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Author: Stormi Gale, PharmD, BCCP
A favorite topic of mine is the optimization of guideline-directed medical therapy (GDMT) in heart failure with reduced ejection fraction (HFrEF). Unfortunately, despite known and impressive outcomes, use of neurohormonal blockade remains wildly suboptimal in practice.1 In fact, in a recent real-world analysis of patients in the United States, only 1% (nope, not a typo!) were on optimized therapy for HFrEF. There are several reasons for suboptimal therapy, including increasing complexity of HF regimens as well as therapeutic inertia.2 Indeed, there have been several new HF therapies introduced since this analysis, most importantly the inhibitors of sodium-glucose cotransporter 2 (SGLT2is) (a previous blog summarizes the evidence for dapagliflozin, and the recently published EMPEROR-Reduced supporting empagliflozin can be found here).3 While we may not have control over all components of therapeutic inertia, I feel strongly as a pharmacist that we cannot let our inpatient formulary decisions be one of them. As such, here are 4 reasons why your institution should add these agents to formulary:
1) Initiating/continuing GDMT in the inpatient setting improves long-term optimization
Admittedly, I cringe when I hear the phrase “initiate as an outpatient”. There is an abundance of data demonstrating that despite our best intent, patients who are discharged without GDMT are less likely to have it initiated and optimized long term; this is more extensively discussed in a previous blog. In fact, a recent analysis of sacubitril/valsartan demonstrated that patients discharged without angiotensin receptor blocker/neprilysin inhibitor (ARNI) had less than 5% chance of being initiated within a year of being discharged.4 This is unacceptably low, especially considering the early benefits demonstrated with inpatient ARNI initiation.5 Similarly, there is evidence that the reduced risk of worsening HFrEF with SGLT2i is seen as early as weeks after initiation.6 In fact, in patients with diabetes and admission for HF, starting SGLT2i peridischarge was associated with a reduction in cardiovascular death, hospitalization, and urgent HF visit, benefits which was seen within a month of discharge.7 This is particularly notable in HF given the institutional pressures to reduce 30-day readmissions.
2) Inpatient use of SGLT2i appears safe
Remember when PARADIGM-HF came out?8 Because this study evaluated the use of sacubitril/valsartan in stable outpatients, most inpatient formularies were slow to adopt ARNI. It wasn’t until the publication of PIONEER-HF in 2019 (previously covered by our blog) that we saw increased initiation of ARNI in the acute setting.9 Yet, studies continue to reveal poor uptake of ARNI in practice.4 Although this is likely multifactorial, I can’t help but wonder how delayed addition to formulary affects optimal practice.10 In addition to the recent study demonstrating safe peridischarge initiation, there is currently one other randomized controlled trial demonstrating safety of SGLT2i (and improved outcomes at 60 days!) in acute decompensated heart failure (ADHF), although several more are underway.7,11 Nonetheless, we don’t necessarily have to study every drug in the hospital setting to have the authority to initiate them prior to discharge. If anything, we can more closely monitor agents initiated while patients are admitted. PARADIGM-HF was published in 2014 (6 years ago for those counting), and there are still institutions that have not added it to formulary! To re-emphasize what evidence consistently suggests, patients are unlikely to be initiated on new agents in the outpatient setting.4 We cannot wait until 2025 to get patients on SGLT2i. Formulary decisions matter.
3) SGLT2i may affect diuretic requirements
Expert consensus recommends observing patients on oral diuretics for 24 hours prior to discharge.12 This recommendation comes from evidence that ensuring an appropriate dose of diuretic prior to discharge decreases HF readmissions.13 As such, initiating agents that affect diuretic doses without subsequent observation could theoretically increase this risk. However, there is conflicting evidence about how much SGLT2is affect diuretic requirements. In acute decompensated heart failure, empagliflozin was associated with increased urinary output, although there was no difference in diuretic response compared to placebo.11 Similarly, in a subanalysis of DAPA-HF, there was no difference in diuretic dose adjustments with dapagliflozin compared to placebo.14 There also may be a role for SGLT2i in diuretic resistance (another reason for inpatient use!), although evidence is still forthcoming.
4) We have other expensive drugs on formulary
SGLT2i *will* be a Class I recommendation in the next HF guidelines. To put this into perspective, excluding these agents from formulary would be like not including angiotensin-converting enzyme inhibitors. This is especially surprising to me when I think about other costly formulary agents that have minimal (if any) impact on outcomes (e.g., dexmedetomidine, chlorothiazide, tolvaptan, vasopressin, oncolytics). Oh, and did I mention the potential return on investment for reduced readmissions? If the costs of the aforementioned agents are worthwhile, why not SGLT2i?
Convinced but don’t know where to start?
Here are some specifics I considered when making a formulary recommendation:
There is probably no single right answer to this. The heart failure benefits with SGLT2i appear to be a class effect. Keep in mind, however, that dapagliflozin is the only agent with (at the time of this writing) Food and Drug Administration approval for HF, although empagliflozin’s approval is expected shortly. That being said, there may be differences in other outcomes, such as reductions in atherosclerotic cardiovascular disease risk with empagliflozin but not dapagliflozin.15,16 Ultimately, the most important consideration is patient access. As such, it is reasonable to select whichever agent is most frequently covered and/or affordable at your institution.
