key: cord-0764650-rky7tip0
authors: De Spiegeleer, A.; Bronselaer, A.; Teo, J. T.; Byttebier, G.; De Tre, G.; Belmans, L.; Dobson, R.; Wynendaele, E.; Van De Wiele, C.; Vandaele, F.; Van Dijck, D.; Bean, D.; Fedson, D.; De Spiegeleer, B.
title: The effects of ARBs, ACEIs and statins on clinical outcomes of COVID-19 infection among nursing home residents
date: 2020-05-15
journal: nan
DOI: 10.1101/2020.05.11.20096347
sha: 284d29e372b4cdb024f703e514666d7b19153797
doc_id: 764650
cord_uid: rky7tip0

Background. COVID-19 infection has limited preventive or therapeutic drug options at this stage. Some of common existing drugs like angiotensin-converting enzyme inhibitors (ACEi), angiotensin II receptor blockers (ARB) and the HMG-CoA reductase inhibitors (statins) have been hypothesised to impact on disease severity. However, up till now, no studies investigating this association were conducted in the most vulnerable and affected population groups, i.e. older people residing in nursing homes. The purpose of this study has been to explore the association of ACEi/ARB and/or statins with clinical manifestations in COVID-19 infected older people residing in nursing homes. Methods and Findings. We undertook a retrospective multi-centre cohort study in two Belgian nursing homes that experienced similar COVID-19 outbreaks. COVID-19 diagnoses were based on clinical suspicion and/or viral presence using PCR of nasopharyngeal samples. A total of 154 COVID-19 positive subjects was identified. The outcomes were defined as 1) serious COVID-19 defined as a long-stay hospital admission (length of stay [≥] 7 days) or death (at hospital or nursing home) within 14 days of disease onset, and 2) asymptomatic, i.e. no disease symptoms in the whole study-period while still being PCR diagnosed. Disease symptoms were defined as any COVID-19-related clinical symptom (e.g. coughing, dyspnoea, sore throat) or sign (low oxygen saturation and fever) for [≥] 2 days out of 3 consecutive days. Logistic regression models with Firth corrections were applied on these 154 subjects to analyse the association between ACEi/ARB and/or statin use with the outcomes. Age, sex, functional status, diabetes and hypertension were used as covariates. Sensitivity analyses were conducted to evaluate the robustness of our statistical significant findings. We found a statistically significant association between statin intake and the absence of symptoms during COVID-19 infection (unadjusted OR 2.91; CI 1.27-6.71; p=0.011), which remained statistically significant after adjusting for age, sex, functional status, diabetes mellitus and hypertension. The strength of this association was considerable and clinically important. Although the effects of statin intake on serious clinical outcome (long-stay hospitalisation or death) were in the same beneficial direction, these were not statistically significant (OR 0.75; CI 0.25-1.85; p=0.556). There was also no statistically significant association between ACEi/ARB and asymptomatic status (OR 1.52; CI 0.62-3.50; p=0.339) or serious clinical outcome (OR 0.79; CI 0.26-1.95; p=0.629). Conclusions. Our data indicate that statin intake in old, frail people could be associated with a considerable beneficial effect on COVID-19 related clinical symptoms. The role of statins and any interaction with renin-angiotensin system drugs need to be further explored in larger observational studies as well as randomised clinical trials.

nursing home) within 14 days of disease onset, and 2) asymptomatic, i.e. no disease symptoms 48 in the whole study-period while still being PCR diagnosed. Disease symptoms were defined as 49 any COVID-19-related clinical symptom (e.g. coughing, dyspnoea, sore throat) or sign (low 50 oxygen saturation and fever) for ≥ 2 days out of 3 consecutive days.

Logistic regression models with Firth corrections were applied on these 154 subjects to analyse 52 the association between ACEi/ARB and/or statin use with the outcomes. Age, sex, functional 53 status, diabetes and hypertension were used as covariates. Sensitivity analyses were conducted 54 to evaluate the robustness of our statistical significant findings. 55 We found a statistically significant association between statin intake and the absence of can prevent experimentally induced ARDS (4). These drugs are also likely to counteract the 75 effects of sepsis-associated coagulopathy, elevated pro-inflammatory cytokines (e.g. IL-6) and 76 sepsis-associated effects on pulmonary vascular permeability (5-12).

