Kanan Patel

Lack of evidence of increased mortality among patients with atrial fibrillation taking digoxin: findings from post hoc propensity-matched analysis of the AFFIRM trial

AIMS Digoxin is recommended for long-term rate control in paroxysmal, persistent, and permanent atrial fibrillation (AF). While some analyses suggest an association of digoxin with a higher mortality in AF, the intrinsic nature of this association has not been examined in propensity-matched cohorts, which is the objective of the current study. METHODS AND RESULTS In Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM), 4060 patients with paroxysmal and persistent AF were randomized to rate (n = 2027) vs. rhythm (n = 2033) control strategies. Of these, 1377 received digoxin as initial therapy and 1329 received no digoxin at baseline. Propensity scores for digoxin use were estimated for each of these 2706 patients and used to assemble a cohort of 878 pairs of patients receiving and not receiving digoxin, who were balanced on 59 baseline characteristics. Matched patients had a mean age of 70 years, 40% were women, and 11% non-white. During the 3.4 years of the mean follow-up, all-cause mortality occurred in 14 and 13% of matched patients receiving and not receiving digoxin, respectively [hazard ratio (HR) associated with digoxin use: 1.06; 95% confidence interval (CI): 0.83-1.37; P = 0.640]. Among matched patients, digoxin had no association with all-cause hospitalization (HR: 0.96; 95% CI: 0.85-1.09; P = 0.510) or incident non-fatal cardiac arrhythmias (HR: 0.90; 95% CI: 0.37-2.23; P = 0.827). Digoxin had no multivariable-adjusted or propensity score-adjusted associations with these outcomes in the pre-match cohort. CONCLUSIONS In patients with paroxysmal and persistent AF, we found no evidence of increased mortality or hospitalization in those taking digoxin as baseline initial therapy.

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

In the Digitalis Investigation Group (DIG) trial, digoxin reduced mortality or hospitalization due to heart failure (HF) in several pre‐specified high‐risk subgroups of HF patients, but data on protocol‐specified 2‐year outcomes were not presented. In the current study, we examined the effect of digoxin on HF death or HF hospitalization and all‐cause death or all‐cause hospitalization in high‐risk subgroups during the protocol‐specified 2 years of post‐randomization follow‐up.

Digoxin reduces 30-day all-cause hospital admission in older patients with chronic systolic heart failure.

BACKGROUND Heart failure is a leading cause of hospital admission and readmission in older adults. The new United States healthcare reform law has created provisions for financial penalties for hospitals with higher than expected 30-day all-cause readmission rates for hospitalized Medicare beneficiaries aged ≥65 years with heart failure. We examined the effect of digoxin on 30-day all-cause hospital admission in older patients with heart failure and reduced ejection fraction. METHODS In the main Digitalis Investigation Group trial, 6800 ambulatory patients with chronic heart failure (ejection fraction ≤45%) were randomly assigned to digoxin or placebo. Of these, 3405 were aged ≥65 years (mean age, 72 years; 25% were women; 11% were nonwhite). The main outcome in the current analysis was 30-day all-cause hospital admission. RESULTS In the first 30 days after randomization, all-cause hospitalization occurred in 5.4% (92/1693) and 8.1% (139/1712) of patients in the digoxin and placebo groups, respectively, (hazard ratio {HR} when digoxin was compared with placebo, 0.66; 95% confidence interval {CI}, 0.51-0.86; P=.002). Digoxin also reduced both 30-day cardiovascular (3.5% vs 6.5%; HR, 0.53; 95% CI, 0.38-0.72; P<.001) and heart failure (1.7 vs 4.2%; HR, 0.40; 95% CI, 0.26-0.62; P<.001) hospitalizations, with similar trends for 30-day all-cause mortality (0.7% vs 1.3%; HR, 0.55; 95% CI, 0.27-1.11; P=.096). Younger patients were at lower risk of events but obtained similar benefits from digoxin. CONCLUSIONS Digoxin reduces 30-day all-cause hospital admission in ambulatory older patients with chronic systolic heart failure. Future studies need to examine its effect on 30-day all-cause hospital readmission in hospitalized patients with acute heart failure.

Angiotensin receptor blockers and outcomes in real‐world older patients with heart failure and preserved ejection fraction: a propensity‐matched inception cohort clinical effectiveness study

To examine the clinical effectiveness of angiotensin receptor blockers (ARBs) in older patients with heart failure and preserved ejection fraction (HF‐PEF).

