Keywords anticoagulation - COVID-19 - novel coronavirus - heparin
Introduction
Severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) is a novel coronavirus
identified as the cause of several cases of severe pneumonia in December 2019 in Wuhan,
China, later designated as novel coronavirus disease 2019 (COVID-19) by the World
Health Organization (WHO).[1 ]
[2 ] It has since spread exponentially to become a global pandemic.[3 ]
[4 ] An increasing body of evidence suggests hypercoagulability as an important component
in the pathogenesis of severe COVID-19. Bedside reports of frequent clotting of central
venous and hemodialysis catheters have now been supplemented by laboratory data consistent
with activation of the coagulation cascade as quantified by elevated D-dimer and fibrinogen
in conjunction with low antithrombin levels.[5 ] The prevalence of disseminated intravascular coagulation (DIC) per International
Society for Thrombosis and Haemostasis (ISTH) criteria was markedly higher in deceased
patients compared with survivors (71 vs. 0.6%).[6 ] Two studies employing thromboelastography have shown a coagulation profile consistent
with hypercoagulability in the context of severe systemic inflammation.[7 ]
[8 ] That hypercoagulability is of particular clinical importance is also supported by
multiple autopsy case series reporting pulmonary and other visceral microthromboses.[9 ]
[10 ]
[11 ]
A case series of thrombotic complications in critically ill patients with COVID-19
noted a high incidence of 31%, with pulmonary embolism as the most frequent manifestation.[12 ] Furthermore, one retrospective study found prophylactic anticoagulation (pAC) to
be associated with lower mortality at 28 days in certain subgroups of patients with
severe disease and demonstrated hypercoagulable profile either by a sepsis-induced
coagulopathy (SIC) score ≥4 or D-dimer >6-fold the upper limit of normal.[13 ] A more recent retrospective analysis reported a possible survival advantage for
severe COVID-19 patients treated with therapeutic AC, especially in a mechanically
ventilated subgroup; the effect observed was duration dependent.[14 ]
These observations prompted several professional societies to publish consensus statements
on management of COVID-19-associated coagulopathy.[4 ]
[15 ]
[16 ] All recommend obtaining initial standard coagulation tests, D-dimer and fibrinogen
levels, frequent retesting, and continuing pAC throughout the hospitalization with
possible extension beyond discharge for patients at higher risk of venous thromboembolism.
Individual papers have also discussed using higher doses of anticoagulation (AC)[12 ] or even tissue plasminogen activator,[17 ] both for prevention of thrombotic disease, and for the anti-inflammatory effect
of heparin.[18 ]
Data regarding the outcomes of severe COVID-19 patients treated with therapeutic AC
(tAC) is scarce and this treatment modality has not been incorporated in guidance
from expert panels. Information on both the efficacy and the safety of tAC is urgently
needed. We aimed to report the impact of tAC on time to death based on cross-sectional
analysis of a prospective cohort followed-up at our institution, where criteria for
initiating tAC have been adopted.
Methods
Study Design
A single-center, cross-sectional analysis of deceased patients included in a prospective
cohort was conducted at William Beaumont Hospital (Royal Oak, Michigan, United States),
a tertiary care academic teaching hospital. Patients aged 18 years or older who tested
positive for SARS-CoV-2 on nucleic amplification testing (NAAT) of nasopharyngeal
secretions over the first 4 weeks of the COVID-19 pandemic in Michigan (March 13–April
8, 2020), and who expired from related complications were identified by active surveillance
of inpatient records. At the time of publication, the majority of COVID-19 patients
remain hospitalized at our institution and the final course of their illness is uncertain.
We chose to focus on a cohort of deceased patients with unequivocal outcome, which
has the added advantage of avoiding confounding by indication. Our institution has
adopted criteria for initiating tAC, which include the presence of worsening respiratory
failure, impending or actual need for mechanical ventilation, and worsening kidney
failure, and/or a D-dimer > 6-fold the upper limit of normal (>3,000 ng/mL FEU). By
consensus, the recommended duration of AC is limited to 5 days, with extension beyond
this timeframe if there is a clear indication for continuing AC or the treating clinician
chooses to continue. The study was approved by Institutional Review Board (IRB no.:
2020–125).
