Initiation, uptitration, and discontinuation of HFrEF drugs after hospitalization for HF

Heart Failure Drug Treatment-Inertia, Titration, and Discontinuation: A Multinational Observational Study (EVOLUTION HF)

Literature - Savarese G, Kishi T, Vardeny O, et al. - JACC Heart Fail. 2022 Sep 7;S2213-1779(22)00508-X [Online ahead of print]. doi: 10.1016/j.jchf.2022.08.009

Introduction and methods


During and immediately after hospitalization for HF (HHF), patients are at high risk of death and rehospitalization [1,2]. For patients recently diagnosed with HFrEF, current European and American guidelines on HF recommend early initiation of multiple guideline-directed medical therapies (GDMTs) and subsequent uptitration of some of these drugs [3-5]. However, these recommendations are often not adequately implemented due to, for example, real or perceived risk of side effects or insufficient reimbursement.

Aim of the study

To improve clinical practice, the authors sought to describe the initiation GDMTs after HHF and their uptitration and discontinuation in contemporary real-world settings.



The EVOLUTION HF (Utilization of Dapagliflozin and Other Guideline Directed Medical Therapies in Heart Failure Patients: A Multinational Observational Study Based on Secondary Data) study is a multinational, observational, longitudinal cohort study that aims to provide insights into GDMT use after HHF. For this purpose, secondary data are extracted from well-established electronic health records or claims data sources in Japan, Sweden, and the USA. Patients who were new users of ≥1 GDMT for HFrEF within 12 months of an HHF discharge were included (n=266,589). Although LVEF measurements were not available, all patients were assumed to have an HFrEF indication based on the required initiation of ≥1 GDMT for HFrEF.

Initiation, uptitration, and discontinuation of the following drugs were assessed: (1) novel GDMTs: dapagliflozin (this was the only SGLT2i approved for HFrEF at study onset, in 2020) and sacubitril/valsartan; and (2) other GDMTs: ACEis, ARBs, beta-blockers, and MRAs. Doses and discontinuation were assessed in the 12 months following initiation of the GDMT. For the titration and discontinuation analyses (n=104,022 patients), only dose optimization after hospital discharge was considered. The target dose was defined as ≥100% of the dose recommended by local guidelines and a low dose as <50% of the recommended dose.

Main results

Time to GDMT initiation after recent HHF

  • The mean time from the qualifying HHF to initiation of a GDMT (as the first GDMT or in addition to others) was generally longer for the 2 novel GDMTs, dapagliflozin and sacubitril/valsartan, than for the other GDMTs: 39 and 44 days versus 12–13 days (Japan), 44 and 33 days versus 22–31 days (Sweden), and 33 and 19 days versus 18–24 days (USA).
  • The cumulative proportions of patients in whom GDMTs were initiated within 30 or 100 days of HHF discharge were lower among patients on novel GDMTs than among those on the other GDMTs.
  • For example, 30 days after discharge, 74.6% and 72.7% of the Japanese patients were taking dapagliflozin or sacubitril/valsartan, respectively, compared with 91.2%–92.2% for the other GDMTs. The corresponding proportions were: 54.9% and 59.5% versus 72.9%–85.2% for Sweden and 37.3% and 62.0% versus 73.7%–80.4% for the USA, respectively.

GDMT initiation during treatment journey

  • Many patients who received a novel GDMT were already taking ≥1 GDMT, commonly 3 other GDMTs.
  • When data from the 3 countries were pooled, 80.0%–96.5% of the patients in whom sacubitril/valsartan treatment was initiated were already taking a beta-blocker, 63.1%–81.8% an ACEi or ARB, and 44.1%–74.6% an MRA. A similar trend was seen for patients starting dapagliflozin treatment.

GDMT titration and discontinuation

  • During the 12-month follow-up, underdosing/slow uptitration, low target dose achievement, and early discontinuation of ACEis, ARBs, beta-blockers, MRAs, and sacubitril/valsartan were common in all 3 countries.
  • For example, 20.3% of the Japanese, 44.4% of the Swedish, and 12.6% of the American patients had achieved the sacubitril/valsartan target dose at the end of follow-up, while 26.6%, 14.7%, and 40.3%, respectively, had discontinued this drug by 12 months.
  • As for dapagliflozin, which does not require uptitration, 70.9%, 83.6%, and 46.5% of the patients in Japan, Sweden, and the USA, respectively, were on the target dose after 12 months.
  • For all GDMTs, discontinuation was more prevalent in the USA than in Japan and Sweden.
  • When data from the 3 countries were pooled, the proportions of patients who had achieved the corresponding target dose at 12 months were: 75.7% (dapagliflozin), 28.2% (sacubitril/valsartan), 20.1% (ACEis), 6.7% (ARBs), 7.2% (beta-blockers), and 5.1% (MRAs).
  • Within 12 months, 23.5% of the patients on dapagliflozin in all 3 countries and 26.4% of those on sacubitril/valsartan had discontinued this drug. The pooled discontinuation rates for the other GDMTs were: 38.4% (ACEis), 33.4% (ARBs), 25.2% (beta-blockers), and 42.2% (MRAs).


In HFrEF patients who had been hospitalized for HF in Japan, Sweden, or the USA, novel GDMTs (dapagliflozin and sacubitril/valsartan) were initiated later than the other GDMTs (ACEis, ARBs, beta-blockers, and MRAs). A year after GDMT initiation, most patients on dapagliflozin received the guideline-recommended dose, while few were prescribed the target dose of a GDMT that required uptitration. The discontinuation rate for dapagliflozin tended to be lower than that for the other GDMTs.


1. Savarese G, Bodegard J, Norhammar A, et al. Heart failure drug titration, discontinuation, mortality and heart failure hospitalization risk: a multinational observational study (US, UK and Sweden). Eur J Heart Fail. 2021;23:1499–1511.

2. Solomon SD, Dobson J, Pocock S, et al. Influence of nonfatal hospitalization for heart failure on subsequent mortality in patients with chronic heart failure. Circulation. 2007;116:1482–1487.

3. McDonagh TA, Metra M, Adamo M, et al. 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur Heart J. 2021;42:3599–3726.

4. Heidenreich PA, Bozkurt B, Aguilar D, et al. 2022 AHA/ACC/HFSA guideline for the management of heart failure: a report of the American College of Cardiology/American Heart Association joint committee on clinical practice guidelines. J Am Coll Cardiol. 2022;79:e263–e421.

5. Rosano GMC, Moura B, Metra M, et al. Patient profiling in heart failure for tailoring medical therapy. A consensus document of the Heart Failure Association of the European Society of Cardiology. Eur J Heart Fail. 2021;23:872–881.

Find this article online at JACC Heart Fail.

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