Digoxin Use and Lower 30-day All-cause Readmission for Medicare Beneficiaries Hospitalized for Heart Failure

BACKGROUND Heart failure is the leading cause for hospital readmission, the reduction of which is a priority under the Affordable Care Act. Digoxin reduces 30-day all-cause hospital admission in chronic systolic heart failure. Whether digoxin is effective in reducing readmission after hospitalization for acute decompensation remains unknown. METHODS Of the 5153 Medicare beneficiaries hospitalized for acute heart failure and not receiving digoxin, 1054 (20%) received new discharge prescriptions for digoxin. Propensity scores for digoxin use, estimated for each of the 5153 patients, were used to assemble a matched cohort of 1842 (921 pairs) patients (mean age, 76 years; 56% women; 25% African American) receiving and not receiving digoxin, who were balanced on 55 baseline characteristics. RESULTS Thirty-day all-cause readmission occurred in 17% and 22% of matched patients receiving and not receiving digoxin, respectively (hazard ratio [HR] for digoxin, 0.77; 95% confidence interval [CI], 0.63-0.95). This beneficial association was observed only in those with ejection fraction <45% (HR 0.63; 95% CI, 0.47-0.83), but not in those with ejection fraction ≥ 45% (HR 0.91; 95% CI, 0.60-1.37; P for interaction, .145), a difference that persisted throughout the first 12 months postdischarge (P for interaction, .019). HRs (95% CIs) for 12-month heart failure readmission and all-cause mortality were 0.72 (0.61-0.86) and 0.83 (0.70-0.98), respectively. CONCLUSIONS In Medicare beneficiaries with systolic heart failure, a discharge prescription of digoxin was associated with lower 30-day all-cause hospital readmission, which was maintained at 12 months, and was not at the expense of higher mortality. Future randomized controlled trials are needed to confirm these findings.

Prevention of heart failure in older adults may require higher levels of physical activity than needed for other cardiovascular events

BACKGROUND Little is known if the levels of physical activity required for the prevention of incident heart failure (HF) and other cardiovascular events vary in community-dwelling older adults. METHODS We studied 5503 Cardiovascular Health Study (CHS) participants, age ≥ 65 years, free of baseline HF. Weekly metabolic equivalent task-minutes (MET-minutes), estimated using baseline total leisure-time energy expenditure, were used to categorize participants into four physical activity groups: inactive (0 MET-minutes; n=489; reference), low (1-499; n=1458), medium (500-999; n=1086) and high (≥ 1000; n=2470). RESULTS Participants had a mean (± SD) age of 73 (± 6) years, 58% were women, and 15% African American. During 13 years of follow-up, centrally-adjudicated incident HF occurred in 26%, 23%, 20%, and 19% of participants with no, low, medium and high physical activity, respectively (trend p<0.001). Compared with inactive older adults, age-sex-race-adjusted hazard ratios (95% confidence intervals) for incident HF associated with low, medium and high physical activity were 0.87 (0.71-1.06; p=0.170), 0.68 (0.54-0.85; p=0.001) and 0.60 (0.49-0.74; p<0.001), respectively (trend p<0.001). Only high physical activity had significant independent association with lower risk of incident HF (HR, 0.79; 95% CI, 0.64-0.97; p=0.026). All levels of physical activity had significant independent association with lower risk of incident acute myocardial infarction (AMI), stroke and cardiovascular mortality. CONCLUSION In community-dwelling older adults, high level of physical activity was associated with lower risk of incident HF, but all levels of physical activity were associated with lower risk of incident AMI, stroke, and cardiovascular mortality.

Effects of enalapril in systolic heart failure patients with and without chronic kidney disease: insights from the SOLVD Treatment trial.

BACKGROUND Angiotensin-converting enzyme inhibitors improve outcomes in systolic heart failure (SHF). However, doubts linger about their effect in SHF patients with chronic kidney disease (CKD). METHODS In the Studies of Left Ventricular Dysfunction (SOLVD) Treatment trial, 2569 ambulatory chronic HF patients with left ventricular ejection fraction ≤ 35% and serum creatinine level ≤ 2.5mg/dl were randomized to receive either placebo (n=1284) or enalapril (n=1285). Of the 2502 patients with baseline serum creatinine data, 1036 had CKD (estimated glomerular filtration rate <60 ml/min/1.73 m(2)). RESULTS Overall, during 35 months of median follow-up, all-cause mortality occurred in 40% (502/1252) and 35% (440/1250) of placebo and enalapril patients, respectively (hazard ratio {HR}, 0.84; 95% confidence interval {CI}, 0.74-0.95; p=0.007). All-cause mortality occurred in 45% and 42% of patients with CKD (HR, 0.88; 95% CI, 0.73-1.06; p=0.164), and 36% and 31% of non-CKD patients (HR, 0.82; 95% CI, 0.69-0.98; p=0.028) in the placebo and enalapril groups, respectively (p for interaction=0.615). Enalapril reduced cardiovascular hospitalization in those with CKD (HR, 0.77; 95% CI, 0.66-0.90; p<0.001) and without CKD (HR, 0.80; 95% CI, 0.70-0.91; p<0.001). Among patients in the enalapril group, serum creatinine elevation was significantly higher in those without CKD (0.09 versus 0.04 mg/dl in CKD; p=0.003) during first year of follow-up, but there was no differences in changes in systolic blood pressure (mean drop, 7 mm Hg, both) and serum potassium (mean increase, 0. /L, both). CONCLUSIONS Enalapril reduces mortality and hospitalization in SHF patients without significant heterogeneity between those with and without CKD.

