key: cord-1029106-z385d0hk
authors: Hara, Hisao; Uemura, Yukari; Hayakawa, Kayoko; Togano, Tomiteru; Asai, Yusuke; Matsunaga, Nobuaki; Terada, Mari; Ohtsu, Hiroshi; Kitajima, Koji; Shimizu, Yousuke; Sato, Lubna; Ishikane, Masahiro; Kinoshita-Iwamoto, Noriko; Shibata, Taro; Kondo, Masashi; Izumi, Kazuo; Sugiura, Wataru; Ohmagari, Norio
title: Evaluation of the efficacy of anticoagulation therapy in reducing mortality in a nationwide cohort of hospitalized patients with coronavirus disease in Japan
date: 2021-09-10
journal: Int J Infect Dis
DOI: 10.1016/j.ijid.2021.09.014
sha: a023eee70c7607fa95cc155d5cdd776c7e38ddab
doc_id: 1029106
cord_uid: z385d0hk

Objectives To determine whether anticoagulation therapy improves outcomes in patients with coronavirus disease (COVID-19) in Japan given their lower risk of thrombosis compared with Western cohorts. Methods The efficacy of anticoagulation therapy in hospitalized COVID-19 patients was evaluated using a nationwide registry, the COVID-19 Registry Japan. Inverse probability of weight treatment method was used to adjust for baseline confounders in the anticoagulation and non-anticoagulation groups. Results Of the 1748 patients included, anticoagulants were used in 367 patients (treatment group). The patients in the anticoagulant group were older and predominantly male and often presented with obesity, hyperlipidemia, hypertension, diabetes, and elevated D-dimer levels. The 29-day mortality was 7.6% in the whole cohort (treatment group, 11.2%; no treatment group, 6.6%), 6% in patients who were not treated with steroids (treatment group, 12.3%; no treatment group, 5.2%), and 11.2% in patients treated with steroids (treatment group, 10.5%; no treatment group, 11.8%). Mortality in the whole cohort was similar between the treatment and no treatment groups (p=0.99), and an insignificant decreasing trend in mortality was observed in those treated with steroids (p=0.075). Conclusions Anticoagulants may be beneficial in Asians whose comorbidity and thrombosis risk may differ from those of other ethnic groups.

Globally, coronavirus disease , caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has affected more than 120 million individuals and caused 2.7 million deaths (Roser et al., 2021) . As of March 23, 2021, there have been 457,754 cases and 8,861 deaths in Japan (Ministry of Health, Labour and Welfare, 2021), which is lower than the number of cases and deaths reported in other countries with a COVID-19 outbreak (Roser et al., 2021) .

Thromboembolism, in addition to inflammation, was reported to be associated with severe SARS-CoV-2 infection (McBane et al., 2020) . Despite controversy regarding appropriate dosing (i.e., prophylactic vs. treatment dosing), several studies have shown that the use of anticoagulants, such as heparin, could cause a reduction in mortality and intubation in patients hospitalized for COVID-19 (Hanif A et al., 2020; Nadkarni et al., 2020; Rentsch et al., 2019) , leading to recommendations for their use in treatment guidelines (National Institutes of Health, 2021; Cuker et al., 2021) .

In contrast, previous studies have shown that patients with COVID-19 in Japan have a lower prevalence of underlying diseases, such as diabetes and obesity, which are associated with the severity of COVID-19, compared to patients in Western countries (Matsunaga et al., 2020) . In addition, the risk of developing venous thromboembolism is lower in Asians than in Caucasians owing to genetic differences (Nicole Tran and Klatsky, 2019) .

Whether anticoagulants have the same effect on COVID-19 in Japanese patients, as they have in overseas patients, should be examined. However, to the best of our knowledge, there have been no large-scale reports on this topic. Therefore, we investigated the efficacy of anticoagulants in reducing mortality, using the COVID-REGISTRY JAPAN (COVIREGI-JP), a nationwide cohort of hospitalized patients.

This study used data from the COVIREGI-JP (Matsunaga et al., 2020) . The inclusion criteria for enrollment were the following: (1) a positive SARS-CoV-2 test result; and (2) inpatient treatment at a health care facility.

We modified the case report form of the International Severe Acute Respiratory and Emerging Infection Consortium for the collection of clinical epidemiological information and treatment data in Japan (ISARIC, 2021). We collected information on the use of anticoagulation therapy, including unfractionated heparin, low-molecular-weight heparin, fondaparinux, and oral anticoagulants (warfarin, direct oral anticoagulants [dabigatran, rivaroxaban, apixaban, and edoxaban]) during hospitalization. In this study, we did not distinguish between prophylactic and therapeutic administration for thromboembolism.

The study data were collected and managed using Research Electronic Data Capture, a secure, web-based data capture application hosted at the JCRAC data center of the National Center for Global Health and Medicine (Harris et al., 2009) .

We used data from cases that contained information on all of the major items, as of November 2, 2020, as described in a previous report (Matsunaga et al., 2020) .

