key: cord-0796859-6b4bts5p
authors: Bhoopat, Lantarima; Martynova, Anastasia; Choi, April; Pattaranithima, Pattharawin; Han, Semi; Du, Senxi; Syed, Ibrahim; Chan, Catherine; Oh, Esther E.; Borok, Zea; Liebler, Janice; Lee Wilson, Melissa; Tantiyavarong, Pichaya; O'Connell, Casey
title: A dynamic, D-dimer-based thromboprophylaxis strategy in patients with COVID-19
date: 2021-06-08
journal: nan
DOI: 10.1016/j.tru.2021.100055
sha: bcb14fe6179df2281e9729fa5b0e3ec8b60d252d
doc_id: 796859
cord_uid: 6b4bts5p

Background While Coronavirus disease 2019 (COVID-19) is associated with increased risk for venous thromboembolism (VTE) during hospitalization despite prophylactic anticoagulation, there is a lack of evidence-based guidelines for dose escalation of anticoagulation for patients hospitalized with COVID-19. Methods This single-center retrospective cohort study was part of a quality improvement program evaluating safety and efficacy of anticoagulation protocols at our large, metropolitan public hospital. We implemented a D-dimer-based guideline for dosing unfractionated heparin (UFH) or low molecular weight heparin (LMWH) in COVID-19 hospitalized patients that allowed for up-titration from standard prophylactic dosing to escalated prophylactic dosing or therapeutic dosing based on patient risk and presence of known or highly suspected VTE. Primary endpoints were International Society on Thrombosis and Haemostasis (ISTH)-defined major and clinically relevant non-major bleeding (CRNMB) events and in-hospital survival. Findings Among 262 COVID-19-infected patients hospitalized between March 15th and June 15th, 2020, 125 (73.1%) were male. Highest anticoagulation dose was: 65.3% prophylactic, 13.4% escalated prophylactic, 21.4% therapeutic. The dose was uptitrated in 83 (31.6%) patients. Bleeding events were comparable between the therapeutic (12.5%) and escalated prophylactic groups (11.4%), but significantly higher than in the prophylactic group (1.2%). In-hospital survival at 28 days was superior among patients whose anticoagulation was uptitrated to either escalated prophylactic or therapeutic (77.6%), compared to those receiving fixed prophylactic (56.7%) or fixed therapeutic (26.7%) dosing (p = 0.001). Conclusion A dynamic, D-dimer based dose escalation of anticoagulation for hospitalized patients with COVID-19 may improve in-hospital mortality without increasing fatal bleeding.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, COVID) has resulted in significant morbidity and mortality worldwide. One important mechanism for its adverse impact appears to be its promotion of arterial and venous thrombosis, endothelial dysfunction and enhanced angiogenesis, particularly in the lungs. (1) (2) (3) (4) Early data from China found an association between D-dimer and mortality (5) (6) (7) (8) (9) , but the actual incidence of thrombotic events was not reported and prophylactic anticoagulation was not standard for all patients. Tang et al, showed that heparin or low molecular weight heparin (LMWH) improved survival in more severe patients with sepsis-induced coagulopathy (SIC) score ≥ 4 or D-dimer value greater than 6 times the upper limit of normal (ULN). (10) However, despite standard heparin or LMWH thromboprophylaxis, the cumulative incidence of thrombotic events in COVID-infected patients was 30-50% over the course of their stay in an intensive care unit (ICU) . (11) (12) (13) (14) (15) (16) (17) The concern for breakthrough thrombosis in hospitalized patients with COVID (11) (12) (13) (14) has prompted interest in using escalated doses of anticoagulants. The use of therapeutic dose heparin may reduce the need for mechanical ventilation and improve survival (10, (18) (19) (20) but there is no consensus on when to use escalated or therapeutic doses without radiologic confirmation of a thrombus given the likely increased risk of bleeding.

Based on these data and COVID-related limitations on access to radiologic testing for deep vein thrombosis (DVT) and pulmonary embolism (PE) at our large metropolitan public hospital, we implemented a D-dimer-stratified anticoagulation protocol for hospitalized patients with COVID ( Figure 1 ). Here we report on the safety and survival impact of this strategy. Primary endpoints were bleeding events and in-hospital survival. Secondary endpoints included incidence of breakthrough thrombosis, survival duration, duration of hospitalization and ICU stay.

