Must I Keep Taking all Thesemedicines? Optimizing Diuretics in Chronic Heart Failure

G. Michael Felker

Disclosures

Eur Heart J. 2019;40(44):3613-3615. 

Congestion is central to the pathophysiology of heart failure.[1] An increase in cardiac filling pressures, sometimes termed haemodynamic congestion, drives many of the cardinal symptoms of heart failure such as oedema, orthopnoea, and dyspnoea on exertion. Given these facts, the successful management of congestion is fundamental to the care of patients with heart failure. Based on decades of clinical experience, loop diuretics are the standard of care for managing congestion in heart failure, and are recommended by clinical practice guidelines despite the relative lack of placebo-controlled data.[2,3]

Current guidelines have emphasized the critical importance of optimization of guideline-directed medical therapy (GDMT) for chronic heart failure. Recent studies have identified important gaps in optimization of heart failure therapies with regard to both baseline dosing[4] and titration of medications over time.[5] These gaps have led to increasing calls for better strategies to facilitate optimization of GDMT.[6] To date, studies focused on a strategy of targeting natriuretic peptide levels to facilitate GDMT optimization have shown mixed results.[7,8] Optimization efforts have generally been appropriately focused on classes of drugs shown to improve long-term outcomes, such as beta-blockers, renin–angiotensin system inhibitors, and mineralocorticoid receptor antagonists. Despite the importance of loop diuretics in heart failure management, little effort has focused on optimizing diuretics—indeed, what it would mean to 'optimize' diuretics is uncertain. Presumably, given observational data suggesting that high doses of chronic diuretics may be associated with worse outcomes, the 'optimized' dose of loop diuretics is the lowest dose that effectively manages signs and symptoms of congestion and prevents hospitalization and disease progression. But are there heart failure patients for whom the correct diuretic dose is zero? Polypharmacy is a substantial issue in the management of patients with cardiovascular disease, and 'de-prescribing' of unnecessary medications is an underappreciated but important part of chronic care.[9] Any clinician who takes care of heart failure patients, many of whom take six or more pills a day just for heart failure therapy, are familiar with the recurring question—'Do I need to keep taking all of these medicines?'

In this context, the study by Rohde et al. in this issue of the European Heart Journal provides critical data with direct relevance for day to day clinical decision making.[10] This study randomized 188 patients with stable chronic heart failure and ejection fraction ≤45% in a prospective, double-blind, randomized controlled trial to either usual care or a strategy of loop diuretic discontinuation at 11 clinics in Brazil. Importantly, patients were carefully selected to identify a lower risk cohort that might tolerate withdrawal of diuretics: enrolled patients had no heart failure hospitalizations or emergency department visits for heart failure within the previous 6 months, were on a stable and relatively low diuretic doses (either 40 or 80 mg of oral furosemide daily) for the previous 6 months, and had optimized GDMT. Patients with clinical evidence of congestion (as defined as a clinical congestion score >5) were excluded. The primary outcomes of interest were patient symptoms (by dyspnoea score) and the proportion of patients successfully maintained off loop diuretics during follow-up.

Key findings of this study included that there was no significant difference in symptoms of dyspnoea between those randomized to furosemide discontinuation vs. continuation. For the co-primary endpoint of 'furosemide re-use', there was no statistically significant difference between groups, although the point estimate for the odds ratio was 1.69 with wide confidence intervals, suggesting that this endpoint was underpowered. The study follow-up period was relatively short (90 days), and clinical events such as heart failure hospitalization were few and similar between the groups.

The authors are to be congratulated on designing and carrying out a study that is both difficult to conduct (strategy trials are notoriously challenging) and clinically relevant. The double-blind design in particular is notable and important to methodological rigour in order to avoid bias from either patients or clinicians. Still, it is important to recognize some key limitations of the study. Fundamentally, the current study is a safety study, designed to test the hypothesis that loop diuretics can be safely withdrawn in selected patients with heart failure with reduced ejection fraction (HFrEF) without adverse clinical effects. The most relevant adverse clinical consequences would be heart failure hospitalization or deaths, but the study was vastly underpowered to assess this outcome (there were only 10 such events in the entire study). The duration of follow-up (90 days) was also quite brief for a chronic heart failure study, and it is possible that a longer follow-up time would have led more patients to need re-initiation of diuretic therapy. The patients enrolled were generally a very low-risk subset of HFrEF patients, who were generally younger, with excellent background heart failure therapy, near normal renal function, and only modestly elevated natriuretic peptide levels.

How can we apply these data in clinical practice? In low risk patients such as those enrolled in the current study, careful withdrawal of loop diuretics with appropriate monitoring seems relatively safe (at least over a short time period) based on the presented data. A potential algorithm for decision making around optimizing diuretics in selected patients is shown in Figure 1. What portion of heart failure patients in routine clinical practice could qualify for such a protocol is uncertain. Patients with chronic heart failure who do not require chronic loop diuretics to maintain clinical stability are known to have a favourable prognosis.[11] In higher risk patients, even brief discontinuation of heart failure therapy has been shown to lead to elevated natriuretic peptides and haemodynamic congestion, making appropriate patient selection a critical concern.[12] In addition to appropriate patient selection, a key aspect of this approach is adequate monitoring—prior evidence from the initial experience with spironolactone in heart failure has shown that therapies that are safe and efficacious under carefully monitored clinical trial conditions may be less safe in routine clinical practice.[13] Finally, the study did not include patients with heart failure and preserved ejection fraction, so these data should not be extrapolated to this large and growing group of heart failure patients.

Figure 1.

A proposed algorithm for diuretic optimization in selected patients with chronic heart failure and reduced ejection fraction.

Although not specifically addressed by the current study, optimization of diuretics may also help facilitate achieving more effective GDMT in some circumstances. Early clinical experience with sacubitril–valsartan suggests that decreasing loop diuretic dosing by 50% at the time of initiation may help mitigate hypotension or orthostasis as a limitation to therapy, particularly in patients with lower blood pressure at baseline. In contrast, initiation of beta-blocker therapy is better tolerated when patients are euvolaemic as opposed to volume overloaded. Optimal therapy for chronic heart failure therefore requires thoughtful application of both the science and the art of medicine. Although diuretic utilization in heart failure is frequently more art than science, these data from Rohde and colleagues add importantly to the slowly growing science of proper diuretic use.

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