Thromboprophylaxis in Patients With COVID-19

BACKGROUND: Patients hospitalized with COVID-19 often exhibit markers of a hypercoagulable state and have an increased incidence of VTE. In response, CHEST issued rapid clinical guidance regarding prevention of VTE. Over the past 18 months the quality of the evidence has improved. We thus sought to incorporate this evidence and update our recommendations as necessary.STUDY DESIGN AND METHODS:This update focuses on the optimal approach to thromboprophylaxis in hospitalized patients. The original questions were used to guide the search, using MEDLINE via PubMed. Eight randomized controlled trials and one observational study were included. Meta-analysis, using a random effects model, was performed. The panel created summaries using the GRADE Evidence-to-Decision framework. Updated guidance statements were drafted, and a modified Delphi approach was used to obtain consensus.RESULTS:We provide separate guidance statements for VTE prevention for hospitalized patients with acute (moderate) illness and critically ill patients in the ICU. However, we divided each original question and resulting recommendation into two questions: standard prophylaxis vs therapeutic (or escalated dose) prophylaxis and standard prophylaxis vs intermediate dose prophylaxis. This led to a change in one recommendation, and an upgrading of three additional recommendations based upon higher quality evidence. CONCLUSIONS: Advances in care for patients with COVID-19 have improved overall outcomes. Despite this, rates of VTE in these patients remain elevated. Critically ill patients should receive standard thromboprophylaxis for VTE, and moderately ill patients with a low bleeding risk might benefit from therapeutic heparin. We see no role for intermediate dose thromboprophylaxis in either setting. CHEST 2022; 162(1):213-225 KEY WORDS: COVID-19; DIC; DVT; hypercoagulability; pulmonary embolism; VTE ABBREVIATIONS: LMWH = low-molecular-weight heparin; OSFD = organ support-free day; PE = pulmonary embolism; RR = risk ratio; UFH = unfractionated heparin

## Summary of recommendations
1. In hospitalized patients with acute illness with COVID-19 who have low risk of bleeding, with consideration for the remarks below, we suggest therapeutic dose heparin (UFH or LMWH) over current standard dose anticoagulant thromboprophylaxis (Conditional Recommendation, Ungraded Consensus-Based Statement).
Remarks: Providers should carefully weigh the risks of thrombosis and bleeding in making this decision. Patients with a significantly elevated D-dimer level (studies have previously defined this as 2-4A the upper limit of normal), those with prior VTE, or those with other comorbidities known to be associated with VTE may be at increased risk of thrombosis. Patients with high risk of bleeding include, but are not limited to, those with known bleeding within the last 30 days requiring ED presentation or hospitalization, known history of an inherited or acquired bleeding disorder, active dual antiplatelet therapy, recent ischemic stroke, intracranial malignancy, history of bleeding diatheses (eg, hemophilia), history of GI bleeding within previous 3 months, thrombolysis within the previous 7 days, presence of an epidural or spinal catheter, recent major surgery < 14 days, or uncontrolled hypertension (systolic BP > 200 mm Hg, diastolic BP > 120 mm Hg).
2. In hospitalized patients with acute illness with COVID-19 who are not receiving therapeutic dose heparin (UFH or LMWH), we recommend current standard dose anticoagulant thromboprophylaxis over intermediate dose anticoagulation (defined as LMWH bid or increased weight-based dosing that is less than recommended therapeutic doses) (Strong Recommendation, Ungraded Consensus-Based Statement).
3. In critically ill patients with COVID-19, we suggest current standard dose anticoagulant thromboprophylaxis (with UFH or LMWH) over therapeutic dose anticoagulation (Conditional Recommendation, Ungraded Consensus-Based Statement).. In critically ill patients with COVID-19, we suggest current standard dose anticoagulant thromboprophylaxis over intermediate dose anticoagulation (defined as LMWH bid or increased weight-based dosing that is less than recommended therapeutic doses) (Conditional Recommendation, Ungraded Consensus-Based Statement).

