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Usefulness of Combined Renin-Angiotensin System Inhibitors and Diuretic Treatment In Patients Hospitalized with COVID-19

Published:January 10, 2022DOI:https://doi.org/10.1016/j.amjcard.2021.12.004
      Antecedent use of renin-angiotensin system inhibitors (RASi) prevents clinical deterioration and protects against cardiovascular/thrombotic complications of COVID-19, for indicated patients. Uncertainty exists regarding treatment continuation throughout infection and doing so with concomitant medications. Hence, the purpose of this study is to evaluate the differential effect of RASi continuation in patients hospitalized with COVID-19 according to diuretic use. We used the Coracle registry, which contains data of hospitalized patients with COVID-19 from 4 regions of Italy. We used Firth logistic regression for adult (>50 years) cases with admission on/after February 22, 2020, with a known discharge status as of April 1, 2020. There were 286 patients in this analysis; 100 patients (35.0%) continued RASi and 186 (65%) discontinued. There were 98 patients treated with a diuretic; 51 (52%) of those continued RASi. The in-hospital mortality rates in patients treated with a diuretic and continued versus discontinued RASi were 8% versus 26% (p = 0.0179). There were 188 patients not treated with a diuretic; 49 (26%) of those continued RASi. The in-hospital mortality rates in patients not treated with a diuretic and continued versus discontinued RASi were 16% versus 9% (p = 0.1827). After accounting for age, cardiovascular disease, and laboratory values, continuing RASi decreased the risk of mortality by approximately 77% (odds ratio 0.23, 95% confidence interval 0.06 to 0.95, p = 0.0419) for patients treated with diuretics, but did not alter the risk in patients treated with RASi alone. Continuing RASi in patients concomitantly treated with diuretics was associated with reduced in-hospital mortality.
      Presentation severity and complications of Coronavirus diseases 2019 (COVID-19) are greatly exacerbated in patients who have cardiovascular disease (CVD), most commonly ischemic heart disease and heart failure.
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      Use of a renin-angiotensin inhibitor (RASi) is the landmark treatment for patients with high cardiovascular risk or established CVD. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) uses the angiotensin-converting enzyme 2 (ACE2) receptor to enter the human cell; because the ACE2 receptor's expression occurs in epithelial cells of the respiratory system and is influenced by RASi, concerns about this therapy emerged early in the pandemic.
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      Hence, we sought to explore differential associations between in-hospital COVID-19 mortality rates and RASi continuation according to combination diuretic treatment and CVD.
      The data used for this study have been previously described.
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      In short, we used the Coracle registry, which contains data of hospitalized patients with COVID-19 from 4 regions of Italy. We performed analyses on adult records from the registry with admission on or after February 22, 2020, with a known discharge status as of April 1, 2020. We restricted this analysis to patients aged 50 years or more to be consistent with previous work. Further, because our primary interest was to evaluate the possibility of a differential effect of RASi (either ACE inhibitor or angiotensin receptor blocker [ARB]) continuation on in-hospital mortality between those treated with diuretics (either thiazide or loop) versus those not treated with diuretics, we additionally excluded patients who were not treated with an ACE inhibitor and/or ARB before hospitalization, as well as those who were missing information regarding diuretic treatment. We did not include spironolactone or eplerenone in this analysis. Informed consent was obtained before including anonymized data from patients in the registry. This work was approved by the ethical committee of Turin and extended to participating centers (Coracle registry: epidemiology clinical characteristics and therapy in real-life patients affected by SARS-CoV-2).
      Categorical variables are reported as frequencies and percentages. Differences in characteristics between patients who continued versus discontinued RASi were assessed by way of chi-square or Fisher's exact test. Analyses were performed within subgroups of patients treated with diuretics and patients not treated with diuretics. We constructed a multivariable logistic regression model including a term for RASi continuation, diuretic use, and an interaction term to answer our primary objective. There were too few events to fully explore adjusted models using traditional logistic regression, so we used Firth logistic regression to build a model adjusting for age, CVD (coronary artery disease/ischemic heart disease and congestive heart failure [CHF]), and laboratory values found to be associated with RASi discontinuation (that is, serum creatinine, urea, potassium). We also considered subgroup analyses according to the type of RASi (ACEi and ARB). Analyses were performed using SAS, version 9.4. (SAS Institute Inc., Cary, North Carolina).
