Dipak Kotecha

Efficacy of β blockers in patients with heart failure plus atrial fibrillation: an individual-patient data meta-analysis

BACKGROUND Atrial fibrillation and heart failure often coexist, causing substantial cardiovascular morbidity and mortality. β blockers are indicated in patients with symptomatic heart failure with reduced ejection fraction; however, the efficacy of these drugs in patients with concomitant atrial fibrillation is uncertain. We therefore meta-analysed individual-patient data to assess the efficacy of β blockers in patients with heart failure and sinus rhythm compared with atrial fibrillation. METHODS We extracted individual-patient data from ten randomised controlled trials of the comparison of β blockers versus placebo in heart failure. The presence of sinus rhythm or atrial fibrillation was ascertained from the baseline electrocardiograph. The primary outcome was all-cause mortality. Analysis was by intention to treat. Outcome data were meta-analysed with an adjusted Cox proportional hazards regression. The study is registered with Clinicaltrials.gov, number NCT0083244, and PROSPERO, number CRD42014010012. FINDINGS 18,254 patients were assessed, and of these 13,946 (76%) had sinus rhythm and 3066 (17%) had atrial fibrillation at baseline. Crude death rates over a mean follow-up of 1·5 years (SD 1·1) were 16% (2237 of 13,945) in patients with sinus rhythm and 21% (633 of 3064) in patients with atrial fibrillation. β-blocker therapy led to a significant reduction in all-cause mortality in patients with sinus rhythm (hazard ratio 0·73, 0·67-0·80; p<0·001), but not in patients with atrial fibrillation (0·97, 0·83-1·14; p=0·73), with a significant p value for interaction of baseline rhythm (p=0·002). The lack of efficacy for the primary outcome was noted in all subgroups of atrial fibrillation, including age, sex, left ventricular ejection fraction, New York Heart Association class, heart rate, and baseline medical therapy. INTERPRETATION Based on our findings, β blockers should not be used preferentially over other rate-control medications and not regarded as standard therapy to improve prognosis in patients with concomitant heart failure and atrial fibrillation. FUNDING Menarini Farmaceutica Internazionale (administrative support grant).

Safety and efficacy of digoxin: systematic review and meta-analysis of observational and controlled trial data

Objective To clarify the impact of digoxin on death and clinical outcomes across all observational and randomised controlled trials, accounting for study designs and methods. Data sources and study selection Comprehensive literature search of Medline, Embase, the Cochrane Library, reference lists, and ongoing studies according to a prospectively registered design (PROSPERO: CRD42014010783), including all studies published from 1960 to July 2014 that examined treatment with digoxin compared with control (placebo or no treatment). Data extraction and synthesis Unadjusted and adjusted data pooled according to study design, analysis method, and risk of bias. Main outcome measures Primary outcome (all cause mortality) and secondary outcomes (including admission to hospital) were meta-analysed with random effects modelling. Results 52 studies were systematically reviewed, comprising 621 845 patients. Digoxin users were 2.4 years older than control (weighted difference 95% confidence interval 1.3 to 3.6), with lower ejection fraction (33% v 42%), more diabetes, and greater use of diuretics and anti-arrhythmic drugs. Meta-analysis included 75 study analyses, with a combined total of 4 006 210 patient years of follow-up. Compared with control, the pooled risk ratio for death with digoxin was 1.76 in unadjusted analyses (1.57 to 1.97), 1.61 in adjusted analyses (1.31 to 1.97), 1.18 in propensity matched studies (1.09 to 1.26), and 0.99 in randomised controlled trials (0.93 to 1.05). Meta-regression confirmed that baseline differences between treatment groups had a significant impact on mortality associated with digoxin, including markers of heart failure severity such as use of diuretics (P=0.004). Studies with better methods and lower risk of bias were more likely to report a neutral association of digoxin with mortality (P<0.001). Across all study types, digoxin led to a small but significant reduction in all cause hospital admission (risk ratio 0.92, 0.89 to 0.95; P<0.001; n=29 525). Conclusions Digoxin is associated with a neutral effect on mortality in randomised trials and a lower rate of admissions to hospital across all study types. Regardless of statistical analysis, prescription biases limit the value of observational data.

