Heart Failure Treatment and the Art of Medical Decision Making

'If it were not for the great variability among individuals, medicine might as well be a science, not an art'. William Osler Therapy for patients with heart failure and reduced ejection fraction (HFrEF) has advanced remarkably over the past three decades but the multitude of treatment options has created a dilemma for clinicians faced with choosing the appropriate sequencing of therapies. In contrast to other chronic cardiovascular conditions such as hypertension, diabetes, or dyslipidaemia, there is no reliable surrogate physiologic target (such as blood pressure level, glycated haemoglobin, or low-density lipoprotein cholesterol) with which to guide therapy in patients with HFrEF. Current guidelines recommend several different classes of medications for patients with HFrEF [guideline-directed medical therapy (GDMT)], with titration of each to the target doses specified in the trial protocols.1 However, even within the ideal circumstances of a randomized trial, only 50% to 78% of trial participants achieve these target doses.2 In clinical practice, patients are often substantially different from those enrolled in trials and the proportion of heart failure (HF) patients prescribed GDMT who either reach or can tolerate randomized trial target doses is even lower.3 Thus, as clinicians we frequently must choose how best to individualize our treatment of a patient with HFrEF: should we prioritize lower doses of multiple agents or higher doses of fewer agents? In order to address this dilemma, several issues should be considered. Each of the five main drug classes making up GDMT target different pathophysiologic pathways and have been shown to improve morbidity and/or survival in most patients with HFrEF: angiotensin-converting enzyme inhibitors (ACEI), angiotensin receptor blockers (ARB), beta-blockers, mineralocorticoid receptor antagonists, and angiotensin receptor–neprilysin inhibitors (ARNI). In addition to recommending three of these agents for most HFrEF patients, guidelines also recommend the use of hydralazine plus long-acting nitrates or ivabradine in some patients, as well as the selective use of other agents to improve symptoms, such as loop diuretics or digoxin. Two network meta-analyses examined the data from all 58 randomized trials of GDMT published between 1987 and 2017 and reported that combinations of drug classes were associated with greater reductions in all-cause mortality and all-cause hospitalizations than single drug therapy, and that triple therapy was more beneficial than dual therapy (Figure 1).4-7 Although guidelines based on expert opinion advocate the use of ACEI/ARB first in congested patients and beta-blockers initially in dry patients or those with faster heart rates,1 no randomized trial evidence definitively informs which class of drugs is best to start first. While it may be tempting to extrapolate from the size of treatment effects reported in network meta-analyses or individual trials, this is inadvisable since the event rates reported therein are also influenced by differences in concomitant therapies and patient profiles between trials. Although the open-label CIBIS-III study was under-powered to establish either non-inferiority or superiority of starting with a beta-blocker first vs. an ACEI first, it did demonstrate that higher doses of either agent were more likely to be achieved if that agent was used first: for example, 86% of participants randomized to bisoprolol first reached high dose of bisoprolol, whereas only 72% of those in the arm receiving bisoprolol second achieved high dose (the corresponding numbers for enalapril were 90% and 82%).8 While studies with surrogate outcomes (such as left ventricular ejection fraction, natriuretic peptides, or other biomarkers) suggest that higher doses of GDMT are more beneficial in reversing the pathophysiologic changes of HF,9 the data on clinical outcomes is decidedly less robust. Interpreting comparative effectiveness observational studies on this topic is not straight-forward due to residual confounding: patients who can tolerate higher doses of GDMT generally have better haemodynamic profiles and are functionally more robust. Thus, we must rely on randomized trial data: however, meta-analysis of six trials (9171 patients) found no differences in all-cause hospitalizations (Figure 1) or HF hospitalizations [relative risk (RR) 0.94, 95% confidence interval (CI) 0.70–1.26] with high-dose ACEI/ARB vs. low-dose, and only a marginal effect on mortality (RR 0.94, 95% CI 0.89–1.00, number need to treat 56).6 While there were no differences in drug discontinuation rates between high and lower doses of these renin–angiotensin system modifiers, another meta-analysis which extracted adverse events from 10 trials documented clear excesses in risks of hypotension [RR 1.60, 95% CI 1.28–2.00, number needed to harm (NNH) 35], hyperkalaemia (RR 1.87, 95% CI 1.39–2.51, NNH 35), and increasing creatinine (RR 1.46, 95% CI 1.18–1.81, NNH 23) with higher doses of ACEI/ARB vs. lower doses.7 However, an analysis of participants in the CHAMP-HF registry suggested