Redefining endpoints in heart failure clinical trials: the emerging role of wearable technologies in contemporary trial design

Arthur Kornberg, who shared with Severo Ochoa the 1959 Nobel Prize for Physiology or Medicine, stated in his autobiography that he had never met a dull enzyme.1 We strongly believe that soluble guanylate cyclase (sGC; E.C.4.6.1.2) is no exception to this. Article see p 2781 Nitric oxide (NO) plays an important physiological role as a signaling molecule as well as a cytotoxic agent. It is produced by 3 distinct NO synthases, specifically endothelial, neuronal, and inducible NO synthase. In the vasculature, endothelial NO synthase plays an important role in vascular homeostasis because NO generated in endothelial cells promotes vascular smooth muscle cell relaxation and inhibits platelet aggregation. Importantly, bioavailability of NO can be reduced in cardiovascular diseases, a condition which has been termed “endothelial dysfunction.” This phenomenon provides a rationale for therapeutic intervention. The primary target of NO is sGC, which is a heterodimeric enzyme consisting of an α- and β-subunit and a prosthetic heme group, which is located in the β-subunit. The heme group contains a ferrous iron atom (Fe2+). Binding of NO to this iron changes the conformation of the enzyme and leads to a >100-fold increase in catalytic rate (ie, the conversion of guanosine triphosphate to the second messenger cyclic guanosine monophosphate [cGMP]). The NO-induced cGMP signal modulates intracellularly the activity of several effector molecules: cGMP-dependent protein kinases, cGMP-regulated phosphodiesterases, and cGMP-gated ion channels. Of note, both heme iron oxidation (Fe3+) and heme removal render sGC unresponsive to NO (Figure). These 2 conditions could therefore provide a mechanism for “vascular smooth muscle cell dysfunction” in cardiovascular disease states, which are often characterized by marked vasoconstriction either systemically or in specific organs. Figure. Schematic illustrating 3 different forms of soluble guanylate cyclase and their respective responsiveness to nitrovasodilators, sGC stimulators (eg, BAY 41–2272), and sGC …

Section 15: Management of Heart Failure in Special Populations

More than 4000 patients have been evaluated in randomized controlled trials of cardiac resynchronization therapy (CRT). These studies have demonstrated that CRT with or without an implantable cardioverter-defibrillator (ICD) consistently improves quality of life, functional status, exercise capacity, and cardiac structure and function and reduces morbidity and mortality in heart failure patients with ventricular dyssynchrony. The magnitude of benefit seen with CRT is comparable to or exceeds that seen with evidence-based drug therapies for heart failure but occurs in patients who are already receiving such medications. Thus, CRT has been added to the list of evidence-based therapies that make heart failure patients feel better and live longer (the Table). Consequently, a strong ethical mandate exists for the use of CRT in heart failure. This mandate is reflected in our current practice guidelines for the management of chronic heart failure, which state that all eligible patients should receive CRT unless contraindicated.1,2 End of debate! CRT should be a routine part of any evidence-based treatment regimen for heart failure. View this table: Major Benefits of Evidence-Based Heart Failure Therapies Of course, things are never quite so simple, so let us take a look at the evidence supporting this clinical mandate for CRT and address patient selection, some of the limitations of CRT, and some of the unanswered questions about the use of CRT in heart failure. None of this discussion will lessen the role of CRT in the treatment of heart failure; rather, it will guide the selection of appropriate patients and speculate on the future application of CRT to an even broader group of heart failure patients. Response by Greenberg and Mehra p 2698 Approximately one third of patients with systolic heart failure exhibit ventricular dyssynchrony, defined as a QRS duration >120 ms on the surface ECG.3,4 Ventricular dyssynchrony produces suboptimal ventricular …

Topical β-Adrenergic Blockers and Glaucoma: A Heart-Stopping Association?