# Background
Within the first few months of the COVID-19 global pandemic, it was recognized that patients hospitalized with SARS-CoV-2 often exhibited markers of a hypercoagulable state and had an increased incidence of VTE. Reports documented significantly elevated D-dimer levels that were associated with increased morbidity and mortality. [bib_ref] Anticoagulant treatment is associated with decreased mortality in severe coronavirus disease 2019..., Tang [/bib_ref] [bib_ref] Characteristics of emergency patients with markedly elevated D-dimer levels, Tang [/bib_ref] This led many professional societies, including CHEST, [bib_ref] Prevention, diagnosis, and treatment of VTE in patients with coronavirus disease 2019:..., Moores [/bib_ref] to develop rapid guidance documents regarding the optimal strategy for prophylaxis of VTE in these patients. [bib_ref] COVID-19 and thrombotic or thromboembolic disease: implications for prevention, antithrombotic therapy, and..., Bikdeli [/bib_ref] [bib_ref] American Society of Hematology 2021 guidelines on the use of anticoagulation for..., Cuker [/bib_ref] [bib_ref] Guidance for the management of patients with vascular disease or cardiovascular risk..., Gerotziafas [/bib_ref] [bib_ref] COVID-19) Treatment Guidelines. National Institutes of Health; 2021. Accessed, Panel [/bib_ref] Initially, evidence was extremely limited and consisted of fewer than 30 retrospective cohort studies of varying size that reported on patients from varied geographic regions and clinical settings. There was no universal approach to screening or diagnosis. Perhaps most importantly, the thromboprophylaxis regimens varied across studies and were sometimes not reported at all. Based upon the limited, low-quality evidence suggesting patients with COVID-19 pneumonia had a higher risk of thrombosis than similarly ill patients without COVID-19, societal guidelines were uniform in their recommendation that all hospitalized patients with COVID-19 pneumonia receive pharmacologic thromboprophylaxis in the absence of a contraindication. Recommendations regarding the optimal dosing, however, varied. Some, including CHEST, recommended standard dose prophylaxis for all patients, while a few suggested that intermediate or therapeutic dosing could be considered, especially in patients admitted to the ICU. [fig_ref] TABLE 1 ]: Early Societal Guidelines Regarding Thromboprophylaxis in COVID-19 [/fig_ref] provides a summary of these early recommendations.
Since then, our understanding of the underlying pathophysiologic mechanisms of this prothrombotic state has advanced. While it is beyond the scope of this manuscript to describe these mechanisms in detail, it should be noted that there are two distinct but related processes: a hypercoagulable state that leads to large vessel macrothrombosis and a primary endotheliopathy that results in extensive in situ, immunothrombosis. A more detailed review of these mechanisms has recently been published. [bib_ref] Pulmonary thrombosis and thromboembolism in COVID-19, Poor [/bib_ref] Over the past 15 months, we have also seen the emergence of randomized controlled trials focusing on the optimal dosing for thromboprophylaxis in both moderately ill hospitalized (non-ICU) and critically ill (ICU) patients. Here we provide updated guidance focused on prevention of thrombosis in hospitalized patients. We are not updating any prior guidance related to pre-or posthospital prophylaxis, diagnosis, or treatment.

