Emerging Treatment Approaches to Improve Outcomes in Patients with Heart Failure : Cardiology Discovery

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Emerging Treatment Approaches to Improve Outcomes in Patients with Heart Failure

Greenberg, Barry H.*,

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Cardiology Discovery 2(4):p 231-240, December 2022. | DOI: 10.1097/CD9.0000000000000060
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Abstract

Introduction

Heart failure (HF) is the end result of a variety of diseases that affect the normal functioning of the heart and impair its ability to supply adequate amounts of oxygenated blood to the remainder of the body at normal cardiac filling pressures. The causes of HF are myriad, and include atherosclerotic cardiovascular disease, hypertension, a variety of infections, infiltrative processes such as amyloidosis, and a host of other conditions. Progression of HF is caused by repeated damage to the myocardium due to the underlying disease as well as to the persistent activation of pathways that lead to maladaptive remodeling, further injury, and continued deterioration in cardiac function. Although the underlying etiologies of HF vary between geographic regions, virtually all nations have experienced substantial increases in the prevalence of HF over the past several decades. It is estimated that there are well over 26 million patients with HF around the world, and the toll on global health has been considerable.[1–4] Patients experience progressive reductions in functional capacity over time and the quality of life deteriorates as the disease advances. Repeated hospitalizations are common, and most importantly, survival is greatly impaired, with recent registry data from the United States and Europe reporting mortality rates of approximately 50% at 5 years after the onset of disease.[5,6]

Over the past 50 years, we have gained numerous insights into the pathophysiologic mechanisms that cause HF and lead to its progression. This knowledge, in turn, has resulted in the successful development, testing, and approval of new drugs to treat the growing HF population. With the discovery of novel treatments proceeding at a rapid pace, the present moment seems like an opportune time to reflect on recent advances in therapy that are now finding their way into clinical practice. What follows in this review is a description of new drug treatments for HF that have been shown to have favorable effects on clinical outcomes in pivotal phase III randomized clinical trials (RCTs). This overview includes discussions of the background, trial results, and the populations most likely to benefit from specific therapies, some of which have already been recommended in recent guidelines, and consensus recommendations for the management of patients with HF.[7,8]

Classifying patients with HF

Before describing the abnormal pathways that are targets for HF therapies, it is worth considering how patients with HF are classified, as this information is used by guidelines around the world for recommending therapy. For the most part, the classification systems that are being used are based on categorizing patients according to their left ventricular ejection fraction (LVEF).[9,10] This system of classification is based on concepts of pathophysiology, which were prevalent during the 1970s, and the limited diagnostic options for identifying the presence of HF which were available at that time. Classification based on LVEF was formalized during the 1980s by clinical trials that required patients to have a reduced LVEF for enrollment. The rationale for this strategy was based on both the need for the investigators to be confident that patients enrolled in the trials actually had HF and that diseases mimicked aspects of HF (eg,chronic obstructive lung disease, end-stage renal disease) were not responsible for the patients’ signs and symptoms. The requirement for a reduced LVEF for trial entry also served to enrich the population with patients who were at increased risk of clinical events (eg,HF hospitalization or death) so that the efficacy of the investigational treatment could be adequately tested. Thus, patients with LVEF ≤35% were categorized as having HF with reduced LVEF (HFrEF). Recognition of the fact that HF was not confined to individuals whose LVEF was reduced but could develop even in the presence of a preserved LVEF resulted in the additional classification of HF with preserved LVEF (HFpEF). Criteria of an LVEF ≥50% was used to define entry into clinical trials in HFpEF to prevent enrolling patients with significant systolic dysfunction.

A classification system based on LVEF has been useful for defining management of patients with HF for many years. It reflected understanding of HF pathophysiology at the time it was developed and enabled clinical trials to enroll relatively homogeneous groups of patients. Many of these trials tested therapies that are now the cornerstones of treatment for patients with HF. In addition, the relative ease and availability of measuring LVEF made it readily applicable in clinical settings. There are, however, problems with classifying patients based on this approach. Separation of patients into HFrEF and HFpEF categories led to the omission of patients with HF from RCTs if they had mildly reduced LVEF (HFmrEF). As a result, there is little information upon which to base therapeutic recommendations for patients with HFmrEF, and guideline recommendations have been, until recently, mostly silent on how to treat this population. This is a remarkable gap in our knowledge base, considering that patients with HFmrEF make up approximately 15% of the HF population and their mortality risk is similar to that seen in patients with HFrEF and HFpEF.[5,6,11] In addition, the use of LVEF to classify patients no longer seems as appealing as in the past as our understanding and ability to assess HF has evolved. As outlined in Table 1, there is abundant information that echocardiographic measurement of LVEF is subject to considerable variability due to technical limitations including the inability to adequately define the endocardial surface of the left ventricle in some patients, biological factors including loading conditions, presence of ongoing myocardial ischemia, effects of medications, recent exercise, presence of arrhythmias, and recent ingestion of myocardial stimulants and depressants, all of which can alter the measurement of LVEF at a given time. Substantial differences in LVEF have also been noted between echocardiography and other imaging modalities.[12] An important consideration in classifying patients with HF is that cardiac function can change over time due to progression (or regression) of the underlying cardiac disease, and classification based on LVEF at a single time point does not adequately capture the trajectory of change which is an important component of the natural history of the disease.[13–15] Another important and relatively recent problem with classifying HF based on LVEF alone is that there is a substantial and growing body of evidence that several of the cornerstone therapies once considered to be effective only in patients with HFrEF have been shown to benefit patients across the spectrum of LVEF. Consequently, the use of LVEF to classify patients with HF seems outdated, and new classification systems will need to be developed in the future. Ideally, such systems would include information about the etiology of disease, genetic causes or influences, presence of significant comorbidities, prediction of the risk of future events, information about cardiac structure (eg,extent of fibrosis, right ventricular function, individual chamber enlargement), and more accurate measures of contractile function than LVEF.[16]

