Heart Failure Clinical Trials Research Articles

Publication Rates of Heart Failure Clinical Trials Remain Low

BackgroundUnder-reporting of clinical trial results inhibits dissemination of knowledge, limits understanding of therapeutic interventions, and may ultimately harm patients. ObjectivesThis study examined the rates and predictors of heart failure clinical trial publication and how they have changed over time. MethodsThis study assessed cross-sectional analysis of all heart failure clinical trials registered on ClinicalTrials.gov with at least 2 years follow-up after trial completion. The content area was chosen for the robust clinical trial activity in the field. The primary outcome was manuscript publication with multivariable proportional hazards adjustment to identify associations with publication. ResultsOf the 1,429 included studies, 806 (56%) were published as manuscripts, 623 were unpublished, and 97 (7%) reported results without manuscript publication. Of the total, 1,243 were completed after 2007, when the mean 1-year publication rate for interventional trials rose from 12.7% to 19.6% (p = 0.049), which was possibly associated with changes in government regulation. However, there was no further sustained improvement over time, and there was no multivariable association between later completion dates and reporting or publication of results. Funding from the National Institutes of Health and use of clinical (death, hospitalization, myocardial infarction, changes in functional classification) rather than nonclinical primary endpoints were associated with earlier publication. Whether the results were consistent with the primary study hypothesis was not associated with likelihood of publication. ConclusionsThe rates of heart failure clinical trial publication or reporting of results remain unacceptably low. Additional efforts by all stakeholders, including investigators, sponsors, regulators, societies, editors, and journals are needed to improve data dissemination.

Editorial introductions

Current Opinion in Cardiology was launched in 1985. It is part of a successful series of review journals whose unique format is designed to provide a systematic and critical assessment of the literature as presented in the many primary journals. The field of cardiology is divided into 14 sections that are reviewed once a year. Each section is assigned a Section Editor, a leading authority in the area, who identifies the most important topics at that time. Here we are pleased to introduce the Section Editors for this issue. SECTION EDITORS Ali J. MarianAli J. MarianDr Ali J. Marian joined the faculty at the Department of Medicine (Cardiology) at Baylor College of Medicine, USA, in 1992 and was recruited to The Brown Foundation Institute of Molecular Medicine for the Prevention of Human Diseases at UTHealth, USA, in 2006. His colleagues nationally and internationally recognize him for his research achievements and expertise in genetics of cardiomyopathies. He received the Young Investigator Award from the American College of Cardiology, the Junior Faculty Award for research from the American Federation of Medical Research, the Award for Excellence in Research at Baylor College of Medicine, the Established Investigator Award by the American Heart Association, the Clinician-Scientist Award in Translational Research from Burroughs Wellcome Fund and the Best Editor Award from the American Heart Association. Dr Marian is an Associate Editor of Cardiovascular Research and Section Editor on Genetics for Current Opinion in Cardiology and Current Atherosclerosis Reports. He was a Deputy Editor of Circulation Research, Associate Editor for Circulation and an Associate Editor for European Journal of Clinical Investigation. He received the Best Editor Award from the American Heart Association for his work for Circulation Research. Dr Marian has co-authored ∼ 200 manuscripts in peer-reviewed journals. He has served as a reviewer for > 100 National Institute of Health, American Heart Association and other organizations study sections. Dr Marian's research is supported by grants from NHLBI-NIH, Leducq Foundation Trans-Atlantic Network of Excellence and local foundations Rebecca CogswellRebecca CogswellDr Cogswell completed internal medicine residency, chief residency, and cardiology fellowship at the University of California, San Francisco, USA. While at UCSF, she also completed a year of advanced clinical research training. She then went on to complete Advanced Heart Failure fellowship at the University of Minnesota, USA. She has been on faculty at the University of Minnesota since 2013 and is presently the Medical Director of Mechanical Circulatory Support Program. Dr Cogswell's research focus is the skeletal muscle changes that occur in end stage heart failure. Specifically, she is interested in what these changes can reveal about optimal timing of advanced heart failure therapies and using these measures to predict outcomes after mechanical circulatory support. She has built a left ventricular assist device database at the University of Minnesota and is collaborating with other centers towards answering several clinical questions in the contemporary continuous flow LVAD population. She is presently the Advanced Heart Failure fellowship director and is an active reviewer for Journal of Heart Lung Transplant and Circulation Heart Failure. She is a principle investigator for several heart failure and LVAD related clinical trials. In 2017, she was appointed to the Medtronic Heart Failure Advisory Board. In addition, she developed and directs to the Infiltrative Cardiomyopathies Clinic at the University of Minnesota. Gene KimGene KimDr Kim is a cardiologist with the Advanced heart failure, Cardiac transplant, and Mechanical Circulatory Support Program at the University of Chicago Medicine, USA. He is an Assistant Professor of Medicine and the Advanced Heart Failure Fellowship Program Director. His medical school, residency, and fellowship training were completed at the University of Chicago. Dr Kim's research interests include the genetic and epigenetic regulation of heart failure and arrhythmogenesis with publications on the role of microRNAs in cardiomyopathy. His interests also include myocardial recovery, extracellular matrix in failing myocardium, and the role of inflammation and angiogenesis in LVAD patients. He has published over 80 articles and book chapters and is an investigator in numerous clinical trials.

