Pump It Up: Quick Titration of Medication Therapies in Heart Failure with Reduced Ejection Fraction, Associated Outcomes


In the treatment of heart failure with reduced ejection fraction, combination therapy is the most effective in reducing all-cause death.


Congestive heart failure is a progressive disease that impairs the heart’s ability to meet the systemic demands of circulation.1 Heart failure has significant morbidity and mortality rates, accounting for 13.8% of deaths in the United States in 2018.2,3

Credit: irissca - stock.adobe.com.

Credit: irissca - stock.adobe.com.

Many studies have been conducted evaluating medication therapies used in heart failure, their optimized doses, and their ability to decrease morbidity and mortality rates.4 In the treatment of heart failure with reduced ejection fraction (HFrEF), where ejection fraction is less than 40%, combination therapy is the most effective in reducing all-cause death.5

The AHA/ACC/HFSA guideline for heart failure management was recently updated, recommending guideline-directed medication therapy (GDMT) for the treatment of HFrEF to include medications from four therapy classes for the optimal treatment of HFrEF.4 It is recommended to start patients on GDMT and titrate to the respective optimal doses of each therapeutic agent as tolerated.

Multiple studies suggest that a majority of patients are not being adequately started on GDMT and/or titrated appropriately.6,7 The STRONG-HF trial evaluated rapidly titrating patients on GDMT and provides insight for better management of patients with HFrEF in the future.8

Cornerstones of HFrEF GDMT

Renin-angiotensin-aldosterone system (RAAS) blocker therapies

Angiotensin converting enzyme inhibitor (ACEI), angiotensin receptor blocker (ARB), and angiotensin receptor/neprilysin inhibitor (ARNI) therapies all work to treat heart failure via inhibition of the RAAS pathway. The PARADIGM-HF trial slated the ARNI as the gold standard of therapy to initiate in HFrEF patients due to its significant reduction in morbidity and rehospitalization rates when compared to ACEI therapy.9

However, when medication cost is a concern, starting or continuing a patient on an ACEI or ARB therapy is acceptable and still significantly improves patient morbidity and mortality outcomes.4

Beta blocker therapy

Cardioprotective beta blockers, including bisoprolol, carvedilol, and metoprolol succinate, are the only beta blocker therapies proven to significantly reduce mortality in HFrEF patients. Several analyses place high value on beta blocker therapy due to its low cost and high rates of efficacy in symptom management and mortality reduction.4

Mineralocorticoid receptor antagonist (MRA) therapies

MRAs have been shown to positively decrease morbidity and mortality rates through the RALES, EPHESUS, and EMPHASIS-HF trials. These trials have shown MRAs significantly improve rates of all-cause mortality, heart failure hospitalization, and sudden cardiac death in patients.4

Sodium-glucose transporter 2 inhibitor (SGLT2-I) therapy

SGLT2-Is are the newest therapies recommended for the treatment of HFrEF (irrespective of a type 2 diabetes diagnosis). Currently dapagliflozin and empagliflozin are the only medications in this class indicated for the treatment of HFrEF.4

Both dapagliflozin and empagliflozin are recommended to be dosed at 10 mg daily for this indication with no additional titration. Evidence for their use was provided through the DAPA-HF and EMPEROR-reduced trials, which showed a 25% composite decrease of heart failure hospitalization and cardiovascular death.

Of note, when the composite outcome of empagliflozin was further assessed, it was found to have no significant cardiovascular mortality benefit and only significant reduction of heart failure hospitalization.10

Table. Optimal doses for HFrEF Therapies (Note: this only lists medications included in the AHA/ACC/HFSA guidelines).

Table. Optimal doses for HFrEF Therapies (Note: this only lists medications included in the AHA/ACC/HFSA guidelines).

Evidence for Quick Titration of HFrEF Therapies

The STRONG-HF trial assessed the safety and efficacy of rapid GDMT initiation before hospital discharge for patients with an acute heart failure admission and during the 2 weeks following with their primary care provider. This was performed through an international, prospective, open-label, randomized control trial of 1008 patients.

The primary outcome evaluated in this study was 180-day heart failure readmission or all-cause death. Participants were randomized into either the usual care group (n= 536)—in which they were discharged and followed up using normal practice procedures—or the high-intensity care group (n=536).

Patients in the high-intensity care group were started on a medication regimen including a cardioprotective beta blocker, a RAAS blocker therapy, and an MRA therapy, which were titrated to at least half their respective target doses within 2 days of anticipated discharge. Patients were then followed and titrated up to full optimal doses of beta blockers and RAAS blocker therapy at 2 weeks after randomization.

MRAs were the last therapeutic class to be dose-adjusted and were only up-titrated to optimal dose if safe for the patient. Safety and efficacy were evaluated 1-, 2-, 3-, and 6-weeks post-randomization via physical exam and laboratory assessment (NT-proBNP, sodium, potassium, glucose, kidney function, and hemoglobin measures).

