A Fourth Pillar for All in the Treatment of Heart Failure

Eldrin F. Lewis


Eur Heart J. 2021;42(43):4452-4454. 

Graphical Abstract: Root causes of limited uptake of heart failure medications into clinical practice

Heart failure (HF) management has evolved over the past four decades with advances in medical, device, and management strategies to collectively reduce morbidity and mortality.[1] The key pillars of HF medical care have been angiotensin-converting enzyme inhibitors (ACEIs)/angiotensin receptor blockers (ARBs)/angiotensin receptor–neprilysin inhibitors (ARNI), beta-blockers, and mineralocorticoid receptor antagonist.[2] Given the recent studies of sodium–glucose co-transporter-2 inhibitors (SGLT2i) suggesting benefit in treating HF patients with and without diabetes in the Empagliflozin Outcome Trial in Patients with Chronic Heart Failure with Reduced Ejection Fraction (EMPEROR-Reduced) and Study to Evaluate the Effect of Dapagliflozin on the Incidence of Worsening Heart Failure or Death in Patients with Chronic Heart Failure (DAPA-HF),[3,4] many are calling for this class of medicine to join the other three medication classes to establish the foundation of HF management.

In this issue of the European Heart Journal, Lam et al. report a more detailed analysis of the regional and ethnic influences of empagliflozin in patients with HF with reduced ejection fraction (HFrEF) with and without diabetes using the EMPEROR-Reduced trial experience.[5] The placebo event rate per 100 patient-years of cardiovascular (CV) death or HF hospitalizations varied widely by region (Europe 17.5 to Asia 27.7) and race/ethnicity (White patients 18.7 to Black patients 34.4), and was driven by HF hospitalization. The ratio of total HF hospitalization to CV death also followed the primary event rate in distribution among region and race/ethnicity. Not surprisingly, the relative risk reduction with empagliflozin was greater among groups with a higher HF hospitalization/CV death ratio given the more consistent impact of SGLT2is on HF hospitalization reduction. When adding outpatient HF treatment to HF events, the regional differences were attenuated.

This study confirms regional variations in event rates in HF, similar to prior publications, which may be driven by a different threshold for hospitalization, individual environmental/behavioural influences that may decrease risk for similar HF severity, and differential reporting of events. Race/ethnicity variations have been demonstrated as well in the past, with higher rates of HF hospitalizations among Black patients.[6] Attempts at assessing interactions between race/ethnicity and region were limited by small numbers and should be interpreted cautiously. The key takeaway messages of this study are that the trend of empagliflozin efficacy was consistent across regions and race/ethnicities, and that groups with higher hospitalization rates derived greater benefit in subgroup analyses. Baseline characteristics of patients are quite different as well and may be more related to the prevalent disease burden in different race/ethnic groups (e.g. hypertension in Black patients and atrial fibrillation in White patients).

There are several findings that one must evaluate in putting this study into context. First, the inclusion of outpatient HF events is complicated even when adjudicated by a central committee. The investigator-reported outpatient events could be biased by regional reporting differences, access to care, and the presence of disease management programmes that adjust HF medications and diuretic dosing. Moreover, the natural diuresis that may happen with SGLT2is could influence decisions to adjust diuretics despite similarities in HF severity and could be a driver of the efficacy of empagliflozin. Assessing the impact on mortality after the outpatient intensification as a time-varying covariate may provide further validation of this endpoint. Secondly, race is a social construct and may not be uniform in different countries. Only 0.2% of participants enrolled in Europe were self-described Black despite a more diverse population in many countries in Western Europe. The use of race in estimated glomerular filtration rate may influence the differences in renal function between Black- and non-Black patients, suggesting that Black patients had better renal function. As CV death was similar between regions and race/ethnicity, the hospitalizations is the key driver of differences and needs further examination. Finally, while the treatment × race interaction was significant for the key outcomes, the skewed distribution of Black and Asian patients to a few countries makes it challenging to form firm conclusions as these two groups lived predominantly in the Americas and Asia, respectively, where the HF hospitalization to CV death was higher.

The potential increased benefit of SGLT2is in Asian and Black patients is interesting and merits further investigations, especially as it is now seen in two large trials. While median N-terminal probrain natriuretic peptide (NT-proBNP) levels were higher in Asia and Latin America, there were no racial differences in these levels and NT-proBNP does not explain the potential natriuretic benefit of SGLT2is in congested patients. Potential explanations for some of the differences in responsiveness may be differences in the decrease in plasma volume, decrease in blood pressure, and baseline plasma renin and aldosterone. Detailed pharmacokinetic/pharmacodynamic studies in different groups may shed some light on responsiveness, including the role of baseline sodium intake and sodium handling/urinary sodium levels.

While regional and racial/ethnic differences may continue to be demonstrated, it is imperative to address the disparities that persist in HF management in order to achieve health equity. These disparities are driven by imbalances in social determinants of health, healthcare systems and access, bias, and structural inequities. Despite strong evidence of the pharmacological benefits of other HF medicines, the real-world utilization remains suboptimal. In the CHAMP-HF registry, patients without contraindication to treatment were not taking standard HF medications; 27%, 33%, and 67% were not prescribed ACEI/ARB/ARNI, beta-blocker, and MRA therapy, respectively,[7] and Black patients were undertreated with hydralazine/nitrates.[8] Given the higher prevalence of concomitant hypertension in Black patients and diabetes in Asian and Latinx patients, it is important to ensure that SGLT2i utilization increases without the typical delay between scientific evidence and clinical practice.

As we further investigate regional and racial/ethnic differences in the efficacy of SGLT2is, we should treat all patients with HFrEF to optimize outcomes regardless of race/ethnicity or place of residence. The collective data of the efficacy of SGLT2is to date are moving this class of medicine to becoming a fourth pillar of HFrEF management. Reliance on subgroups may lead to disparities in treatment and delayed access to care. With increasing choices for treating the HFrEF patient, we should think strategically about optimization to maximize outcomes (Graphical Abstract). This includes addressing physician factors that may lead to reduced use of meds, such as misinterpreting research findings, limited clinician experience and potential lack of comfort with newer therapies, and general inertia focused on the perceived stability of patients. Patient factors include polypharmacy, absolute out of pocket costs, side effects, and matching outcomes that are meaningful to the patient. Yet other needs include addressing structural inequities, third- party payer costs, and improving healthcare delivery. Improvements in these factors will help improve implementation of the decades of progress that have been made due to innovative research to impact all people living with heart failure. As we continue to understand the variations in practice across regions of the world and investigate both racial/ethnic differences and disparities, it is imperative to not use these differences as reasons to avoid treating patients with HF optimally.