To the Editor:
We read the recent publication in Pharmacological Research on the impact of pre-admission
antithrombotic therapy in coronavirus disease 2019 (COVID-19) patients with great
interest [1]. A recent retrospective cohort study demonstrated that the use of heparin
improved the 28-day mortality of severe COVID-19 patients at risk of sepsis-induced
coagulopathy. [2] Another study found that patients who received treatment-dose anticoagulants
were more likely to require invasive mechanical ventilation [3]. However, few population-based
studies have examined the effects of prophylactic antithrombotic therapy on the risk
of severe COVID-19. Thus, the present study aims to evaluate whether anticoagulant
and anti-platelet use is associated with a lower risk of severe COVID-19 infection
through a territory-wide, propensity score-matched cohort study.
Ethics approval for this study was obtained from the Institutional Review Board of
the University of Hong Kong/Hospital Authority Hong Kong West Cluster. The inclusion
criteria were patients who tested positive for the severe acute respiratory syndrome
coronavirus-2 under reverse-transcriptase polymerase chain reaction (RT-PCR) between
January 1st to August 22nd, 2020 in Hong Kong. The patient data were extracted from
the Clinical Data Analysis and Reporting System (CDARS), a Hong Kong-wide electronic
health record database that compiles data from all public hospitals to establish a
comprehensive and accessible medical record for each patient, and has been used by
our team and other groups to conduct population-based studies in the past [4]. The
following information was extracted from CDARS: (1) demographics; (2) prior comorbidities;
(3) hospitalization characteristics before the COVID-19 related admission; (4) medications
prescribed; (5) laboratory tests (complete blood count, biochemical tests, cardiac
function tests, C-reactive protein, and arterial blood gas); (6) the need for intensive
care unit (ICU) admission and intubation. The codes from the International Classification
of Disease-Ninth Edition (ICD-9) documenting the comorbidities and intubation procedure
are shown in Supplementary Tables 1 and 2, respectively. Patient mortality was extracted
from the Hong Kong Death Registry, a governmental registry compiling the registered
death records of Hong Kong citizens. The primary outcome is the need for admission
to the intensive care unit (ICU), intubation, or death followed-up until September
8th, 2020. Detailed information on the statistical analyses is shown in the Supplementary
Appendix.
The procedures of data processing are detailed in
Fig. 1. The present study consists of 4445 consecutive patients who have been tested
positive for the severe acute respiratory syndrome coronavirus-2 (median age 44.8
years old, 95% CI: [28.9, 60.8]; 50% male). Of these, 212 met the primary outcome
(Supplementary Table 3). The baseline clinical characteristics of the cohort stratified
by anticoagulant or antiplatelet use before and after propensity score matching for
baseline demographics, past medical comorbidities (including the Charlson Comorbidity
Index score), medication history, platelet and prothrombin time/international normalized
ratio (INR) are shown in Supplementary Table 4. The percentage of COVID-19 patients
meeting the primary outcome was significantly higher in anticoagulants users compared
to non-users, both before (n = 145/292, 41.7% vs. n = 67/4097, 1.6%; P < 0.0001) and
after propensity score matching (n = 145/292, 41.7% vs. n = 46/696, 6.6%; P < 0.0001).
Similarly, antiplatelet users also showed a higher percentage compared to non-users
before (n = 70/292, 24.0% vs. n = 142/4153, 3.4%; P < 0.0001) and after matching (n = 70/292,
24.0% vs. n = 91/584, 15.6%; P < 0.0001). Kaplan-Meier curves stratified by anticoagulants
or antiplatelets use for the unmatched and matched cohorts are shown in
Fig. 2 and
Fig. 3, respectively. Based on the propensity score-matched cohort, univariable Cox
regression showed that the use of anticoagulants (hazard ratio [HR]: 4.65, 95% confidence
interval [CI]: [3.36, 6.43], P < 0.0001) or antiplatelets (HR: 1.54, 95% CI: [1.13,
2.10], P = 0.0061) was associated with a higher risk of the primary outcome (Supplementary
Table 5). For anticoagulant/antiplatelet users vs. non-users, the HR was 5.19 (95%
CI: [3.89–6.90] P < 0.0001). Regarding individual drug classes, the use of dabigatran,
enoxaparin, clopidogrel or aspirin was a significant predictor. Multivariate Cox analyses
showed that anticoagulant/antiplatelet use remained a significant predictor after
adjusting for age, past comorbidities and/or medication classes (Supplementary Table
6).
