Marcelo C. Shibata

Effect of fish oil on arrhythmias and mortality: systematic review.

Objective To synthesise the literature on the effects of fish oil—docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA)—on mortality and arrhythmias and to explore dose response and formulation effects. Design Systematic review and meta-analysis. Data sources Medline, Embase, the Cochrane Library, PubMed, CINAHL, IPA, Web of Science, Scopus, Pascal, Allied and Complementary Medicine, Academic OneFile, ProQuest Dissertations and Theses, Evidence-Based Complementary Medicine, and LILACS. Studies reviewed Randomised controlled trials of fish oil as dietary supplements in humans. Data extraction The primary outcomes of interest were the arrhythmic end points of appropriate implantable cardiac defibrillator intervention and sudden cardiac death. The secondary outcomes were all cause mortality and death from cardiac causes. Subgroup analyses included the effect of formulations of EPA and DHA on death from cardiac causes and effects of fish oil in patients with coronary artery disease or myocardial infarction. Data synthesis 12 studies totalling 32 779 patients met the inclusion criteria. A neutral effect was reported in three studies (n=1148) for appropriate implantable cardiac defibrillator intervention (odds ratio 0.90, 95% confidence interval 0.55 to 1.46) and in six studies (n=31 111) for sudden cardiac death (0.81, 0.52 to 1.25). 11 studies (n=32 439 and n=32 519) provided data on the effects of fish oil on all cause mortality (0.92, 0.82 to 1.03) and a reduction in deaths from cardiac causes (0.80, 0.69 to 0.92). The dose-response relation for DHA and EPA on reduction in deaths from cardiac causes was not significant. Conclusions Fish oil supplementation was associated with a significant reduction in deaths from cardiac causes but had no effect on arrhythmias or all cause mortality. Evidence to recommend an optimal formulation of EPA or DHA to reduce these outcomes is insufficient. Fish oils are a heterogeneous product, and the optimal formulations for DHA and EPA remain unclear.

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).

Systematic review of the impact of beta blockers on mortality and hospital admissions in heart failure

Heart failure is a common condition that carries a high burden of mortality and morbidity. Several randomised trials have evaluated the effects of beta blockers in heart failure. This paper gives a systematic overview of published randomised trials of beta blockers in heart failure using standard methods. In all, 22 randomised controlled trials were identified with a total of 10480 patients, and an average of 11 months of treatment. The average age was 61 years and 4% were female. Most studies excluded patients with severe heart failure. Death rates in patients randomised to receive beta blockers compared to controls were 458/5657 (8.0%) and 635/4951 (12.8%) respectively, odds ratio 0.63, 95% CI 0.55–0.72, P < 0.00001. Similar reductions were observed for hospital admissions for worsening heart failure (11.3 vs. 17.1%, respectively, odds ratio 0.63) and for the composite outcome of death or heart‐failure hospital admission (19.4 vs. 26.9%, respectively, odds ratio 0.66). These results show that beta blockers reduce the risk of mortality or the need for heart‐failure hospital admission by approximately one third. Absolute reductions of 5–6% in event rates were observed over approximately 1 year of treatment period. These important benefits should be implemented as a priority, since treatment with beta blockers is inexpensive and heart failure carries a high risk of death and disability. Further information on the effect of beta blockers in elderly patients and women would be helpful.

Predictors of clinical outcomes in elderly patients with heart failure

Heart failure (HF) in the elderly carries a poor prognosis. We used the SENIORS dataset of elderly HF patients aged ≥70 years in order to develop a risk model for this population.

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.

Utilization of evidence‐based therapies for heart failure in the institutionalized elderly

Heart failure (HF) is a major source of morbidity and mortality in elderly populations. A significant proportion of the elderly with HF are living in long‐term care facilities. Little is known about their management. The aim of this study was to evaluate the use of evidence‐based therapies in institutionalized elderly patients with HF.

