The safety and tolerability of beta blockers in heart failure with reduced ejection fraction: is the current underutilization of this evidence-based therapy justified?

Introduction: Beta blockers are one of the cornerstones for treatment of Heart Failure with Reduced Ejection fraction (HFRef), yet their use is often limited by adverse effects, either perceived or real. We performed a review of available data using PubMed.gov utilizing beta blocker, heart failure, reduced ejection fraction and safety as key words.

Areas covered: Several well designed, large scale randomized clinical trials including CIBS-II (bisoprolol), MERIT-HF (metoprolol succinate), and Copernicus (carvedilol) among others, have been conducted in patients with HFRef and demonstrated an improvement in cardiac mortality and morbidity. Despite the preponderance of data supporting the use of beta blockers for patients HFRef, these medications remain underutilized and/or are often prescribed at lower than recommended dosages. Some of the reluctance to embrace beta blockade may be attributed to concern on the part of both the patient and prescriber about the non-cardiac adverse effects of this class of drugs. We have reviewed several recent reviews and meta-analyses of trials of beta blocker in heart failure which have conclusively demonstrated their tolerability in the populations studied.

Expert opinion: In the final section of this paper we provide our opinions regarding initiating and optimizing beta blocker therapy for patients with HFRef.     

Feature Tracking Myocardial Strain Incrementally Improves Prognostication in Myocarditis Beyond Traditional CMR Imaging Features

ObjectivesThis study investigated the association of cardiovascular cardiac magnetic resonance (CMR) feature tracking (FT) with outcome in a patient cohort with myocarditis and evaluated the possible incremental prognostic benefit beyond clinical features and traditional CMR features.BackgroundCMR is used to diagnose and risk stratify patients with myocarditis. CMR-FT allows quantitative strain analysis of myocardial function; however, its prognostic benefit in myocarditis is unknown.MethodsConsecutive patients with clinically suspected myocarditis and presence of midmyocardial or epicardial late gadolinium enhancement (LGE) and/or myocardial edema in CMR were included. Clinical and CMR features were analyzed with regard to major adverse cardiovascular events (MACE) (i.e., hospitalization for heart failure, sustained ventricular tachycardia, and all-cause mortality).ResultsOf 740 patients with clinically suspected myocarditis, 455 (61%) met our final diagnostic criteria based on CMR tissue characterization. At a median follow-up of 3.9 years, MACE occurred in 74 (16%) patients. In the univariable analysis, CMR-FT global longitudinal peak strain (GLS) was significantly associated with MACE. In a multivariable model adjusting for clinical variables (age, sex, body mass index, and acuteness of symptoms) and traditional CMR features (left ventricular ejection fraction [LVEF] and LGE extent), GLS remained independently associated with outcome (GLS hazard ratio: 1.21; 95% confidence interval: 1.08 to 1.36; p = 0.001) and incrementally improved prognostication (chi-square increases from 42.6 to 79.8 to 88.5; p < 0.001).ConclusionsMyocardial strain using CMR-FT provides independent and incremental prognostic value over clinical features, LVEF, and LGE in patients with myocarditis. CMR-FT may serve as a novel marker to improve risk stratification in myocarditis. (CMR Features in Patients With Suspected Myocarditis [CMRMyo]; NCT03470571)     

Exercise E/e′ Is a Determinant of Exercise Capacity and Adverse Cardiovascular Outcomes in Chronic Kidney Disease

