Evolving Landscape of Clinical Trials in Heart Failure: Patient Populations,Endpoint Selection,and Regions of Enrollment

Purpose of Review

Clinical trial design and execution are evolving as increasingly important considerations with respect to the success of heart failure trials. The current review highlights temporal trends in characteristics of heart failure clinical trials.

Recent Findings

Recent trials in heart failure have required longer recruitment phases, displayed inefficient enrollment rates, increased use of composite and nonfatal endpoints, undergone rapid globalization, and gradually increased focus on heart failure with preserved ejection fraction.

Summary

Understanding patterns and trends in clinical trial design and execution may inform future planning and conduct of trials of heart failure therapeutics.

     

Implantierbare Sensoren zur ambulanten Beurteilung des ventrikulären Füllungsdrucks bei fortgeschrittener Herzinsuffizienz

Introduction

Patients with advanced heart failure suffer from frequent hospitalizations. Non-invasive hemodynamic telemonitoring for assessment of ventricular filling pressure has been shown to reduce hospitalizations. We report on the right ventricular (RVP), the pulmonary artery (PAP) and the left atrial pressure (LAP) sensor for non-invasive assessment of the ventricular filling pressure.

Methods

A literature search concerning the available implantable pressure sensors for noninvasive haemodynamic telemonitoring in patients with advanced heart failure was performed.

Results

Until now, only implantation of the PAP-sensor was able to reduce hospitalizations for cardiac decompensation and to improve quality of life. The right ventricular pressure sensor missed the primary endpoint of a significant reduction of hospitalizations, clinical data using the left atrial pressure sensor are still pending.

Conclusion

The implantation of a pressure sensor for assessment of pulmonary artery filling pressure is suitable for reducing hospitalizations for heart failure and for improving quality of life in patients with advanced heart failure.

     

Contemporary Perspectives in Durable Mechanical Circulatory Support: What Did We Learn in the Last 3 Years?

Purpose of Review

In this paper, we will review developments in the field of durable mechanical circulatory support over the past 3 years.

Recent Findings

The role of left ventricular assist device (LVAD) placement in non-inotrope-dependent ambulatory heart failure patients remains controversial in light of recent clinical trials. New devices are on the horizon for destination therapy in advanced heart failure patients. The concept of hemocompatibility and the calculation of hemocompatibility scores represent a novel approach to common adverse events.

Summary

Recent research in mechanical circulatory support has impacted our approach to durable LVAD therapy and set the stage for further advancements in the field.

     

An Appraisal of Biomarker-Based Risk-Scoring Models in Chronic Heart Failure: Which One Is Best?

Purpose of Review

While prediction models incorporating biomarkers are used in heart failure, these have shown wide-ranging discrimination and calibration. This review will discuss externally validated biomarker-based risk models in chronic heart failure patients assessing their quality and relevance to clinical practice.

Recent Findings

Biomarkers may help in determining prognosis in chronic heart failure patients as they reflect early pathologic processes, even before symptoms or worsening disease. We present the characteristics and describe the performance of 10 externally validated prediction models including at least one biomarker among their predictive factors. Very few models report adequate discrimination and calibration. Some studies evaluated the additional predictive value of adding a biomarker to a model. However, these have not been routinely assessed in subsequent validation studies.

Summary

New and existing prediction models should include biomarkers, which improve model performance. Ongoing research is needed to assess the performance of models in contemporary patients.

     

Revisiting the Diabetes-Heart Failure Connection

Purpose of the Review

To summarize current clinical data investigating the link between diabetes and heart failure pathophysiology, the association of glucose control with heart failure, and the impact of current antihyperglycemic drugs on heart failure.

Recent Findings

Although heart failure is one of the most prevalent outcomes occurring in real life and cardiovascular outcome trials, insufficient attention was given to this condition in diabetes research over the last decades. With both beneficial and detrimental findings for heart failure hospitalization in the health authority–mandated outcome trials for new antihyperglycemic agents, research on heart failure and its interplay with diabetes mellitus gained momentum.

Summary

Diabetes mellitus and heart failure are both prevalent and intertwined conditions. While currently available heart failure therapies have a similar degree of effectiveness in patients with and without diabetes, the choice of glucose-lowering agents can substantially affect heart failure-related outcome.

