseline characteristics and drugs to investigate the association of digoxin with all-cause mortality, vascular death, and sudden death. ROCKET AF was registered with ClinicalTrials.gov, number NCT00403767. FINDINGS: In 14,171 randomly assigned patients, digoxin was used at baseline in 5239 (37%). Patients given digoxin were more likely to be female (42% vs 38%) and have a history of heart failure (73% vs 56%), diabetes (43% vs 38%), and persistent AF (88% vs 77%; p<0·0001 for each comparison). After adjustment, digoxin was associated with increased all-cause mortality (5·41 vs 4·30 events per 100 patients-years; hazard ratio 1·17; 95% CI 1·04-1·32; p=0·0093), vascular death (3·55 vs 2·69 per 100 patient-years; 1·19; 1·03-1·39, p=0·0201), and sudden death (1·68 vs 1·12 events per 100 patient-years; 1·36; 1·08-1·70, p=0·0076). INTERPRETATION: Digoxin treatment was associated with a significant increase in all-cause mortality, vascular death, and sudden death in patients with AF. This association was independent of other measured prognostic factors, and although residual confounding could account for these results, these data show the possibility of digoxin having these effects. A randomised trial of digoxin in treatment of AF patients with and without heart failure is needed. FUNDING: Janssen Research & Development and Bayer HealthCare AG.

Clinical Implications of Serum Albumin Levels in Acute Heart Failure: Insights From DOSE-AHF and ROSE-AHF.

BACKGROUND: Hypoalbuminemia is common in patients with chronic heart failure and, as a marker of disease severity, is associated with an adverse prognosis. Whether hypoalbuminemia contributes to (or is associated with) worse outcomes in acute heart failure (AHF) is unclear. We sought to determine the implications of low serum albumin in patients receiving decongestive therapies for AHF. METHODS AND RESULTS: Baseline serum albumin levels were measured in 456 AHF subjects randomized in the DOSE-AHF and ROSE-AHF trials. We assessed the relationship between admission albumin levels (both as a continuous variable and stratified by median albumin [≥3.5 g/dL]) and worsening renal function (WRF), worsening heart failure (WHF), and clinical decongestion by 72 hours; 7-day cardiorenal biomarkers; and post-discharge outcomes. The mean baseline albumin level was 3.5 ± 0.5 g/dL. Albumin was not associated with WRF, WHF, or clinical decongestion by 72 hours. Furthermore, there was no association between continuous albumin levels and symptom change according to visual analog scale or weight change by 72 hours. Albumin was not associated with 60-day mortality, rehospitalization, or unscheduled emergency room visits. CONCLUSIONS: Baseline serum albumin levels were not associated with short-term clinical outcomes for AHF patients undergoing decongestive therapies. These data suggest that serum albumin may not be a helpful tool to guide decongestion strategies.

Hemodynamic Predictors of Heart Failure Morbidity and Mortality: Fluid or Flow?

BACKGROUND: Patients with advanced heart failure may continue for prolonged times with persistent hemodynamic abnormalities; intermediate- and long-term outcomes of these patients are unknown. METHODS AND RESULTS: We used ESCAPE (Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness) trial data to examine characteristics and outcomes of patients with invasive hemodynamic monitoring during an acute heart failure hospitalization. Patients were stratified by final measurement of cardiac index (CI; L/min/m2) and pulmonary capillary wedge pressure (PCWP; mmHg) before catheter removal. The study groups were CI ≥ 2/PCWP < 20 (n = 74), CI ≥ 2/PCWP ≥ 20 (n = 37), CI < 2/PCWP < 20 (n = 23), and CI < 2/PCWP ≥ 20 (n = 17). Final CI was not associated with the combined risk of death, cardiovascular hospitalization, and transplantation (hazard ratio [HR]1.03, 95% confidence interval 0.96-1.11 per 0.2 L/min/m2 decrease, P = .39), but final PCWP ≥ 20 mmHg was associated with increased risk of these events (HR 2.03, 95% confidence interval 1.31-3.15, P < .01), as was higher final right atrial pressure (HR 1.09, 95% confidence interval 1.06-1.12 per mmHg increase, P < .01). CONCLUSION: Final PCWP and final right atrial pressure were stronger predictors of postdischarge outcomes than CI in patients with advanced heart failure. The ability to lower filling pressures appears to be more prognostically important than improving CI in the management of patients with advanced heart failure. ClinicalTrials.govIdentifier: NCT00000619.

Timing and Causes of Readmission After Acute Heart Failure Hospitalization-Insights From the Heart Failure Network Trials.

BACKGROUND: Readmission or death after heart failure (HF) hospitalization is a consequential and closely scrutinized outcome, but risk factors may vary by population. We characterized the risk factors for post-discharge readmission/death in subjects treated for acute heart failure (AHF). METHODS AND RESULTS: A post hoc analysis was performed on data from 744 subjects enrolled in 3 AHF trials conducted within the Heart Failure Network (HFN): Diuretic Optimization Strategies Evaluation in Acute Heart Failure (DOSE-AHF), Cardiorenal Rescue Study in Acute Decompensated Heart Failure (CARRESS-HF), and Renal Optimization Strategies Evaluation in Acute Heart Failure (ROSE-AHF). All-cause readmission/death occurred in 26% and 38% of subjects within 30 and 60 days of discharge, respectively. Non-HF cardiovascular causes of readmission were more common in the ≤30-day timeframe than in the 31-60-day timeframe (23% vs 10%, P = .016). In a Cox proportional hazards model adjusting a priori for left ventricular ejection fraction <50% and trial, the risk factors for all-cause readmission/death included: elevated baseline blood urea nitrogen, angiotensin-converting enzyme inhibitor (ACEI)/angiotensin receptor blocker (ARB) non-use, lower baseline sodium, non-white race, elevated baseline bicarbonate, lower systolic blood pressure at discharge or day 7, depression, increased length of stay, and male sex. CONCLUSIONS: In an AHF population with prominent congestion and prevalent renal dysfunction, early readmissions were more likely to be due to non-HF cardiovascular causes compared with later readmissions. The association between use of ACEI/ARB and lower all-cause readmission/death in Cox proportional hazards model suggests a role for these drugs to improve post-discharge outcomes in AHF.

