Simultaneous or rapid sequence initiation of medical therapies for heart failure: seeking to avoid the case of ‘too little, too late’

Abstract

This article refers to ‘Heart failure drug titration, discontinuation, mortality and heart failure hospitalization risk: a multinational observational study (US, UK and Sweden)’ by G. Savarese et al., published in this issue on pages 1499–1511. Similar to many cancers, a new diagnosis of heart failure (HF) in routine clinical practice continues to carry a roughly 50% chance of death within the next 5 years.1, 2 However, commonalities in prognosis notwithstanding, the culture and approach to therapy for cancer and HF remain remarkably different. In the setting of active or progressive disease, oncologists and cancer patients are often aggressive in decisions to initiate or change chemotherapy, even in the absence of new or worsening symptoms. This sense of urgency is the norm in cancer care, readily accepted by cancer patients and clinicians, and maintained by keen awareness of the benefits of therapy and the risk of no therapy. By comparison, the culture of care for HF with reduced ejection fraction (HFrEF) does not include this same sense of therapeutic urgency. Instead, despite robust clinical trial evidence and strong guideline recommendations, there remains a strong culture of hesitancy towards initiating and titrating lifesaving medications among eligible patients. Clinical risk is frequently underappreciated, and stable symptoms are often misconstrued as ‘low risk’ and as justification for not making an indicated change in therapy.3, 4 As a consequence, many eligible patients with HFrEF never receive therapies proven to extend survival, receive them with significant delay, or receive them at perpetually low doses.3, 5 Moreover, when medication changes are made, there is often prolonged sequencing of beneficial therapies. It can take several months to a year using this ‘one medication change at a time’ approach before patients achieve target or maximally tolerated doses of guideline-directed medical therapy (GDMT), and at each step, the culture of clinical inertia must again be overcome (Figure 1).6 In this issue of the Journal, Savarese and colleagues examine initiation and subsequent medication changes in GDMT for HFrEF in clinical practice across Sweden, the United Kingdom (UK), and the United States (US).7 Using claims-based registries from each country, medication fills for five foundational medications were independently examined: angiotensin-converting enzyme inhibitors (ACEI), angiotensin II receptor blockers (ARB), beta-blockers, mineralocorticoid receptor antagonists (MRA), and angiotensin receptor–neprilysin inhibitor (ARNI). In an effort to restrict the population to patients using these medications for HF rather than hypertension or other indications, populations were restricted to patients with a recent HF hospitalization prior to the new medication use (except for ARNI since indication for the therapy is restricted to HF). The follow-up period was 12 months or until death or end of the registry. Outcomes were medication dose titration and discontinuation within each medication class, as well time-to-first HF hospitalization and all-cause mortality endpoints. For defining dosing and drug discontinuation, both were based on the duration of each filled prescription and the number of days covered. Patients were considered to have discontinued treatment once the pills within the last dispensation were over, up until the time the next medication fill was collected. Across the three countries, the authors found 68 172 new users of HF drugs, with 8426 receiving an ACEI, 2303 an ARB, 10 476 a beta-blocker, 17 421 a MRA and 29 546 ARNI. In the 12 months following initiation, rates of target dose achievement were 15%, 10%, 12%, 30% for ACEI, ARB, beta-blockers and ARNI, respectively. Corresponding rates of discontinuation were 55%, 33%, 24% and 27%. For ACEI, ARB, and beta-blocker, among patients who were initiated on a starting or low dose, 68–80% were receiving the same dose or were discontinued within 12 months. MRA dose was titrated to 50 mg in <5% of patients and discontinuation was observed in 40% of the patients. Across the populations of new users of each medication, rates of the composite endpoint of HF hospitalization or death ranged from 40 per 100 patient-years for ACEI/ARB users to 87 per 100 patient-years for ARNI users. The results were largely consistent across all three countries. Savarese and colleagues should be congratulated for an elegant study that broadens our understanding of real-world patterns of GDMT use, persistence, and titration following initiation.7 Nonetheless, limitations should be noted. First, the diagnosis of HF was based on diagnosis codes from a recent hospitalization, and data on left ventricular ejection fraction were not available. Hence, although likely high, the exact proportion of patients in this analysis with HFrEF is unknown. This issue may be particularly relevant when interpreting rates of drug discontinuation, as thresholds to discontinue these medications may be lower among patients with mid-range or preserved ejection fraction. Second, this study does not address the precise clinician-reported reasons for longitudinal medication changes. Thus, the degree to which medication discontinuations were appropriate or inappropriate is unclear. Likewise, the clinical circumstances surrounding medication changes (such as vital signs, laboratory values, and presence of absolute or relative contraindications) are not available, nor is it known whether the sub-target doses achieved were maximally vs. sub-maximally tolerated. Lastly, since medication discontinuation was defined by medication fills from pharmacies, it is unknown what proportion of