Atrial fibrillation in heart failure: what should we do?

Heart failure (HF) and atrial fibrillation (AF) are two conditions that are likely to dominate the next 50 years of cardiovascular (CV) care. Both are increasingly prevalent and associated with high morbidity, mortality, and healthcare cost. They are closely inter-related with similar risk factors and shared pathophysiology. Patients with concomitant HF and AF suffer from even worse symptoms and poorer prognosis, yet evidence-based evaluation and management of this group of patients is lacking. In this review, we evaluate the common mechanisms for the development of AF in HF patients and vice versa, focusing on the evidence for potential treatment strategies. Recent data have suggested that these patients may respond differently than those with HF or AF alone. These results highlight the clear clinical need to identify and treat according to best evidence, in order to prevent adverse outcomes and reduce the huge burden that HF and AF are expected to have on global healthcare systems in the future. We propose an easy-to-use clinical mnemonic to aid the initial management of newly discovered concomitant HF and AF, the CAN-TREAT HFrEF + AF algorithm (Cardioversion if compromised; Anticoagulation unless contraindication; Normalize fluid balance; Target initial heart rate <110 b.p.m.; Renin–angiotensin–aldosterone modification; Early consideration of rhythm control; Advanced HF therapies; Treatment of other CV disease).

Efficacy and safety of nebivolol in elderly heart failure patients with impaired renal function: insights from the SENIORS trial

To determine the safety and efficacy of nebivolol in elderly heart failure (HF) patients with renal dysfunction.

Erythropoietin as a treatment of anemia in heart failure: Systematic review of randomized trials

BACKGROUND Anemia in heart failure is both common and associated with worse symptoms and increased mortality. Several small randomized controlled trials (RCTs) have assessed erythropoiesis-stimulating agents (ESAs), but definitive evaluation and clinical guidance are required. We sought to systematically review the effects of ESAs in chronic heart failure. METHODS An extensive search strategy identified 11 RCTs with 794 participants comparing any ESA with control over 2 to 12 months of follow-up. Published and additionally requested data were incorporated into a Cochrane systematic review (CD007613). RESULTS Nine studies were placebo controlled, and 5, double blinded. Erythropoiesis-stimulating agent treatment significantly improved exercise duration by 96.8 seconds (95% CI 5.2-188.4, P = .04) and 6-minute walk distance by 69.3 m (95% CI 17.0-121.7, P = .009) compared with control. Benefit was also noted for peak oxygen consumption (+2.29 mL/kg per minute, P = .007), New York Heart Association class (-0.73, P < .001), ejection fraction (+5.8%, P < .001), B-type natriuretic peptide (-226.99 pg/mL, P < .001), and quality-of-life indicators with a mean increase in hemoglobin level of 2 g/dL. There was a significantly lower rate of heart failure-related hospitalizations with ESA therapy (odds ratio 0.56, 95% CI 0.37-0.84, P = .005). No associated increase in adverse events or mortality (odds ratio 0.58, 95% CI 0.34-0.99, P = .047) was observed, although the number of events was limited. CONCLUSION Meta-analysis of small RCTs suggests that ESA treatment can improve exercise tolerance, reduce symptoms, and have benefits on clinical outcomes in anemic patients with heart failure. Confirmation requires larger, well-designed studies with careful attention to dose, attained hemoglobin level, and long-term outcomes.

Atrial fibrillation and heart failure due to reduced versus preserved ejection fraction: A systematic review and meta-analysis of death and adverse outcomes.

