Our study showed that among hospitalized COVID-19 patients with AF anticoagulated with edoxaban or LMWH, approximately 13% of patients required admission to the intensive care unit, 19% died, and 10% had a bleeding complication. Although peak D-dimer and average length of stay were higher with LMWH than with edoxaban, no other significant differences in outcomes were observed between both anticoagulant regimens. These data suggest that although edoxaban and LMWH can be safely used in this context, once-daily edoxaban may provide additional benefits.
AF is very common in hospitalized COVID-19 patients. In a survey performed in 76 countries, 21% of respondents reported cases of AF in this population.17 While COVID-19 may predispose patients to arterial and venous thrombosis, the optimal preventive strategy warrants further investigation and should take patients with AF into consideration.18
Our study included 232 patients with non-valvular AF (mean age was 80 years, 89% had hypertension, and 36% had heart failure). Our patients were older and had more comorbidities than patients hospitalized in China, although their characteristics were closer to those of patients hospitalized in countries similar to ours, such as Italy.8 19 20 In the ENGAGE AF-TIMI 48 trial, which compared edoxaban with warfarin among patients with non-valvular AF, mean age was 72 years, nearly 94% of patients had hypertension, and 58% had heart failure.21 In ETNA-AF-Europe, a multinational, multicenter, post-authorization, observational study of 13,980 patients with AF taking edoxaban, mean age was 74 years, 77% had hypertension, and 6% had heart failure.22 These data point to marked variability in the clinical profile not only among hospitalized COVID-19 patients, but also compared with other AF populations taking edoxaban. Notwithstanding, patients with AF anticoagulated with edoxaban are generally older and have many comorbid conditions.
In our study, 13% of patients required admission to the intensive care unit, 19% of patients died, and 10% had a bleeding complication. These figures are much higher than those reported in the 60 mg edoxaban arm of the ENGAGE AF-TIMI 48 trial (death, 4%/year; any bleeding, 2.75%/year)21 but lower than those reported in the first publications of hospitalized COVID-19 patients,19 20 even though the patients in our study had a worse clinical profile. A review of various studies showed that in patients with COVID-19 infection who had not received anticoagulation therapy or were receiving prophylactic doses, venous thromboembolism and stroke occurred in approximately 20% and 3%, respectively.23 Other authors reported that despite adequate thromboprophylaxis, symptomatic venous thromboembolism occurred in 4.4% of patients and ischemic stroke in 2.5%.5 In our study, these numbers were 1.7% and 0.9%, respectively, possibly because patients in our study received better treatment, particularly with full-dose anticoagulation. This observation is in line with the results of a recent study showing that among elderly patients with COVID-19, those on long-term oral anticoagulant treatment for AF may have a lower risk of all-cause mortality than those not receiving anticoagulation therapy.24
During the first wave of the SARS-CoV-2 pandemic, some authors have recommended switching from oral anticoagulation to LMWH in hospitalized COVID-19 patients.11 12 15 25 26 In the case of DOACs, this recommendation is based mainly on the risk of drug-drug interactions, leading to under/over treatment caused by significant pharmacological interferences.15 26 Similar data were reported in a study that analyzed 12 patients treated with DOACs and antiviral drugs, in which C-trough levels were approximately 6 times higher during hospitalization than before hospitalization.14 Furthermore, it has been reported that heparin can decrease inflammatory biomarker levels, thus reducing the inflammatory response to COVID-19.27 In addition, some data suggest that heparin may reduce mortality among hospitalized COVID-19 patients.5 27 By contrast, some studies have reported that oral factor Xa inhibitors have a role in factor Xa-dependent enhancement of fibrinolysis.28 In our study, the peak D-dimer was significantly lower in the edoxaban group, suggesting that edoxaban have a role in fibrinolysis and this could have a positive clinical impact. In this sense, our data showed that the percentage of patients admitted to the intensive care unit, mortality rates, arterial and venous thromboembolic complications, and bleeds did not significantly differ between patients treated with