Abstract 310: Variability in Patient-Reported Health Status by NYHA Classification: Implications for Clinical Trials

Background: A foundation of current clinical trials is to categorize the severity of heart failure (HF) by New York Heart Association (NYHA) classification to ensure that enrolled patients have similar disease severity. Because the NYHA represents a clinician’s assessment of patients’ health status, it may vary from patients’ perspectives and can lead to more or less symptomatic patients being enrolled in clinical trials. We sought to directly compare the ranges of patient-reported health status, as assessed by the well-validated and reliable Kansas City Cardiomyopathy Questionnaire (KCCQ), with NYHA class in recent clinical studies. Methods: We used data from 2 contemporary HF clinical trials, HF-ACTION in patients with Heart Failure with Reduced Ejection Fraction (HFrEF) and TOPCAT in patients with Heart Failure with Preserved Ejection Fraction (HFpEF), and 1 prospective cohort study, the KCCQ Interpretability study (KCCQINT) in patients with HFrEF, where both NYHA and the KCCQ were contemporaneously collected. The distributions of KCCQ Overall Summary (KCCQ-os) scores by NYHA and the variation in assigned NYHA classes among patients with KCCQ scores ≥80 (congruent with NYHA Class I) were then described. Results: A total of 6,072 patients (mean age 64±12 years, 41% female) were included across the 3 studies. Figure 1 shows marked overlap in KCCQ scores across NYHA classes. In KCCQINT, 148 (27%) out of 545 patients reported a KCCQ-os score ≥80, of whom 39 (26%), 81 (55%) and 28 (19%) were coded as NYHA Class I, II and III. None were classified as NYHA Class IV. In HF-ACTION, 677 (32%) of 2129 patients reported a KCCQ-os score ≥80, of whom 548 (81%), 128 (19%) and 1 (<1%) were coded as NYHA Class II, III and IV, respectively. In TOPCAT, 484 (14%) out of 3398 patients reported a KCCQ-os score ≥80, of whom 410 (85%) and 74 (15%) were considered NYHA Class I-II and III-IV, respectively. Conclusions: Although the NYHA is used to identify similarly ill patients for enrollment in clinical trials, there is marked variability within and across studies in patients’ self-reported health status. Future trials should consider patient-reported outcome measures as the basis for defining patient eligibility to enroll a more homogenous cohort of disease severity.

Trends in prevalence of comorbidities in heart failure clinical trials.

The primary objective of this systematic review was to estimate the prevalence and temporal changes in chronic comorbid conditions reported in heart failure (HF) clinical trials. We searched MEDLINE for HF trials enrolling more than 400 patients published between 2001 and 2016.Trials were divided into HF with reduced ejection fraction (HFrEF), HF with preserved ejection fraction (HFpEF), or trials enrolling regardless of ejection fraction. The prevalence of baseline chronic comorbid conditions was categorized according to the algorithm proposed by the Chronic Conditions Data Warehouse, which is used to analyse Medicare data. To test for a trend in the prevalence of comorbid conditions, linear regression models were used to evaluate temporal trends in prevalence of comorbidities. Overall, 118 clinical trials enrolling a cumulative total of 215 508 patients were included. Across all comorbidities examined, data were reported in a mean of 35% of trials, without significant improvement during the study period. Reporting of comorbidities was more common in HFrEF trials (51%) compared with HFpEF trials (27%). Among trials reporting data, hypertension (63%), ischaemic heart disease (44%), hyperlipidaemia (48%), diabetes (33%), chronic kidney disease (25%) and atrial fibrillation (25%) were the major comorbidities. The prevalence of comorbidities including hypertension, atrial fibrillation and chronic kidney disease increased over time while the prevalence of smoking decreased in HFrEF trials. Many HF trials do not report baseline comorbidities. A more rigorous, systematic, and standardized framework needs to be adopted for future clinical trials to ensure adequate comorbidity reporting and improve recruitment of multi-morbid HF patients.