Fig. 1
Procedures of data processing.
Fig. 1
Fig. 2
Kaplan-Meier curve for the severe disease outcome in PCR-positive COVID-19 patients
stratified by anticoagulant (AC)/ antiplatelet (AP) use after 1:2 propensity score
matching.
Fig. 2
Fig. 3
Kaplan-Meier curve for the severe disease outcome in PCR-positive COVID-19 patients
receiving antiviral or steroid therapy, stratified by anticoagulant (AC)/ antiplatelet
(AP) use after 1:2 propensity score matching.
Fig. 3
As the inclusion of PCR-positive asymptomatic cases may introduce bias. Subgroup analysis
including only COVID-19 patients receiving anti-viral or steroid therapy (lopinavir/ritonavir,
ribavirin, interferon beta-1b, hydroxychloroquine, steroids) was performed. This subgroup
cohort consists of 1064 patients, in whom 82 (7.7%) met the primary outcome (Supplementary
Table 7). Their unmatched and matched baseline characteristics are shown in Supplementary
Table 8. After propensity score matching, univariate Cox regression showed that the
use of antiplatelets/anticoagulants was a significant predictor of severe disease
(HR: 8.88, 95% CI: [5.11, 15.43]; P < 0.0001; Supplementary Table 9). Regarding individual
drug classes, only the use of edoxaban or enoxaparin was a significant predictor.
The relationship between anticoagulant/antiplatelet use remained significant in multivariate
Cox analyses adjusting for age, past comorbidities and/or medication classes (Supplementary
Table 10).
Finally, 1:1 propensity score matching was performed between anticoagulant and antiplatelet
users receiving antiviral/steroid therapy (n = 63 for each group, 28 patients prescribing
both anticoagulants and antiplatelets were excluded; Supplementary Table 11). Univariate
Cox regression showed that the use of antiplatelets was associated with a lower risk
of severe disease compared to anticoagulant users (HR: 0.17, 95% CI: [0.07, 0.44];
P < 0.0001; Supplementary Table 12). The lower risk observed for antiplatelet users
remained significant in multivariate Cox analyses adjusting for age, past comorbidities
and/or medication classes (Supplementary Table 13).
COVID-19 has placed a significant burden on healthcare systems worldwide. It particularly
affects patients with existing comorbidities more severely [5], [6], [7], complicated
by important effects of individual drug classes [8], [9], [10] or drug-drug interactions
[11]. Our data indicate that the use of anticoagulants or antiplatelets is associated
with a higher risk of severe COVID-19 disease after propensity score matching in a
Chinese cohort. However, antiplatelet use was associated with lower risk of severe
disease compared to anticoagulant use. Our findings should be validated in future
studies.
Funding
This study was supported by the
10.13039/501100001809
National Natural Science Foundation of China
(NSFC) Grant Nos. 72042018, 71972164 and 71672163, in part by the
10.13039/501100005847
Health and Medical Research Fund
Grant (HMRF), the
10.13039/501100005407
Food and Health Bureau
, The Government of the Hong Kong Special Administrative Region No. 16171991, and
in part by The Theme‐Based Research Scheme of the Research Grants Council of Hong
Kong Grant No. T32‐102/14N.
Conflicts of Interest
The authors declare no potential or actual conflicts of interest.