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Patient-specific pharmacotherapy plan may reduce HF hospitalizations
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HF remains a complex clinical syndrome. It is estimated that nearly 6 million Americans have HF and more than 800,000 new cases of HF are diagnosed annually in the United States. Current projections suggest that the prevalence of HF will increase 46% by 2030, to an estimated 8 million Americans with HF. Despite decades of therapeutic development and advances in the understanding of the etiology and pathophysiology, the overall 5-year survival rate remains approximately 50% for patients with a diagnosis of HF.
Hospitalizations remain an important factor in HF. Annually, there are more than 1 million discharges for HF. For patients older than 65 years, HF remains the most common discharge diagnosis.
Compounding the gravity of the issue is the economic burden the disease state poses. Annual estimated costs exceed $30 billion, with more than half directed toward the cost of hospitalization. Projections approximate the annual cost of HF increasing to nearly $70 billion by 2030.
Over the decades of pharmacotherapeutic development, mortality has long been a primary endpoint and has resulted in strong evidence-based, guideline-directed medical therapy, which includes ACE inhibitors, beta-blockers, aldosterone antagonists and hydralazine/isosorbide (for persistently symptomatic black patients).
However, as hospitalizations remain prominent in the HF population, one should consider the outcome of hospitalization in core HF pharmacotherapy trials. The Table below provides a summary of the evidence demonstrating impact of HF pharmacotherapy on HF hospitalizations. Many of these trials included hospitalizations as either a component of a composite primary endpoint or as a separate or composite secondary endpoint. These therapies are directed for HF with reduced ejection fraction. Although several clinical trials have evaluated therapies for HF with preserved ejection fraction, unfortunately, no therapy has been shown to reduce hospitalizations for HFpEF.
RAAS inhibition
Mainstays of HF treatment are directed at neurohormonal blockade through inhibition of the renin-angiotensin-aldosterone system (RAAS) and the sympathetic nervous system, and all agents with these pharmacological properties have demonstrated in some capacity a reduction in HF hospitalizations. Looking at the effects of enalapril on combined mortality and hospitalizations, the SOLVD trial demonstrated that in those patients receiving enalapril, hospitalizations were significantly reduced compared with placebo. The ATLAS trial, which looked at low and high doses of ACE inhibitor therapy, demonstrated that patients in the high-dose group had significantly fewer hospitalizations for HF. Among patients who sustained an acute MI with resulting left ventricular dysfunction, results of the SAVE trial demonstrated a reduction in HF hospitalizations for patients receiving ACE inhibitor therapy after MI.
RAAS inhibition with angiotensin receptor blockers yields similar results as ACE inhibitor therapy. In CHARM-Alternative, a randomized controlled trial that compared candesartan vs. placebo in patients intolerant to ACE inhibitor therapy, patients randomly assigned to an angiotensin receptor blocker experienced significantly fewer hospitalizations in a composite primary endpoint of CV death or hospital admission for HF. When added to ACE inhibitor therapy in CHARM-Added, candesartan reduced the number of hospital admissions for HF. Results of the HEAAL study demonstrated that patients who were treated with high-dose angiotensin receptor blocker therapy — losartan 150 mg — had fewer hospitalizations for HF compared with low-dose therapy. Finally, regarding RAAS inhibition with aldosterone antagonists, both spironolactone and eplerenone have demonstrated reduction in hospitalization for HF in the RALES, EPHESUS and EMPHASIS-HF trials.
Beta-blockers key
Given the robust mortality benefit demonstrated over decades of trials, unless intolerant due to limiting bradycardia, every patient with HFrEF should receive therapy with a beta-blocker. As part of composite secondary endpoints in CIBIS II and COPERNICUS, treatment with beta-blocker therapy has been demonstrated to reduce hospitalizations for HF.
Special attention should be given to digoxin. Several placebo-controlled trials have demonstrated that treatment with digoxin can improve symptoms, exercise tolerance and health-related quality of life. However, in a 3- to 5-year trial comparing digoxin vs. placebo in patients with an EF of 45% or less, treatment with digoxin had no effect on mortality, but did reduce the combined risk for a composite of death and hospitalization. This was the first trial to report a reduction in hospitalization for HF but not a reduction in mortality.
Newer therapies
More recently, data from SHIFT and PARADIGM-HF have launched us into a novel era of HF pharmacotherapy. As heart rate is directly related to risk for death or hospitalization in patients with HF, therapy directed to reduce heart rate may portend therapeutic benefit. Ivabradine (Corlanor, Amgen) is an inhibitor of the If current in the sinoatrial node, reducing heart rate, while not altering intracardiac conduction or myocardial contractility. In SHIFT, patients were randomly assigned to therapy with ivabradine or placebo. The primary endpoint was driven by a reduction in hospital admissions for worsening HF, 21% in the placebo group vs. 16% in ivabradine.
Neprilysin, which is a neutral endopeptidase, degrades endogenous vasoactive peptides, including natriuretic peptides. Increasing the levels of natriuretic peptides counters the maladaptive effects of neurohormonal overactivation. In PARADIGM-HF, patients with class II to IV HF were randomly assigned to treatment with sacubitril/valsartan (Entresto, Novartis), a combined angiotensin receptor-neprilysin inhibitor, or enalapril. The trial was stopped early due to the overwhelming benefit of sacubitril/valsartan. Of note, this therapy reduced the risk of hospitalization for HF by 21% vs. enalapril. A recent cost-effectiveness analysis calculated that there would be 220 fewer hospital admissions per 1,000 patients with HF treated with sacubitril/valsartan over 30 years, further supporting its utility as an agent to reduce hospitalizations for HF.
Risk prediction models
Although hospitalization for HF may provide the opportunity for tailoring of pharmacotherapy and patient re-education, statistics demonstrate that mortality increases after hospitalization. Of note, in the interest of promoting high-quality care and accountability, CMS expanded publicly reported outcome measures to include HF readmission as a 30-day risk standardized measure, which ultimately will affect reimbursement. A variety of readmission risk prediction models have been developed to address not only the 30-day measure, but the sheer burden HF hospitalizations cause on the health system and patient morbidity and mortality. Unfortunately, no one risk model has performed above another, and several centers are developing institution-specific tools to capture their own readmission risk. Although selection of guideline-directed medical therapy is paramount, and reported as a quality measure, a complex myriad of risk factors apart from lack of guideline-directed medical therapy have been associated with an increase in hospital readmission in several readmission risk prediction models. These factors include diabetes, CAD, chronic obstructive pulmonary disease, low serum sodium, older age, sex, polypharmacy, history of prior hospitalization, cognitive impairment, poor health literacy, socioeconomic status, depression and increased length of hospital stay.
Predicting and preventing readmission for HF is a complex and involved process, currently with suboptimal tools to predict readmission risk. Patient-centric care plans and multidisciplinary strategies are paramount to successful care and reducing the risk of readmission. To optimally position the patient to prevent readmission, it is imperative that a patient-specific pharmacotherapy plan be created that consists of agents associated with a reduction in hospitalizations, in tandem with addressing the variety of risk factors contributing to readmission risk. Still, as future HF therapies are developed, reduction in hospitalization should remain a key consideration.
- References:
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- For more information:
- Jeremy D. Moretz, PharmD, BCPS, is a clinical pharmacist at Advanced Heart Failure/Mechanical Circulatory Support, Vanderbilt University Medical Center, Nashville, TN 37232.
- Sarah A. Spinler, PharmD, FCCP, FAHA, FASHP, AACC, BCPS (AQ Cardiology), is the Cardiology Today Pharmacology Consult column editor. She is adjunct professor at the University of Pennsylvania Department of Medicine, Philadelphia, PA 19104. She can be reached at saspinler@gmail.com.
Disclosure: Moretz reports no relevant financial disclosures.