that it was not blood pressure that was limiting up-titration of therapies as rates were similarly low regardless of whether systolic blood pressure was greater or less than 110 mmHg.10 A meta-regression analyses of the 23 beta-blocker HF trials (19 209 patients) demonstrated that while the adverse effects of beta-blockade are dose-related, the mortality benefits were significantly associated with the magnitude of heart rate reduction achieved.11 This was consistent with another meta-analysis12 of 26 beta-blocker trials which reported a strong correlation (R2 0.53, P < 0.005) between magnitude of heart rate reduction and improvements in left ventricular ejection fraction and an individual patient data meta-analysis of data from 11 of these trials (18 637 patients) confirming that lower achieved heart rates were associated with better prognosis for patients in sinus rhythm.13 There is a host of evidence that patient adherence with prescribed medications, even for symptomatic conditions like HF, is suboptimal and poor adherence is associated with poorer outcomes and higher costs.14 While numerous factors influence medication adherence, particularly relevant to the decision-making process for HF patients is the fact that 'patient unfriendly treatment regimens' (for example, those requiring frequent doses per day or including a higher number of prescribed medications) are associated with poorer adherence.15 Thus, for patients in whom adherence is a concern, an argument could be made for simpler treatment regimens (fewer drugs at higher doses); this may be a less important consideration in other patients. Moving beyond the individual patient interaction, we believe there is a need for the development and evaluation of combination tablets containing lower doses of multiple GDMT. While there have not yet been any randomized trials testing polypill options in HF populations, there is randomized trial evidence in patients with hypertension that use of low-dose fixed combination therapies from the outset improves adherence and achievement of blood pressure treatment targets compared to maximization of single drug doses before step-wise addition of other agents.16 A recent cluster-randomized trial confirmed the effectiveness of a polypill in reducing major cardiovascular events in a mostly primary prevention cohort.17 However, given the numerous medication dosage changes that may be required due to illness trajectory, a polypill approach is more challenging to implement in HF clinical practice and we would need randomized trial evidence that a polypill improves morbidity and/or mortality in HF before such an approach could be advocated. As the population ages and more patients survive with HF (a tribute to the successes of cardiovascular trials over the past three decades), the frequency and import of co-morbid conditions is increasing.18 Already more than half of Medicare patients with HF have four or more non-cardiac co-morbidities, and more than a quarter have six or more.1 Despite this, patients with multimorbidity continue to be under-represented in randomized trial populations, leaving uncertainties about the balance between benefits and harms for many medications in such patients.19 HF patients with co-morbidities report poorer quality of life,20 and many all-cause hospitalizations or deaths in patients with HF are due to their co-morbidities rather than their HF. For example, in the Trieste HF registry, 22% of deaths and 17% of hospitalizations in HF patients were attributed to their chronic kidney disease, 21% and 14% to their anaemia, 18% and 11% to their diabetes, and chronic obstructive pulmonary disease (COPD) was the attributable cause for 12% of deaths and 15% of hospitalizations.21 Thus, it is not surprising that HF prognostic risk scores include various non-cardiac co-morbidities. The import of co-morbidities on prognosis is undoubtedly even larger than currently appreciated since several other important co-morbidities such as depression, frailty, urinary incontinence, and sleep disorders are under-ascertained in clinical registries due to lack of systematic screening for them. Finally, there is increasing evidence that there may well be racial differences in co-morbidity profiles as well as responsiveness to some GDMT and outcomes in HF.22 Given that co-morbidity profiles in HF patients change over time, the dosing of GDMT needs frequent re-assessment as renal and hepatic function change or as co-morbidity profiles evolve. Therapy for co-morbid conditions also often complicates management in patients with HF. It is well recognized that some concomitant therapies may worsen HF: for example, steroids for COPD exacerbations or non-steroidal antiinflammatory drugs for arthritic conditions induce fluid retention. It is also well known that some concomitant therapies may interact with HF medications: for example, sodium–glucose co-transporter 2 (SGLT2) inhibitors induce natriuresis and their introduction frequently necessitates a reduction in dose of diuretics in patients with HF. However, less well recognized is that treatment targets for co-morbid conditions may differ in patients with