Sympathetic overdrive and sudden cardiac death. Beta-blocker`s capabilities with a focus on bisoprolol

The recommendations of the European Society of Cardiology for the treatment of ventricular arrhythmias and the prevention of sudden cardiac death (2015) identified more than 20 risk factors for sudden death, 3 of them due to sympathetic overdrive (sympathetic hyperactivation): increased heart rate at rest, decreased heart rate variability (standard the deviation of the RR intervals is less than 40–50 ms per day), the elongation and increase in the variance of the QT interval is more than 85–100 ms.Beta-blockers are the only drugs that affect all parts of the pathogenesis of sudden cardiac death. Therefore, they act as first-line drugs (IA) both in the aforementioned Recommendations and in the Recommendations of the European Society of Cardiology for the Diagnosis and Treatment of Acute and Chronic Heart Failure (2016) as a primary component of the combination therapy of symptomatic chronic heart failure with a reduced ejection fraction of the left ventricle.According to the results of clinical trials of chronic heart failure, beta-blockers effectively reduce the risk of sudden cardiac death. Bisoprolol is the leader among them: in the CIBIS II study, it reduced the risk of sudden death by 44 %, and in the CIBIS-III study, by 46 %.

Clinical characteristics and prognostic factors in elderly patients with chronic heart failure -A report from the CHART-2 study-

BackgroundSince most of the randomized clinical trials for heart failure (HF) were designed to exclude elderly patients, limited data are available on their clinical characteristics, prognosis, and prognostic factors. MethodsWe compared clinical characteristics, prognosis, and prognostic factors among Stage C/D HF patients in our CHART-2 Study (N = 4876, mean 69 years, women 32%, 6.3-year follow-up) by age (G1, ≤64 years, N = 1521; G2, 65–74 years, N = 1510; and G3, ≥75 years, N = 1845). ResultsFrom G1 to G3, the prevalence of women, left ventricular ejection fraction (LVEF) and plasma levels of B-type natriuretic peptide (BNP) increased (all P < 0.001). Similarly, 5-year mortality increased (9.9, 17.3 to 39.9%, P < 0.001) along with a decrease in proportion of cardiovascular death and an increase in non-cardiovascular death in both sexes. While all-cause and cardiovascular mortality was comparable between the sexes, women had significantly lower incidence of non-cardiovascular death than men in G2 and G3, which was attributable to the higher incidence of cancer death and pneumonia death in men than in women. Although NYHA functional class III-IV, chronic kidney disease, cancer, LVEF, and BNP had significant impacts on all-cause death in all groups, their impacts were less evident in G3 as compared with G1. ConclusionsThe elderly HF patients, as compared with younger HF patients, were characterized by more severe clinical background, increased proportion of non-cardiovascular death and worse prognosis with different impacts of prognostic factors across the age groups.

Abstract P167: Patient Perspectives on Experience During Collection, Results Communication and Overall Impact of Patient-reported Outcomes in Heart Failure: A Mixed Methods Study

