Davide Castagno

Benefits of β blockers in patients with heart failure and reduced ejection fraction: network meta-analysis

Objective To clarify whether any particular β blocker is superior in patients with heart failure and reduced ejection fraction or whether the benefits of these agents are mainly due to a class effect. Design Systematic review and network meta-analysis of efficacy of different β blockers in heart failure. Data sources CINAHL(1982-2011), Cochrane Collaboration Central Register of Controlled Trials (-2011), Embase (1980-2011), Medline/PubMed (1966-2011), and Web of Science (1965-2011). Study selection Randomized trials comparing β blockers with other β blockers or other treatments. Data extraction The primary endpoint was all cause death at the longest available follow-up, assessed with odds ratios and Bayesian random effect 95% credible intervals, with independent extraction by observers. Results 21 trials were included, focusing on atenolol, bisoprolol, bucindolol, carvedilol, metoprolol, and nebivolol. As expected, in the overall analysis, β blockers provided credible mortality benefits in comparison with placebo or standard treatment after a median of 12 months (odds ratio 0.69, 0.56 to 0.80). However, no obvious differences were found when comparing the different β blockers head to head for the risk of death, sudden cardiac death, death due to pump failure, or drug discontinuation. Accordingly, improvements in left ventricular ejection fraction were also similar irrespective of the individual study drug. Conclusion The benefits of β blockers in patients with heart failure with reduced ejection fraction seem to be mainly due to a class effect, as no statistical evidence from current trials supports the superiority of any single agent over the others.

Are propensity scores really superior to standard multivariable analysis

Clinicians often face difficult decisions despite the lack of evidence from randomized trials. Thus, clinical evidence is often shaped by non-randomized studies exploiting multivariable approaches to limit the extent of confounding. Since their introduction, propensity scores have been used more and more frequently to estimate relevant clinical effects adjusting for established confounders, especially in small datasets. However, debate persists on their real usefulness in comparison to standard multivariable approaches such as logistic regression and Cox proportional hazard analysis. This holds even truer in light of key quantitative developments such as bootstrap and Bayesian methods. This qualitative review aims to provide a concise and practical guide to choose between propensity scores and standard multivariable analysis, emphasizing strengths and weaknesses of both approaches.

Incidence and predictors of coronary stent thrombosis: Evidence from an international collaborative meta-analysis including 30 studies, 221,066 patients, and 4276 thromboses

BACKGROUND Stent thrombosis remains among the most feared complications of percutaneous coronary intervention (PCI) with stenting. However, data on its incidence and predictors are sparse and conflicting. We thus aimed to perform a collaborative systematic review on incidence and predictors of stent thrombosis. METHODS PubMed was systematically searched for eligible studies from the drug-eluting stent (DES) era (1/2002-12/2010). Studies were selected if including ≥ 2000 patients undergoing stenting or reporting on ≥ 25 thromboses. Study features, patient characteristics, and incidence of stent thrombosis were abstracted and pooled, when appropriate, with random-effect methods (point estimate [95% confidence intervals]), and consistency of predictors was formally appraised. RESULTS A total of 30 studies were identified (221,066 patients, 4276 thromboses), with DES used in 87%. After a median of 22 months, definite, probable, or possible stent thrombosis had occurred in 2.4% (2.0%; 2.9%), with acute in 0.4% (0.2%; 0.6%), subacute in 1.1% (1.0%; 1.3%), late in 0.5% (0.4%; 0.6%), and very late in 0.6% (0.4%; 0.8%). Similar figures were computed for studies reporting only on DES. From a total of 47 candidate variables, definite/probable stent thrombosis was more commonly and consistently predicted by early antiplatelet therapy discontinuation, extent of coronary disease, and stent number/length, with acute coronary syndrome at admission, diabetes, smoking status, and bifurcation/ostial disease also proving frequent predictors, but less consistently. CONCLUSIONS Despite numerous possible risk factors, the most common and consistent predictors of stent thrombosis are early antiplatelet therapy discontinuation, extent of coronary disease, and stent number/length.

What have we learned about patients with heart failure and preserved ejection fraction from DIG-PEF, CHARM-Preserved, and I-PRESERVE?

