Worsening Heart Failure: The How, Why, and When of Novel Treatment Options

Author: Shelley Zieroth, MD

Background
Heart failure (HF) is classified into three subtypes according to a patient’s ejection fraction, natriuretic peptide levels, and the presence of structural heart disease and diastolic dysfunction: (1) HF with reduced ejection fraction (HFrEF), (2) HF with preserved ejection fraction (HFpEF), and (3) HF with mid-range ejection fraction (HFmrEF).¹ Patients with HFrEF and worsening heart failure (WHF) are a subpopulation with notably high mortality and hospitalization rates.

WHF is defined as the need for intravenous diuretics and/or escalation of current treatment or initiation of new therapy, with or without hospitalization. WHF can be identified by patients needing escalation of diuretics, an urgent visit requiring intravenous (IV) diuretics, an emergency department visit, and hospital admission.² WHF will develop in one of six patients with HFrEF within 18 months of the initial HF diagnosis.

Patients with HFrEF have a high risk for 2-year mortality and recurrent HF hospitalizations. One study of more than 11,000 patients with worsening HF found a 2-year mortality rate of 22.5% and very poor use of guideline-directed medical therapies (GDMTs): Only 14% of these patients were receiving triple therapy, and almost half were taking <50% of the maximum daily dose of b-blocker and/or angiotensin-converting enzyme inhibitors (ACEIs)/angiotensin receptor blockers (ARBs).³

Vericiguat is now included in GDMTs recommendations for treatment for patients with high-risk HFrEF and a recent HF exacerbation or hospitalization based on standard therapy. Other recommendations include the use of sodium glucose co-transporter-2 (SGLT2) inhibitors (i.e., dapagliflozin and empagliflozin) that—when added to the historical foundational triple therapy—reduce the risk for premature death by 30%.^4-6

Novel Therapies: Mechanisms of Action
The discovery of soluble guanylate cyclase (sGC) stimulators and activators provided novel therapeutic opportunities for treating cardiovascular and, possibly, kidney diseases.⁷ Almost a decade ago, riociguat was the first sGC stimulator approved for use in patients with pulmonary hypertension. Vericiguat, an oral sGC stimulator, is a newer sGC stimulator that is among the novel therapies recommended to treat HFrEF. It increases cGMP production and has improved bioavailability with a longer duration of action, allowing for once-daily dosing, vs riociguat’s three-times-daily dosing ⁷

Vericiguat targets sGC, which is an important enzyme in the nitric oxide (NO) signaling pathway. When NO binds to sGC, the enzyme catalyzes the synthesis of intracellular cyclic guanosine monophosphate (cGMP), a second messenger that plays a role in the regulation of vascular tone, cardiac contractility, and cardiac remodeling. HF is associated with impaired synthesis of NO and decreased activity of sGC, which may contribute to myocardial and vascular dysfunction. By directly stimulating sGC, independently of and synergistically with NO, vericiguat augments levels of intracellular cGMP, leading to smooth muscle relaxation and vasodilation (Figure 1).⁸

Figure 1. Mechanism of action of vericiguat

Source: Armstrong PW, Roessig L, Patel MJ, et al. A Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial of the Efficacy and Safety of the Oral Soluble Guanylate Cyclase Stimulator: The VICTORIA Trial. JACC Heart Fail. 2018;6(2):96-104.

Recent Clinical Trial Data Supporting Approval of Novel Agents in Patients With HF
The effects of vericiguat were examined in the VICTORIA phase 3 trial (Figure 2), which compared the efficacy and safety of the drug with standard-of-care GDMT. Patients enrolled in the VICTORIA trial represent a group with high-risk HF in whom HF treatments are rarely investigated. The participants in the trial had chronic HF (New York Heart Association [NYHA] class II-IV), left ventricular ejection fraction (LVEF) <45%, were not receiving nitrates, had recent HF decompensation treated with hospitalization (within 6 months) or outpatient intravenous diuretics (within 3 months), and elevated brain natriuretic peptide (BNP) levels. The primary outcome was a composite of death from cardiovascular causes or first heart failure hospitalization (HFH).⁹

Figure 2. The VICTORIA Trial

Source: 1. Zieroth, S. Worsening Heart Failure: Reducing Residual Risk in HF Presentation 2022. 2. Adapted from Armstrong PW, Roessig L, Patel MJ, et al. The VICTORIA Trial. JACC Heart Fail. 2018;6(2):96-104. 

