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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

Ishaq Natsheh March 7, 2022

How fortunate that the FDA requires the cvs studies that indirectly resulted in discovering these benefits of SLG2Is from their studies for DM2 .They are very expensive but likely will have a net benefit

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

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.

Les auteurs n’ont aucun conflit d’intérêts à déclarer.