Examination of patients with reduced and preserved ejection fraction in the DIG (Digitalis Investigation Group) trials and the CHARM (Candesartan in Heart Failure: Assessment of Reduction in Mortality and Morbidity) trials provides comparisons of outcomes in each of these types of heart failure. Comparison of the patients in these trials, along with the I-PRESERVE (Irbesartan in Heart Failure with Preserved Systolic Function Trial), with patients of similar age, sex distribution, and comorbidity in trials of hypertension, diabetes mellitus, angina pectoris, and atrial fibrillation provides even more interesting insights into the relation between phenotype and rates of death and heart failure hospitalization. The poor clinical outcomes in patients with heart failure and preserved ejection fraction do not seem easily explained on the basis of age, sex, comorbidity, blood pressure, or left ventricular structural remodeling but do seem to be explained by the presence of the syndrome of heart failure.

Association of Heart Rate and Outcomes in a Broad Spectrum of Patients With Chronic Heart Failure: Results From the CHARM (Candesartan in Heart Failure: Assessment of Reduction in Mortality and morbidity) Program

OBJECTIVES The aim of this study was to explore the relationship between baseline resting heart rate and outcomes in patients with chronic heart failure (HF) according to baseline left ventricular ejection fraction (LVEF) and cardiac rhythm. BACKGROUND Elevated resting heart rate is associated with worse outcomes in patients with HF and reduced LVEF. Whether this association is also found in patients with HF and preserved LVEF is uncertain, as is the predictive value of heart rate in patients in atrial fibrillation (AF). METHODS Patients enrolled in the CHARM (Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity) Program were divided into groups by tertiles of baseline heart rate. Cox proportional hazard models were used to investigate the association between heart rate and pre-specified outcomes in the overall population as well as in subgroups defined according to LVEF (≤ 40% vs. >40%) and presence (or absence) of AF at baseline. RESULTS After adjusting for predictors of poor prognosis, patients in the highest heart rate tertile had worse outcomes when compared with those in the lowest heart rate group (e.g., for the composite of cardiovascular death or HF hospital stay hazard ratio: 1.23, 95% confidence interval: 1.11 to 1.36, p < 0.001). The relationship between heart rate and outcomes was similar across LVEF categories and was not influenced by beta-blocker use (p value for interaction >0.10 for both endpoints). However, amongst patients in AF at baseline, heart rate had no predictive value (p value for interaction <0.001). CONCLUSIONS Resting heart rate is an important predictor of outcome in patients with stable chronic HF without AF, regardless of LVEF or beta-blocker use.

Intensive glycemic control has no impact on the risk of heart failure in type 2 diabetic patients: Evidence from a 37,229 patient meta-analysis

BACKGROUND More intensive glycemic control reduces the risk of microvascular disease in patients with diabetes mellitus but has not been proven to reduce the risk of macrovascular events such as myocardial infarction and stroke. Poorer glycemic control, as indicated by glycated hemoglobin level concentration, is associated with an increased risk of heart failure (HF), but it is not known whether improved glycemic control reduces this risk. We conducted a meta-analysis of randomized controlled trials comparing strategies of more versus less intensive glucose-lowering that reported HF events. METHODS Two investigators independently searched PubMed, the Cochrane CENTRAL register of controlled trials, metaRegister, pre-MEDLINE, and CINAHL from January 1970 to October 2010 for prospective controlled randomized trials comparing a more intensive glucose-lowering regimen to a standard regimen. The outcome of interest was HF-related events (both fatal and nonfatal). Odds ratios (ORs) were calculated from published data from relevant trials and pooled with a random-effects meta-analysis. RESULTS A total of 37,229 patients from 8 randomized trials were included in the analysis. Follow-up ranged from 2.3 to 10.1 years, and the overall number of HF-related events was 1469 (55% in the intensive treatment arm). The mean difference in glycated hemoglobin level between patients given standard treatment and those allocated to a more intensive regimen was 0.9%. Overall, the risk of HF-related events did not differ significantly between intensive glycemic control and standard treatment (OR 1.20, 95% CI 0.96-1.48), but the effect estimate was highly heterogeneous (I(2) = 69%). At subgroup analysis, intensive glycemic control achieved with high thiazolidinediones use significantly increased HF risk (OR 1.33, 95% CI 1.02-1.72). CONCLUSIONS More intensive glycemic control in patients with type 2 diabetes mellitus did not reduce the occurrence of HF events. Furthermore, intensive glycemic control with thiazolidinediones increased the risk of HF. These findings question a direct mechanistic link between hyperglycemia and HF.

