View Article PDF

There has been an unprecedented interest generated in the medical community and on social media around the interaction of coronavirus (SARS-CoV2) and ACE inhibitors (ACEi) and angiotensin receptor blockers (ARB), and whether these medications increase the risk of COVID-19.

This was triggered by correspondences published in high-impact medical journals, Lancet Respiratory Medicine and BMJ.1,2 They observed that the COVID-19 patients with comorbidities such as hypertension and diabetes, had more severe symptoms. The authors hypothesised that diabetes and hypertension treatment with ACE2-stimulating drugs increases the risk of developing severe and fatal COVID-19. They suggest that ACEi and ARB can increase ACE2, which is an enzyme used by the virus to gain entry into host cells. Therefore, these drugs could potentially increase the risk of severe infection.

We reviewed the evidence supporting this hypothesis, and would like to make the following observations:

1. The studies from China report higher prevalence of hypertension in those who developed severe COVID-19 disease.3,4 However, a conclusion cannot be drawn that hypertension results in severe infection as these analyses were unadjusted for confounders such as age, and there was no reported data on ACEi and ARB use in these studies. Another recently published study evaluating cardiovascular implications of COVID-19 did not find any association between use of ACEi/ARB and mortality.5

2. Previous animal studies6 showed that ACEi and ARB increase ACE2 activity. Based on this, Fang et al proposed that this would enhance infectivity of the SARS CoV2 virus.1 However, other studies did not find any change in ACE2 mRNA expression in rat heart cells treated with an ACEi7 and no change in plasma ACE2 activity in the presence of either ACEi or ARBs in humans.8 Therefore, it is questionable whether these drugs increase either the expression or enzymatic activity of ACE2 in tissues to cause severe viral infection.

3. To the contrary, there is evidence that ACEi might confer protection in some viral pneumonias.9 Based on this, there are ongoing trials studying the effect of Losartan (an ARB) in patients with COVID-19 in outpatient and inpatient settings.10,11

Therefore, given the available evidence, we DO NOT advise patients on ACEi or ARB to change therapy. These commonly used medications confer benefits in patients with cardiovascular disease, kidney disease and diabetes, and should not be changed unless clinically indicated. The current evidence on COVID-19 and hypertension, and ACEi or ARB medication is inadequately adjusted and prone to bias, and therefore remains inconclusive.

Our recommendation to prescribed use of ACEi and ARBs is consistent with the viewpoint of numerous societies from around the world including the American College of Cardiology, American Heart Association, and Heart Failure Society of America, European Society of Cardiology, the International Society for Hypertension, European Renal Association and European Dialysis and Transplant Association.

Summary

Abstract

There has been a lot of speculation that patients with coronavirus disease 2019 (COVID-19) who are receiving angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) may be at increased risk for adverse outcomes. We reviewed the available evidence, and have not found this to be the case. We recommend that patients on such medications should continue on them unless there is a clinical indication to stop their use.

Aim

Method

Results

Conclusion

Author Information

Hari Talreja, Consultant Nephrologist, Counties Manukau DHB; Jasmine Tan, Consultant Nephrologist, Waitematā DHB; Matt Dawes, Cardiovascular Physician/Clinical Pharmacologist, Auckland DHB and Sr lecturer, University of Auckland; Sharen Supershad, Consultant Nephrologist, Northland DHB; Kannaiyan Rabindranath, Consultant Nephrologist, Waikato DHB; James Fisher, Department of Physiology, University of Auckland; Sajed Valappil, Consultant Nephrologist, Waitematā DHB; Veronica van der Merwe, Nurse Specialist, The Hypertension Clinic, Auckland; Lisa Wong, Research Operations Manager, Manaaki Mānawa – The Heart Research Centre; Walter van der Merwe, Consultant Hypertension Specialist, The Hypertension Clinic, Auckland; Julian Paton, Director, Manaaki Mānawa – The Heart Research Centre, and Department of Physiology, University of Auckland; The consensus has also been supported by Professor Rob Doughty (Heart Foundation Chair, ADHB, University of Auckland) and Associate Professor Gerry Devlin (Medical Director, Heart Foundation).