Table 1 - Factors that influence the measurement of LVEF.
Items Factors
Technical Differences in equipment or sonographer
Definition of endocardial border
Intra- and inter-observer variability
Equation used to measure LVEF
Differences in measuring LVEF between imaging modalities
Physiologic Pressure or volume load on the heart
Heart rate and rhythm
Presence of myocardial ischemia, stunning, or hibernation
Recent exercise or ongoing stress
Pharmacologic Medications that enhance or depress contractile function
Alcohol
Drugs with cardiac depressant or stimulatory effects
Changes in underlying cardiac function Disease progression
Recovery from underlying cause of cardiac disease
Reverse remodeling
LVEF: Left ventricular ejection fraction.

Targets for drug therapy of HF

Until recently, the main focus of drug therapy for HF was blocking maladaptive neurohormonal activation. Enhanced activity of the renin-angiotensin-aldosterone system (RAAS) and sympathetic nervous system (SNS) was identified as being a main factor in the development of HFrEF. Angiotensin II (Ang II) and the catecholamines, the most important mediators of these systems, act synergistically to promote vasoconstriction, retention of salt and water, deposition of fibrous tissue in the heart, kidney, and blood vessels, and ventricular hypertrophy. Moreover, treatment with angiotensin-converting enzyme inhibitors (ACEIs) and later angiotensin receptor blockers (ARBs), mineralocorticoid receptor antagonists (MRAs), and beta-blockers were all shown to improve outcomes in patients with HFrEF.[8,9] Over the past decade, a variety of new targets for treating HF have been identified. Targets for drug therapies used to treat HF are listed in Table 2. An important advance over recent years has been evidence that drugs that were developed to target some of the pathways listed in Table 2 have been shown to improve outcomes in patients with HF across a wide spectrum of LVEF values.

Table 2 - Targets for heart failure drug therapy.
Target pathway Therapy
Renin-angiotensin-aldosterone system ACEIs, ARBs, ARNIs, MRAs
Sympathetic nervous system Beta-blockers
Compensatory peptide systems (natriuretic peptides and others) Neprilysin inhibitors, ARNIs
Vascular tone/oxidative stress Hydralazine/isosorbide dinitrate combination
Elevated heart rate Beta-blockers, ivrabadine, digoxin
Guanylyl cyclase/cGMP Soluble guanylyl cyclase stimulators
Fluid retention/congestion Diuretics
Sodium glucose cotransporter 2 SGLT2 inhibitors
Impaired myocardial contractility Calcitropes, myotropes, mitotropes
ACEI: Angiotensin-converting enzyme inhibitor; ARB: Angiotensin receptor blocker; ARNI: Angiotensin receptor neprilysin inhibitor; cGMP: Cyclic guanylate monophosphate; MRA: Mineralocorticoid receptor antagonist; SGLT2: Sodium glucose cotransporter

Angiotensin receptor neprilysin inhibitors (ARNIs)

As noted above, inhibition of the effects of Ang II by either blocking generation of the peptide using ACEIs or its interaction with the Ang II Type I (AT1) receptor (which is responsible for most of the deleterious effects of Ang II in patients with HF) has proved to be a successful strategy in treating patients with HFrEF.[8,9] There is also information from 1 clinical trial in which candesartan, an ARB, can reduce HF hospitalization in patients with HFpEF.[17] Neurohormonal activation is, however, widespread in the setting of HF. In addition to RAAS and SNS activation, counter-regulatory systems including those that increase release of prostaglandins, bradykinin, apelin, adrenomedullin, and the family of natriuretic peptides (NPs), including atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP), are also stimulated.[18–21] These peptide mediators promote vasodilation and salt and water diuresis, and they have anti-fibrotic and anti-remodeling properties. Overall, these “counter-regulatory” peptides modulate and prevent adverse effects mediated by RAAS and SNS activation. Breakdown of these peptides involves several pathways including neprilysin, a ubiquitous ectoenzyme that is found on the surface of cells throughout the body as well as in the circulation.[22–24] Theoretically, at least, neprilysin inhibition should be beneficial in the setting of HF as it would tend to augment circulating levels of the “counter-regulatory” peptides. However, as neprilysin also recognizes Ang II as a substrate, use of a neprilysin inhibitor alone would have the unfavorable effect of increasing Ang II levels. Consequently, clinical approaches directed at neprilysin inhibition focused on the combination of RAAS and neprilysin inhibition.