## Study design and methods
The panel followed standard CHEST process for the development of rapid guidance statements, as detailed in the first version of this guideline. [bib_ref] Prevention, diagnosis, and treatment of VTE in patients with coronavirus disease 2019:..., Moores [/bib_ref] Conflict of interest declarations were reviewed for all panelists by the Professional Standards Committee. No panelist required any management for the topic areas being updated. The panel was aware of recently published or studies expected to be published soon regarding optimal thromboprophylaxis and thus chose to limit this update to guidance statements in this topic area. The original Population, Intervention, Comparator, Outcome questions were used to guide the search, using MEDLINE via PubMed. Screening and full text selection were performed in duplicate by pairs of panel members. Additional studies were identified by panel members as they were published. Included studies [bib_ref] Therapeutic versus prophylactic anticoagulation for severe COVID-19: a randomized phase II clinical..., Lemos [/bib_ref] [bib_ref] Therapeutic versus prophylactic anticoagulation for patients admitted to hospital with COVID-19 and..., Lopes [/bib_ref] [bib_ref] Standard prophylactic versus intermediate dose enoxaparin in adults with severe COVID-19: a..., Perepu [/bib_ref] [bib_ref] Effect of intermediatedose vs standard-dose prophylactic anticoagulation on thrombotic events, extracorporeal membrane..., Sadeghipour [/bib_ref] [bib_ref] Effectiveness of therapeutic heparin versus prophylactic heparin on death, mechanical ventilation, or..., Sholzberg [/bib_ref] [bib_ref] Efficacy and safety of therapeutic-dose heparin vs standard prophylactic or intermediatedose heparins..., Spyropoulos [/bib_ref] are outlined in.
Risk of bias was assessed by the methodologist using Version 2 of the Cochrane risk-of bias tool for randomized trials (RoB 2). [bib_ref] RoB 2: a revised tool for assessing risk of bias in randomised..., Sterne [/bib_ref] Data abstraction was done in duplicate. Any discrepancies were resolved through consensus. Primary outcomes included VTE (pulmonary embolism and DVT), fatal PE, major bleeding, fatal bleeding, mortality, and organ support-free days (OSFDs). As our original guideline focused on VTE, we did not include arterial thrombosis as an outcome. A meta-analysis, using a random effects model, was performed. The panel then created summaries using the GRADE Evidence-to-Decision framework. [bib_ref] GRADE Evidence to Decision (EtD) frameworks: a systematic and transparent approach to..., Alonso-Coello [/bib_ref] These summaries were discussed by the entire group, and updated guidance statements were suggested and voted upon using a modified Delphi approach. This approach utilized several rounds of anonymous voting, with survey results and comments presented to the panel after each round until consensus was achieved. Per CHEST policy, consensus was defined as at least 80% agreement for each recommendation with at least 75% voting participation rate from the panel. Recommendation 1 was controversial and required four rounds of voting (see context comments below). Recommendation 2 reached consensus in three rounds of voting. Recommendations 3 and 4 each reached consensus after two rounds of voting.

# Results and recommendations
As in the first version of the guideline, we chose to provide separate guidance statements for VTE prevention for hospitalized patients with acute illness (also described as moderately ill, or non-ICU patients) and critically ill patients either hospitalized in the ICU or receiving ICU level care. However, we divided each original Population, Intervention, Comparator, Outcome question and resulting recommendation into two questions: standard prophylaxis vs therapeutic (or escalated dose) prophylaxis and standard prophylaxis vs intermediate dose prophylaxis.

