key: cord-0763474-acg50cou
authors: Lukito, Antonia Anna; Widysanto, Allen; Lemuel, Theo Audi Yanto; Prasetya, Ignatius Bima; Massie, Billy; Yuniarti, Mira; Lumbuun, Nicolaski; Pranata, Raymond; Meidy, Cindy; Wahjoepramono, Eka Julianta; Yusuf, Irawan
title: Candesartan as a tentative treatment for COVID-19: a prospective non-randomized open-label study
date: 2021-05-24
journal: Int J Infect Dis
DOI: 10.1016/j.ijid.2021.05.019
sha: ff593c4e9b8d5300b283bfe6d7f68e0597bca795
doc_id: 763474
cord_uid: acg50cou

Background This study aimed to investigate whether the addition of candesartan to the standard care regimen improved the outcome in patients with coronavirus 2019 (COVID-19). Methods A prospective non-randomized open-label study was undertaken from May to August 2020 on 75 subjects (aged 18–70 years) hospitalized in Siloam Kelapa Dua Hospital. Uni- and multi-variable Cox regression analyses were performed to obtain hazard ratios (HRs). The primary outcomes were: (1) length of hospital stay; (2) time to negative swab; and (3) radiological outcome (time to improvement on chest x ray). Results None of the 75 patients with COVID-19 required intensive care. All patients were angiotensin-receptor-blocker naïve. In comparison with the control group, the candesartan group had a significantly shorter hospital stay [adjusted HR 2.47, 95% confidence interval (CI) 1.16–5.29] after adjusting for a wide range of confounders, and no increased risk of intensive care. In the non-obese subgroup, the candesartan group had a shorter time to negative swab (unadjusted HR 2.11, 95% CI 1.02–4.36; adjusted HR 2.40, 95% CI 1.08–5.09) and shorter time to improvement in chest x ray (adjusted HR 2.82, 95% CI 1.13–7.03) compared with the control group. Conclusion Candesartan significantly reduces the length of hospital stay after adjustment for covariates. All primary outcomes improved significantly in the non-obese subgroup receiving candesartan.

This research was approved by the Mochtar Riady Institute for Nanotechnology Ethics Committee (MRIN EC) with Ethical Approval Number 004/MRIN-EC/ECL/V/2020 and Protocol Number 2005003.

Data are available on reasonable request is a global public health emergency (WHO, 2021) , it has infected hundreds of millions of people globally at the time this paper was written. Even though most of the patients with COVID-19 were asymptomatic or experienced only mild influenza-like illness , a significant fraction of patients may develop severe pneumonia, acute respiratory distress syndrome (ARDS), multi-organ failure (MOF), and death. Due to the novelty of the disease, evidence-based treatments remained uncertain. The studies assessing specific medications for COVID-19 are mostly inconclusive. Viral surface spike (S) protein of COVID-19 binds to Angiotensin-converting Enzyme 2 (ACE2) after spike protein activation by transmembrane protease serine 2 (TMPRSS2). (Hoffmann et al., 2020) At first, the increase in ACE2 expression in patients receiving angiotensin-converting enzyme (ACE) inhibitor and angiotensin-receptor blocker (ARB) were thought to increase susceptibility to COVID-19 infection. However, studies have shown that COVID-19 downregulates ACE2 expression and hindering it's organoprotective effect. It is hypothesized that the unregulated angiotensin-II activity leads to multiple organ injury. Furthermore, ACE2 has been shown to protect lung from ARDS. Hence, drugs that may increase ACE2 may actually offer protection rather than harm. This is strengthened by recent findings that indicate the potential benefit of ARB use in patients with COVID-19 and hypertension. In this prospective nonrandomized study, we aimed to evaluate the efficacy and safety of candesartan on top of J o u r n a l P r e -p r o o f 6 standard care in patients infected with COVID-19 at the time this trial was conducted compared to standard care regimen.

This was a prospective non-randomized study, coordinated by The Medical Science Group of Pelita Harapan University, Siloam Hospitals, and Mochtar Riady Institute of Nanotechnology (MRIN) in Tangerang, Indonesia. Patients were recruited from Siloam Hospitals Kelapa Dua, a COVID-19 referral hospital starting from 4 th April 2020. All COVID-19 patients in the hospital received hydroxychloroquine unless contraindicated. Patients were then proposed a treatment regimen comprising standard of care and candesartan. Patients that agree with the standard of care + candesartan regimen were recruited into the intervention group. Patients that were treated with standard of care without candesartan were recruited into the control group. Hydroxychloroquine was included in the hospital standard treatment protocol at the time of this study.

Patients included in this study were hospitalized COVID-19 patients that were 18 to 70 yearsold, and PCR documented SARS-CoV-2 carriage in nasopharyngeal swab sample at admission regardless of clinical status.

Patients were excluded if they had a history of allergy to hydroxychloroquine or candesartan or had another known contraindication to treatment with the study drug, including retinopathy, G6PD deficiency, and QT prolongation. Patients with other terminal illnesses 7 were also excluded. Breastfeeding and pregnant patients were excluded based on their declaration and pregnancy test results when required.