edoxaban and those treated with LMWH. These findings were recorded even though a relevant pharmacological interaction has been reported between edoxaban and some antivirals (i.e., ritonavir/lopinavir)13 and the vast majority of patients treated with edoxaban were also treated with these antiviral drugs. Consequently, we must ask whether this drug-drug interaction is clinically relevant. Of note, length of hospital stay was significantly lower with edoxaban than with LMWH, likely due to a simplification of treatment. This is important, as a lower length of stay may lead to less excessive caseloads and costs.29 Furthermore, taking an oral medication (edoxaban) may reduce exposure of health care practitioners when compared to giving LMWH.30
Remarkably, the therapeutic approach of COVID-19 pneumonia has substantially changed in the last months. In fact, some drugs, such as hydroxychloroquine, azithromycin or lopinavir/ritonavir are no longer being used, but other drugs, including dexamethasone, tocilizumab, baricitinib, remdesivir, or even new antivirals, such as molnupiravir or nirmatrelvir plus ritonavir (Paxlovid), are being prescribed at present in these patients. However, as the risk of drug-drug interactions of these drugs with edoxaban seems low, the main conclusions of our study remain in effect, despite changes in the current therapeutic approach of COVID-19 pneumonia.13 31 32 33
As a result, although edoxaban and LMWH can be safely used in hospitalized COVID-19 patients with AF, edoxaban may provide an additional benefit. In line with our study, observational studies have shown that in patients with COVID-19 interstitial pneumonia, chronic DOAC intake may be associated with a decrease in mortality risk.34 35
We also compared clinical profile and outcomes according to the dose of edoxaban. Remarkably, CHA2DS2-VASc and HAS-BLED scores were higher among patients taking edoxaban 30 mg than among those taking 60 mg. In the ETNA-AF-Europe registry, patients taking edoxaban 30 mg were older and had a higher thromboembolic and bleeding risk.22 Mortality rates were similar among patients taking edoxaban 60 mg and those taking 30 mg. However, there were more total bleeds among patients taking edoxaban 60 mg, with no significant differences in the severity of the bleeds. Nevertheless, in order to ensure adequate protection with edoxaban, the dose of edoxaban should be adjusted according to the summary of product characteristics.13
Clinical profile and outcomes were also compared according to the dose of LMWH. Nearly half of the patients were taking the therapeutic dose of LMWH, although, remarkably, differences in clinical profile were detected according to the dose of LMWH, namely, patients taking the therapeutic dose were younger, and mortality rates were higher in patients taking the prophylactic dose. Considering that anticoagulation has been associated with reduced mortality in hospitalized COVID-19 patients owing to the high risk of thrombosis and that some authors recommend higher therapeutic doses of LMWH than prophylactic doses, in patients with AF, only full anticoagulation doses of LMWH should be recommended unless contraindicated.1 5
This study is subject to some limitations. First, it was not a randomized clinical trial, but an observational study. While randomized clinical trials are the best format for providing information about differences between 2 therapies, patients were consecutively included in our study, thus reducing this potential bias. In fact, not many significant differences were observed in the clinical profile of patients taking edoxaban or LMWH. Total mean duration of follow-up reached 32 days. Therefore, it is uncertain whether the results observed in our study would remain valid over time. Studies with longer follow-ups are warranted. Finally, our results should only be applied to patients whose clinical profile and therapeutic management are similar to those presented here.
In conclusion, approximately 1 in every 5 hospitalized COVID-19 patients with AF anticoagulated with edoxaban or LMWH died and 1 out of 10 presented a bleeding complication during hospitalization. No significant differences were found between patients treated with edoxaban and patients treated with LMWH in terms of the percentage admitted to the intensive care unit, mortality rates, arterial and venous thromboembolic complications, and bleeds. However, the duration of hospitalization was significantly lower with edoxaban than with LMWH. Therefore, while both drugs are safe in this population, edoxaban may provide an additional benefit.