Initial attempts at dual RAAS/neprilysin inhibition focused on omapatrilat, a combined ACE and neutral endopeptidase inhibitor.[25] This approach, however, proved problematic due to an increased risk of angioedema, a serious and potentially fatal side effect related to increases in bradykinin levels, a peptide which is degraded by both neprilysin and ACE. Subsequent efforts combining sacubitril, a neprilysin inhibitor, and valsartan, an ARB, into a single molecule (termed an ARNI) proved to be a better approach. The sacubitril/valsartan combination was initially studied in the PARADIGM-HF (Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in HF) trial, a large RCT in which 8441 patients with HFrEF were assigned in a double-blinded manner (after a single-blind run-in period during which the ability to take the optimal dose of each drug was confirmed) to either enalapril 20 mg twice daily or sacubitril/valsartan 97/103 mg twice daily.[26,27] The 97/103 mg dose of sacubitril/valsartan provided the equivalent of 160 mg of valsartan, once the molecule dissolved, thereby allowing comparison between treatment groups receiving optimal dose renin-angiotensin system (RAS) blockade or the combination of RAAS blockade with a neprilysin inhibitor. The study was terminated prematurely based on the recommendation of the PARADIGM-HF Data Safety Monitoring Board which concluded that the ARNI was superior to the ACEI in improving outcomes.[27] The key primary and secondary results of the PARADIGM-HF trial are summarized in Table 3. There was a 20% relative risk reduction in the primary composite endpoint of time to the first event of HF hospitalization or cardiovascular death in patients treated with the ARNI compared to those who were assigned to the ACEI. This effect was equally driven by significant reductions in each of the 2 components in this composite. Significant reductions were also noted for sudden cardiac death, death due to progressive pump failure, and all-cause mortality with the ARNI compared to the ACEI. Quality of life, as assessed by the Kansas City Cardiomyopathy Questionnaire (KCCQ), improved to a greater extent with sacubitril/valsartan than with enalapril. Subgroup analysis demonstrated that the superiority of the ARNI over the ACEI was present in virtually all subgroups of patients including those separated by sex, region, age, comorbid conditions (eg,atrial fibrillation, diabetes), etiology of HF, and background therapies. In addition, the ARNI maintained superiority over the ACEI in patients considered to be at lower risk for clinical events based on the New York Heart Association (NYHA) Class (I and II vs. III and IV) or absence of prior HF hospitalization.

Table 3 - Primary and secondary outcomes of the PARADIGM-HF study.
Endpoint Hazard ratio (95% CI) P
Composite HF hospitalization and cardiovascular mortality* 0.80 (0.73–0.87) <0.001
HF hospitalization 0.79 (0.71–0.89) <0.001
Cardiovascular mortality 0.80 (0.71–0.89) <0.001
All-cause mortality 0.84 (0.76–0.93) <0.001
Sudden death 0.80 (0.68–0.94) 0.008
Worsening HF death 0.79 (0.64–0.98) 0.034
*Primary endpoint. CI: Confidence interval; HF: Heart failure.

Further studies in patients with HFrEF have confirmed the benefits of ARNI therapy and helped provide direction for use of this new class of drugs in clinical practice. The PIONEER-HF study enrolled patients with HFrEF during hospitalization for worsening HF. Patients were randomized after they had stabilized in-hospital to receive either the sacubitril/valsartan combination or enalapril (at doses determined by their systolic blood pressure).[28,29] For entry into the study, patients were required to have an LVEF ≤ 40% over the preceding 6 months and an N-terminal pro-BNP (NT-proBNP) level ≥ 1600 pg/mL or BNP level ≥ 400 pg/mL. Patients were started on the study drug after a period of stabilization during which there was no increase in intravenous diuretics within the previous 6 hours nor administration of intravenous vasodilators or inotropic agents within the previous 24 hours. Whereas all patients in the PARADIGM-HF study had been treated with an ACEI or ARB prior to enrollment, nearly half (48%) of the PIONEER-HF population was naive to drugs in either class at the time of entry. The results showed that over the 8-week duration of the trial, the patients randomized to the sacubitril/valsartan combination experienced a significant improvement in the primary endpoint, which was reduction in NT-proBNP levels from baseline, compared to patients who were randomized to enalapril. As shown in Figure 1, an exploratory composite clinical endpoint of death, HF-readmission, placement of a left ventricular assist device or cardiac transplantation was reduced by 46% in patients who were assigned to the ARNI group as opposed to the ACEI group. Both drugs were tolerated equally well and there was no evidence of an increase in side effects commonly associated with RAS inhibitors, including hypotension, with the use of ARNI compared to ACEI. Despite the relatively small numbers in the study and relatively short duration of treatment, these results provide important information demonstrating the safety and tolerability of sacubitril/valsartan for initiation in patients during an HF hospitalization, regardless of whether they have been previously treated with an ACEI or ARB or were naive to either of these therapies, and they support the possibility that an ARNI is superior to an ACEI or ARB in reducing the risk of future clinical events.