      We reviewed 956 patient records; 175 (18%) were excluded because of age <50 years, 477 (50%) records were excluded because of lack of RASi treatment before hospitalization, and 18 (2%) records were excluded because of unknown use of diuretics. Hence, 286 patients were included in this analysis (Figure 1). Overall, 100 patients (35%) continued RASi and 186 (65%) discontinued. There were no significant differences in patient characteristics between those who continued versus discontinued treatment, except for laboratory values (Table 1). Of the 186 patients who discontinued RASi, 60 (32%) did so for acute kidney injury, 20 (11%) for hyperkalemia, 80 (43%) for hypotension, 19 (10%) for other illnesses (e.g., digestive disorder, cognitive status), 5 (3%) for a combination of factors, and 2 (1%) for unknown reasons. A total of 98 patients were treated with a diuretic, 51 (52%) of those patients continued RASi, and 47 (48%) discontinued. The in-hospital mortality rates in patients treated with a diuretic and continued versus discontinued RASi were 8% versus 26% (p = 0.0179). The median time from admission to RASi discontinuation for those who were treated with a diuretic was 42,5 days; such patients had a median length of stay of 73,12 days. Patients treated with a diuretic who continued RASi had a median length of stay of 106,13 days. A total of 188 patients were not treated with a diuretic; 49 (26%) of those continued RASi and 139 (74%) discontinued. The in-hospital mortality rates in patients who were not treated with a diuretic and continued versus discontinued RASi were 16% versus 9% (p = 0.1827). The median time from admission to RASi discontinuation for those who were not treated with a diuretic was 32,5 days; such patients had a median length of stay of 96,14 days. Patients who were not treated with a diuretic had a median length of stay of 7.55,14 days.
      Table 1Characteristics of patients hospitalized with COVID-19 according to RASi continuation and diuretic use
      Diuretics UtilizedDiuretics Not Utilized
      RASi Continued (n = 51)RASi Discontinued (n = 47)p ValueRASi Continued (n = 49)RASiDiscontinued (n = 139)p Value
      Age (years)73±976.12±8.270.139872±1270±100.2914
      Men25 (49%)24 (51%)0.839836 (74%)95 (68%)0.5022
      Hypertension49 (96%)45 (96%)1.000049 (100%)136 (98%)0.5688
      Obstructive lung disease4 (8%)8 (17%)0.16614 (8%)16 (12%)0.5134
      Diabetes mellitus18 (35%)9 (19%)0.064210 (20%)33 (24%)0.6329
      Smoker0.97940.8420
       Yes4 (8%)4 (9%)5 (10%)16 (12%)
       No41 (80%)38 (81%)40 (82%)111 (80%)
       Former6 (12%)5 (11%)3 (6%)12 (9%)
       Missing001 (2%)0
      Serum creatinine1.1 [0.9, 1.4]2.5 [1.6, 2.9]<0.00011.05 [0.9, 1.2]1.4 [1.3, 1.8]<0.0001
      Potassium4.5 [4.3, 4.7]4.8 [4.3, 5.2]0.02174.5 [4.2, 4.6]4.2 [3.7, 4.7]0.0171
      Urea41 [36, 46]68 [53, 79]<0.000140 [37, 45.5]47 [41, 62]<0.0001
      Chronic heart failure13 (26%)13 (28%)0.80803 (6%)4 (3%)0.3023
      Coronary artery disease19 (37%)12 (26%)0.21257 (14%)13 (9%)0.3355
      Beta blocker20 (39%)17 (36%)0.75608 (16%)39 (28%)0.1030
      Calcium channel antagonist16 (31%)11 (23%)0.377718 (37%)37 (27%)0.1808
      Thiazide diuretic40 (78%)25 (53%)0.008300
      Loop diuretic20 (39%)31 (66%)0.008100
      Invasive ventilation6 (12%)5 (11%)0.85997 (14%)21 (15%)0.9429
      High flow ventilation without intubation23 (45%)21 (45%)0.966921 (43%)46 (33%)0.2070
      Oxygen low flow20 (39%)17 (36%)0.756021 (43%)61 (44%)0.9258
      Overall, patients concomitantly treated with diuretics were at an increased risk for in-hospital mortality (Table 2). Conversely, when considering all patients, (dis)continuing RASi was not associated with in-hospital mortality. However, we found evidence to support a differential effect of RASi continuation on in-hospital mortality, according to diuretic treatment (interaction p = 0.0098). Specifically, continuing RASi in patients who were not treated with diuretics did not have a significant association with in-hospital mortality; however, continuing RASi in patients concomitantly treated with diuretics was associated with a decreased risk of in-hospital mortality by approximately 75% (OR 0.25, 95% CI 0.07 to 0.84). After accounting for age, which conferred an increased risk of in-hospital mortality of approximately 9% per year of life (OR 1.09, 95% CI 1.04 to 1.13, p <0.0001), as well as congestive heart failure, coronary heart disease/ischemic heart disease, and laboratory values (serum creatinine, urea, potassium), none of which were associated with the risk of mortality, continuing RASi was associated with a decreased risk of mortality by approximately 77% (OR 0.23, 95% CI 0.06 to 0.95, p = 0.0419) for patients treated with diuretics, but did not alter the risk in patients who were treated with RASi alone (Figure 2, Table 2). The Hosmer-Lemeshow statistic did not indicate any problems with the model fit.
