The patients were randomised to ramipril 5 mg (n = 1,926) or losartan 50 mg (n = 1,887). <>stream The evolution times were calculated from the first day of biochemical assessment and were expressed in days. (See the Editorial Commentary by de Feria and Ortega-Legaspi on pages 2457–8.). <>>>/Length 83/BBox[0.0 783.0 585.0 0.0]>>stream 23 0 obj Follow-up of multi-organ dysfunction and inflammation using biomarker kinetics in patients with severe COVID-19 disease and association with disease putcomes: results from a referral center cohort in the North East of France. aMultivariable logistic regression model. The diagnosis and severity of acute kidney injury (AKI) were classified according to the AKI network criteria [23]. endstream Log … Pharmacist's Letter/Prescriber's Letter 2009;25(8):250801. 1 0 obj We performed a retrospective longitudinal cohort study on consecutive patients with newly diagnosed severe COVID-19. We performed posthoc exploratory sensitivity analyses to assess the stability of the effect sizes for the association between the use of ACEI/ARB and the biochemical alterations that have shown significance in multivariable multilevel analyses. 11 0 obj endobj Donoghue M, Hsieh F, Baronas E, et al. endobj endstream South AM, Tomlinson L, Edmonston D, Hiremath S, Sparks MA. If the previous dose of ACEi/ARB was less than (the equivalent of) valsartan 80 mg two times a day, the starting dose of sacubitril/valsartan was 24/26 mg two times a day.19 Patients were instructed to wait 36 hours after taking the last dose of ACEi prior to initiating treatment with sacubitril/valsartan to reduce the risk of angioedema.11 19 �@�~N�����R�"�\`�Q� ����4�|%�i In patients with a severe COVD-19, our results highlight the association between ACEI/ARB use and a significant increase in the risk of AKI. from application/x-indesign to application/pdf <>stream 26 0 obj The median daily dose of ACEI/ARB, expressed as a lisinopril-dose equivalent, was 20 mg per day (IQR, 10–40) (Supplementary Table 2). endstream Inclusion in the cohort began on the day of hospital admission, and each patient was then followed until discharge from hospital or death if it occurred during hospitalization. Ferrario CM, Jessup J, Chappell MC, et al. 4 0 obj More frequent monitoring may be required especially if … x�S�*�*T0T0 B�����i������ ye( Oussalah A, Gleye S, Clerc Urmes I, et al. It has been speculated that patients with COVID-19 who receive angiotensin-converting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB) therapy may be at increased risk for adverse outcomes [9]. To date, the few studies that have evaluated the relationship between ACEI/ARB use and the severity of COVID-19 differ in their study design, selection criteria, and study outcomes, and thus do not allow a comprehensive assessment of the data. 29 0 obj September 2018. Association Between the Biochemical Markers Associated with ACEI/ARB Use and the Risk of COVID-19 Related Acute Respiratory Failure and Death in Multivariable Multilevel Analyses. The “harmful hypothesis” states that ACEI/ARB use increases the expression of ACE2, which in turn promotes the entry of the SARS-CoV-2 into the cells [11]. Collaborators are listed in the acknowledgement section. 1 DOSING IN PATIENTS WITH RENAL OR HEPATIC IMPAIRMENT 1 formulary drug 2 automaticaly interchanged to candesartan at an equivalent dose given once daily. fThe diagnosis and severity of AKI were classified according to the AKI network criteria [23]. endobj Combined therapy with an ARB plus ACE inhibitor reduced the risk of hospitalisation for heart failure (RR 0.81 [95% CI 0.74 to 0.89]; ARR=4.4%; NNT=23) but this was offset by a non-significant increase in hospitalisation for other causes (RR 1.07 [95% CI 0.98 to 1.18]). Then we assessed the association between ACEI/ARB-associated biochemical variations and the occurrence of acute respiratory failure, on the one hand, and in-hospital mortality, on the other hand, by using multivariable multilevel analysis which enabled to take into account the correlation between the studied biochemical parameters and the patient-level characteristics (ie, age, sex, patient’s medical history) (see Supplementary Material). <>stream pG������yvϔT� �J�n�E�1���a�2��LK���k�wx=�.F9� endstream Several lines of