Introduction
It is highly improbable and incredibly fortuitous for a therapy to work across an entire syndrome. As luck would have it, that syndrome is heart failure—perhaps the most common cause of suffering and mortality across the world—and the therapy is sodium-glucose cotransporter-2 (SGLT2) inhibitors, whose glycosuric mechanism cannot fully explain its ability to reduce adverse clinical events and improve quality of life across large phenotypic swaths of heart failure.1 Randomized controlled trials of SGLT2 inhibitors in all iterations of heart failure, ranging from acute to chronic, across the spectrum of left ventricular ejection fraction, with and without type 2 diabetes and chronic kidney disease, have consistently showed significant reductions in both surrogate and clinical endpoints. Especially given the safety and tolerability of these medications, absent rare contraindications, SGLT2 inhibitors should be considered for all patients with heart failure.
In this issue of the Journal of the American College of Cardiology, Cunningham et al2 further bolster the evidence in support of near universal benefit of SGLT2 inhibitors in heart failure and address a key question: when should these medications be initiated? In a secondary analysis of the DELIVER (Dapagliflozin Evaluation to Improve the LIVEs of Patients With PReserved Ejection Fraction Heart Failure) trial that randomized 6,263 patients with heart failure and LVEF >40% to dapagliflozin or placebo, the authors examined whether the benefits of the therapy were present in patients who were randomized during their index hospitalization or within 30 days of discharge. Approximately 10% of the patients (n = 654) met this criterion; as expected, they were sicker at baseline and had higher event rates than more stable outpatients with heart failure. Notably, only 90 patients were enrolled while hospitalized, with an additional 167 subjects randomized within the 7 days of discharge. Unfortunately, the authors do not provide information on the proportion of patients who had never been hospitalized or the median time from a prior hospitalization in the no recent hospitalization group. Nonetheless, the relative reductions in the primary outcome of worsening heart failure or cardiovascular death were consistent across these strata of patient risk: dapagliflozin reduced the primary outcome by 22% in the “perihospitalized” population (18% in all others) and had a consistent benefit in improving quality of life, as measured by the Kansas City Cardiomyopathy Questionnaire Total Symptom Score. Most importantly, because of the increased absolute risk of the perihospitalized population compared with those enrolled without a recent hospitalization, the absolute risk reduction in the primary outcome with dapagliflozin vs placebo was nearly 3 times greater (4.4 events vs 1.5 events per 100 patient-years) corresponding to a substantial difference in the number needed to treat with dapagliflozin vs placebo in those recently hospitalized (28 patient-years) compared with those enrolled without recent hospitalization (65 patient-years). Similarly, serious adverse events or drug discontinuation did not differ.
These data extend prior findings from EMPULSE (A Study to Test the Effect of Empagliflozin in Patients Who Are in Hospital for Acute Heart Failure), which demonstrated that in-hospital initiation of empagliflozin, compared with placebo, led to a significant clinical benefit (a broad composite of death, heart failure events, and change in symptom burden) among individuals hospitalized with acute heart failure, regardless of ejection fraction.3 Additionally, SOLOIST-WHF (Effect of Sotagliflozin on Cardiovascular Events in Patients With Type 2 Diabetes Post Worsening Heart Failure) showed that in patients with diabetes and recent worsening heart failure, sotagliflozin therapy, initiated before or shortly after discharge, resulted in a significantly lower total number of deaths from cardiovascular causes and hospitalizations and urgent visits for heart failure than placebo.4
Given the results of the DELIVER trial overall and the prior published data, there is now a vast body of evidence to support a foundational role of SGLT2 inhibitors in heart failure, and this is reflected in the recent guidelines from the American College of Cardiology/American Heart Association.5 The data from Cunningham et al2 coupled with insights from EMPULSE and SOLOIST provide important practical evidence (efficacy and safety) to substantiate initiation of SGLT2 inhibitors during or right after a hospitalization for heart failure. Indeed, given the obvious improvements in hospitalization metrics and the greater absolute risk reduction achieved in the recently hospitalized group, one might predict that health care systems, insurance companies, and clinicians would be clamoring to promote widespread prescriptions, especially in their highest-risk patients—those currently or recently hospitalized. Unfortunately, this is not the case, and the sobering gap between clinical evidence and clinical practice persists, revealing the important work that lies ahead if we are to achieve high-quality, cost-effective heart failure care. We believe that there is an urgent need for a multifaceted approach to close the implementation gap in heart failure, and the ongoing experience with SGLT2 inhibitors can serve as an exemplar for the pathways needed for success. The following approaches should be considered in order to make substantial progress in closing these gaps.
