Polypharmacy in Heart Failure with Reduced Ejection Fraction: Progress - not Problem

Heart failure (HF) affects over 6.5 million adults in the US¹ and carries a survival comparable to many cancers with ~50% mortality at 5 years after diagnosis.² Almost half of these patients have HF with reduced ejection fraction (HFrEF). Medical therapy for HFrEF has evolved based on the results of landmark trials and the current HF guidelines recommend multiple medications proven to increase survival and quality of life.^3–5 These include beta blockers (BB), angiotensin-converting enzyme inhibitors (ACEi) / angiotensin II receptor blockers (ARB) or angiotensin receptor-neprilysin inhibitors (ARNI), mineralocorticoid receptor antagonists (MRA), and most recently sodium-glucose cotransporter-2 inhibitors (SGLT2i).^3–5 Contemporary HFrEF trials have seen a progressively increasing proportion of background therapy, especially with a larger proportion of patients taking MRA and taking triple therapy. This however is not the case in practice with even the most contemporary data showing major gaps in implementation of evidenced based medications. While there are many reasons for this trend, one commonly perceived ‘problem’ is polypharmacy and the presence of numerous therapeutic options.

Polypharmacy in Heart Failure: The Good and The Bad

The widespread availability of life-prolonging therapies has been met with slow uptake in clinical practice, and many eligible patients are not prescribed optimal guideline-directed medical therapies (GDMT).⁶ The recent introduction of ARNI and SGLT2i continues to face the same barriers of clinical inertia. The opportunity cost of failing to prescribe GDMT is substantial, as optimal prescription can prevent >100,000 deaths in just in the US per year.^{7, 8} Optimal GDMT is projected to offer 55 year-old person an additional 6 years of survival.⁹

Patients with HF often have other comorbidities, and the number of prescribed medications increases with age, yet use of GDMT remains low in the elderly population.¹⁰ Most older patients hospitalized with HF are prescribed greater than 10 medications at discharge and this rate has increased from 41% in 2003–2006 to 68% in 2011–2014.¹⁰ Polypharmacy is generally described as taking at least 5 medications, and it has several downsides including increased risk for drug-interactions, risk for adverse events, difficulties with adherence, and costs.¹¹

With increasing availability of evidence-based options for HFrEF treatment, there is a perceived risk for increasing rates of adverse events, especially among older patients. While this may be true, it is not universally relevant and alternate scenario of avoiding optimal therapy definitely poses an increased risk for worse quality of life, recurrent hospitalizations, and mortality.^3–5 Risks and benefits of polypharmacy thus need to be weight against the risk of growing polymorbidity and its subsequent impact. We therefore strongly contend that availability of multiple medications provides the clinicians and patients with potent therapeutic options and that the negative connotations around polypharmacy needs to be curbed to appropriate proportion.

Patients with HFrEF may have various comorbidities that may prohibit their eligibility for morbidity- and mortality-reducing therapies, such as chronic kidney disease, and orthostatic hypotension. An example as such includes progressive renal disease where ACEi, ARB, ARNI, or MRA may not be suitable; yet providers may still provide BB and SGLT2i due to their cardiac and/or renal protective effects in HFrEF.¹² Alternatively, a patient with orthostatic hypotension may have increased adverse symptoms to BB, ACEi, ARB, or ARNI,¹³ but may tolerate MRA and SGLT2i due to their lower hemodynamic profile.¹² While such medication sequencing or prioritizing among certain HFrEF subtypes are lacking, the growing arsenal of HFrEF therapies warrants a tailored approach in such vulnerable subpopulations. Additionally, as there are no new pharmaceutical agents or classes in advanced stages of investigation in chronic stable HFrEF, now is the time to balance implementation of maximally prescribing existing GDMT that work with minimizing patient intolerances or adverse symptoms (Figure).

Figure:

Benefits and risks of polypharmacy in heart failure with reduced ejection fraction

The plethora of GDMT choices in chronic HFrEF treatment offer new opportunities to improve outcomes through implementation and prescribing practices, as well as tailored therapies among patients likely to be intolerant to taking greater than 10 medications or multiple classes. The need is clear – HFrEF affects a large proportion of the population with multiple health care workers involved in their care, and these important medications do not belong to any one provider or specialty. A collaborative effort between heart failure, kidney, endocrinology, pharmacy, and primary care specialists is needed to maximize the benefits of multiple GDMT classes in HFrEF on optimize quality of life and survival outcomes, while minimizing adverse perceptions to misperceived risk for adverse effects of polypharmacy in HFrEF. Inappropriate polypharmacy should definitely be avoided. Polypharmacy should definitely be tailored according to cost and tolerability related individualization. Efforts to improve adherence by instituting polypills should be evaluated (Table). But the negative rhetoric around polypharmacy needs to be carefully gauged as avoiding optimal medical therapy also has its consequences, and they are likely worse than the issues with polypharmacy itself.

Table:

Unresolved questions in regards to polypharmacy in heart failure with reduced ejection fraction

Open Questions in Regards to Polypharmacy
Optimal sequencing of medications
Optimal matching of medications to patient profile
In-hospital guideline-directed medical therapy implementation
Efficacy of polypill
Educating and engaging patients and their families in heart failure treatment