F1
Figure 1::
Serious clinical composite endpoint in the PIONEER-HF trial. Kaplan-Meier (KM) estimates for a composite of death, heart failure re-hospitalization, left ventricular assist device placement or listing for transplant during the 8-week period after randomization to either enalapril or sacubitril/valsartan. CI: Confidence interval; HR: Hazard ratio; NNT: Number needed to treat.

The PROVE-HF study was an open-label trial that included 760 patients with symptomatic HFrEF (LVEF ≤ 40%), all of whom were treated with sacubitril/valsartan.[30,31] The aim of the study was to determine the association of changes in NT-proBNP levels caused by the ARNI with changes in cardiac structure and function. The study results showed that initiation of treatment with sacubitril/valsartan was associated with a rapid, highly significant reduction in NT-proBNP, with the majority of the reduction occurring within the first 2 weeks of therapy. At the end of 1-year follow-up, LVEF had increased on the average by 9.4 points and left ventricular end-diastolic volume index and end-systolic volume index (LVESVi) had decreased by 12.25 and 15.29 mL/m2, respectively. As shown in Figure 2, patients with the largest reduction in NT-proBNP and LVESVi by 6 months had the lowest rates of death or HF hospitalization at 12 months. The findings of PROVE-HF are consistent with reversal of maladaptive remodeling being a plausible mechanism for the clinical benefits of sacubitril/valsartan in patients with HFrEF.

F2
Figure 2::
Association between reduction in NT-proBNP levels and LVESVi by 6 months and reduction in the composite endpoint of death and HF hospitalization at 12 months. Patients with the largest reduction in NT-proBNP and LVESVi from baseline by 6 months experienced the lowest rates of subsequent death or hospitalization for HF at 12 months after initiating treatment with sacubitril/valsartan. The median value for reduction in Log2-NT-proBNP at 6 months was −35% from baseline. The median value for reduction in LVESVi at 6 months was −14.1% from baseline. HF: Heart failure; LVESVi: Left ventricular end-systolic volume index; NT-proBNP: N-terminal pro-B-type natriuretic peptide.

The results of the trials described above assessing the effects of sacubitril/valsartan on clinical outcomes in patients with HFrEF have had a strong impact on guideline recommendations. Whereas in the past, either an ACEI or ARB was the preferred approach for blocking RAS activation, use of an ARNI has now been added as a possibility. In the 2021 Update to the 2017 American College of Cardiology (ACC) Expert Consensus Decision Pathway for Optimization of Heart Failure Treatment, all 3 classes of drugs (ie,ACEIs, ARBs, and ARNIs), along with beta-blockers and MRAs, are listed as the cornerstones of medical therapy for patients with Stage C HFrEF. The Update further states that an ARNI is now the preferred approach with either an ACEI or ARB considered when ARNI administration is not possible. In addition, initiation of an ACEI or an ARB prior to switching is no longer required and patients can be started directly on an ARNI as the initial therapy. Similarly, the 2021 European Society of Cardiology (ESC) Guidelines for the treatment of HF give the use of an ARNI a Class I recommendation stating that sacubitril/valsartan is recommended as a replacement for an ACEI in patients with HFrEF who remain symptomatic to reduce the risk of HF hospitalization and death, and that de novo initiation without prior initiation of an ACEi or ARB may be considered.

While PARADIGM-HF, PIONEER-HF, and PROVE-HF were all performed in patients with HFrEF, PARAGON-HF sought to determine the efficacy of sacubitril/valsartan in patients with HFpEF, a population for which effective disease modifying therapies have been lacking. In PARAGON-HF, symptomatic patients with LVEF ≥ 45%, elevated NP-proBNP levels, and evidence of structural heart disease were randomly assigned to receive either the sacubitril/valsartan combination up-titrated to a dose of 97/103 mg twice daily or valsartan alone at a dose up-titrated to 160 mg twice daily.[32,33] As in the earlier PARADIGM-HF trial, randomization of the 4822 patients to one of these treatments in PARAGON-HF was carried out in a double-blind manner following a single-blinded run-in period designed to ensure tolerability of both drugs at their optimal dose. Unlike PARADIGM-HF, the comparator drug in PARAGON-HF was an ARB as opposed to an ACEI. The primary composite endpoints were total HF hospitalizations and death due to cardiovascular causes. Overall, there were 894 primary events in 526 patients assigned to the ARNI and 1009 primary events in the 557 patients who received the ARB. The risk reduction in composite events of 13% (P = 0.06) was driven predominantly by a 15% risk reduction in HF hospitalizations in the ARNI-treated patients (P = 0.05). Patients treated with sacubitril/valsartan were also more likely to improve NYHA Class and less likely to experience deterioration in renal function than those who were treated with valsartan. Patients in the sacubitril/valsartan group had a higher incidence of hypotension and angioedema and a lower incidence of hyperkalemia than those in the valsartan alone group. Analysis of pre-specified subgroups was consistent with heterogeneity in effects between the groups, with significantly greater reductions in the primary endpoint with the ARNI compared to the ARB noted in patients with LVEF ≤ the median value of 57% and in female patients.

