Newer drugs for heart failure: hype or hope?

KEYWORDS:

• Heart failure
• novel investigational drugs
• clinical trials
• concordance between phase II and phase III studies

1. Introduction

Heart failure continues to represent a major global health problem [1]. Aging of the population, advancement in the management of coronary artery disease and heart failure, adoption of western diet and urbanization in developing countries are contributing factors to the expected increase in the prevalence of heart failure. Heart failure is classified broadly into acute and chronic. Despite the fact that the majority of patients with acute heart failure (AHF) present with progressive symptoms and not acutely we label all patients needing hospitalization for heart failure as having AHF. Heart failure is also broadly classified into heart failure with reduced left ventricular ejection fraction (HFrEF) and heart failure with preserved ejection fraction (HFpEF) despite the fact that some of the patients with HFpFE do not preserve their ejection fraction. Regardless of terminology, the gravity of heart failure on the wellbeing and survival of large segment of an increasingly elder population has stimulated tremendous efforts in the search for newer treatment of this syndrome.

2. Potential new drugs

In this issue of the Journal et al. [2] provides a comprehensive review of potential new drugs for the treatment of heart failure. The authors highlight the interplay among the many derangements involved in the development as well as the progression of heart failure that include remodeling, fibrosis, endothelial dysfunction, sarcomeric deterioration and myocyte death, thus providing the rational for having a wide variety of drugs involving different pathological pathways.

The authors begin by addressing drugs for the management of AHF. They briefly comment on the failure of nesiritide in the ASCEND-HF [3] to reduce 30 day or hospitalization and point out the possibility that the delay in instituting therapy with nesitiride could have contributed to the lack of efficacy with this intervention, thus, raising the issue of a study design as a factor to be considered in explaining a failed intervention. They subsequently mention briefly levosimendan and its association in the REVIVE study [4] with hypotension and arrhythmias and potentially a higher risk of death, thus citing another example of a promising drug that fell short of expectation. The three drugs that the authors cover in details are serelaxin, ularitide and a biased ligand TRV027. For serelaxin, they describe its major mechanism of action, serving as a ligand for the relaxing family peptide receptors and leading to nitric oxide production [5]. They propose that a potential explanation for the surprising results of a significant reduction of cardiovascular as well as total mortality at 180 days in the RELAX-HF study [6] is a rapid relief of congestion achieved by seralaxin resulting in minimized damage to various vital organs that carried a long-term benefit. The need to confirm this finding by the ongoing prospective study RELAX-AHF is mentioned. Ularitide which is a synthetic form of urodilantin, a member of the natriuretic peptide family secreted by the kidneys is discussed next with presentation of SIRUS I [7] and SIRUS II studies [8] that confirmed its vasodilating and lowering of NT-proBNP effects, findings that stimulated the launching of the ongoing phase III TRUE-AHF trial. The rational for selecting a biased ligand that antagonizes angiotensin II while stimulating the B-arrestin pathway that potentially would enhance cardiac contractility and cardiac protection is discussed along with the phase II BLAST-HF trial exploring its short-term clinical effects in AHF.

The authors then discuss drugs for managing HFrEF. They first mention LCZ 696 which is a combined angiotensin receptor II blocker(valsartan) and neprilysin inhibitor (sacubitril) recently approved by the Food and Drug Administration (FDA) based on the overwhelmingly positive PARADIGM-HF trial [9] and the heart rate lowering drug ivabradine that was also approved by the FDA based on data from the SHIFT trial [10]. The rational for introducing omecamtiv mecarbil which increases the force of contraction without increasing calcium store is discussed along with the results of the phase II COSMIC-HF [11] study that showed favorable effect on remodeling and NT-proBNP. The initial concern for precipitating ischemia was alleviated by an exercise study [12], phase III is being launched at the present time. The authors then detail the mechanisms of the soluble guanylate cyclase (sGC) stimulator vericiguat and summarize the findings of the SOCRATES-REDUCED trial [13] in which compared to placebo vericiguat showed a significant reduction of NT-proBNP with the 10 mg dose of vericiguat.[13] A phase III the VerICiguaT Global Study in Subjects with Heart Failure with Reduced Ejection Fraction (VICTORIA) trial is being launched and it will determine the role of this drug in the management of HFrEF. The authors then discuss finerenone the nonsteroidal mineralocorticoid receptor antagonist that has superior cardiac selectivity as compared to spironolactone and eplerenone. The ARTS study [14] confirmed the association of finerenone with a lower increase in serum potassium compared to spironolactone in patients with mild to moderate chronic kidney disease. The subsequently completed larger ARTS-HF trial in patients with diabetes and or mild to moderate kidney disease that compared finerenone to eplerenone showed promising results that included reduction of all secondary end points including CV hospitalization, CV death and total mortality. The study, however, failed to achieve its primary end point of superior reduction of NTproBNP. At the present time there is no plan to proceed with a larger trial to confirm the superiority of finerenone to eplerenone; the FINESS trial has been placed on hold.

The last drug the authors review is Neuregulin-1which is a member of the neuregulins, growth promoting proteins of the epidermal growth factor family of ligands. It plays a defining role in chamber differentiation and cardiac function. A limited clinical experience suggests a beneficial and sustained effect in reversing remodeling and improving symptoms [15,16].

3. Expert opinion

The authors have nicely presented a collection of promising new drugs in the treatment of heart failure and wisely mentioned the results of the phase III studies ASCEND [3] and REVIVE [4]. It is a grim reminder of the almost consistent divergence between phase II and phase III trials. Many of what appear to be promising drugs in phase II studies fail miserably in larger adequately powered trials. Some of the reasons include study design or inappropriate dose selection, an overly optimistic interpretation of phase II studies and different population between the two phases (Table 1). Another emerging major challenge is the rapid uptake and dissemination of newer recently approved medications or devices that may have significant impact on the course of heart failure.

Table 1. Potential causes of discrepancies between phase II and III studies.

1. Underpowered small trial

2. Overestimation of the benefit

3. Different patient population (severity of heart failure, comorbidities etc.

4. Different pharmacodynamics and pharmacokinetics (related to different patient population)

5. Inappropriate design of the trial

6. Inappropriate end points

7. Inappropriate dose selection

8. Chance findings

9. Ignoring negative signals

One would hope that with the accumulated experience in conducting so many trials with so many different compounds that the divergence between phase II and III studies become a phenomenon of the past and that many of the promising new drugs will find its way to become an effective tool in the management of heart failure.

In two previous editorials [17,18], I outlined the challenges from a clinician point of view of applying the knowledge obtained in clinical trials to every day clinical practice including different populations [19] and lack of personalized medicine. It is unlikely that no matter what improvement we make in successfully replicating the results of phase II studies that these challenges could be overcome in the very near future.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Additional information

Funding

This paper was not funded.