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Abstract Aims Recent updates of international treatment guidelines for heart failure with reduced ejection fraction (HFrEF) differ regarding the use of angiotensin receptor neprilysin inhibitor (ARNI) as first‐line treatment. The American Heart Association/American College of Cardiology/Heart Failure Society of America (AHA/ACC/HFSA) 2022 guidelines gives ARNI a Class IA recommendation for HFrEF patients while the European Society of Cardiology's guidelines are less clear when ARNI could be considered as first line treatment option in de novo patients. This study aimed to model the clinical and budgetary outcomes of implementing these guidelines, comparing conservative ARNI prescription patterns with less conservative in Sweden and in the United Kingdom. Methods and results A health economic model was developed to compare different treatment patterns for HFrEF. Incident cohorts were included on an annual basis and followed over 10 years. The model included treatment specific all‐cause mortality and hospitalization rates, as well as drug acquisition, monitoring, and hospitalization costs. Increasing the use of ARNI could lead to about 7000–12 300 life years gained and 2600–4600 hospitalizations prevented in Sweden. These health benefits come with an additional cost of 112–195 million euros. Similar results were estimated for the United Kingdom, albeit on a larger population. Conclusions Increasing the proportion of patients receiving ARNI instead of angiotensin converting enzyme inhibitors as first‐line treatment of HFrEF will lead to a considerable number of additional life years gained and prevented hospitalizations but with additional cost in terms of health care expenditure in Sweden and in the United Kingdom.