key: cord-1036979-n1oovybv authors: Spiegelenberg, Janneke P.; van Gelder, Marleen M. H. J.; Maas, Martje L.; Hovens, Marcel M. C.; Esselink, Anne; Dofferhoff, Anton S. M.; Janssen, Rob; van de Maat, Josephine; Janssen, Nico; Blaauw, Marc; Hassing, Robert‐Jan; van Apeldoorn, Marjan; Kerckhoffs, Angèle; Veerman, Karin; Hoogerwerf, Jacobien; Kramers, Cornelis; Leentjens, Jenneke title: Prior use of therapeutic anticoagulation does not protect against COVID‐19 related clinical outcomes in hospitalized patients: A propensity score‐matched cohort study date: 2021-05-07 journal: Br J Clin Pharmacol DOI: 10.1111/bcp.14877 sha: 51a3e516843f1f410d75bd5c29e364ccbc1b197f doc_id: 1036979 cord_uid: n1oovybv The hypercoagulable state observed in COVID‐19 could be responsible for morbidity and mortality. In this retrospective study we investigated whether therapeutic anticoagulation prior to infection has a beneficial effect in hospitalized COVID‐19 patients. This study included 1154 COVID‐19 patients admitted to 6 hospitals in the Netherlands between March and May 2020. We applied 1:3 propensity score matching to evaluate the association between prior therapeutic anticoagulation use and clinical outcome, with in hospital mortality as primary endpoint. In total, 190 (16%) patients used therapeutic anticoagulation prior to admission. In the propensity score matched analyses, we observed no associations between prior use of therapeutic anticoagulation and overall mortality (risk ratio 1.02 [95% confidence interval; 0.80–1.30]) or length of hospital stay (7.0 [4–12] vs. 7.0 [4–12] days, P = .69), although we observed a lower risk of pulmonary embolism (0.19 [0.05–0.80]). This study shows that prior use of therapeutic anticoagulation is not associated with improved clinical outcome in hospitalized COVID‐19 patients. the Dutch Radiology Society) were included. 13 Patients were excluded when COVID-19 was not PCR or radiographically confirmed, or when patients had insufficient clinical documentation because they were transferred to or from another hospital due to capacity constraints. The index date was the day of hospital admission. Patients were followed until hospital discharge or death. Data on the occurrence of thrombotic events, length of hospital stay, intensive care unit (ICU) admission, type of oxygen ventilation, and mortality were obtained from the patients' records (EPIC, EPIC Systems Corporation, Verona, WI, USA; HiX, ChipSoft, Amsterdam, The Netherlands; What is already known about this subject • Patients with COVID-19 have a hypercoagulable state with increased risk of thrombotic events. • Several studies investigated the association between therapeutic anticoagulation prior to hospitalization and mortality with ambivalent results, probably due to methodological limitations. • A rigorous statistical analysis with thorough adjustment for confounding to properly investigate the treatment effect of prior therapeutic anticoagulation on different clinically relevant outcomes in a large cohort of hospitalized COVID-19 patients. • This study provides convincing evidence that therapeutic anticoagulation used prior to infection is associated with a decreased risk of pulmonary embolism, but not with mortality and other disease severity parameters. The primary outcome was all-cause in hospital mortality. Secondary outcomes included admission to the ICU, need for invasive mechanical ventilation, critical respiratory status (defined as a composite endpoint of the need for invasive mechanical ventilation and/or need of venturi mask and/or nonrebreathing mask), imaging-proved pulmonary embolism (PE) and length of hospital stay. We identified potential confounders a priori by performing a literature review. Directed acyclic graphs were subsequently drawn to visualize causal assumptions to identify confounders ( Figure S1 in the online supplement). Age, sex, body mass index (BMI), medical history of chronic pulmonary disease, diabetes mellitus, active malignancy, hypertension, obstructive coronary heart disease, myocardial infarction, nonischaemic cardiomyopathy, heart failure, previous heart surgery, electronic heart device, cerebrovascular accidents, and/or peripheral artery disease, use of immunosuppressive medication, and no-ICU policy were identified as confounders that were available in our database. Descriptive statistics were used to compare the patients with and without prior therapeutic anticoagulation and to estimate the preva- Baseline patient characteristics are shown in Table 2 . Patients who used therapeutic anticoagulation prior to hospitalization were older, more likely to be male, and more likely to have cardiovascular comorbidities or a no-ICU policy compared to patients who did not use prior therapeutic anticoagulation. Subsequent propensity score matching retained 164 (86%) patients who used prior therapeutic anticoagulation and 410 unexposed patients. The main covariates were balanced between the groups after the propensity score matching ( Table 2 ). The results from the total cohort and the propensity scorematched analysis on the associations between therapeutic anticoagulation use and the dichotomous outcomes are presented in Figure S2 ). In addition, therapeutic anticoagulation use was not associated with length of hospital stay (Table 3B) . Similar to the primary analysis, no associations were found between VKA or DOAC use prior to admission and COVID-19 related clinical outcome parameters after propensity score matching (see Tables S1-S6 ). The main findings of this study are that therapeutic anticoagulation used prior to SARS-CoV-2 infection is associated with a lower risk for PE but is not associated with a decreased risk of other COVID-19 related outcomes in hospitalized COVID-19 patients, including inhospital mortality. In addition, we did not observe differences in outcomes between DOAC or VKA-treated subgroups. The acute inflammatory phenomenon in COVID-19 amplifies hypercoagulability and increases the risk of thrombosis even under prophylaxis of LMWH. 3, 4 It has been hypothesized that therapeutic anticoagulation used prior to infection could improve the prognosis of COVID-19 by hampering coagulation activation. Indeed, a previous study showed that the use of therapeutic anticoagulation at hospital admission resulted in a much lower incidence of VTE compared to thromboprophylaxis alone. 