Sacubitril/valsartan in real‐life European patients with heart failure and reduced ejection fraction: a systematic review and meta‐analysis

Abstract

AimsWe systematically reviewed the European real-world evidence (RWE) about sacubitril-valsartan for heart failure with reduced ejection fraction. Methods and results Twenty-one articles, including 16 952 subjects, were identified until 31 October 2020. Taking as reference the PARADIGM-HF cohort, few baseline characteristics were presented in >80% of these studies, most often with high heterogeneity. In random-effects model meta-analysis, age was higher (mean difference +3.84, 95% CI 1.92-5.76), ischaemic aetiology (OR 0.76, 95% CI 0.64-0.91), hypertension (OR 0.55, 95% CI 0.37-0.82), and diabetes (OR 0.77, 95% CI 0.64-0.92) were less common, and the use of mineralocorticoid receptor antagonists was more frequent (OR 3.54, 95% CI 2.27-5.53) in real-life than in PARADIGM-HF. Other clinical and medical features were presented in 19-76% of the selected publications and suggested more severe heart failure with reduced ejection fraction. Sacubitril-valsartan was titrated to 97/103 mg b.i.d. in 35% (95% CI 23-47) and discontinued in 12.8% (95% CI 7.4-18.3) patients. When reported, the incidence of hyperkalaemia (six studies, no. 1076), all-cause mortality (five studies, no. 684), and any hospitalization (three studies, no. 390) was 12 (95% CI 5-19)/100 person-year, 8 (95% CI 4-12)/100 person-year, and 24 (95% CI 5-42)/100 person-year, respectively. Knowledge contribution, a metric measuring the proportion of RWE provided by each article based on the number of reported variables and the sample size, was 58.8% and 13.6% for the two biggest investigations (12 082 and 2037 patients), and <5% for all others (most with <100 subjects). Conclusions Limited-quality RWE indicates that there are important differences between European patients prescribed sacubitril-valsartan and the PARADIGM-HF population, including the frequency of target dose achievement.

Sacubitril/Valsartan in Heart Failure with Reduced Ejection Fraction: Real-World Experience from Italy (the REAL.IT Study)

“…When compared with the population of PARADIGM-HF, our population was characterized by a similar mean age of patients, (64.5 years in REAL.IT, compared with 63.8 years in the PARADIGM-HF) [ 8 ]. Further, the patients were younger than those of European and international real-world studies on sacubitril/valsartan utilization, whose ages ranged between 66 and 70 years [ 7 , 9 , 10 , 11 , 12 ]. Moreover, when compared with PARADIGM-HF, a lower percentage of patients were affected by diabetes (25.4% vs. 34.7%) and atrial fibrillation (23.2% vs. 36.2%).…”

“…In fact, although sacubitril/valsartan has been established as a foundational treatment for HF based on clinical trial data, there remains a paucity of data from real-world settings about its use, the characteristics of patients treated in routine practice, their resource utilization and the effect on outcomes. Furthermore, evidence from clinical experience of sacubitril/valsartan in Italian settings is limited [ 7 ]. Therefore, observational studies using data from patients already treated with sacubitril/valsartan are needed to evaluate the use of this therapy in the real-world setting of everyday clinical practice in Italy, considering the indication criteria provided by the therapeutic plan.…”

Impact of the COVID‐19 pandemic on prescription of sacubitril/valsartan in Italy

“…European real‐world data show that only 35% of heart failure patients are titrated to the highest dose of sacubitril/valsartan. 15 It is reassuring that, in PARADIGM‐HF, patients requiring dose reduction still derived benefit of sacubitril/valsartan over enalapril at lower than target dosing. 16 On the contrary, as shown by the TITRATION study, 17 up‐titration is necessary in patients with low systolic blood pressure or taking low‐dose angiotensin‐converting enzyme inhibitors/angiotensin receptor blockers.…”

“…However, this does not relate only to angiotensin receptor–neprilysin inhibitors but to the majority of cardiovascular and non‐cardiovascular medicines. European real‐world data show that only 35% of heart failure patients are titrated to the highest dose of sacubitril/valsartan 15 . It is reassuring that, in PARADIGM‐HF, patients requiring dose reduction still derived benefit of sacubitril/valsartan over enalapril at lower than target dosing 16 .…”

Haemodynamic Effects of Sacubitril/Valsartan Initiation in Outpatients with Chronic Heart Failure

“…In contrast, in real-world practice, S/V is usually initiated at a low dose with subsequent up-titration to prevent adverse events. However, real-world studies show unanimously that most patients do not achieve the S/V target dose [ 3 , 4 , 45 ]. In clinical practice, the main adverse event and deterrent to up-titration is symptomatic hypotension, followed by rising serum potassium levels and worsening renal function [ 3 , 46 – 48 ].…”