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#310 Medications for Heart Failure with Preserved or Mildly-Reduced Ejection Fraction: Heart Failure or Heart Success?

Which medications reduce death or hospitalization in patients with heart failure (HF) with preserved or mildly-reduced ejection fraction (EF >40%)?

In patients with HF with EF >40%, only mineralocorticoid receptor antagonists (MRA) and sodium-glucose cotransporter 2 inhibitors (SGLT2i) reduce HF hospitalizations, and nothing has been shown to reduce death. Compared to placebo, one patient avoids HF hospitalization for every 41 receiving an MRA for ~3 years, or for every 32 receiving an SGLT2i for ~2 years.

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  • Five systematic reviews in last 5 years assessed medications in HF with EF >40%.1-5 Focusing on the most complete (results statistically significant unless otherwise stated):
    • MRAs [13 randomized controlled trials (RCTs), 4459 patients, follow-up ~3 years]:1
      • HF hospitalization: 11.2% versus 13.6% (placebo), number needed to treat (NNT)=41.
      • Hyperkalemia (≥5.5mmol/L): 17.5% versus 8.3% (placebo), number needed to harm (NNH)=11.
    • SGLT2i:
      • Meta-analysis (5 RCTs, 9726 patients):5 29% relative risk reduction in HF hospitalization with SGLT2i versus placebo, regardless of diabetes
        • EMPEROR-Preserved:6 Largest blinded RCT (industry-funded): Empagliflozin 10mg/day versus placebo for 2.2 years (5988 patients, age 72, 55% male)
          • HF hospitalization: 8.6% versus 11.8% (placebo), NNT=32.
          • Adverse events: Hypotension (not defined) [6.6% versus 5.2% (placebo), NNH=56], urinary tract infections [9.9% versus 8.1% (placebo), NNH=56], and genital infections [2.2% versus 0.7% (placebo), NNH=67].
  • Medications that do not reduce hospitalizations or deaths:1
    • ACE inhibitors (8 RCTs, 2061 patients)
    • Angiotensin-receptor blockers (ARBs) (8 RCTs, 8755 patients)
    • Beta-blockers (10 RCTs, 3087 patients)
    • Sacubitril-valsartan (3 RCTs, 7702 patients)
      • Original meta-analysis erroneously suggested reduced hospitalizations. When re-analyzed, no benefit found.7
  • No RCTs of clinical outcomes for loop diuretics in HF.8,9
  • No medication reduces mortality.1-6
  • “HF with preserved EF”:
    • Means EF ≥50%.10
    • Many trials include patients with EF 41-49% (now called mildly-reduced ejection fraction10).1-6
  • ~50% of patients with HF have an EF >40%.11
  • Guidelines (published before EMPEROR-Preserved) recommend treating hypertension and using loop diuretics for fluid overload,12-14 ± MRA and/or candesartan (based on limited evidence and options at the time of writing).12
  • Costs: Spironolactone 25mg $140/year, empagliflozin splitting 25mg in half=12.5mg (trial dose=10 mg) $560/year.15

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  • Michael R Kolber BSc MD CCFP MSc
  • Nicolas Dugré PharmD MSc BCPAC
  • Ricky D Turgeon BSc (Pharm) ACPR PharmD

1. Martin N, Manoharan K, Davies C, et al. Cochrane Database Syst Rev. 2021; (5):CD012721.

2. Zheng SL, Chan FT, Nabeebaccus AA, et al. Heart. 2018; 104:407-15

3. Kuno T, Ueyama H, Fujisaki T, et al. Am J Cardiol. 2020;125:1187-93.

4. Khan MS, Fonarow GC, Khan H, et al. ESC Heart Fail. 2017; 4:402-8.

5. Tsampasian V, Elghazaly H, Chattopadhyay R, et al. Eur J Prev Cardiol. 2021;zwab189 [Epub ahead of print). doi: 10.1039/eurjpc/zwab189

6. Anker SD, Butler J, Filippatos G, et al. N Engl J Med. 2021; 385:1451-61.

7. Turgeon R. Erroneous use of fixed-effect model instead of random-effects model in analysis of sacubitril-valsartan. Available at: Accessed 14 Feb 2022.

8. Singh A, Agarwal A, Wafford QE, et al. Heart. 2021 Aug 2 [Epub ahead of print]. doi: 10.1136/heartjnl-2021-319643.

9. Kapelios CJ, Bonou M, Malliaras K, et al. Heart Fail Rev. 2022; 27:147-61.

10. Bozkurt B, Coats AJS, Tsutsui H, et al. Eur J Heart Fail 2021; 23:352-80.

11. Bhambhani V, Kizer JR, Lima JA, et al. Eur J Heart Fail 2018; 20:651-9.

12. Ezekowitz JA, O’Meara E, McDonald M, et al. Can J Cardiol 2017; 33:1342-433.

13. Yancy CW, Jessup M, Bozkurt B, et al. J Am Coll Cardiol 2017; 70:776-803.

14. McDonagh TA, Metra M, Adamo M, et al. Eur Heart J 2021; 42:3599-726.

15. Alberta College of Family Physicians Price Comparison of Commonly Prescribed Pharmaceuticals in Alberta 2020. Accessed 27 Jan 2022.

Authors do not have any conflicts of interest to declare.