Evolving Therapies in Heart Failure: A Contemporary Review

 

Evolving Therapies in Heart Failure: A Contemporary Review for the Internist

Dr Neeraj Manikath , claude.ai

Abstract

Heart failure (HF) remains a leading cause of morbidity and mortality worldwide, affecting over 64 million people globally. The past decade has witnessed a paradigm shift in HF management, moving from symptomatic relief to disease modification through neurohormonal antagonism and, more recently, metabolic modulation. This review synthesizes current evidence on emerging and established therapies for heart failure with reduced ejection fraction (HFrEF) and heart failure with preserved ejection fraction (HFpEF), highlighting practical pearls for the practicing internist and exploring therapies on the horizon.

Introduction

The therapeutic landscape of heart failure has undergone revolutionary changes since the landmark CONSENSUS trial established ACE inhibitors as foundational therapy in 1987. Contemporary HF management now encompasses multiple pillars of guideline-directed medical therapy (GDMT), with recent additions fundamentally altering outcomes. For the internist managing HF patients, understanding these evolving therapies—their mechanisms, implementation strategies, and emerging data—is essential for optimizing patient care.

The Four Pillars of HFrEF Therapy: Current Standard of Care

1. Renin-Angiotensin-Aldosterone System Inhibition: The ARNI Era

The PARADIGM-HF trial (2014) demonstrated that sacubitril/valsartan, an angiotensin receptor-neprilysin inhibitor (ARNI), reduced cardiovascular death and HF hospitalization by 20% compared to enalapril in HFrEF patients. This combination inhibits neprilysin (enhancing natriuretic peptides, bradykinin, and adrenomedullin) while blocking angiotensin II receptors.

Clinical Pearl: The "36-hour washout rule" between ACE inhibitors and ARNI initiation prevents angioedema by allowing ACE inhibitor clearance before introducing neprilysin inhibition. However, many patients can safely transition with shorter intervals under careful monitoring.

Oyster: Hypotension is the most common barrier to ARNI uptitration. Start with sacubitril/valsartan 24/26 mg twice daily in hypotension-prone patients (systolic BP 100-110 mmHg), and educate patients that transient dizziness during uptitration often resolves. Consider splitting doses between morning and evening to minimize symptomatic hypotension.

2. Beta-Blockade: Evidence-Based Selectivity

Carvedilol, metoprolol succinate, and bisoprolol remain the only beta-blockers with mortality benefit in HFrEF. The CIBIS, MERIT-HF, and COPERNICUS trials collectively established 30-35% reductions in mortality.

Hack Around the Corner: Contrary to dogma, beta-blockers can be initiated during hospitalization for acute decompensated HF once hemodynamic stability is achieved. The IMPACT-HF study showed that in-hospital beta-blocker initiation improved long-term adherence without safety concerns.

Clinical Pearl: In patients with severe bradycardia or high-degree AV block preventing beta-blocker use, consider cardiac resynchronization therapy (CRT) or His-bundle pacing, which can improve outcomes independent of beta-blockade.

3. Mineralocorticoid Receptor Antagonists: Beyond Spironolactone

Spironolactone (RALES trial) and eplerenone (EMPHASIS-HF) reduce mortality by 30% and 27% respectively in HFrEF. The non-steroidal MRA finerenone shows promise with reduced hyperkalemia and hormonal side effects.

Oyster: The "hyperkalemia phobia" leads to underutilization of MRAs. Modern management includes:

• Potassium binders (patiromer, sodium zirconium cyclosilicate) allowing MRA continuation
• Targeting potassium 4.5-5.0 mEq/L, not <4.0 mEq/L
• Recognizing that mild hyperkalemia (5.0-5.5 mEq/L) with MRAs may not require discontinuation if stable

Hack: In patients with recurrent hyperkalemia, consider switching to finerenone, which demonstrates lower hyperkalemia rates in chronic kidney disease populations (FIDELIO-DKD, FIGARO-DKD trials).

4. SGLT2 Inhibitors: The Game-Changing Fourth Pillar

Sodium-glucose cotransporter-2 inhibitors represent the most significant advance in HF therapeutics since beta-blockers. Dapagliflozin (DAPA-HF) and empagliflozin (EMPEROR-Reduced) reduced the composite of cardiovascular death and HF hospitalization by 26% and 25% respectively in HFrEF patients, independent of diabetes status.

Mechanism Beyond Glucose: SGLT2 inhibitors exert pleiotropic effects including:

• Enhanced natriuresis and osmotic diuresis
• Metabolic shift toward ketone body utilization (more efficient ATP generation)
• Reduced myocardial inflammation and fibrosis
• Improved mitochondrial function
• Favorable hemodynamic effects through reduced preload

Clinical Pearl: SGLT2 inhibitors work across the entire ejection fraction spectrum. The DELIVER and EMPEROR-Preserved trials extended benefits to HFpEF patients (EF >40%), with particular efficacy in those with EF 41-49%.

