Chronic anti-coagulation therapy reduced mortality in patients with high cardiovascular risk early in COVID-19 pandemic

Early in the Coronavirus 19 (COVID-19) pandemic, this viral illness was a pervasive public health threat. In October 2021, the cumulative number of global cases had exceeded 240 million with nearly 5 million deaths. In addition to the interactions of the SARS-CoV-2 virus with human cells, severe COVID-19 disease was associated with a provoked hypercoagulable state that resulted in microvascular angiopathy and thromboembolic complications [1, 2]. Likewise, marked elevations in coagulation markers such as D-dimer were associated with severe COVID-19 disease states and increased mortality [3].

Cardiovascular risk factors such as hypertension, diabetes and coronary artery disease were highly prevalent among COVID-19 patients and carried a higher risk of morbid events as well as in-hospital mortality [4, 5]. Although acute respiratory distress syndrome was one of the hallmarks of the COVID-19 viral infection, multi-organ system complications (MOSC) was observed in patients with severe disease. A proportion of these patients presented with cardiovascular events, including myocardial infarction, arrhythmias, myocarditis and acute heart failure [6]. Early in the pandemic, cardiac injury was a common occurrence and conferred a higher risk of in-hospital mortality [7]. In addition to cardiac ischemia noted in autopsy studies, pathological micro-thrombosis was a common observation among patients with severe COVID-19 illness, suggesting a pro-thrombotic state may be contributing to these cardiovascular complications and overall poor recovery outcomes [8, 9].

Since the early phase of the pandemic there has been an abundance of evidence to suggest that thrombosis alongside inflammation contributed to the poor outcomes observed with COVID-19 illness. The impact of anticoagulation in improving outcomes in already infected COVID-19 patients was therefore previously explored. In one multiplatform randomized controlled clinical trial, administration of therapeutic anticoagulation appeared to reduce thrombotic complications but not improve cardiopulmonary outcomes in already hospitalized critically-ill patients with COVID-19 [10‐12]. It is argued that hypercoagulable states associated with COVID-19 infection are often present during the early phase of the disease process, and this could in part account relatively modest benefits observed with therapeutic anticoagulation.

However, the data regarding the role of chronic anticoagulation in outcomes of COVID-19 has since remained conflicting. Parker et al. reported reduced rates of mechanical ventilation (8.5% vs 17.4%) in chronically anticoagulated patients with COVID-19 but a higher (40.2% vs 30%) mortality rate [13]. On the other hand, Tremblay et al. demonstrated no mortality benefit in a propensity matched cohort of 241 patients receiving anticoagulation prior to COVID-19 infection [14]. As such, we sought to evaluate the incidence of multisystem organ failure in individuals with high cardiovascular risks during the early phase of the COVID-19 pandemic. We hypothesize that patient who contracted COVID-19 during this time period, while already receiving therapeutic anticoagulation would have potentially benefited from reduced COVID-19-related complications.

Our study investigated whether continuous therapeutic AC decreased the risk of MOSC, ICU admission and in-hospital mortality in patients infected with COVID-19 during the early phase of the pandemic in the US. In the study cohort, the rate of in-hospital mortality was lower in the AC group compared to the control group, despite a higher incidence of GI bleeding. However, the rate of MOSC and ICU admission were similar between the two groups.

Several studies reported an increased risk of hypercoagulable state in COVID-19 positive patients [16‐22]. In a meta-analysis of 91 studies evaluating 35,017 COVID-19 patients, Mansory et al. found the overall incidence of VTE events in all hospitalized and ICU patients was 12.8 and 24.1% respectively [22]. Reports showed hyper-thrombotic laboratory changes (e.g., d-dimer) in COVID-19 patients, and these changes are observed to be negative independent predictors of end-organ-damage and death [1, 23‐25]. In addition, critically-ill COVID-19 patients manifest with a wide range of clinical symptoms that include interstitial pulmonary edema, ST elevation myocardial infarction, brainstem infarcts, gastro-intestinal mucosal bleeding, acute kidney failure, liver dysfunction, and skin petechial rashes [7, 26‐30]. The mechanism by which COVID-19 viremia and cytokines induce thrombosis and inflammation is still not fully understood. However, some have postulated that hypercoagulability and MSOC in patients with COVID-19 results from a sequence of events that first starts with endothelial cell dysfunction and excess thrombin generation and fibrinolysis shutdown [31, 32]. Next hypoxia associated with severe COVID-19 can lead to further thrombosis via activation of hypoxia-inducible transcription factor-dependent signaling pathway [33]. Lastly, immobilization during critically-ill states, can lead to blood flow stasis and higher incidence of in situ thrombosis.