     

Myocardial Energetics and Heart Failure: a Review of Recent Therapeutic Trials

Purpose of review

Several novel therapeutics being tested in patients with heart failure are based on myocardial energetics. This review will provide a summary of the recent trials in this area, including therapeutic options targeting various aspects of cellular and mitochondrial metabolism.

Recent findings

Agents that improve the energetic balance in myocardial cells have the potential to improve clinical heart failure status. The most promising therapies currently under investigation in this arena include (1) elamipretide, a cardiolipin stabilizer; (2) repletion of iron deficiency with intravenous ferrous carboxymaltose; (3) coenzyme Q10; and (4) the partial adenosine receptor antagonists capadenoson and neladenosone.

Summary

Myocardial energetics-based therapeutics are groundbreaking in that they utilize novel mechanisms of action to improve heart failure symptoms, without causing the adverse neurohormonal side effects associated with current guideline-based therapies. The drugs appear likely to be added to the heart failure therapy armamentarium as adjuncts to current regimens in the near future.

     

Heart Failure with Recovered EF and Heart Failure with Mid-Range EF: Current Recommendations and Controversies

Purpose of review

This review explores key features and potential management controversies in two emerging populations in heart failure: heart failure with recovered ejection fraction (HF-recovered EF) and heart failure with mid-range ejection fraction (HFmrEF).

Recent findings

While HF-recovered EF patients have better outcomes than heart failure with reduced ejection fraction (HFrEF), they continue to have symptoms, persistent biomarker elevations, and abnormal outcomes suggesting a continued disease process. HFmrEF patients appear to have features of HFrEF and heart failure with preserved ejection fraction (HFpEF), but have a high prevalence of ischemic heart disease and may represent a transitory phase between the HFrEF and HFpEF. Management strategies have insufficient data to warrant standardization at this time.

Summary

HF-recovered EF and HFmrEF represent new populations with unmet needs and expose the pitfalls of an EF basis for heart failure classification.

     

Palliative Care in Heart Failure

Purpose of review

This review illustrates the dynamic role of palliative care in heart failure management and encapsulates the commonly utilized pharmacologic and non-pharmacologic therapeutic strategies for symptom palliation in heart failure. In addition, we provide our experience regarding patient care issues common to the domain of heart failure and palliative medicine which are commonly encountered by heart failure teams.

Recent findings

Addition of palliative care to conventional heart failure management plan results in improvement in quality of life, anxiety, depression, and spiritual well-being among patients.

Summary

Palliative care should not be confused with hospice care. Palliative care teams should be involved early in the care of heart failure patients with the aims of improving symptom palliation, discussing goals of care and improving quality of life without compromising utilization of evidence-based heart failure therapies. A consensus on the appropriate timing of involvement and evidence for many symptom palliation therapies is still emerging.

     

Identifying and Managing Hibernating Myocardium: What’s New and What Remains Unknown?

Purpose of Review

Hibernation is an important and reversible cause of myocardial dysfunction in ischaemic heart failure.

Recent Findings

Hibernation is an adaptive process that promotes myocyte survival over maintaining contractile function. It is innate to mammalian physiology, sharing features with physiological hibernation in other species. Advanced imaging methods have reasonable accuracy in identifying hibernating myocardium. Novel superior hybrid methods may provide diagnostic potential. New evidence supports the role of surgical revascularisation in ischaemic heart failure, but the role of viability tests in planning such procedures remains unclear. Research to date has exclusively involved patients with ambulatory heart failure: Investigating the role of hibernation in ADHF is a key avenue for the future.

Summary

Whilst our understanding of hibernation pathophysiology has improved dramatically, the clinical utility of identifying and targeting hibernation remains unclear.

     

Cardiac Rehabilitation: Current Review of the Literature and Its Role in Patients with Heart Failure

Purpose of review

Cardiovascular (CV) disease remains the leading cause of death in the USA despite major advances in its treatment. With time, cardiac rehabilitation (CR) programs have gathered interest to help increase CV health and improve functional status after a CV event. Patients with heart failure have also been shown to benefit. In this review, we will evaluate the current literature showcasing the benefits of CR, particularly in patients with heart failure, discuss current limitations, and avenues for future investigation.