A post hoc analysis that combined the results of PARADIGM-HF and PARAGON-HF has helped clarify the role of sacubitril/valsartan in managing patients with HF across the spectrum of LVEF.[34] Since PARADIGM-HF included patients with LVEF < 40% and PARAGON-HF included patients with a LVEF > 45%, both studies compared the ARNI to a RAS blocking agent, and the 2 trials had similar primary and secondary endpoints, there was an opportunity to assess how sacubitril/valsartan compared to the RAS blocker over a wide range of LVEF. The results of this analysis, demonstrate that the ARNI did better than standard RAS inhibition not only in HFrEF patients but also in patients with HFmrEF and in those with HFpEF whose LVEF was in the lower (but still normal) range.

The results of the studies described above have now begun to influence guideline recommendations for patients with HFmrEF and HFpEF. The 2021 ESC guidelines recommend that sacubitril/valsartan may be considered for patients with HFmrEF to reduce the risk of HF hospitalization and death. While these guidelines do not yet recognize a role for this approach in patients with HFpEF, they acknowledge that the field is evolving and that the recommendations for managing HFpEF may need to incorporate the use of an ARNI in the future. A notable indication that this is likely to happen is the recent US Food and Drug Administration (FDA) decision to expand the indications for sacubitril/valsartan to reduce the risk of cardiovascular death and hospitalization in adult patients with HF. While the new indication notes that the benefits are more clearly evident in patients with LVEF below normal, there is no specific recommendation for the use of the drug based on a particular number. The FDA recognized that LVEF is a variable measure and the revised indication for sacubitril/valsartan concludes by stating that clinical judgment should be used in deciding who to treat. This recommendation both acknowledges problems that are inherent in the use of LVEF alone for making decisions that were described earlier in this article and also evidence that the superiority of ARNI therapy over standard RAS therapies extends beyond the arbitrary cutoff used to classify patients as having HFrEF.

Sodium glucose cotransporter 2 (SGLT2) inhibitors

Patients with HF often have co-existent diabetes, which may be both a cause of the underlying cardiac disease and a condition that complicates management.[35–37] In the past, therapies that focused on glycemic control had either neutral effects on cardiovascular outcomes or were associated with harm.[38,39] Drugs that are SGLT2 inhibitors function as hypoglycemic agents based on their ability to block glucose reabsorption by the SGLT2 receptor, which is expressed predominantly in the initial segment of the proximal convoluted tubules of the kidneys, where it is responsible for approximately 90% glucose reabsorption.[40] Blockade of the SGLT2 receptor leads to increased glucose loss in the urine. The SGLT2 inhibitors have also been shown to produce weight loss and loss of adipose tissue, both of which would be expected to favorably affect diabetic patients.

The use of SGLT2 inhibitors is a relatively recent approach for treating patients with diabetes. Initial clinical trials that assessed the effects of SGLT2 inhibitors in patients with type 2 diabetes (T2D) demonstrated significant benefits on cardiovascular and renal outcomes.[41] Results of the EMPA-REG,[42] CANVAS,[43] and DECLARE-TIMI 58 trials[44] using empagliflozin, canagliflozin, and dapagliflozin, respectively, in patients with T2D demonstrated a substantial reduction in mortality, progression of renal disease, and HF events with these agents [Figure 3]. Of note was that a reduction in the HF hospitalization event rate was seen regardless of whether or not patients had a prior history of HF at the time of entry into the study. These findings suggested that beyond their ability to control blood glucose levels, SGLT2 inhibitors might have additional effects on the heart, kidney, and elsewhere that could be of particular benefit to patients with HF, including (1) promotion of osmotic dieresis; (2) direct effects on key regulatory pathways in the heart; (3) reduction in SNS overdrive; (4) improved myocardial efficiency; (5) stimulation of erythropoietin production in the kidneys; (6) anti-inflammatory properties; (7) reduction in oxidative stress; (8) blood pressure lowering; (9) diminished vascular stiffness; and (10) weight loss.

