Renin-Angiotensin-Aldosterone System Inhibitors and Outcome in Patients With SARS-CoV-2 Pneumonia
2020; Lippincott Williams & Wilkins; Volume: 76; Issue: 2 Linguagem: Inglês
10.1161/hypertensionaha.120.15312
ISSN1524-4563
AutoresAndrea Conversano, Francesco Melillo, Antonio Napolano, Evgeny Fominskiy, Marzia Spessot, Fabio Ciceri, Eustachio Agricola,
Tópico(s)Long-Term Effects of COVID-19
ResumoHomeHypertensionVol. 76, No. 2Renin-Angiotensin-Aldosterone System Inhibitors and Outcome in Patients With SARS-CoV-2 Pneumonia Free AccessLetterPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessLetterPDF/EPUBRenin-Angiotensin-Aldosterone System Inhibitors and Outcome in Patients With SARS-CoV-2 PneumoniaA Case Series Study Andrea Conversano, Francesco Melillo, Antonio Napolano, Evgeny Fominskiy, Marzia Spessot, Fabio Ciceri and Eustachio Agricola Andrea ConversanoAndrea Conversano From the Cardiovascular Imaging Unit, Cardiothoracic Department (A.C., F.M., A.N., E.A.), San Raffaele Hospital, IRCCS, Milan, Italy , Francesco MelilloFrancesco Melillo From the Cardiovascular Imaging Unit, Cardiothoracic Department (A.C., F.M., A.N., E.A.), San Raffaele Hospital, IRCCS, Milan, Italy , Antonio NapolanoAntonio Napolano From the Cardiovascular Imaging Unit, Cardiothoracic Department (A.C., F.M., A.N., E.A.), San Raffaele Hospital, IRCCS, Milan, Italy , Evgeny FominskiyEvgeny Fominskiy Anesthesia and Intensive Care Department (E.F.), San Raffaele Hospital, IRCCS, Milan, Italy , Marzia SpessotMarzia Spessot Emergency Department (M.S.), San Raffaele Hospital, IRCCS, Milan, Italy , Fabio CiceriFabio Ciceri Hematology and Bone Marrow Transplantation Unit (F.C.), San Raffaele Hospital, IRCCS, Milan, Italy Vita-Salute San Raffaele University, Milan, Italy (F.C., E.A.). and Eustachio AgricolaEustachio Agricola Correspondence to Agricola Eustachio, San Raffaele Hospital, IRCCS, Milan, Italy. Email E-mail Address: [email protected] From the Cardiovascular Imaging Unit, Cardiothoracic Department (A.C., F.M., A.N., E.A.), San Raffaele Hospital, IRCCS, Milan, Italy Vita-Salute San Raffaele University, Milan, Italy (F.C., E.A.). Originally published8 May 2020https://doi.org/10.1161/HYPERTENSIONAHA.120.15312Hypertension. 2020;76:e10–e12is corrected byCorrection to: Renin-Angiotensin-Aldosterone System Inhibitors and Outcome in Patients With SARS-CoV-2 Pneumonia: A Case Series StudyOther version(s) of this articleYou are viewing the most recent version of this article. Previous versions: July 8, 2020: Previous Version of Record May 8, 2020: Ahead of Print ACE (angiotensin-converting enzyme) 2—an enzyme that physiologically counters the activation of the renin-angiotensin-aldosterone system (RAAS)—is the functional receptor for SARS-CoV-2—the virus responsible for the coronavirus disease 2019 (COVID-19) pandemic. Since ACE inhibitors and angiotensin receptor blockers (ARBs) may affect ACE2 expression,1 concerns regarding their safety in patients with COVID-19 have been raised.Aim of the present study was to describe patient characteristics, ongoing pharmacological treatment at the time of admission, and any association between chronic use of ACE inhibitors/ARBs and adverse COVID-19 clinical outcome in the first 191 consecutive patients admitted to our institution.This is a retrospective, observational study from a single tertiary center (San Raffaele Hospital, Milan) involved in frontline care during COVID-19 outbreak in Italy. We included all adult patients admitted to our hospital from February 27 to March 17, 2020, with a confirmed diagnosis of SARS-CoV-2 pneumonia by chest radiograph or computed tomographic scan and real-time polymerase chain reaction. Data were obtained from electronic medical records. Heart failure (HF) and chronic kidney disease were defined according to the European Society of Cardiology and Kidney Disease Improving Global Outcome guidelines. Multivariate analysis was performed including only covariates that were significantly associated with the risk of death at univariate