Should I continue or discontinue angiotensin converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) in my patients with possible Coronavirus/Covid-19 infection?

The original reports of an association between hypertension and increased risk of mortality in hospitalized patients with Covid-19 infection raised concern over the potential deleterious role of ACEIs or ARBs in such patients.1-4 However, as stated by a joint statement of several cardiology societies, including the American Heart Association, American College of Cardiology and the European Society of Cardiology on March 13, 2020, there is no clinical or scientific evidence that ACEI or ARBS should be routinely discontinued in patients with Covid-19 infection.5

In fact, some have argued for the opposite ie, consideration for the use of ARBs, such as losartan (an angiotensin receptor 1 [AT1R] antagonist), in patients with Covid-19.6,7  Although it is true that Covid-19 appears to use ACE2 as a binding site to infect cells (just as in SARS) and that ACE2 may be upregulated in patients on chronic ACEI or ARBs,8,9 ACE2 may also potentially protect against severe lung injury associated with infections.10,11  

Two complementary mechanisms have been posited for the potential protective effect of ARBs in Covid-19 infection-related lung injury: 1. Blocking the excessive AT1R activation caused by the viral infection; and 2. Upregulation of ACE2, thereby reducing production of angiotensin II and increasing the production of the vasodilator angiotensin 1-7.7

In the absence of proper clinical studies, it is premature, however, to recommend use of losartan or other AT1R antagonists as a means of reducing the likelihood of ARDS in patients with Covid-19 at this time.

Bonus Pearl: Did you know that ARDS is a major cause of death in Covid-19 infection?12

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References

  1. Guan W, Ni Z, Hu Y, et al. Clinical characteristics of coronavirus disease 2019 in China. N Engl J Med 2020, March 6. https://www.nejm.org/doi/pdf/10.1056/NEJMoa2002032?articleTools=true
  2. O’Mara GJ. Could ACE inhibitors, and particularly ARBs, increase susceptibility to COVID-19 infection? BMJ 2020;368:m406 ARTICLE
  3. Sommerstein R, Grani C. Preventing a Covid-19 pandemic: ACE inhibitors as a potential risk factor for fatal Covid-19. BMJ2020;368:m810. https://www.bmj.com/content/368/bmj.m810/rr-2
  4. Li X, Geng M, Peng Y, et al. Molecular immune pathogenesis and diagnosis of COVID-19. Journal of Pharmaceutical Analysis 2020, doi htps://doi.org/10.106/j.jpha.2020.03.001. https://www.sciencedirect.com/science/article/pii/S2095177920302045
  5. Cardiology societies recommend patients taking ACE inhibitors, ARBs who contract COVID-19 should continue treatment. March 17, 2020. https://www.healio.com/cardiology/vascular-medicine/news/online/%7Bfe7f0842-aecb-417b-9ecf-3fe7e0ddd991%7D/cardiology-societies-recommend-patients-taking-ace-inhibitors-arbs-who-contract-covid-19-should-continue-treatment
  6. Gurwitz D. Angiotensin receptor blockers as tentative SARS-CoV-2 therapeutics. Drug Dev Res 2020;1-4. https://www.ncbi.nlm.nih.gov/pubmed/32129518/
  7. Phadke M, Saunik S. Response to the emerging novel coronavirus outbreak. BMJ 2020;368:m406. https://www.bmj.com/content/368/bmj.m406/rr-2
  8. Zheng YY, Ma YT, Zhang JY, et al. COVID-19 and the cardiovascular system. Nature Reviews/Cardiology 2020; https://doi.org/10.1038/s41569-020-0360-5 .
  9. Ferrario CM, Jessup J, Chappell MC, et al. Effect of angiotensin-converting enzyme inhibition and angiotensin II receptor blockers on cardiac angiotensin-converting enzyme 2. Circulation 2005;111:2605-2610. https://www.ahajournals.org/doi/full/10.1161/circulationaha.104.510461
  10. Kuba K, Imai Y, Rao S, et al. A crucial role of angiotensin converting enzyme 2 (ACE2) in SARS coronavirus-induced lung injury. Nature Medicine 2005;11:875-79. Doi:10.1038/nm1267 https://www.nature.com/articles/nm1267?v=1
  11. Tikellis C, Thomas MC. Angiotensin-converting enzyme 2 (ACE2) is a key modulator of the renin angiotensin system in health and disease. International Journal of Peptides. Volume 2012, Article ID 256294, 8 pages. Doi:10.1155/2012/256294. https://research.monash.edu/en/publications/angiotensin-converting-enzyme-2-ace2-is-a-key-modulator-of-the-re

12 . Huang C, Wang Y, Li X, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 2020. https://doi.org/10.1016/S0140-6736(20)30183-5

 

Disclosures: The listed questions and answers are solely the responsibility of the author and do not necessarily represent the official views of Massachusetts General Hospital, Harvard Catalyst, Harvard University, its 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 continue or discontinue angiotensin converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) in my patients with possible Coronavirus/Covid-19 infection?