Do Calcium Channel Blockers Increase the Diagnosis of Heart Failure in Patients With Hypertension

Calcium channel blockers (CCBs) are widely used to control hypertension. Previous work suggested that their use could increase heart failure (HF), which is 1 of the consequences of uncontrolled hypertension. Information about the effect of CCBs on incident HF in patients with hypertension is scarce. A systematic review was conducted to evaluate patients with hypertension treated with CCBs and incident HF. An electronic search of publications was conducted using 8 major databases. Studies were eligible if they (1) were randomized clinical trials, (2) performed comparisons of CCBs versus active control, (3) randomized >200 patients, (4) had follow-up periods >6 months, and (5) provided data regarding incident HF. Trials of renal transplantation patients, placebo-controlled trials, and HF trials were excluded. A total of 156,766 patients were randomized to CCBs or control, with a total of 5,049 events. The analysis indicated a significant increase in the diagnosis of HF in patients allocated to CCBs (odds ratio 1.18, 95% confidence interval 1.07 to 1.31). The effect observed was independent of incident myocardial infarction. Subgroup analyses indicated that patients with diabetes were at higher risk for developing HF (odds ratio 1.71, 95% confidence interval 1.21 to 2.41). In conclusion, the results suggest that patients with hypertension treated with CCBs have increased incident HF.

Reply to comment

We would like to thank Chris Metcalfe for his interest in our paper and it is important for us to clarify the following issues. Firstly, our systematic overview was based on tabular data, which of course excludes individual patient data. Our conclusion regarding hospital admissions was based on the available 1447 hospitalizations due to heart failure reported in the published trials. In the Metoprolol CR XL Randomized Intervention Trial in CongesŽ . tive Heart Failure MERIT-HF , 494 patients had at least one hospital admission and Metcalfe correctly pointed out the 768 total hospitalizations in this group due to multiple hospital admissions by individual patients 1 . The report on total number of hospital days and total number of hospitalizations are rare in randomized clinical trials addressing the effect of beta blocker in heart failure. Trials often report time to first event regarding the combined endpoint of hospitalizations due to heart failure or death, which makes difficult the evaluation of individual hospital readmissions. Therefore, as in any other systematic overview, the results should be interpreted as an overall estimation of the effect of treatment on a particular disease or condition. Funck-Brentano et al. suggested that bisoprolol might be more effective in patients with lower ejection fraction or those who have non-lethal cardiovascular events 2 . The notion that treatment is more effective in higher risk individuals is known, and for this particular subgroup of patients, the treatment effect derived from overall population is often underŽ estimated provide the treatment under question is . effective . We used the best available evidence to Ž . estimate the number needed to treat NNT . One can expect on average to avoid one hospital admission Ž . time to event by treating 16 heart failure patients with beta-blockers for 1 year. Second, we disagree with Metcalfe when he states, ‘an initial hospitalization may be indicative of susceptibility of further hospitalization due to diseaserelated or social factors’. This may happen, if no action is taken after their first hospital admission, to adequately treat or prevent heart failure. Disease-related or social factors when managed appropriately can reduce further hospitalizations 3 . Third, we did not attempt to draw conclusions about the effect of treatment on individual hospitalizations nor on health economic impact of such treatment. Instead, we wrote ‘The demonstration of a reduction in hospital admission for patients with heart failure, using a simple intervention such as beta blocker administration, is likely to have an important impact on quality of life and health economics’. It seems likely that beta-blocker will influence quality of life and health economics, but a detailed discussion about this issue was out of the scope of our systematic overview. Finally, our conclusion about the effect of beta blockers on hospitalizations was derived from time to first event, simply because that is the evidence availŽ . able except in MERIT-HF . We agree with Metcalfe that data about total hospital days or total number of hospital admissions would help to evaluate more precisely the burden of heart failure.

Prevention of cardiovascular disease in women: evidence for the use of hormone replacement therapy

Coronary artery disease (CAD) is the number one cause of death and disability in the Western world. Its incidence increases with age and women present with symptomatic CAD on average about ten years later than men. Rationale for using hormone replacement therapy (HRT) is based on its effects on vasoreactivity, progression of atherosclerosis, lipids and lipoproteins, effects on the haemostatic system and impaired glucose tolerance. However, unopposed oestrogen might be related to an increased risk of endometrial cancer. The overall beneficial effect of HRT on cardiovascular diseases is derived from prospective cohort studies. The Heart and Estrogen/progestin Replacement Study showed no beneficial effect of HRT on cardiovascular morbidity and mortality. However, there are uncertainties about the duration and optimal type of HRT regimen. Ongoing trials addressing similar questions are not expected to be published within the next five years. The Womens Hormone Intervention Secondary Prevention (WHISP) pilot study addresses the effect of a novel HRT regimen on lipid and haemostatic risk markers of heart disease and may pave the way for a large trial evaluating the effect of HRT on morbidity and mortality.