Recent findings

Studies have shown that CR is beneficial in reducing morbidity, mortality, hospitalizations, activity-related symptoms, and increasing quality of life. Similar findings have also been observed in patients with heart failure who underwent CR in addition to optimal medical management.

Summary

The positive effects of CR are well established in patients with coronary disease. Recent literature is also showing a trend to benefit in patients with heart failure, though much of the evidence is limited to patients with systolic dysfunction. Despite recommendations by professional societies, the use of CR remains underutilized. Further investigation is needed to better understand the impact of CR in heart failure. Moreover, strategies to increase CR utilization must be explored.

     

Improving Provider Adherence to Guideline Recommendations in Heart Failure

Purpose of Review

Heart failure clinical practice guidelines are fundamental and serve as framework for providers to deliver evidence-based care that correlates with enhanced patient outcomes. However, adherence, particularly to guideline-directed medical therapy, remains suboptimal for a multitude of reasons.

Recent Findings

Despite robust clinical trials, updated guidelines and an expert consensus statement from American Heart Association, American College of Cardiology, and Heart Failure Society of America registry data signal that heart failure patients do not receive appropriate pharmacotherapy and may receive an intracardiac device without prior initiation or optimization of medical therapy.

Summary

Strategies to improve provider adherence to heart failure guidelines include multidisciplinary models and appropriate referral and care standardization. These approaches can improve morbidity, mortality, and quality of life in HF patients.

     

Gender Disparities in CAD: Women and Ischemic Heart Disease

Purpose of Review

The goal of this article is to review the disparities that exist for women who present for treatment of ischemic heart disease.

Recent Findings

It is well known that women are more likely to present with ischemic heart disease at an advanced age with more comorbidities when compared to male counterparts. Despite correction of risk factors, women experience worse outcomes, even in the absence of obstructive coronary artery disease. A review of the literature highlights the importance of a thoughtful approach to medical therapy and revascularization.

Summary

While most recommendations applied to women are derived mostly from male data, further study of sex-specific differences may lead to approaches which can ultimately reduce disparities for the treatment of ischemic heart disease in women.

     

Clinical Profile of Statin Intolerance in the Phase 3 GAUSS-2 Study

Purpose

Recent evidence suggests that statin intolerance may be more common than reported in randomized trials. However, the statin-intolerant population is not well characterized. The goal of this report is to characterize the population enrolled in the phase 3 Goal Achievement after Utilizing an anti-PCSK9 antibody in Statin Intolerant Subjects Study (GAUSS-2; NCT 01763905).

Methods

GAUSS-2 compared evolocumab, a fully human monoclonal antibody to proprotein convertase subtilisin/kexin type 9 (PCSK9) to ezetimibe in hypercholesterolemic patients who discontinued statin therapy due to statin-associated muscle symptoms (SAMS). GAUSS-2 was a 12-week, double-blind, placebo-controlled, randomized study that enrolled patients with elevated LDL-C who were either not on a statin or able to tolerate only a low-dose due to SAMS. Patients had received ≥2 statins and were unable to tolerate any statin dose or increase in dose above a specified weekly dose due to SAMS.

Results

Three hundred seven patients (mean [SD] age, 62 [10] years; 54 % males) were randomized 2:1 (evolocumab:ezetimibe). Mean (SD) LDL-C was 4.99 (1.51) mmol/L. Patients had used ≥2 (100 %), ≥3 (55 %), or ≥4 (21 %) statins. Coronary artery disease was present in 29 % of patients. Statin-intolerant symptoms were myalgia in 80 % of patients, weakness in 39 %, and more serious complications in 20 %. In 98 % of patients, SAMS interfered with normal daily activity; in 52 %, symptoms precluded moderate exertion.

Conclusion

Evaluation of the GAUSS-2 trial population of statin-intolerant patients demonstrates that most patients were high risk with severely elevated LDL-C and many had statin-associated muscle symptoms that interfered with their quality of life.