analysis and the convention of limiting the number of independent variables to 1 for ≈10 events was followed. The study was approved by the local ethics committee.During the index period, 212 patients were admitted to the emergency department of our hospital and then hospitalized for SARS-CoV-2 pneumonia. Excluding patients with incomplete data collection and lost to follow-up, the final study population consisted of 191 patients (mean age, 63.4±14.9 years; 68.6% men) of whom 22 (11.5%) required intensive care unit admission. Baseline clinical characteristics are reported in the Table.Table 1. Baseline Clinical Characteristics Among Overall Population and Hypertensive PatientsSurvivorsNonsurvivorsP ValueOverall populationn=149n=42 Age, y60.4±13.775.3±12.90.001* Men100 (67.6%)31 (73.8%)0.440 Symptom onset to admission, d6.5±3.86.4±3.90.827 O2 saturation at admission, %93.0±8.986.7±10.20.001* EF, %†58.7±6.143.2±17.40.028* ICU length of stay, d14.6±7.35.2±3.10.001* Comorbidities Hypertension62 (42.3%)34 (81.0%)0.003* HF2 (1.3%)7 (16.7%)0.001* CAD19 (12.8%)9 (21.4%)0.160 Diabetes mellitus17 (11.4%)11 (26.2%)0.017* COPD4 (2.7%)6 (14.3%)0.003* Cancer16 (10.7%)11 (26.2%)0.011* CKD28 (18.8%)22 (55.0%)0.001* Antihypertensive therapy ACE inhibitor/ARBs48 (32.2%)21 (50.0%)0.034* β-Blocker31 (21.1%)21 (50.0%)0.010* CCB16 (10.8%)9 (21.4%)0.072 Thiazide12 (8.1%)4 (9.5%)0.771 No. of drugs0.7±0.61.3±0.90.001 Other Loop diuretic7 (4.7%)12 (28.6%)0.001* Statin21 (14.2%)9 (21.4%)0.256 Laboratory findings WBC, 109/L7.7±4.610.0±5.40.371 Creatinine, mg/dL1.1±1.01.4±1.00.043* eGFR, mL/min per 1.73 m280.3±20.365.9±33.60.046* CRP, mg/L93.7±71.9134.0±84.90.099 Radiograph findings Interstitial texture52 (44.4%)10 (30.3%)0.145 Consolidation26 (22.2%)7 (21.2%)0.902 Bilateral consolidation35 (29.9%)16 (48.5%)0.047*Hypertensive patientsn=62n=34 Age, y67.3±10.376.9±10.90.001* Men Symptom onset to admission, d7.1±4.06.8±3.70.753 O2 saturation, %92.9±4.387.0±10.10.001* Comorbidities HF2 (3.2%)6 (17.6%)0.013* CAD18 (28.6%)9 (26.5%)0.826 Diabetes mellitus13 (20.6%)9 (26.5%)0.513 COPD4 (6.3%)5 (14.7%)0.176 Cancer8 (12.7%)8 (23.5%)0.170 CKD20 (31.7%)20 (62.5%)0.004*Antihypertensive therapy ACE inhibitor/ARBs47 (74.6%)21 (61.8%)0.188 ACE inhibitor21 (33.3%)14 (41.2%)0.443 ARBs26 (41.3%)7 (20.6%)0.040* β-Blocker29 (46.8%)21 (61.8%)0.160 CCB16 (25.8%)9 (26.5%)0.943 Thiazide12 (19.4%)4 (11.8%)0.256 No. of drugs1.6±0.71.6±0.70.837ACE indicates angiotensin-converting enzyme; ARB, angiotensin receptor blocker; CAD, coronary artery disease; CCB, calcium channel blocker; CKD, chronic kidney disease; COPD, chronic obstructive pulmonary disease; CRP, C-reactive protein; EF, ejection fraction; eGFR, estimated glomerular filtrartion rate; HF, heart failure; ICU, intensive care unit; WBC, white blood cell count.*Statistically significant.†Data on ejection fraction were available on 31 patients.Table 2. Predictors of All-Cause Mortality Among the Overall Population and Hypertensive PatientsOverall populationUnivariateMultivariate cox (model 1)Multivariate cox (model 2)HR (95% CI)P valueHR (95% CI)P valueHR (95% CI)P value Age, y1.1 (1.0–1.2)0.001*1.1 (1.0–1.2)0.001*1.1 (1.0–1.1)0.001* Female sex0.8 (0.4–1.5)0.518 Hypertension4.7 (2.2–10.3)0.001*NS HF6.1 (2.7–14.0)0.001*3.1 (1.3–7.5)0.008* CAD1.7 (0.8–3.6)0.142 Diabetes mellitus2.3 (1.1–4.5)0.017*NS COPD3.3 (1.4–7.9)0.007*NS Cancer2.6 (1.1–5.3)0.005*NS CKD4.2 (2.3–7.9)0.001*2.1 (1.1–4.0)0.033* ACE inhibitor/ARBs1.8 (1.0–3.3)0.047*NS β-Blocker3.0 (1.6–5.6)0.001*NSHypertensive patientsUnivariateMultivariate cox HR (95% CI)P valueHR (95% CI)P value Age, y1.1 (1.0–1.2)0.004*1.1 (1.0–1.1)0.009* Women0.8 (0.2–2.0)0.753 HF3.7 (1.5–9.0)0.004*2.8 (1.1–6.9)0.023* CAD0.9 (0.4–2.0)0.919 Diabetes mellitus1.3 (0.6–2.7)0.494 CKD2.9 (1.4–5.9)0.003*NS COPD2.5 (0.6–10.1)0.187 Cancer2.0 (0.9–4.4)0.083 ACE inhibitor/ARBs0.5 (0.2–1.2)0.133 ACE inhibitor1.2 (0.6–2.4)0.591 ARBs0.4 (0.2–1.1)0.059 β-Blocker1.7 (0.8–3.3)0.145Overall population: multivariate model 1: age, hypertension, HF; diabetes mellitus; ACE inhibitor/ARBs. C statistic, 0.83 (95% CI, 0.76–0.90); Hosmer-Lemeshow test, P=0.57. Multivariate model 2: age, CKD; COPD, cancer, β-blocker. C statistic, 0.82 (95% CI, 0.74–0.89); Hosmer-Lemeshow test, P=0.97. Hypertensive patients: multivariate: age, HF, CKD. C statistic, 0.78 (95% CI, 0.69–0.89); Hosmer-Lemeshow test, P=0.148. ACE indicates angiotensin-converting enzyme; ARB, angiotensin receptor blocker; CAD, coronary artery disease; CKD, chronic kidney disease; COPD, chronic obstructive pulmonary disease; HF, heart failure; HR, hazard ratio; NS, nonsignificant.