What existing drugs are currently being evaluated or repurposed for treatment of Coronavirus (Covid-19) infection?

There are currently no drugs specifically approved for treatment of Covid-19 infections. However, there are legions of therapies that are being considered, tried, and/or evaluated in clinical trials. Many experts believe a combination of drugs may be necessary for optimal therapy. Here is my select list of potentially promising drugs from gleaning the literature and online resources to date.1-16

  • Remdisivir: A broad spectrum investigational nucleoside analogue, originally developed to treat a variety of viruses, including Ebola, SARS and MERS. Active in vitro against Covid-19. Favorable results have been reported in some cases, including the first reported patient in the U.S.
  • Chloroquine: An old drug used for its antimalarial activity as well as for its immune modulation and anti-inflammatory properties. Has also been found to be active in mice against a variety of viruses, including certain enteroviruses, Zika virus, influenza A H5N1.  Active in vitro against Covid-19, though hydroxychloroquine may be more effective. Evidence for its efficacy in treating acute viral infections in humans is currently lacking.
  • Lopinavir/ritonavir: Protease inhibitor combo used in HIV infection with possibly some benefit in the treatment of SARS. Recent study showed no significant efficacy in severe Covid-19 disease. 
  • Interferon-alpha: An antiviral cytokine used against hepatitis B and C viruses. May be more effective for prophylaxis than post-exposure, based on experimental animal studies involving SARS.
  • Ribavirin: Another nucleoside analogue approved for hepatitis C (in combination with other drugs) and respiratory syncytial virus (RSV) infections but also evaluated in SARS and MERS. Has been reported to be active in vitro against Covid-19.
  • Sofosbuvir: Inhibits RNA-dependent RNA polymerase. Approved for treatment of hepatitis C, but also with in vitro activity against Covid-19.
  • Tocilizumab: Anti-interleukin-6 monoclonal antibody used in rheumatoid and giant cell arthritis. Theoretically, may mitigate cytokine storm observed in some patients during the later stages of Covid-19 disease.

Of course, there are many more drugs some of which would not be expected to be effective against Covid-19, based on what we so far know this virus. These include darunavir/cobicistat, oseltamivir, immunoglobulins, arbidol (an antiviral used in Russia and China vs influenza), angiotensin receptor blockers, stem cell therapy, convalescent plasma, and traditional Chinese medicine.

Remember corticosteroids are currently not recommended in the absence of other indications for their use (see related PEARL).