Among all patients registered as COVID-19 cases in the COVIREGI-JP, we excluded the following:

1. Those who received antiplatelet and/or anticoagulation therapy prior to the study (we employed the new user approach to avoid bias introduced by the inclusion of prevalent users into the study cohort) 2. Those who died within 4 days after admission to the hospital (to exclude those who were already in a severe condition to facilitate an effective evaluation of treatment efficacy)

3. Those who were categorized as "severe" (i.e., invasive or non-invasive mechanical ventilation, requiring supplemental oxygen, SpO 2 ≤94% on room air, or tachypnea [respiratory rate ≥24 breaths per min]) at the time of admission (to exclude patients who were already severely ill at admission and, thus, were less likely to show clinical benefit from anticoagulation therapy thereafter) (Matsunaga et al., 2020; Beigel et al., 2020) .

We used the inverse probability of treatment weight (IPTW) method to adjust for baseline confounders. IPTW creates a pseudo-population, in which all participants are considered conditionally exchangeable by achieving a balance between the treated and non-treated groups on the baseline covariates. The weight for each participant is defined as the inverse of the probability of receiving the observed treatment conditional upon the baseline covariate. That is, the weight of each patients receiving the anticoagulant drug is the inverse of the probability of receiving the drug (propensity score: PS), whereas the weight of a patient not receiving the anticoagulant drug is the inverse of 1-PS. PS was estimated using multivariable logistic regression models, including the baseline variables in the model, which are listed in Table 1 . The association between the anticoagulant drug administration and 29-day mortality was estimated using the IPTW of the marginal structural Cox model. Similarly, the associations between the administration of an anticoagulant drug and overall death were estimated for patients who received steroid treatment and those who did not receive during admission. The subgroup-specific propensity score model was used to account for the differences between the steroid and no steroid treatment groups. Time-varying confounding factors were not adjusted because the timing of anticoagulant prescription was not observed. Missing values were imputed using the mean values for continuous variables and median values for categorical variables. All statistical analyses were performed using SAS, version 9.4 (SAS Institute, Cary, NC, USA).

This study was approved by the NCGM Ethics Review Board (NCGM-G-003494-0).

Of the 8912 patients, a total of 1748 patients did not meet the exclusion criteria (anticoagulation treatment group, n=367; non-treatment group, n=1381). Table 1 shows the differences in background characteristics according to whether or not the patients were treated with anticoagulants during hospitalization. The patients of the treated group were older, predominantly male, had a higher body mass index (BMI), and had a higher D-dimer level at admission. Hypertension, hyperlipidemia, diabetes, and obesity (as diagnosed by the physician) were more common in the treatment than in the non-treatment group. The use of angiotensin II receptor blockers (ARBs) before hospitalization was more common in the treatment group. After adjustment for multivariate models to generate PS, most of these variables were still significantly different between the two groups, although the differences in obesity and ARB use disappeared. A significant difference was observed in dementia after adjustment. In the whole cohort, the survival probability tended to decrease more in the anticoagulant group after approximately 15 days of hospitalization. A stratified analysis according to the presence or absence of steroid use during hospitalization showed that, the survival probability among patients who did not receive steroids in the anticoagulant group tended to be lower than that in the non-anticoagulant group from day 5 after hospitalization, and this trend continued until day 29. In contrast, in patients who received steroids, the survival probability in the non-anticoagulant group tended to be lower from approximately 1 week after admission compared with that in the anticoagulant group; this trend continued until day 29. Table 2 shows a comparison of the 29-day mortality between patients who received and did not receive anticoagulation therapy. In the whole cohort, the hazard ratio (HR) for day-29 mortality was slightly higher in the anticoagulant than in the non-anticoagulant group, without any statistically significant difference observed (HR, Table 3 shows the complications during hospitalization in patients who received and did not receive anticoagulation therapy. Overall, complications were more frequently observed in the anticoagulant than in the non-anticoagulant group.

To the best of our knowledge, this is the largest study to evaluate the efficacy of anticoagulants in reducing mortality in patients hospitalized for COVID-19 in Japan.

After PS IPTW adjustment, we found no clear effect of anticoagulant use or non-use on mortality in the entire cohort; however, we did find a trend toward lower mortality in the steroid use group.

Past studies on the use of anticoagulants in other countries have reported their effectiveness against severe illness and death in hospitalized patients with COVID-19 (Hanif A et al., 2020; Nadkarni et al., 2020; Rentsch et al., 2019) . In our study, the trend anticoagulation benefit was found in the steroid-use group only, which may be attributed to several reasons. First, in most previous studies, anticoagulation therapy was initiated at 24-48 h after admission (Nadkarni et al., 2020; Rentsch et al., 2019) .

Unfortunately, the COVIREGI-JP does not collect data concerning neither the timing of anticoagulation therapy initiation nor the length of the treatment. Especially, the treatment might have been interrupted. Although patients who were already critically ill on admission were not included in this study, it is possible that the study included a population, in which anticoagulation therapy was initiated too late. Notably, there were significantly more patients in the anticoagulant group on IMV/ECMO during their hospitalization than in the non-use group (49% vs. 9.4%), indicating a higher number of critically ill patients in this group. As the PS used for adjustment was based on factors at the time of admission (e.g., patient background, D-dimer, and others), it is possible that it was not entirely accurate, as it did not account for other conditions, including severity of illness at the time of anticoagulant initiation.

