Another reason to embrace quadruple medical therapy for heart failure: medications enabling tolerance of each other

This article refers to ‘Effect of sacubitril/valsartan vs. enalapril on changes in heart failure therapies over time: the PARADIGM-HF trial’ by A.S. Bhatt et al., published in this issue on pages 1518–1524. To date, the care of heart failure (HF) with reduced ejection fraction (HFrEF) has accumulated multiple medications proven to improve patient survival: evidence-based beta-blocker, angiotensin-converting enzyme inhibitor (ACEI)/angiotensin II receptor blocker, angiotensin receptor–neprilysin inhibitor (ARNI), mineralocorticoid receptor antagonist (MRA), and sodium–glucose co-transporter 2 inhibitor (SGLT2i). In large randomized clinical outcome trials among patients with chronic HFrEF, each medication class has been shown to significantly reduce all-cause mortality, in addition to significant reductions in HF hospitalizations and improved patient-reported health status. Moreover, the clinical benefits of each therapy are fully additive and incremental to the others.1 Taken together, combination therapy with ARNI, beta-blocker, MRA, and SGLT2i is projected to provide a 73% relative reduction in 2-year mortality.2 Framed another way, compared with traditional dual therapy with an ACEI and beta-blocker, treating a 55-year-old patient with comprehensive disease-modifying quadruple medical therapy is estimated to add an additional 6 years of life.3 However, parallel to the substantial therapeutic advances in clinical trials, there continues to remain widespread underuse of both newer and older evidence-based therapies for HFrEF in clinical practice. In US outpatient practice, among patients with HFrEF eligible for therapy, more than one in four are not prescribed a renin–angiotensin system inhibitor (RASi), one in three are not prescribed an evidence-based beta-blocker, and two in three are not prescribed an MRA.4 Only 13% may be prescribed ARNI therapy.4 Likewise, among patients with HFrEF and diabetes, 5.0 mEq/L) over 1-year follow-up, and such events are associated with discontinuation of RASi therapy.11, 12 In the QUALIFY (Quality of Adherence to Guideline Recommendations for Life-saving Treatment in Heart Failure) survey of European patients with HFrEF, among patients who did not tolerate MRA, hyperkalaemia was the specific reason in 31% of cases.6 Likewise, recent clinical practice data spanning three countries found that HF patients initiating GDMT have high rates of discontinuation in the subsequent 12 months, including a 40% discontinuation rate for MRA.13 While data regarding reasons and appropriateness of discontinuation decisions were not captured, these findings emphasize the fragile state of GDMT utilization in real-world practice.13 Although new medications that reduce mortality and morbidity in clinical trials should be embraced, studying the effects of medications on the safety and tolerability of the other recommended lifesaving therapies is important for understanding the true magnitude of patient-centred benefit. In this issue of the Journal, Bhatt et al.14 present findings from the PARADIGM-HF (Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure) trial examining the effect of sacubitril/valsartan vs. enalapril on longitudinal use and changes in beta-blocker and MRA therapies. For beta-blocker, baseline use was high (87%), and mean doses were not significantly different between sacubitril/valsartan and enalapril at any point during follow-up. Moreover, changes in beta-blocker use over time (both initiations and discontinuations) were relatively rare, and similar between treatment arms. With regard to MRA, despite effects of randomization, there was a modest imbalance at baseline between assigned treatment arms with slightly lower use of MRA in the sacubitril/valsartan group. This difference dissipated over time, and rates of MRA use were similar between treatment arms at 12 months. This finding was explained by less MRA discontinuation at 12 months with sacubitril/valsartan than enalapril (6.2% vs. 9.0%, P = 0.001). Among patients not receiving MRA at baseline, there was no significant difference in rates of initiation of MRA between treatment arms, although there were numerically fewer MRA initiations over 12 months with sacubitril/valsartan (7.6% vs. 9.2%, P = 0.10). These data from Bhatt et al. provide further reassurance that routine initiation of sacubitril/valsartan can be achieved without untoward consequences on tolerability of other foundational GDMTs. In fact, the notable reduction in MRA discontinuation highlights the potential favourable effect of sacubitril/valsartan on tolerance of other GDMTs, as compared with ACEI. Nonetheless, as noted by the authors, limitations of this study should be recognized. Importantly, PARADIGM-HF included patients who tolerated sequential open-label run-in periods of enalapril and sacubitril/valsartan, and the ability to meet these criteria could have impacted results seen here for downstream use and tolerance to beta-blocker and