DIG Trial Research Articles

Use of the Win Ratio in Cardiovascular Trials

ObjectivesThe purpose of this study was to compare the win ratio (WR) with the corresponding hazard ratios (HRs) and 1/HR. BackgroundThe primary outcome in many cardiovascular trials is a composite that includes nonfatal and fatal events. The time-to-first event analysis gives equal statistical weighting to each component event. The WR, which takes into account the clinical importance and timing of the outcomes, has been suggested as an alternative approach. MethodsCox proportional hazards models and WR. ResultsIn the these trials (n = 16) the WR and HR differed only slightly. For example, in the PARADIGM-HF (sacubitril/valsartan vs. enalapril), the primary outcome of time to first heart failure hospitalization (HFH) or cardiovascular death (CVD) and use of the Cox model gave a 1/HR of 1.25 (95% confidence interval [CI]: 1.12 to 1. 41; z-score = 4.8). Using WR for testing this composite in the hierarchical order of CVD and HFH gave a WR of 1.27 (95% CI: 1.15 to 1.39; z-score = 4.7), reflecting an effect similar to that of sacubitril/valsartan therapy on CVD and HFH. In the DIG (digoxin vs. placebo) trial, the outcome of time-to-first HFH or CVD using Cox gave a 1/HR of 1.18 (95% CI: 1.10 to 1.27; z-score = 4.5). Using the WR for testing this composite in the hierarchical order of CVD and HFH gave a WR of 1.14 (95% CI: 1.05 to 1.20; z-score = 3.1), reflecting a larger effect of digoxin on HFH than on CVD. Several other trials and endpoints including patient-reported measurements were studied. ConclusionsIn 16 large cardiovascular outcome trials, HR and WR provided similar estimates of treatment effects. The WR allows prioritization of fatal outcomes and the hierarchical testing of broader composite endpoints including patient-reported outcomes. In this way, the WR allows for the incorporation of patient-centered and other outcomes, while prioritizing the competing risk of death and hospital admission.

Heart Failure with Preserved Ejection Fraction Trials Have Heterogeneous Control Groups: a Comparison of Kaplan-Meier Curves.

Previous studies have evaluated intra-study heterogeneities of heart failure with preserved ejection fraction (HFpEF), but inter-study heterogeneities remain poorly understood. We investigate the heterogeneities of outcomes among control groups of HFpEF trials. We included randomized controlled trials recruiting HFpEF patients with ejection fraction ≥ 40% and reporting Kaplan-Meier curves for at least 36months. The Kaplan-Meier curves of control groups were extracted and calculated for hazard ratios and 95% confidence intervals. Two virtual trials were developed to validate the reliability and accuracy of our method. Of 4161 studies, we included six trials containing 7682 HFpEF patients in control groups. The DIG trial had the highest all-cause mortality, cardiovascular mortality, heart failure mortality, and composite endpoints of cardiovascular mortality and heart failure hospitalization (all p < 0.001). The TOPCAT trial had the lowest all-cause mortality, cardiovascular mortality, heart failure hospitalization, and composite of cardiovascular mortality and heart failure hospitalization (all p < 0.001). Adoption of different ejection fraction cut-off values for HFpEF diagnosis did not significantly change the outcomes of control groups in the DIG trial (45% vs. 50%: hazard ratio, 1.05, 95% confidence interval, 0.97-1.13, p = 0.271), or in the CHARM-Preserved trial (40% vs. 50%: hazard ratio, 1.01, 95% confidence interval, 0.93-1.09, p = 0.864) during 36-month follow-up. The control groups of HFpEF trials have heterogeneous outcomes. Future trials should consider these heterogeneities when designing protocols.