Limited studies to date have assessed outcomes of therapeutic AC in patients with COVID-19, and the few that have provide contradictory findings. Early observational studies and a meta-analysis reported no difference in mortality in patients with COVID-19 who received AC therapy relative to those who did not receive AC, but these studies suffered from small sample sizes, heterogenous patient populations, and unclear inclusion and exclusion criteria [14, 34, 35]. In a recent meta-analysis of 11 studies investigating the impact of AC on mortality in a cohort of 20,748 hospitalized COVID-19 patients, AC therapy was found to be associated with a lower rate of in-hospital mortality in patients with COVID-19 (RR = 0.70, 95% CI 0.52 – 0.93, p = 0.01) [36]. A large observational study including 4,389 patients from New York, demonstrated that therapeutic AC was associated with a 47% reduction in the risk of in-hospital mortality (aHR = 0.53; 95% CI: 0.45—0.62; p < 0.001) and 31% reduction in the intubation rate (aHR = 0.69; 95% CI: 0.51—0.94; p = 0.02) compared with no AC [37]. In addition, Paranjpe et al. showed longer duration of AC treatment reduced the risk of in-hospital mortality (aHR of 0.86 per day; 95% CI: 0.82 – 0.89; p < 0.001) [38]. On the other hand, AC was not shown to reduce the incidence or severity of MSOC such as acute kidney injury [13].

In the present study, patients who were on a continuous prescription of therapeutically-dosed AC therapy for at least 90 days prior to their initial COVID-19 positive test, demonstrated reduced risk of in-hospital mortality when compared to control patients (aOR 0.67, 95% CI: 0.46 – 0.99, p = 0.04). Interestingly, our study observed that COVID-19 positive patients who received AC and had higher cardiovascular co-morbidities, actually had an equivalent incidence of MOSC. However, the potential benefits of AC in this higher risk population needs to be weighed against the risk of bleeding. Our study observed that AC therapy was associated with a higher incidence of GI bleeding, which is consistent with prior literature [24]. As treatment protocols continue to evolve for patients afflicted with COVID-19, personalized assessments of the risks and benefits of AC therapy should be tailored to meet the most favorable anticipated outcomes.

The findings of this study should be interpreted with certain limitations. First, the associations explored were retrospective in nature and as such can include inherent biases associated with the study design, and method of data extraction and analysis. Second, there are factors that were not included in our propensity score matching that could also potentially impact mortality and morbidity. One such risk factor is smoking status, which was not discernable in the CDW. Third, within our study cohort we were unable to determine the primary cause of death for patients with COVID-19 during the early phase of the pandemic, which we found was often not clearly defined in the patient’s medical record. Lastly, our study does not include information about inpatient AC regimens, and whether patients who contracted COVID19 were maintained on fully therapeutic AC during their hospital and/or ICU courses.

In summary, our study demonstrates that among U.S. veterans afflicted by COVID-19, chronic AC therapy reduced the risk of in-hospital death. However, AC therapy did not ameliorate the risk of MOSC. These findings suggest that MOSC in patients with COVID-19 are unlikely to be mainly determined by the patient’s pro-thrombotic state. Randomized control trials are needed to further evaluate the effectiveness of AC in preventing COVID-19-related MOSC, particularly in later and ongoing stages of this evolving viral illness.