      Table 2Odds of in-hospital mortality according to RASi and diuretic treatments
      Variable (Unadjusted Model)Odds Ratio95% Confidence Interval Boundsp Value
      Diuretic use vs non-use
       In patients who discontinued RASi3.321.397.930.0068
       In patients who continued RASi0.440.121.560.2008
      RASi continuation versus discontinuation
       In patients without diuretics1.890.734.880.188
       In patients treated with diuretics0.250.070.840.0244
      Variable (adjusted model)
      Diuretic use vs non-use
       In patients who discontinued RASi3.131.079.170.0375
       In patients who continued RASi0.50.141.80.2885
      RASi continuation vs discontinuation
       In patients without diuretics1.450.514.090.4886
       In patients with diuretics0.230.060.950.0419
      Age (per year increase)1.091.041.13<0.0001
      Coronary artery disease (yes vs no)1.460.583.680.4221
      Congestive heart failure (yes vs no)0.380.11.380.1415
      Urea1.010.961.070.6944
      Potassium0.70.242.070.5228
      Serum creatinine0.90.491.670.7451
      Adjusted model: overall effect of RASi continuation p = 0.4886, overall effect of diuretic use p = 0.0375, interaction term p = 0.0285.
      Unadjusted model: overall effect of RASi continuation p = 0.1880, overall effect of diuretic use p = 0.0068, interaction term p = 0.0098.
      RASi = renin-angiotensin system inhibitor.
      Figure 2
      Figure 2Differences in hospital mortality for patients who continued versus discontinued renin-angiotensin inhibitor (RASi) treatment according to concomitant use of diuretics.
      Upon admission, 160 (56%) patients were using an ACEi and 126 (44%) were using an ARB. In subgroup analyses, we failed to find an association between RASi (dis)continuation and in-hospital mortality in ACEi users, regardless of diuretic use (Table 3). However, there was evidence to support a differential role of RASi continuation on in-hospital mortality in ARB users according to diuretic use. Specifically, the mortality rates for ARB continuation versus discontinuation in patients treated with a diuretic were 4% versus 35% (p = 0.0142), whereas the rates were 18% versus 8% (p = 0.3568) in patients who were not treated with a diuretic.
      Table 3In-hospital mortality rates according to RASi type, continuation, and diuretic use
      DiureticsNo Diuretics
      RASi ContinuedRASi Discontinuedp ValueRASi ContinuedRASi Discontinuedp Value
      ACEi3/25 (12%)5/27 (19%)0.70505/32 (16%)8/76 (11%)0.5213
      ARB1/26 (4%)7/20 (35%)0.01423/17 (18%)5/63 (7.9%)0.3568
      N (ARB) = 126; N (ARB and diuretic) = 46; N (ARB and no diuretic) = 80; RASi = renin-angiotensin system inhibitor; ACEi = angiotensin-converting enzyme inhibitor; ARB = angiotensin II receptor blocker; n (ACEi) = 160; n (ACEi and diuretic). = 52; n (ACEi and no diuretic) = 108.
      All p values were calculated using Fisher's exact test.
      In this analysis of 286 patients hospitalized with COVID-19 in the early phase of the pandemic, we found that patients taking combination RASi and diuretic were at higher risk of in-hospital mortality than patients taking RASi alone. We also found that discontinuing RASi therapy was associated with greater in-hospital mortality for patients who were concomitantly treated with a diuretic; an observation driven by ARB users. We did not find an association between RASi (dis)continuation and in-hospital mortality for patients who were not treated with a diuretic. These trends remained true after accounting for age, which was also associated with increased risk of mortality, and coronary artery disease, and CHF. Although diuretic treatment was more prevalent in HF patients, the diagnosis was based on clinical history in the health record. It was not confirmed by specific examinations during the current hospitalization; the in-hospital treatment was based on domiciliary therapy.