In a non-COVID-19 context, clinical investigators have observed that pneumonia patients who 78 had been taking statins, ARBs or ACEis had improved survival (13, 14) . Moreover, recent 79 observational studies have reported similar findings for hospitalized . Recently, randomized controlled clinical trials have begun to evaluate the clinical effects 81 . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted May 15, 2020 . . https://doi.org/10.1101 /2020 We aimed to replicate the hospital findings to a frail, high-risk population living in nursing 93 homes. While we wait for the results of prospective clinical trials, our findings allow us to make 94 suggestions about the use of ACEis/ARBs and statins for these COVID-19 patients. activates Akt-kinase, leading to phosphorylation and hence inhibition of the transcription factor Foxo1. Unphosphorylated or 100 active Foxo1 initiates the transcription of genes leading to increased inflammation, decreased endothelial barrier integrity 101 and hypercoagulability. Angpt-2 is a partial antagonist of the Tie-2 receptor, stimulating inflammation, endothelial 102 . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)

The copyright holder for this preprint this version posted May 15, 2020 . . https://doi.org/10.1101 /2020 dysfunction and hypercoagulability. COVID-19 infection and ARDS are associated with increased Angpt-2 levels in blood, while 103 statins simulate the Angpt-1 pathways. 2) The RAS system activates angiotensin-1 receptors (AT1R), stimulating inflammation, 104 hypercoagulability and endothelial permeability. The Ang II-ACE2-Ang(1-7)-Mas receptor pathway counteracts the effects of 105 this RAS system. COVID-19 enters the cell through ACE2 receptors, thereby decreasing these membrane-bound receptors, and 106 relatively stimulating the RAS system. ACEis/ARBs inhibit the RAS system, while concomitantly increasing ACE-2 expression, 107 which protects against ARDS. Statins also increase ACE-2 expression. 3) In ARDS there is an increase in the activation of the 108 were analysed for symptoms suggesting COVID-19 infection. The first day of suggestive 120 symptoms on two out of three consecutive days was considered as the day of disease onset. For 121 the PCR-diagnosed residents, the suggestive symptoms used for disease onset were cough, 122 shortness of breath (dyspnoea), sore throat, runny nose, general weakness, headache, confusion, 123 muscle pain, arthralgia, diarrhoea, abdominal pain, vomiting, fever (T° > 37.6°C), increased 124 oxygen need or low oxygen saturation (SpO2 ≤ 92%). In cases where no symptoms were 125 mentioned (while still being PCR COVID-19-positive diagnosed), the date of nasopharyngeal 126 sampling was used as the day of disease onset. For the clinically diagnosed residents without a 127 confirmatory PCR lab test, the symptoms used for determining disease onset were defined more 128 strictly, i.e., respiratory complaints (cough, shortness of breath, sore throat, runny nose), fever 129 (T° > 37.6°C), increased oxygen-need or low oxygen saturation (SpO2 ≤ 92%).

. CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted May 15, 2020. . https://doi.org/10. 1101 /2020 The primary outcomes were 1) serious COVID-19, i.e. long-stay hospital admission (length of 131 stay ≥ 7 days) or death (at nursing home or hospital) within 14 days of disease onset, and 2) 132 asymptomatic, i.e. no disease symptoms as defined above throughout the whole study-period 133 while still being PCR diagnosed.

All residents were stratified according to drug exposure to ACEi or ARB within 7 days before 135 the day of disease onset or during the disease (prior to an outcome being reached). Specifically, 136 we considered as treated all residents taking ≥ 2 days an ACEi (ramipril, lisinopril, enalapril, 137 captopril, quinapril, imidapril, fosinopril, trandolapril) or ARB (candesartan, irbesartan, 138 losartan, olmesartan, telmisartan, valsartan) up to 7 days before or 14 days after disease onset.

An identical protocol was used to stratify according to drug exposure to statins (atorvastatin, 140 fluvastatin, pravastatin, rosuvastatin, simvastatin). 141 We developed a mapping table based on clinical prescriptions to determine the diabetic and 142 hypertension status of all residents. It was designed by a specialist in elderly care and validated 143 by two independent physicians, one a general physician and the other a cardiologist.

The functional status of all residents was a dichotomous variable (high vs. low functioning).

This definition was based on the available Katz scale for residents before day of disease onset.

The Katz scale is a measure of independent activity of daily living.

Data processing and quality control 148 Anonymized data were imported in a relational database for processing, using Extract, 149 Transform, and Load (ETL) techniques. All received anonymized data were then evaluated on 150 basic data quality attributes such as completeness (i.e., the extent of missing data) and accuracy 151 (i.e., whether or not suspicious outliers were present in the individual attributes). Data were CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted May 15, 2020. . https://doi.org/10. 1101 /2020 Language Processing (NLP) techniques were used. For the residents still in the hospital on the 155 moment of data extraction, median imputation was used to estimate length of hospital duration.

Two independent physicians manually verified all recorded symptoms as well as all data for a 157 random subsample.

