HFpEF;

Should I consider treating my patient with heart failure with an SGLT2 inhibitor?

FA Manian MD, MPH, , , , , , , , , , , , , , 1 Comment

Absolutely! Although sodium glucose cotransporter 2 (SGLT2) inhibitors are often used for their antidiabetic properties, more recently they have been shown to have extraordinary benefits in patients with heart failure.

 In 2015, a large randomized controlled trial, EMPA-REG OUTCOME, showed that empagliflozin significantly lowered overall death, death from cardiovascular events, and hospitalizations for heart failure in patients who had type II diabetes (T2DM) and cardiovascular disease1.

Later, 2 other randomized controlled trials showed that patients with heart failure with reduced ejection fractions (HFrEF), irrespective of a diagnosis of T2DM, had lower rates of death from cardiovascular causes and better heart failure outcomes when treated with SGLT2 inhibitors2,3.

In 2021, the EMPEROR Preserved trial showed that SGLT2 inhibitors provide significant clinical benefit for patients with heart failure with preserved ejection fraction (HFpEF), irrespective of the presence of T2DM4. In addition, multiple studies have shown substantial benefit to starting SGLT2 inhibitors during or shortly after a hospitalization for heart failure.5,6,7

 The effectiveness of SGLT2 inhibitors in heart failure is also reflected in the updated guidelines from the American College of Cardiology/American Heart Association8  that recommend  use of SGLT2 inhibitors in patients with chronic symptomatic HFrEF.  In addition,  the guidelines state that SGLT2 inhibitors can be beneficial in decreasing heart failure hospitalizations and cardiovascular mortality for patients mildly reduced ejection fraction and those with HFpEF.

 Potential mechanisms of action of SGLT2 inhibitors in heart failure include reduction in myocardial oxidative stress, decrease cardiac preload and afterload, increase endothelial function, decrease arterial stiffness, and increase muscle free fatty acid uptake which leads to increased availability of ketones during times of stress.9 

So the data to date suggest that we should consider SGLT2 inhibitors as part of our armamentarium for treatment of heart failure unless, of course, there are contraindications, including pregnancy/risk of pregnancy, breastfeeding, eGFR <30mL/min/1.73 m2, symptoms of hypotension, systolic blood pressure <95mmHg, or a known allergic/other adverse reactions. 10

Bonus Pearl: Did you know that SGLT 2 inhibitors are derived from phlorizin, a naturally occurring phenol glycoside first isolated back in 1835 from the bark of apple tree in 1835? 11

