Discussion
The main findings of this study are that therapeutic anticoagulation used prior to SARS-CoV-2 infection lowers the risk of pulmonary embolism but does not have an effect on other COVID-19 related outcomes in hospitalized COVID-19 patients, including in-hospital 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.21 It has been hypothesized that therapeutic anticoagulation used prior to infection could improve the prognosis of COVID-19 by hampering coagulation activation. Indeed, previous studies showed that the use of therapeutic anticoagulation at hospital admission resulted in a lower incidence of VTE compared to thromboprophylaxis alone.23,24 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.26,27,31 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.27However, 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 that investigated the effects of therapeutic anticoagulation subgroups, i.e. vitamin K antagonists (VKAs) and direct oral anticoagulants (DOACs), in hospitalized COVID-19 patients. There are different hypotheses why VKAs could have unfavorable effects, and DOACs on the other hand could be of benefit in COVID-19. Dofferhoff 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.28 VKA’s are evident causes of reduced vitamin K status, but the relationship between VKA versus 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 DAG and the subsequent high and relevant number of included covariates in the propensity score matching, make this a valid approach. Other limitations are that there was no routine screening for pulmonary embolism, which may have resulted in underdiagnosis of this outcome especially in patients already treated with therapeutic anticoagulation.
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 analysis between subgroups also showed no differences in clinical outcomes between VKA or DOAC treated patients.