15 Other studies, however, showed ambivalent results on COVID-19 severity and mortality due to comparison of dissimilar cohorts and lack of proper statistical adjustments for imbalances in baseline characteristics including comorbidities (Table 1) . Tremblay et al. also used a propensity score-matched comparison and found no statistically significant difference in mortality, time to mechanical ventilation, or hospitalization when comparing patients with and without therapeutic oral anticoagulation prior to SARS-CoV-2 infection. 23 However, they included both ambulatory and hospitalized patients, and only adjusted for age, sex, race, Charlson comorbidity index and obesity in their propensity-score analysis while we illustrated that adjustment for more potential confounders is relevant. Moreover, they did not include thrombotic complications as an outcome parameter whereas our study showed a benefit on PE incidence, but not on other clinical endpoints. This is also the first study to investigate the effects of therapeutic anticoagulation subgroups, ie vitamin K antagonists (VKAs) and direct oral anticoagulants (DOACs), in hospitalized COVID-19 patients. There are different hypotheses as to why VKA could have unfavourable effects, and DOACs, by contrast, could be of benefit in COVID-19. Dofferhof et al. detected reduced extrahepatic vitamin K status in patients with COVID-19 and showed that low vitamin K status was related to poor prognosis in these patients. 24 VKAs are evident causes of reduced vitamin K status, but the relationship between VKA vs. other therapeutic anticoagulation on the prognosis of COVID-19 patients has never been studied before. Our study has several limitations that need to be addressed. Most importantly, its observational and retrospective nature limit causal inference, although the propensity score matching increases the credibility of our observations. Noteworthy, propensity score matching is often criticized because of its dependence on the included covariates. Confounders not included in the propensity score could lead to significant bias. However, in our study, the prior visualization of relevant covariates in the directed acyclic graph and the subsequent high and relevant number of included covariates in the propensity score matching, make this a valid approach. It is possible that a history of atrial fibrillation (AF) is a potential confounder since AF is the most important indication for prescribing therapeutic oral anticoagulation. T A B L E 3 A Risk estimates for COVID-19 outcome associated with therapeutic anticoagulation vs. no therapeutic anticoagulation in the total cohort and the propensity score (PS)-matched cohort The propensity scores included the following characteristics: age, sex, body mass index, active malignancy, chronic pulmonary disease, diabetes mellitus, hypertension, obstructive coronary artery disease, myocardial infarction, heart failure, nonischaemic cardiomyopathy, previous heart surgery, electronic heart device, cerebrovascular accident, peripheral artery disease, immunosuppressive medication, no ICU policy. However, patients with AF are at higher risk for poor prognosis as they are older and more likely to have other cardiovascular risk factors. 25 In our study we have thoroughly corrected for these confounders and thus reduced the risk for residual confounding. Although our database represents 1 of the largest matched cohorts of anticoagulation users in the literature (Table 1) , the relatively small sample size could potentially lead to a type II error. However, in our study, we found no suggestion of an effect on mortality with a risk ratio close to 1. Furthermore, the increased risk observed for PE is in line with previous studies. Nevertheless, our study population might have been too small to detect small differences in clinical outcomes between the exposure groups. Other limitations are that there was no routine screening for PE, which may have resulted in underdiagnosis of this outcome. Strengths of our study include the rigorous statistical analysis with thorough adjustment for confounding to properly investigate the treatment effect of prior therapeutic anticoagulation on different clinically relevant outcomes in a large cohort of hospitalized COVID-19 patients. Furthermore, we are the first to investigate the effect of therapeutic anticoagulation subgroups, i.e. vitamin K antagonists and DOACs. In summary, although prior therapeutic anticoagulation use is associated with reduced PE occurrence, it is not associated with better outcome parameters in hospitalized COVID-19 patients in terms of all-cause mortality, ICU admittance, need for mechanical ventilation and length of hospital stay. Secondary analyses between subgroups also showed no differences in clinical outcomes between VKA-and DOAC-treated patients. The study was internally funded by the participating departments. 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