In the VICTORIA trial, over a median of 10.8 months, death from CV causes or first HFH occurred in 35.5% of the vericiguat group and in 38.5% of the placebo group (hazard ratio [HR] 0.90; 95% confidence interval [CI], 0.82-0.98; P=0.02). 27.4% of patients in the vericiguat group and 29.6% of the placebo group were hospitalized for HF (HR 0.90; 95% CI, 0.81-1.00). Death from cardiovascular causes occurred in 16.4% of the vericiguat group and in 17.5% of the placebo group (HR 0.93; 95% CI, 0.81-1.06). The composite of death from any cause or HFH occurred in 37.9% of the vericiguat group and in 40.9% of the placebo group (HR 0.90; 95% CI, 0.83-0.98; P=0.02).⁹ Over the course of the study, there was a 4.2% annualized absolute risk reduction with vericiguat compared with placebo.⁸

The benefit from treatment with vericiguat appeared to be consistent in patients aged <75 years, those with LVEF <40%, renal insufficiency, not on an angiotensin receptor neprilysin inhibitor (ARNI), and patients with NYHA class III or IV disease.⁹

Prespecified adverse events of interest in the VICTORIA trial were symptomatic hypotension and syncope. Symptomatic hypotension occurred in 9.1% of patients in the vericiguat group versus 7.9% in the control group (P=0.12); syncope occurred in 4.0% patients in the vericiguat group versus 3.5% in the control group (P=.30). Anemia developed in more patients in the vericiguat group than in the placebo group (7.6% vs. 5.7% of cases). Of these patients with anemia, 1.6% in the vericiguat group and 0.9% in the placebo group were considered serious.⁹

Keeping Patients Out of the Hospital: How and When to Escalate/Switch GDMT and When to Add Novel Agents
Updated recommendations for treatment of HFrEF are reflected in the guidelines of international organizations including the American College of Cardiology, the American Heart Association, the Heart Failure Society of America,⁵ the Canadian Cardiovascular Society, and the Canadian Heart Failure Society.⁶

Guidelines emphasize early initiation of the four foundational treatments after diagnosis/during hospitalization to leverage the additive clinical benefits that are apparent in the first 30 days. This strategy allows clinicians to identify patients with refractory disease who can receive additional therapies in a timely manner (Figure 3).³

Figure 3. Benefits of early initiation of HF therapy on patients with HFrEF*

The basic content of the updated guidelines includes 4 elements: (1) initiation of quadruple foundational therapy for HFrEF (i.e., ACEi, β-blockers, and mineralocorticoid receptor antagonists, and SGLT2 inhibitors); (2) consideration of add-on therapies (including vericiguat); (3) consideration of electrophysiology device therapies; and (4) management of comorbidities (Figure 4).

Figure 4. Updated Content of the Canadian Cardiovascular Society/Canadian Heart Failure Society Guidelines ⁶

Source: McDonald M, Virani S, Chan M, et al. CCS/CHFS HF guidelines update: defining a new pharmacologic standard of care for heart failure with reduced ejection fraction. Can J Cardiol. 2021;37(4):531-546.

Initiation of all 4 foundational therapies simultaneously or in rapid sequence is recommended. Starting with low doses and uptitrating over several weeks allows for all 4 foundational therapies to be started (Figure 5). 

Figure 5. Example of schedule for initiation and optimizing of quad four medications in patients with HFrEF⁹

Sharma A, et al. J Am Coll Caridiol Basic Trans Science. 2022;7(5):504-517.