We calculated the distributions for dependent and independent variables for the total cohort 160 using appropriate measures of central tendency and dispersion. For our main analysis, we 161 investigated the association between ACEi/ARB and/or statin treatment and 1) serious disease, 162 measured as long-stay hospital admission or death, or 2) asymptomatic disease using a series 163 of logistic regressions applying Firth's correction. This procedure has been used previously by 164 our group and shown to be robust for low prevalence events and low-dimensional settings (16, 165 22, 23). We first explored the independent association between ACEi/ARB and both outcomes, 166 as well as the association between statins and the same outcomes. Then we adjusted the models CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted May 15, 2020. . https://doi.org/10.1101/2020.05.11.20096347 doi: medRxiv preprint

The study cohort included 154 COVID-19-diagnosed residents aged 86±7 (mean±SD) years, 180 evenly distributed over the two nursing homes (76 and 78 residents, respectively). Baseline 181 characteristics are shown in Table 1 . In our cohort (33% male), 20% were taking ACEis/ARBs 182 (16% ACEi and 4% ARB), and 20% were taking a statin. Eight residents (5%) were taking both CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted May 15, 2020. . https://doi.org/10.1101/2020. 05.11.20096347 doi: medRxiv preprint ACEi/ARB and statin combination remained asymptomatic throughout the study period. Only 204 one of them (13%) experienced serious COVID-19.

Although not reaching statistical significance, findings from unadjusted logistic regression 206 suggested a potential beneficial effect on COVID-19 symptoms among residents taking ACEis 207 or ARBs (OR 1.52; CI 0.62-3.50; p=0.329). Odds ratios adjusted for age, sex, functional status, 208 diabetes and hypertension were of similar magnitude ( Table 2 ). The results for the statins were 209 most interesting, as we observed a clear and statistically significant association between statin 210 intake and asymptomatic status (unadjusted OR 2.91; CI 1.27-6.71; p=0.011). This association 211 was partially attenuated but remained statistically significant when adjusted for gender, age, 212 functional status, diabetes and hypertension ( Table 2) . 213 We also examined associations between ACEis/ARBs and statins, and serious Although the available data failed to reach statistical significance, the directionality of the odds 215 ratios suggested a potential beneficial clinical effect of both ACEi/ARB and statins on serious 216 COVID-19 outcome. All odds ratios (unadjusted as well as adjusted for covariates), were 217 between 0.48 (CI 0.10-1.97; p=0.316) and 0.84 (CI 0.27-2.14; p=0.736) ( Table 3) . 218 We did not undertake regression analyses on the combined ACEi/ARB+statin group as there 219 were only eight residents in our cohort; nor did we undertake separate analyses for the ACEi or 220 ARB groups; only six residents were treated with an ARB.

Sensitivity analyses were conducted on the statistically significant association between statins 222 and symptoms. We found that estimates of the impact of statin treatment on asymptomatic 223 status were consistently of the same magnitude and statistically significant as the original 224 analyses. CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted May 15, 2020 . . https://doi.org/10.1101 /2020 

. CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted May 15, 2020 . . https://doi.org/10.1101 /2020 The safety profile of statins is well known and excellent, even in the old population. Moreover, 258 these drugs are relatively inexpensive and widespread, some even as food supplements as red 259 yeast rice, making them easily available throughout the world. Although this observational 260 . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted May 15, 2020. result is promising, our sample size was too small to allow us to draw firm conclusions.

One strength of this study is the specific population, i.e., old people (mean age > 85years) 271 residing in nursing homes. Although they are considered highly vulnerable to COVID-19 272 clinical outcomes, no study has yet reported on the effects of ARB/ACEi and/or statin treatment 273 on COVID-19 in this population. Extracting reliable data from nursing homes with COVID-19 274 outbreaks is far more cumbersome than extracting data from hospitals. Another strength is that 275 drug treatment was based on real intake, in contrast to most hospital-based studies that use 276 prescriptions as proxies for drug treatment. Lastly, in contrast to most hospital studies, 277 asymptomatic COVID-19 patients were included in the study. People admitted to hospitals are 278 evidently always symptomatic.

One limitation of our study is its relatively small cohort size. Consequently, absence of 280 statistical significance should be interpreted with caution. However, the consistency in the 281 observed effect sizes, even without statistical significance due to small sample size, should be 282 considered in the overall evaluation. As number of cases increase, further analyses will be 283 undertaken to better understand our findings and confirm these associations. Also, another 284 limitation was the lack of other potential confounders, including chronic kidney injury and 285 . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)

The copyright holder for this preprint this version posted May 15, 2020 . . https://doi.org/10.1101 /2020 BMI. Finally, our results apply to a very specific population (elderly people living in nursing 286 homes) and cannot be generalized to other groups such as young people or hospitalized people.

Our study, based on available data, indicates that in elderly nursing home residents, statin 290 treatment is associated with beneficial effects on COVID-19-related clinical symptoms.

Although not statistically significant, our findings also suggested that statin treatment in 292 combination with an ACEi or ARB was associated with less severe clinical outcomes. In the 293 light of these findings, a prudent recommendation is to continue or initiate statin treatment for 294 older people residing in nursing homes and at high risk for COVID-19 infection. CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)

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We thank all of the staff of VZW Zorg-Saam Zusters Kindsheid Jesu for their daily care of 298 older people and for their collaboration on this study during these difficult times. We also thank 299 the staff of the Corilus Health IT Center who helped with the data extraction.