Patient demographics (age, sex, and ethnicity), laboratory data, and information about
therapeutic modalities (AC, corticosteroids [CS], vasopressor, etc.) were obtained
from review of electronic medical records prospectively on a daily basis, using an
IRB-approved data collection checklist. Therapeutic AC (tAC) was defined as use of
unfractionated heparin (UFH) as an intravenous infusion with documented activated
partial thromboplastin time (aPTT) in the AC range (≥45 seconds), subcutaneous enoxaparin
at doses of 1 mg/kg twice daily or 1.5 mg/kg once daily (while allowing for dose adjustment
based on creatinine clearance), or oral AC prescribed for a preexisting established
indication in the form of warfarin with documented therapeutic international normalized
ratio (2–4) or direct oral anticoagulants (apixaban and rivaroxaban). The pAC was
defined as subcutaneous injection of UFH at doses of 5,000 units twice or three daily,
or subcutaneous enoxaparin injection at doses of 30 to 40 mg once daily. Immunosuppressive
CS therapy was defined as at least one dose of 15 mg methylprednisolone or equivalent
dose of other CS.
Major bleeding was defined according to the ISTH definition as having a symptomatic
presentation and (1) fatal bleeding; and/or (2) bleeding in a critical area or organ
such as intracranial, intraspinal, intraocular, retroperitoneal, intra-articular or
pericardial, or intramuscular with compartment syndrome; and/or (3) bleeding causing
a fall in hemoglobin level of 20 g L−1 (1.24 mmol L−1 ) or more, or leading to transfusion of two or more units of whole blood or red cells.[19 ] Active cancer was also defined according to ISTH as cancer diagnosed within the
previous 6 months, recurrent, regionally advanced or metastatic cancer, cancer for
which treatment had been administered within 6 months, or hematologic cancer that
was not in complete remission.
Outcomes and Statistical Analysis
The main outcome was the time to death of COVID-19 patients compared between patients
who received tAC, pAC, and no AC. Time zero was the time of admission for patients
admitted for COVID-19 and the time of positive NAAT for SARS-CoV-2 for those who developed
symptoms during the hospitalization. A multivariate Cox proportional hazards model
was performed to assess the impact of candidate variables on the retrieval rate. Candidate
variables were preliminarily tested for significance in univariate Cox proportional
hazards model using backward and forward regression.
Statistical analysis was performed using JMP version 14 and SAS 9.4 (SAS Institute,
Cary, North Carolina, United States). Categorical variables are described as frequency
(percentage). Normal or approximately normal variables are reported using the mean
(±standard deviation), whereas skewed variables are reported with the median (interquartile
range [IQR]). Categorical variables were compared using the Chi-square test or Fisher's
exact test. Normal variables were compared using a two-sided Student's t -test and ordinal variables used the Kruskal–Wallis test. All p -values were two-sided and a p < 0.05 was considered to indicate statistical significance.
Results
Over 30 days (March 13–April 8, 2020), 750 patients diagnosed with COVID-19 were admitted
and there were 127 (17%) COVID-19-related deaths. [Fig. 1 ] provides an outline of the study population. The mean age was 74 years (±15) and
68 (54%) patients were male. Racial distribution was notable for a predominance of
African Americans (71, 56%); 51 were Caucasian (40%) and 2 (2%) were Southeast Asian.
Information about ethnicity was not available for two patients.
Fig. 1 Study population. COVID-19, novel coronavirus disease 2019.