Written informed signed consent was obtained from patients meeting inclusion criteria that agree to participate in the study. An information document that indicates the risks and the benefits associated with the participation to the study was given to each patient. Patients received information about their clinical status during care regardless of whether they participate in the study or not. Regarding patient identification, a study number was assigned sequentially to included participants, according to the range of patient numbers allocated to the study. The study was conducted following the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) guidelines of good clinical practice, the Helsinki Declaration, and applicable standard operating procedures. The protocol and any other relevant documentation were submitted to the MRIN Ethics Committee for reviewing and approval.

Patients were seen at baseline for enrolment, initial data collection, and treatment at day-0, day 7 and again for daily follow-up during 14 days. Each day, patients received a standardized clinical examination and a nasopharyngeal sample was collected at day 0, day 5 then every 2 days until negative before discharged. Day 0, and day 14 for low radiation dose Thorax CT or chest X-ray, then every 5 days. All clinical data were collected using standardized questionnaires. Investigators provided symptomatic treatment and antibiotics as a measure to prevent bacterial super-infection based on clinical judgment. 

Patients were grouped into two categories: mild-moderate and severe. Mild-moderate status includes mild fever, cough (dry), sore throat, nasal congestion, malaise, headache, muscle pain, or malaise. Severe COVID-19 was defined as per WHO interim guidance for the clinical management of patients with severe acute respiratory infection (SARI), this comprised of patients who had any of the following features at the time of, or after, admission: (1) respiratory distress (≥30 breaths per min); (2) oxygen saturation at rest ≤93%; (3) ratio of partial pressure of arterial oxygen (PaO2) to fractional concentration of oxygen inspired air (fiO2) ≤300 mmHg; or (4) critical complication (respiratory failure, septic shock, and or multiple organ dysfunction/failure).(World Health Organization and Mission China Joint, 2020)

In the intervention group, patients were given candesartan 4 mg to 32 mg once daily, titrated according to blood pressure tolerance and not given for eGFR less than 30 ml/min/1.73m 2 .

Candesartan was postponed if systolic blood pressure (SBP) falls below 90 mmHg, it was restarted when the SBP >100 mmHg. Patients were also given azithromycin 500 mg once daily or Levofloxacin IV 750 mg once daily, hydrochloroquine 400 mg once daily, and Vitamin C 1000 mg IV. Patients also received symptomatic medications and additional antibiotics based on physician's discretion.

J o u r n a l P r e -p r o o f Patients were also given azithromycin 500 mg once daily or Levofloxacin IV 750 mg once daily, hydrochloroquine 400 mg once daily and Vitamin C 1000 mg IV, along with symptomatic medications and additional antibiotics based on physician's discretion.

The primary endpoint were clinical outcomes including: 1) length of stay, 2) Time-to-Negative Swab, and 3) radiological outcomes (Time-to-Improvement on Chest X-Ray). Secondary outcomes were change in NLR and CRP on follow-up, occurrence of side-effects, intensive care unit admission, and mortality.

A 85% power, a type I error rate of 5% and 10% loss to follow-up, we calculated that a total of 60 COVID-19 patients (ie, 30 cases in the candesartan and 30 cases in the control group with the usual care) would be required for the analysis (Fleiss with CC). The continuous data were tested for normal distribution; t-test was used for normally distributed data and Mann-Whitney test was used for abnormally distributed data. Normally distributed data were reported as mean and standard deviation (SD); while abnormally distributed data were reported as median and interquartile range (IRQ). Chi-square or Fischer-exact test was performed for categorical variables. Cox-regression was performed to obtain the hazard ratio (HR) for candesartan use and length of stay, time-to-improvement of chest x-ray, time-tonegative swab. Multivariable Cox-regression analysis was performed using age, gender, hypertension, and type 2 diabetes mellitus as covariates. To avoid model-overfitting, only 5 covariates were included in the multivariable Cox-regression analysis at a time. Subgroup analysis was performed for patients without obesity. We used SPSS 25.0 to conduct the statistical analysis.

This prospective non-randomized open-label study was conducted in the early months of COVID-19 pandemic, along with early protocol, which frequently changes until recently.

Seventy-five subjects were included in this study, 35 subjects in Candesartan group, age 41 ± 13.65, male 70.67%, hypertensive 9.3%, diabetic 5.3%, BMI 23.35 ± 3.77 kg/m2, and current smoking 12 %, clinical mild-moderate case 89.33% and severe case 10.67%. All patients in this study was ARB naïve. One patient in control group has a history of candesartan use, but has not actively taking candesartan for months. There were no significant differences in baseline characteristics, including comorbidities among the two groups [ Table 1 ].

Of 75 patients who had COVID-19, none received ICU care. Candesartan was not associated with significant difference in length of stay (unadjusted HR 1.50, 95% CI 0.91 -2.48) [ Figure   2A ], Time-to-Negative Swab (unadjusted HR 1.41, 95% CI 0.85 -2.32) [ Figure 2B ], and Timeto-Improvement on Chest X-Ray (unadjusted HR 1.60, 95% CI 0.78 -3.29) [ Figure 2C ].

Multivariable analysis indicates that candesartan significantly shortens the length of stay (adjusted HR 1.74, 95% CI 1.01 -2.97) [ Figure 3A ] after adjustment to age, gender, hypertension, and type 2 diabetes mellitus; but not Time-to-Negative Swab (adjusted HR 1.55, 95% CI 0.92 -2.63) [ Figure 3B ] and Time-to-Improvement on Chest X-Ray (adjusted HR 1.45, 95% CI 0.82 -2.55) [ Figure 3C ] [ Table 2 ].