Acknowledgements

Correspondence

Dr Hari Talreja, Consultant Renal Physician, Dept of Renal Medicine, Counties Manukau Health, 100 Hospital Road, Otahuhu, Auckland 1640.

Correspondence Email

hari.talreja@middlemore.co.nz

Competing Interests

Nil.

1. Fang L, Karakiulakis G, Roth M. (2020). Are patients with hypertension and diabetes mellitus at increased risk for COVID-19 infection? Lancet Respir Med. 2020 Mar 11; doi: 10.1016/S2213-2600(20)30116-8. [Epub ahead of print]

2. Sommerstein R. Re: Preventing a covid-19 pandemic: ACE inhibitors as a potential risk factor for fatal Covid-19. BMJ 2020; 368:m810

3. Yang X, Yu Y, Xu J, et al. Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study. Lancet Respir Med 2020; published online Feb 24. http://doi.org/10.1016/S2213-2600(20)30079-5

4. Guan W, Ni Z, Hu Y, et al. Clinical characteristics of coronavirus disease 2019 in China. N Engl J Med 2020; published online Feb 28. DOI:10.1056/NEJMoa2002032.

5. Guo T, Fan Y, Chen M, et al. Cardiovascular Implications of Fatal Outcomes of Patients with Coronavirus Disease 2019 (COVID-19). JAMA Cardiol. Published online March 27, 2020. doi:10.1001/jamacardio.2020.1017

6. 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 May 24; 111(20):2605-10. Epub 2005 May 16.

7. Burrell L, Risvanis J, Kubota E, et al. Myocardial infarction increases ACE2 expression in rat and humans, European Heart Journal, Volume 26, Issue 4, February 2005, Pages 369–375, http://doi.org/10.1093/eurheartj/ehi114

8. Walters TE, Kalman JM, Patel SK et al. Angiotensin converting enzyme 2 activity and human atrial fibrillation: increased plasma angiotensin converting enzyme 2 activity is associated with atrial fibrillation and more advanced left atrial structural remodelling. Europace. 2017 Aug 1; 19(8):1280–1287. doi: 10.1093/europace/euw246.

9. Henry C, Zaizafoun M, Stock E et al. Impact of angiotensin-converting enzyme inhibitors and statins on viral pneumonia. Proc (Bayl Univ Med Cent). 2018 Oct 26; 31(4):419–423. doi: 10.1080/08998280.2018.1499293.

10. Randomized Controlled Trial of Losartan for Patients With COVID-19 Not Requiring Hospitalization. ClinicalTrials.gov Identifier: NCT04311177.

11. Randomized Controlled Trial of Losartan for Patients With COVID-19 Requiring Hospitalization. ClinicalTrials.gov Identifier: NCT04312009.

Contact diana@nzma.org.nz
for the PDF of this article

View Article PDF

There has been an unprecedented interest generated in the medical community and on social media around the interaction of coronavirus (SARS-CoV2) and ACE inhibitors (ACEi) and angiotensin receptor blockers (ARB), and whether these medications increase the risk of COVID-19.

This was triggered by correspondences published in high-impact medical journals, Lancet Respiratory Medicine and BMJ.1,2 They observed that the COVID-19 patients with comorbidities such as hypertension and diabetes, had more severe symptoms. The authors hypothesised that diabetes and hypertension treatment with ACE2-stimulating drugs increases the risk of developing severe and fatal COVID-19. They suggest that ACEi and ARB can increase ACE2, which is an enzyme used by the virus to gain entry into host cells. Therefore, these drugs could potentially increase the risk of severe infection.

We reviewed the evidence supporting this hypothesis, and would like to make the following observations:

1. The studies from China report higher prevalence of hypertension in those who developed severe COVID-19 disease.3,4 However, a conclusion cannot be drawn that hypertension results in severe infection as these analyses were unadjusted for confounders such as age, and there was no reported data on ACEi and ARB use in these studies. Another recently published study evaluating cardiovascular implications of COVID-19 did not find any association between use of ACEi/ARB and mortality.5

2. Previous animal studies6 showed that ACEi and ARB increase ACE2 activity. Based on this, Fang et al proposed that this would enhance infectivity of the SARS CoV2 virus.1 However, other studies did not find any change in ACE2 mRNA expression in rat heart cells treated with an ACEi7 and no change in plasma ACE2 activity in the presence of either ACEi or ARBs in humans.8 Therefore, it is questionable whether these drugs increase either the expression or enzymatic activity of ACE2 in tissues to cause severe viral infection.