Baseline Characteristics. Treatment with Anticoagulation
Sixty-seven (53%) patients received tAC with intravenous UFH employed in 87%; for
3% treatment was with subcutaneous enoxaparin, whereas 10% of patients were continued
on home oral anticoagulants (7% direct oral anticoagulants and 3% warfarin). None
of the patients were receiving pAC upon admission. Of the remaining 60 patients who
did not receive tAC, 47 (37%) received pAC, while only 13 (10%) did not receive any
ACs. The baseline characteristics of patients are shown in [Table 1 ]. The median duration of tAC was 5 days (IQR: 3–8 days) and it was initiated on median
day 6 of hospitalization (IQR: 2–9 days). The number of days on tAC did not significantly
differ between patients who were treated in the intensive care unit (ICU) and those
who were not (median = 5 days [IQR: 3–10 days] vs. 4.5 days [IQR: 2–6 days]; p = 0.267). For most patients (37, 55%), tAC was initiated empirically for hypercoagulability
related to COVID-19. Atrial fibrillation accounted for the majority of remaining indications
(21, 31%), followed by chronic venous thromboembolism (5, 7%), acute arterial thromboembolism
(2, 3%), and acute coronary syndromes (2, 3%). In our analysis, one patient experienced
arterial embolism and one was diagnosed with incidental aortic thrombus during their
hospitalization for COVID-19. It is important to note that, due to institutional policy
aimed at preventing viral spread, the number of diagnostic imaging obtained was significantly
limited: only seven (6%) patients had venous Doppler ultrasound to investigate for
deep vein thrombosis (three were positive) and only three (2%) had computed tomography
of the chest with intravenous contrast to diagnose pulmonary embolism (one was positive).
Table 1
Baseline characteristics and comorbid conditions in study population
All patients (n = 127)
Therapeutic anticoagulation (n = 67)
Not on therapeutic anticoagulation (n = 60)
Significance
Age in years (SD)
74 (15)
72 (12)
77 (18)
0.051
Male sex
68 (54)
36 (54)
32 (53)
0.964
Caucasian race
51 (40)
21 (31)
30 (50)
0.032
BMI > 30 kg/m2
53 (42)
39 (58)
14 (23)
<0.0001
Diabetes
59 (46)
34 (51)
25 (42)
0.305
Hypertension
96 (76)
52 (78)
44 (73)
0.575
Coronary artery disease
37 (29)
17 (25)
20 (33)
0.324
Heart failure
27 (21)
16 (24)
11 (18)
0.444
VTE
14 (12)
9 (14)
5 (9)
0.407
Atrial fibrillation
12 (10)
9 (14)
3 (5)
0.134
Ischemic stroke or TIA
19 (16)
13 (21)
6 (11)
0.209
AKI[a ] on admission
63 (50)
27 (53)
36 (75)
0.022
CKD grade 3 and above
34 (27)
15 (22)
19 (32)
0.238
Hemodialysis-dependent
9 (7)
3 (4)
6 (10)
0.226
Chronic lung disease
29 (23)
16 (24)
13 (22)
0.766
Active cancer
8 (6)
4 (6)
4 (7)
0.871
Ever smoker
63 (50)
32 (48)
31 (52)
0.660
ICU stay
75 (59)
55 (82)
20 (33)
<0.0001
Corticosteroid treatment
65 (51)
43 (64)
22 (37)
0.002
Abbreviations: AKI, acute kidney injury; BMI, body mass index; CKD, chronic kidney
disease; ICU, intensive care unit; SD, standard deviation; TIA, transient ischemic
attack; VTE, venous thromboembolism.
Note: Age is presented as mean (standard deviation). Other numbers presented as n (%).
a Defined by an elevation in serum creatinine of 0.3 mg/dL or more relative to known
baseline value (data available for 99 patients).
