Background— About half of the 5 million heart failure patients in the United States have diastolic heart failure (clinical heart failure with normal or near-normal ejection fraction). Except for candesartan, no drugs have been tested in randomized clinical trials in these patients. Although digoxin was tested in an appreciable number of diastolic heart failure patients in the Digitalis Investigation Group ancillary trial, detailed findings from this important study have not previously been published. Methods and Results— Ambulatory chronic heart failure patients (n=988) with normal sinus rhythm and ejection fraction >45% (median, 53%) from the United States and Canada (1991 to 1993) were randomly assigned to digoxin (n=492) or placebo (n=496). During follow-up with a mean length of 37 months, 102 patients (21%) in the digoxin group and 119 patients (24%) in the placebo group (hazard ratio [HR], 0.82; 95% confidence interval [CI], 0.63 to 1.07; P =0.136) experienced the primary combined outcome of heart failure hospitalization or heart failure mortality. Digoxin had no effect on all-cause or cause-specific mortality or on all-cause or cardiovascular hospitalization. Use of digoxin was associated with a trend toward a reduction in hospitalizations resulting from worsening heart failure (HR, 0.79; 95% CI, 0.59 to 1.04; P =0.094) but also a trend toward an increase in hospitalizations for unstable angina (HR, 1.37; 95% CI, 0.99 to 1.91; P =0.061). Conclusions— In ambulatory patients with chronic mild to moderate diastolic heart failure and normal sinus rhythm receiving angiotensin-converting enzyme inhibitor and diuretics, digoxin had no effect on natural history end points such as mortality and all-cause or cardiovascular hospitalizations.

Aims Non-potassium-sparing diuretics are commonly used in heart failure (HF). They activate the neurohormonal system, and are potentially harmful. Yet, the long-term effects of chronic diuretic use in HF are largely unknown. We retrospectively analysed the Digitalis Investigation Group (DIG) data to determine the effects of diuretics on HF outcomes. Methods and results Propensity scores for diuretic use were calculated for each of the 7788 DIG participants using a non-parsimonious multivariable logistic regression model, and were used to match 1391 (81%) no-diuretic patients with 1391 diuretic patients. Effects of diuretics on mortality and hospitalization at 40 months of median follow-up were assessed using matched Cox regression models. All-cause mortality was 21% for no-diuretic patients and 29% for diuretic patients [hazard ratio (HR) 1.31; 95% confidence interval (CI) 1.11–1.55; P=0.002]. HF hospitalizations occurred in 18% of no-diuretic patients and 23% of diuretic patients (HR 1.37; 95% CI 1.13–1.65; P=0.001). Conclusion Chronic diuretic use was associated with increased long-term mortality and hospitalizations in a wide spectrum of ambulatory chronic systolic and diastolic HF patients. The findings of the current study challenge the wisdom of routine chronic use of diuretics in HF patients who are asymptomatic or minimally symptomatic without fluid retention, and are on complete neurohormonal blockade. These findings, based on a non-randomized design, need to be further studied in randomized trials.

Aims To determine the effects of digoxin on all-cause mortality and heart failure (HF) hospitalizations, regardless of ejection fraction, accounting for serum digoxin concentration (SDC). Methods and results This comprehensive post-hoc analysis of the randomized controlled Digitalis Investigation Group trial (n=7788) focuses on 5548 patients: 1687 with SDC, drawn randomly at 1 month, and 3861 placebo patients, alive at 1 month. Overall, 33% died and 31% had HF hospitalizations during a 40-month median follow-up. Compared with placebo, SDC 0.5–0.9 ng/mL was associated with lower mortality [29 vs. 33% placebo; adjusted hazard ratio (AHR), 0.77; 95% confidence interval (CI), 0.67–0.89], all-cause hospitalizations (64 vs. 67% placebo; AHR, 0.85; 95% CI, 0.78–0.92) and HF hospitalizations (23 vs. 33% placebo; AHR, 0.62; 95% CI, 0.54–0.72). SDC≥1.0 ng/mL was associated with lower HF hospitalizations (29 vs. 33% placebo; AHR, 0.68; 95% CI, 0.59–0.79), without any effect on mortality. SDC 0.5–0.9 reduced mortality in a wide spectrum of HF patients and had no interaction with ejection fraction >45% (P=0.834) or sex (P=0.917). Conclusions Digoxin at SDC 0.5–0.9 ng/mL reduces mortality and hospitalizations in all HF patients, including those with preserved systolic function. At higher SDC, digoxin reduces HF hospitalization but has no effect on mortality or all-cause hospitalizations.