discontinuation was due to clinician de-prescribing vs. patient non-adherence. More specifically, these data cannot discern the degree to which rates of discontinuation may be due to (i) true medication intolerance, (ii) patients or clinicians having low thresholds for perceiving potential side effects or misattributing symptoms of HF as adverse medication effects, or (iii) patient non-compliance. Limitations notwithstanding, the current study provides an important examination of the current outpatient care delivered to patients with HF. While prior registries have described rates of medication use, dosing, and titration in outpatient practice, most studies have generally enrolled prevalent users of medication among patients with chronic HFrEF.3, 8 This prevalent user bias may impact results from registry follow-up in multiple ways. For example, patients already established on medication for some time before enrollment may be less likely to discontinue treatment during the study period. Likewise, populations with prevalent medication use may already be expected to include at least some patients at maximally tolerated doses, which may reduce overall rates of dose escalation during study follow-up. Also, for patients not receiving medication at baseline, it is often unclear from registries if patients with chronic HF may have previously been trialed on medications before enrollment but proven to be intolerant. In a novel approach, the current study examines ambulatory patients who are naïve to each of these medications, and provides a unique perspective on real-world care patterns at a likely earlier juncture in the HF journey when patients are first being initiated on therapy. Despite conceivably a greater impetus to titrate and optimize therapy after first beginning a medication, rates of dose escalation were low, and the vast majority of patients failed to achieve target doses of ACEI, ARB, beta-blocker, or MRA within 12 months of initiation.7 In contrast, rates of drug discontinuation at 12 months in this cohort of new users were alarmingly high, with approximately 1 in 2 patients discontinuing ACEI, 1 in 4 discontinuing beta-blockers, 1 in 4 discontinuing ARNI, and more than 1 in 3 discontinuing MRA. As we integrate the new findings from Savarese et al. with existing data, we are again reminded of one disturbing conclusion – the status quo approach to initiation and titration of medical therapy for HFrEF in routine clinical practice is grossly inadequate. In the landmark clinical trials for ACEI, ARNI, beta-blocker, and MRA, using gradual tolerance-limited up-titration every few weeks, most patients (∼40–80%) achieved target doses within a few months of medication initiation.9-12 Likewise, randomized trials show higher doses of ACEI/ARB and beta-blocker confer benefits incremental to lower doses, without excess risk of drug discontinuation.13, 14 Yet, in real-world practice, Savarese and team show that despite an ample 12-month time horizon, disturbingly few patients successfully achieve target doses, many discontinue therapy, and many patients suffer death and hospitalization in the meantime.7 These data, combined with prior real-world studies strongly suggest that a simpler and faster strategy for initiation of GDMT is urgently needed, as well as a comprehensive approach to prevent instances of inappropriate drug discontinuation. In this context, we have previously proposed rapid sequence or simultaneous initiation (with subsequent prompt up-titration) of comprehensive-disease modifying quadruple medical therapy for HFrEF (Figure 1).6 The goal is to immediately provide eligible patients the opportunity to benefit from lifesaving therapy, rather than needlessly withholding medications and exposing patients to excess risk of clinical worsening or subsequent development of medication contraindications. Instead, up-front immediate initiation of comprehensive disease-modifying quadruple therapy [ARNI, beta-blocker, MRA, sodium–glucose co-transporter 2 inhibitor (SGLT2i)] and subsequent prompt dose up-titration leverages the fact that (i) each member of quadruple therapy substantially reduces risk for death and hospitalization within days to weeks of initiation, and (ii) risk reductions with each individual therapy are substantial and fully additive.6 Moreover, in the context of high rates of drug discontinuation in the current study, simultaneous or very early use of quadruple therapy should be considered as a strategy for maximizing overall tolerance to the four-drug regimen.15 For example, multiple studies have suggested that apart from exposing patients to excess risk of death and hospitalization, delaying initiation of SGLT2i and delaying a switch from ACEI to ARNI may needlessly expose patients to excess risk of hyperkalaemia and risk of MRA discontinuation.16-18 Likewise, there is no evidence to suggest that the traditional and needlessly protracted and sequential approach to GDMT titration accomplishes anything beneficial, and there is no evidence that this approach improves medication tolerance. Rather, the data by Savarese and colleagues highlight that for many patients with HFrEF, following the traditionally long road to optimal GDMT means that for many patients it will be too little, too late. Conflict of interest: M.S.K. reports no disclosures. J.B. has served as a consultant to 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. S.J.G. has received research support from the Duke University Department of Medicine Chair's Research Award, American Heart Association, Amgen, AstraZeneca, Bristol-Myers Squibb, Cytokinetics, Merck, Novartis, and Pfizer; has served on advisory boards for Amgen, AstraZeneca, and Cytokinetics; and has served as a consultant for Amgen, Bayer, Merck, and Vifor.

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