Overall, the tAC group was younger (72 vs. 77 years; difference 5.3 years; 95% confidence
interval [CI], −0.03 to 10.7 years; p = 0.051), had a higher frequency of obesity (58 vs. 23%; p < 0.0001) and had fewer Caucasian patients (31 vs. 50%; p = 0.032). Patients who received tAC were also more frequently treated in an ICU (82
vs. 33%; p < 0.0001). Peak D-dimer levels recorded throughout admission were significantly higher
in the tAC group (median = 10,000 ng/mL [IQR: 4,195–10,000 ng/mL] versus median of
2,230 ng/mL [IQR: 1,453–6,698 ng/mL]; p = 0.001). By contrast, peak fibrinogen measurements were similar in both groups (672
[±191] vs. 587 [±209] mg/dL; p = 0.090).
Patients who did not receive tAC had a higher frequency of acute kidney injury defined
as elevation in serum creatinine of >0.3 mg/dL compared with known baseline (75 vs.
53%; p = 0.022). For the 118 patients who were not dialysis dependent prior to admission,
27 (42%) in the tAC group compared with 6 (11%) in the no AC group were provided renal
replacement therapy during their hospitalization (p < 0.001).
Treatment with Corticosteroids
A total of 65 (51%) patients were treated with immunosuppressive doses of CS. Treatment
was initiated on a median day 4 (IQR: day 2–7) of hospitalization and the median duration
of treatment was 5 (IQR: 3–7) days. CS treatment was more prevalent in the tAC group
(64 vs. 37%; p = 0.002) and was administered for a longer duration (median = 6 days [IQR: 5–7 days]
vs. 4 days [IQR: 2–5 days]; p < 0.001), but it was initiated later in the hospital course (median day 4 of admission
[IQR: day 2–8] vs. day 2 [IQR: day 1–4]; p = 0.013). The most commonly used CS formulation was intravenous methylprednisolone
at doses between 40 and 90 mg daily (77% of patients received 40 mg twice daily).
Patients Treated in the Intensive Care Unit
Seventy-five patients were treated in the ICU and most required intubation with mechanical
ventilation (68, 91%) and vasopressor support (63, 84%). The mean time from admission
to intubation was 5 (±3) days and the median duration of mechanical ventilation was
7 days (IQR: 4–9 days). Approximately one-third of patients (24, 32%) required paralytics
to ensure optimal ventilation and one quarter underwent prone ventilation (17, 23%).
Nearly half of ICU patients (32, 43%) required initiation of continuous renal replacement
therapy or intermittent hemodialysis.
Complications to Specific Therapies
Bleeding rates were similar between the tAC and non-AC groups. Estimates included
bleeding of any severity (19 vs. 18%; p = 0.877), any bleeding requiring transfusion (7 vs. 8%; p = 0.855), and major bleeding (3 vs. 8%; p = 0.18).
The rate of bacterial and fungal superinfections was estimated using the results of
microbiological studies. Blood cultures were obtained in 110 (87%) and respiratory
cultures in 85 (67%) patients. Overall, patients who received CS had a higher frequency
of positive blood (18 vs. 8%; p = 0.116) and respiratory cultures (13 vs. 8%; p = 0.510), but these differences did not reach statistical significance.
Impact of Therapeutic Anticoagulation and other Patient Variables on Time to Death
The median time from admission to death in the entire population was 9 days. In addition
to patient factors which differed significantly in group comparison (age, Caucasian
race, body mass index [BMI] > 30 kg/m2 , ICU stay, and CS treatment), Cox regression identified additional candidate variables.
Those which predicted an increase in time to death were: hypertension (p = 0.21), CS treatment (HR = 0.56; p = 0.001), and duration of CS treatment (p < 0.001). Ever smoker status was associated with a shorter time to death (p = 0.019). Other demographics or comorbid conditions (sex, diabetes, heart failure,
etc.) did not exhibit a significant relation (defined as p < 0.25) with time to death in univariate analysis.
The Kaplan–Meier curve comparing time to death for patients who received AC at different
doses or no AC is presented in [Fig. 2 ]. In univariate analysis, death was increasingly delayed with increasing doses of
AC: median of 11 days for tAC, 8 days for pAC, and 4 days for no AC (p < 0.001). [Fig. 3 ] compares time to death for patients treated with CS and for those who were not (median:
11 vs. 8 days; p = 0.001).