Contributed by Yisrael Wallach, MD, St. Louis, Missouri

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References

  1. Zinman, B., Wanner, C., Lachin, J. M., Fitchett, D., Bluhmki, E., Hantel, S., … & Inzucchi, S. E. (2015). Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. New England Journal of Medicine, 373(22), 2117-2128. https://pubmed.ncbi.nlm.nih.gov/26378978/
  2. McMurray, J. J., Solomon, S. D., Inzucchi, S. E., Køber, L., Kosiborod, M. N., Martinez, F. A., … & Langkilde, A. M. (2019). Dapagliflozin in patients with heart failure and reduced ejection fraction. New England Journal of Medicine, 381(21), 1995-2008. https://pubmed.ncbi.nlm.nih.gov/31535829/
  3. Packer, M., Anker, S. D., Butler, J., Filippatos, G., Pocock, S. J., Carson, P., … & Zannad, F. (2020). Cardiovascular and renal outcomes with empagliflozin in heart failure. New England Journal of Medicine, 383(15), 1413-1424. https://pubmed.ncbi.nlm.nih.gov/32865377/
  4. Anker, S. D., Butler, J., Filippatos, G., Ferreira, J. P., Bocchi, E., Böhm, M., … & Packer, M. (2021). Empagliflozin in heart failure with a preserved ejection fraction. New England Journal of Medicine, 385(16), 1451-1461. https://pubmed.ncbi.nlm.nih.gov/34449189/
  5. Cunningham, J. W., Vaduganathan, M., Claggett, B. L., Kulac, I. J., Desai, A. S., Jhund, P. S., … & Solomon, S. D. (2022). Dapagliflozin in Patients Recently Hospitalized With Heart Failure and Mildly Reduced or Preserved Ejection Fraction. Journal of the American College of Cardiology. https://pubmed.ncbi.nlm.nih.gov/36041912/
  6. Voors, A. A., Angermann, C. E., Teerlink, J. R., Collins, S. P., Kosiborod, M., Biegus, J., … & Ponikowski, P. (2022). The SGLT2 inhibitor empagliflozin in patients hospitalized for acute heart failure: a multinational randomized trial. Nature medicine, 28(3), 568-574. https://pubmed.ncbi.nlm.nih.gov/35228754/
  7. Bhatt, D. L., Szarek, M., Steg, P. G., Cannon, C. P., Leiter, L. A., McGuire, D. K., … & Pitt, B. (2021). Sotagliflozin in patients with diabetes and recent worsening heart failure. New England Journal of Medicine, 384(2), 117-128. https://pubmed.ncbi.nlm.nih.gov/33200892/
  8. Heidenreich, P. A., Bozkurt, B., Aguilar, D., Allen, L. A., Byun, J. J., Colvin, M. M., … & Yancy, C. W. (2022). 2022 AHA/ACC/HFSA guideline for the management of heart failure: Executive summary: a report of the American College of Cardiology/American heart association joint Committee on clinical practice guidelines. Journal of the American College of Cardiology, 79(17), 1757-1780. https://pubmed.ncbi.nlm.nih.gov/35379504/
  9. Muscoli, S., Barillà, F., Tajmir, R., Meloni, M., Della Morte, D., Bellia, A., … & Andreadi, A. (2022). The New Role of SGLT2 Inhibitors in the Management of Heart Failure: Current Evidence and Future Perspective. Pharmaceutics, 14(8), 1730. https://pubmed.ncbi.nlm.nih.gov/36015359/
  10. Aktaa, S., Abdin, A., Arbelo, E., Burri, H., Vernooy, K., Blomström-Lundqvist, C., … & Gale, C. P. (2022). European Society of Cardiology Quality Indicators for the care and outcomes of cardiac pacing: developed by the Working Group for Cardiac Pacing Quality Indicators in collaboration with the European Heart Rhythm Association of the European Society of Cardiology. EP Europace, 24(1), 165-172. https://pubmed.ncbi.nlm.nih.gov/34455442/
  11. Petersen, C. (1835). Analyse des phloridzins. Annalen der pharmacie, 15(2), 178-178. 

Disclosures: The listed questions and answers are solely the responsibility of the author and do not necessarily represent the official views of Mercy Hospital-St. Louis, Massachusetts General Hospital, Harvard Catalyst, Harvard University, their affiliate academic healthcare centers, or its contributors. Although every effort has been made to provide accurate information, the author is far from being perfect. The reader is urged to verify the content of the material with other sources as deemed appropriate and exercise clinical judgment in the interpretation and application of the information provided herein. No responsibility for an adverse outcome or guarantees for a favorable clinical result is assumed by the author. Thank you!

 

 

Should I consider treating my patient with heart failure with an SGLT2 inhibitor?

Is it safe to use diltiazem or verapamil for treatment of my hospitalized patient with heart failure with reduced ejection fraction (HFrEF) and atrial fibrillation?

FA Manian MD, MPH, , , , , , , , , , Leave a comment

Short answer, no! It is generally recommended to avoid the use of diltiazem or verapamil, both a non-dihydropyridine calcium channel blocker (CCB), in patients with HFrEF.  Multiple randomized controlled trials involving patients with HFrEF have shown that use of diltiazem [1] or verapamil [2] is associated with increased cardiovascular mortality and morbidity, especially congestive heart failure (CHF) exacerbations.

Although you might argue that most studies [1,2] on HFrEF on CCBs have been based on patients on chronic (weeks to months) therapy, these agents are also sometimes used in the acute inpatient setting for rate control in atrial fibrillation and even blood pressure control. Even in acute settings, avoidance of these agents–or at least using them with great caution— in patients with HFrEF is prudent. Fortunately, for blood pressure control, another CCB, amlodipine [3] has been deemed safe to use in patients with HFrEF.