     

Cardiorespiratory Fitness and Cardiovascular Disease Prevention: an Update

Purpose of Review

Cardiovascular diseases account for nearly one third of all deaths globally. Improving exercise capacity and cardiorespiratory fitness (CRF) has been an important target to reduce cardiovascular events. In addition, the American Heart Association defined decreased physical activity as the fourth risk factor for coronary artery disease. Multiple large cohort studies have evaluated the impact of CRF on outcomes. In this review, we will discuss the role of CRF in reducing cardiovascular morbidity and mortality.

Recent Findings

Recent data suggest that CRF has an important role in reducing not only cardiovascular and all-cause mortality, but also incident myocardial infarction, hypertension, diabetes, atrial fibrillation, heart failure, and stroke. Most recently, its role in cancer prevention started to emerge. CRF protective effects have also been seen in patients with prior comorbidities like prior coronary artery disease, heart failure, depression, end-stage renal disease, and stroke.

Summary

The prognostic value of CRF has been demonstrated in various patient populations and cardiovascular conditions. Higher CRF is associated with improved survival and decreased incidence of cardiovascular diseases (CVD) and other comorbidities including hypertension, diabetes, heart failure, and atrial fibrillation.

     

Die Rolle der Selbsthilfegruppen in der Onkologie

Background

Little is known about self-help associations and their possibilities. Obstacles often prevent early contacts between affected people.

Objectives

The psychosocial support given by self-help associations in different phases is evaluated.

Materials and methods

Based on the experience of the Deutsche ILCO and from cooperation with other organizations and institutions, various dimensions of self-help groups are investigated.

Results

On the professional side, there is a lack of knowledge and of attitude. Suitable structures are rare.

Conclusions

The removal of barriers and development of effective structures are overdue.

     

Effect of Pharmacist Counseling Intervention on Health Care Utilization Following Hospital Discharge: A Randomized Control Trial

Background

Reduction in 30-day readmission rates following hospitalization for acute coronary syndrome (ACS) and acute decompensated heart failure (ADHF) is a national goal.

Objective

The aim of this study was to determine the effect of a tailored, pharmacist-delivered, health literacy intervention on unplanned health care utilization, including hospital readmission or emergency room (ER) visit, following discharge.

Design

Randomized, controlled trial with concealed allocation and blinded outcome assessors

Setting

Two tertiary care academic medical centers

Participants

Adults hospitalized with a diagnosis of ACS and/or ADHF

Intervention

Pharmacist-assisted medication reconciliation, inpatient pharmacist counseling, low-literacy adherence aids, and individualized telephone follow-up after discharge

Main Measures

The primary outcome was time to first unplanned health care event, defined as hospital readmission or an ER visit within 30 days of discharge. Pre-specified analyses were conducted to evaluate the effects of the intervention by academic site, health literacy status (inadequate versus adequate), and cognition (impaired versus not impaired). Adjusted hazard ratios (aHR) and 95 % confidence intervals (CI) are reported.

Key Results

A total of 851 participants enrolled in the study at Vanderbilt University Hospital (VUH) and Brigham and Women’s Hospital (BWH). The primary analysis showed no statistically significant effect on time to first unplanned hospital readmission or ER visit among patients who received interventions compared to controls (aHR?=?1.04, 95 % CI 0.78-1.39). There was an interaction of treatment effect by site (p?=?0.04 for interaction); VUH aHR?=?0.77, 95 % CI 0.51-1.15; BWH aHR?=?1.44 (95 % CI 0.95-2.12). The intervention reduced early unplanned health care utilization among patients with inadequate health literacy (aHR 0.41, 95 % CI 0.17-1.00). There was no difference in treatment effect by patient cognition.

Conclusion

A tailored, pharmacist-delivered health literacy-sensitive intervention did not reduce post-discharge unplanned health care utilization overall. The intervention was effective among patients with inadequate health literacy, suggesting that targeted practice of pharmacist intervention in this population may be advantageous.

     

How Heart Rate Should Be Controlled in Patients with Atherosclerosis and Heart Failure

Purpose of Review

Resting heart rate is an independent risk factor for all-cause and cardiovascular mortality in patients with heart failure. The main objectives are to discuss the prognosis of heart rate, its association with coronary atherosclerosis, and the modalities of control of the heart rate in sinus rhythm and in the rhythm of atrial fibrillation in patients with chronic heart failure.