BACKGROUND Atrial fibrillation (AF) and heart failure frequently coexist, commonly resulting in serious adverse events. With both conditions increasing in prevalence and justified concerns about treatment efficacy, it is vital to understand how the type of heart failure impacts on prognosis. METHODS We performed a systematic review of studies examining cardiovascular outcomes in AF patients with heart failure and reduced ejection fraction (AF-HFrEF) compared to those with preserved ejection fraction (AF-HFpEF). The primary outcome was all-cause mortality, meta-analyzed using a random-effects model. Prospective registration: PROSPERO-CRD42014007305. RESULTS Thirteen studies were included in the systematic review (n=54,587) with 10 suitable for meta-analysis, including retrospective/prospective cohorts and sub-group analyses of randomized trials. AF-HFrEF was present in 49% and these patients were younger, more often male and with higher NYHA class than AF-HFpEF. Oral anticoagulation use was 55% versus 50% respectively (p<0.001). All-cause mortality was significantly higher in AF-HFrEF; risk ratio (RR) 1.24, 95% CI 1.12-1.36, p<0.001 (n=45,100), with absolute death rates of 24% compared to 18% in AF-HFpEF over 2 years. There were no significant differences in incident stroke (RR 0.85, 95% CI 0.70-1.03, p=0.094; n=33,773) or heart failure hospitalization (RR 1.21, 95% CI 0.96-1.53, p=0.115; n=31,583). The risk of bias was generally low, but heterogeneity was substantial. CONCLUSIONS All-cause mortality is significantly higher in AF patients with HFrEF compared to HFpEF, although stroke risk and heart failure hospitalization are similar. Further studies are needed to address the prevention of adverse outcomes in all AF patients with heart failure, regardless of ejection fraction.

Effect of age and sex on efficacy and tolerability of β blockers in patients with heart failure with reduced ejection fraction: individual patient data meta-analysis

Objectives To determine the efficacy and tolerability of β blockers in a broad age range of women and men with heart failure with reduced ejection fraction (HFrEF) by pooling individual patient data from placebo controlled randomised trials. Design Prospectively designed meta-analysis of individual patient data from patients aged 40-85 in sinus rhythm at baseline, with left ventricular ejection fraction <0.45. Participants 13 833 patients from 11 trials; median age 64; 24% women. Main outcome measures The primary outcome was all cause mortality; the major secondary outcome was admission to hospital for heart failure. Analysis was by intention to treat with an adjusted one stage Cox proportional hazards model. Results Compared with placebo, β blockers were effective in reducing mortality across all ages: hazard ratios were 0.66 (95% confidence interval 0.53 to 0.83) for the first quarter of age distribution (median age 50); 0.71 (0.58 to 0.87) for the second quarter (median age 60); 0.65 (0.53 to 0.78) for the third quarter (median age 68); and 0.77 (0.64 to 0.92) for the fourth quarter (median age 75). There was no significant interaction when age was modelled continuously (P=0.1), and the absolute reduction in mortality was 4.3% over a median follow-up of 1.3 years (number needed to treat 23). Admission to hospital for heart failure was significantly reduced by β blockers, although this effect was attenuated at older ages (interaction P=0.05). There was no evidence of an interaction between treatment effect and sex in any age group. Drug discontinuation was similar regardless of treatment allocation, age, or sex (14.4% in those give β blockers, 15.6% in those receiving placebo). Conclusion Irrespective of age or sex, patients with HFrEF in sinus rhythm should receive β blockers to reduce the risk of death and admission to hospital. Registration PROSPERO CRD42014010012; Clinicaltrials.gov NCT00832442.