Adverse effects of diltiazem and verapamil are often attributed to their negative inotropic effects. As a result, patients with preexisting left ventricular dysfunction may be expected to have worse outcomes. In contrast, amlodipine primarily acts on the peripheral vasculature without significant negative inotropic effect. [4]

What about the use of these agents in patients with heart failure and preserved ejection fraction? Studies to date have found that CCBs are safe in this setting, although no mortality benefit has been shown with their use either [1]. 

Bonus Pearl: Did you know that use of another CCB, nifedipine, a close cousin of amlodipine (both 1,4- dihydropyridines), has been associated with increased cardiovascular morbidity (worsening CHF and increased hospitalizations) in patients with HFrEF? [5]

Contributed by Fahad Tahir, MD, Mercy Hospital-St. Louis, St. Louis, Missouri

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References:

  1. Goldstein RE, Boccuzzi SJ, Cruess D, Nattel S. Diltiazem increases late-onset congestive heart failure in postinfarction patients with early reduction in ejection fraction. The Adverse Experience Committee; and the Multicenter Diltiazem Postinfarction Research Group. Circulation. 1991 Jan;83(1):52-60. doi: 10.1161/01.cir.83.1.52. PMID: 1984898.https://www.ahajournals.org/doi/epdf/10.1161/01.CIR.83.1.52
  2. Effect of verapamil on mortality and major events after acute myocardial infarction (the Danish Verapamil Infarction Trial II–DAVIT II). Am J Cardiol. 1990 Oct 1;66(10):779-85. doi: 10.1016/0002-9149(90)90351-z. PMID: 2220572.https://www.ajconline.org/article/0002-9149(90)90351-Z/pdf
  3. Packer M, Carson P, Elkayam U, Konstam MA, Moe G, O’Connor C, Rouleau JL, Schocken D, Anderson SA, DeMets DL; PRAISE-2 Study Group. Effect of amlodipine on the survival of patients with severe chronic heart failure due to a nonischemic cardiomyopathy: results of the PRAISE-2 study (prospective randomized amlodipine survival evaluation 2). JACC Heart Fail. 2013 Aug;1(4):308-314. doi: 10.1016/j.jchf.2013.04.004. Epub 2013 Aug 5. PMID: 24621933.https://reader.elsevier.com/reader/sd/pii/S2213177913001844?token=510153852A5AEBBDF5CA9F8B16C671C4E2F4B511B6F723227BA1D2180CDAA4726EC329D5ABC4118738CB1D8B67A3CF6B&originRegion=us-east-1&originCreation=20220316135803
  4. Zamponi, G. W., Striessnig, J., Koschak, A., & Dolphin, A. C. (2015). The Physiology, Pathology, and Pharmacology of Voltage-Gated Calcium Channels and Their Future Therapeutic Potential. Pharmacological reviews, 67(4), 821–870.https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4630564/
  5. Elkayam U, Amin J, Mehra A, Vasquez J, Weber L, Rahimtoola SH. A prospective, randomized, double-blind, crossover study to compare the efficacy and safety of chronic nifedipine therapy with that of isosorbide dinitrate and their combination in the treatment of chronic congestive heart failure. Circulation. 1990 Dec;82(6):1954-61. doi: 10.1161/01.cir.82.6.1954. PMID: 2242521.https://www.ahajournals.org/doi/epdf/10.1161/01.CIR.82.6.1954

Disclosures: The listed questions and answers are solely the responsibility of the author and do not necessarily represent the official views of Mercy Hospital-St. Louis, Massachusetts General Hospital, Harvard Catalyst, Harvard University, their affiliate academic healthcare centers, or its contributors. Although every effort has been made to provide accurate information, the author is far from being perfect. The reader is urged to verify the content of the material with other sources as deemed appropriate and exercise clinical judgment in the interpretation and application of the information provided herein. No responsibility for an adverse outcome or guarantees for a favorable clinical result is assumed by the author. Thank you!

Is it safe to use diltiazem or verapamil for treatment of my hospitalized patient with heart failure with reduced ejection fraction (HFrEF) and atrial fibrillation?

Should I routinely screen my patients with heart failure for iron deficiency?