Beta-blockers in older patients with heart failure and preserved ejection fraction: Class, dosage, and outcomes

BACKGROUND We examined the clinical effectiveness of beta-blockers considered evidenced-based to heart failure and reduced ejection fraction (HFrEF) and their recommended target doses in older adults with HF and preserved ejection fraction (HFpEF). METHODS In OPTIMIZE-HF (2003-2004) linked to Medicare (2003-2008), of the 10,570 older (age ≥ 65 years, mean, 81 years) adults with HFpEF (EF ≥ 40%, mean 55%), 8373 had no contraindications to beta-blocker therapy. After excluding 4614 patients receiving pre-admission beta-blockers, the remaining 3759 patients were potentially eligible for new discharge prescriptions for beta-blockers and 1454 received them. We assembled a propensity-matched cohort of 1099 pairs of patients receiving beta-blockers and no beta-blockers, balanced on 115 baseline characteristics. Evidence-based beta-blockers for HFrEF, namely, carvedilol, metoprolol succinate, and bisoprolol and their respective guideline-recommended target doses were 50, 200, and 10mg/day. RESULTS During 6 years of follow-up, new discharge prescriptions for beta-blockers had no association with the primary composite endpoint of all-cause mortality or HF rehospitalization (hazard ratio, 1.03; 95% confidence interval {CI}, 0.94-1.13; p=0.569). This association did not vary by beta-blocker evidence class or daily dose. Hazard ratios for all-cause mortality and HF rehospitalization were 0.99 (95% CI, 0.90-1.10; p=0.897) and 1.17 (95% CI, 1.03-1.34; p=0.014), respectively. The latter association lost significance when higher EF cutoffs of ≥45%, ≥50% and ≥55% were used. CONCLUSIONS Initiation of therapy with beta-blockers considered evidence-based for HFrEF and in target doses recommended for HFrEF had no association with the composite or individual endpoints of all-cause mortality or HF rehospitalization in HFpEF.

Angiotensin-converting Enzyme Inhibitors and Outcomes in Heart Failure and Preserved Ejection Fraction

BACKGROUND The role of angiotensin-converting enzyme (ACE) inhibitors in patients with heart failure and preserved ejection fraction remains unclear. METHODS Of the 10,570 patients aged ≥65 years with heart failure and preserved ejection fraction (≥40%) in the Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients With Heart Failure (2003-2004) linked to Medicare (through December 2008), 7304 were not receiving angiotensin receptor blockers and had no contraindications to ACE inhibitors. After excluding 3115 patients with pre-admission ACE inhibitor use, the remaining 4189 were eligible for new discharge prescriptions for ACE inhibitors, and 1706 received them. Propensity scores for the receipt of ACE inhibitors, calculated for each of the 4189 patients, were used to assemble a cohort of 1337 pairs of patients, balanced on 114 baseline characteristics. RESULTS Matched patients had a mean age of 81 years and mean ejection fraction of 55%, 64% were women, and 9% were African American. Initiation of ACE inhibitor therapy was associated with a lower risk of the primary composite end point of all-cause mortality or heart failure hospitalization during 2.4 years of median follow-up (hazard ratio [HR], 0.91; 95% confidence interval [CI], 0.84-0.99; P = .028), but not with individual end points of all-cause mortality (HR, 0.96; 95% CI, 0.88-1.05; P = .373) or heart failure hospitalization (HR, 0.93; 95% CI, 0.83-1.05; P = .257). CONCLUSION In hospitalized older patients with heart failure and preserved ejection fraction not receiving angiotensin receptor blockers, discharge initiation of ACE inhibitor therapy was associated with a modest improvement in the composite end point of total mortality or heart failure hospitalization but had no association with individual end point components.

Impairment of activities of daily living and incident heart failure in community‐dwelling older adults

Instrumental activities of daily living (IADLs) are tasks that are necessary for independent community living. These tasks often require intact physical and cognitive function, the impairment of which may adversely affect health in older adults. In the current study, we examined the association between IADL impairment and incident heart failure (HF) in community‐dwelling older adults.