Meta-Analysis of the Usefulness of Mitraclip in Patients With Functional Mitral Regurgitation

Midterm outcomes for patients presenting with heart failure and functional mitral regurgitation (MR) treated with Mitraclip remain unclear. Pubmed, Medline, and Google Scholar were systematically searched for studies enrolling patients with severe-moderate MR who underwent Mitraclip implantation. All events after at least 6 months were the primary safety end point (including death, rehospitalization for heart failure, and reinterventions), whereas change in the ejection fraction, left ventricular volumes, arterial pulmonary pressure, and left atrial diameters were considered as secondary end points. Meta-regression analysis was performed to evaluate the effect of baseline clinical and echocardiographic parameters on efficacy outcomes: 875 patients were included in 9 studies; 1.48 clips (1.3 to 1.7) for patients were implanted, and after a median follow-up of 9 months (6 to 12), 409 patients (78% [75% to 83%]) were in class New York Heart Association I/II and 57 (11% [8% to 14%]) still had moderate-to-severe MR. Overall adverse events occurred in 137 (26% [20% to 31%]) of the patients and 78 (15% [1% to 17%]) of them died; 6-minute walk test improved by 100 m (83 to 111), whereas a significant reduction in left ventricular volumes and systolic pulmonary pressure was reported. At meta-regression analysis, an increase in left ventricle systolic volumes positively affected reduction of volumes after Mitraclip, whereas atrial fibrillation reduced the positive effect of the valve implantation on ejection fraction on end-diastolic and -systolic volumes. In conclusion, Mitraclip represents an efficacious strategy for patients with heart failure and severe MR. It offers a significant improvement in functional class and in cardiac remodeling, in patients with severely dilated hearts as well, although its efficacy remains limited in the presence of atrial fibrillation.

Should we SHIFT our thinking about digoxin? Observations on ivabradine and heart rate reduction in heart failure.

AIMS The importance of heart rate in the pathophysiology of heart failure with reduced LVEF has recently attracted attention. In particular, the findings of the Systolic Heart failure treatment with the I(f) inhibitor ivabradine Trial (SHIFT) have put special emphasis on heart rate reduction with ivabradine for improvement in clinical outcomes. Of course, there is a much older drug that reduces heart rate, i.e. digoxin. METHODS AND RESULTS In this short commentary, we retrospectively analyse the Digitalis Investigation Group (DIG) Trial looking at the primary composite endpoint used in SHIFT (i.e. cardiovascular death or hospital admission for worsening heart failure) and compare the effect of digoxin on this endpoint with that of ivabradine. A remarkably similar risk reduction in the composite outcome and in its components appears evident among patients receiving the active treatment in both studies (although ivabradine was added to a beta-blocker, whereas digoxin was not). CONCLUSIONS This raises the question of whether the Cardiological community dismissed digoxin too readily and if we should reappraise its potential role in the treatment of heart failure.

Improved survival with bisoprolol in patients with heart failure and renal impairment: an analysis of the cardiac insufficiency bisoprolol study II (CIBIS-II) trial.

Information on the effectiveness of beta‐blockade in patients with heart failure (HF) and concomitant renal impairment is scarce and beta‐blockers are underutilized in these patients.

Spinal cord stimulation for the treatment of refractory angina pectoris: a multicenter randomized single-blind study (the SCS-ITA trial).

&NA; Spinal cord stimulation (SCS) is believed to be effective in treating refractory angina. The need for SCS‐related chest paresthesia, however, has hitherto made impossible placebo‐controlled trials. Subliminal (non paresthesic) SCS, however, might be also effective on anginal pain. In this trial we compared subliminal SCS with paresthesic SCS and with sham SCS. Twenty‐five refractory angina patients, who had never received SCS before, underwent SCS device implantation and were randomized to three groups: paresthesic SCS (group PS; n = 10), subliminal SCS (group SS; n = 7) or “sham” SCS (group NS; n = 8). After 1 month group NS patients were randomized to either group PS or SS. After 1 month, changes in angina episodes (p = 0.016), nitroglycerin use (p = 0.015), angina class (p = 0.02), quality of life score (p = 0.05), and items 2 (p = 0.008) and 3 (p = 0.009) of Seattle angina questionnaire differed significantly among groups. Group PS showed significant improvement in outcomes compared to group NS, whereas there were no significant differences between groups SS and NS; furthermore, only nitroglycerin use differed significantly between groups PS and SS. At 3 months, a significant difference between groups PS and SS was observed in angina attacks (p = 0.002), but not in other variables. Thus, in this study, paresthesic, but not subliminal SCS was superior to sham SCS in improving clinical status in refractory angina patients. The lack of significant differences between PS and SS groups in this small study suggests that a possible role for subliminal SCS in individual patients deserves to be assessed in larger trials with appropriate statistical power.