The combined neprilysin/renin-angiotensin system (RAS) inhibitor sacubitril/valsartan reduced cardiovascular death or heart failure hospitalization, cardiovascular death, and all-cause mortality in a large outcomes trial. While sacubitril/valsartan is the only currently available drug in its class, there are two prior clinical trials in heart failure with omapatrilat, another combined neprilysin/RAS inhibitor. Using all available evidence can inform clinicians and policy-makers. We performed a meta-analysis using data from three trials in heart failure with reduced EF that compared combined neprilysin/RAS inhibition with RAS inhibition alone and reported clinical outcomes: IMPRESS (n = 573), OVERTURE (n = 5770), and PARADIGM-HF (n = 8399). We assessed the pooled hazard ratio (HR) for all-cause death or heart failure hospitalization, and for all-cause mortality in random-effects models, comparing combined neprilysin/RAS inhibition with ACE inhibition alone. The composite outcome of death or heart failure hospitalization was reduced numerically in patients receiving combined neprilysin/RAS inhibition in all three trials, with a pooled HR of 0.86, 95% confidence interval (CI) 0.76-0.97, P = 0.013. For the endpoint of all-cause mortality, the pooled HR was 0.88, 95% CI 0.80-0.98, P = 0.021. Combined neprilysin/RAS inhibition compared with ACE inhibition was associated with more hypotension, but less renal dysfunction and hyperkalaemia in all three trials. Pooled estimates from three trials with two separate drugs of combined neprilysin/RAS inhibition support the use of combined neprilysin/RAS inhibition in heart failure with reduced EF.

Metabolic assessment of exercise in chronic heart failure patients treated with short-term vasodilators.

Heart failure is a deadly disease that has reached epidemic proportions in industrialized countries. Patients living with heart failure carry a heavy burden in terms of morbidity. Many patients require repeated hospitalizations for cardiovascular problems, especially for episodes of worsening heart failure. In fact, heart failure is one of the most important causes of hospital admissions in the United States, accounting for over 2.5 million admissions per year. Once hospitalized, patients with heart failure have an increased risk of recurrent hospitalizations and death. Approximately 30% to 40% of patients are readmitted within 6 months of an index hospitalization. Angiotensin-converting enzyme (ACE) inhibitors, digitalis, and spironolactone decrease the risk of hospitalization in heart failure patients; however, the annual rate of hospital admission for worsening heart failure has remained high.1–3⇓⇓ See p 2194 Given these challenges, clinical trials conducted in the mid 1990s that demonstrated that β-blocker therapy in addition to ACE inhibitors and digitalis reduces the risk of hospitalization in heart failure patients by about 20% to 30% represented remarkable progress. These beneficial effects of β-blocking agents on morbidity were recognized well before favorable effects on survival were unequivocally established (Table). In some, but not all, trials, the clinical benefits of β-blocker treatment included improved heart failure symptoms as assessed by physicians and patients. View this table: Large-Scale Clinical Trials Reporting β-Blocker Effects on Heart Failure Morbidity Previous trials addressing the effects of β-blockers on morbidity have been conducted in patients …

Changing the Face of Cardiovascular Trial Participation: Moving Beyond Middle-Aged White Guys

Efficacy of sodium-glucose cotransporter 2 inhibitors and angiotensin receptor-neprilysin inhibitors for heart failure in black patients: a systematic review and meta-analysis of randomized controlled trials.

Most hospitalized older persons do not meet the enrollment criteria for clinical trials in heart failure

Use of loop diuretics in chronic heart failure: do we adhere to the Hippocratian principle 'do no harm'?