This single-center retrospective cohort study is part of an ongoing quality improvement initiative conducted at our large, urban public medical center on the use of an anti-factor Xadriven heparin protocol, which includes a low-dose intravenous (IV) unfractionated heparin (UFH) option. A guideline for the use of anticoagulation in COVID-infected patients was implemented to standardize the management of these patients ( Figure 1 ). Those who presented with DVT or PE were started on treatment dose anticoagulation as per the hospital protocol. Those without existing thrombosis were stratified into two groups based on their D-dimer: those with a D-dimer below 6 mcg/ml FEU (3.0 ug/mL) were given standard prophylactic anticoagulation and those with a D-dimer above this cutoff received escalated prophylactic dosing (LMWH 0.5 mg/kg subcutaneous every 12 hours or low dose heparin intravenous continuous drip titrated to an anti-Xa level of 0.1-0.3). Subsequent dosing increases were made based on a rise in D-dimer to above 6mcg/mL FEU or an increase of more than 2mcg/mL FEU/mL despite >48 hours of prophylactic anticoagulation. Patients who demonstrated acute respiratory decompensation while receiving prophylactic or escalated prophylactic dosing were further escalated to full therapeutic dosing. Data on the type, dose, and indication for anticoagulation, COVID-specific therapies, as well as outcomes including thrombosis, bleeding and survival were collected for all inpatients diagnosed with COVID between March 15th and June 15th, 2020. Patients who required therapeutic anticoagulation for other indications at the time of admission were excluded. Patients treated with different anticoagulation regimens during their hospitalization were categorized based on the highest level of anticoagulation received. A category was also created for patients who required uptitration of dosing based on the guideline. Development of thrombosis at any level of anticoagulation was recorded as breakthrough thrombosis on that level.

Based on our hospital's anticoagulation protocol (Figure 1 ), we categorized anticoagulant use as follows: Standard Prophylactic which includes subcutaneous UFH 5,000 units every 8 hours (if creatinine clearance <30 mL/min), or subcutaneous LMWH with enoxaparin 40 mg once daily (40 mg twice daily if BMI>30; 30 mg once daily if Creatinine Clearance <30 mL/min) Escalated Prophylactic which includes low-dose IV UFH titrated to achieve an anti-factor Xa level of 0.1-0.3 anti-Xa units (if creatinine clearance <30 mL/min) or enoxaparin 0.5 mg per kilogram body weight subcutaneously every 12 hours (if creatinine clearance ≥ 30 mL/min), or Standard Therapeutic dose used, which includes therapeutic dose IV UFH titrated to achieve an anti-factor Xa level of 0.3-0.7 anti-Xa units, or enoxaparin 1 mg per kilogram body weight every 12 hours during the hospitalization.

The primary endpoints assessed were International Society on Thrombosis and Haemostasis (ISTH) defined major and clinically relevant non-major bleeding events (21) and in-hospital survival of each treatment group based on the highest dose received as well as of patients who were uptitrated to either escalated or therapeutic dose compared to those who received only standard prophylactic dose or fixed therapeutic dose throughout their hospitalization. Secondary endpoints included incidence of breakthrough thrombosis, survival duration, duration of hospitalization and ICU stay. We collected baseline demographic data including age, sex, body mass index (BMI), ethnicity, comorbidities, baseline inflammatory markers, and clinical parameters including requirement for high flow nasal cannula (HFNC) or mechanical ventilation (MV) and sepsis-induced coagulopathy score (SICS).

To compare demographic data among the three treatment groups, ANOVA or Kruskal-Wallis were used for continuous data, and Pearson's Chi-Squared or Fisher's exact test for categorical data. The bleeding outcomes among the groups were compared using exact probability tests without p-value adjustment for multiplicity. Dichotomous secondary outcomes were assessed using univariate logistic regression. In-hospital survival stratified by treatment groups was visualized by Kaplan-Meier curve and tested by log-rank test. Cox proportional hazard model was used to identify potential predictive factors for in-hospital mortality. D-dimer levels were divided by their standard deviation to allow for interpretation of effect estimates per change in standard deviation. We also evaluated peak D-dimer >6 vs <6 mcg/mL FEU. Variables were included in the model if they were either predictors or confounders, defined as any variable that alters the effect size by >15% when included in the model. We evaluated the following potential covariates: D-dimer levels, heparin dose, uptitration to a higher heparin dosing group, age, race, BMI, comorbidities, ICU admission, smoking status, mechanical ventilation, HFNC, HAS-BLED risk score (22) , Sequential Organ Failure Assessment (SOFA) score (23) , SIC score (24) , and bleeding events. Scale Schoenfeld residuals were tested in the final model and showed a valid proportional hazard assumption. We also plotted the Kaplan-Meier estimates against predicted survival, which also indicated no violation.

Additionally, we compared and graphically presented the mean profiles over time of D-dimer among treatment groups by random-intercept linear mixed model. This model incorporated the correlation of D-dimer measures within individuals. The fixed effects were time measuring Ddimer, treatment groups, and interaction of both variables. Restricted cubic spline with 3 degrees of freedom was applied for time to relax linearity assumption. All analyses were performed by STATA 14.2 or 16.0 (Statacorp, College Station, TX). We present 95% confidence interval of any effect measures with two-sided p value of 0.05 for statistical significance.

The cohort includes 262 hospitalized, COVID-infected patients of whom 125 (73.1%) were male. The majority, 171 (65.26%), of patients received prophylactic dosing; 35 (13.36%) patients received escalated prophylactic dosing; and 56 (21.37%) patients received therapeutic dosing (Table 1 ). Of those, 34 patients were up-titrated to escalated prophylactic dose and 49 patients to therapeutic dose, over the course of hospital stay based on their D-dimer trend. The patients in the therapeutic group were significantly older than the patients in the prophylactic group (mean age 60.412.3 vs 54.5 15.8 years, respectively p=0.017, Table 1 ). Patients treated with therapeutic dosing had more comorbidities (83.9% vs 57.1% in the escalated group, and 33.9% in the prophylactic group). The patients in the therapeutic and escalated dosing groups had higher rates of ICU admission (89.1% and 74.3% in therapeutic and escalated dosing groups compared to 33.3% in prophylactic dosing group), HFNC requirement (70.4%, 68.6% in therapeutic and escalated group vs 24.6% in prophylactic group) and MV requirement (69.6%, 42.9% in therapeutic and escalated group vs 11.1% in prophylactic group). However, the rate of MV use in the therapeutic dosing group was higher than in the escalated dosing group (69.6% vs 42.9%). Baseline D-dimer and lactate dehydrogenase (LDH) were higher in the therapeutic and escalated dosing groups compared to the prophylactic dosing group (mean D-dimer 3.5, 4.8, and 1.7 mcg/mL FEU) in therapeutic, escalated and prophylactic dosing groups, mean LDH 481.8, 507.7 and 383.6 U/L in therapeutic, escalated and prophylactic groups respectively).

The mortality rate in this cohort of hospitalized COVID-infected patients was 12.97%. When we compared to survival duration of the patients who expired during admission, the therapeutic group showed statistically significantly longer in-hospital survival duration with median survival of 23 days compared to 17 and 7 days in the escalated and prophylactic groups, respectively ( Table 2) . 28-day in-hospital survival was 56.65% in the prophylactic group, 62.96% in the escalated group, and 74.98% in the therapeutic group (Figure 2A) . Based on the multivariable Cox regression, we found several factors that independently increased in-hospital mortality: increasing age (HR 1.10 (Table 3) . We also compared survival between the patients whose heparin was uptitratred to escalated or therapeutic dose and the patients whose doses remained either standard prophylactic or fixed therapeutic dose from the beginning of their hospital stays. We found that the 28-day in-hospital survival was 56.65% in the prophylactic group, 26.67% in the fixed therapeutic group, and 77.55% in the uptitrated group ( Figure 2B ). The in-hospital survival was not statistically significantly different between the patients who received fixed therapeutic heparin dose since the beginning and the prophylactic group. The multivariable Cox regression was also applied by replacing heparin treatment group as uptitrated, fixed therapeutic or prophylactic. We found that receiving uptitrated heparin was an independent factor associated with decreasing in-hospital mortality.

[HR 0.18, 95%CI [0.07, 0.49].

There was only 1 major bleeding event in therapeutic group. Across the cohort, 12 (4.58%) patients experienced a clinically relevant non-major bleeding (CRNMB) event by ISTH criteria (21) . The prevalence of bleeding was comparable between the therapeutic and escalated heparin groups; however, both the therapeutic (12.5% (OR 10.3, 95%CI [2.0, 52.9]) and the escalated (11.4% (OR 10.9, 95%CI [1.9, 62.1]) groups experienced significantly more bleeding events than the prophylactic group (2 events among 171 patients, 1.2%, Table 3 ). After adjusting for other confounding factors in the Cox regression model, bleeding did not have an independent effect on in-hospital survival (OR=0.78, 95% CI [0.43, 1.40], Table 3 ).

The overall incidence of breakthrough thrombotic events was 2.67%, but this is likely underestimated due to a limited number of diagnostic studies performed. The patients who received therapeutic dose heparin experienced more thrombotic events compared to the escalated and prophylactic heparin groups (8.9% (OR 16.7, 95%CI [1.9, 145.9]), 2.9% (OR 5.0, 95%CI [0.31, 81.9] and 0.6%, respectively, Table 2 ).

We also analyzed the D-dimer trend among treatment groups after starting anticoagulant by comparing the mean D-dimer of individuals in each treatment group over time. Mean D-dimer levels were higher in the therapeutic dosing group than the other treatment groups over time and the peak effect of escalated and therapeutic heparin on D-dimer level occurred within the first week of treatment (Figure 3) . A peak D-dimer level above or equal to 6 mcg/ml FEU (3.0 ug/mL) or below 6 FEU/ml (3.0 ug/mL) was not associated with survival outcome nor was it a confounder; therefore, it was not included in the survival model.

In our evaluation of a quality improvement initiative to utilize a D-dimer-titrated anticoagulation strategy for COVID-infected inpatients, both escalated and therapeutic dosing regimens were independently associated with lower in-hospital mortality. Moreover, survival was superior among patients in whom the dosing was uptitrated during the hospital stay based on rising D-dimer. Although the prevalence of bleeding events was higher in the patients who received escalated and therapeutic doses of anticoagulation, as compared to prophylactic, there were no fatal or major bleeds. All bleeding events were CRNMB, which were managed with standard supportive care, and bleeding was not independently associated with survival outcome. We chose a D-dimer-based strategy because we had limited access to radiologic studies to evaluate for DVT and PE in COVID-infected patients earlier in the pandemic and because of reports by Tang (6, 10) and others (5) indicating that elevated D-dimer was associated with mortality, possibly due to thrombotic complications.

A recent report from Nadkarni et al suggests a survival benefit for use of therapeutic dose anticoagulation with lower in-hospital mortality and intubation rates in COVID-infected patients. (16) Other observational studies also suggest that the use of higher doses of anticoagulation is associated with a survival benefit among severely ill patients with COVID. (10, 19, 25) Similar to these studies, the patients in our cohort who required higher levels of anticoagulation tended to be sicker with more baseline comorbidities, longer hospital stays, higher rates of ICU admission, MV and HFNC use. We stratified patients into three groups, based on D-dimer level on admission and followed a stepwise up-titration of anticoagulation based on D-dimer values, which could occur at any time during the hospitalization. The D-dimer cutoff of 6 mcg/ml FEU that we used to trigger use of escalated dose prophylaxis was not itself associated with survival in our multivariate analysis, but we did see suppression of the values within the first week of using higher doses of anticoagulation (Figure 3 ). Of note, the 8 patients who received fixed therapeutic dose since the beginning of their hospitalization did not show survival benefit compared to those who were uptitrated later in the hospital course. The finding that a fixed therapeutic dose from admission shows no survival benefit is also found in other observational studies and meta-analyses. (13, 26) J o u r n a l P r e -p r o o f

The risk of bleeding with anticoagulation in COVID-infected patients appears variable based on published literature (13, 18, 27, 28) ; the number of bleeding events in our cohort was lower than reported in a study from Duke University which applied escalated and therapeutic heparin in a manner similar to our study, (27) higher than reported by Mount Sinai, where therapeutic dose heparin was utilized more frequently, (18) and comparable to that reported in a center where prophylactic doses were mostly used. (28) The decision to use higher doses of anticoagulation was not consistent across studies, nor was dosing. In the Duke study, escalated prophylaxis with heparin used an anti-Xa target of 0.3-0.5, higher than in our study, which could have contributed to the higher rate of bleeding.

The strengths of our D-dimer-titrated anticoagulation strategy included the use of a simple diagnostic test to stratify patient risk and allow for a dynamic reassessment over the course of the hospitalization. Using the rise in D-dimer as a trigger to increase AC allowed us to intervene early in the disease course, which may have reduced the need for mechanical ventilation in our patient cohort. SIC or SOFA scores were found to be associated with survival prognosis in our study and previous studies. (10, 29) However, because calculation of these scores was not routine practice for our house staff, we felt these were not optimal for use in our algorithm, but they may be reasonable alternatives to guide intensity of prophylaxis in future studies. Another alternative would be to use a clinical variable such as mechanical ventilation or ICU status to prompt use of a higher dose of anticoagulation, but the potential impact of higher dose anticoagulation on reduced use of mechanical ventilation requires earlier initiation. (18, 20) Our study is limited by its retrospective nature and lack of uniform diagnostic evaluation for DVT/PE in COVID-infected patients, even in those with suggestive symptoms. Previously, Demelo-Rodriguez et al reported that 15% of patients with COVID and elevated D-dimer levels have asymptomatic DVT. (30) COVID infection is notably associated with a high risk of thrombotic complications, even in anticoagulated patients; therefore, the number of VTE reported in our cohort is likely underestimated. Furthermore, we did not collect data regarding thrombotic events that might have occurred after patients were discharged, and no autopsies were performed at our site to confirm the causes of death. Finally, we did not include a de-escalation strategy in our guideline, so this was done based on physician discretion. Prospective randomized studies are needed to confirm the safety and efficacy of utilizing escalated anticoagulation strategies, as well as the dosing targets, for hospitalized patients with COVID.

In this quality improvement evaluation of a D-dimer-titrated anticoagulation strategy for hospitalized patients with COVID, we found that higher dose anticoagulation was associated with reduced in-hospital mortality without compromising safety by increasing major or fatal bleeding. J o u r n a l P r e -p r o o f 2 Hazard ratios (HR) can be interpreted as the risk of death for a one-unit change in the independent variable.

Lantarima Bhoopat performed study design, investigation, data curation, formal analysis, data interpretation, writing -original draft, writing -review & editing

Anastasia Martynova performed investigation, data curation, formal analysis, data interpretation, writing-original draft, writing -review & editing

April Choi performed investigation, data curation, writing -original draft, writingreview & editing

Pattharawin Pattharanitima performed formal analysis, review & editing

Semi Han performed Data acquisition, review & editing

Ibrahim Syed performed data curation, review & editing

Catherine Chan performed data curation, review & editing

Esther E Oh performed data curation, investigation, review & editing

Zea Borok performed conceptualization, review and editing

Janice Liebler performed conceptualization, review and editing

Melissa Lee Wilson performed data analysis and interpretation, drafting statistical methods section, writing-review and editing

Pichaya Tantiyavarong performed data analysis, data interpretation, writing-review & editing

Connell performed conceptualization, project administration, supervision, validation, writing -review & editing

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P-values were obtained using one-way ANOVA or Kruskall-Wallis for continuous variables and Fisher's Exact Test for categorical variables. Odds ratios (OR) were obtained for categorical variables using univariate logistic regression

For continuous variables, no ORs could be calculated. This is noted as "NA

hospitalized patients with COVID-19  D-dimer based dose escalation of heparin or low molecular weight heparin for hospitalized patients with COVID-19 improves in-hospital mortality without increasing the risk of fatal bleeding  In a multivariate analysis, lower in-hospital mortality was associated with uptitrated heparin or low molecular weight heparin doses, high flow nasal canula use, and steroid treatment.

☒ The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.☒The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Casey O'Connell: consulting fee from AbbVie Inc. Advisory Board Janice Liebler: Grants or contracts from Immunexpress, St. Michaels Hospital, Toronto, Canada, CDC Foundation No conflict of interest for other authors.