Background: Patient-reported outcome (PRO) assessments are commonly used in clinical heart failure (HF) trials and have been shown to be valid, reliable, sensitive measures of patients’ symptoms, function and quality of life, as well as prognostic of clinical events. To be used in routine care, they also need to be interpretable to providers and patients. Patients’ perspectives on PRO collection and results communication have not been studied. Methods: We conducted a mixed methods study of 24 ambulatory adult HF patients (50% men) who completed PROs as part of care at a HF clinic. Study procedures included (1) qualitative telephone interviews and (2) quantitative surveys following interviews. We employed thematic analysis to analyze and code transcripts using an iterative coding process and descriptive statistics to analyze the survey. Qualitative findings were purposefully linked to quantitative results. Findings: Three themes in qualitative analyses were linked to the quantitative survey: 1. Utility of data: Most participants noted that PRO questionnaires were a useful tool to better understand their health if their providers discussed the results with them, and to provide additional information to help improve their treatment. Ninety-two % (22/24) of participants strongly agreed or agreed (SA/A) and 8% (2/24) were neutral that completing the questionnaires changed their care and improved their health. Ninety-six % (23/24) of participants SA/A and 4% (1/24) were neutral that completing the questionnaires would make evaluation of their well-being more accurate. 2. Length and frequency of data collection: Most participants felt that questionnaire length (13-29 questions completed in 3-8 minutes on average) and frequency of implementation (at every visit) were satisfactory. Sixty-three % (15/24) and 37% (9/24) of participants felt that maximum number of questions should be 5-15 and &gt;15, respectively. Eighty-three % (20/24) and 17% (4/24) of participants felt that maximum time required for completion should be 5 or 10 and &gt;10 minutes, respectively. 3. Communication with providers: Most participants noted that their providers discussed results of PRO questionnaires with them only once or not at all and participants who had this discussion with their providers felt that providers understood their responses. Sixty-two % (15/24), 21% (5/24) and 17% (4/24) of participants SA/A, were neutral and disagreed or strongly disagreed that their providers effectively discussed results of their PROs with them. Conclusions: Qualitative results provided depth and interpretability of quantitative survey results. These results indicate successful implementation and utility of PRO questionnaires in the HF clinic, while highlighting a need for more frequent discussion of PRO results between providers and patients. Further use of PROs may lead to improved cardiovascular health and prognosis in HF.

REAL-WORLD VERSUS CLINICAL TRIAL OUTCOMES FROM LVADS

Outcomes in heart failure clinical trials are generally better than those in the real-world. This may be due to stricter inclusion criteria. We compared patient characteristics and clinical outcomes in clinical trial patients and those in a real-world registry who received an axial flow left

Sex Differences in Comorbidity, Therapy, and Health Services' Use of Heart Failure in Spain: Evidence from Real-World Data.

Heart failure (HF) is becoming increasingly prevalent and affects both men and women. However, women have traditionally been underrepresented in HF clinical trials. In this study, we aimed to analyze sex differences in the comorbidity, therapy, and health services’ use of HF patients. We conducted a cross-sectional study in Aragón (Spain) and described the characteristics of 17,516 patients with HF. Women were more frequent (57.4 vs. 42.6%, p < 0.001) and older (83 vs. 80 years, p < 0.001) than men, and presented a 33% lower risk of 1-year mortality (p < 0.001). Both sexes showed similar disease burdens, and 80% suffered six or more diseases. Some comorbidities were clearly sex-specific, such as arthritis, depression, and hypothyroidism in women, and arrhythmias, ischemic heart disease, and COPD in men. Men were more frequently anti-aggregated and anti-coagulated and received more angiotensin-converting-enzyme (ACE) inhibitors and beta-blockers, whereas women had more angiotensin II antagonists, antiinflammatories, antidepressants, and thyroid hormones dispensed. Men were admitted to specialists (79.0 vs. 70.6%, p < 0.001), hospital (47.0 vs. 38.1%, p < 0.001), and emergency services (57.6 vs. 52.7%, p < 0.001) more frequently than women. Our results highlight the need to conduct future studies to confirm the existence of these differences and of developing separate HF management guidelines for men and women that take into account their sex-specific comorbidity.

Use of sodium-glucose co-transporter-2 inhibitors in patients with and without type 2 diabetes: implications for incident and prevalent heart failure.