<i>Circulation</i> : Clinical Summaries

Background Renal endpoints like end stage renal disease (ESRD) and a 50% decline in estimated glomerular filtration rate (eGFR) have been used in recent randomized clinical trials in heart failure (HF). However, the distribution of these events in larger real-life HF cohorts is unknown Purpose We examined the risk of traditional HF endpoints like death and worsening HF and the risk of these new renal endpoints in HF with and without severe chronic kidney disease (+/−eGFR 30 ml/min/1.73 m2) at the time of diagnosis of HF. Methods From nationwide registries, we identified patients receiving a diagnosis of HF from 2014–2018. Patients were included if they had creatinine available in proximity of the diagnosis (90 days before inclusion). Outcomes comprised of: (i) all-cause mortality, (ii) HF worsening, (iii) end stage renal disease and (iv) sustained 50% eGFR decline. 4-year rates of the primary outcomes were estimated using cumulative incidence function adjusted for competing risk of death, and multivariable Cox proportional hazards models were used to examine the association of covariates with a combined endpoint of the primary outcomes. Results We included 21,959 patients with HF and known CKD status. Median age was 73.9 years, and 7% had an eGFR &amp;lt;30 mL/min/1.73 m2. There were few differences in baseline characteristics for patients with and without eGFR below 30. Patients with eGFR below 30 were elder and had more comorbidities. The mortality rate was 33.9% for patients with eGFR≥30 and 70.4% for patients with eGFR &amp;lt;30. For patients with eGFR &amp;lt;30 at the time of HF diagnosis renal outcomes were more pronounced as the first event as compared to patients with eGFR ≥30. The risk of all-cause mortality and HF hospitalization as first event was comparable between eGFR ≥30 and eGFR&amp;lt;30 (22.7% vs 22.5% and 25.8% vs 22.5%, respectively). The risk of end-stage renal disease as first event was significantly higher for patients with eGFR &amp;lt;30 (0.03% vs. 33.8%). The risk of a sustained 50% decline in eGFR was 4.6% for patients with eGFR ≥30 and 1.0% for patients with eGFR&amp;lt;30 (figure 1). Across all important subgroups an eGFR &amp;lt;30 ml/min/1.73 m2 was associated with an increased rate of the composite endpoint of death, worsening HF or a renal endpoint, and no interactions were observed (P&amp;gt;0.01 for all) (figure 2). Conclusion The risks of newly introduced renal trial-endpoints in a large real-life cohort of HF patients was low compared to the risks of death or worsening HF if eGFR ≥30 ml/min/1.73 m2 at the time of diagnosis of HF. However, this pattern changed in HF patients with a eGFR &amp;lt;30 ml/min/1.73 m2 at the time of diagnosis time of HF. The present study provides important insights into cardiorenal epidemiology in HF and have implications for planning of future trials. Funding Acknowledgement Type of funding sources: Public hospital(s). Main funding source(s): Herlev/Gentofte Hospital

Heart failure is an important clinical and public health issue. There is an urgent need to improve the efficiency of clinical trials in heart failure to rapidly identify new therapies and evidence-based implementation strategies for currently existing therapies. Electronic health (eHealth) platforms and digital health tools are being integrated into heart failure care. In this manuscript, we review opportunities to use these tools to potentially improve the design of and reduce the complexity of clinical trials in heart failure. The PRECIS-2 tool outlines clinical trial design domains that are targets for pragmatism. We believe incorporating pragmatic design elements with the aid of eHealth platforms and digital health tools into clinical trials may help address the current complexity of clinical trials in heart failure and improve efficiency. In the manuscript, we provide examples from recent clinical trials across clinical trial design domains. We believe the current adoption of eHealth platforms and digital health tools is an opportunity improve the design of heart failure clinical trials. We specifically believe these tools can enhance pragmatism in clinical trials and reduce delays in generating high-quality evidence for new heart failure therapeutics.

Despite significant advances in the treatment of chronic heart failure during the past 30 years, there is a broad consensus that new treatments are needed because morbidity and mortality in this disorder remain unacceptably high.1 Nevertheless, the development of new drugs for chronic heart failure has waned during the past 20 years; the quantity of novel agents in clinical testing and the number of well-designed clinical trials have diminished to a small fraction of that seen in the 1980s and 1990s.2 Some have suggested that investment in heart failure has declined because the primary mechanisms of the disorder are poorly understood, because the promising results of phase II trials are frequently not confirmed in large-scale definitive studies, and because the large-scale clinical trials needed for regulatory approval have often become prohibitively expensive.2,3 We know that clinical research in heart failure is extremely challenging, and so we beg innovators in the pharmaceutical and device industries to be patient, and we plead with sponsors to invest in large-scale investigations because the need is so great. Yet, when we critically examine how we react to data, it may not be too surprising that meaningful clinical trials in heart failure are becoming increasingly scarce.2 Do cardiologists act as if the results of clinical trials in heart failure really matter? Most heart failure trials yield results that are disappointing or difficult to interpret. Yet, such studies would nevertheless be enormously useful if we learned from these setbacks and moved on. But do we? At the 2015 Scientific Sessions of the American Heart Association, every randomized trial in heart failure presented in the late-breaking sessions yielded distressing results. A phase II trial of the soluble guanylate cyclase stimulator vericiguat failed to meet its primary end point, even though the change …