FA Manian MD, MPH, , , , , , , Leave a comment

Even in the absence of anemia, screening for iron deficiency (ID) has been recommended in patients with heart failure (HF) with reduced ejection fraction (HFrEF) by some European and Australia-New Zealand cardiology societies. 1

In contrast, the 2017 American College of Cardiology/American Heart Association/Heart Failure Society of America guidelines do not mention routine screening for ID in such patients but instead state (under “Anemia”) that in patients with NYHA class II and III HF and ID (ferritin < 100 ng/mL or 100 to 300 ng/mL plus transferrin saturation <20%), IV iron replacement “might be reasonable” to improve functional status and quality of life (IIb-weak recommendation).2

As these guidelines are primarily based on data derived from patients with HFrEF, whether patients with HF with preserved (eg, >45%) ejection fraction (HFpEF) should undergo routine screening for ID is even less clear due to conflicting data based on limited small studies 3,4

What is known is that up to 50% or more of patients with HF with or without anemia may have ID. 5 Although most studies involving ID and HF have involved patients with HFrEF, similarly high prevalence of ID in HFpEF has been reported. 6,7

A 2016 meta-analysis involving patients with HFrEF and ID found that IV iron therapy alleviates HF symptoms and improves outcomes, exercise capacity and quality of life irrespective of concomitant anemia; all-cause and cardiovascular mortality rates were not significantly impacted, however.8  

Fortunately, larger trials in the setting of acute and chronic systolic HF are underway (Affirm-AHF, 9 IRONMAN 10).  Stay tuned!

Bonus Pearl: Did you know that iron deficiency directly affects human cardiomyocyte function by impairing mitochondrial respiration  and reducing its contractility and relaxation?11

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References

  1. Silverberg DS, Wexler D, Schwartz D. Is correction of iron deficiency a new addition to the treatment of the heart failure? Int J Mol Sci 2015;16:14056-74. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4490538/
  2. Yancy CW, Jessup M, Bozkurt B, et al. 2017 ACC/AHA/HFSA focused update of the 2013 ACCF/AHA guideline for the management of heart failure. Circulation 2017;136:e137-e161. https://www.ahajournals.org/doi/pdf/10.1161/CIR.0000000000000509
  3. Kasner M, Aleksandrov AS, Westermann D, et al. Functional iron deficiency and diastolic function in heart failure with preserved ejection fraction. International J of Cardiol 2013;168:12:4652-57. https://www.ncbi.nlm.nih.gov/pubmed/23968714
  4. Enjuanes C, Klip IT, Bruguera J, et al. Iron deficiency and health-related quality of life in chronic heart failure: results from a multicenter European study. Int J Cardiol 2014;174:268-275. https://www.ncbi.nlm.nih.gov/pubmed/24768464
  5. Drodz M, Jankowska EA, Banasiak W, et al. Iron therapy in patients with heart failure and iron deficiency: review of iron preparations for practitioners. Am J Cardiovasc Drugs 2017;17:183-201. https://www.ncbi.nlm.nih.gov/pubmed/28039585
  6. Bekfani T, Pellicori P, Morris D, et al. Iron deficiency in patients with heart failure with preserved ejection fraction and its association with reduced exercise capacity, muscle strength and quality of life. Clin Res Cardiol 2018, July 26. Doi: 10. 1007/s00392-018-1344-x. https://www.ncbi.nlm.nih.gov/pubmed/30051186
  7. Nunez J, Dominguez E, Ramon JM, et al. Iron deficiency and functional capacity in patients with advanced heart failure with preserved ejection fraction. International J Cardiol 2016;207:365-67. https://www.internationaljournalofcardiology.com/article/S0167-5273(16)30185-1/abstract
  8. Jankowska EA, Tkaczynszyn M, Suchocki T, et al. Effects of intravenous iron therapy in iron-deficient patients with systolic heart failure: a meta-analysis of randomized controlled trials. Eur J Heart Failure 2016;18:786-95. https://www.ncbi.nlm.nih.gov/pubmed/26821594
  9. https://clinicaltrials.gov/ct2/show/NCT02937454
  10. https://clinicaltrials.gov/ct2/show/NCT02642562
  11. Hoes MF, Beverborg NG, Kijlstra JD, et al. Iron deficiency impairs contractility of human cardiomyoctyes through decreased mitochondrial function. Eur J Heart Failure 2018;20:910-19. https://www.ncbi.nlm.nih.gov/pubmed/29484788  

 

Should I routinely screen my patients with heart failure for iron deficiency?