Intensification of Medication Therapy for Cardiorenal Syndrome in Acute Decompensated Heart Failure.

BACKGROUND: Worsening renal function in heart failure may be related to increased venous congestion, decreased cardiac output, or both. Diuretics are universally used in acute decompensated heart failure, but they may be ineffective and may lead to azotemia. We aimed to compare the decongestive properties of a urine output-guided diuretic adjustment and standard therapy for the management of cardiorenal syndrome in acute decompensated heart failure. METHODS AND RESULTS: Data were pooled from subjects randomized to the stepwise pharmacologic care algorithm (SPCA) in the CARRESS-HF trial and those who developed cardiorenal syndrome (rise in creatinine >0.3 mg/dL) in the DOSE-AHF and ROSE-AHF trials. Patients treated with SPCA (n = 94) were compared with patients treated with standard decongestive therapy (SDT) that included intravenous loop diuretic use (DOSE-AHF and ROSE-AHF; n = 107) at the time of cardiorenal syndrome and followed for net fluid balance, weight loss, and changing renal function. The SPCA group had higher degrees of jugular venous pressure (P < .0001) at the time of cardiorenal syndrome. The group that received SPCA had more weight change (-3.4 ± 5.2 lb) and more net fluid loss (1.705 ± 1.417 L) after 24 hours than the SDT group (-0.8 ± 3.4 lb and 0.892 ± 1.395 L, respectively; P < .001 for both) with a slight improvement in renal function (creatinine change -0.1 ± 0.3 vs 0.0 ± 0.3 mg/dL, respectively; P = .03). CONCLUSIONS: Compared with SDT, patients who received an intensification of medication therapy for treating persisting congestion had greater net fluid and weight loss without being associated with renal compromise.

Clinical outcomes in patients with atrial fibrillation according to sex during anticoagulation with apixaban or warfarin: a secondary analysis of a randomized controlled trial.

AIM: To assess clinical outcomes, efficacy, and safety according to sex during anticoagulation with apixaban compared with warfarin in patients with atrial fibrillation. METHODS AND RESULTS: Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) was a randomized, double-blind, placebo-controlled, multicentre trial that included 11 785 (64.7%) men and 6416 (35.3%) women with atrial fibrillation or flutter randomized to receive either warfarin or apixaban. The primary efficacy endpoint was stroke or systemic embolism; secondary efficacy endpoints were death from any cause and cardiovascular death. The primary safety endpoint was major bleeding; secondary safety endpoints were a composite of major bleeding and non-major clinically relevant bleeding. The risk of stroke or systemic embolism was similar in women vs. men [adjusted hazard ratio (adjHR): 0.91; 95% confidence interval (CI): 0.74-1.12; P = 0.38]. However, among patients with history of stroke or transient ischaemic attack, women had a lower risk of recurrent stroke compared with men (adjHR: 0.70; 95% CI: 0.50-0.97; P = 0.036). Women also had a lower risk of all-cause death (adjHR: 0.63; 95% CI: 0.55-0.73; P < 0.0001) and cardiovascular death (adjHR: 0.62; 95% CI: 0.51-0.75; P < 0.0001), and a trend towards less major bleeding (adjHR: 0.86; 95% CI: 0.74-1.01; P = 0.066) and major or non-major clinically relevant bleeding (adjHR: 0.89; 95% CI: 0.80-1.00; P = 0.049). The efficacy and safety benefits of apixaban compared with warfarin were consistent regardless of sex. CONCLUSION: In the ARISTOTLE trial, women had a similar rate of stroke or systemic embolism but a lower risk of mortality and less clinically relevant bleeding than men. The efficacy and safety benefits of apixaban compared with warfarin were consistent in men and women. TRIAL REGISTRATION: ARISTOTLE ClinicalTrials.gov number, NCT00412984.

The MitraClip and survival in patients with mitral regurgitation at high risk for surgery: A propensity-matched comparison.

BACKGROUND: We compared 30-day and 1-year survival among high-risk mitral regurgitation (MR) patients treated with the MitraClip (Abbott Vascular, Abbott Park, IL) with matched non-surgically treated patients from the Duke Echocardiography Laboratory Database (DELD). METHODS AND RESULTS: High-risk patients with 3+/4+ MR managed non-surgically between years 2000 and 2010 in the longitudinal DELD were matched to high-risk MitraClip patients. Patient matching was performed using the method of nearest available Mahalanobis distance metric within calipers defined by the propensity score. Kaplan-Meier estimates and stratified Cox proportional hazards models were used to compare survival at 30 days and 1 year. Among 953 high-risk DELD patients available for matching, 30-day and 1-year mortality were 6.5% and 26.2%. Close matches were obtained for 239 of the 351 MitraClip patients. The 30-day mortality in MitraClip patients was lower (4.2%) when compared with matched DELD patients (7.2%). The 1-year relative risk of mortality of the MitraClip compared with non-surgical treatment was 0.64 (95% CI 0.45-0.91; log-rank P = .013). These results in favor of the MitraClip remained significant upon further adjustment for baseline differences between groups (P = .043). CONCLUSIONS: This matched comparison of severe MR patients at high surgical risk supports the safety of the MitraClip relative to medical therapy at 30 days and a survival benefit at 1 year.