Type 2 diabetes (T2D) is associated with an increased risk of heart failure (HF), with recent reports indicating that HF with preserved ejection fraction (HFpEF) may be more common than HF with reduced ejection fraction (HFrEF) in patients with T2D. T2D and HF result in worse outcomes than either disease alone. Sodium-glucose co-transporter-2 inhibitors (SGLT-2is) have significantly improved HF outcomes in patients with T2D and may represent a new therapeutic alternative for patients with T2D at risk for or with HF. Current guidelines recommend prevention of HF through risk factor management. Once developed, treatment of HFrEF should include neurohormonal and haemodynamic modulations; however, there are no specific treatments available for HFpEF. SGLT-2is are the first class of glucose-lowering therapy to prevent HF in clinical trials and real-world studies in patients with T2D (with or without established cardiovascular disease and with or without baseline HF). Mechanistic studies suggest that SGLT-2is have beneficial effects on both systolic and diastolic function and additional systemic effects that could benefit HF outcomes. In patients with HFrEF, SGLT-2i treatment as add-on to standard HF therapy has had beneficial effects on HF outcomes, irrespective of T2D status. These results and those of ongoing outcomes trials with SGLT-2is may help establish this drug class as a treatment for HF in patients with HFrEF and HFpEF, as well as HF in patients without T2D.

Sex differences in heart failure

The overall lifetime risk of heart failure (HF) is similar between men and women, however, there are marked sex differences in the landscape of this condition that are both important and under-recognized. Men are predisposed to HF with reduced ejection fraction (HFrEF), whereas women predominate in HF with preserved ejection fraction (HFpEF). Sex differences are also notable in the penetrance of genetic cardiomyopathies, risk factors, e.g. breast cancer which may be associated with cancer treatment-induced cardiomyopathy, as well as sex-specific conditions such as peripartum cardiomyopathy (PPCM). This review outlines the key sex differences with respect to clinical characteristics, pathophysiology, and therapeutic responses to HF treatments. Finally, we address important differences in the prognosis of HF. A central hypothesis is that the higher risk of HFrEF in men compared to women may be attributable to their predisposition to macrovascular coronary artery disease and myocardial infarction, whereas coronary microvascular dysfunction/endothelial inflammation has been postulated to play a key role in HFpEF and maybe the common link among HF syndromes that women are predisposed to Takotsubo cardiomyopathy, PPCM, and breast cancer radiotherapy-induced cardiomyopathy. Under-pinning current sex disparities in HF, there is a paucity of women recruited to HF clinical trials (20-25% of cohorts) and thus treatment guidelines are predominantly based on male-derived data. Large gaps in knowledge exist in sex-specific mechanisms, optimal drug doses for women and sex-specific criteria for device therapy.

Monitoring of iron status in patients with heart failure.

The 2016 ESC/HFA heart failure (HF) guidelines emphasize the importance of identifying and treating iron deficiency (ID) in patients with HF. Iron deficiency can occur in half or more of HF sufferers, depending on age and the phase of the disease. Iron deficiency can be a cause of anaemia, but it is also common even without anaemia, meaning that ID is a separate entity, which should be screened for within the HF population. Although assessment of iron stores in bone marrow samples is the most accurate method to investigate iron status, it is not practical in most HF patients. Levels of circulating iron biomarkers are an easily available alternative; especially, ferritin and transferrin saturation (Tsat). In patients with HF serum ferritin level <100 µg/L (regardless of Tsat value) or between 100 and 299 µg/L with Tsat <20% are considered as recommended criteria for the diagnosis of ID, criteria which have been used in the clinical trials in HF that have led to a recommendation to treat ID with intravenous iron. We discuss the optimal measures of iron biomarkers in patients with HF in order to screen and monitor iron status and introduce some novel ways to assess iron status.

Representativeness of a Heart Failure Trial by Race and Sex: Results From ASCEND-HF and GWTG-HF