Recent Findings

As a therapeutic option for control heart rate, medications such as beta-blockers, digoxin, and finally ivabradine have been studied. Non-dihydropyridine calcium channel blockers are contraindicated in patients with heart failure and reduced ejection fraction. The influence of the magnitude of heart rate reduction and beta-blocker dose on morbidity and mortality will be discussed. Regarding the patients with heart failure and atrial fibrillation, there are different findings in heart rate control with the use of a beta-blocker. Patients eligible for ivabradine have clinical benefits and increased ejection fraction. Vagal nerve stimulation has low efficacy for the control of heart rate. Complementary therapies such as tai chi and yoga showed no effect on heart rate.

Summary

In this review, we discuss the main therapeutic options for the control of heart rate in patients with atherosclerosis and heart failure. More research is needed to examine the effects of therapeutic options for heart rate control in different population types, as well as their effects on clinical outcomes and impact on morbidity and mortality.

     

Sex-Based Differences in Chronic Total Occlusion Management

?

Chronic total occlusions (CTOs) are an important and increasingly recognized subgroup of coronary lesions, documented in at least 30%, but up to 52% of patients with coronary artery disease (CAD) undergoing coronary angiography. Percutaneous coronary intervention (PCI) of these lesions is increasingly pursued, with excellent success rates.

Purpose of Review

It is known that gender differences exist in the presentation of CAD, as well as in clinical outcomes after routine PCI; however, it is not well described how these differences pertain to management of CTOs. This review summarizes the available data regarding sex-based differences in CTO management and outcomes.

Recent Findings

Women comprise approximately 20% of CTO registry and trial participants.

Summary

As has been demonstrated in PCI studies, women comprise a minority of patients in CTO PCI registries and trials. Sex-based differences exist in complication rates, collateral formation, and outcomes and need further evaluation in future studies.

     

Aspirin for Primary Prevention of Cardiovascular Disease and Renal Disease Progression in Chronic Kidney Disease Patients: a Multicenter Randomized Clinical Trial (AASER Study)

Background

Patients with chronic kidney disease (CKD) are at high risk for developing cardiovascular events. However, limited evidence is available regarding the use of aspirin in CKD patients to decrease cardiovascular risk and to slow renal disease progression.

Study Design

Prospective, multicenter, open-label randomized controlled trial.

Setting and Participants

One hundred eleven patients with estimated glomerular filtration rate (eGFR) 15–60 ml/min/1.73 m² without previous cardiovascular events.

Intervention

Aspirin treatment (100 mg/day) (n?=?50) or usual therapy (n?=?61). Mean follow-up time was 64.8?±?16.4 months.

Outcomes

The primary endpoint was composed of cardiovascular death, acute coronary syndrome (nonfatal MI, coronary revascularization, or unstable angina pectoris), cerebrovascular disease, heart failure, or nonfatal peripheral arterial disease. Secondary endpoints were fatal and nonfatal coronary events, renal events (defined as doubling of serum creatinine, ≥?50% decrease in eGFR, or renal replacement therapy), and bleeding episodes.

Results

During follow-up, 17 and 5 participants suffered from a primary endpoint in the control and aspirin groups, respectively. Aspirin did not significantly reduce primary composite endpoint (HR, 0.396 (0.146–1.076), p?=?0.069. Eight patients suffered from a fatal or nonfatal coronary event in the control group compared to no patients in the aspirin group. Aspirin significantly reduced the risk of coronary events (log-rank, 5.997; p?=?0.014). Seventeen patients in the control group reached the renal outcome in comparison with 3 patients in the aspirin group. Aspirin treatment decreased renal disease progression in a model adjusted for age, baseline kidney function, and diabetes mellitus (HR, 0.272; 95% CI, 0.077–0.955; p?=?0.043) but did not when adjusted for albuminuria. No differences were found in minor bleeding episodes between groups and no major bleeding was registered.

Limitations

Small sample size and open-label trial.

Conclusions

Long-term treatment with low-dose aspirin did not reduce the composite primary endpoint; however, there were reductions in secondary endpoints with fewer coronary events and renal outcomes. ClinicalTrials.gov Identifier: NCT01709994.