3. To the contrary, there is evidence that ACEi might confer protection in some viral pneumonias.9 Based on this, there are ongoing trials studying the effect of Losartan (an ARB) in patients with COVID-19 in outpatient and inpatient settings.10,11

Therefore, given the available evidence, we DO NOT advise patients on ACEi or ARB to change therapy. These commonly used medications confer benefits in patients with cardiovascular disease, kidney disease and diabetes, and should not be changed unless clinically indicated. The current evidence on COVID-19 and hypertension, and ACEi or ARB medication is inadequately adjusted and prone to bias, and therefore remains inconclusive.

Our recommendation to prescribed use of ACEi and ARBs is consistent with the viewpoint of numerous societies from around the world including the American College of Cardiology, American Heart Association, and Heart Failure Society of America, European Society of Cardiology, the International Society for Hypertension, European Renal Association and European Dialysis and Transplant Association.

Summary

Abstract

There has been a lot of speculation that patients with coronavirus disease 2019 (COVID-19) who are receiving angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) may be at increased risk for adverse outcomes. We reviewed the available evidence, and have not found this to be the case. We recommend that patients on such medications should continue on them unless there is a clinical indication to stop their use.

Aim

Method

Results

Conclusion

Author Information

Hari Talreja, Consultant Nephrologist, Counties Manukau DHB; Jasmine Tan, Consultant Nephrologist, Waitematā DHB; Matt Dawes, Cardiovascular Physician/Clinical Pharmacologist, Auckland DHB and Sr lecturer, University of Auckland; Sharen Supershad, Consultant Nephrologist, Northland DHB; Kannaiyan Rabindranath, Consultant Nephrologist, Waikato DHB; James Fisher, Department of Physiology, University of Auckland; Sajed Valappil, Consultant Nephrologist, Waitematā DHB; Veronica van der Merwe, Nurse Specialist, The Hypertension Clinic, Auckland; Lisa Wong, Research Operations Manager, Manaaki Mānawa – The Heart Research Centre; Walter van der Merwe, Consultant Hypertension Specialist, The Hypertension Clinic, Auckland; Julian Paton, Director, Manaaki Mānawa – The Heart Research Centre, and Department of Physiology, University of Auckland; The consensus has also been supported by Professor Rob Doughty (Heart Foundation Chair, ADHB, University of Auckland) and Associate Professor Gerry Devlin (Medical Director, Heart Foundation).

Acknowledgements

Correspondence

Dr Hari Talreja, Consultant Renal Physician, Dept of Renal Medicine, Counties Manukau Health, 100 Hospital Road, Otahuhu, Auckland 1640.

Correspondence Email

hari.talreja@middlemore.co.nz

Competing Interests

Nil.

1. Fang L, Karakiulakis G, Roth M. (2020). Are patients with hypertension and diabetes mellitus at increased risk for COVID-19 infection? Lancet Respir Med. 2020 Mar 11; doi: 10.1016/S2213-2600(20)30116-8. [Epub ahead of print]

2. Sommerstein R. Re: Preventing a covid-19 pandemic: ACE inhibitors as a potential risk factor for fatal Covid-19. BMJ 2020; 368:m810

3. Yang X, Yu Y, Xu J, et al. Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study. Lancet Respir Med 2020; published online Feb 24. http://doi.org/10.1016/S2213-2600(20)30079-5

4. Guan W, Ni Z, Hu Y, et al. Clinical characteristics of coronavirus disease 2019 in China. N Engl J Med 2020; published online Feb 28. DOI:10.1056/NEJMoa2002032.

5. Guo T, Fan Y, Chen M, et al. Cardiovascular Implications of Fatal Outcomes of Patients with Coronavirus Disease 2019 (COVID-19). JAMA Cardiol. Published online March 27, 2020. doi:10.1001/jamacardio.2020.1017

6. 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 May 24; 111(20):2605-10. Epub 2005 May 16.