F3
Figure 3::
Meta-analysis of the association of SGLT2 inhibitors with cardiovascular and kidney outcomes in patients with type 2 diabetes. (A) Overall cardiovascular outcomes; (B) Overall kidney outcomes. SGLT2: Sodium glucose cotransporter 2. Adapted from McGuire et al.[ 41 ]

The insights gained from trials that assessed SGLT2 inhibitors in patients with T2D led to a remarkable series of studies that addressed whether these drugs could improve outcomes in patients with HF regardless of whether or not they had T2D. Studies using empagliflozin in patients with either reduced LVEF (EMPORER Reduced)[45,46] or preserved LVEF (EMPORER Preserved),[47,48] dapagliflozin in patients with HFrEF (DAPA-HF),[49,50] and sotagliflozin (SOLOIST-WHF)[51] in patients hospitalized for worsening HF have all now demonstrated that this is the case. The results of these studies are summarized in Table 4.[45–51] Each of the trials successfully reduced the risk of their primary efficacy endpoint, which was a composite of cardiovascular mortality and HF events. In the EMPORER trials and in DAPA-HF, SGLT2 inhibitors significantly reduced the risk of worsening HF events. In the DAPA-HF study, dapagliflozin was associated with a reduction in cardiovascular and all-cause mortality, while in the EMPORER Reduced trial, empagliflozin was associated with a reduction in the annual rate of decline of the estimated glomerular filtration rate (eGFR) compared to patients randomized to placebo. In each of the trials, the beneficial effects of SGLT2 inhibition were not dependent on whether patients had a history of diabetes. Both diabetics and non-diabetics experienced similar improvements in outcome in all of these studies. Furthermore, subgroup analysis demonstrated that SGLT2 inhibitors were effective across a broad spectrum of the HF population without regard to age, LVEF, NYHA class, renal function, presence of comorbidities, and region from which patients were recruited into the trial. Of particular note is that improved outcomes with SGLT2 inhibitors persisted when patients were taking other guideline-recommended therapies (eg,ANRIs and MRAs) that have been shown to improve outcomes in patients with HF, indicating that their effects are additive and that these drugs should be used in combination. Side effects associated with the use of SGLT2 inhibitors include hypotension, urinary tract infection, genital mycotic infections (ie,Fournier gangrene), diarrhea, bone fractures, and adverse events leading to limb amputation, but these are uncommon.

Table 4 - Studies of SGLT2 inhibitors in patients with heart failure.
Trial Agent Patient number Status Entry LVEF criteria T2D on entry (%) Primary
endpoint
Secondary cardiac Renal function
EMPORER Reduced[45,46] Empagliflozin 3730 NYHA Class II–IV <40% 50 CV death or HF hospitalization (HR: 0.75; 95% CI: 0.65–0.86; P < 0.001) Number of HF hospitalizations (HR: 0.70; 95% CI: 0.58–0.85; P < 0.001) Annual rate of decline in eGFR (−0.55 vs. −2.28 mL/(min·1.73 m2) BSA/year; P < 0.001);
Composite renal outcome (chronic dialysis or renal transplantation or a profound, sustained reduction in the eGFR) (1.6% vs. 3.1%; HR: 0.50; 95% CI: 0.32–0.77)
EMPORER Preserved[47,48] Empagliflozin 5988 NYHA Class II–IV >40% 49 CV or HF hospitalization (HR: 0.79; 95% CI: 0.69–0.90; P < 0.001) Number of HF hospitalizations (HR: 0.73; 95% CI: 0.61–0.88; P < 0.001) Annual rate of decline in eGFR (−1.25 vs. −2.62 ml/(min·1.73 m2) BSA/year P < 0.001)
DAPA-HF[49,50] Dapagliflozin 4744 NYHA Class II–IV <40% 41 CV death or worsening HF event (HR: 0.74; 95% CI: 0.65–0.85; P < 0.001) First worsening HF event (HR: 0.70; 95% CI: 0.59–0.83);
CV death (HR: 0.82; 95% CI:0.69–0.98);
All-cause death (HR: 0.83; 95% CI: 0.71–0.97)
Change in KCCQ (6.1 vs. 3.3; HR: 1.18; 95% CI: 1.11–1.26; P < 0.001)
SOLOIST-WHF[51] * Sotagliflozin 1222 Recently hospitalized for worsening HF None Required for entry CV death and HF events (HR: 0.67; 95% CI: 0.52–0.85; P < 0.001) HF events (HR: 0.64; 95% CI: 0.49–0.83; P < 0.001) None
*Trial terminated prematurely by the sponsor due to lack of funding. BSA: Body surface area; CI: Confidence intervals; CV: Cardiovascular; eGFR: Estimated glomerular filtration rate; HF: Heart failure; HR: Hazard ratio; KCCQ: Kansas City Cardiomyopathy Questionnaire; LVEF: Left ventricular ejection fraction; NYHA: New York Heart Association; SGLT2: Sodium glucose cotransporter 2; T2D: Type 2 diabetes.