      Others have suggested that RASi treatment may be protective in patients with COVID-19.
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      Management of renin-angiotensin-aldosterone system blockade in patients admitted to hospital with confirmed coronavirus disease (COVID-19) infection (The McGill RAAS-COVID- 19): a structured summary of a study protocol for a randomized controlled trial.
      There are clinical scenarios in which patients may need to discontinue RASi. Patients with severe hemodynamic impairment, lower blood pressure, and dehydration may benefit from discontinuing RASi.
      • Chan CK
      • Huang YS
      • Liao HW
      • Tsai IJ
      • Sun CY
      • Pan HC
      • Chueh JS
      • Wang JT
      • Wu VC
      • Chu TS
      National Taiwan University Hospital Study Group of ARF, the Taiwan Primary Aldosteronism Investigators and the Taiwan Consortium for Acute Kidney Injury and Renal Diseases. Renin-angiotensin-aldosterone system inhibitors and risks of severe acute respiratory syndrome coronavirus 2 infection: a systematic review and meta-analysis.
      Notably, A double-edged mechanism related to clinical presentation and underlying CVD may be posed. In this context, it is important to know the clinical status related to the underlying CVD, inflammation, and baseline condition before infection.
      • Naveed H
      • Elshafeey A
      • Al-Ali D
      • Janjua E
      • Nauman A
      • Kawas H
      • Kaul R
      • Saed Aldien AS
      • Elshazly MB
      • Zakaria D.
      The interplay between the immune system, the Renin Angiotensin Aldosterone System (RAAS) and RAAS inhibitors may modulate the outcome of COVID-19: a systematic review.
      In the Swedish meta-analysis including more than 1 million patients, a protective effect of RASi was observed for all types of CVD studied. Unfortunately, that study investigated only antecedent use of RASi; the effect of continuation was not evaluated.
      • Savarese G
      • Benson L
      • Sundström J
      • Lund LH.
      Association between renin-angiotensin-aldosterone system inhibitor use and COVID-19 hospitalization and death: a 1.4 million patient nationwide registry analysis.
      Overall, our findings reveal the importance of considering the basal clinical condition, severity of the infection, and concomitant treatments that may influence drug discontinuation and outcomes.
      This is a retrospective observational analysis with a relatively small number of patients meeting inclusion criteria; thus, the findings are limited by the small sample size. Further, because of the small event count, we required specialized statistical methods to produce tractable estimates and confidence intervals for the multivariable-adjusted model. Additionally, we did not record information regarding before hospitalizations and/or severity of extracardiac diseases affecting these patients. Similarly, we lacked information on RASi dose and whether doses were altered for those who continued therapy. We did not analyze the effects of aldosterone antagonists and our results are limited to RASi administration. Because of these limitations and the observational nature of this work, we are unable to conclude causality; discontinuation may simply be a proxy for an adverse health state. The observational period was strictly limited to the hospital setting; no data were available after discharge. Our findings cannot be extended to ambulatory patients with less severe symptoms. Finally, these data reflect patients hospitalized during the first wave of the pandemic in Italy and may not reflect characteristics of patients hospitalized more recently since evidence of viral mutations.
      In conclusion, diuretic use in hospitalized patients with COVID-19 who were on RASi before admission was associated with an increased risk of in-hospital mortality. Whether this combined therapy increases risk or is the reflection of a more severe presentation deserves further investigation. Although discontinuing RASi therapy for hypertension was not associated with in-hospital mortality, discontinuing RASi therapy in patients who were concomitantly treated with diuretics was associated with a greater risk of in-hospital mortality. Because our results showed that ACEi/ARB discontinuation in diuretic-users was associated with increased mortality, it may be beneficial to analyze the effect of reducing, not discontinuing, RASi in such patients.

      Disclosures

      The authors have no conflicts of interest to declare.

      Acknowledgment

      We are grateful to the following collaborators for the data collection: Massimo Mancone and Fabio Infusino: Department of Clinical Internal Anesthesiological and Cardiovascular Sciences La Sapienza, Rome, Italy; Gaetano M. Ruocco: Cardiology Division, Ospedale Regina Montis Regalis Mondovì, Cuneo, Italy; Maurizio Landolina and Erika Taravelli: Cardiology Division, Ospedale Maggiore, Crema, Italy; Federico Franchi and Alex Di Nizio: AOUS le Scotte Hospital University of Siena, Italy; and Anna Palazzo: Infectious Diseases Department of Medical Sciences University of Turin, Italy.

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