key: cord-331030-3icwei3e authors: Saleknezhad, N.; Khosravi, B.; Anushiravani, A.; Eslahi, M.; Radmard, A. R.; Sirusbakht, A.; Pourabbas, S. M.; Abdollahi, M.; Kasaeian, A.; Sorouri, M.; Sima, A. R. title: COVID-19 and heart medications: What's the connection? date: 2020-08-26 journal: nan DOI: 10.1101/2020.08.24.20174367 sha: doc_id: 331030 cord_uid: 3icwei3e Aim: To determine association between clinical outcome of COVID-19 and prior usage of cardiovascular and metabolic drugs, including, Aspirin, ACEIs, ARBs, Clopidogrel, metformin, and Statins. Methods: Statistical examination of the demographic, clinical, laboratory and imaging features of 353 patients with SARS-CoV-2 disease admitted from February to April 2020. Result: Minor discrepancies were observed in the clinical presentations, radiologic involvement and laboratory results across groups of patients under treatment with specific drugs. Aspirin-users had better clinical outcome with lower need of ventilation support, whereas, metformin-users had increased chance of intubation and of mortality. Conclusion: Although not being conclusive, our findings suggest the possibility of the effect of previous drug usages on the various presentations and clinical course of COVID-19 infection. Due to the notable death toll of SARS-CoV-2, risk factors that predispose patients to mortality and more severe forms of the disease are under investigation. It has been well observed that individuals burdened with hypertension, diabetes or ischemic heart disease are at higher risk of developing severe manifestations of SARS-CoV-2, or of mortality due to the infection [3] [4] [5] . Although it is reasonable to maintain drugs that high-risk patients take due to their chronic medical conditions, there are certain considerations about their safety during infection. For instance, statins and angiotensin receptor blockers (ARBs) may actually worsen the outcome of COVID-19 patients, who, due to their underlying diseases, have poorer prognosis [6] . On the other hand, certain drugs that are used in similar conditions are thought to have a protective effect against the novel coronavirus. For example, metformin has been suggested to be added as an adjuvant therapy to diabetic, old, and even obese patients' treatment for the sake of better outcome in COVID-19 setting [7] . Therefore, we conducted a study based on our registry of COVID-19 patients to evaluate the effect of those drugs, which are widely used in chronic diseases such as hypertension, diabetes mellitus and ischemic heart disease, on the clinical outcome and mortality rate of the patients inflicted with the novel coronavirus. In a retrospective cross-sectional study at Shariati Hospital in Tehran, Iran, we included all patients admitted with the diagnosis of COVID-19 based on the criteria published by WHO on January 12th, 2020 [8] , from February 25th, 2020, to April 21st, 2020. Patients with respiratory symptoms and one of the following were admitted: 1) loss of consciousness, 2) Respiratory rate more than 24, 3) pulse rate more than 90, 4) Systolic blood pressure less than 90 mmHg, 5) abnormal respiratory sounds, or 6) O2 saturation less than 93%. Furthermore, high-risk patients with respiratory symptoms or fever underwent computed tomography scans of the lung (CT scans). In case of a suggestive lung CT scan of COVID-19 infection, the patients were transferred to the COVID ward. Patients with a negative lung CT scan underwent further workup. Patients who were already admitted to the hospital were transferred to the COVID ward if they experienced COVID-19 infection during hospitalization. We used the census sampling method, and after exclusion of cases with missed data, four hundred and four patients were selected. Two radiologists reviewed all the images and patients with not suggestive lung CT scan and negative SARS-CoV2 RT-PCR were excluded. We extracted clinical data, laboratory findings, and lung CT scans from the remaining three hundred fifty-four patients' medical records. The study was approved by the ethics committee of Tehran University of Medical Sciences. The ethics committee waived the requirement for informed patient consent for this retrospective study subject to the anonymity of patients. The variables recorded are given in Table 1 . The q-SOFA score was calculated for all patients, and a patient with q-SOFA Score ≥ 2 was categorized as high risk [9] . Outcomes included days of hospital stay, intubation, ICU admission, and in-hospital death. Categorical variables were described in frequencies and percentages. Quantitative variables were described with the mean (Standard deviation (SD)) or median and Our study was based on clinical, laboratory, and imaging data of 353 patients admitted with Six sub-groups of patients were defined with respect to their drug histories. Each sub-group included patients who were under treatment with one of the following drugs or drug classes: aspirin, angiotensin II receptor blockers (ARBs), angiotensin-converting enzyme inhibitors (ACEIs), statins, clopidogrel, and metformin. The comprehensive information of these subgroups is presented in detail in Table 2 . We explored