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Influence of inhibitors of the renin–angiotensin system on risk of acute respiratory distress syndrome in Danish hospitalized COVID-19 patients

Holt et al., Journal of Hypertension, doi:10.1097/hjh.0000000000002515
May 2020  
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Death/ICU -129% Improvement Relative Risk Spironolactone for COVID-19  Holt et al.  Prophylaxis Is prophylaxis with spironolactone beneficial for COVID-19? Retrospective 689 patients in Denmark (March - April 2020) Higher death/ICU with spironolactone (p=0.00072) c19early.org Holt et al., J. Hypertension, May 2020 Favorsspironolactone Favorscontrol 0 0.5 1 1.5 2+
34th treatment shown to reduce risk in February 2022
 
*, now with p = 0.00046 from 12 studies.
Lower risk for mortality, progression, and recovery.
No treatment is 100% effective. Protocols combine treatments. * >10% efficacy, ≥3 studies.
4,400+ studies for 79 treatments. c19early.org
Retrospective 689 hospitalized COVID-19 patients in Denmark, showing higher risk of ICU/death with spironolactone use in unadjusted results subject to confounding by indication.
This study is excluded in the after exclusion results of meta analysis: unadjusted results with no group details.
Study covers aspirin and spironolactone.
risk of death/ICU, 129.5% higher, RR 2.29, p < 0.001, treatment 16 of 31 (51.6%), control 148 of 658 (22.5%).
Effect extraction follows pre-specified rules prioritizing more serious outcomes. Submit updates
Holt et al., 7 May 2020, retrospective, Denmark, peer-reviewed, median age 70.0, 4 authors, study period 1 March, 2020 - 1 April, 2020.
This PaperSpironolactoneAll
Influence of inhibitors of the renin–angiotensin system on risk of acute respiratory distress syndrome in Danish hospitalized COVID-19 patients
Anders Holt, Ikram Mizrak, Morten Lamberts, Per Lav Madsen
Journal of Hypertension, doi:10.1097/hjh.0000000000002515
OVID-19, the disease associated with SARS-CoV-2 infection, is in some 20% of acutely affected patients associated with respiratory distress syndrome (ARDS) often necessitating respirator treatment and associated with a high mortality [1] [2] [3] . Epidemics in Wuhan in China and Lombardy in Italy have been devastating, and SARS-CoV-2 has developed into a pandemic necessitating urgent worldwide co-operation. Until effective treatment of COVID-19 including a useful vaccination against SARS-CoV-2 is found, it is important to seek ways of limiting or avoiding ARDS. Virus-related ARDS is initiated from a high level of angiotensin II (Ang-II) via the type 1 receptor pathway [4], and Ang-II has already been demonstrated to be high in COVID-19 and linearly associated with lung injury [5] . Inhibitors of the renin-angiotensin system (RASi), cornerstones of treatment of patients with hypertension and heart failure, have attracted attention as they may in theory influence the Ang-II level in COVID-19 and thereby the risk of ARDS [4, 6] . In short, Ang-II activity is influenced by the balance of Ang-converting enzyme (ACE) and ACE2 receptor activity. The activity of ACE2 normally lowers the level of Ang-II, but SARS-CoV-2 virus binds to ACE2 receptors, lower their activity and hence increase Ang-II activity [1] . While RASi lower Ang-II levels, and may in this respect be helpful, chronic RASi treatment may on the other hand also increase pulmonary ACE2-receptor numbers hence providing a possible higher SARS-CoV-2 viral load. As suggested from animal experiments, chronic treatment with RASi can therefore, in theory, both increase and lower the risk of ARDS in SARS-CoV-2-infected patients. Studies early listed heart disease, hypertension, and diabetes as risk factors for ARDS [1-3], but unfortunately medication has not yet been reported on, and clinical data on the relative importance of RASi for outcome in COVID-19 are now urgently needed. Approved by the Danish Patient Safety Authority and the Danish Data Protection Agency, we related medication to outcome in all SARS-CoV-2 PCR positive patients, who,
References
Esler, Esler, Can angiotensin receptor-blocking drugs perhaps be harmful in the COVID-19 pandemic?, J Hypertens
Grasselli, Zangrillo, Zanella, Antonelli, Cabrini et al., Baseline characteristics and outcomes of 1591 patients infected with SARS-CoV-2 admitted to ICUs of the Lombardy Region, Italy, JAMA
Liu, Yang, Zhang, Huang, Wang et al., Clinical and biochemical indexes from 2019-nCOV infected patients linked to viral loads and lung injury, Sci China Life Sci
Vaduganathan, Vardeny, Michel, Mcmurray, Pfeffer et al., Renin-angiotensin-aldosterone system inhibitors in patients with COVID-19, N Engl J Med
Yang, Zheng, Gou, Pu, Chen et al., Prevalence of comorbidities in the novel Wuhan coronavirus (COVID-19) infection: a systematic review and meta-analysis, Int J Infect Dis
Zhou, Yu, Du, Fan, Liu et al., Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study, Lancet
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