TARGET EU: The risk of angiooedema and other safety events in heart failure patients treated with sacubitril/valsartan compared to angiotensin-converting enzyme inhibitors

Study type

• Study topic:
  Disease /health condition

  Human medicinal product
• Study type:
  Non-interventional study
• Scope of the study:
  Safety study (incl. comparative)
• Data collection methods:
  Secondary use of data

Non-interventional study

• Non-interventional study design:
  Cohort

Study drug and medical condition

• Medicinal product name:
  ENTRESTO
• Anatomical Therapeutic Chemical (ATC) code:
  (C09DX04) valsartan and sacubitril

  valsartan and sacubitril
• Medical condition to be studied:
  Heart failure with reduced ejection fraction

  Heart failure with midrange ejection fraction

  Heart failure with preserved ejection fraction

Population studied

• Short description of the study population:
  This study will be conducted using routinely collected electronic health records from 2014 to 2023 and to 2024, for the CPRD and PHARMO databases, respectively. It will be set primarily in primary care and will draw on longitudinal data from general practices, with linkage to hospital and mortality records. Data will be sourced from two European countries: the United Kingdom and the Netherlands. In the UK, data will be obtained from the Clinical Practice Research Datalink (CPRD) Aurum database while in the Netherlands, data will be obtained from the PHARMO database. ; ; The study population will consist of adults with HF who initiate SV or are treated with ACEIs during the study period. Cohort entry (index date) will be defined as the date of the first SV prescription or the matched ACEI prescription (matched ACEI prescription is identified after applying the prevalent new user design). To be eligible, individuals must have a recorded diagnosis of HF prior to the index date and be aged 18 years or older at cohort entry. In addition, individuals must have at least one year of recorded medical history prior to the index date to allow adequate assessment of baseline characteristics. Several exclusion criteria will be applied to ensure appropriate cohort definition. Individuals will be excluded if they have a history of angioedema or severe hepatic impairment at any time before index date. They will also be excluded if they have overlapping prescriptions for ACEIs and ARBs in the 60 days before index date, a hospitalization for HF in the 7 days before index date, a diagnosis of peripartum cardiomyopathy or cardiomyopathy induced by external agents in the 1 year before index date and a diagnosis of hyperkalaemia or hypotension in the 30 days before index date.; ; Overall, the final study population will comprise adults aged 18 years or older with HF diagnosis who newly initiate SV or are treated with ACEI between 2014 and 2023 or 2024, for CPRD and PHARMO, respectively and meet all inclusion and exclusion criteria.
• Age groups:
  • Adult and elderly population (≥18 years)

    • Adults (18 to < 65 years)

      • Adults (18 to < 46 years)
      • Adults (46 to < 65 years)
    • Elderly (≥ 65 years)

      • Adults (65 to < 75 years)
      • Adults (75 to < 85 years)
      • Adults (85 years and over)

Study design details

• Study design:
  To emulate the target trial, we will use the prevalent new user (PNU) cohort design. This design includes an active comparator per definition. It matches new users of SV to ACEI comparators on their prior treatment history with ACEI/ARB.
• Main study objective:
  The primary objective of this observational study is to estimate the effect of treatment with sacubitril/valsartan versus ACEi on time to first angioedema event in patients with HF while the patients remain alive and while on treatment, i.e. before treatment discontinuation, switching or new add-on of any of the three HF medications (ACEi, ARB, SV).
• Setting:
  This study is conducted using routinely collected electronic health records from 2014 to 2024, reflecting the period of SV use in routine clinical practice. The study is set primarily in primary care, drawing on longitudinal data from general practices with linkage to hospital data. Data are sourced from two European countries, the United Kingdom (Clinical Practice Research Datalink [CPRD]) and Netherlands (PHARMO), providing population-based and representative coverage of real-world clinical care.
• Comparators:
  We chose an active comparator design because it is the most appropriate for the observational study, considering also that HF patients are likely already being treated. The 2021 guidelines of European Society of Cardiology recommend ACEIs or SV among the treatments of the first-line therapy of HF with reduced or mildly reduced ejection fraction. SV is also recommended as a replacement of ACEIs in suitable patients who remain symptomatic despite optimal treatment with all the recommended first line treatments. ARBs are considered as an alternative option in patients who are intolerant to ACEIs. Considering this information, ACEIs are the most appropriate comparator in our study.
• Outcomes:
  Angioedema is a safety outcome of particular interest because of the mechanism of action of both the intervention treatment and the control. From a clinical perspective it is important to know the risk of angioedema that treatments are associated with for two reasons. First and foremost, because it may necessitate hospitalization and may be life-threatening when it involves the upper airway. Secondly, because it usually leads to treatment discontinuation, which is the only way it can be addressed, depriving patients of the beneficial effects of HF treatments.
• Data analysis plan:
  The analyses are conducted within a target trial emulation framework to estimate the effect of SV compared with ACEIs on the risk of angioedema. ; ; For Estimand 1, the main estimand supporting decision making, the primary causal effect summary measure is the hazard ratio for time to first angioedema using a stratified Cox proportional hazards model in the PSM sample. The Cox model will be fitted separately within each data source (CPRD and BIFAP), and the resulting hazard ratios will be combined using a random-effects meta-analysis; potential sources of heterogeneity will be described qualitatively, including structural differences (e.g., coding systems, population coverage) and measurement differences (e.g., recording practices) and their implications (e.g., residual confounding or misclassification). ; ; Sensitivity analyses will assess robustness of the primary findings to key assumptions, including inverse probability of censoring weighting (IPCW), best/worst case scenario, and probabilistic bias analysis for non-differential outcome misclassification (details in Section 7.6.5). ; ; Two supplemental estimands are also defined: Estimand 2, applying a treatment policy strategy for intercurrent events, and Estimand 3, estimating treatment effects using restricted mean survival time (RMST) derived from a PSM Weibull accelerated failure time (AFT) model. In addition, supplemental analyses (e.g., crude and PS-matching adjusted Kaplan–Meier curves, crude Cox models, event counts and incidence rates, propensity score and weight distributions, covariate balance before and after PSM, censoring and intercurrent event patterns, proportional hazards diagnostics, positivity checks, and multiple-imputation diagnostics) will be conducted to support interpretation of the main analysis.
• Summary results:
  Not yet available