Real-World Dosing of Evidence-Based Medications for Heart Failure: Embracing Guideline Recommendations and Clinical Judgement

This article refers to ‘Physicians’ guideline adherence is associated with better prognosis in outpatients with heart failure with reduced ejection fraction: the QUALIFY international registry' by M. Komajda et al., published in this issue on pages 1414–1423. Heart failure (HF) is a global public health problem affecting an estimated 38 million patients worldwide.1 Among the countries represented by the European Society of Cardiology (ESC), there are more than 15 million patients living with HF and one million hospitalizations annually.2-4 Despite the growing burden of HF, the management of HF with a reduced ejection fraction (HFrEF) has been revolutionized by guideline-directed medical and device-based therapies. Although the proliferation of evidence-based medications has dramatically improved the prognosis of patients with HFrEF, the additional therapeutic options may inadvertently lead to tradeoffs between the initiation and up-titration of the available classes of medications, which may be limited by blood pressure, renal function and electrolyte levels (i.e. K+). This issue of the journal features the primary results of the international QUALIFY (Quality of Adherence to Guideline Recommendations for Life-Saving Treatment in Heart Failure Survey) survey, which evaluated the association between provider adherence to guideline-recommended target doses of evidence-based medications and clinical outcomes.5 The QUALIFY study is an international, prospective, observational and longitudinal survey that enrolled 7117 patients between September 2013 and December 2014 at 547 centres in 36 countries in Africa, Asia, Australia, Europe, the Middle East, and North, Central and South America.6 All patients aged >18 years with HF, an ejection fraction of <40% within the past 2 years, and discharged from hospital within the prior 1–15 months were eligible for participation. The registry assessed provider adherence to the following five classes of medications recommended for HFrEF by the ESC guidelines: angiotensin-converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs), beta-blockers, mineralocorticoid receptor antagonists (MRAs), and ivabradine.7 For each medication, 0, 0.5 and 1 point, respectively, were assigned for not prescribing a medication in the absence of a documented intolerance or contraindication, prescribing a medication at <50% of the target dose, and prescribing a medication at >50% of the target dose. Global adherence was assessed using the ratio of the sum of the medication regimen actually prescribed to the ideal treatment plan according to guideline-recommended target doses. The QUALIFY investigators defined three levels of adherence: good (i.e. a score of 1), moderate (i.e. a score of >0.5 to <1), and poor (i.e. a score of <0.5). Patients were followed for 6 months for all-cause, cardiovascular (CV)-specific and HF-related mortality, and CV-specific and HF-related readmission. A total of 6669 ambulatory patients with HFrEF with available follow-up data (94%) were included in the present analysis.5 Global adherence scores at baseline were good, moderate and poor, respectively, in 23%, 55% and 22% of patients. Of note, patients with a poor global adherence score tended to be elderly and were more likely to have a prior history of cancer and to report New York Heart Association (NYHA) functional class IV symptoms. Although patients with good global adherence scores had higher prevalences of most cardiac and non-cardiac co-morbidities, they were also more likely to report NYHA functional class I symptoms and to have higher systolic and diastolic blood pressure. After adjustments for potential confounders, poor adherence was associated with increased risk for all-cause mortality at 6 months [hazard ratio (HR) 2.21, 95% confidence interval (CI) 1.42–3.44; P = 0.001] and a trend towards an increased risk for HF hospitalization that approached but did not reach the threshold for statistical significance (HR 1.32, 95% CI 1.04–1.68; P = 0.069).5 It is important to highlight that the present analysis5 and the existing guidelines are based on the assumption that using higher doses of evidence-based medications will invariably reduce CV morbidity and mortality.7, 8 However, few clinical trials have directly compared high-dose with low-dose neurohormonal blockade and the available data are somewhat conflicting. For instance, the MOCHA (Multicenter Oral Carvedilol Heart Failure Assessment) trial found that carvedilol resulted in dose-dependent improvements in left ventricular systolic function and survival among patients with HFrEF and mild–moderate symptoms.9 In contrast, clinical trials of ACEIs and ARBs in HFrEF have shown that high-dose compared with low-dose renin–angiotensin inhibition led to a reduction in hospitalizations for HF, which was partially offset by higher incidences of hypotension, renal insufficiency and hyperkalaemia.10, 11 In addition, patients participating in the QUALIFY registry with a poor global adherence score tended to be older and more symptomatic, and to have lower blood pressure, suggesting that the association between global adherence and CV morbidity and mortality may be confounded by HF disease severity despite multivariable adjustment. Additional research is required to replace the generic approach in which medications are up-titrated to the maximal tolerated dose with a more personalized approach that takes into account demographic factors (i.e. age and gender), medical history, vital signs, laboratory values and/or biomarkers. To this aim, the ongoing GUIDE-IT (Guiding Evidence-Based Therapy Using Biomarker Intensified Treatment) study is a pivotal trial testing the efficacy, safety and tolerability of a natriuretic