In unadjusted analysis of non-obese subgroup, candesartan use was associated with shorter length of stay (unadjusted HR 2.47, 95% CI 1.16 -5.29) [ Figure 4A ] and Time-to-Negative Swab was shorter in patients receiving candesartan (unadjusted HR 2.11, 95% CI 1.02 -4.36) [ Figure   4B ], but not Time-to-Improvement on Chest X-Ray (unadjusted HR 1.06, 95% CI 0.40 -2.80)

[ Figure 4C ]. In the adjusted analysis of non-obese subgroup, shorter length of stay (adjusted J o u r n a l P r e -p r o o f 11 HR 3.07, 95% CI 1.33 -7.12) [ Figure 5A ], Time-to-Negative Swab (adjusted HR 2.40, 95% CI 1.08 -5.09) [ Figure 5B ], and Time-to-Improvement on Chest X-Ray (adjusted HR 2.82, 95% CI 1.13 -7.03) [ Figure 5C ] [ Table 2 ]. Time to improvement of chest X-ray is a parameter of lung injury resolution in patients infected with There was no significant difference in terms of NLR and CRP at baseline, day 7, and on discharge [ Table 3 ]. There were no reported side effects related to medications in both groups.

There were no patients requiring intensive care unit admission. The mortality rate in both groups was 0%.

This prospective non-randomized open-label study showed that candesartan use resulted in a trend towards reduced length of stay, Time-to-Improvement on Chest X-Ray, and Time-to-Negative Swab, although the finding is not statistically significant. The lower confidence interval for reduction in length of stay was close to one, and it is possible that a statistical significance can be achieved with larger sample size. Multivariable analysis indicates that candesartan significantly shortens the length of stay after adjustment to age, gender, hypertension, and type 2 diabetes mellitus. Additionally, subgroup analysis in patients without obesity indicates that the length of stay, Time-to-Improvement on Chest X-Ray, and Time-to-Negative Swab were significantly improved in patients receiving candesartan. There were no patients requiring intensive care unit admission or died, possibly because most of the patients only have mild-moderate severity.

Candesartan is widely used to treat hypertension, and there is an abundant clinical experience with its use, all representatives of this group being characterized by their excellent tolerance.

Candesartan is a selective antagonist of AT1 receptor that exerts an inhibitory effect on the ACE-Ang II-AT1 axis in the RAS system, a known molecular pathway for end-organ fibrosis.

Thus, candesartan may be suggested as a potential agent of protection from lung damage induced by COVID-19. Candesartan may also have a protective function against lung fibrosis through other molecular mechanisms such as the downregulation of TGF-β1.

ACE2 reduces the expression of interleukin-6 by converting angiotensin II into angiotensin 1-7, thus promoting antioxidant function, increasing alveolar surfactants concentration, and triggering vasodilation . These potentially protect the lung from ARDS . Additionally, ACEI/ARB use increases the number of CD3 and CD8 T cells, with a decreased peak viral load, compared to the other antihypertensive drugs . SARS-CoV-2 downregulate ACE2 expression that eventually cause unregulated angiotensin-2 activity , which is one of the possible mechanisms that may incite multiple organ injury (Gurwitz, 2020b; [ Figure 6 ]. Cardiovascular injuries, pre-existing or new, were commonly encountered in patients with COVID-19 , prescribing ARB in COVID-19 may help to mitigate the pathology. Our study support use of ARB in patients without comorbidities such as hypertension or diabetes, in view that ARB will provide protection to lung injury or cardiovascular complications.

In this study, non-obese subgroup receiving candesartan in adjusted model showed shorter length of stay, shorter time to negative Swab, and time to lung injury improvement compared to patients receiving standard care. While the exact mechanisms are unclear, there are several possible explanations. This phenomenon in line with Ecelbarger et al, whom evaluated the inflammation profile of lean zucker and obese zucker rats. The experiment was done by feeding the rats with candesartan for 14 weeks. It was found that candesartan decreased J o u r n a l P r e -p r o o f 13 renal IL-1, IL-2, IL-4, IL-6, and IL-10, tumor necrosis factor-alpha, interferon-gamma in obese zucker rat. However, the levels of growth-regulated oncogene, transforming growth factor-beta1 and IL-18 were elevated in obese zucker rats compared to lean zucker rats. This phenomenon remains unclear and need further study, however, it may indicate different response in obesity and lean subjects. Obesity increases the severity of the COVID-19 infection, reported by Pranata R et al, in a dose-response meta-analysis that showed obesity was associated with composite poor outcome, mortality, and severity of COVID-19. The pro-inflammatory state in the obese environment may reduce benefit in patients receiving candesartan.

Additionally, patients with obesity expresses larger number for ACE2 receptors which may cause increased risk for severe COVID-19.(Al Heialy et al., 2020; Iannelli et al., 2020) Higher number of ACE2 receptors may translate to increased candesartan dose requirement, thus explaining why the benefit is more readily observed in patients without obesity. These hypotheses need to be confirmed in larger randomized controlled trials.