Oyster: Euglycemic diabetic ketoacidosis (euDKA) is rare but serious. Risk factors include insulin-dependent diabetes, prolonged fasting, low-carbohydrate diets, and acute illness. Counsel patients to temporarily discontinue during major surgery or severe illness and maintain adequate carbohydrate intake.

Hack Around the Corner: Consider SGLT2 inhibitors as first-line add-on therapy (with beta-blockers) in newly diagnosed HFrEF patients. The STRONG-HF trial paradigm suggests early, rapid optimization improves outcomes. Don't wait for "stability"—start early during hospitalization once euvolemia is approached.

Emerging and Evolving Therapies

Vericiguat: Soluble Guanylate Cyclase Stimulation

The VICTORIA trial demonstrated that vericiguat, a soluble guanylate cyclase stimulator, reduced cardiovascular death and HF hospitalization by 10% in high-risk HFrEF patients recently hospitalized for HF.

Clinical Niche: Vericiguat is indicated for worsening chronic HF patients despite GDMT, particularly those with recent hospitalization. It enhances cyclic GMP signaling, improving myocardial contractility and promoting vasodilation.

Pearl: Vericiguat is most beneficial in patients with NT-proBNP 1000-4000 pg/mL. Benefits attenuate at very high NT-proBNP levels (>8000 pg/mL), suggesting a "sweet spot" for therapy.

Cardiac Myosin Activators: Omecamtiv Mecarbil

Omecamtiv mecarbil selectively binds cardiac myosin, prolonging systolic ejection without increasing oxygen consumption. The GALACTIC-HF trial showed modest 8% reduction in HF events, with greater benefit in patients with EF <28% and elevated natriuretic peptides.

Oyster: Unlike inotropes, omecamtiv doesn't increase intracellular calcium or myocardial oxygen demand, avoiding the adverse outcomes associated with traditional inotropic agents.

Iron Supplementation: Beyond Anemia

Iron deficiency (ferritin <100 ng/mL or ferritin 100-299 ng/mL with transferrin saturation <20%) occurs in 30-50% of HF patients and correlates with worse outcomes independent of anemia. The AFFIRM-AHF trial demonstrated that intravenous ferric carboxymaltose reduced HF hospitalizations by 26% in iron-deficient patients hospitalized for acute HF.

Clinical Pearl: Screen all HF patients for iron deficiency. Oral iron is generally ineffective due to hepcidin-mediated absorption impairment in HF. Use IV iron (ferric carboxymaltose 500-1000 mg doses) for repletion.

Hack: IV iron administration can be done in office-based infusion settings, avoiding hospitalization costs. Repeat iron studies every 3-6 months as deficiency recurs in most patients.

The Elusive HFpEF: Finally, Some Progress

HFpEF has historically been a therapeutic graveyard, with multiple failed trials. Recent breakthroughs include:

SGLT2 Inhibitors: As noted, empagliflozin and dapagliflozin reduce HF events across the EF spectrum. SGLT2 inhibitors are now first-line therapy for all HF patients regardless of EF.

Finerenone: The FINEARTS-HF trial (2024) demonstrated that finerenone reduced cardiovascular death and HF events in HFpEF patients, with benefits seen across multiple subgroups. This non-steroidal MRA offers improved tolerability compared to spironolactone.

GLP-1 Receptor Agonists: Beyond weight loss and glycemic control, semaglutide shows promise in obese HFpEF patients. The SELECT trial demonstrated cardiovascular benefits in obesity, and ongoing trials (STEP-HFpEF) specifically target HFpEF populations.

Oyster: HFpEF is heterogeneous. Phenotyping patients may guide therapy:

• Obese/metabolic phenotype: SGLT2 inhibitors, GLP-1 agonists, weight loss
• Hypertensive phenotype: ARNI, MRAs, optimal BP control
• Atrial fibrillation-related: Rate/rhythm control, anticoagulation
• Infiltrative/restrictive: Specific therapies (tafamidis for ATTR, if applicable)

Implementation Strategies: Rapid Sequencing and Titration

Traditional stepwise GDMT initiation is obsolete. Contemporary evidence supports rapid, simultaneous initiation of multiple therapies:

The STRONG-HF Paradigm: This trial demonstrated that intensive, rapid uptitration of GDMT (started before discharge, with close outpatient follow-up) reduced 180-day readmission or death by 34% compared to usual care.

