“why should a remedy be certain because it is unique”- Celsus 25 B.C.- A.D. 50
This Editorial refers to “Angiotensin receptor-neprilysin inhibitors and mortality among patients with HFrEF” by Svanstrӧm and colleagues.
The management of heart failure with reduced left ventricular ejection fraction (HFrEF) is based on a large number of randomized clinical trials (RCTs) including many thousands of patients, demonstrating the clinical benefit of inhibitors of the renin-angiotensin-aldosterone system, beta blockers and SGLT2 inhibitors. Based upon the results of these trials, the pharmacological management of HFrEF is strongly evidence-based, and is ensconced in guidelines from specialist societies in both North America and Europe.
Clinical trials are, by definition, limited by the study inclusion and exclusion criteria and, invariably include select patient populations which may not be representative of the patients seen in usual practice. This presents the clinician with challenges, and contributes to the phenomenon of clinical inertia, whereby clinicians are slow to introduce novel, evidence-based treatments in to their practice. Those patients who do receive the novel treatment are in themselves selected to some degree, based upon factors such as clinician specialization, experience and understanding, peer-support and patient understanding. Importantly, it is difficult in the extreme for clinicians to gauge the effect in routine practice of the introduction of a new treatment.
The seminal PARADIGM-HF trial published in 2014 demonstrated the superior clinical benefits of the novel ARNi agent sacubitril valsartan to what was at the previous gold standard, ACE inhibitor (ACEi). In the current issue of AJC, Svanstrӧm et al present data from a Danish national registry comparing outcomes for patients newly started on sacubitril valsartan, compared to patients prescribed alternative renin-angiotensin-aldosterone system (RAAS) inhibition with ACEi or angiotensin receptor blockade (ARB). In keeping with the observations in PARADIGM-HF, the authors report superior outcomes with sacubitril valsartan compared to alternative RAAS inhibition; all cause mortality was 15% lower, and the largest effect was observed in patients with more “severe” HF.
Svanstrӧm et al have utilized present what is an observational study of the comparative effects of alternative treatments based on a cohort design; they have considered outcomes seen with the new agent sacubitril valsartan with, quite appropriately, an older drug class (ACEi or ARB) that has been available for a considerable time. The study utilized a propensity, new-user cohort design; this allows assessment of possible early benefits (or indeed harm) and to time confounders appropriately. Essentially, patients had to be exposed to sacubitril valsartan for the first time, and were very well matched to patients prescribed ACEi/ARB, in terms of age, NTproBNP, renal function, and other clinically relevant parameters.
Importantly, the diagnosis of HFrEF had to be made by a cardiology specialist and was supported by recent measurement of elevated NTproBNP levels. Patients win the Danish registry study resembled those recruited to PARADIGM HF; 75% were male (80% in PARADIGM), had a mean of 69 (64 in PARADIGM), mean LVEF 26% (29% in PARADIGM) and had meadian NTproBNP of 1400 pg/ml (1600 in PARADIGM).
On this background the results of this analysis are clinically relevant to clinicians caring for patients with HFrEF. Sacubitril valsartan was associated with lower all-cause mortality (Hazard Ratio 0.85) not dissimilar to that seen in PARADIGM HF (HR 0.80). Treatment with ARNi in the Denmark registry was associated with lower risk of cardiovascular death (HR 0.81) again similar to that seen in PARADIGM but not of hospitalization due to cardiovascular causes. The greatest benefit of ARNi was seen in patients who might be considered to have more advanced HFrEF based upon recent hospitalization for HF, greater symptom burden, and higher NTproBNP levels.
The current report has a number of strengths. The authors utilized the Danish Heart Failure Registry (DHR), a national registry to which reporting of first-time specialist care, primary diagnosis of heart failure is mandatory. Identification of index cases was secure, and patients were propensity matched (on a 1 ARNi; 2 ACEi/ARB basis) according to relevant clinical parameters. With regard to potential weaknesses in this analysis, the authors do not present data regarding the doses of either of ARNi, or of ACEi/ARB. This is relevant considering the average doses of ARNi (375 mg/day) and enalapril (18.9 mg/day)achieved in PARADIGM HF were very high and are unlikely to have been replicated in patients in DHR.
The PARADIGM HF investigators were aware of the limitations common to all RCTs; highly selected patients often unrepresentative of routine practice. The PARADIGM HF investigators PARADIGM attempted to address, this at least in part, by reporting consistent benefits of ARNi compared to ACEi across the spectrum of age, sex and LVEF, and in substudies addressing baseline risk score and geographic location.
Svanstrӧm and colleagues are to be congratulated for carrying out a well-designed analysis of data from a national registry, addressing an important clinical issue. The results give reassurance to clinicians that treatment with ARNi is indeed better for patients with HFrEF than treatment with ACEi/ARB. We must encourage and reassure colleagues who may be prone to clinical inertia to implement what we know is best-practice for the benefit of our patients.
CRediT authorship contribution statement
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