data in our registry to find notable correlations of drug use with different aspects of COVID-19. With regards to the clinical manifestations of the disease it is noteworthy that, as our data suggests, previous use of aspirin is correlated with decreased level of consciousness upon admission (p < 0.05), and on the other hand, patients who were under treatment with ACEIs are more probable to be symptom-free (p < 0.05). Radiologic involvement of the lungs showed a quite specific pattern with respect to the drug used (Table 3) . Ground-glass opacities were more common in those receiving ARBs (p < 0.05) and ACEI (p < 0.05), consolidations with statins (p < 0.05), and emphysema and its severity with clopidogrel (p < 0.05) and metformin (p = 0.005) respectively. Chest lymphadenopathies were more probable in the setting of using aspirin (p < 0.005), Clopidogrel (p < 0.005), and ACEI (p < 0.05). Specific localization pattern of lung involvement was concomitant with the usage of metformin and ACEI. Metformin usage is correlated with the involvement of left lung lower lobe (p < 0.05), whereas ACEI usage is associated with right lung involvements, revealed by its correlation with the upper lobe involvement (p < 0.05) and lower lobe involvement score (p < 0.05). All rights reserved. No reuse allowed without permission. (which was not certified by peer review) 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 August 26, 2020. . https://doi.org/10.1101/2020.08.24.20174367 doi: medRxiv preprint Correlations between the pattern of laboratory results and drug usage were detected in our study. Notable findings were the association of aspirin with elevated levels of d-dimer (p < 0.05), ARBs with the elevated levels of cardiac troponin I (CTNI) (p < 0.05), lactate dehydrogenase (LDH) (p < 0.05) and lactate (p < 0.05), ACEI with the elevated level of LDH (p < 0.05), metformin with high levels of CTNI (p < 0.005) and amylase (p < 0.05), and Clopidogrel with high levels of amylase (p = 0.005). After conducting the analysis, the clinical data of about 100 other patients were added to our database. We re-evaluated our data and re-analysed them. The results were totally consistent with what is presented here and no significant change was found to exclude any of the previous results. However, it is noteworthy that these new analyses suggested that there is a correlation between the usage of statins and aspirin with having a normal white blood cell and lymphocyte count upon admission. Results are not shown. The outcome of patients, including mortality, ventilation requirement and ICU admission showed no correlation with receiving ARBs, ACEIs, statins, or Clopidogrel. However, aspirinusers were more likely to need no ventilation support (p = 0.05), whereas, metformin-usage were more associated with the chance of intubation in the course of hospitalization (p < 0.05) and also of the mortality (p < 0.05). Details are shown in Table 4 . There are many studies showing positive and negative effects of drugs like statins, ACEI, ARBS, metformin. and anti-platelets. We have shown that COVID-19 patients receiving these drugs prior to admission were neither better nor worse regarding their outcomes. In theory, there are at least 4 reasons statins might be useful for COVID-19 patients. First, cardiovascular disease is the All rights reserved. No reuse allowed without permission. (which was not certified by peer review) 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 August 26, 2020. . most significant risk factor (10-15% case fatality rate) [10] for severe COVID-19, therefore, these patients would likely already benefit from their use. Second, a number of cardiovascular complications such as thrombosis and myocarditis have been reported in association with this disease and statins might be beneficial in preventing them. Third, statins might have a role in protecting innate immune responses to viral respiratory infections (including to SARS-CoV-2) via inhibiting the MYD88 pathway. Usually, statins do not change the level of MYD88, they only keep its level in a normal range during hypoxia and stress [11] . And last but not least, epidemiological studies have shown that statins may prevent severe viral pneumonias [12] . A study conducted in Belgium reported that nursing home residents taking a statin were three times more likely to be free of symptoms of COVID-19 during their infection than those who did not. Length of admission and death was also slightly less in those receiving statins, even though the difference was not significant statistically [13] . We have shown that statins did not protect COVID-19 patients from having worse outcomes, although those receiving statins probably had baseline cardiovascular diseases and/or diabetes which could have worsened their prognosis per se. Statins have been widely prescribed with a good safety index. Data on anti-platelets such as aspirin and clopidogrel and their effects on COVID-19 are scarce. We didn't find any significant difference in outcomes in our patients. However, thrombosis remains a major complication of this disease and trails on anticoagulants are showing promise. Zhang P. et