Second, we may not have found benefit as a whole cohort because the included patients with COVID-19 had fewer thrombotic events, comorbidities associated with severe disease, and severity of disease than those in other studies. The median D-dimer level at admission in our study participants was lower than that reported in a previous study (Nadkarni et al., 2020) . There were few episodes of deep vein thrombosis and pulmonary embolism in our study, although they may have been underreported. Overall, 28% of patients did not receive oxygen during hospitalization, and although the mortality rate in the anticoagulant group was similar to that reported in a previous study (Rentsch et al., 2019) , the corresponding rate in the non-anticoagulant group was considerably lower than those previously reported (Nadkarni et al., 2020; Rentsch et al., 2019) . The frequency of comorbidities (such as diabetes and high BMI) that can lead to serious illness was also lower than that reported in previous cohort studies (Nadkarni et al., 2020; Rentsch et al., 2019) .

Since June 2020, steroids have been used actively in Japan to reduce mortality (Horby et al., 2021) . This study was novel in that the use of steroids was not included in the PS model but was analyzed in a stratified manner to more accurately assess the benefit of anticoagulation. In patients who did not receive steroids, the non-anticoagulant group included many mildly ill patients (i.e., more than 40% did not use oxygen), which may have contributed to the failure to prove the efficacy of anticoagulants in patients in this stratum or in the whole cohort (including patients in this stratum).

The steroid population, which included more severely ill patients compared to the overall cohort, still had a higher rate of IMV/ECMO use in the anticoagulated than in the non-anticoagulated group; however, the difference was narrowed compared with that in the whole cohort. Assuming that all the patients who died in this study cohort were treated with IMV/ECMO, the fatality rates among intubated patients would be as Notably, more patients (62.1%) in the steroid use group were enrolled in the COVIREGI-JP after June than those in the non-steroid use group (35.2%). As novel evidence of COVID-19 emerges over time, it is necessary to consider the impact of improved management other than steroid use. This point might, at least partially, explain the finding that the IPTW-adjusted HR, adjusting age and dementia by including those in the Cox model, showed that anticoagulation therapy might have been more harmful to the patients who did not receive steroid therapy.

The involvement of thrombosis in the severity of COVID-19 has been highlighted since the early stages of the pandemic, and an algorithm for anticoagulation was issued by Mount Sinai Hospital in April 2020 (Mount Sinai Health System, 2021).

DOACs have been approved for thromboprophylaxis in Japan. The use of warfarin is also considered suboptimal because of the difficulty in controlling thrombosis. Although we issued a recommendation for the subcutaneous administration of unfractionated heparin or low-molecular-weight heparin for hospitalized patients (Sato et al., 2020) , this occurred later than the recommendations in overseas reports; therefore, the use of anticoagulants did not become a standard practice in Japan immediately. The rate of anticoagulant use was low in the present study cohort (367/1748 [21%]) of hospitalized patients with COVID-19.

In addition to the points discussed thus far, there are several caveats to the interpretation of the results of this study. As this was an observational study using registry data, it is subject to limitations as described previously (Matsunaga et al., 2020) , such as bias from the overall inpatient population in Japan and future data updates.

Although the COVIREGI data provided information on the indications for anticoagulant use (e.g., therapeutic or prophylactic), there were cases, in which it was difficult to make a strict distinction because the doses of anticoagulants were not collected.

Therefore, we did not distinguish between the two. This is an area where there is still insufficient evidence on the appropriate target population and the superiority of prophylactic or therapeutic dosing (National Institute of Health, 2021; Sadeghipour et al., 2021) .

In conclusion, we found that anticoagulation therapy tended to reduce the 29-day mortality in hospitalized patients with COVID-19 in Japan who were also treated with steroids. These results suggested that anticoagulants would be beneficial, even in Asians whose comorbidity and thrombosis risk may differ from those of other ethnic groups and provide a rationale for promoting anticoagulation therapy in hospitalized patients in Asian countries, including Japan. Further studies are needed to determine the appropriate target population and treatment initiation. 

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The authors thank all the participating facilities for their care of patients with COVID-19 and their cooperation in data entry to the registry.

The data are not publicly available. The dataset was approved for use only for this study.

H. Ohtsu reports personal fees as a statistician and as an external consultant for clinical trials from EPS International, outside the submitted work. S. Saito reports grants from Shionogi, outside the submitted work. No other disclosures were reported.

This research was funded by the Health and Labor Sciences Research grant, "Research for risk assessment and implementation of crisis management functions for emerging and re-emerging infectious diseases" [grant number 19HA100].

 (Matsunaga et al., 2020) . The results are presented for the following three groups: whole cohort (a), patients who did not receive steroids (b), and patients who received steroids (c).