A Comparison of Digitalis use on Mortality and Morbidity among Special Populations with Heart Failure Reduced Ejection Fractions

Introduction The DIG trial introduced the benefit of digitalis (dig) in HFrEF, a reduction in HF hospitalizations. However, the study consisted of less than 15% nonwhite patients, making generalizability difficult. Genetic polymorphisms have been described to add variability in drug responses for varying races. No studies have compared outcomes of dig use among races. In this study, we assessed the effect of dig use on the length of hospitalization, readmission rates, and mortality in different racial groups with HFrEF. Method A retrospective cohort study of 1,047 patients admitted from 2005-2014 with decompensated HFrEF. Patients were split into three groups, Hispanic, African American (AA), and Caucasian. The primary outcomes of interest at 1, 6 and 12 months were length of hospital stay, readmission rates, and overall mortality. Results Out of 1,047 HFrEF patients, 244 patients were on dig treatment and 803 patients were not. There was racial discordance among groups; AA and Hispanics were more likely to receive dig compared to Caucasians. There was no difference among the Caucasian group with or without dig. Among the Hispanic group who received dig, they had lower ejection fractions (EF), higher 30-day, 6 month, and 1-year readmission rates compared to the non-dig group. Among the AA group, the dig group was composed of lower EF and had lower 30-day, 6 month and 1-year readmission rates compared to non-dig group. However, readmission rates were not statistically significant. Conclusion Our study concluded that among HFrEF patients, Hispanics had worse outcomes with dig use while Caucasians had no difference. In the AA group, dig use had lower EF but insignificantly lower 30-day, 6 month and 1 year readmission rates. However, our study may suggest benefit in AA. More trials assessing dig are needed in these populations to effectively manage the mortality and morbidity of HFrEF.

HEART FAILURE HOSPITALIZATION (HFH) DESPITE DIGOXIN THERAPY VERSUS NO HFH DESPITE PLACEBO IN THE DIGITALIS INVESTIGATION GROUP (DIG) TRIAL: INSIGHTS INTO RISK FACTORS FOR HFH IN HF AND REDUCED EJECTION FRACTION (HFREF)

Background: In the DIG trial, 6800 patients with HFrEF (EF≤45%) were randomized to receive either placebo (n=3403) or digoxin (n=3397) and followed for a mean of 37 months. Digoxin significantly reduced the risk of HFH by 28% (HR, 0.72; 95% CI, 0.66–0.79). However, 27% of patients in the digoxin

Digitalis, a drug to be scrapped?

We performed a comprehensive review of the scientific literature on the use of digoxin in heart failure and atrial fibrillation. In congestive heart failure (CHF) there is only one randomized trial with a statistical sample sufficiently large. In this trial (DIG trial), which enrolled patients with systolic left ventricular dysfunction in sinus rhythm, digoxin had a neutral action on mortality and modestly reduced the overall need of hospitalization. The study was conducted in the pre-beta-blocker era and, therefore, it has a doubtful application to the current clinical context. There are no randomized trials on atrial fibrillation, either with or without heart failure. Several observational and retrospective studies and meta-analysis have shown an association between the use of digoxin and increased mortality about 20%. Both in the European and American guidelines, even in class I recommendations, evidence is not supported by randomized or observational trials, but just by experts' opinions. Digoxin use in CHF and atrial fibrillation is related to the physician's clinical judgment, based more on consolidated custom that on established scientific evidence. In our opinion, this therapy should be withdrawn until new randomized controlled trials will provide evidence of its efficacy. Two trials have been planned to this aim. Also the issue of toxicity threshold is still unresolved; digoxinemia values should be <1 ng/ml if digoxin is used, to avoid overdosing and toxicity with increased mortality.

Assumption versus evidence: the case of digoxin in atrial fibrillation and heart failure.

Despite development of new and innovative medical therapies, still millions of patients with chronic heart failure (HF) with reduced ejection fraction and/or atrial fibrillation (AF) are treated with cardiac glycosides (overall 122 millions of patients defined daily dose prescriptions 2013 in Germany).1 Randomized evidence for efficacy of this treatment strategy is, however, sparse. For HF with reduced ejection fraction (HFrEF), the only randomized controlled outcome trial (RCT) of reasonable size is the DIG trial.2 Although the DIG Trial could not demonstrate a benefit on total mortality in the overall trial population, hospitalization for worsening of HF was significantly reduced. Moreover, subgroup analysis suggested a benefit on total mortality in patients with low plasma levels of digoxin.3,4 Randomized controlled outcome trials prospectively investigating the impact of digoxin on mortality and morbidity in patients with AF are not available. In the very recent past, quite a number of cohort studies, post hoc analyses of RCTs (initiated to investigate other treatments), and meta-analyses,5–11 which are all liable to prescription bias as randomization was not targeting digoxin therapy,12 retrospectively investigated whether digoxin treatment would eventually increase mortality in AF. These analyses surely are invaluable sources to generate important hypotheses to be investigated in prospective RCTs, which are costly, time consuming, and in need of high resources. However, it is very important to interpret their results with caution, and potential sources of bias require careful assessment and discussion. The AFFIRM study originally investigated survival outcome of patients with AF randomized to treatment for either rate (defined as therapy with beta blocker, calcium-channel blocker, digoxin, and combinations of these drugs) or rhythm control (antiarrhythmic drug use upon discretion of the treating physician).13 Rhythm control did not offer advantages over rate control. In a first post hoc analysis of …