*Statistically significant.Ninety-six patients (50.2%) were affected by hypertension (76.3% men; mean age, 70.6±11.8 years) of whom 68 (70.1%) were on ACE inhibitors/ARBs (ACE inhibitors, n=35; ARBs, n=33). Medications were continued in all patients during hospital stay, unless not tolerated, with close monitoring of blood pressure and renal function, while they were withdrawn in case of intensive care unit admission.At a median follow-up of 28 (21–32) days, 42 patients (22%) died during hospitalization and 121(63.3%) were discharged. As of April 9, 28 patients were still hospitalized, of whom 4 were in the intensive care unit. Intensive care unit stay was longer in survivors compared with nonsurvivors. Nonsurvivors were significantly older and were more frequently affected by comorbidities (Table). Univariate predictors of mortality are shown in the Table. Only age, HF, and chronic kidney disease, but not hypertension, were independently associated with all-cause mortality. Treatment with ACE inhibitors/ARBs was not an independent predictor of poor outcome.At sensitivity analysis, no differences were observed in the severity of pulmonary involvement at chest radiograph (bilateral consolidation, 36.5% versus 41.7%; P=0.586) or in laboratory findings on admission (CRP [C-reactive protein], 111±69 versus 112±90 mg/L, P=0.959; creatinine, 1.3±1.6 versus 1.5±1.2 mg/dL, P=0.430) between patients treated with or without ACE inhibitors/ARBs. Although a decline in renal function (difference between estimated glomerular filtration rate at admission and nadir estimated glomerular filtration rate during hospital stay) was evident in the overall population, there was no significant difference according to concomitant ACE inhibitor/ARB treatment (−7.8±19.0 versus −10.8±24.8 mL/min per 1.73 m2 patients with and without ACE inhibitors/ARBs, respectively; P=0.28). According to the Acute Kidney Injury Network criteria, 38 patients (19.8%) developed acute kidney injury, with no difference between patients treated with or without ACE inhibitors/ARBs (P=0.18). At Cox regression analysis, age and HF were the only independent predictors of mortality (Tables 1 and 2).This is one of the first studies that evaluated COVID-19 outcome with relation to antihypertensive treatment with RAAS blockers. We demonstrated that in patients hospitalized for pneumonia, chronic treatment with ACE inhibitors/ARBs was not burdened by excess mortality, worse clinical presentation, or deterioration of renal function. Overall mortality was high (22%) and identified predictors of poor prognosis were age and comorbidities such as HF and chronic kidney disease, all findings consistent with prior reports from Wuhan, China.2Since the expression of ACE2 is upregulated by RAAS inhibitors,1 concerns have been raised over a potential facilitation of infection and viral propagation by these drugs as in SARS a higher viral load was associated with a worse prognosis.3 On the contrary, lung injury is partially mediated by RAAS activation, with evidence of ACE2 downregulation after SARS-CoV infection and reduction of IL (interleukin)-6 levels in Acute Respiratory Distress Syndrome after Recombinant Human Angiotensin-converting Enzyme 2 injection,4 thus providing support for lack of harm by chronic treatment with RAAS blockers in our study.The prevalence of hypertension in our population was high, but the data are consistent with its expected prevalence in this age group