As stated above, the HF benefits with SGLT2i appear to be a class effect. Thus, it is reasonable to include a therapeutic interchange to your formulary agent. This can be complicated by indication but reducing patients with diabetes to HF doses during a hospitalization is no worse for glycemic control than discontinuing therapy on admission. We have evidence that unnecessary discontinuation of other GDMT during ADHF decreases the likelihood that these agents will be optimized later on (a blog on what we know about beta-blockers here). Therefore, unless contraindications exist, continuing therapy during acute decompensation (keeping in mind the risk for euglycemic ketoacidosis in certain populations) may be preferable.
Should it be restricted?
At minimum, cardiology services should be able to initiate these agents in the acute setting. However, given the impressive outcomes in patients with diabetes and/or chronic kidney disease, use by endocrinology and nephrology are also reasonable restrictions. Since a lot of patients with HF are managed on general internal medicine services, allowing hospitalists to initiate therapy may improve use. However, given the cost and lack of familiarity, it is reasonable to require restrictions as part of the initial formulary approval.
Given the combination of safety and efficacy outcomes (e.g., improved discharge GDMT, reduced 30-day readmissions, anticipated Class I recommendation), it’s hard to justify not including SGLT2i on formulary. Our formulary decisions matter, and we cannot allow them to contribute to slow uptake of new therapies and suboptimal care of patients.
Stormi Gale, PharmD, BCCP
Reviewed by: Sandeep Devabhakthuni, PharmD, BCCP
- Greene SJ, Butler J, Albert NM, et al. Medical Therapy for Heart Failure With Reduced Ejection Fraction: The CHAMP-HF Registry. Journal of the American College of Cardiology. 2018;72(4):351-366.
- Dixon DL, Sharma G, Sandesara PB, et al. Therapeutic Inertia in Cardiovascular Disease Prevention: Time to Move the Bar. Journal of the American College of Cardiology. 2019;74(13):1728-1731.
- Packer M, Anker SD, Butler J, et al. Cardiovascular and Renal Outcomes with Empagliflozin in Heart Failure. New England Journal of Medicine. 2020;0(0):null.
- Carnicelli AP, Greene S, Lippmann S, et al. Sacubitril/valsartan Initiation and Adherence Patterns Following Hospitalization for Heart Failure. Journal of Cardiac Failure. 2020;26(10):S91.
- Pascual-Figal D, Wachter R, Senni M, et al. NT-proBNP Response to Sacubitril/Valsartan in Hospitalized Heart Failure Patients With Reduced Ejection Fraction: TRANSITION Study. J Am Coll Cardiol HF. 2020;8(10):822-833.
- Docherty Kieran F., Jhund Pardeep S., Anand Inder, et al. Effect of Dapagliflozin on Outpatient Worsening of Patients with Heart Failure and Reduced Ejection Fraction: A Prespecified Analysis of DAPA-HF. Circulation. 0(0).
- Bhatt DL, Szarek M, Steg PG, et al. Sotagliflozin in Patients with Diabetes and Recent Worsening Heart Failure. New England Journal of Medicine. 2020;0(0):null.
- McMurray JJV, Packer M, Desai AS, et al. Angiotensin–Neprilysin Inhibition versus Enalapril in Heart Failure. N Engl J Med. 2014;371(11):993-1004.
- Velazquez EJ, Morrow DA, DeVore AD, et al. Angiotensin–Neprilysin Inhibition in Acute Decompensated Heart Failure. New England Journal of Medicine. 2019;380(6):539-548.
- Luo Nancy, Lippmann Steven J., Mentz Robert J., et al. Relationship Between Hospital Characteristics and Early Adoption of Angiotensin‐Receptor/Neprilysin Inhibitor Among Eligible Patients Hospitalized for Heart Failure. Journal of the American Heart Association. 2019;8(3):e010484.
- Damman K, Beusekamp JC, Boorsma EM, et al. Randomized, double-blind, placebo-controlled, multicentre pilot study on the effects of empagliflozin on clinical outcomes in patients with acute decompensated heart failure (EMPA-RESPONSE-AHF). European Journal of Heart Failure. 2020;22(4):713-722.
- Hollenberg SM, Stevenson LW, Ahmad T, et al. 2019 ACC Expert Consensus Decision Pathway on Risk Assessment, Management, and Clinical Trajectory of Patients Hospitalized With Heart Failure: A Report of the American College of Cardiology Solution Set Oversight Committee. J Am Coll Cardiol. 2019;74(15):1966-2011.
- Laliberte B, Reed BN, Devabhakthuni S, et al. Observation of Patients Transitioned to an Oral Loop Diuretic Before Discharge and Risk of Readmission for Acute Decompensated Heart Failure. Journal of Cardiac Failure. 2017;23(10):746-752.
- Jackson Alice M., Dewan Pooja, Anand Inder S., et al. Dapagliflozin and Diuretic Use in Patients With Heart Failure and Reduced Ejection Fraction in DAPA-HF. Circulation. 2020;142(11):1040-1054.
- Wiviott SD, Raz I, Bonaca MP, et al. Dapagliflozin and Cardiovascular Outcomes in Type 2 Diabetes. New England Journal of Medicine. 2019;380(4):347-357.
- Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes. N Engl J Med. 2015;373(22):2117-2128.
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