This study was notably stopped early per the research team’s data and safety monitoring board’s recommendation due to greater-than-expected differences between the usual and high-intensity care group outcomes. By day 90, the high-intensity care group when compared to the usual care group had 53% more patients on optimal dose RAAS blocker therapy, 45% more patients on an optimal dose beta blocker therapy, and 38% more patients on optimal MRA therapy.

By day 180, incidence of heart failure readmissions or all-cause death was 8.1% less in the high-intensity group when compared to the usual-care group (p= 0.0021, RR= 0.66, NNT= 12). The high-intensity group also saw greater reduction in NT-proBNP levels (p= 0.0003), indicating reduced cardiac stress in these patients.

The incidence of adverse effects was 28% more common in the high intensity versus usual care group at day 90, with cardiac failure (NNH= 100), hypotension (NNH= 28), hyperkalemia (NNH= 33), and renal impairment (NNH= 45) being the most common. There were no significant differences in the incidence of serious or fatal adverse events between the 2 groups.

Overall, high-intensity treatment strategies aligning with GDMT recommendations with close follow-up after an acute heart failure admission is considered safe and associated with several positive outcomes, including reduced risk of heart failure readmission and all-cause death when compared to usual care. Patients also saw reduced symptoms and greater quality of life, making it a good dosing strategy to consider in the future.8

Caveats of the STRONG-HF trial

It is notable that SGLT2-I therapies were excluded from this study because they were not approved for use in heart failure or widely available in all countries when the study was conducted. Additional studies will need to be performed to assess the safety and efficacy of SGLT2-I therapies and the role they play in the rapid titration of GDMT.

Another challenge is the number of visits required for patients undergoing high-intensity titration. The high-intensity group was found to have an average of 4.8 visits, whereas the usual care group only had 1 visit.

This requires commitment from the patient and their provider, which could pose both a logistical challenge for safe monitoring of patients and financial burden on patients due to several clinic visits over a short period of time.8

The Role Pharmacists Can Play Moving Forward

It has been shown that pharmacist involvement in therapy dosing in heart failure clinics through collaborative practice agreements results in significantly more patients achieving targeted doses of desired therapy.11 Pharmacists are well equipped to assist with rapid-titration as modeled in the STRONG-HF trial, both in the inpatient and outpatient setting, to help achieve reduced risk of heart failure readmission, all-cause mortality, and heart failure symptoms.


  1. Malik A, Brito D, Vaqar S, et al. Congestive Heart Failure. [Updated 2022 Nov 7]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK430873/
  2. Bytyçi I, Bajraktari G. Mortality in heart failure patients. Turkish Society of Cardiology. 2015;15(1):63-68. doi:10.5152/akd.2014.5731
  3. Heart failure. Centers for Disease Control and Prevention. https://www.cdc.gov/heartdisease/heart_failure.htm. Published January 5, 2023. Accessed March 11, 2023.
  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. Circulation. 2022;145(18). doi:10.1161/cir.0000000000001063
  5. Tromp J, Ouwerkerk W, van Veldhuisen DJ, et al. A systematic review and network meta-analysis of pharmacological treatment of heart failure with reduced ejection fraction. JACC: Heart Failure. 2022;10(2):73-84. doi:10.1016/j.jchf.2021.09.004
  6. Greene S, Fonarow G, DeVore A, et al. Titration of Medical Therapy for Heart Failure With Reduced Ejection Fraction. J Am Coll Cardiol. 2019 May, 73 (19) 2365–2383. https://doi.org/10.1016/j.jacc.2019.02.015
  7. Keisuke Brownell N, Ziaeian B, Fonarow GC. Simultaneous versus sequential initiation of HFREF therapies. Latest in Cardiology. https://www.acc.org/latest-in-cardiology/articles/2022/03/04/17/40/simultaneous-vs-sequential-initiation-of-hfref-therapies. Published March 7, 2022. Accessed March 11, 2023.
  8. Mebazaa A, Davison B, Chioncel O, et al. Safety, tolerability and efficacy of up-titration of guideline-directed medical therapies for acute heart failure (strong-HF): A multinational, open-label, randomised, trial. The Lancet. 2022;400(10367):1938-1952. doi:10.1016/s0140-6736(22)02076-1
  9. McMurray JJV, Packer M, Desai AS, et al. Angiotensin–NEPRILYSIN inhibition versus enalapril in heart failure. New England Journal of Medicine. 2014;371(11):993-1004. doi:10.1056/nejmoa1409077
  10. Zannad F, Ferreira JP, Pocock SJ, et al. SGLT2 inhibitors in patients with heart failure with reduced ejection fraction: A meta-analysis of the emperor-reduced and Dapa-HF trials. The Lancet. 2020;396(10254):819-829. doi:10.1016/s0140-6736(20)31824-9
  11. Noschese LA, Bergman CL, Brar CK, Kansal MM. The Pharmacist's Role in Medication Optimization for Patients With Chronic Heart Failure. Fed Pract. 2017;34 (Suppl 10): S10-S15.
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