in Italy. Despite the relatively small number of patients, our findings are consistent with treatment of hypertensive patients in Italy, 70% of whom receive RAAS inhibitors.In recently published studies, hypertension was associated with a 1.8- to 3-fold hazard ratio of in-hospital mortality for COVID-19, but it was not included in the multivariate model,2,5 whereas in our study, only age, HF, and chronic kidney disease were independent predictors of mortality.The relatively small sample size and the lack of power to detect the effect of withdrawal of therapy during hospital stay are the main limitations of our study. Finally, whether chronic use of RAAS blockers would facilitate infection with SARS-CoV-2 is yet to be determined.In conclusion, in hospitalized patients for COVID-19 during the early outbreak in Italy, chronic treatment with RAAS blockers was not associated with increased mortality: this represents one of the first clinical evidence supporting the continuation of chronic RAAS blockers in the context of COVID-19.Sources of FundingNone.DisclosuresNone.Footnotes*These authors contributed equally to this work as first coauthors.Correspondence to Agricola Eustachio, San Raffaele Hospital, IRCCS, Milan, Italy. Email agricola.eustachio@hsr.itReferences1. Li W, Moore MJ, Vasilieva N, Sui J, Wong SK, Berne MA, Somasundaran M, Sullivan JL, Luzuriaga K, Greenough TC, et al. Angiotensin-converting enzyme 2 is a functional receptor for the SARS coronavirus.Nature. 2003; 426:450–454. doi: 10.1038/nature02145CrossrefMedlineGoogle Scholar2. Zhou F, Yu T, Du R, Fan G, Liu Y, Liu Z, Xiang J, Wang Y, Song B, Gu X, et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study.Lancet. 2020; 395:1054–1062. doi: 10.1016/S0140-6736(20)30566-3CrossrefMedlineGoogle Scholar3. Chu CM, Poon LL, Cheng VC, Chan KS, Hung IF, Wong MM, Chan KH, Leung WS, Tang BS, Chan VL, et al. Initial viral load and the outcomes of SARS.CMAJ. 2004; 171:1349–1352. doi: 10.1503/cmaj.1040398CrossrefMedlineGoogle Scholar4. Guo J, Huang Z, Lin L, Lv J. Coronavirus disease 2019 (COVID-19) and cardiovascular disease: a viewpoint on the potential influence of angiotensin-converting enzyme inhibitors/angiotensin receptor blockers on onset and severity of severe acute respiratory syndrome coronavirus 2 infection.J Am Heart Assoc. 2020; 9:e016219. doi: 10.1161/JAHA.120.016219LinkGoogle Scholar5. Wu C, Chen X, Cai Y, Xia J, Zhou X, Xu S, Huang H, Zhang L, Zhou X, Du C, et al. Risk factors associated with acute respiratory distress syndrome and death in patients with coronavirus disease 2019 pneumonia in Wuhan, China.JAMA Intern Med. 2020. doi: 10.1001/jamainternmed.2020.0994CrossrefGoogle Scholar eLetters(0)eLetters should relate to an article recently published in the journal and are not a forum for providing unpublished data. Comments are reviewed for appropriate use of tone and language. Comments are not peer-reviewed. Acceptable comments are posted to the journal website only. Comments are not published in an issue and are not indexed in PubMed. Comments should be no longer than 500 words and will only be posted online. References are limited to 10. 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Pirola C and Sookoian S (2020) Estimation of Renin-Angiotensin-Aldosterone-System (RAAS)-Inhibitor effect on COVID-19 outcome: A Meta-analysis, Journal of Infection, 10.1016/j.jinf.2020.05.052, 81:2, (276-281), Online publication date: 1-Aug-2020. Related articlesCorrection to: Renin-Angiotensin-Aldosterone System Inhibitors and Outcome in Patients With SARS-CoV-2 Pneumonia: A Case Series StudyHypertension. 2020;76:e39-e39 August 2020Vol 76, Issue 2 Advertisement Article InformationMetrics © 2020 American Heart Association, Inc.https://doi.org/10.1161/HYPERTENSIONAHA.120.15312PMID: 32383626 Originally publishedMay 8, 2020 Keywordsangiotensin receptor antagonistsCOVID-19longitudinal studiesrenin-angiotensin systemSARS virusPDF download Advertisement SubjectsHypertension
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