Background: The reported incidence of peripartum cardiomyopathy ( PPCM ) in the United States varies widely. Furthermore, limited information is available on the temporal trends in incidence and outcomes of PPCM . Methods and Results: We queried the 2004‐2011 Nationwide Inpatient Sample databases to identify all women aged 15 to 54 years with the diagnosis of PPCM . Temporal trends in incidence (per 10 000 live births), maternal major adverse events ( MAE ; defined as in‐hospital mortality, cardiac arrest, heart transplant, mechanical circulatory support, acute pulmonary edema, thromboembolism, or implantable cardioverter defibrillator/permanent pacemaker implantation), cardiogenic shock, and mean length of stay were analyzed. From 2004 to 2011, we identified 34 219 women aged 15 to 54 years with PPCM . The overall PPCM rate was 10.3 per 10 000 (or 1 in 968) live births. PPCM incidence increased from 8.5 to 11.8 per 10 000 live births ( P _trend <0.001) over the past 8 years. MAE occurred in 13.5% of patients. There was no temporal change in MAE rate, except a small increase in in‐hospital mortality and mechanical circulatory support ( P _trend <0.05). Cardiogenic shock increased from 1.0% in 2004 to 4.0% in 2011 ( P _trend <0.001). Mean length of stay decreased during the study period. Conclusion: From 2004 to 2011, the incidence of PPCM has increased in the United States. Maternal MAE rates overall have remained unchanged while cardiogenic shock, utilization of mechanical circulatory support, and in‐hospital mortality have increased during the study period. Further study of the mechanisms underlying these adverse trends in the incidence and outcomes of PPCM are warranted.

Background— Studies of the effect of right ventricular ejection fraction (RVEF) on outcomes in heart failure (HF) are limited by small sample size and short follow-up. Methods and Results— We examined the effect of baseline RVEF on outcomes in 2008 Beta-Blocker Evaluation of Survival Trial (BEST) participants with HF and left ventricular ejection fraction ≤35% during 24 months of mean follow-up. RVEF, estimated by gated-equilibrium radionuclide ventriculography, was used to categorize patients into 4 RVEF groups: ≥40% (n=733), 30% to 39% (n=531), 20% to 29% (n=473), and <20% (n=271). Unadjusted rates for all-cause mortality in patients with RVEF ≥40%, 30% to 39%, 20% to 29%, and <20% were 27%, 32%, 35%, and 47%, respectively. When compared with patients with RVEF ≥40%, unadjusted hazard ratios and 95% confidence intervals for all-cause mortality for those with RVEF 30% to 39%, 20% to 29%, and <20% were 1.19 (0.97 to 1.46; P =0.087), 1.45 (1.17 to 1.78; P =0.001), and 1.98 (1.59 to 2.47; P <0.0001), respectively. Respective multivariable-adjusted hazard ratios (95% confidence intervals) for all-cause mortality associated with RVEF 30% to 39%, 20% to 29%, and <20% were 1.07 (0.87 to 1.32; P =0.518), 1.12 (0.89 to 1.40; P =0.328), and 1.32 (1.02 to 1.71; P =0.034), respectively. Adjusted hazard ratios (95% confidence intervals) for other outcomes associated with RVEF <20% (compared with ≥40%) were as follows: cardiovascular mortality, 1.33 (1.01 to 1.76; P =0.041); HF mortality, 1.61 (1.03 to 2.52; P =0.037); sudden cardiac death, 1.29 (0.87 to 1.91; P =0.212); all-cause hospitalization, 1.21 (1.00 to 1.47; P =0.056); and HF hospitalization, 1.39 (1.10 to 1.77; P =0.007). Conclusions— Baseline RVEF <20% is a significant independent predictor of mortality and HF hospitalization in systolic HF.

Background: Quercetin, the most abundant dietary flavonol, has antioxidant effects in cardiovascular disease, but the evidence regarding its effects on blood pressure ( BP ) has not been conclusive. We assessed the impact of quercetin on BP through a systematic review and meta‐analysis of available randomized controlled trials. Methods and Results: We searched PUBMED , Cochrane Library, Scopus, and EMBASE up to January 31, 2015 to identify placebo‐controlled randomized controlled trials investigating the effect of quercetin on BP . Meta‐analysis was performed using either a fixed‐effects or random‐effect model according to I ² statistic. Effect size was expressed as weighted mean difference ( WMD ) and 95% CI . Overall, the impact of quercetin on BP was reported in 7 trials comprising 9 treatment arms (587 patients). The results of the meta‐analysis showed significant reductions both in systolic BP ( WMD : −3.04 mm Hg, 95% CI : −5.75, −0.33, P =0.028) and diastolic BP ( WMD : −2.63 mm Hg, 95% CI : −3.26, −2.01, P <0.001) following supplementation with quercetin. When the studies were categorized according to the quercetin dose, there was a significant systolic BP and diastolic BP ‐reducing effect in randomized controlled trials with doses ≥500 mg/day ( WMD : −4.45 mm Hg, 95% CI : −7.70, −1.21, P =0.007 and −2.98 mm Hg, 95% CI : −3.64, −2.31, P <0.001, respectively), and lack of a significant effect for doses <500 mg/day ( WMD : −1.59 mm Hg, 95% CI : −4.44, 1.25, P =0.273 and −0.24 mm Hg, 95% CI : −2.00, 1.52, P =0.788, respectively), but indirect comparison tests failed to significant differences between doses. Conclusions: The results of the meta‐analysis showed a statistically significant effect of quercetin supplementation in the reduction of BP , possibly limited to, or greater with dosages of >500 mg/day. Further studies are necessary to investigate the clinical relevance of these results and the possibility of quercetin application as an add‐on to antihypertensive therapy.