Fig. 2 Kaplan–Meier analysis of time to death in patients who received therapeutic (tAC),
prophylactic (pAC) or no anticoagulation (AC).
Fig. 3 Kaplan–Meier analysis of time to death in patients who received immunosuppressive
doses of corticosteroids and those who did not.
Results of the multivariate Cox proportional hazards model including the remaining
significant variables after backward and forward regression are summarized in [Table 2 ]. The final model found that AC was an independent predictor of longer time to death,
both when administered at prophylactic doses (HR = 0.29; 95% CI: 0.15–0.58; p < 0.001) and at therapeutic doses (HR = 0.15; 95% CI: 0.07–0.32; p < 0.001) compared with no AC. The duration of CS treatment was similarly associated
with increased time to death (HR = 0.89 per 1-day increase; 95% CI: 0.84–0.93; p < 0.001). Ever smoker status, by contrast, predicted a shorter time to death (HR = 1.86;
95% CI: 1.25–2.8; p = 0.002). None of the other suggested variables showed an impact on time to death
in the multiple regression model.
Table 2
Multivariate Cox proportional hazards model (all patients, n = 127)
Hazard ratio
Confidence interval
Significance
Ever smoker
1.86
1.25–2.8
0.002
CKD grade 3 or above
0.70
0.46–1.05
0.085
ICU stay
0.92
0.60–1.43
0.738
Prophylactic anticoagulation[a ]
0.29
0.15–0.58
<0.001
Therapeutic anticoagulation[a ]
0.15
0.07–0.32
<0.001
CS treatment duration (day)
0.89[b ]
0.84–0.93
<0.001
Abbreviations: CKD, chronic kidney disease; CS, corticosteroid; ICU, intensive care
unit.
a Compared with No anticoagulation.
b Per 1-day increase.
Results of four variations of the same model with single-variable changes are shown
in [Table 3 ]. When AC duration replaced the categorical variable (tAC, pAC, and no AC), the number
of days on AC was an important predictor of longer time to death (HR = 0.89 per 1-day
increase; 95% CI: 0.85–0.94; p < 0.001). The timing of tAC (first 1–2 days of hospitalization vs. day 3 and beyond)
was also explored in multivariate analysis and earlier initiation of tAC did not appear
to provide the same benefit (HR = 0.63; 95% CI: 0.38–1.01; p = 0.055) compared with later initiation (HR = 0.32; 95% CI: 0.19–0.55; p < 0.001). As a binary variable, the effect of CS treatment remained significant (HR = 0.62;
95% CI: 0.43–0.91; p = 0.016). Initiation of CS treatment on days 1 to 2 of hospitalization (HR = 1.41;
95% CI: 0.84–2.30; p = 0.187) had no effect on time to death, whereas initiation on day 3 and later showed
a decrease in risk of death (HR = 0.48; 95% CI: 0.28–0.68; p = 0.001). In all variant models, other variables from the original model had similar
effects.
Table 3
Variant multivariate Cox proportional hazards models
Hazard ratio
Confidence interval
Significance
1
AC treatment duration
0.89[a ]
0.85–0.94
<0.001
2
AC started day 1–2
0.63
0.38–1.01
0.055
AC started day ≥3
0.32
0.19–0.55
<0.001
3
CS treatment[b ]
0.62
0.43–0.91
0.016
4
CS started day 1–2
1.41
0.84–2.30
0.187
CS started day ≥3
0.48
0.28–0.68
<0.001
Abbreviations: AC, anticoagulation; CS, corticosteroid.
a Per 1-day increase.
b Compared to No CS treatment.