peptide-guided strategy, compared with usual care, in high-risk patients with HFrEF.12 Although the QUALIFY registry provides important data on provider adherence to guideline-directed medical therapies,5 several questions remain unanswered. Firstly, no data were provided on geographic variation in rates of prescription of evidence-based medications. Overall, the utilization of MRAs in QUALIFY approached 80% in patients with moderate–good global adherence scores, yet the fact of tremendous regional variation in MRA use is well established and improving adherence to this life-prolonging medication may be an important objective of future quality improvement initiatives.13, 14 Secondly, only approximately 10% of patients had an implantable cardioverter defibrillator and/or biventricular pacemaker at baseline, although the vast majority of patients were potentially eligible.5 This finding is consistent with prior international clinical trials15-17 and additional research is necessary to explore strategies to improve the global utilization of device-based therapies, particularly in more resource-constrained environments. Thirdly, the QUALIFY survey reveals no additional insight into provider reasons and patient factors contributing to non-adherence to evidence-based medications and/or guideline-recommended target dosing. Although only 30% of patients achieved target doses of ACEIs/ARBs, beta-blockers and MRAs in the ESC Heart Failure Long-Term Registry, a specific contraindication and/or intolerance was documented in close to two-thirds of patients.18 Thus, the rate of physician non-adherence to guideline-recommended target dosing may be much lower than suggested by the QUALIFY registry. Finally, implementation science must move beyond provider adherence to guideline recommendations and evaluate patient-level adherence and persistence in the use of evidence-based medications in real-world clinical settings. The major limitation of the QUALIFY survey5 in relation to the contemporary management of ambulatory HFrEF patients is that it was conducted prior to the approval of sacubitril/valsartan, a dual-acting angiotensin receptor–neprilysin inhibitor (ARNI), by the European Medicines Agency (EMA). The landmark PARADIGM-HF (Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure) trial found that the use of sacubitril/valsartan, compared with enalapril, led to a 20% relative reduction in the risk for CV death or HF hospitalization in ambulatory patients with HFrEF.19, 20 As a result, the EMA approved sacubitril/valsartan and the ESC updated its guideline recommendations to include switching from an ACEI or an ARB to an ARNI to further reduce the risk for CV morbidity and mortality in HFrEF patients who remain symptomatic despite optimal medical therapy.21 Of note, the PARADIGM-HF protocol incorporated sequential, single-blind, run-in phases during which patients were required to tolerate target dosing with enalapril (i.e. 10 mg by mouth twice per day) and sacubitril/valsartan (i.e. 200 mg by mouth twice per day) prior to undergoing randomization. Overall, 2079 patients (19.8%) discontinued the study drug during the run-in period, including 1102 patients (10.5%) during the enalapril phase and 977 patients (9.3%) during the sacubitril/valsartan phase.22 In addition, more than 40% of patients required a dose reduction in study medication during follow-up, a factor associated with increased risk for CV morbidity and mortality.23 However, the magnitude of the treatment benefit in patients on lower doses of sacubitril/valsartan vs. enalapril was comparable with that in patients remaining on target doses of both study medications.23 As a result of the relatively high rates of run-in non-completion and requirements for dose reductions in randomized patients during follow-up, both principally as a result of hypotension, the manufacturer has made available a lower dose (i.e. a 50-mg tablet) of sacubitril/valsartan not previously tested in clinical trials, which is the label-recommended starting dose for patients not currently taking an ACEI/ARB or previously taking a low dose of either agent. Thus, additional research is required to clarify the efficacy, safety and tolerability of low-dose vs. high-dose ARNI therapy, in the context of clinical trials and real-world practice. In conclusion, the QUALIFY investigators should be commended for prospectively evaluating the association between provider adherence to guideline-recommended target doses of evidence-based medications and clinical outcomes. However, it is important to remember that guideline recommendations should not supplant clinical judgement and there may be provider reasons and patient factors that discourage the initiation or up-titration of evidence-based medications to target doses. Compared with clinical trial cohorts, real-world patient populations are often older and have higher prevalences of cardiac and non-cardiac co-morbidities which may limit the tolerability and titration of background HF therapy due to deleterious changes in blood pressure, renal function and electrolyte levels (i.e. K+). Thus, the target dose may not be the right dose for an individual patient and additional research is required to personalize the initiation and titration of evidence-based medications in order to ensure safety and tolerability and to improve outcomes. Conflict of interest: A.P.A. declares no conflicts of interest. M.G. has been a consultant for Abbott Laboratories, Astellas, AstraZeneca, Bayer HealthCare AG, CorThera, Cytokinetics, DebioPharm SA, Errekappa Terapeutici, GlaxoSmithKline, Ikaria, Johnson & Johnson, Medtronic, Merck, Novartis Pharma AG, Otsuka Pharmaceuticals, Palatin Technologies, Pericor Therapeutics, Protein Design Laboratories, Sanofi-Aventis, Sigma Tau, Solvay Pharmaceuticals, Takeda Pharmaceutical and Trevena Therapeutics.