Candesartan group had shorter length of stay compared to standard care only group, after adjusting for age, gender, hypertension and diabetes, this finding supports the studies reported renin angiotensin system (RAS) inhibitors that may have a beneficial effect in preventing lung injury due to COVID-19 infection. (Chen et al., 2020; Moreover, Pranata R et al, in a systematic meta-analysis also reported that administration of a RAS inhibitor, was not associated with increased mortality or severity of COVID-19 in patients with hypertension, and specifically, ARB and not ACEI use, was associated with lower mortality. Recently, Gurwitz (2020) proposed the tentative use of agents such as losartan and telmisartan as alternative options for treating COVID-19 patients prior to development of ARDS. Interestingly, found that among patients with hypertension hospitalized with COVID-19, inpatient treatment with ACEI/ARB was associated with lower risk of all-cause mortality compared with ACEI/ARB nonusers. In accordance with these studies, a randomized open-label controlled trial has begun enrolling patients in Hospital de Clínicas "José de San Martín" (School of Medicine, University of Buenos Aires, Argentina). The proposed intervention in the clinical trial setting will be Telmisartan (Bertel®, Laboratorio Elea Phoenix, Buenos Aires, Argentina), 80 mg twice daily, oral administration, beginning upon positive PCR test for COVID-19 versus standard care (NCT04355936). In line with our study, in the large population-based study, although ARBs prescription were associated with a reduced risk of COVID-19 positive PCR-recovery time in a hospital setting adjusting for a wide range of demographic factors, potential comorbidities, and other medication, there was no evidence of an increased or decreased risk associated with ARBs for ICU admission. Inflammatory markers are usually associated with prognosis in patients with COVID-19. The lack of improvement in inflammation markers, might be due to the inflammation process was not entirely subsided in average 2 weeks hospitalized duration, Doykov I et al, reported that that biochemical and inflammatory pathways within the body could remain perturbed long after SARS-CoV-2 infections have subsided even in asymptomatic and moderately affected patients, even 40-60 days post-viral infection. Several drugs such as metformin and dipeptidyl peptidase-4 inhibitor may affect prognosis in patients with COVID-19.(Lukito et al., 2020; Rakhmat et al., 2021) In this study, there is no demonstrable difference between the drug use in patients in the candesartan and control group.

This study has several limitations. First, this study has an open-label design, which is not as robust as randomized controlled trials. Secondly, although the sample size was calculated based on formula for sample size requirement in analytical studies, it seemed that the study is underpowered and statistical significance might be reached if the sample is added. Thirdly, despite potential self-selection bias, there was no significant difference between the baseline characteristics of the two groups. Randomized controlled trials should be conducted in patients with severe COVID-19 to evaluate benefit in terms of mortality and intensive care unit admission.

This is the first prospective non-randomized open-label study using candesartan, an ARB, as a tentative treatment for COVID-19 infected patients, we found that candesartan has a nonstatistically significant trend towards reduced length of stay, time to improvement of chest Xray, and time to negative swab. Interestingly Candesartan shortened length of stay in nonobese subgroup, while after adjusted for age, gender, hypertension and diabetes, Candesartan shortened the length of stay of both overall group and non-obese subgroup, and shortened the time to improvement of chest X-ray in non-obese subgroup compared to standard care regimen. Candesartan was also associated with shorter time to negative PCR swab in adjusted model. Time to improvement of chest X-ray is a proxy of lung injury resolution in patients infected with COVID-19. inconclusive. Viral surface spike (S) protein of COVID-19 binds to Angiotensin-converting Enzyme 2 (ACE2) after spike protein activation by transmembrane protease serine 2 (TMPRSS2). (Hoffmann et al., 2020) At first, the increase in ACE2 expression in patients receiving angiotensin-converting enzyme (ACE) inhibitor and angiotensin-receptor blocker (ARB) were thought to increase susceptibility to COVID-19 infection. However, studies have shown that COVID-19 downregulates ACE2 expression and hindering it's organoprotective effect. It is hypothesized that the unregulated angiotensin-II activity leads to multiple organ injury. Furthermore, ACE2 has been shown to protect lung from ARDS. Hence, drugs that may increase ACE2 may actually offer protection rather than harm. This is strengthened by recent findings that indicate the potential benefit of ARB use in patients with COVID-19 and hypertension. In this prospective nonrandomized study, we aimed to evaluate the efficacy and safety of candesartan on top of J o u r n a l P r e -p r o o f 6 standard care in patients infected with COVID-19 at the time this trial was conducted compared to standard care regimen.

This was a prospective non-randomized study, coordinated by The Medical Science Group of Pelita Harapan University, Siloam Hospitals, and Mochtar Riady Institute of Nanotechnology (MRIN) in Tangerang, Indonesia. Patients were recruited from Siloam Hospitals Kelapa Dua, a COVID-19 referral hospital starting from 4 th April 2020. All COVID-19 patients in the hospital received hydroxychloroquine unless contraindicated. Patients were then proposed a treatment regimen comprising standard of care and candesartan. Patients that agree with the standard of care + candesartan regimen were recruited into the intervention group. Patients that were treated with standard of care without candesartan were recruited into the control group. Hydroxychloroquine was included in the hospital standard treatment protocol at the time of this study.

Patients included in this study were hospitalized COVID-19 patients that were 18 to 70 yearsold, and PCR documented SARS-CoV-2 carriage in nasopharyngeal swab sample at admission regardless of clinical status.