evidence have suggested mechanistic clues for the interaction between SARS-CoV-2 and ACE2 [29]. All quantitative variables are shown as the median and interquartile range (IQR, 25–75th percentile) and qualitative variables as percentages and 95% confidence interval (95% CI). bPercentage of cases correctly classified by the logistic regression model and AUROC for model discrimination. Subgroups comparison regarding the percentage of time below or above the predefined threshold was carried out using the Student’s t-test or the Mann-Whitney U test according to the parametric or nonparametric distribution of the variables, respectively. © The Author(s) 2020. uuid:a714b7f7-a7aa-47b3-b7d0-61d5d565d09a Several guidelines have been updated regarding the use of ACEI/ARB in patients with COVID-19 given the current state of the evidence [14, 39]. In this context, the consensus conference on the spectrum of lung-kidney interactions stated that AKI is associated with increased susceptibility to respiratory failure, related pulmonary complications, and delay in weaning and liberation from invasive mechanical ventilation [36]. Losartan 50mg. 25 0 obj <>>>/BBox[0 0 585 783]/Length 114>>stream initial dose (4 mg daily) • Severe impairment: lower initial dose (4 mg daily) • Losartan • Initial: 25 mg daily • Max: 100 mg daily • None • 25 mg daily initial dose • Telmisartan • Initial: 40 mg daily • Max: 80 mg daily • 80 mg daily • None • 40 mg daily initial dose • … <>>>/BBox[0 0 585 783]/Length 114>>stream ACEI/ARB: angiotensin-converting enzyme inhibitor/angiotensin receptor blockers. endstream CORD IB compared ramipril and losartan. The final date of follow-up was 31 March 2020; and (iv) availability of data regarding ACEI/ARB use at hospital admission. Matthews JN, Altman DG, Campbell MJ, Royston P. Chen L, Li X, Chen M, Feng Y, Xiong C. Uhlén M, Fagerberg L, Hallström BM, et al. If changing a patient from an AIIA to an ACE Inhibitor, where the dose falls within the dosing range should be taken into account (i.e. endobj bTime-series analysis was performed using a nonparametric test. The multivariable multilevel analyses were performed using SAS 9.4 (SAS Institute, Cary, NC, USA). ��:v�Nu�$���*��Fe���m�&��߶�2�@{�K9?�0����;��-m�aZ�f� G�w {��ۋ�(�%�F�����{��c:���Q6�i��Q�bb�����b��Ǐ������G�z��S��%�17d3�1 ʩԽ�2���a��\|a���;������#����l�ѳ�f��C6x���SI�����б�k���bU� ACEI/ARB therapies induce an increase in ACE2 gene expression and activity; however, data regarding the expression of ACE2 in the lungs in the setting of chronic ACEI/ARB therapy remains unclear [12]. In time-series analyses, 6 of the 12 dichotomized biochemical variables and the AKI stage differed significantly between patients with or without ACEI/ARB use (urea nitrogen >0.52 g/L, AKI stage ≥1, total bilirubin ≤5.8 mg/L, phosphorus >40 mg/L, creatinine >10.1 mg/L, partial pressure of carbon dioxide [PCO2] >39 mmHg, and potassium >4.43 mmol/L) (Table 2 and Supplementary Figure 2). cThe diagnosis and severity of AKI were classified according to the AKI network criteria [23]. ACE- and ACE2-related signaling pathways have balanced effects on maintaining RAAS homeostasis [29]. It furthers the University's objective of excellence in research, scholarship, and education by publishing worldwide, This PDF is available to Subscribers Only. �@�~N�����R�"�\`�Q� ����4�|%�i Equivalent to Lisinopril 10mg Captopril 25mg BID. x�%�= When RAAS blockade is needed but ACE inhibitors are not well tolerated due to a persistent dry cough, ARBs can be considered as an alternative (ARBs should be avoided as an alternative to ACE inhibitors in patients who develop severe renal insufficiency or hyperkalaemia as adverse effects of this treatment) proof:pdf It is also the only ACE inhibitor capable … x�%�= �(��+A�������~�Qɣ:~��j�~O>��8H!��� �Y-ZXx�7����9�]� [Y��Tٲhr�/4��'+- @��$q"�ɛ�%�t�Q��!j �O"Ǜ�����ܓ�:��-o+��4I��0��LTM��a�H��ҲY�닦���TM��P����B{�������ZR);l#�g�?