European Primary Care Cardiovascular Society

Increased mortality risk if initiation of HF therapy is delayed

Zaman S et al., Eur J Heart Fail 2017


The mortality risk of deferring optimal medical therapy in heart failure: a systematic comparison against norms for surgical consent and patient information leaflets

Zaman S, Zaman SS, Scholtes T, et al.
Eur J Heart Fail 2017;19:14011409

Introduction and Methods

Recommended therapeutic options for HF are often under-utilized, or under-dosed, resulting in an increased risk for death [1,2]. The exact magnitude of the increased mortality risk, the clinicians’ perception and the patients’ understanding of this risk are not known.
Previous studies have shown that clinicians behave asymmetrically when discussing therapy for HF. They discuss potential adverse effects of therapy with great care, even when such effects are not more common than in the placebo arm. In contrast, few clinicians report that they communicate the magnitude of benefit, an increase in lifespan, of HF therapy [3,4]. In addition, it is not known whether clinicians have any consistent threshold for mentioning the possibility of death when discussing an intervention with a patient, and, if so, where this threshold lies.
In this study, the absolute risk of deferring HF therapy for 1 year was calculated based on a meta-analysis. Moreover, a clinicians’ survey was conducted to evaluate their risk estimates, as well as the thresholds at which mortality should be mentioned in written informed consent documents. In comparison, official UK NHS patient information leaflets were reviewed to establish which levels of risk for death are considered high to warrant discussion.
RCTs studying chronic HF with reduced EF were included in the meta-analysis, only if they had a placebo-controlled arm. 70 RCTs were included: 38 on ACE inhibitors, 21 on beta-blockers, and 11 on aldosterone antagonists. The primary endpoint was all-cause mortality. The mortality risk associated with deferring HF therapy for 1 year was calculated according to the following formula:
Mortality attributable to deferral = (mortality without deferral/risk ratio of the intervention)-mortality without deferral.
Clinicians were asked the following questions (response rate: 205/288, 88%)::
  • What level of absolute risk for death from a clinical decision makes that risk worth mentioning?
  • Your patient with heart failure is not prescribed an ACE inhibitor/beta-blocker/aldosterone antagonist. By how much will their absolute risk of death over 1 year be increased?
The review of patient information was based on the centralized patient information leaflet repository on the NHS website [4]. Leaflets were reviewed for any diagnostic or therapeutic intervention in which risk was expressed numerically, as either a percentage or a fraction.

Main results

  • There was a significant reduction in mortality with ACE inhibitors (RR: 0.80; 95%CI: 0.70–0.92; P=0.002; no evidence of heterogeneity), as well with beta-blocker therapy (RR: 0.73; 95%CI: 0.64–0.83; P<0.001; moderate heterogeneity: I2=43.9%; P=0.02), and with aldosterone antagonist therapy (RR: 0.77; 95%CI: 0.69–0.85; P<0.001; no evidence of heterogeneity).
  • 1-year deferral of a) an aldosterone antagonist (in a patient on ACE inhibitor and beta-blocker) has a mortality risk of 3.0 in 100, b) a beta-blocker (in a patient treated with an ACE inhibitor) has a mortality risk of 4.8 in 100, and c) an ACE inhibitor antagonist has a mortality risk of 4.4 in 100. Deferral of all three classes of therapy has a combined mortality risk of 12.2 in 100.
  • Clinicians recognized and even overestimated the absolute risk due to deferral of HF therapy. 20% of clinicians obtain written consent for a risk for death of 1 in 10 000, 33% for a risk for death ≤ 1 in 1000, 32% for a risk for death of ≤ 1 in 100, and 15% of clinicians would not mention death when taking written consent until the risk was greater than 1 in 100.
  • The thresholds at which individual clinicians include reference to death when taking verbal consent for a clinical decision were highly correlated with their behavior when taking written consent (Spearman’s rho=0.69, P<0.001).
  • 89 patient information leaflets designed to help patients make decisions about a test or a treatment were identified in the centralized NHS repository, of which 49 quantified a total of 149 risks numerically. Of the risks described, 13 (8.7%) referred to death or a combination of death and another complication. The risk of death quoted varied from 1 in 28.6 (death in the first year after pancreas transplant) to 1 in 150 000 (death from general anesthesia). The median risk was 1 in 300 (IR: 1 in 75 - 1 in 1000).
  • Every leaflet quoted a risk of death that was lower than the risk arising from the deferral of ACE inhibitor therapy for 1 year (1 in 22), or beta-blocker therapy (1 in 21). Twelve of 13 (92%) leaflets quoted a risk of death that was lower than the risk arising from the deferral of aldosterone antagonist therapy for 1 year (1 in 33). Every leaflet quoted a risk of death lower than the risk associated with the deferral of medical therapy with all three drug classes in combination for 1 year (1 in 8).


Deferral of ACE inhibitors, beta-blockers, and aldosterone antagonists for 1 year carries an absolute mortality risk of around 1% per month, even in patients with low-risk HF. Deferring HF treatment for 1 year carries 18 000 times more risk than the level at which patient information leaflets begin to mention death. Moreover, since clinicians appreciate the magnitude of risk in this context and even overestimate this risk, written informed consent should be used more often to document HF therapy deferral, which may help to focus patients and their clinicians on the importance of maximal early application of life-saving therapy.

Editorial comment [6]

In their editorial article, Böhm, Laufs, Mahfoud, Schirmer and Kindermann, state that ‘Zaman et al. should be applauded for developing an interesting idea and presenting a novel way of examining improvement in the implementation of various therapies.’ They recommend that patient information and informed consent for not implementing a suggested therapy should be further discussed and included in future guidelines, considering not only the no-harm principle when treating patients, but also the possible legal and health-economic implications.
The authors conclude: ‘The challenge posed to our profession by the fact that it is often necessary to risk causing harm in order to obtain therapeutic benefit is an old one. The provocative paper by Zaman et al. reminds us that making non-maleficence a priority can result in therapeutic nihilism that is indeed harmful to patients. The two important principles of non-maleficence and beneficence must be counterbalanced with one another in patient care in a manner that gives due respect to the patient’s autonomy.’
Find this article online at Eur J Heart Fail


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6. Böhm M, Laufs U, Mahfoud F, et al. Primum non nocere: the dangers of deferring heart failure therapy. European Journal of Heart Failure (2017) 19, 1410–1411.