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References

  1. US National Library of Medicine. https://clinicaltrials.gov/ct2/results?cond=2019nCoV&term=&cntry=&state=&city=&dist
  2. Li Guangdi, De Clercq E. Therapeutic options for the 2019 novel coronavirus (2019-nCoV). Nature Reviews Drug Discovery 2020; Feb 19, 2010. https://www.nature.com/articles/d41573-020-00016-0
  3. Harrison C. Coronavirus puts drug repurposing on the fast track. Nature Biotechnology 020, Feb 27. https://www.nature.com/articles/d41587-020-00003-1
  4. Velavan TP, Meyer CG. The COVID-19 epidemic. Tropical Medicine and International Health 2020;25:278-280. https://onlinelibrary.wiley.com/doi/full/10.1111/tmi.13383
  5. Elfiky AA. Anti-HCV, nucleotide inhibitors, repurposing against COVID-19. Life Sciences 2020;248. 11747. https://www.sciencedirect.com/science/article/pii/S0024320520302253
  6. Wang Y, Wang Y, Chen Y, et al. Unique epidemiological and clinical features of the emerging 2019 novel coronavirus pneumonia (COVID-19) implicate special control measures. J Med Virol 2020;March 5. https://www.ncbi.nlm.nih.gov/pubmed/32134116
  7. Huang C, Wang Y, Li X, et al. Clinical features of patients infected with 2029 novel coronavirus in Wuhan, China. Lancet 2020;395:497-506. https://www.ncbi.nlm.nih.gov/pubmed/31986264
  8. Paules CI, Marston HD, Fauci AS. Coronavirus infections—More than just the common cold. JAMA 2020;323:707-78. https://jamanetwork.com/journals/jama/fullarticle/2759815
  9. Touret F, de Lamballerie X. Of chloroquine and COVID-19. Antiviral Research 2020;177. 104762. https://www.sciencedirect.com/science/article/pii/S0166354220301145
  10. Gurwitz D. Angiotensin receptor blockers as tentavie SARS-CoV-2 therapeutics. https://www.ncbi.nlm.nih.gov/pubmed/32129518/
  11. Wang M, Cao R, Zhang L, et al. Remdesivir and chlorquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell Research 2020;30:269-71. https://www.nature.com/articles/s41422-020-0282-0
  12. Roques P, Thiberville SD, Dupuis-Maguirara L, et al. Paradoxical effect of chloroquine treatment in enhancing Chikungunya virus infection. Viruses 2018;10, 268. https://www.ncbi.nlm.nih.gov/pubmed/29772762
  13. Young BE, Ong SWX, Kalimuddin S, et al. Epidemiologic features and clinical course of patients infected with SARS-CoV-2 in Singapore. JAMA 2020;March 3. https://jamanetwork.com/journals/jama/fullarticle/2762688
  14. Holshue ML, DeBolt C, Lindquist S, et al. First case of 2019 novel coronavirus in the United States. N Engl J Med 2020; March 5. https://www.nejm.org/doi/full/10.1056/NEJMoa2001191
  15. Yao X, Ye F, Zhang M, et al. In vitro antiviral activity and projection of optimized dosing design of hydroxychloroquine for the treatment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Clin Infect Dis 2020. March 9. https://www.ncbi.nlm.nih.gov/pubmed?term=32150618
  16. Cao B, Wang Y, Wen D, et al. A trial of lopinavir-ritonavir in adults hospitalized with severe Covid-19. N Engl M Med 2020, March18. DOI:10.1056/NEJMoa2001282. https://www.nejm.org/doi/full/10.1056/NEJMoa2001282

 

Disclosures: The listed questions and answers are solely the responsibility of the author and do not necessarily represent the official views of Massachusetts General Hospital, Harvard Catalyst, Harvard University, its 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!

What existing drugs are currently being evaluated or repurposed for treatment of Coronavirus (Covid-19) infection?

Why is my relatively healthy elderly patient so prone to hyperkalemia?

Hyporeninemic hypoaldosteronism (HH)—without impairment of cortisol synthesis— is associated with hyperkalemic (type IV) renal tubular acidosis (RTA) and is not uncommon among older patients despite glomerular filtration rates (GFRs) >20 ml/min, and absence of diabetes mellitus or chronic tubulointerstitial disease (1-7).  

Hyperkalemia due to HH in the elderly should come as no surprise because the renin-angiotensin-aldosterone system (RAAS) function declines with age, reaching its lowest level by age 60. 1-4   In fact, older people have comparatively lower mean levels of plasma renin and aldosterone at baseline and have an impaired ability to mount appropriate responses to RAAS stimuli, such as upright posture, volume depletion, catecholamines, or potassium administration (3-5).

The impaired RAAS capacity in the elderly often becomes more obvious when they are prescribed medications that further suppress RAAS (3). These include angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, beta-blockers, calcium-channel blockers, nonsteroidal anti-inflammatory agents and heparin (3,7). 

Drugs that increase aldosterone resistance, including potassium-sparing diuretics (eg, spironolactone, amiloride, triamterene, eplerenone) and certain antibiotics (eg, trimethoprim, pentamidine) may also aggravate hyperkalemia associated with HH (7). 

A variety of mechanisms leading to HH with aging have been proposed. These include impaired conversion of prorenin to renin, prostaglandin deficiency, sympathetic nervous system dysfunction and increased plasma levels of atrial natriuretic factors as found in congestive heart failure (1,7). 