7. Burrell L, Risvanis J, Kubota E, et al. Myocardial infarction increases ACE2 expression in rat and humans, European Heart Journal, Volume 26, Issue 4, February 2005, Pages 369–375, http://doi.org/10.1093/eurheartj/ehi114

8. Walters TE, Kalman JM, Patel SK et al. Angiotensin converting enzyme 2 activity and human atrial fibrillation: increased plasma angiotensin converting enzyme 2 activity is associated with atrial fibrillation and more advanced left atrial structural remodelling. Europace. 2017 Aug 1; 19(8):1280–1287. doi: 10.1093/europace/euw246.

9. Henry C, Zaizafoun M, Stock E et al. Impact of angiotensin-converting enzyme inhibitors and statins on viral pneumonia. Proc (Bayl Univ Med Cent). 2018 Oct 26; 31(4):419–423. doi: 10.1080/08998280.2018.1499293.

10. Randomized Controlled Trial of Losartan for Patients With COVID-19 Not Requiring Hospitalization. ClinicalTrials.gov Identifier: NCT04311177.

11. Randomized Controlled Trial of Losartan for Patients With COVID-19 Requiring Hospitalization. ClinicalTrials.gov Identifier: NCT04312009.

Contact diana@nzma.org.nz
for the PDF of this article

View Article PDF

There has been an unprecedented interest generated in the medical community and on social media around the interaction of coronavirus (SARS-CoV2) and ACE inhibitors (ACEi) and angiotensin receptor blockers (ARB), and whether these medications increase the risk of COVID-19.

This was triggered by correspondences published in high-impact medical journals, Lancet Respiratory Medicine and BMJ.1,2 They observed that the COVID-19 patients with comorbidities such as hypertension and diabetes, had more severe symptoms. The authors hypothesised that diabetes and hypertension treatment with ACE2-stimulating drugs increases the risk of developing severe and fatal COVID-19. They suggest that ACEi and ARB can increase ACE2, which is an enzyme used by the virus to gain entry into host cells. Therefore, these drugs could potentially increase the risk of severe infection.

We reviewed the evidence supporting this hypothesis, and would like to make the following observations:

1. The studies from China report higher prevalence of hypertension in those who developed severe COVID-19 disease.3,4 However, a conclusion cannot be drawn that hypertension results in severe infection as these analyses were unadjusted for confounders such as age, and there was no reported data on ACEi and ARB use in these studies. Another recently published study evaluating cardiovascular implications of COVID-19 did not find any association between use of ACEi/ARB and mortality.5

2. Previous animal studies6 showed that ACEi and ARB increase ACE2 activity. Based on this, Fang et al proposed that this would enhance infectivity of the SARS CoV2 virus.1 However, other studies did not find any change in ACE2 mRNA expression in rat heart cells treated with an ACEi7 and no change in plasma ACE2 activity in the presence of either ACEi or ARBs in humans.8 Therefore, it is questionable whether these drugs increase either the expression or enzymatic activity of ACE2 in tissues to cause severe viral infection.

3. To the contrary, there is evidence that ACEi might confer protection in some viral pneumonias.9 Based on this, there are ongoing trials studying the effect of Losartan (an ARB) in patients with COVID-19 in outpatient and inpatient settings.10,11

Therefore, given the available evidence, we DO NOT advise patients on ACEi or ARB to change therapy. These commonly used medications confer benefits in patients with cardiovascular disease, kidney disease and diabetes, and should not be changed unless clinically indicated. The current evidence on COVID-19 and hypertension, and ACEi or ARB medication is inadequately adjusted and prone to bias, and therefore remains inconclusive.

Our recommendation to prescribed use of ACEi and ARBs is consistent with the viewpoint of numerous societies from around the world including the American College of Cardiology, American Heart Association, and Heart Failure Society of America, European Society of Cardiology, the International Society for Hypertension, European Renal Association and European Dialysis and Transplant Association.