Patients were excluded if they had a history of allergy to hydroxychloroquine or candesartan or had another known contraindication to treatment with the study drug, including retinopathy, G6PD deficiency, and QT prolongation. Patients with other terminal illnesses 7 were also excluded. Breastfeeding and pregnant patients were excluded based on their declaration and pregnancy test results when required.

Written informed signed consent was obtained from patients meeting inclusion criteria that agree to participate in the study. An information document that indicates the risks and the benefits associated with the participation to the study was given to each patient. Patients received information about their clinical status during care regardless of whether they participate in the study or not. Regarding patient identification, a study number was assigned sequentially to included participants, according to the range of patient numbers allocated to the study. The study was conducted following the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) guidelines of good clinical practice, the Helsinki Declaration, and applicable standard operating procedures. The protocol and any other relevant documentation were submitted to the MRIN Ethics Committee for reviewing and approval.

Patients were seen at baseline for enrolment, initial data collection, and treatment at day-0, day 7 and again for daily follow-up during 14 days. Each day, patients received a standardized clinical examination and a nasopharyngeal sample was collected at day 0, day 5 then every 2 days until negative before discharged. Day 0, and day 14 for low radiation dose Thorax CT or chest X-ray, then every 5 days. All clinical data were collected using standardized questionnaires. Investigators provided symptomatic treatment and antibiotics as a measure to prevent bacterial super-infection based on clinical judgment. 

Patients were grouped into two categories: mild-moderate and severe. Mild-moderate status includes mild fever, cough (dry), sore throat, nasal congestion, malaise, headache, muscle pain, or malaise. Severe COVID-19 was defined as per WHO interim guidance for the clinical management of patients with severe acute respiratory infection (SARI), this comprised of patients who had any of the following features at the time of, or after, admission: (1) respiratory distress (≥30 breaths per min); (2) oxygen saturation at rest ≤93%; (3) ratio of partial pressure of arterial oxygen (PaO2) to fractional concentration of oxygen inspired air (fiO2) ≤300 mmHg; or (4) critical complication (respiratory failure, septic shock, and or multiple organ dysfunction/failure).(World Health Organization and Mission China Joint, 2020)

In the intervention group, patients were given candesartan 4 mg to 32 mg once daily, titrated according to blood pressure tolerance and not given for eGFR less than 30 ml/min/1.73m 2 .

Candesartan was postponed if systolic blood pressure (SBP) falls below 90 mmHg, it was restarted when the SBP >100 mmHg. Patients were also given azithromycin 500 mg once daily or Levofloxacin IV 750 mg once daily, hydrochloroquine 400 mg once daily, and Vitamin C 1000 mg IV. Patients also received symptomatic medications and additional antibiotics based on physician's discretion.

Patients were also given azithromycin 500 mg once daily or Levofloxacin IV 750 mg once daily, hydrochloroquine 400 mg once daily and Vitamin C 1000 mg IV, along with symptomatic medications and additional antibiotics based on physician's discretion.

The primary endpoint were clinical outcomes including: 1) length of stay, 2) Time-to-Negative Swab, and 3) radiological outcomes (Time-to-Improvement on Chest X-Ray). Secondary outcomes were change in NLR and CRP on follow-up, occurrence of side-effects, intensive care unit admission, and mortality.

A 85% power, a type I error rate of 5% and 10% loss to follow-up, we calculated that a total of 60 COVID-19 patients (ie, 30 cases in the candesartan and 30 cases in the control group with the usual care) would be required for the analysis (Fleiss with CC). The continuous data were tested for normal distribution; t-test was used for normally distributed data and Mann-Whitney test was used for abnormally distributed data. Normally distributed data were reported as mean and standard deviation (SD); while abnormally distributed data were reported as median and interquartile range (IRQ). Chi-square or Fischer-exact test was performed for categorical variables. Cox-regression was performed to obtain the hazard ratio (HR) for candesartan use and length of stay, time-to-improvement of chest x-ray, time-tonegative swab. Multivariable Cox-regression analysis was performed using age, gender, hypertension, and type 2 diabetes mellitus as covariates. To avoid model-overfitting, only 5 covariates were included in the multivariable Cox-regression analysis at a time. Subgroup analysis was performed for patients without obesity. We used SPSS 25.0 to conduct the statistical analysis.

This prospective non-randomized open-label study was conducted in the early months of COVID-19 pandemic, along with early protocol, which frequently changes until recently.

Seventy-five subjects were included in this study, 35 subjects in Candesartan group, age 41 ± 13.65, male 70.67%, hypertensive 9.3%, diabetic 5.3%, BMI 23.35 ± 3.77 kg/m2, and current smoking 12 %, clinical mild-moderate case 89.33% and severe case 10.67%. All patients in this study was ARB naïve. One patient in control group has a history of candesartan use, but has not actively taking candesartan for months. There were no significant differences in baseline characteristics, including comorbidities among the two groups [ Table 1 ].

Of 75 patients who had COVID-19, none received ICU care. Candesartan was not associated with significant difference in length of stay (unadjusted HR 1.50, 95% CI 0.91 -2.48) [ Figure   2A ], Time-to-Negative Swab (unadjusted HR 1.41, 95% CI 0.85 -2.32) [ Figure 2B ], and Timeto-Improvement on Chest X-Ray (unadjusted HR 1.60, 95% CI 0.78 -3.29) [ Figure 2C ].