al. conducted a retrospective, multicentre study of 1,128 COVID-19 patients with hypertension in which 188 were taking ACEI/ARBs. They concluded that these patients had a lower all-cause mortality compared to those not receiving ACEI/ARBs [14] . All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. There is an urgent need for available and safe drugs to treat COVID-19, however, we must take caution in their prescription since they may exacerbate this disease. We recommend guidelinedirected administration and continuation of these drugs, and we emphasize that our primary role as physicians is to do no harm. All rights reserved. No reuse allowed without permission. (which was not certified by peer review) 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 August 26, 2020. (which was not certified by peer review) 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 August 26, 2020. • Patients who were under treatment with ACEIs are more probable to be symptomfree (p < 0.05). All rights reserved. No reuse allowed without permission. (which was not certified by peer review) 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 August 26, 2020. . https://doi.org/10.1101/2020.08.24.20174367 doi: medRxiv preprint AA and MS designed the study; AK performed statistical analysis; AR analyzed the radiological documents; AA and NS wrote and revised the manuscript. BK, AA, AS, ME, AS, SMP, MS, MA all collaborated in gathering data and confirmed the final version of manuscript. We thank all our patients who participated in the study. The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript. The study was approved by the ethics committee of Tehran University of Medical Sciences. The ethics committee waived the requirement for informed patient consent for this retrospective study subject to the anonymity of patients. All rights reserved. No reuse allowed without permission. (which was not certified by peer review) 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 August 26, 2020. . https://doi.org/10.1101/2020.08.24.20174367 doi: medRxiv preprint (which was not certified by peer review) 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 August 26, 2020. . 29) 6 (7.14) 2 (10.53) 3 (6.12) 4 (6.45) AIDS 0 (0.00) 0 (0.00) 0 (0.00) 0 (0.00) 0 (0.00) 0 (0.00) Immunodeficiency 0 (0.00) 0 (0.00) 0 (0.00) 0 (0.00) 0 (0.00) 0 (0.00) ESRD 3 (3.57) 0 (0.00) 2 (2.38) 0 (0.00) 0 (0.00) 0 (0.00) CVA 5 (5.95) 0 (0.00) 4 (4.76) 1 (5.26) 0 (0.00) 3 (4.84) CKD 6 (7.14) 0 (0.00) 6 (7.14) 1 (5 (which was not certified by peer review) 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 August 26, 2020. . (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. bilirubin; U/A: Urine analysis. All rights reserved. No reuse allowed without permission. (which was not certified by peer review) 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 August 26, 2020. . https://doi.org/10.1101/2020.08.24.20174367 doi: medRxiv preprint (which was not certified by peer review) 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 August 26, 2020. . (which was not certified by peer review) 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 August 26, 2020. . https://doi.org/10.1101/2020.08.24.20174367 doi: medRxiv preprint The outbreak of COVID-19: An overview Coronavirus Diseases (COVID-19) Current Status and Future Perspectives: A Narrative Review Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study Risk factors for severity and mortality in adult COVID-19 • Clinical and laboratory indicators of severe SARS-CoV-2 infection Predictors of mortality for patients with COVID-19 pneumonia caused by SARS-CoV-2: a prospective cohort study Are certain drugs associated with enhanced mortality in COVID-19? QJM Metformin and COVID-19: A novel deal of an Old Drug All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity Assessment of Clinical Criteria for Sepsis: For the Third International Consensus Definitions for Sepsis and Septic Shock Characteristics of and Important Lessons From the Coronavirus Disease 2019 (COVID-19) Outbreak in China: Summary of a Report of 72 314 Cases From the Chinese Center for Disease Control and Prevention Decrease the Fatality Rate of Middle East Respiratory Syndrome Infection • By keeping MYD88 in normal ranges, statins reduced the mortality of SARS-CoV Defining the Epidemiology of Covid-19 -Studies Needed The effects of ARBs, ACEIs and statins on clinical outcomes of COVID-19 infection among nursing home residents • The impact of ARBs, ACEIs and statins on the severity of SARS-CoV-2 infection Association of Inpatient Use of Angiotensin Converting Enzyme Inhibitors and Angiotensin II Receptor Blockers with Mortality Among Patients With Hypertension Hospitalized With COVID-19 No reuse allowed without permission. (which was not certified by peer review) 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 doi: medRxiv preprint • The effect of ACEI/ARBs treatment on the mortality of SARS-CoV-2 infection 15. Nahum LH. The renin angiotensin-aldosterone system (RAAS) in normal man Effect of Angiotensin-Converting Enzyme Inhibition and Angiotensin II Receptor Blockers on Cardiac Angiotensin-Converting Enzyme 2