Leveraging the Electronic Health Record
Health care delivery in the United States has moved toward integrated systems of care that are linked by a shared electronic health record backbone. This allows for a move toward data-driven population health, where clinicians can be nudged to prescribe evidence-based therapies, and real-time monitoring of patient treatment can allow for rapid evaluations of any interventions.6 For example, we recently demonstrated in PROMPT-HF (A Cluster Randomized PRagmatic Trial Aimed At ImprOving Use Of Guideline Directed Medical Therapy In OutPatienTs With Heart Failure) that a personalized electronic health record–based alert to clinicians seeing outpatients with heart failure dramatically improved prescription rates of guideline-directed medical therapies.7 A parallel study in the inpatient setting is ongoing, and efforts are well underway to expand this low-cost and easily scalable intervention to health care systems across the world.
Improving Affordability
Despite widespread recognition of the importance of quadruple therapy for heart failure with reduced ejection fraction and now the emergence of evidence-based therapies for heart failure with preserved ejection fraction, there are major access and financial barriers that impede and undermine patient adoption. Broadly speaking, about 1 in 6 patients with heart failure report forgoing or delaying care primarily because of financial causes.8 More specifically, we have seen that while payer access to evidence-based medical therapy for heart failure has improved, cost barriers persist. In fact, in a recent analysis of Medicare Advantage and stand-alone Medicare Part D prescription drug plans, 99% required at least tier 3 cost-sharing. For an entire year of quadruple therapy, the median out-of-pocket price was U.S. $2,271, which included $976 for the angiotensin receptor-neprilysin inhibitor and $939 for the SGLT2 inhibitor.9 This degree of cost-sharing undermines adherence to highly effective therapies and must be examined as part of any comprehensive strategy to improve heart failure care.
Reassessing Heart Failure Quality Improvement Efforts
Current strategies at improving heart failure quality are beset by fragmentation and an excessive focus on evidence agnostic metrics. For example, health care systems invest enormously in resource intensive translational care programs that are assembled around concepts such as fluid and salt restriction that have a limited likelihood to improve patient outcomes.10 Furthermore, emerging evidence suggests that existing readmission prevention programs could even harm patients.11 A more effective approach might be to refocus efforts on increasing prescription of evidence-based therapies across the spectrum of heart failure patients; ongoing data continues to show that the majority of eligible patients remain untreated. This approach would be truly value-dominant, resulting in substantial improvements in patient quality of life, cardio-reno-metabolic outcomes, and reductions in health care utilization.
In conclusion, the data clearly shows that SGLT2 inhibitors should be considered for all patients with heart failure. Their lackluster implementation at the bedside uncovers an ongoing and much needed shift in heart failure care delivery: away from fee-for-service to value-based models. The current system has contributed to suboptimal quality, marked variation in outcomes and performance, spiraling costs, and glaring inequities. As health systems and other providers expand participation in alternative payment models and hold financial risk for the patients and populations they are caring for, we will have better alignment of incentives and could finally deliver on the promise of optimal heart failure care for all. All evidence suggests that SGLT inhibitors should be integral to this new and improved ecosystem.
ARYAN'S BLOG 