ObjectivesThis study sought to determine the degree to which U.S. patients enrolled in a heart failure (HF) trial represent patients in routine U.S. clinical practice according to race and sex. BackgroundBlack patients and women are frequently under-represented in HF clinical trials. However, the degree to which black patients and women enrolled in trials represent such patients in routine practice is unclear. MethodsThe ASCEND-HF (Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure) trial randomized patients hospitalized for HF to receive nesiritide or placebo from May 2007 to August 2010 and was neutral for clinical endpoints. This analysis compared non-Hispanic white (n = 1,494) and black (n = 1,012) patients enrolled in ASCEND-HF from the U.S. versus non-Hispanic white and black patients included in a U.S. hospitalized HF registry (i.e., Get With The Guidelines–Heart Failure [GWTG-HF]) during the ASCEND-HF enrollment period and meeting trial eligibility criteria. ResultsAmong 79,291 white and black registry patients, 49,063 (62%) met trial eligibility criteria (white, n = 37,883 [77.2%]; black, n = 11,180 [22.8%]). Women represented 35% and 49% of the ASCEND-HF and trial-eligible GWTG-HF cohorts, respectively. Compared with trial-enrolled patients, trial-eligible GWTG-HF patients tended to be older with higher blood pressure and higher ejection fraction. Trial-eligible patients had higher in-hospital mortality (2.3% vs. 1.3%), 30-day readmission (20.2% vs. 16.8%), and 180-day mortality (21.2% vs. 18.6%) than those enrolled in the trial (all p < 0.02), with consistent mortality findings by race and sex. After propensity score matching, mortality rates were similar; however, trial-eligible patients continued to have higher rates of 30-day readmission (23.1% vs. 17.3%; p < 0.01), driven by differences among black patients and women (all p for interaction ≤0.02). ConclusionsPatients with HF seen in U.S. practice and eligible for the ASCEND-HF trial had worse clinical outcomes than those enrolled in the trial. After accounting for clinical characteristics, trial-eligible real-world patients continued to have higher rates of 30-day readmission, driven by differences among black patients and women. Social, behavioral, and other unmeasured factors may impair representativeness of patients enrolled in HF trials, particularly among racial/ethnic minorities and women. (Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure [ASCEND-HF]; NCT00475852)

P6300Endothelial cell activation by pro-inflammatory cytokines exerts novel paracrine effects on co-cultured cardiomyocytes

Abstract Background Anti-inflammatory therapies have failed to meet expectations in recent clinical trials for heart failure, despite the number of studies demonstrating pro-fibrotic, arrhythmogenic and hypertrophic effects of inflammation. To enlighten this, we sought to examine the contribution of non-myocytes in the cardiac inflammatory response. Endothelial cells (EC) can regulate cardiomyocyte (CM) function with multiple soluble factors. While many studies have shown the effects of pro-inflammatory cytokines on EC or CM separately, it is still unclear how the activation of EC can affect CM function. Purpose We studied the effect of pro-inflammatory pre-conditioning of EC on CM in indirect co-culture systems and in an ex vivo model of cardiac tissue. We hypothesised that pro-inflammatory activation of EC would alter the contractility of co-cultured CM. Methods Human cardiac microvascular EC were first pre-conditioned for 24h with Cytomix (1 ng/ml TNF-α, 1 ng/ml IL-1β, 25 ng/ml IL-6 Rα/IL-6 chimera) and co-cultured in a transwell system (pore size: 0.4μm) with adult rat ventricular CM. Co-culture supernatants were screened using a Cytokine Profiler Array. In vitro analysis of calcium handling in CM utilised the optical mapping technique and Fluo-4. Contractility of cardiac tissue was measured ex vivo using myocardial slices of 300 μm, prepared from left ventricles of adult rat and cultured for 24h with field stimulation and a fixed stretch producing a sarcomeric length of 2.2 μm. Results Treatment of EC by Cytomix prior to co-cultures induced a release of CC and CXC chemokines, G-/GM-CSF, ST2 and the adhesion molecule ICAM-1. Using published RNAseq datasets we noticed that adult CM do not constitutively express the receptors for the chemokines identified with the Profiler Array. However, duration of calcium transients in CM was significantly reduced from 454 to 322 ms in co-cultures with EC pre-conditioned by Cytomix, compared to untreated EC. Amplitude and time to peak were unchanged. In contrast, myocardial slices treated with Cytomix demonstrated a significant increase in contractility compared to control (from 3.3 to 5.3 mN/mm2) but no significant change in the duration of contraction (from 467 to 434 ms) or the rate of relaxation. Conclusions Pre-conditioned EC exert paracrine effects on the calcium handling of isolated CM, suggesting pro-inflammatory activation of proximal EC can affect CM function. In myocardial slices, pro-inflammatory stimulation provoked an inotropic response. The divergence of effect with findings in isolated cells may reflect differences in experimental design and multicellularity. Future work will aim to characterise the soluble mediators involved, and selectively target EC in slices to contextualise the effects described in co-cultures. Ultimately, this may inform the development of novel anti-inflammatory strategies for clinical use. Acknowledgement/Funding British Heart Foundation

What causes sudden death in patients with chronic heart failure and a reduced ejection fraction?