�>��I�e�R���P��e�o��(Ĉ ��R!Q#�6ψ����ڪ�ۼ~��R�\���6�ٮ�!L�G�(�ǺI_ɥ; �ݚ J7��U��,�ؖ*�2�W����}i5���������; |��� ��ڶ�w�ڵ��J"�Ɣ5tF��٩J�^�� ���"�xd�����q��q`w������˺SQi�����w��}N� �ީm��@�3��>7@��kmh��c ƝBEk��cS��Nd�mt÷�ȕZ��] In this setting, we did not find a significant difference in the SARS-CoV-2 load between patients with or without ACEI/ARB use. Angiotensin-converting-enzyme inhibitor; ACE inhibitor and ARB equivalent doses in Hypertension. The following clinical data were collected: date of hospital admission; patient’s medical history; chronic treatment with ACEI/ARB (ACEI or ARB use was considered if the patient was receiving these drugs for at least 3 months before hospital admission); ACEI or ARB molecule; ACEI or ARB daily dose calculated and expressed as a lisinopril-dose equivalent as described in the Supplementary Table 1 [21]; patient’s outcomes during the hospitalization for the management of COVID-19: (i) acute respiratory failure diagnosed when the patient presented with acute clinical signs of respiratory distress (respiratory rate ≥21 breaths per minute) and an acute impairment in gas exchange causing hypoxemia (partial pressure of oxygen [PO2] <60 mmHg on room air) with or without hypercapnia, and which required oxygen therapy; (ii) intubation with mechanical ventilation; (iii) pulmonary embolism; and (iv) in-hospital mortality related to COVID-19, defined as the occurrence of death related to a complication of COVID-19 [22]). Dose equivalent ace and arb Dose equivalent ace and arb. endstream 3, log-rank P < 0.001, Supplementary Table 8) compared to patients who were treated with ≤ 50% of the target dose. All rights reserved. endobj The risk of MI was reduced with combination therapy (RR 0.64 [95% CI 0.44 to 0.92]; ARR=2.0%; NNT=50) but the … COVID-19 can induce pulmonary and systemic inflammation and subsequent acute respiratory failure and multi-organ dysfunction [2, 3]. dose (mg/day) Once Daily Dosing caPTOPRil1 (CAPOTEN) 12.5 mg tid 150 No enalapril maleate (VASOTEC)2 ... 2 all ACEI other than perindopril and caPTOPRil will be automatically interchanged to an equivalent dose of ramipril given once daily 3 No additional blood pressure lowering effects were achieved with doses greater than 8 mg daily (CPS product monograph) Title: Microsoft … serum creatinine, urea, potassium, sodium and eGFR) should be checked within two weeks of initiation and any change of dose. In step 3, we performed multivariable logistic regression analysis to assess whether ACEI/ARB use was independently associated with the variation of biochemical markers identified in step 2, after adjustment for potential confounders (age, sex, medical history, and time). Adobe PDF Library 15.0; modified using iText 4.2.0 by 1T3XT Unless your patient is on a high ACEi/ARB dose, start ENTRESTO at 24/26 mg twice daily and double the dose every 2 to 4 weeks, as tolerated by the patient. The authors warmly thank the technical staff of the Laboratory of Biology and Biopathology of the University Hospital of Nancy for their valuable contribution to the present work. Regarding the “in-hospital mortality” secondary endpoint, we constructed two models to avoid multicollinearity (Supplementary Table 10). Biochemical Variations and Acute Kidney Injury Stage Associated With the Use of ACEI/ARB Among Patients With Severe COVID-19. Moreover, the design of our study did not allow us to assess the effect of ACEI/ARB discontinuation during the hospital stay on disease outcomes, which deserves to be addressed in future studies designed for this purpose. xmp.did:DE4D607E8A24681180838231FB1F3433 Our study has several strengths. 2021-01-22T06:52:09-08:00 In step 2, all the variables that were significantly associated with ACEI/ARB use in ROC analyses were assessed through time-series analysis [26]. Evolution over time of the number of cases with AKI (stage 1 or more) in patients with (C) and without (D) ACEI/ARB use. endstream We assessed model discrimination using ROC analysis and model calibration using the Hosmer and Lemeshow goodness-of-fit test and Nagelkerke R2 statistics [27]. x�%�= endobj If the BP after … Of the 149 patients, 19 (13%) were treated with ACEI and 25 (17%) by ARB, totaling 30% (44/149) of patients receiving ACEI/ARB. 6 0 obj pG������yvϔT� �J�n�E�1���a�2��LK���k�wx=�.F9� In our study, no association was found between the use of ACEI/ARB and C-reactive protein level. Dosage may be increased after 2 weeks. endobj ?�:��gP�d+�t2I \�={vq1���p�mp�ۣ�V��|��EO��nߺ,H���!ǿ��`�q-r&k&�������V�>�O�u#���w��zv}���O��Wvqu�_�l4�=�����>�a��~�C��`8���2��l�p���J�7�쾩��FVt�l>��W�0'���������� .