Effect of oral digoxin in high-risk heart failure patients: a pre-specified subgroup analysis of the DIG trial

Effect of oral digoxin in high-risk heart failure patients: a pre-specified subgroup analysis of the DIG trial

A new indication for digoxin: To enable introduction and dose-escalation of ß-blocker therapy in severe heart failure

After over two centuries of usage, digoxin is still being prescribed in modern therapeutics in cardiology. However, since the publication of the DIG trial [1], there have been debates about its use because of the neutral primary all-cause mortality endpoint. Subsequent analyses of the data showed that lower doses of digoxin produced beneficial survival benefits [2]. Since the positive inotropic effects of digitalis have been shown mostly at higher doses [3], a question has been raised regarding how digoxin could possibly produce beneficial effects if used at low doses.

Individual dosage of digoxin in patients with heart failure

After the publication of DIG trial, the therapeutic target of serum digoxin concentration (SDC) for the treatment of heart failure (HF) has been lowered (0.40-1.00 ng/ml). However, the majority of equations to calculate digoxin dosages were developed for higher SDCs. Recently, a new equation was validated in Asian population for low SDCs by Konishi et al., but results in Caucasians are unknown. This study was aimed to test the Konishi equation in Caucasians specifically targeting low SDCs. Furthermore, the Konishi equation was compared with other frequently used equations. This was a prospective, multicenter study. Clinically indicated digoxin was given in 40 HF patients. The dosage was calculated with the Konishi equation. The SDC was measured at 1 and 6 months after starting digoxin. Adherence to digoxin was monitored with a specific questionnaire. After exclusion of patients admitting poor adherence, we found a reasonable correlation between predicted and measured SDC (r=0.48; P<0.01) by the Konishi equation. Excluding patients with poor adherence and relevant worsening of renal function, the measured SDC (n=54 measurements) was within the pre-defined therapeutic range in 95% of the cases. The mean, maximal and minimal measured SDC were 0.69±0.19, 1.00 and 0.32 ng/ml, respectively. The correlation was weaker for the Jelliffe, the Koup and Jusko, and the Bauman equations. This study supports the clinical validity of the Konishi equation for calculating individual digoxin dosage in Caucasians, targeting SDCs according to current HF guidelines.

Relation of sex to morbidity and mortality in patients with heart failure and reduced or preserved left ventricular ejection fraction

Previous studies indicate a survival advantage for women over men with chronic heart failure associated with reduced or preserved ejection fraction. Whether women with chronic heart failure are at less risk for hospitalization for worsening heart failure has not been well investigated. Using data from the DIG trial, the relationship between sex and adverse outcomes, especially the risk of hospitalization for various causes, was evaluated in patients with reduced or preserved left ventricular ejection fraction. Survival was worse for men than women with either reduced (HR 1.48, 95% CI 1.33-1.65, P < .001) or preserved ejection fraction (HR 1.60, 95% CI 1.20-2.13, P = .001), with P =.406 for sex interaction. In contrast, the risk of hospitalization for heart failure was greater in men than women when ejection fraction was reduced (HR 1.19, 95% CI 1.07-1.33, P = .001) but not preserved (HR 0.90, 95% CI 0.67-1.22, P = .494), with P = .003 for sex interaction. The relative risk of hospitalization for worsening failure between reduced and preserved ejection fraction was greater in men than women (HR 5.97, 95% CI 1.40-25.56, P = .001 in men vs HR 2.65, 95% CI 0.68-10.31, P = .159 in women). A survival advantage for women was seen in heart failure with reduced or preserved ejection fraction. In contrast, women appeared to be at lower risk for hospitalization for heart failure only when left ventricular systolic dysfunction was present.