In analyses conducted separately on severe (no ICU stay, n = 52) and critical disease (required ICU stay, n = 75), the impact of tAC and pAC remained significant with a larger effect size in
delaying death in the critical COVID-19 population ([Supplementary Tables S1 ] and [S2 ]).
No interactions between considered variables were noted; furthermore, there was no
interaction between tAC and D-dimer (p = 0.260) in a model including only patients for whom the latter was known (n = 94).
Discussion
To the best of our knowledge, ours is among the first studies to investigate the impact
of therapeutic AC on clinical outcomes of severe or critical COVID-19 patients. Our
main findings are as follows: (1) AC delayed death in a dose- and duration-dependent
manner; (2) CS treatment delayed death in a duration-dependent manner; and (3) the
rate of bleeding was not significantly higher for patients treated with AC, but there
are concerns about increased infectious complications in patients treated with CS.
In our study population, nearly all patients (90%) received some form of AC and more
than half received therapeutic doses. The most frequently used anticoagulant was intravenous
unfractionated heparin (87%), which was likely preferred for its superior safety profile,
especially in the setting of renal failure. Over half of patients who received tAC
did so empirically to treat COVID-19-associated hypercoagulability. It is unknown
how many of these patients had unidentified venous thromboembolic disease as the use
of diagnostic imaging was severely limited.
The optimal time, dosing, and duration of tAC are unknown. For most patients, AC treatment
was initiated relatively late in the hospital course (median of day 6) as a consequence
of rapidly changing practice patterns as new data becomes available. Our analysis
suggests that timing of tAC may be important. Specifically, later initiation of tAC
(day 3 of hospitalization and later) appears to have a higher impact. This observation
highlights that tAC is likely more beneficial in a later phase of COVID-19 when severe
inflammation and activation of the coagulation cascade play the major role in pathogenesis.
The median duration of AC was 5 days. Our data demonstrated an increase in time to
death with increasing duration of tAC (∼10% decrease in the risk of death per 1-day
increase of tAC duration).
Most striking, however, was the increasing impact on time to death with increasing
doses of AC. Compared with no AC, the use of prophylactic doses decreased the risk
of dying by over 70% and therapeutic doses by 85%. When factored in as duration of
treatment, tAC showed a decrease in the risk of death at any time point (HR = 0.89
per 1-day increase; 95% CI: 0.85–0.94; p < 0.001). These effects were independent of other life-support modalities (vasopressor
use, mechanical ventilation, and renal replacement therapy) and CS treatment. Our
findings are consistent with those reported by Tang et al,[13 ] whose retrospective analysis found that pAC decreased 28-day mortality in a subgroup
of patients with SIC score ≥ 4 (40 vs. 64.2%; p = 0.029) or with D-dimer > 6-fold the upper limit of normal (32.8 vs. 52.4%; p = 0.017). Our data showed a difference in time to death regardless of D-dimer level,
but it is important to note that pAC was employed in nearly all patients and tAC was
preferentially initiated per institutional criteria based on the Tang et al study
in the presence of D-dimer > 6-fold the upper limit of normal. In a recently published
research letter, Paranjpe et al[14 ] analyzed the impact of tAC in a large cohort of COVID-19 patients. In-hospital mortality
was similar in those who received tAC and those who did not (22.5 vs. 22.8%), but
median survival time was significantly better in the AC group (21 vs. 14 days). A
much larger benefit for tAC was observed in mechanically ventilated patients, who
had lower in-hospital mortality (29.1 vs. 62.7%) and improved median survival (21
vs. 9 days). In a multivariate model, the duration of tAC was independently associated
with a decrease in the risk of death at any time point (HR = 0.86 per 1-day increase;
95% CI: 0.82–0.89; p < 0.001), which was similar in effect size to the one observed in our population
(HR = 0.89). It is unclear if the patients in the analysis by Paranjpe et al who did
not receive tAC received any form of pAC. The authors acknowledge several important
limitations such as the observational nature of the study, hidden confounding, and
difficulties with classification of disease severity. By focusing on deceased patients
only, our analysis hopes to, at minimum, avoid confounding by indication. Although
it remains difficult to extrapolate what the true, prospective benefit of tAC is in
a population that has had time to complete the disease course, our findings complement
and strengthen those of Paranjpe et al.