Summary

Abstract

There has been a lot of speculation that patients with coronavirus disease 2019 (COVID-19) who are receiving angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) may be at increased risk for adverse outcomes. We reviewed the available evidence, and have not found this to be the case. We recommend that patients on such medications should continue on them unless there is a clinical indication to stop their use.

Aim

Method

Results

Conclusion

Author Information

Hari Talreja, Consultant Nephrologist, Counties Manukau DHB; Jasmine Tan, Consultant Nephrologist, Waitematā DHB; Matt Dawes, Cardiovascular Physician/Clinical Pharmacologist, Auckland DHB and Sr lecturer, University of Auckland; Sharen Supershad, Consultant Nephrologist, Northland DHB; Kannaiyan Rabindranath, Consultant Nephrologist, Waikato DHB; James Fisher, Department of Physiology, University of Auckland; Sajed Valappil, Consultant Nephrologist, Waitematā DHB; Veronica van der Merwe, Nurse Specialist, The Hypertension Clinic, Auckland; Lisa Wong, Research Operations Manager, Manaaki Mānawa – The Heart Research Centre; Walter van der Merwe, Consultant Hypertension Specialist, The Hypertension Clinic, Auckland; Julian Paton, Director, Manaaki Mānawa – The Heart Research Centre, and Department of Physiology, University of Auckland; The consensus has also been supported by Professor Rob Doughty (Heart Foundation Chair, ADHB, University of Auckland) and Associate Professor Gerry Devlin (Medical Director, Heart Foundation).

Acknowledgements

Correspondence

Dr Hari Talreja, Consultant Renal Physician, Dept of Renal Medicine, Counties Manukau Health, 100 Hospital Road, Otahuhu, Auckland 1640.

Correspondence Email

hari.talreja@middlemore.co.nz

Competing Interests

Nil.

1. Fang L, Karakiulakis G, Roth M. (2020). Are patients with hypertension and diabetes mellitus at increased risk for COVID-19 infection? Lancet Respir Med. 2020 Mar 11; doi: 10.1016/S2213-2600(20)30116-8. [Epub ahead of print]

2. Sommerstein R. Re: Preventing a covid-19 pandemic: ACE inhibitors as a potential risk factor for fatal Covid-19. BMJ 2020; 368:m810

3. Yang X, Yu Y, Xu J, et al. Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study. Lancet Respir Med 2020; published online Feb 24. http://doi.org/10.1016/S2213-2600(20)30079-5

4. Guan W, Ni Z, Hu Y, et al. Clinical characteristics of coronavirus disease 2019 in China. N Engl J Med 2020; published online Feb 28. DOI:10.1056/NEJMoa2002032.

5. Guo T, Fan Y, Chen M, et al. Cardiovascular Implications of Fatal Outcomes of Patients with Coronavirus Disease 2019 (COVID-19). JAMA Cardiol. Published online March 27, 2020. doi:10.1001/jamacardio.2020.1017

6. 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 May 24; 111(20):2605-10. Epub 2005 May 16.

7. Burrell L, Risvanis J, Kubota E, et al. Myocardial infarction increases ACE2 expression in rat and humans, European Heart Journal, Volume 26, Issue 4, February 2005, Pages 369–375, http://doi.org/10.1093/eurheartj/ehi114

8. Walters TE, Kalman JM, Patel SK et al. Angiotensin converting enzyme 2 activity and human atrial fibrillation: increased plasma angiotensin converting enzyme 2 activity is associated with atrial fibrillation and more advanced left atrial structural remodelling. Europace. 2017 Aug 1; 19(8):1280–1287. doi: 10.1093/europace/euw246.

9. Henry C, Zaizafoun M, Stock E et al. Impact of angiotensin-converting enzyme inhibitors and statins on viral pneumonia. Proc (Bayl Univ Med Cent). 2018 Oct 26; 31(4):419–423. doi: 10.1080/08998280.2018.1499293.

10. Randomized Controlled Trial of Losartan for Patients With COVID-19 Not Requiring Hospitalization. ClinicalTrials.gov Identifier: NCT04311177.

11. Randomized Controlled Trial of Losartan for Patients With COVID-19 Requiring Hospitalization. ClinicalTrials.gov Identifier: NCT04312009.

Contact diana@nzma.org.nz
for the PDF of this article

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