Sudden death characterizes the mode of demise in 30–50% of patients with chronic heart failure and a reduced ejection fraction. Occasionally, these events have an identifiable pathophysiological trigger, e.g. myocardial infarction, catecholamine surges, or electrolyte imbalances, but in most circumstances, there is no acute precipitating mechanism. Instead, adverse left ventricular remodelling and fibrosis creates an exceptionally fragile and highly vulnerable substrate, which can be characterized using the model developed in theoretical physics of ‘self-organizing criticality’. This framework has been applied to describe the genesis of avalanches, nodes of traffic congestion unrelated to an accident, the abrupt system-wide failure of electrical grids, and the initiation of cancer and neurodegenerative diseases. Self-organizing criticality within the ventricular myocardium relies on complex adaptations to progressive stress and stretch, which evolve inevitably to an abrupt end (termed ‘cascading failure’), even though the rate of deterioration of the underlying disease process has not changed. The result is acute circulatory collapse (i.e. sudden death) in the absence of an identifiable triggering event. Cascading failure in a severely remodelled or fibrotic heart can become manifest electrically as a first-time ventricular tachyarrhythmia that is responsive to the shock delivered by an implantable cardioverter-defibrillator (ICD). Alternatively, it may present as an acute mechanical failure, which is manifest as (i) asystole, bradyarrhythmia, or electromechanical dissociation; or (ii) incessant ventricular fibrillation that persists despite repetitive ICD discharges; in both instances, the sudden deaths cannot be prevented by an ICD. This conceptual framework explains why anti-remodelling and antifibrotic interventions (i.e. neurohormonal antagonists and cardiac resynchronization) reduce the risk of sudden death in patients with heart failure in the absence of an ICD and provide incremental benefits in those with an ICD. The adoption of anti-remodelling and antifibrotic treatments may explain why the incidence of sudden death in clinical trials of heart failure has declined dramatically over the past 10–15 years, independent of the use of ICDs.

Differences between Academic and Non-Academic Institutions in Heart Failure Clinical Trials in North America: Insights from the HFSA Research Network Survey

Background The conduct of rigorous HF clinical trials requires participation from a wide variety of institutions and partnerships across academic, non-academic, Veterans Affairs, and industry. We aimed to examine differences between academic and non-academic centers in the conduct of HF clinical trials in North America. Methods HFSA distributed an electronic survey to examine the current state of HF clinical trial activity. Surveys were distributed to current or past HFSA members and affiliates, HF members of AHA and ACC. Pearson's chi-squared test was applied to categorical data. Results A total of615 surveys were returned. Of these, 410 respondents reported being currently active in the conduct of HF trials and were included in this analysis. Respondents represented 45 states and 331 distinct institutions. Most respondents were physicians (n=269, 66%), followed by nurses or nurse practitioners (n=83, 20%) and pharmacists (n=20, 5%). The majority of respondents were from academic centers (n=311, 75.5%), followed by non-academic (n=59, 14%), industry (n=22, 5%), and Veterans Affairs (n=18, 4%). Academic and non-academic institutions participated in a similar number of trials per year and reported similar numbers of subjects enrolled per year (Table). In addition, regulatory and staff resources including time to Institutional Review Board (IRB) approval, access to a central IRB, timeline for execution of contracts and number of study coordinators were not different between academic and non-academic institutions. Respondents from academic institutions did report more publications per year than those from non-academic institutions and participation differed in types of trials. Involvement as a lead national primary investigator or co-investigator for multi-centered trials was higher in academic institutions than non-academic institutions (40% vs 29%). Conclusion Academic and non-academic institutions contributed similarly to the conduct of HF clinical trials across North America. Regulatory and staff resources were also comparable. Opportunities exist to better engage non-academic investigators in publications and other leadership opportunities within multi-centered HF clinical trials.