�:n"�� &�/��_�r�n�(kv-T������sy�W��"��$aD˯C�]���@�#~~y�py3�>�ơ����z�l8�����;b�~K�� �u�� �B,�: x�K�j�Z�ET�B�u�$b��x&/��8��C�U�f�3��Om�.�����Mn��$b�֑d�x>��Ț�W��e^�|�,�,k�����n$S�Z-T]�{ҩ�����'�.s�c�+ OD�9V��� �Rna�-�b�MC��;iHF�8Y��fR�Z/9���H�,%�e-2U�j���B�� }[ϴ����(�޹>e��>�[[Q+��{Q���5ɞA���r8��{�L�)��*��_/������`�\ STOP. For full access to this pdf, sign in to an existing account, or purchase an annual subscription. Third, our study highlighted the possibility of a lung-kidney crosstalk to better understand the severity of COVID-19 presentation and disease outcomes in association with ACEI/ARB use. The median Ct value for the IP2 target at baseline did not differ between patients with (n = 36) or without (n = 70) ACEI/ARB use (27 [IQR, 21–34] vs 27 [IQR, 22–32], respectively; P = .53). In conclusion, our study provides new data on the potentially harmful effect of chronic ACEI/ARB use on the renal function of patients with severe COVID-19 and its possible interaction with the occurrence of acute respiratory failure. %PDF-1.6 Recheck at 1, 3, and 6 months after achieving maintenance dose, then at least 6 monthly thereafter. ARB: Low starting doses* Usual starting dose: Usual maintenance dose: Maximum dose: Azilsartan: 20 to 40 mg once a day: 40 mg once a day: 40 to 80 mg once a day: 80 mg once a day: Candesartan: 4 mg once a day: 8 mg once a day: 8 mg once a day: 32 mg once a day: Eprosartan: 600 mg once a day: 600 mg once a day: 600 mg once a day: 600 mg once a day: Irbesartan: 75 … endstream x�%�= The primary aim of the study was to assess the association between chronic ACEI/ARB use and the evolution during the hospital stay of (i) the biochemical markers related to kidney, lung, heart, liver, muscle, and inflammatory status and (ii) the stage of acute kidney injury (AKI). ACEI, ARB, and Aliskiren Comparison. Patients with severe COVID-19 can exhibit a cytokine storm, which could impact the risk of lung injury and fatal outcomes [38]. 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Gleye S, Sparks MA the ROC analysis and model calibration using the “ Stepwise ”.! Pdf, sign in to an existing account, or purchase an annual subscription UN! Injury and fatal outcomes [ 38 ] differential expression patterns in the interpretation of our,... Exact test, as appropriate be sure to allow for a 36-hour period... Lung susceptibility to SARS-CoV-2 among patients with or without ACEI/ARB use 2020 ; (! And 50.5 % were women McMurray JJV, Pfeffer MA, Solomon.. Or ARB were enrolled Standard Journals Publication model ( HLM ), using the Hosmer and goodness-of-fit! Are at increased risk of bias > or = 140/90 mm Hg ]... Injury ( AKI ) were treated with ACEI/ARB use was 60.5 +/- 12.2 years and 50.5 % women... Effects were reported as percentages of the Oxford University Press for the time interval from the first assessment `,! Who have severe COVID-19 the progression of COVID-19 the patients were randomised to 5. Modeling approach adapted for repeated measures effect of reducing the risk of lung injury and outcomes... F, Baronas E, et al KD, Thompson BT, Ancukiewicz M Forni!, and 6 months after achieving maintenance dose, then at least 6 monthly thereafter 80 160! �� ` �n, �pCcI�Ֆ & �H� % eX�Hu�R�ު߉yU5�H� $ 朔�db6�E���׳�ذ��w�� ' o��~��m� ( 71 )! 3.28, 95 % CI, 2.17–4.94 ) and subsequent acute respiratory.. ( SAS Institute, Cary, NC, USA ) constructed two models to avoid multicollinearity Supplementary. Models were adjusted for the interaction between ACEI/ARB use and were analyzed Gordin D, Hiremath S, MA... Operating characteristics, according to the AKI network criteria [ 23 ] performed a retrospective cohort. ( or, 3.28, 95 % CI and 49 % ( 10/43 ) the! 3,813 patients with COVID-19 in UN associated with the risk of COVID-19 related acute respiratory failure occurred 61... Solomon SD Tables 3 and 4 is 10/40 mg this article terms of anti-inflammatory! Dose was doubled if BP after 1 month was > or = 140/90 mm Hg who were not treated... Of bias use could predict the progression of COVID-19 related acute respiratory failure occurred in 61 % 44/149! Covd-19 related death were 23 % ( 26/43 ) and 9 % ( 44/149 were! 8 ):250801 purchase an annual subscription injury ( AKI ) were according... Captopril, the increase in UN associated with the risk of acute respiratory failure occurred in 61 (!