Bonus pearl: Did you know that the first case of “pure hypoaldosteronism” was described in 1957 in a 71 year old non-diabetic patient with hyperkalemia in the setting of congestive heart failure? (8)

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References

  1. Bauer JH. Age-related changes in the renin-aldosterone system. Physiological effects and clinical implications. Drugs & Aging 1993;3:238-45. https://www.ncbi.nlm.nih.gov/pubmed/8324299
  2. Musso CG, Jauregui JR. Renin-angiotensin-aldosterone system and the aging kidney. Expert Rev Endocrinol Metab 2014;9:543-46. https://www.tandfonline.com/doi/full/10.1586/17446651.2014.956723
  3. Yoon HE, Choi BS. The renin-angiotensin system and aging in the kidney. Korean J Intern Med 2014;29:291-95. https://www.researchgate.net/publication/262530577_The_renin-angiotensin_system_and_aging_in_the_kidney
  4. Nadler JL, Lee FO, Hsueh W, et al. Evidence of prostacyclin deficiency in the syndrome of hyporeninemic hypoaldosteronism. N Engl J Med 1986;314:1015-20. https://www.ncbi.nlm.nih.gov/pubmed/3515183
  5. Williams GH. Hyporeninemic hypoaldosteronism. N Engl J Med 1986;314:1041-42. https://www.ncbi.nlm.nih.gov/pubmed/3515186
  6.  Block BL, Bernard S, Schwartzstein RM. Hypo-hypo: a complex metabolic disorder. Ann Am Thorac Soc 2016;13:127-133. https://www.ncbi.nlm.nih.gov/pubmed/26730868
  7. Michelis MF. Hyperkalemia in the elderly. Am J Kid Dis 1990;16:296-99.https://www.ajkd.org/article/S0272-6386(12)80005-9/pdf
  8. Hudson JB, Chobanian AV, Relman AS. Hypoaldosteronism. A clinical study of a patient with an isolated adrenal mineralocorticoid deficiency, resulting in hyperkaliemia and Stokes-Adams attack. N Engl J Med 1957;257:529-36. https://www.ncbi.nlm.nih.gov/pubmed/13464977

 

Why is my relatively healthy elderly patient so prone to hyperkalemia?

Should my patient with compensated heart failure be placed on a sodium-restricted diet?

Although sodium restriction is routinely recommended for patients with heart failure (HF), the data is often conflicting with a number of studies even suggesting that it may be harmful in some patients.

Two randomized trials (by the same group) involving patients with compensated HF recently discharged from the hospital reported that “less restricted” sodium diet (2.8 gm/d) along with fluid restriction (1 L/day) and high dose furosemide (at least 125-250 mg furosemide twice daily) was associated with less rates of readmissions and improved levels of brain natriuretic peptide, aldosterone and plasma renin activity compared to patients on more restricted sodium diet (1.8 gm/d). 1,2

Analysis of data from the multihospital HF Adherence and Retention Trial enrolling New York Heart Association functional class II/III HF patients found that sodium restriction (<2.5 gm/d) was associated with significantly higher risk of death or HF hospitalization but only in patients not on an angiotensin converting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB). 3

In normal subjects who are not sodium deprived, excess sodium intake has been shown to cause expansion of intravascular volume without increasing total body water. 4 Thus, sodium restriction combined with diuretics may reduce intravascular volume and renal perfusion, further stimulating the renin-angiotensin-aldosterone system and fluid retention. 5

Bonus Pearl: Did you know that the 2013 American College of Cardiology Foundation/American Heart Association guidelines downgraded the recommendation for sodium restriction to Class IIa (reasonable) with Level of Evidence:C? 6

References

  1. Paterna S, Gaspare P, Fasullo S, et al. Normal-sodium diet compared with low-sodium diet in compensated congestive heart failure: is sodium an old enemy or a new friend? Clin Sci 2008;114:221-230. https://www.ncbi.nlm.nih.gov/pubmed/17688420
  2. Paterna S, Parrinello G, Cannizzaro S, et al. Medium term effects of different dosage of diuretic, sodium, and fluid administration on neurohormonal and clinical outcome in patients with recently compensated heart failure. Am J Cardiol 2009;103:93-102. https://www.ncbi.nlm.nih.gov/pubmed/19101237
  3. Doukky R, Avery E, Mangla A, et al.Impact of dietary sodium restriction on heart failure outcomes. J Am Coll Cariol HF 2016;4:24-35. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4705447/
  4. Heer M, Baisch F, Kropp J et al. High dietary sodium chloride consumption may not induce body fluid retention in humans. Am J Physiol Renal Physiol 2000;278:F585-F595. https://www.ncbi.nlm.nih.gov/pubmed/10751219
  5. Rothberg MB, Sivalingam SK. The new heart failure diet: less salt restriction, more micronutrients. J Gen Intern Med 25;1136-7. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2955483/
  6. Yancy CW, Jessup M, Bozkurt B, et al. 2013 CCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2013;62:e147-239. https://www.ncbi.nlm.nih.gov/pubmed/23741058

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Should my patient with compensated heart failure be placed on a sodium-restricted diet?