ObjectivesThis study sought to assess the relationship between E/e′ and exercise capacity in patients with chronic kidney disease (CKD) and evaluate its prognostic role.BackgroundPatients with CKD have diastolic dysfunction, reduced physical fitness, and elevated risk of cardiovascular disease.MethodsPatients with stage 3 and 4 CKD without previous cardiac disease underwent resting and exercise stress echocardiograms with assessment of exercise E/e′. Patients were compared to age-, sex-, and risk factor–matched control individuals and were followed annually for 5 years for cardiovascular death and major adverse cardiovascular event(s) (MACE). Exercise capacity was assessed as metabolic equivalents (METs), with reduced exercise capacity defined as METs of ≤7. Raised exercise E/e′ was defined as >13.ResultsA total of 156 patients with CKD (age 62.8 ± 10.6 years; male: 62%) were compared to 156 matched control individuals. Patients with CKD were more likely to be anemic (p < 0.01) and had increased left ventricular mass (p < 0.01), larger left atrial volumes (p < 0.01), and higher resting (p < 0.01) and exercise E/e′ (p < 0.01). Patients with CKD achieved lower exercise METs (p < 0.01), and more patients with CKD had METs of ≤7 (p < 0.01). Receiver-operating characteristic curves showed exercise E/e′ (area under the curve [AUC]: 0.89; 95% CI: 0.84 to 0.95; p < 0.01) as the strongest predictor of reduced exercise capacity in patients with CKD. Over a follow-up period of 41.4 months, a raised exercise E/e′ of >13 was an independent predictor of cardiovascular death and MACE on unadjusted and adjusted hazard models.ConclusionE/e′ is a strong predictor of exercise capacity and METs achieved by patients with CKD. Exercise capacity was reduced in patients with CKD, presumably consequent to diastolic dysfunction. Elevated exercise E/e′ in patients with CKD is an independent predictor of cardiovascular death and MACE.     

Clinical Outcomes With Transcatheter Edge-to-Edge Repair in Atrial Functional MR From the EXPAND Study

BackgroundAlthough transcatheter edge-to-edge repair (TEER) has been shown to improve clinical outcomes and improve quality of life in patients with symptomatic secondary mitral regurgitation (SMR) and left ventricular dysfunction, its effect in patients with atrial SMR (aSMR) has not been well described.ObjectivesThe aim of this study was to assess the safety, echocardiographic outcomes, and clinical effectiveness of TEER for aSMR.MethodsPatients with aSMR in the prospective, observational, multicenter EXPAND (A Contemporary, Prospective, Multi-Center Study Evaluating Real-World Experience of Performance and Safety for the Next Generation of MitraClip Devices) study were identified by an echocardiography core laboratory. Follow-up occurred at discharge, 30 days, and 1 year. Key endpoints included mitral regurgitation (MR) severity, functional class, heart failure hospitalizations, mortality, and 30-day major adverse events.ResultsAmong 1,041 patients enrolled in EXPAND, 835 patients had evaluable echocardiograms at baseline. Of these, 53 patients had aSMR and 360 had ventricular SMR (vSMR). In the aSMR cohort, TEER resulted in a significant reduction in MR through 1 year (MR grade ≤2 in 100.0%), significantly increased 1-year Kansas City Cardiomyopathy Questionnaire score (+26.6 ± 30.5 points; P < 0.0001), and improved functional class from baseline, similar to the effects among patients with vSMR (MR grade ≤2 in 99.5% at 1 year, 1-year increase in Kansas City Cardiomyopathy Questionnaire score 21.23 ± 24.92 points). Major adverse events at 30 days and leaflet adverse events at 1 year were infrequent in both groups.ConclusionsIn a prospective, real-world, global registry, TEER for aSMR was associated with significant MR reduction and improvement in quality of life and functional class, similar to patients with vSMR. This suggests that TEER may provide clinical benefit in patients with atrial fibrillation with SMR in the setting of heart failure with preserved ejection fraction. (The MitraClip® EXPAND Study of the Next Generation of MitraClip® Devices; NCT03502811)     

Gallbladder ejection fraction and its relationship to sphincter of Oddi dysfunction

Theoretically, relative distal common bile duct obstruction due to sphincter of Oddi dysfunction may be a cause of poor gallbladder evacuation observed on quantitative cholescintigraphy. In this study, the relationship of sphincter of Oddi dysfunction to the gallbladder ejection fraction by quantitative cholescintigraphy was explored. Eighty-one patients with biliary-type pain and otherwise normal evaluations underwent quantitative cholescintigraphy, sphincter of Oddi manometry, and ERCP. Abnormalities of stimulated quantitative cholescintigraphy and/or sphincter of Oddi manometry were present in 70% of this study group. Manometric evidence of sphincter dysfunction was present in patients with similar frequency irrespective of the degree of gallbladder evacuation. In conclusion, abnormalities of quantitative cholescintigraphy and sphincter manometry appear to be independent factors, although frequent findings in this patient population.     