Guideline Directed Medical Therapy in Heart Failure Trials: A New Proposed Scoring System

Background Current guidelines recommend multiple drugs titrated to maximally-tolerated dose as Guideline Directed Medical Therapy (GDMT) for chronic heart failure (HF). In clinical trials, background therapy at randomization is often stated as being “optimized” but objective criteria supporting such assertion are lacking. We propose a simple scoring system to define GDMT, set thresholds for optimal therapy, and standardize comparisons across HF clinical trials. Methods We evaluated current ACC/AHA/HFSA and ESC HF guidelines and the GDMT definition in 8 HF drug and device trials. We created a score based on strength of evidence, literature review, and data regarding dose effects. The score was tested in 10 hypothetical clinical scenarios based on likely drug combinations in the Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients With Functional Mitral Regurgitation (COAPT) Trial. Results Figure 1 shows the proposed score. Of the 10 clinical scenarios based on COAPT, 3 patients were not optimized according to the proposed score. The score performed well in defining GDMT in most of these clinical scenarios. Conclusion We propose a simple score for measuring GDMT, which validates well in clinical scenarios from a modern clinical trial. Utilizing this system will help establish a quality threshold for background therapy according to guideline recommendations, and provide standards for comparison across clinical trials. Further research should be conducted to determine whether the proposed score correlates with clinical outcomes.

BAOXIN Granules Protected Mouse Model With Elevated Afterload From Cardiac Hypertrophy by Suppressing Both Inflammatory Reaction and Collagen Deposition.

BAOXIN Pill was reported to be effective clinically for chronic heart failure based on the principles of traditional Chinese medicine (TCM), invigorating qi and activating blood. The present study evaluated preclinically the effects of the improved dosage form, BAOXIN Granules, on cardiac hypertrophy. Transverse aortic constriction (TAC) was performed in mice to model cardiac hypertrophy by aortic stenosis for 4 weeks. The sham and TAC group were intragastrically administrated with saline as the controls. Two treatment groups were administrated orally with 10 mg/kg⋅d Enalapril (positive control) or 0.77 g/kg⋅d BAOXIN Granules for 4 weeks respectively. The effects were evaluated by echocardiography, morphology, and biological markers for cardiac function. The specific genes involved in inflammation and fibrosis were also examined for their expressions to investigate the pathways involved in early heart failure. Just as Enalapril, BAOXIN Granules administration markedly attenuated left ventricular hypertrophy and improved heart function as evidenced by echo cardiography, morphology. Accordingly, the biomarkers of the early stage heart failure, ANP, BNP and β-MHC, were decreased in the two treatment groups. We also found that mRNA expressions of some inflammatory factors and fibrosis associated genes were down-regulated in the tissue of heart after treatment. BAOXIN Granules may protect the heart from myocardial hypertrophy caused by increasing left ventricular afterload. It can suppress both inflammatory reaction and collagen deposition during pressure overload. BAOXIN Granules is advised to be tested in clinical trials for heart failure in the future.

Update in recent clinical trials in heart failure.

Heart failure represents a major growing health problem in developed world. This article aims to review recent heart failure trials that have significantly impacted the management of heart failure. Despite advances in heart failure, mortality and morbidity remains elevated amongst patients. Recent clinical trials demonstrate promising treatment strategies that likely impact clinical practice; including heart failure prevention with the use of SGLT2-inhibitors in patients with diabetes and cardiovascular risk, new treatments that may abrogate disease progression in cardiac amyloidosis, intravenous iron therapy in iron deficiency anemia in chronic systolic heart failure, predischarge treatment with angiotensin receptor blocker with neprilysin inhibition (ARNi) in patients hospitalized for acute decompensated heart failure, and newer continuous flow left ventricular assist device with increased durability and efficacy in patients with Stage D heart failure. Recent clinical trials with SGLT2 inhibitors, therapies targeting transthyretin cardiac amyloidosis, iron, angiotensin receptor blocker with neprilysin inhibition and newer mechanical circulatory support devices are very promising as practice changing new treatment strategies in prevention and treatment of heart failure. This article presents a summary of important trials and should be of practical value to both clinicians and researchers.

Evidence-based drug therapy for heart failure-an update

Chronic heart failure affects millions of people worldwide and is associated with high morbidity and mortality. Because of steadily increasing ageing populations and improved survival rates after myocardial infarction, the incidence of chronic heart failure is rising. As acute decompensated heart failure is one of the leading causes for hospitalization in Germany, heart failure imposes ahuge economic burden on its health care system. Guideline directed therapy is important to improve prognosis. In the following, we give an overview about novel heart failure clinical trial results and point to important comorbidities.