Use of Biomarkers to Track Response to HF Therapy (NT-Pro BNP)
Natriuretic peptides (NPs) are cardioprotective hormones released by cardiomyocytes in response to pressure or volume overload. B-type NP (BNP) and N-terminal pro-B-type NP (NT-proBNP) are emerging tools for diagnosis and risk stratification of HF in population screening and as guides for timing initiation of treatment of subclinical HF.  Evidence is conflicting, however, regarding use of NPs to guide HF therapy.¹¹

A principal novel finding of the VICTORIA trial was that the treatment effect of vericiguat compared with placebo on the primary composite endpoints (CV death and first HFH) was greatest in patients with N-terminal pro-B-type NP (NT-proBNP) levels <8,000 pg/mL at randomization, which was further amplified if these levels were <4,000 pg/mL (Figure 6). This finding suggests the potential for a broader range of patients who could benefit from treatment. ¹¹

Figure 6. Treatment effects of vericiguat on cardiovascular death and HF hospitalization by NT-pro-BNP 

Source: Ezekowitz JA, O'Connor CM, Troughton RW, et al. N-Terminal Pro-B-Type Natriuretic Peptide and Clinical Outcomes: Vericiguat Heart Failure With Reduced Ejection Fraction Study. JACC Heart Fail. 2020;8(11):931-939.

Real-world Patient Case
Mrs. NS is a 66-year-old woman with a history of nonischemic cardiomyopathy (NICM) and was initially diagnosed in 1997 with heart failure with reduced ejection fraction (HFrEF). She has mild coronary artery disease (30% blockage of the left anterior descending artery and right coronary artery), paroxysmal atrial fibrillation, and an estimated glomerular filtration rate (eGFR) of 25-30 mL/min/m². Additionally, a cardiac resynchronization device (CRT-D) was implanted in 2007.

Mrs. NS is currently on the following medications:

• Amiodarone 100 mg daily
• Apixaban 5 mg bid
• Atorvastatin 20 mg daily
• Bisoprolol 2.5 mg daily
• Empagliflozin 10 mg daily
• Furosemide 80 mg bid
• Sacubitril-valsartan 97-103 mg bid
• Spironolactone 25 mg daily

In July 2020, Mrs. NS presented to the clinic with worsening symptoms and an echocardiogram was performed.

Echocardiogram results:

• Left ventricular end diastolic diameter of 6.2 cm with an ejection fraction of 20%
• Grade 2 diastolic dysfunction
• Mild right ventricular dysfunction
• 1+ mitral regurgitation with 2+ tricuspid regurgitation
• Right ventricular systolic pressure: 30 mm Hg

Subsequently, diuretics were increased, metolazone was added, she was referred for a tricuspid valve clip, and she declined advanced therapies (Figure 7). 

Mrs. NS’s condition continued to deteriorate in August with recurrent worsening symptoms, an increase in NTproBNP from 6,527 ng/L in July to 8,561 ng/L in August, and a decrease in kidney function from an eGFR of 36 to 29 ml/min/m².

To reduce residual risk, at this time vericiguat (2.5 mg po OD) was added and titrated over a period of 2 months to 10 mg.  At next follow-up in September, her eGFR eventually stabilized at 32 mL/min/m² with a dose reduction of mineralocorticoid receptor antagonist.  At the 6-month follow-up appointment, Mrs. NS was classified with NYHA II symptoms with no recurrent hospitalizations.  Blood pressure was normal at 90/60.

Conclusion
HFrEF is a progressive and complex condition with very high rates of mortality and hospitalizations. The treatment of HFrEF requires one or more drugs from several classes, as recommended in the guidelines. Many factors need to be considered when selecting therapy for these patients, including how to initiate, add, or switch therapies, and how to assess the effectiveness of these treatments using imaging and biomarkers, for example. Recent additions to guidelines including SGLT2 inhibitors and vericiguat have the potential to significantly decrease risk for hospitalization for patients with HFrEF. Timely implementation of these therapies is critical to achieve the anticipated health benefits.

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11. Ezekowitz JA, O'Connor CM, Troughton RW, et al. N-Terminal Pro-B-Type Natriuretic Peptide and Clinical Outcomes: Vericiguat Heart Failure With Reduced Ejection Fraction Study. JACC Heart Fail. 2020;8(11):931-939.