vs. without HF. For example, glycated haemoglobin exhibits a U-shaped association with mortality in patients with diabetes and HF which is different from the pattern seen in diabetic individuals without HF.20, 23 The clinician caring for a patient with HF must take all of these factors into account when coordinating a patient's therapy. For example, in a patient with poorly controlled diabetes and atherosclerotic disease, the initiation of SGLT2 inhibitor should take priority over optimization of ACEI/ARB or ARNI dosing if blood pressures preclude up-titration of all agents. Similarly, when a patient with benign prostatic hypertrophy requires alpha-blocker therapy this may also limit the ability to maximize dose of GDMT agents that also lower blood pressure. The discussion about up-titrating therapy in a patient with stable HF often requires overcoming the inertia of both the physician and the patient who are reluctant to make adjustments due to (i) misperception that stability of symptoms equates to clinical stability or concerns over (ii) inducing side effects, or (iii) creating the need for more healthcare encounters and/or laboratory investigations for therapeutic monitoring. Yet even apparently stable New York Heart Association class II HF patients receiving standard GDMT are at substantial risk: over one quarter experience a decline of five points or more in their Kansas City Cardiomyopathy Questionnaires in the subsequent year, between 8–12% die annually (depending on QRS duration and co-morbidity burdens), and up to 40% of these deaths are sudden hence waiting until such a patient exhibits signs of deterioration is ill advised.24-26 In weighing the benefits/risks of using multiple low-dose agents vs. higher doses of single/dual therapy, clinicians must also consider the psychosocial circumstances of individual patients and integrate patient preferences.27 Fully informed patients may well elect to take higher doses of only one or two medications as opposed to lower doses of three or four medications. Regardless of whether to start with multiple agents at once or to introduce drugs in a step-wise fashion, it seems prudent to commence with low doses while monitoring individual responsiveness and side effects and schedule appropriate follow-up to balance the urgency to increase to target dose. While benefits may (but not always) take months/years to accrue, adverse effects typically occur soon after dosage changes. It is unknown whether rapid or slow up-titration regimens are more effective and better tolerated in patients with HF, although our clinical experience suggests the latter, especially in frail patients. Unfortunately, judging individual responsiveness still relies on clinical acumen (often based on subtle changes in patient quality of life) given the lack of an easily measured physiologic variable for assessing HF therapy efficacy. While there were hopes that natriuretic peptides could serve as a surrogate biomarker target for titrating drugs in HF (in the way low-density lipoprotein cholesterol, glycated haemoglobin, or blood pressure are for the other chronic cardiovascular conditions), the GUIDE-IT trial failed to detect a benefit with B-type natriuretic peptide-guided therapy over usual care.28 In conclusion, we recommend that clinicians, where possible, prescribe GDMT in the doses supported by clinical trial evidence but consider the issues we raise in this essay when tailoring therapy for an individual patient. This will require clinical judgement about barriers to achieving optimal GDMT in each patient, including medication tolerance, patient preference, blood pressure, heart rate, volume status, laboratory values, and affordability. We encourage researchers to incorporate patient-reported endpoints (quality of life measures, symptom scores, and the like) into future trials to further inform the choice of treatment strategies. We also support the pressing need for research to find biologic surrogates which can help guide the initiation and dosing of GDMT in HF and exploration of artificial intelligence approaches to interrogate existing datasets to identify subgroups of patients who stand to benefit most/least from specific GDMT agents. Ultimately, advances in pharmacogenomics and artificial intelligence may permit the identification of the optimal agents and doses for each patient with HF, thus facilitating true personalization of therapy. Until then, this decision will remain more an art than a science. The authors thank Dr. Leiah Luoma for her assistance in creating the figure. F.A.M. is supported by the Alberta Health Services Chair in Cardiovascular Outcomes Research. Conflict of interest: J.A.E. reports grants or honoraria from Amgen, AztraZeneca, Bayer, Bristol-Myers Squibb/Pfizer, Merck, Novartis, Sanofi, Servier, Johnson & Johnson, Heart and Stroke Foundation of Canada, National Institutes of Health, and the Canadian Institutes for Health Research. P.W.A. reports grants or honoraria from AstraZeneca, Merck, Bayer, Novartis, Sanofi, Boehringer Ingelheim, and CSL Limited. F.A.M. reports no conflicts of interest.

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