All-Cause Mortality as an End Point for Heart Failure With Preserved Ejection Fraction: Underperformance or Overambitious?

Abstract

EMPEROR-PRESERVED, which examined sodium-glucose co-transporter 2 inhibitor empagliflozin, is the first study among patients with heart failure with preserved ejection fraction (HFpEF) to meet its primary end point.1Anker SD Butler J Filippatos G Ferreira JP Bocchi E Bohm M EMPEROR-Preserved Trial InvestigatorsEmpagliflozin in heart failure with a preserved ejection fraction.N Engl J Med. 2021; 385: 1451-1461Crossref PubMed Scopus (827) Google Scholar This is a major development for patients with HFpEF and the broader scientific community; all previous studies in HFpEF have failed to meet their primary end point. This includes the phase III clinical trials of sacubitril-valsartan and spironolactone, which served as the foundations for endorsement as treatment for HFpEF by the US Food and Drug Administration, despite failing to meet their prespecified primary end points. Given this historical context, it is likely that empagliflozin will also receive US Food and Drug Administration endorsement. However, based on early chatter on media outlets including Twitter, this endorsement will not occur without debate and controversy. One of the early critiques of the EMPEROR-PRESERVED results was that empagliflozin did not decrease all-cause mortality. Naturally, many compare this study with other studies in HF that have met their primary end point. However, such prior studies enrolled patients with HF with reduced ejection fraction (HFrEF) and included a younger cohort than that studied in EMPEROR-PRESERVED. These distinctions are important and raise concern about the appropriateness of comparing EMPEROR-PRESERVED to these prior studies. Whereas the pathophysiology of HFrEF is primarily driven by neurohormonal activation even across different etiologies, the pathophysiology of HFpEF is highly heterogeneous with varied mechanisms that span numerous cardiovascular domains and multiple organ systems.2Shah SJ Kitzman DW Borlaug BA van Heerebeek L Zile MR Kass DA et al.Phenotype-specific treatment of heart failure with preserved ejection fraction: a multiorgan roadmap.Circulation. 2016; 134: 73-90Crossref PubMed Scopus (564) Google Scholar Accordingly, single agents (including empagliflozin, which has multiple targets relevant to HFpEF), may have modest effects when compared with agents targeting neurohormonal pathways in HFrEF. The mean age of landmark pharmacologic studies in HFrEF have been in the low to mid 60s, whereas the mean age of EMPEROR-PRESERVED was approximately 72 years (Table 1). This difference reflects contemporary intentionality to include older adults in clinical trials, and also reflects the fact that most patients with HFpEF are older adults with multiple comorbid conditions, along with notable geriatric conditions like polypharmacy, cognitive impairment, and frailty.3Gorodeski EZ Goyal P Hummel SL Krishnaswami A Goodlin SJ Hart LL Forman DE Geriatric Cardiology Section Leadership Council, American College of CardiologyDomain management approach to heart failure in the geriatric patient: present and future.J Am Coll Cardiol. 2018; 71: 1921-1936Crossref PubMed Scopus (108) Google Scholar This point is especially relevant when considering clinical trial end points like all-cause mortality. Indeed, multimorbidity and concurrent geriatric conditions contribute to the risk of competing causes of death. In other words, patients with serious medical conditions other than HFpEF can die as a consequence of these other conditions, unrelated to the disease of HFpEF and unrelated to the therapy under investigation. Since treating HFpEF will not directly address these other causes, it is intrinsically more challenging for any HFpEF drug to decrease all-cause mortality.Table 1HFpEFmortalityDrugStudyMean AgePrimary End Point Met?Reduction in Mortality?Endorsed by FDA?Heart failure with reduced ejection fraction Beta-blockerMERIT-HF64 years√√√COPERNICUS63 years√√√ ACEISOLVD61 years√√√ ARNIPARADIGM-HF64 years√√√ MRARALES65 years√√√ H-ISDNA-HEFT57 years√√√Heart failure with preserved ejection fraction ARBCHARM-PRESERVED67 years××× MRATOPCAT69 years××√ ARNIPARAGON-HF73 years××√ SGLT-2iEMPEROR-PRESERVED72 years√×?ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; ARNI, angiotensin receptor-neprilysin inhibitor; FDA, Food and Drug Administration; H-ISDN, hydralazine-isosorbide dinitrate; MRA, mineralocorticoid receptor antagonist; SGLT-2i, sodium-glucose cotransporter-2 inhibitor. Open table in a new tab ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; ARNI, angiotensin receptor-neprilysin inhibitor; FDA, Food and Drug Administration; H-ISDN, hydralazine-isosorbide dinitrate; MRA, mineralocorticoid receptor antagonist; SGLT-2i, sodium-glucose cotransporter-2 inhibitor. The presence of a complex pathophysiology and competing causes of death does not mean that we should abandon all-cause mortality as an end point for HFpEF studies. Studies like the recently completed Dapagliflozin Evaluation to Improve Lives of Patients with Preserved Ejection Fraction Heart Failure (DELIVER) will provide additional insight on the impact of sodium-glucose co-transporter 2 inhibitor on all-cause mortality. However, regardless of those results, these inherent challenges of improving all-cause mortality are important to consider when interpreting clinical trials in HFpEF. In our opinion, the absence of mortality reduction on a population-level should not undermine the potential impact of a therapy for HFpEF, particularly when fully considering end points that may be important to patients suffering from this condition. For example, hospitalization for HF may be a particularly relevant end point, given the harm associated with such an event. Indeed, overall survival decreases with each subsequent hospitalization for HF.4Setoguchi S Stevenson LW. Schneeweiss S. Repeated hospitalizations predict mortality in the community population with heart failure.Am Heart J. 2007; 154: 260-266Crossref PubMed Scopus (394) Google Scholar With hospitalization, there is also an increased risk for being discharged to a nursing home and losing independence—an event that many older adults fear more than death itself.5Mattimore TJ Wenger NS Desbiens NA Teno JM Hamel MB Liu H et al.Surrogate and physician understanding of patients' preferences for living permanently in a nursing home.J Am Geriatr Soc. 1997; 45: 818-824Crossref PubMed Scopus (159) Google Scholar Although hospitalization is certainly a marker of illness severity, the hospitalization itself may contribute to observed decreases in survival, independence, and quality of life. Posthospitalization syndrome has been defined as a state of vulnerability in the period immediately after hospital discharge when there is a heightened risk of disability, morbidity, mortality, and rehospitalization and may have a disproportionate impact in older adults who already contend with deficits in cognition and function (i.e., patients with HFpEF). Taken together, medications that can decrease HF hospitalizations (even in the absence of decreasing other causes of hospitalizations) provide significant value to patients with HFpEF. HFpEF has been a challenging condition to understand and ultimately treat. In the context of multiple clinical trials that have failed to meet their primary end points, HFpEF is understood to be a complex heterogeneous condition that requires a phenotype-matching approach to treatment.2Shah SJ Kitzman DW Borlaug BA van Heerebeek L Zile MR Kass DA et al.Phenotype-specific treatment of heart failure with preserved ejection fraction: a multiorgan roadmap.Circulation. 2016; 134: 73-90Crossref PubMed Scopus (564) Google Scholar However, there is another lesson to be learned here, which has emerged from the early discussions about the EMPEROR-PRESERVED study—all-cause mortality may be an overambitious clinical end point in HFpEF. Patient-reported outcomes like quality of life and functional capacity have considerable value to patients, especially older adults who may prioritize these outcomes over longevity.6Redfield MM, Borlaug BA. Quality of life and exercise ability in heart failure with preserved ejection fraction: no time for therapeutic complacency.JAMA. 2021; 326: 1913-1915Crossref PubMed Scopus (3) Google Scholar We thus advocate for patient-centered outcomes such as these, as well as emerging concepts like days at home, or home time, as reasonable clinical end points for future trials. We hope that ongoing discussions about the EMPEROR-PRESERVED study will re-emphasize the importance of patient-centered end points beyond all-cause mortality, and subsequently guide future clinical trial design for HFpEF. Dr Goyal is supported by American Heart Association grant 20CDA35310455, National Institute on Aging grant K76AG064428, and Loan Repayment Program award L30AG060521; Dr Goyal receives personal fees for medicolegal consulting related to HF; and has received honoraria from Akcea inc and Bionest inc. Drs Sauer and Rich have no relevant disclosures to report.