Five-minute heart rate variability can predict obstructive angiographic coronary disease

Objective Obstructive coronary artery disease (CAD) is evident in only half of patients referred for diagnostic angiography. Five-minute heart rate variability (HRV) is a non-invasive marker for autonomic control of the vasculature, which this study hypothesised could risk-stratify cardiac patients and reduce unnecessary angiograms. Design A prospective observational study (the Alternative Risk Markers in Coronary Artery Disease (ARM–CAD) study). Setting Three cardiac centres in Melbourne, Australia. Patients 470 consecutive patients undergoing elective angiography (with predominantly normal cardiac rhythm), regardless of co-morbidity. Main outcome measures The presence of obstructive CAD (≥50% stenosis) on angiography. Results Patients with obstructive CAD had significantly reduced HRV, particularly in the low frequency (LF) range (median 180 vs 267 ms2 without CAD; p<0.001). There was a linear trend with the severity of CAD; median LF power (IQR) in patients with normal coronaries was 275 (612), with minor coronary irregularities 255 (400), single-vessel CAD 212 (396) and more severe disease 170 (327) ms2; p value for trend 0.003. There was a similar reduction in LF power regardless of the anatomical location of coronary stenoses. Comparing patients with LF less than 250 and 250 ms2 or greater, the adjusted OR for obstructive CAD using multivariate regression was 2.42, 95% CI 1.33 to 4.38 (p=0.004). No interactions were noted in subgroup analysis and HRV added to risk prediction irrespective of the baseline Framingham risk (p<0.0001). Conclusion Low HRV is strongly predictive of angiographic coronary disease regardless of other co-morbidities and is clinically useful as a risk predictor in patients with sinus rhythm. Clinical trial registration information http://clinicaltrials.gov/ct2/show/NCT00403351 www.armcad.com

Digoxin: The good and the bad

After 230 years of use, digitalis remains an important and useful therapy for patients with atrial fibrillation, heart failure, and the 30-50 % of patients with both conditions. Although the combination of positive inotropic activity with negative chronotropic effects has been shown to reduce hospital admissions in heart failure, there is a distinct lack of robust trial data, particularly in patients with atrial fibrillation. We recently performed a comprehensive meta-analysis of all digoxin studies and demonstrated a neutral effect on mortality. This contradicts prior observational data that overlook the fact that digitalis is usually given as second-line therapy to the sickest patients. Use of these agents in clinical practice should take account of appropriate dose, serum concentration, drug interactions, and potential side effects. The aim of this review is to evaluate the evidence base for cardiac glycosides and provide a pragmatic guide to their advantages and disadvantages.

Residual Risk of Stroke and Death in Anticoagulated Patients According to the Type of Atrial Fibrillation: AMADEUS Trial

Background and Purpose— Atrial fibrillation (AF) and heart failure frequently coexist and are associated with increased morbidity and mortality. We investigated the prognosis of anticoagulated patients with permanent AF and nonpermanent AF according to preexisting heart failure in the AMADEUS (Evaluating the Use of SR34006 Compared to Warfarin or Acenocoumarol in Patients With Atrial Fibrillation) trial. Methods— The primary outcome was a composite of cardiovascular death and stroke or systemic embolism, analyzed using a Cox proportional hazards model, adjusted for baseline age, sex, diabetes mellitus, hypertension, creatinine, and previous cardiovascular diseases. The median follow-up was 11.6 months (interquartile range, 6.2–15.2). Results— Nonpermanent AF was present in 2072 patients (46% of cohort), of which 339 (16%) had preexisting heart failure. A total of 2484 patients had permanent AF (54% of cohort), with a higher burden of heart failure including 730 patients (29%; P<0.001). Overall, death because of cardiovascular causes occurred in 57 patients and 45 had stroke or systemic embolism (1.4/100 person-years for each). Overall, the adjusted incidence of the composite outcome was higher in patients with permanent AF than in patients with nonpermanent AF. In multivariate analysis, permanency of AF, creatinine, prior cerebrovascular events, and previous coronary disease were independently associated with the primary outcome. The hazard ratio for permanent versus nonpermanent AF was 1.68 (95% confidence interval, 1.08–2.55; P=0.02). The presence of heart failure increased the risk of adverse outcomes in a similar way in both permanent and nonpermanent AF (interaction P value=0.76). Conclusions— The risk of cardiovascular death, stroke, or systemic embolism is higher in anticoagulated patients with permanent AF than in those with nonpermanent AF, regardless of preexisting heart failure.