Juggling While Dancing

Abstract

T he management of patients with heart failure with reduced ejection fraction (HFrEF) has evolved significantly over time, and these advancements are perhaps most significant with respect to medical therapy. In addition to longstanding therapies whose survival benefit is wellestablished, such as beta-blockers, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, mineralocorticoid receptor antagonists, along with other conventional therapies such as nitrates, hydralazine, and digoxin, there now exist multiple newer agents and classes also demonstrating efficacy, including angiotensin receptor neprilysin inhibitors, sinus node inhibitors (ivabradine), sodiumglucose cotransporter-2 inhibitors (SGLT2Is), soluble guanylate cyclase stimulators (vericiguat), and cardiac myosin activators (omecamtiv mecarbil). Furthermore, older therapies such as intravenous iron supplementation have demonstrated new benefits (1), with expanded indications currently under investigation. Although these exciting developments have significantly improved the prognosis of patients with HFrEF, they have also led to a very complex therapeutic landscape that clinicians must now navigate for a disease that has always been complex and challenging (2). Furthermore, when the advancements in medical therapy are considered in the context of improvements in device therapies, treatments for valvular heart disease, advanced heart failure therapies, and remote monitoring capabilities, the challenge of optimal HFrEF management becomes even more complicated. And although the prognosis of HFrEF has significantly improved in recent years due to these advances, it should be noted that it remains a disease that is associated with a high level of risk for patient morbidity and mortality (3,4). As a result, there are multiple other investigational agents and therapeutic clinical trials that are presently in various stages of development that may further complicate the management of HFrEF in the future. How can busy clinicians keep up with this rapidly shifting landscape to provide their patients the best therapy that modern medicine can offer? Before determining the best strategy for optimizing medical therapy for HFrEF patients in the current era, it is helpful to understand how we got here and how clinical evidence has shaped our approaches thus far. Clinical trials have historically evaluated a single new therapy’s efficacy on the background of existing optimal medical therapy, and therefore clinical practice has mirrored this approach of adding a single therapy sequentially to the current standard guideline-directed medical therapy (GDMT) (4,5). Although this approach has resulted in strong evidence supporting the incremental value of newer therapies in addition to the standard GDMT regimen that was current at the time of the clinical trial, there is very little evidence comparing the efficacy of specific medical therapies head to head. This frequently translates into uncertainty in clinical practice with respect to sequence and timing of titration of medical therapy. Furthermore, enrollment criteria in clinical trials are frequently chosen to minimize competing risk of significant comorbidities rather than on the basis of biology and safety alone. Although scientifically sound for demonstrating efficacy of the therapy under study, this can also create uncertainty in clinical practice regarding potential benefit in different HFrEF population subgroups.