MRA. Indeed, comparison of the absolute rates of MRA discontinuation at 12 months seen here (i.e. 6–9%) vs. a recent claims-based analysis (i.e. 40%) suggests potential selection bias.13, 14 Future research in unselected cohorts, including patients who are RASi-naïve, would further contextualize the tolerability of MRA therapy with ARNI vs. ACEI/ARB. Likewise, rates of background therapy in this clinical trial population were generally higher than those observed in clinical practice, including >50% of patients receiving MRA at baseline.4 The degree to which longitudinal results for initiation and discontinuation of beta-blocker and MRA therapies seen here generalize to populations receiving less intensive GDMT and follow-up is unclear. Likewise, with substantial global differences in rates of MRA therapy, it is possible that any effect of sacubitril/valsartan on MRA prescribing could vary significantly by region. As clinical practice continues to struggle with implementation of GDMT for HFrEF, the study by Bhatt et al. adds to the mounting evidence suggesting that the two newest additions to quadruple therapy, ARNI and SGLT2i, may improve the tolerability of other foundational medications (Figure 1). These effects may be largely mediated via potassium handling, as data from large clinical outcome trials suggest that both ARNI and SGLT2i decrease risk of hyperkalaemia compared with ACEI and placebo, respectively, particularly in the setting of concurrent MRA therapy.15-17 Indeed, similar to the current findings from PARADIGM-HF, investigators from the EMPEROR-Reduced (Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Reduced Ejection Fraction) trial recently showed that among patients on baseline MRA therapy, those randomized to empagliflozin were 22% less likely to discontinue or interrupt MRA therapy.17 Although significantly lower rates of MRA initiation with empagliflozin were also seen and may suggest enhanced clinical inertia or fewer HF hospitalizations with empagliflozin as explanations for fewer overall changes in MRA therapy, the strong possibility of a causal relationship between less hyperkalaemia and less MRA discontinuation cannot be ignored.17, 18 While trends towards lower MRA initiation with ARNI were also seen in the current study, the totality of data suggest that in addition to superior effects on clinical outcomes, use of ARNI should be prioritized above ACEI for purposes of maximizing chances of sustained tolerability and long-term use of MRA therapy. As we weigh the impact of the present analysis from PARADIGM-HF on clinical practice, it is worth considering these data in the context of ongoing questions and debate regarding optimal medication sequencing in HFrEF. Notably, the recent American College of Cardiology expert consensus document supports a direct-to-ARNI approach for RASi-naïve patients.19 Likewise, the rationale for rapid-sequence or simultaneous initiation of all four arms of quadruple medical therapy has been recently proposed.1 Combined with prior data on risk of hyperkalaemia with ARNI, these data from Bhatt et al. add further justification to these approaches.14, 16 Specifically, initiating or maintaining patients on ACEI and delaying a switch to ARNI may needlessly expose patients to excess risk of hyperkalaemia and MRA discontinuation. While MRA therapy could be theoretically retried after a delayed switch to ARNI, challenges with clinical inertia towards GDMT in routine practice suggest that every effort must be made to proactively prevent any initial MRA discontinuation. Similar rationale can be applied to SGLT2i where (aside from early clinical benefits on risk of death and HF hospitalization) early initiation may maximize long-term tolerance of the complete quadruple therapy regimen, as compared with the traditional, prolonged, sequential approach to GDMT initiation.1, 18 In total, available data suggest that early use of evidence-based therapy among eligible patients should be prioritized within a comprehensive patient-centred strategy to maximize collective medication tolerance and optimally prevent withdrawal of lifesaving medications. Conflict of interest: S.J.G. has received research support from the Duke University Department of Medicine Chair's Research Award, American Heart Association, Amgen, AztraZeneca, Bristol-Myers Squibb, Cytokinetics, Merck, Novartis, and Pfizer; has served on advisory boards for Amgen, AstraZeneca, and Cytokinetics; and serves as a consultant for Amgen, Bayer, Merck, and Vifor. J.B. has served as a consultant for Abbott, Adrenomed, Arena Pharma, Array, Amgen, Applied Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Cardior, CVRx, Eli Lilly, G3 Pharma, Imbria, Impulse Dynamics, Innolife, Janssen, LivaNova, Luitpold, Medtronic, Merck, Novartis, Novo Nordisk, Sequana Medical, V-Wave Limited, and Vifor. M.M. has received personal consulting honoraria from Abbott, Actelion, Amgen, Bayer, Edwards Therapeutics, Servier, Vifor Pharma, and Windtree Therapeutics for participation in advisory board meetings and executive committees of clinical trials.