Postoperative Atrial Fibrillation or Flutter Following Transcatheter or Surgical Aortic Valve Replacement: PARTNER 3 Trial

ObjectivesThe aim of this study was to assess the incidence and prognostic impact of early and late postoperative atrial fibrillation or flutter (POAF) in patients with severe aortic stenosis (AS) treated with transcatheter aortic valve replacement (TAVR) or surgical aortic valve replacement (SAVR).BackgroundThere is an ongoing controversy regarding the incidence, recurrence rate, and prognostic impact of early (in-hospital) POAF and late (postdischarge) POAF in patients with AS undergoing TAVR or SAVR.MethodsIn the PARTNER (Placement of Aortic Transcatheter Valve) 3 trial, patients with severe AS at low surgical risk were randomized to TAVR or SAVR. Analyses were performed in the as-treated population excluding patients with preexistent atrial fibrillation or flutter.ResultsAmong 781 patients included in the analysis, early POAF occurred in 152 (19.5%) (18 of 415 [4.3%] and 134 of 366 [36.6%] following TAVR and SAVR, respectively). Following discharge, 58 new or recurrent late POAF events occurred within 1 year following the index procedure in 55 of 781 patients (7.0%). Early POAF was not an independent predictor of late POAF following discharge (odds ratio: 1.04; 95% CI: 0.52-2.08; P = 0.90). Following adjustment, early POAF was not an independent predictor of the composite outcome of death, stroke, or rehospitalization (hazard ratio: 1.10; 95% CI: 0.64-1.92; P = 0.72), whereas late POAF was associated with an increased adjusted risk for the composite outcome (hazard ratio: 8.90; 95% CI: 5.02-15.74; P < 0.0001), irrespective of treatment modality.ConclusionsIn the PARTNER 3 trial, early POAF was more frequent following SAVR compared with TAVR. Late POAF, but not early POAF, was significantly associated with worse outcomes at 2 years, irrespective of treatment modality.     

A Noncontrast CMR Risk Score for Long-Term Risk Stratification in Reperfused ST-Segment Elevation Myocardial Infarction

ObjectivesThis study compared the prognostic value of a noncontrast CMR risk score for the composite of all-cause death, nonfatal myocardial infarction, and new congestive heart failure.BackgroundA cardiovascular magnetic resonance (CMR) risk score including left ventricular ejection fraction (LVEF), myocardial infarct (MI) size, and microvascular obstruction (MVO) was recently proposed to risk-stratify patients with ST-segment elevation myocardial infarction (STEMI).MethodsThe Eitel CMR risk score and GRACE (Global Registry of Acute Coronary Events) score were used as a reference (Score 1: acute MI size ≥19% LV, LVEF ≤47%, MVO >1.4% LV and GRACE score). MVO was replaced by intramyocardial hemorrhage (IMH) in Score 2 (acute MI size ≥19% LV, LVEF ≤47%, IMH, and GRACE score). Score 3 included only LVEF ≤45%, IMH, and GRACE score.ResultsThere were 370 patients in the derivation cohort and 234 patients in the validation cohort. In the derivation cohort, the 3 scores performed similarly and better than GRACE score to predict the 1-year composite endpoint with C-statistics of 0.83, 0.83, 0.82, and 0.74, respectively. In the validation cohort, there was good discrimination and calibration of score 3, with a C-statistic of 0.87 and P = 0.71 in a Hosmer-Lemeshow test for goodness of fit, on the 1-year composite outcome. Kaplan-Meier curves for 5-year composite outcome showed that those with LVEF ≤45% (high-risk) and LVEF >45% and IMH (intermediate-risk) had significantly higher cumulative events than those with LVEF >45% and no IMH (low-risk), log-rank tests: P = 0.02 and P = 0.03, respectively. The HR for the high-risk group was 2.3 (95% CI: 1.1-4.7) and for the intermediate-risk group was 2.0 (95% CI: 1.0-3.8), and these remained significant after adjusting for the GRACE score.ConclusionsThis noncontrast CMR risk score has performance comparable to an established risk score, and patients with STEMI could be stratified into low risk (LVEF >45% and no IMH), intermediate risk (LVEF >45% and IMH), and high risk (LVEF ≤45%). (A Trial of Low-dose Adjunctive alTeplase During prIMary PCI [T-TIME]; NCT02257294) (Detection and Significance of Heart Injury in ST Elevation Myocardial Infarction [BHF MR-MI]; NCT02072850)     