The rapid appearance of the clinical trials outlined above over the past few years has resulted in the inclusion of SGLT2 inhibitors in guidelines for the management of HF. In response to the results of Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients trial (EMPA-REG OUTCOME), the 2016 ESC Guidelines for the Diagnosis and Treatment of Acute and Chronic Heart Failure gave a Class IIa recommendation at the level of evidence (LOE) B to empagliflozin, indicating that it should be considered in patients with T2D to prevent or delay the onset of HF and prolong life.[52] By 2021, with the appearance of the trials summarized in Table 4, the ESC Guidelines provided a Class I recommendation, based on LOE A, for the use of empagliflozin and dapagliflozin to reduce the risk of HF hospitalization and death in all patients with symptomatic HF (ie,NYHA Class II–IV) and LVEF < 40%. The 2021 Update to the 2017 ACC Expert Consensus Decision Pathway for Optimization of Heart Failure Treatment recommends that either empagliflozin or dapagliflozin be added to an ACEI, ARB, or ARNI (preferred), and evidence-based beta-blocker and diuretics (as needed) in patients with symptomatic HF. The document goes on to recommend that patients have eGFR > 20 mL/(min·1.73 m2) for empagliflozin and > 30 mL/(min·1.73m2) for dapagliflozin, based on clinical trial entry criteria.

Guideline recommendations for SGLT2 inhibitors in the future are almost certain to expand after the results of the EMPORER Preserved Trial. As noted in earlier comments in this article, difficulties in classifying patients according to LVEF and the ability of drugs such as ARNIs and SGLT2 inhibitors to improve outcomes across a wide spectrum of the HF population have resulted in less emphasis on LVEF-based classifications for therapeutic recommendations. Further evidence regarding the safety and efficacy of this class of drugs in patients with HFpEF from ongoing trials such as DELIVER with dapagliflozin will determine if the recommendations will include all patients with HF regardless of their LVEF.[53]

Soluble guanylate cyclase stimulators

Vericiguat is a novel oral soluble guanylate cyclase stimulator that works by enhancing the cyclic guanosine monophosphate (GMP) pathway through direct stimulation of soluble guanylate cyclase through a binding site independent of nitric oxide (NO); additionally, it sensitizes soluble guanylate cyclase to endogenous NO by stabilizing NO binding to the binding site.[54–56] The guanylate cyclase pathway is an important regulator of cardiovascular function. In the setting of HF, a combination of endothelial cell dysfunction and generation of reactive oxygen species reduces NO bioavailability. A deficiency in NO, in turn, reduces the production of cyclic GMP. Unlike nitrate preparations, vericiguat does not cause oxidative stress or induce endothelin-1 nor is it associated with drug tolerance. Vericiguat was initially tested in a phase 2b dose-finding trial involving patients with worsening high-risk HF and a reduced ejection fraction. Although the drug failed to reach its primary endpoint of a reduction in the level of NT-proBNP, there was evidence suggesting a dose effect, with higher doses associated with greater reductions in the biomarker.[57] Rates of adverse events were similar between the 2 study groups suggesting that it could be administered safely.

The VICTORIA study assessed the efficacy and safety of vericiguat in 5050 patients with chronic symptomatic HF, LVEF <45%, and recently decompensated HF.[58] The primary outcome was a composite of death from cardiovascular causes or first hospitalization for HF. As a result of the high-risk profile of this population, clinical events occurred early and the study reached the pre-defined number of endpoint events after a mean patient follow-up period of only 10.8 months, which was considerably shorter than other recent trials of drugs for treating HF. The incidence of the primary endpoint of death from cardiovascular causes or hospitalization for HF was lower among those who received vericiguat than among those who received placebo (hazard ratio (HR): 0.90; 95% confidence interval (CI): 0.82–0.98; P = 0.02); however, there was no reduction in either all-cause or cardiovascular mortality. Anemia occurred in the VICTORIA trial in 10% of patients who received vericiguat compared to 7% who received placebo. Hypotension was equally common in the groups and there were no significant differences in the rates of symptomatic hypotension or syncope in the groups. Of note is that subgroup analysis demonstrated that vericiguat did not reduce the primary endpoint in patients with baseline entry NT-proBNP in the highest quartile (>5314 pg/mL). In contrast, the drug was associated with a 23% risk reduction in patients with levels < 4000 pg/mL.[59] These findings raise the possibility that there is a level of severity of HF (manifest by extremely high levels of NPs) beyond which the ability of vericiguat to favorably affect outcomes may be diminished. Regardless, based on the results of VICTORIA, the 2021 ESC Guidelines provide a Class IIb recommendation that vericiguat may be considered, in addition to standard therapy for HFrEF, to reduce the risk of cardiovascular mortality and hospitalization in this population.