Poststroke Care

See related article, pages 1899–1904. “Thinking is easy, acting is difficult, and to put one’s thoughts into action is the most difficult thing in the world”. — —Goethe (1749–1832) Major advances in acute stroke management have been seen over the past decade, including the use of thrombolysis, antithrombotic therapy, and organized in-hospital stroke care. However, relatively few studies have evaluated the effectiveness of these interventions in routine clinical practice, or have assessed issues related to delivery of services, access to care, and long-term care after discharge from stroke. In this issue of Stroke , Bravata et al1 contribute to our understanding of outcomes after stroke by analyzing readmissions and deaths in the first 5 years after a hospitalization for stroke. The target population included stroke survivors aged over 65 years who were Medicare beneficiaries and who were discharged from Connecticut acute care hospitals in 1995. This population was followed from discharge in 1995 through 2000 using Medicare claims and Social Security Administration mortality data. Among 2603 patients discharged alive, 40% were readmitted at least once within the first year of discharge, 53% had died or been readmitted within 1 year and only 15% survived admission-free for 5 years. Leading causes for readmission included pneumonia (8.2% to 9.0%), stroke (3.9% to 6.1%) and acute myocardial infarction (4.2% to 6.0%). There was no apparent association between length of hospital stay and readmission rate (unreported data kindly provided by the authors, 2007), and no information was available on potential patient and system factors associated with higher hospital readmission rates. Lower readmission rates of 25% to 27% within 1 year have been previously reported.2,3 These studies found that the average number of days of rehospitalization was 23.2 Stroke was the single most frequent reason for readmission followed by cardiac disease, …

Effects of digoxin at low serum concentrations on mortality and hospitalization in heart failure: A propensity-matched study of the DIG trial

Background In heart failure (HF), digoxin at low serum digoxin concentrations (SDC) reduces all-cause mortality and HF hospitalizations. However, the effects of digoxin on other cause-specific outcomes have not been studied in a propensity-matched cohort. Methods The Digitalis Investigation Group trial, conducted during 1991–1993, enrolled 7788 ambulatory chronic HF patients. This analysis focuses on 4843 patients: 982 receiving digoxin with low (0.5–0.9 ng/ml) SDC at one month, and 3861 receiving placebo and alive at one month. Propensity scores for low SDC, calculated using a non-parsimonious multivariable logistic regression model, were used to match 982 low-SDC patients with 982 placebo patients. Matched Cox regression analyses were used to determine the effect of digoxin at low SDC on outcomes. Results All-cause mortality occurred in 315 placebo (rate, 1071/10,000 person-years) and 288 low-SDC digoxin (rate, 871/10,000 person-years) patients, respectively, during 2940 and 3305 years of follow up (hazard ratio {HR}, 0.81, 95% confidence interval {CI}, 0.68–0.98; p = 0.028). Cardiovascular hospitalizations occurred in 493 placebo (2359/10,000 person-year) and 471 low-SDC digoxin (1963/10,000 person-year) patients, respectively during 2090 and 2399 years of follow up (HR, 0.82, 95% CI, 0.70–0.95; P = 0.010). Low-SDC digoxin to placebo HR (95%CI) for HF mortality and HF hospitalizations were respectively, 0.65 (0.45–0.92; P = 0.015) and 0.63 (0.52–0.77; P < 0.0001). Low-dose digoxin (≤ 0.125 mg/day) was the strongest independent predictor of low SDC (adjusted odd ratio, 2.07, 95% CI 1.54–2.80). Conclusions Digoxin at low SDC significantly reduced mortality and hospitalizations in ambulatory chronic systolic and diastolic HF patients.