Practical Rapid Sequencing Protocol:

1. Day 1-3 (hospitalization): Initiate beta-blocker and SGLT2 inhibitor once approaching euvolemia
2. Pre-discharge: Start low-dose ARNI (or ACE-I if ARNI unavailable) and MRA if potassium <5.0 mEq/L
3. Week 1-2 post-discharge: Telephone contact, assess symptoms/BP/HR, begin uptitration
4. Week 2-4: Clinic visit with labs, continue uptitration every 1-2 weeks until target or maximally tolerated doses

Hack: Utilize remote monitoring, telephone follow-ups, and pharmacist-led titration clinics to achieve rapid GDMT optimization without overburdening physician schedules.

On the Horizon: Therapies in Development

Gene Therapy and RNA-Based Interventions

Small interfering RNA (siRNA) targeting PCSK9 and transthyretin shows promise. Gene therapy approaches for restoring sarcoplasmic reticulum calcium handling (SERCA2a gene transfer) continue development after early setbacks.

Novel Neurohormonal Targets

• Selective cardiac myosin inhibitors for obstructive HCM may have broader HF applications
• Glucagon receptor antagonists targeting metabolic dysfunction
• Mitochondrial-targeted therapies addressing energetic deficiency

Device Innovations

• Wireless pulmonary artery pressure monitors (CardioMEMS) reduce hospitalizations by enabling preemptive diuretic adjustment
• Cardiac contractility modulation for patients ineligible for CRT
• Baroreflex activation therapy modulating sympathetic overdrive

Practical Pearls for the Internist

1. Think beyond EF: SGLT2 inhibitors work across all EF categories. Don't withhold based on EF alone.

2. Monitor, but don't fear: Transient worsening of renal function during GDMT initiation often improves and shouldn't prompt discontinuation unless severe (>30% creatinine rise with volume depletion).

3. Low BP isn't low cardiac output: Systolic BP 90-100 mmHg is often tolerated well if perfusion is adequate (warm extremities, adequate mentation, normal lactate). Don't automatically reduce GDMT for asymptomatic hypotension.

4. Diuretic resistance strategies: Consider sequential nephron blockade (loop + thiazide), switch to torsemide (better bioavailability than furosemide), or use continuous infusions.

5. Palliative care integration: For advanced HF patients, early palliative involvement improves quality of life. HF prognostication scores (Seattle Heart Failure Model, MAGGIC) can guide discussions.

Conclusion

The therapeutic armamentarium for heart failure has expanded dramatically, offering renewed hope for improved outcomes. The contemporary internist must embrace rapid GDMT implementation, understand mechanistic distinctions between drug classes, and remain alert to emerging therapies. The shift from symptomatic management to true disease modification represents one of cardiology's greatest successes. For our patients, these advances translate to longer lives with better quality—the ultimate goal of medical innovation.

Early initiation, aggressive uptitration, and comprehensive implementation of all four GDMT pillars should be standard practice. As we await novel therapies including gene therapy and advanced metabolic modulators, maximizing current evidence-based treatments remains our most powerful intervention.

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Key References

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2. McMurray JJV, et al. DAPA-HF Trial Committees and Investigators. Dapagliflozin in patients with heart failure and reduced ejection fraction. N Engl J Med. 2019;381:1995-2008.

3. Packer M, et al. EMPEROR-Reduced Trial Investigators. Cardiovascular and renal outcomes with empagliflozin in heart failure. N Engl J Med. 2020;383:1413-1424.

4. Solomon SD, et al. DELIVER Trial Committees and Investigators. Dapagliflozin in heart failure with mildly reduced or preserved ejection fraction. N Engl J Med. 2022;387:1089-1098.

5. Anker SD, et al. AFFIRM-AHF investigators. Ferric carboxymaltose in patients with heart failure and iron deficiency. N Engl J Med. 2009;361:2436-2448.

6. Armstrong PW, et al. VICTORIA Study Group. Vericiguat in patients with heart failure and reduced ejection fraction. N Engl J Med. 2020;382:1883-1893.

7. Mebazaa A, et al. STRONG-HF Investigators. Safety, tolerability and efficacy of up-titration of guideline-directed medical therapies for acute heart failure. Lancet. 2022;400:1938-1952.

8. Pitt B, et al. FINEARTS-HF Committees and Investigators. Finerenone in heart failure with mildly reduced or preserved ejection fraction. N Engl J Med. 2024 (in press).

9. Teerlink JR, et al. GALACTIC-HF Committees and Investigators. Cardiac myosin activation with omecamtiv mecarbil in systolic heart failure. N Engl J Med. 2021;384:105-116.

10. Heidenreich PA, et al. 2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure. J Am Coll Cardiol. 2022;79:e263-e421.