Multivariable analysis indicates that candesartan significantly shortens the length of stay (adjusted HR 1.74, 95% CI 1.01 -2.97) [ Figure 3A ] after adjustment to age, gender, hypertension, and type 2 diabetes mellitus; but not Time-to-Negative Swab (adjusted HR 1.55, 95% CI 0.92 -2.63) [ Figure 3B ] and Time-to-Improvement on Chest X-Ray (adjusted HR 1.45, 95% CI 0.82 -2.55) [ Figure 3C ] [ Table 2 ].

In unadjusted analysis of non-obese subgroup, candesartan use was associated with shorter length of stay (unadjusted HR 2.47, 95% CI 1.16 -5.29) [ Figure 4A ] and Time-to-Negative Swab was shorter in patients receiving candesartan (unadjusted HR 2.11, 95% CI 1.02 -4.36) [ Figure   4B ], but not Time-to-Improvement on Chest X-Ray (unadjusted HR 1.06, 95% CI 0.40 -2.80)

[ Figure 4C ]. In the adjusted analysis of non-obese subgroup, shorter length of stay (adjusted J o u r n a l P r e -p r o o f 11 HR 3.07, 95% CI 1.33 -7.12) [ Figure 5A ], Time-to-Negative Swab (adjusted HR 2.40, 95% CI 1.08 -5.09) [ Figure 5B ], and Time-to-Improvement on Chest X-Ray (adjusted HR 2.82, 95% CI 1.13 -7.03) [ Figure 5C ] [ Table 2 ]. Time to improvement of chest X-ray is a parameter of lung injury resolution in patients infected with Covid-19.

There was no significant difference in terms of NLR and CRP at baseline, day 7, and on discharge [ Table 3 ]. There were no reported side effects related to medications in both groups.

There were no patients requiring intensive care unit admission. The mortality rate in both groups was 0%.

This prospective non-randomized open-label study showed that candesartan use resulted in a trend towards reduced length of stay, Time-to-Improvement on Chest X-Ray, and Time-to-Negative Swab, although the finding is not statistically significant. The lower confidence interval for reduction in length of stay was close to one, and it is possible that a statistical significance can be achieved with larger sample size. Multivariable analysis indicates that candesartan significantly shortens the length of stay after adjustment to age, gender, hypertension, and type 2 diabetes mellitus. Additionally, subgroup analysis in patients without obesity indicates that the length of stay, Time-to-Improvement on Chest X-Ray, and Time-to-Negative Swab were significantly improved in patients receiving candesartan. There were no patients requiring intensive care unit admission or died, possibly because most of the patients only have mild-moderate severity.

Candesartan is widely used to treat hypertension, and there is an abundant clinical experience with its use, all representatives of this group being characterized by their excellent tolerance.

Candesartan is a selective antagonist of AT1 receptor that exerts an inhibitory effect on the ACE-Ang II-AT1 axis in the RAS system, a known molecular pathway for end-organ fibrosis.

Thus, candesartan may be suggested as a potential agent of protection from lung damage induced by COVID-19. Candesartan may also have a protective function against lung fibrosis through other molecular mechanisms such as the downregulation of TGF-β1.

ACE2 reduces the expression of interleukin-6 by converting angiotensin II into angiotensin 1-7, thus promoting antioxidant function, increasing alveolar surfactants concentration, and triggering vasodilation . These potentially protect the lung from ARDS . Additionally, ACEI/ARB use increases the number of CD3 and CD8 T cells, with a decreased peak viral load, compared to the other antihypertensive drugs . SARS-CoV-2 downregulate ACE2 expression that eventually cause unregulated angiotensin-2 activity , which is one of the possible mechanisms that may incite multiple organ injury (Gurwitz, 2020b; [ Figure 6 ]. Cardiovascular injuries, pre-existing or new, were commonly encountered in patients with COVID-19 , prescribing ARB in COVID-19 may help to mitigate the pathology. Our study support use of ARB in patients without comorbidities such as hypertension or diabetes, in view that ARB will provide protection to lung injury or cardiovascular complications.

In this study, non-obese subgroup receiving candesartan in adjusted model showed shorter length of stay, shorter time to negative Swab, and time to lung injury improvement compared to patients receiving standard care. While the exact mechanisms are unclear, there are several possible explanations. This phenomenon in line with Ecelbarger et al, whom evaluated the inflammation profile of lean zucker and obese zucker rats. The experiment was done by feeding the rats with candesartan for 14 weeks. It was found that candesartan decreased J o u r n a l P r e -p r o o f 13 renal IL-1, IL-2, IL-4, IL-6, and IL-10, tumor necrosis factor-alpha, interferon-gamma in obese zucker rat. However, the levels of growth-regulated oncogene, transforming growth factor-beta1 and IL-18 were elevated in obese zucker rats compared to lean zucker rats. This phenomenon remains unclear and need further study, however, it may indicate different response in obesity and lean subjects. Obesity increases the severity of the COVID-19 infection, reported by Pranata R et al, in a dose-response meta-analysis that showed obesity was associated with composite poor outcome, mortality, and severity of COVID-19.(Pranata et al., 2021) The pro-inflammatory state in the obese environment may reduce benefit in patients receiving candesartan.