We agree with the reservations about the use of tAC in severe COVID-19 voiced by professional
societies,[4 ]
[16 ] given the potential for serious adverse events, chiefly bleeding. It is important
to note, however, that in our cohort the rates of all types of bleeding were similar
among those who received tAC and those who did not, suggesting that this therapeutic
strategy can be relatively safe. Similarly, Paranjpe et al found no significant increase
in bleeding events with tAC (3 vs. 1.9%, p = 0.02) and reported that more than half the bleeding events in the tAC group occurred
before initiation of AC.
An additional interesting observation was the effect of CS treatment in increasing
time to death. At least one prior retrospective analysis[20 ] has reported a mortality benefit with methylprednisolone treatment in COVID-19 patients
with acute respiratory distress syndrome (62% decrease in univariate analysis). Nonetheless,
experience with CS in the treatment of acute respiratory distress syndrome caused
by related viruses SARS-CoV-1 and Middle east respiratory syndrome (MERS) was associated
with frequent side effects without any observed clinical benefit.[21 ]
[22 ] Furthermore, quality data have demonstrated increased mortality in influenza pneumonia
treated with CS.[23 ]
With the above caveats in mind, we note that in our population, the use of CS showed
a 44% decrease in the risk of death in univariate analysis (comparable to[20 ]) and a more modest 38% decrease in multivariate analysis. Results suggested that
CS treatment duration (median = 5 days, consistent with institutional guidelines)
may also be important, and we observed an 11% reduction in risk of death per day of
treatment. Once again, this data should be interpreted with great caution. We did
notice an increased rate of infectious complications among patients treated with CS
(13–18 vs. 8% positive blood or respiratory cultures). Similar to tAC, CS treatment
had a stronger effect when initiated later during hospitalization. However, in contrast
to criteria for tAC, institutional guidelines do not clearly define when CS are warranted
and the decision is made primarily by clinical impression. It is likely that recognition
of more severe disease resulted in earlier initiation of CS.
Limitations
This cross-sectional, observational study has several important limitations and we
advise caution in interpreting results. Beyond inherent bias stemming from hidden
confounders, our selection of only deceased patients makes it impossible to derive
conclusions about the effect of any therapeutic modality on long-term survival. By
design, the study can only report associations and cannot investigate causality. Furthermore,
the population that was available for analysis was inhomogeneous in terms of practice,
as institutional guidelines were adopted halfway through the study period and have
resulted in significant practice changes.
Despite these limitations, the study offers new and urgently needed data on the effect
of AC in the treatment of severe COVID-19, a disease that suffers from a serious lack
of available therapeutic modalities of proven efficacy. Ours represents an interim
analysis of prospective data that aim to further investigate the effect of AC and
immunosuppression on outcomes in COVID-19.
Conclusion
Activation of the coagulation cascade resulting in a hypercoagulable state with subsequent
visceral microthrombosis is increasingly recognized as a hallmark of the pathogenesis
of COVID-19. The impact of AC on delaying death in severe COVID-19 appears to be dose-
and duration-dependent, with greater effect seen for therapeutic compared with prophylactic
doses. Immunosuppressive doses of CS also delayed death to a more modest extent. Despite
important limitations, our findings support those of others who have reported a survival
advantage with prophylactic and therapeutic AC in this population. Although, bleeding
complications were similar to nonanticoagulated patients, the decision to initiate
AC should remain individualized and always take into consideration of the individual
risk of bleeding. Despite seemingly encouraging results for CS, the rate of infectious
complications was higher. We recognize the urgent need for further randomized controlled
trials to explore the therapeutic effects of tAC and CS in critically ill patients
with COVID-19.