Diabetes Reduces the Likelihood of More Favorable Outcomes in Women Than Men with Heart Failure: Retrospective Analysis of the DIG Trial

Diabetes Reduces the Likelihood of More Favorable Outcomes in Women Than Men with Heart Failure: Retrospective Analysis of the DIG Trial

Digoxin and reduction in mortality in systolic and diastolic heart failure at low serum digoxin concentrations

The DIG trial is the largest trial of digoxin and a very important trial that is not likely to be replicated soon. Therefore, the analyses of Ahmed et al .1 is useful and welcomed. One important conclusion of …

Association of Mortality Risk with High Serum Digoxin Concentrations

Background There are data suggesting a possible association of serum digoxin concentrations (SDC) and risk of mortality in patients treated with digoxin. Objective To determine whether SDCs in the therapeutic range of 1.2 to 2 ng/mL increase the risk of mortality when compared to a lower range of 0.5 to 1.1 ng/mL. Methods Retrospective cohort study to compare the risk of mortality in male patients with SDCs less than 1.2 ng/mL to patients with SDCs of 1.2 to 2 ng/mL. Results A total of 261 male patients were included, 191 (73%) had SDCs in the low range (0.5 to 1.1 ng/mL), and 70 (27%) had SDCs in the high range (at least 1.2 to 2 ng/mL). A high SDC showed a significant increase in risk for mortality with a hazard ratio (HR) of 1.656; 95 % HR confidence interval, 1.153 to 2.38; P = 0.0063. Conclusion Our results showed an increased risk of mortality in the high SDC group (1.2 to 2 ng/mL). This study's findings are consistent with the results of a post hoc evaluation of SDC in male patients in the DIG trial. 1 A prospective trial is warranted to confirm our findings.

Higher New York Heart Association classes and increased mortality and hospitalization in patients with heart failure and preserved left ventricular function

The association between higher New York Heart Association (NYHA) class and outcomes in patients with heart failure and preserved systolic function is not well known. We performed a retrospective follow-up study of 988 patients with heart failure with ejection fraction > 45% who participated in the DIG trial. Using Cox proportional hazard models, we estimated risks and all-cause mortality, heart failure mortality, all-cause hospitalization, and hospitalization due to worsening heart failure during a median follow-up of 38.5 months. Patients had a median age of 68 years; 41.2% were women and 13.9%, nonwhites. Overall, 23.4% of patients died, and 19.9% were hospitalized because of worsening heart failure. Proportion of patients with NYHA classes I, II, III, and IV were 19.9%, 58.0%, 20.9%, and 1.2%, respectively, and 14.7%, 21.1%, 35.9%, and 58.3%, respectively, died of all causes (P < .001 for trend). Respective rates for heart failure-related hospitalizations were 14.2%, 17.1%, 32.5%, and 33.3% (P < .001 for trend). Compared with NYHA class I patients, adjusted hazard ratios (HRs) for all-cause mortality for class II, III, and IV patients were 1.54 (95% CI 1.02-2.32, P = .042), 2.56 (95% CI 1.64-24.01, P < .001), and 8.46 (95% CI 3.57-20.03, P < .001), respectively. Respective adjusted HRs (95% CI) for hospitalization due to heart failure for class II, III, and IV patients were 1.16 (0.76-1.77) (P = .502), 2.27 (1.45-3.56) (P < .001), and 3.71 (1.25-11.02) (P = 018). New York Heart Association classes II through IV were also associated with higher risk of all-cause hospitalization. Higher NYHA classes were associated with poorer outcomes in patients with heart failure and preserved systolic function.

694 Diabetes reduces the likelihood of more favorable outcomes in women than men with heart failure: Retrospective analysis of the DIG trial

694 Diabetes reduces the likelihood of more favorable outcomes in women than men with heart failure: Retrospective analysis of the DIG trial

Digoxin and reduction in mortality and hospitalization in heart failure: a comprehensive post hoc analysis of the DIG trial

Digoxin and reduction in mortality and hospitalization in heart failure: a comprehensive post hoc analysis of the DIG trial

Digoxin and reduction in mortality and hospitalization in heart failure: a comprehensive post hoc analysis of the DIG trial.

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). 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> or =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). 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.

Women Have Reduced Risk for Hospitalization in Heart Failure Due to Left Ventricular Dysfunction but Not Preserved Ejection Fraction: Retrospective Analysis of the DIG Trial

Women Have Reduced Risk for Hospitalization in Heart Failure Due to Left Ventricular Dysfunction but Not Preserved Ejection Fraction: Retrospective Analysis of the DIG Trial