Additionally, patients with obesity expresses larger number for ACE2 receptors which may cause increased risk for severe COVID-19.(Al Heialy et al., 2020; Iannelli et al., 2020) Higher number of ACE2 receptors may translate to increased candesartan dose requirement, thus explaining why the benefit is more readily observed in patients without obesity. These hypotheses need to be confirmed in larger randomized controlled trials.

Candesartan group had shorter length of stay compared to standard care only group, after adjusting for age, gender, hypertension and diabetes, this finding supports the studies reported renin angiotensin system (RAS) inhibitors that may have a beneficial effect in preventing lung injury due to COVID-19 infection. (Chen et al., 2020; Moreover, Pranata R et al, in a systematic meta-analysis also reported that administration of a RAS inhibitor, was not associated with increased mortality or severity of COVID-19 in patients with hypertension, and specifically, ARB and not ACEI use, was associated with lower mortality. Recently, Gurwitz (2020) proposed the tentative use of agents such as losartan and telmisartan as alternative options for treating COVID-19 patients prior to development of ARDS. Interestingly, Zhang et al. (2020) found that among patients with hypertension hospitalized with COVID-19, inpatient treatment with ACEI/ARB was associated with lower risk of all-cause mortality compared with ACEI/ARB nonusers. In accordance with these studies, a randomized open-label controlled trial has begun enrolling patients in Hospital de Clínicas "José de San Martín" (School of Medicine, University of Buenos Aires, Argentina). The proposed intervention in the clinical trial setting will be Telmisartan (Bertel®, Laboratorio Elea Phoenix, Buenos Aires, Argentina), 80 mg twice daily, oral administration, beginning upon positive PCR test for COVID-19 versus standard care (NCT04355936). In line with our study, in the large population-based study, although ARBs prescription were associated with a reduced risk of COVID-19 positive PCR-recovery time in a hospital setting adjusting for a wide range of demographic factors, potential comorbidities, and other medication, there was no evidence of an increased or decreased risk associated with ARBs for ICU admission. Inflammatory markers are usually associated with prognosis in patients with COVID-19. The lack of improvement in inflammation markers, might be due to the inflammation process was not entirely subsided in average 2 weeks hospitalized duration, Doykov I et al, reported that that biochemical and inflammatory pathways within the body could remain perturbed long after SARS-CoV-2 infections have subsided even in asymptomatic and moderately affected patients, even 40-60 days post-viral infection. Several drugs such as metformin and dipeptidyl peptidase-4 inhibitor may affect prognosis in patients with COVID-19.(Lukito et al., 2020; Rakhmat et al., 2021) In this study, there is no demonstrable difference between the drug use in patients in the candesartan and control group.

This study has several limitations. First, this study has an open-label design, which is not as robust as randomized controlled trials. Secondly, although the sample size was calculated based on formula for sample size requirement in analytical studies, it seemed that the study is underpowered and statistical significance might be reached if the sample is added. Thirdly, despite potential self-selection bias, there was no significant difference between the baseline characteristics of the two groups. Randomized controlled trials should be conducted in patients with severe COVID-19 to evaluate benefit in terms of mortality and intensive care unit admission.

This is the first prospective non-randomized open-label study using candesartan, an ARB, as a tentative treatment for COVID-19 infected patients, we found that candesartan has a nonstatistically significant trend towards reduced length of stay, time to improvement of chest Xray, and time to negative swab. Interestingly Candesartan shortened length of stay in nonobese subgroup, while after adjusted for age, gender, hypertension and diabetes, Candesartan shortened the length of stay of both overall group and non-obese subgroup, and shortened the time to improvement of chest X-ray in non-obese subgroup compared to standard care regimen. Candesartan was also associated with shorter time to negative PCR swab in adjusted model. Time to improvement of chest X-ray is a proxy of lung injury resolution in patients infected with COVID-19. 

A Trial of Lopinavir-Ritonavir in Adults Hospitalized with Severe Covid-19

Structure analysis of the receptor binding of 2019-nCoV

Organ-protective effect of angiotensin-converting enzyme 2 and its effect on the prognosis of COVID-19

Organ-protective effect of angiotensin-converting enzyme 2 and its effect on the prognosis of COVID-19

Covid-19: four fifths of cases are asymptomatic, China figures indicate

The effect of chronic candesartan therapy on the metabolic profile and renal tissue cytokine levels in the obese zucker rat

Are patients with hypertension and diabetes mellitus at increased risk for COVID-19 infection?

Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial

Angiotensin receptor blockers as tentative SARS-CoV-2 therapeutics

Angiotensin receptor blockers as tentative SARS-CoV-2 therapeutics

Angiotensin receptor blockers as tentative SARS-CoV-2 therapeutics

Regulation of Angiotensin-Converting Enzyme 2 in Obesity: Implications for COVID-19

The long tail of Covid-19" -The detection of a prolonged inflammatory response after a SARS-CoV-2 infection in asymptomatic and mildly affected patients

Risk of severe COVID-19 disease with ACE inhibitors and angiotensin receptor blockers: Cohort study including 8.3 million people

C-reactive protein, procalcitonin, Ddimer, and ferritin in severe coronavirus disease-2019: a meta-analysis

ACE 2, the Missing Tile

Angiotensin-converting enzyme 2 protects from severe acute lung failure

Angiotensin-converting enzyme 2 protects from severe acute lung failure

Multiorgan Failure With Emphasis on Acute Kidney Injury and Severity of COVID-19: Systematic Review and Meta-Analysis

Clinical and biochemical indexes from 2019-nCoV infected patients linked to viral loads and lung injury

The Effect of Metformin Consumption on Mortality in Hospitalized COVID-19 patients: a systematic review and metaanalysis

Tricuspid annular plane systolic excursion (TAPSE) measured by echocardiography and mortality in COVID-19: A systematic review and meta-analysis

Renin-angiotensin system inhibitors improve the clinical outcomes of COVID-19 patients with hypertension

COVID-19, diabetes mellitus and ACE2: The conundrum

Impact of Cerebrovascular and Cardiovascular Diseases on Mortality and Severity of COVID-19 -Systematic Review, Metaanalysis, and Meta-regression

Body mass index and outcome in patients with COVID-19: A dose-response meta-analysis

The use of renin angiotensin system inhibitor on mortality in patients with coronavirus disease 2019 (COVID-19): A systematic review and meta-analysis

Dipeptidyl peptidase-4 (DPP-4) inhibitor and mortality in coronavirus disease

A systematic review, meta-analysis, and meta-regression

Potential harmful effects of discontinuing ACE-inhibitors and ARBs in COVID-19 patients

Telmisartan as tentative angiotensin receptor blocker therapeutic for COVID-19

Renin-Angiotensin-Aldosterone System Inhibitors in Patients with Covid-19

Renin-Angiotensin-Aldosterone System Inhibitors in Patients with Covid-19

Prognostic performance of troponin in COVID-19: A diagnostic meta-analysis and meta-regression

Left and right ventricular longitudinal strains are associated with poor outcome in COVID-19: a systematic review and meta-analysis

Report of the WHO-China Joint Mission on REFERENCES

A Trial of Lopinavir-Ritonavir in Adults Hospitalized with Severe Covid-19

Structure analysis of the receptor binding of 2019-nCoV

Organ-protective effect of angiotensin-converting enzyme 2 and its effect on the prognosis of COVID-19

Organ-protective effect of angiotensin-converting enzyme 2 and its effect on the prognosis of COVID-19

Covid-19: four fifths of cases are asymptomatic, China figures indicate

The effect of chronic candesartan therapy on the metabolic profile and renal tissue cytokine levels in the obese zucker rat

Are patients with hypertension and diabetes mellitus at increased risk for COVID-19 infection?

Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial

Angiotensin receptor blockers as tentative SARS-CoV-2 therapeutics

Angiotensin receptor blockers as tentative SARS-CoV-2 therapeutics

Angiotensin receptor blockers as tentative SARS-CoV-2 therapeutics

Regulation of Angiotensin-Converting Enzyme 2 in Obesity: Implications for COVID-19

The long tail of Covid-19" -The detection of a prolonged inflammatory response after a SARS-CoV-2 infection in asymptomatic and mildly affected patients

Risk of severe COVID-19 disease with ACE inhibitors and angiotensin receptor blockers: Cohort study including 8.3 million people

Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor

C-reactive protein, procalcitonin, Ddimer, and ferritin in severe coronavirus disease-2019: a meta-analysis

ACE 2, the Missing Tile

Angiotensin-converting enzyme 2 protects from severe acute lung failure

Angiotensin-converting enzyme 2 protects from severe acute lung failure

Multiorgan Failure With Emphasis on Acute Kidney Injury and Severity of COVID-19: Systematic Review and Meta-Analysis

Clinical and biochemical indexes from 2019-nCoV infected patients linked to viral loads and lung injury

The Effect of Metformin Consumption on Mortality in Hospitalized COVID-19 patients: a systematic review and metaanalysis

Tricuspid annular plane systolic excursion (TAPSE) measured by echocardiography and mortality in COVID-19: A systematic review and meta-analysis

Renin-angiotensin system inhibitors improve the clinical outcomes of COVID-19 patients with hypertension

COVID-19, diabetes mellitus and ACE2: The conundrum

Impact of Cerebrovascular and Cardiovascular Diseases on Mortality and Severity of COVID-19 -Systematic Review, Metaanalysis, and Meta-regression

Body mass index and outcome in patients with COVID-19: A dose-response meta-analysis

The use of renin angiotensin system inhibitor on mortality in patients with coronavirus disease 2019 (COVID-19): A systematic review and meta-analysis

Dipeptidyl peptidase-4 (DPP-4) inhibitor and mortality in coronavirus disease

A systematic review, meta-analysis, and meta-regression

Potential harmful effects of discontinuing ACE-inhibitors and ARBs in COVID-19 patients

Telmisartan as tentative angiotensin receptor blocker therapeutic for COVID-19

Renin-Angiotensin-Aldosterone System Inhibitors in Patients with Covid-19

Renin-Angiotensin-Aldosterone System Inhibitors in Patients with Covid-19

Prognostic performance of troponin in COVID-19: A diagnostic meta-analysis and meta-regression

Left and right ventricular longitudinal strains are associated with poor outcome in COVID-19: a systematic review and meta-analysis

World Health Organization, Mission China Joint

We would like to thank the following groups for their support: