Worsening heart failure and current management

Reviews

Worsening Heart Failure and Current Management Strategies

with a Focus on Soluble Guanylate Cyclase Stimulators

 

Khawaja M. Talha¹, Stephen J. Greene², Vijay K. Chopra³, Javed Butler^1,4
1Department of Medicine, University of Mississippi Medical Center, Jackson, MS, ²Division of Cardiology, Department of Medicine, Duke University Hospital, Durham,
NC, USA, ³Department of Cardiology, Medanta Medicity to Max Super Specialty Hospital, New Delhi, Delhi, India, ⁴Baylor Scott & White Research Institute, Baylor
University Medical Center, Dallas, TX, USA

Abstract

Worsening heart failure (WHF) represents a critical point in the disease trajectory of heart failure (HF) patients and significantly affects prognosis negatively. WHF is understood to be defined as worsening signs and symptoms of HF requiring intensification of therapies, including escalation of oral diuretics, initiation of intravenous diuretics at an urgent care center or the emergency room, or requiring hospitalization for close monitoring. Currently, no international HF society guidelines provide a standard definition or a therapeutic approach to the management of WHF. Recent evidence suggests that rapid in-hospital initiation of guideline-directed medical therapy and post-discharge optimization with close surveillance led to improved outcomes. Moreover, the role of intravenous diuretics in treating acute decongestion has been well defined, and addition of carbonic anhydrase inhibitors and sodium-glucose cotransporter-2 inhibitors has shown to augment diuretic efficacy leading to effective decongestion and possibly early discharge. Soluble guanylate cyclase stimulator, vericiguat, has shown promise in the management of HF patients with a reduced ejection fraction after a recent WHF event in addition to optimized medical therapy. In this review, we discuss the evolving definition of WHF, its precipitants and importance, and the current paradigm of management strategies with a focus on soluble guanylate cyclase stimulators.

Keywords: Management of heart failure, soluble guanylyl cyclase stimulators, worsening heart failure
 

Heart failure (HF) affects approximately 60 million people globally^[1] and is associated with significant mortality that has remained high, despite the development of numerous disease- modifying therapies. Therapies are usually directed toward prevention of death and “worsening heart failure” (WHF), a term that has gained traction recently due to its impact on prognosis.^[2] WHF is described as an event when patients experience worsening of signs and symptoms of HF from a baseline despite being on stable medical therapy and symptom stabilization in the past. The term was widely considered synonymous with a HF hospitalization; however, many patients may undergo escalation of oral therapies, or administration of intravenous medications in an outpatient setting or at an emergency room, who also suffer significantly poor prognosis. A WHF event is considered a vulnerable point in an individual’s HF journey when, if appropriate measures are not taken, patients experience steep stepwise decline in clinical status and are at an incremental risk of adverse clinical outcomes [Figure 1]. Unfortunately, there currently exist several gaps in evidence with regards to the definition, diagnostic approach, and management of WHF.

DEFINING WORSENING HEART FAILURE

There is currently no standard definition of WHF, and the term has been loosely
associated with worsening signs and symptoms of HF requiring escalation of

Submitted: 27-01-2023 Revised: 08-02-2023
Accepted: 30-01-2023 Published: 11-04-2023

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How to cite this article: Talha KM, Greene SJ, Chopra VK, Butler J. Worsening heart failure and
current management strategies with a focus on soluble guanylate cyclase stimulators. Heart
Failure Journal of India 2023;1:5-11.

 

Talha, et al.: Worsening heart failure and current management strategies

Figure 1: An illustration summarizing the definition, prognostic significance, precipitants,
and therapeutic approach to worsening heart failure

therapy. The escalation can occur both in an in-patient hospitalized setting or at an urgent outpatient setting or emergency room visit. Hospitalization is considered more significant due to a high rate of readmission and mortality associated with such an event^[3]; however, evidence shows that an urgent visit for intravenous diuretics is associated with a similar increase in risk of death compared to hospitalizations.^[4,5] A post hoc analysis from the Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure (DAPA-HF) trial^[6] reported that the risk of death is higher in patients who receive urgent outpatient intravenous diuretic escalation by threefold, but is much more elevated in patients hospitalized for HF (sixfold). Nevertheless, both hospitalization and urgent care events appear to increase the risk of mortality and are included in the definition of WHF. Currently, WHF is understood to be defined as worsening signs and symptoms of HF in patients on optimal medical therapy, with or without elevated serum natriuretic peptides requiring (1) escalation of outpatient oral diuretic therapy, (2) intravenous diuretic therapy at an outpatient or emergency care setting, and (3) hospitalization for decongestion, treatment of precipitants, and close monitoring of hemodynamic status. 

International society HF guidelines did not address WHF as an independent entity until recently; the European society of cardiology HF guidelines 2021^[7] identified WHF as a separate entity but did not provide a definition or a specific recommendation for management. The American college of cardiology/American heart association/heart failure society of America 2022 guidelines^[8] recognized WHF as part of the progression of disease in patients with stage C HF, although specific recommendations for a therapeutic approach were not included. WHF is better defined in large, randomized HF clinical trials, as it is used as an inclusion criterion to enroll high-risk patients and is also adjudicated as a study end point to assess treatment efficacy.^[9] No current guidelines exist for the management of WHF events.

PRECIPITANTS OF WORSENING HEART FAILURE

A WHF event may be precipitated by a cardiovascular or noncardiovascular event, and it is imperative to promptly identify these precipitants. An analysis of patients hospitalized for WHF in the International Registry to Assess Medical Practice with Longitudinal Observation for Treatment of Heart Failure (REPORT-HF) registry^[10] revealed that the most common trigger for WHF was pneumonia/other infection (~11%), followed by acute coronary syndrome (~9%), arrhythmia (~9%), hypertension (~5%), and worsening renal function (~3%). All these conditions are commonly observed in clinical practice but may be missed when evaluating patients with WHF in the hospital, as the initial focus is usually to treat decongestion rather than the underlying cause of worsening. However, in most cases (approximately 50% in REPORT-HF), there was no identifiable trigger, meaning that a WHF event was an indicator of progression of disease.

Talha, et al.: Worsening heart failure and current management strategies


 

WORSENING HEART FAILURE NOT REQUIRING HOSPITALIZATION

There are varying degrees of WHF events that are addressed at different levels of healthcare encounters. The most severe form of WHF requires hospitalization for close monitoring requiring appropriate escalation of medical therapy and optimization of background guideline-directed medical therapy. However, a less known and researched entity is WHF that does not require hospitalization and can be addressed by the administration of intravenous diuretics at an urgent outpatient center or an emergency room, or by escalation of oral diuretic therapy. As discussed earlier, patients not requiring hospitalization for WHF also have a poor prognosis. Post hoc analyses from the Multicenter Automatic Defibrillator Implantation Trial–Cardiac Resynchronization Therapy (MADIT-CRT)^[4] reported that patients with a nonfatal WHF requiring outpatient management had a similar risk of death compared to those that had a WHF event requiring hospital stay (15.8 vs. 18.5 per 100 patient-years) over a median follow-up of 3.3 years. Another analysis from the Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure (PARADIGM-HF) trial^[5] reported that patients who were treated with the outpatient intensification of therapy or had an emergency room visit had a similar risk of death compared to patients that required hospitalization. Hence, these events have prognostic significance and are formally included as end points in large, randomized HF clinical trials. The only exception is that of the escalation of oral diuretic therapy, as this entity is still not adequately well characterized to be formally included as a study end point in clinical trials; however, it does hold prognostic significance in routine care. 

MANAGEMENT OF WORSENING HEART FAILURE EVENTS

The development of contemporary medical therapy has been focused toward not only reducing mortality but also toward decreasing the frequency of WHF events and improving patient-reported outcomes. Foundational therapy for HF with reduced ejection fraction includes beta-blockers, angiotensin receptor and neprilysin inhibitors, mineralocorticoid receptor antagonists, and sodium glucose cotransporter-2 inhibitors, which have shown to significantly reduce WHF events [Table 1].

OPTIMIZATION OF GUIDELINE-DIRECTED MEDICAL THERAPY

Multiple experts have recommended rapid simultaneous initiation of HF medications during hospitalization with close follow-up after discharge to achieve target dosing, to prevent frequent readmissions and avoid delay in providing a mortality benefit.^[11,12] The Safety, tolerability, and efficacy of up-titration of guideline- directed medical therapies for acute heart failure (STRONG-HF) trial[13] was a recent multinational randomized controlled study that evaluated the efficacy of an aggressive, intensive approach to in-hospital initiation and post-discharge titration of GDMT following an episode of WHF event necessitating hospitalization. The prespecified protocol in the intensive care group included a mandatory 2-week post-discharge follow-up with at least 4 outpatient visits over 2 months including routine laboratory assessment and clinical status evaluation, with additional visits 1 week after dose modifications. At 90 days, a higher proportion of patients were found to be on GDMT uptitrated to recommended doses (renin-angiotensin antagonists 55% vs. 2%; beta-blockers 49% vs. 4%; and MRA 84% vs. 46%). At 180 days, a significant reduction in HF hospitalizations or all-cause death was reported in the intensive care group (15.5% vs 23.3%, adjusted risk difference 8.1%; risk ratio 0.66 [95% CI 0.50, 0.86]). Moreover, the intensive care strategy was reported to be safe with no significant differences in serious adverse events between the usual and intensive care groups. 

APPROACH TO DECONGESTIVE THERAPIES

Intravenous loop diuretics are the mainstay of treating congestion in patients with WHF; however, a standard approach to dosing had not been established until 2011. The Diuretic Optimization Strategies Evaluation (DOSE) trial^[14] evaluated the efficacy of a high dose of intravenous diuretics (2.5 times oral home dose) in 308 patients hospitalized for HF, compared to a low-dose strategy. The trial did not meet any of the primary endpoints of global assessment of symptoms and a change in creatinine after 72 h; however, the high dose strategy caused significantly reduced dyspnea, higher net volume and weight loss, had a higher proportion of patients free of congestion, and had a greater reduction in serum natriuretic peptides. Guidelines also recommend the addition of another class of diuretic to augment the efficacy of loop diuretics for rapid and successful resolution of a volume overload state in patients that do not respond well to initial intravenous loop diuretic therapy. The most used strategy in hospitals is that of the addition of a thiazide diuretic, e.g., metolazone, 30 minutes prior to dosing of loop diuretics, which has been shown previously to allow more effective decongestion, compared to a loop diuretic only strategy. Recently, the Acetazolamide in Decompensated heart failure with Volume Overload (ADVOR) trial^[15] evaluated the use of carbonic anhydrase inhibitor (acetazolamide) in potentiating the effects of intravenous loop diuretics in 519 patients hospitalized for HF. The probability of successful decongestion was higher at day 3 in the combination therapy group (42%) compared to only intravenous loop diuretic therapy (30%). This decongestive effect persisted throughout hospitalization with a better decongested

COMPOSE: BAY58-2667 Dose Finding Trial Investigating Fixed Doses in Patients With Acute
Decompensated Chronic Congestive Heart Failure, LEPHT: Left Ventricular Systolic
Dysfunction Associated With Pulmonary Hypertension Riociguat Trial, SOCRATES-REDUCED:
Soluble Guanylate Cyclase Stimulator in Heart Failure with Reduced Ejection Fraction Study,
VICTORIA: Clinical Outcome Predictions for the VerICiguaT Global Study in Subjects With
Heart Failure With Reduced Ejection Fraction, SOCRATES-PRESERVED: Soluble Guanylate
Cyclase Stimulator in Heart Failure Patients with Preserved Ejection Fraction, VITALITY-
HFpEF: Evaluate the Efficacy and Safety of the Oral sGC Stimulator Vericiguat to Improve
Physical Functioning in Daily Living Activities of Patients With Heart Failure and Preserved
Ejection Fraction, LVEF: left ventricular ejection fraction, KCCQ: Kansas City
Cardiomyopathy Questionnaire, PLS: physical limitation score, mPAP: mean pulmonary
artery pressure, PCWP: pulmonary capillary wedge pressure, NT-proBNP: N-terminal
propeptide brain natriuretic peptide

state at discharge and a lower median length of hospital stay with combination therapy.

SGLT-2 inhibitors have intrinsic diuretic activity and their concomitant use with intravenous diuretics has been found to improve diuretic efficacy and clinical outcomes in patients with WHF. The Effects of Empagliflozin on Clinical Outcomes in Patients With Acute Decompensated Heart Failure (EMPA-RESPONSE-AHF) trial^[16] found a significant increase in urinary output with empagliflozin compared to placebo in patients hospitalized for acute HF and caused a significant reduction in the composite end point of death and HF hospitalizations at 60 days. SGLT-2 inhibitors was also evaluated for efficacy in patients hospitalized for HF in the SGLT2 inhibitor empagliflozin in patients hospitalized for acute heart failure (EMPULSE) trial.[^17] Patients were randomized to study drugs at a median of 3 days following the date of admission. The trial met the primary end point of clinical benefit (defined as a hierarchical composite outcome of allcause death, WHF event rate, and improvement in quality-of-life scores) at 90 days with empagliflozin compared to placebo. Moreover, patients in the empagliflozin group had a greater reduction in serum N-terminal propetide brain natriuretic peptide (NT-proBNP) from baseline and augmented diuretic efficiency leading to greater weight loss at day 15 and day 30 of randomization compared to placebo. Sotagliflozin, a nonselective SGLT-1 and SGLT-2 inhibitor, was also found to reduce the occurrence of cardiovascular deaths and WHF events in patients with HF and type 2 diabetes when prescribed before or shortly after discharge following HF hospitalization in the Effect of Sotagliflozin on Cardiovascular Events in Patients with Type 2 Diabetes Post Worsening Heart Failure (SOLOIST-WHF) trial^[18]; however, the drug is not currently commercially available for use.

SOLUBLE GUANYLATE CYCLASE STIMUATORS IN WORSENING HEART FAILURE

The Nitric oxide-soluble guanylate cyclase-cyclic guanosine mono-phosphate pathway has been long studied as a therapeutic target for HF. The sGC is majorly located on myocardial cells and binds to nitric oxide to catalyze conversion of guanosine triphosphate to cyclic guanosine mono-phosphate, which is a key regulator of cardiac performance and endothelial function.^[19] Isosorbide dinitrate and hydralazine are limited in their therapeutic efficacy to effect this pathway due to the development of high rates of tolerance, intolerance in terms of achieving target doses, and the fact that the combination has been shown to be efficacious mainly in the African-American population.^[20] HF is characterized by a heightened inflammatory state along with generalized endothelial dysfunction, which reduces the availability of nitric oxide in systemic circulation, and hence reduces cyclic guanosine mono-phosphate synthesis.^[21] This, in turn, leads to vascular dysfunction which is amplified in the renal and coronary vasculature, resulting in adverse hemodynamic effects and myocardial fibrosis. Direct soluble guanylate cyclase stimulators directly bind to sGC receptors to catalyze the conversion of guanosine triphosphate to cyclic guanosine mono-phosphate, leading to systemic vasodilation and prevention of myocardial hypertrophy and fibrosis. This drug class has been evaluated for use in patients with WHF with a reduced ejection fraction.

PHASE 2 STUDIES IN HEART FAILURE WITH REDUCED EJECTION FRACTION

There have been several phase 2 clinical trials for sGC stimulators in patients with HF with a reduced ejection fraction. The BAY58-2667 Dose Finding Trial Investigating Fixed Doses in Patients With Acute Decompensated Chronic Congestive Heart Failure (COMPOSE) program^[22] was a phase 2 study that evaluated the hemodynamic effect of short-term cinaciguat therapy in HFrEF patients with WHF (defined as requiring hospitalization, with a need for right heart catheterization, and a pulmonary capillary wedge pressure ≥18 mmHg). The study revealed favorable hemodynamic effects—cinaciguat was associated with a higher reduction in pulmonary capillary wedge pressure from baseline (−7.7 mmHg) compared to placebo (−3.7 mmHg; p-interaction = 0.0001). Similarly, the reduction in right atrial pressure was significantly higher in the cinaciguat group (−2.7 mmHg) compared to placebo (−0.6 mmHg; p-interaction = 0.0019). However, the rates of hypotension were much higher in the cinaciguat group (73%) compared to placebo (26%) and the trial was terminated prematurely due to excessive rates of hypotension at higher doses of cinaciguat exceeding ≥200 mcg/h. Nevertheless, sGC stimulators were found to be effective in a reduction in preload. The Left Ventricular Systolic Dysfunction Associated With Pulmonary Hypertension Riociguat (LEPHT) trial^[23] evaluated the hemodynamic effects of riociguat in 201 patients with pulmonary hypertension and HFrEF. The participants were randomized to placebo and 4 parallel arms of riociguat treatment based on incremental dosages (0.5, 1, 2, and 3 mg) and were followed over 16 weeks for the primary end point of placebo-corrected change in mean pulmonary artery pressure. The trial did not meet its primary end point but did report a significant improvement in cardiac index and stroke volume and a reduction in systemic and pulmonary vascular resistance in the 2 and 3 mg arms. The Soluble Guanylate Cyclase Stimulator in Heart Failure with Reduced Ejection Fraction Study (SOCRATES-Reduced) trial^[24] was a phase 2 trial that evaluated the efficacy and tolerability of vericiguat therapy within 4 weeks of a WHF event (defined as requiring hospitalization or intravenous diuretics, having signs and symptoms of HF with elevated serum natriuretic peptides) in patients with chronic HF with a left ventricular ejection fraction (LVEF) of less than 45%. The study also assessed the dose–response relationship of 4 different doses of vericiguat (1.25, 2.5, 5, and 10 mg) with a primary end point of changes in NT-proBNP from baseline to 12 weeks. The study did not find a significant difference in change in serum NT-proBNP between pooled vericiguat groups and placebo (difference of means, −0.122; 90% CI, −0.32 to 0.07; ratio of geometric means on original scale, 0.885; 90% CI, 0.73–1.08; P = 0.15). However, on further exploratory analysis, a dose–response relationship was observed with a higher reduction in NT-proBNP in patients treated with higher doses of vericiguat.

THE VICTORIA TRIAL

The Clinical Outcome Predictions for the Vericiguat Global Study in Subjects with Heart Failure With Reduced Ejection Fraction (VICTORIA) trial^[25] evaluated the efficacy of vericiguat compared to placebo in 5050 HF patients with LVEF ≤45% with WHF over a median follow-up of 10.8 months. The trial enrolled a high-risk cohort with recent WHF episodes defined as a hospitalization within 6 months, or if patients received intravenous diuretics over the past 3 months. Patients were on optimally tolerated background therapy with 60% of the recruited cohort on mineralocorticoid receptor antagonists, beta-blockers, and renin-angiotensin antagonists. There was a significant reduction in the primary composite end point of cardiovascular death and HF hospitalizations in the vericiguat group compared to placebo (33.6 per 100 patient-years vs. 37.8 per 100 patient-years; HR, 0.90; 95% CI, 0.82–0.98). The target dose was achieved in 89% of patients, and the risk of serious adverse events, including prespecified events (symptomatic hypotension and syncope), was numerically similar in the vericiguat and placebo groups. The trial results were important as they provide an additional target to mitigate the effects of HF, specifically in high-risk patients with a recent WHF event. Based on these results, the recent ESC and AHA/ACC/HFSA HF guidelines denoted a class 2 recommendation to vericiguat for use in patients with WHF and an LVEF <45% while on optimal GDMT.

RELATIVE VERSUS ABSOLUTE RISK REDUCTION

There was a 10% risk reduction in the primary endpoint based on an HR of 0.90 in the VICTORIA trial. The follow-up period for the VICTORIA trial was ~11 months compared to 2–3 years typically observed in other large HF outcome trials, which precludes the ability to robustly assess the impact of therapy in each individual component of the primary endpoint. Moreover, the absolute risk reduction for the primary endpoint in the VICTORIA trial was 4.2 events per 100 patient-years, which is sizable, in the context of a high baseline population risk (event rate for primary endpoint: vericiguat 33.6 per 100 patient years vs placebo 37.8 per 100 patient years). When comparing 3 large HF outcome trials (DAPA-HF, PARADIGM-HF, and VICTORIA): for the absolute risk reduction using annualized event rates, the outcome benefits were found to be similar across the 3 trials, despite differences in the relative risk reduction.^[26]

SAFETY

Several phase 2 trials of sGC stimulators reported relatively high rates of hypotension which was feared to be a limiting factor for assessing efficacy in a larger clinical trial setting. In the VICTORIA trial, the findings of similar rates of serious adverse events in the vericiguat group compared to placebo, including symptomatic hypotension (9.1% vs. 7.9%; P = 0.12) and syncope (4.0% vs. 3.5%; P = 0.30), were reassuring. Lam et al.^[27] further reported that rates of these events were not significantly greater in high-risk patient groups (age >75 years, low baseline systolic blood pressure of 100–110 mmHg, and those on other vasoactive medications e.g., neprilysin inhibitors).

Notable post hoc analyses

Several secondary analyses from the VICTORIA trial provided further insight into the differential effect of vericiguat on various patient subgroups. Ezekowitz et al.^[28] reported that vericiguat reduced the occurrence of the primary endpoint and its constituents (HF hospitalization and cardiovascular death) in patients with a serum NT-proBNP level of up to 8000 pg/mL. Vericiguat was also found to have consistent benefit across the spectrum of renal function^[29] and in patients with or without atrial fibrillation.^[30] Moreover, patients on vericiguat had a higher incidence of anemia with a modestly lower hemoglobin 16 weeks after randomization; however, this effect did not affect the treatment effect of vericiguat.^[31] When stratified by baseline Kansas City Cardiomyopathy Questionnaire (KCCQ) scores, the reduction in the primary endpoint was consistent across all tertiles.^[32]
 

CONCLUSIONS

WHF is increasingly recognized as an important entity in the realm of HF and signifies a vulnerable, highrisk state in a patient’s HF journey with a major unmet need of therapeutic approaches to attenuate adverse clinical outcomes. Augmentation of loop diuretics for decongestion and escalation of GDMT post WHF event if recommended yields beneficial outcomes. Moreover, vericiguat has shown to improve outcomes in patients who experience WHF events [Figure 1].However, residual risk of future WHF events and death remains high, and further investigation is needed to ensure earlier identification, prompter management, and prevention of WHF events.

FINANCIAL SUPPORT AND SPONSORSHIP

Dr. Greene has received research support from the American Heart Association, Amgen,
AstraZeneca, Bristol Myers Squibb, Cytokinetics, Merck, Novartis, Pfizer, and Sanofi; has served on advisory boards for Amgen, AstraZeneca, Bristol Myers Squibb, Cytokinetics, and Sanofi; and has served as a consultant for Amgen, Bayer, Bristol Myers Squibb, Merck, Sanofi, and Vifor. 
Dr. Chopra reports personal fees from Novo Nordisk, Pfizer, Bayer, AstraZeneca, Boehringer Ingelheim, and Novartis. Dr. Butler reports personal consulting fees from Abbott, Adrenomed, Amgen, Applied Therapeutics, Array, AstraZeneca, Bayer, Boehringer Ingelheim, CVRx, G3 Pharma, Impulse Dynamics, Innolife, Janssen, LivaNova, Luitpold, Medtronic, Merck, Novartis, Novo Nordisk, Relypsa, Sequana Medical, and Vifor Pharma; and payment for lectures, presentations, speakers’ bureaus, manuscript writing, or educational events from AstraZeneca, BI-Lilly, Janssen, and Novartis. Dr. Talha has nothing to disclose.

Conflicts of interest
There are no conflicts of interest.