Omecamtiv mecarbil

Inotropic agents currently being used for treating depressed systolic function, such as milrinone, dobutamine, and levosimendan have been termed calcitropes, since their mechanism of action involves modulating calcium signaling in the heart. Although these agents have been useful in providing short-term support of patients with profound depression in cardiac pump function or cardiogenic shock, their use over extended periods of time has been associated with poor outcomes.[60] Newer classes of drugs that improve cardiac contractility have novel mechanisms of action including myotropes, which affect molecular motor and scaffolding, and mitotropes, which influence energetics.[61]

Omecamtiv mecarbil is the first of a new class of myotropes.[61–64] It works to improve cardiac function by stabilizing the pre-power stroke state of myosin, thereby enabling more myosin heads to undergo a power stroke during systole. In a manner akin to having multiple hands available to pull on a rope, the availability of an increased number of myosin heads to bind to the actin filaments and undergo a power stroke produces more force during each cycle of cardiac contraction. By increasing the number of hands (eg,myosin heads) that can grasp and pull the rope (the actin filament), more force is produced during each contractile cycle. While this improves myocardial contractility, sustained interaction between the myofilaments prolongs systolic ejection and shortens the time available for diastolic filling. Since coronary artery flow takes place predominantly during diastole when the left ventricle is relaxed and intracavitary pressures are low, a reduction in diastolic filling time could decrease myocardial perfusion and increase the likelihood of myocardial ischemia. Preliminary studies helped define doses of omecamtiv mecarbil that would produce blood levels that improved myocardial contractility without clinically meaningful reductions in coronary blood flow. To address this issue, pharmacokinetic guidance was used to help define safe and tolerable doses of omecamtiv to use in clinical practice.[65] In a study of patients with ischemic cardiomyopathy and angina, a population considered to be particularly vulnerable to myocardial ischemia, doses of omecamtiv mecarbil producing plasma concentrations previously shown to increase systolic function were well tolerated during exercise, and there was no indication that treatment increased the likelihood of myocardial ischemia in this high-risk population.[66]

A pilot study, COSMIC-HF, randomized patients with HFrEF and LVEF ≤ 40% to receive 25 mg oral omecamtiv mecarbil twice daily (fixed-dose group), 25 mg twice daily titrated to 50 mg twice daily guided by pharmacokinetics (pharmacokinetic-titration group), or placebo for 20 weeks to determine the maximum concentration of omecamtiv mecarbil in plasma (primary endpoint) and changes in cardiac function and ventricular diameter.[67] The results showed that the mean blood level after 12 weeks of treatment was (200 ± 71) ng/mL in a fixed-dose group and (318 ± 129) ng/mL in the pharmacokinetic-titration group. Patients who received omecamtiv using pharmacokinetic guidance demonstrated significant improvements in systolic ejection, left ventricular stroke volume, left ventricular systolic and diastolic diameters, heart rate, and NT-proBNP levels compared to those who received placebo. These findings demonstrated that pharmacokinetic-guided dosing of omecamtiv mecarbil could be used in clinical practice to achieve plasma concentrations of the drug that are associated with improved cardiac function and decreased ventricular diameter. The results of COSMIC-HF set the stage for further study of this agent, including a pivotal phase III RCT.

In the phase III GALACTIC-HF trial, 8256 patients with symptomatic chronic HF and LVEF ≤ 35% were enrolled from both in- and out-patient settings and were randomized to pharmacokinetic-guided doses of 25, 37.5, and 50 mg of omecamtiv mecarbil. Patients were then followed over a median of 21.8 months.[68,69] Risk for the composite primary outcome of the first HF event or cardiovascular death was reduced in patients randomized to omecamtiv mecarbil compared to placebo (HR: 0.92; 95% CI: 0.86–0.99; P = 0.03) due to predominantly a reduction in HF events without a significant impact on mortality. There were no significant differences in total score from the KCCQ, but omecamtiv mecarbil treatment was associated with a 10% reduction in levels of NT-proBNP. As in previous studies, small increases in the cardiac troponin I level were seen but these were not accompanied by an increase in ventricular arrhythmia or ischemic events. Further post hoc analysis of the results of GALACTIC-HF was performed in the 2258 (27.4%) patients with severe HF defined as NYHA class III to IV, LVEF ≤ 30%, and hospitalization for HF within the previous 6 months.[70] The results demonstrated a significantly better effect of the drug on the primary study outcome than in patients not meeting criteria for severe HF, a finding that suggests greater utility of this agent in HF patients with more advanced disease. Further analysis of the GALACTIC-HF study is ongoing and recommendations for the use of omecamtiv in future guidelines are anticipated.

Conclusion

The novel therapies described in this article provide new opportunities for improving outcomes in patients with HF. As more information about their use becomes available, the place of ARNIs, SGLT2 inhibitors, soluble guanylate cyclase stimulation, and omecamtiv mecarbil in the HF guidelines and in clinical practice will become clear. Of particular importance is that the benefits of ARNI and SGLT2 inhibitors extend beyond patients with HFrEF, indicating that the traditional ways of classifying patients with HF will need to change in the future as additional agents that target more universal pathways in the HF population become available.

Funding

None.

Conflicts of interest

None.

Editor note: Barry H. Greenberg is an Editorial Board Member of Cardiology Discovery. The article was subject to the journal’s standard procedures, with peer review handled independently of this editor and his research groups.

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Keywords:

Heart failure; Left ventricular ejection fraction: Angiotensin receptor neprilysin inhibitor; Sodium glucose cotransporter 2; Vericiguat; Omecamtiv mecarbil

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