Regression of Left Ventricular Mass After Transcatheter Aortic Valve Replacement: The PARTNER Trials and Registries

BackgroundGreater early left ventricular mass index (LVMi) regression is associated with fewer hospitalizations 1 year after transcatheter aortic valve replacement (TAVR). The association between LVMi regression and longer-term post-TAVR outcomes is unclear.ObjectivesThe purpose of this study was to determine the association between LVMi regression at 1-year post-TAVR and clinical outcomes between 1 and 5 years.MethodsAmong intermediate- and high-risk patients who received TAVR in the PARTNER (Placement of Aortic Transcatheter Valves) I, II, and S3 trials or registries and were alive at 1 year, we included patients with baseline moderate or severe left ventricular hypertrophy (LVH) and paired measurements of LVMi at baseline and 1 year. The associations between LVMi regression (percent change between baseline and 1 year) and death or rehospitalization from 1 to 5 years were examined.ResultsAmong 1,434 patients, LVMi was 146 g/m² (interquartile range [IQR]: 133 to 168 g/m²) at baseline and decreased 14.5% (IQR: 4.2% to 26.1%) to 126 g/m² (IQR: 106 to 148 g/m²) at 1 year. After adjustment, greater LVMi regression at 1 year was associated with lower all-cause death (adjusted hazard ratio [aHR]: 0.95 per 10% decrease in LVMi; 95% confidence interval [CI]: 0.91 to 0.98; p = 0.004; aHR of the quartile with greatest vs. least LVMi regression: 0.61; 95% CI: 0.43 to 0.86; p = 0.005). Severe LVH at 1 year was observed in 39%, which was independently associated with increased all-cause death (aHR of severe LVH vs. no LVH: 1.71; 95% CI: 1.20 to 2.44; p = 0.003). Similar associations were found for rates of cardiovascular mortality and rehospitalization.ConclusionsAmong patients with moderate or severe LVH treated with TAVR who are alive at 1 year, greater LVMi regression at 1 year is associated with lower death and hospitalization rates to 5 years. These findings may have implications for the timing of valve replacement and the role of adjunctive medical therapy after TAVR.     

Management of Patients With Aortic Valve Stenosis

With increased life expectancy and aging of the population, aortic stenosis is now one of the most common valvular heart diseases. Early recognition and management of aortic stenosis are of paramount importance because untreated symptomatic severe disease is universally fatal. The advent of transcather aortic valve replacement technologies provides exciting avenues of care to patients with this disease in whom traditional surgical procedures could not be performed or were associated with high risk. This review for clinicians offers an overview of aortic stenosis and updated information on the current status of various treatment strategies. An electronic literature search of PubMed, MEDLINE, EMBASE, and Scopus was performed from conception July 1, 2016, through November 30, 2017, using the terms aortic stenosis, aortic valve replacement, transcatheter aortic valve replacement (TAVR), transcatheter aortic valve insertion (TAVI), surgical aortic valve replacement, aortic stenosis flow-gradient patterns, low-flow aortic valve stenosis, natural history, stress testing, pathophysiology, bicuspid aortic valve, and congenital aortic valve disease.