## Hospitalized patients with acute illness
Question 1: Should patients with acute illness with COVID-19 be treated with therapeutic anticoagulation or thromboprophylaxis for prevention of VTE?
There were four studies reporting on 3,475 patients addressing this question, the largest being the multiplatform ATTACC, ACTIV-4a, and REMAP-CAP studychestjournal.org malignancy, history of bleeding diatheses (eg, hemophilia), history of GI bleeding within previous 3 months, thrombolysis within the previous 7 days, presence of an epidural or spinal catheter, recent major surgery < 14 days, or uncontrolled hypertension (systolic BP > 200 mm Hg, diastolic BP > 120 mm Hg).
Context: The panel struggled to come to consensus on this recommendation. From a pure VTE perspective, these trials are consistent with historical trialstherapeutic heparin, either intravenous UFH or full dose LMWH, reduces VTE at the cost of increased bleeding, without any benefit in overall mortality. The reporting of decreased OSFDs in the multiplatform trial 12 deserves notice but is not a typical outcome used in VTE studies. That said, in balance, the benefits of therapeutic vs prophylactic dosing appear to favor the former. Several nuanced issues beyond this were discussed. The ACTION [bib_ref] Therapeutic versus prophylactic anticoagulation for patients admitted to hospital with COVID-19 and..., Lopes [/bib_ref] trial, which was the only one to use therapeutic doses of rivaroxaban as opposed to heparin, showed no overall benefit. To explain this, we might invoke that there are additional pleiotropic and/or antiinflammatory effects of heparin that are beneficial beyond the benefits of thromboprophylaxis. While plausible, studies in similarly ill patients without COVID-19 have been inconclusive. The panel also noted the inconsistency in effect between hospitalized patients with acute (moderate) illness and critically ill patients, -Outcomes in moderately ill hospitalized patients receiving therapeutic anticoagulation vs standard thromboprophylaxis.
with the OSFD benefit only being seen in the former. This invokes a hypothesis regarding timing of the initiation. Perhaps early administration of therapeutic heparin does indeed affect the underlying pathophysiologic mechanisms in a way that reduces macrothrombosis and microthrombosis, but once patients develop more severe end-organ damage, the harmful effects outweigh any benefit. This is also plausible but not fully studied. Another concern raised was the likelihood of ascertainment bias (patients in the therapeutic arm of an open-label trial may be less likely to undergo diagnostic testing for VTE). Finally, the panel raised concern that the extremely low rate of bleeding in these trials does not match real-world rates, perhaps because patients with high risk of bleeding were excluded, and thus assessment of bleeding risk is paramount in decision-making. Panel members also pointed out the heterogeneous populations included in the trials and the known changes in standard management over time. Given all of this, the panel voted to make a conditional recommendation in favor of therapeutic anticoagulation, while noting in the remarks that the decision should be based upon the risk of thrombosis (those with higher D-dimer levels or other risks for VTE may be at higher risk) and the risk of bleeding (see [fig_ref] TABLE 3 ]: High Bleeding Risk Patients [/fig_ref] for a more extensive list of factors associated with an increased risk of bleeding). Although consensus was reached, one panel member strongly disagreed with this recommendation. There were no randomized trials addressing this question. The only study to inform this question was an observational cohort that reported on rates of VTE stratified by thromboprophylaxis received.The rate of VTE in the intermediate dosing group was 7/33 (21%) and in the prophylactic dose group, 20/67 (30%). Bleeding estimates were not reported. Given our original recommendation against intermediate dosing in these patients, the evidence already presented above for consideration of therapeutic dosing in this cohort, and the lack of any evidence suggesting clear benefit of this approach, the panel voted to endorse the prior recommendation, with consensus reached after one round of voting.
2. In hospitalized patients with acute illness with COVID-19 who are not receiving therapeutic dose heparin (UFH or LMWH), we recommend current standard dose anticoagulant thromboprophylaxis over intermediate dose anticoagulation (defined as LMWH bid or increased weight-based dosing that is less than recommended therapeutic doses) (Strong Recommendation, Ungraded Consensus-Based Statement).
Context: Given the lack of randomized controlled trials to address this question, there was unanimous agreement regarding this recommendation. Panel members also noted that "intermediate dose anticoagulation" leaves too much room for error and confusion in clinical practice.

## Critically ill patients
Question 3: Should critically ill patients with COVID-19 be treated with therapeutic anticoagulation or thromboprophylaxis for prevention of VTE?
For this analysis, we chose to include all studies that compared standard thromboprophylaxis dosing vs "escalated" dosing (intermediate or therapeutic). This was done because the panel recognized that common practice in many ICU settings includes varying escalated dosing protocols. There were five studies to inform this question, which included a total of 1,947 patients. Again, the largest was the multiplatform ATTACC, ACTIV-4a, and REMAP-CAP 13 trial, which accounted for 1,089 patients. Additional studies included the [fig_ref] Question 2: Should patients with COVID-19 hospitalized in the ward setting be treated with... [/fig_ref]. days in the therapeutic dose cohort vs 0 (0-11) ventilator-free days in the prophylactic group, which was significant (P 14 .028). In the HEP-COVID 20 trial, 10/38 (26.3%) in the therapeutic group required mechanical ventilation compared with 8/35 (22.9%) in the thromboprophylaxis group. Six trials were included in the mortality analysis. In addition to the trials mentioned above, the ACTION 16 trial also included a small number of critically ill patients (n 14 39) who were incorporated in the analysis. There was no significant difference in mortality between the two groups (RR, 1.03 [95% CI, 0.91-1.15]) [fig_ref] Question 2: Should patients with COVID-19 hospitalized in the ward setting be treated with... [/fig_ref].
3. In critically ill patients with COVID-19, we suggest current standard dose anticoagulant thromboprophylaxis (with UFH or LMWH) over therapeutic dose anticoagulation (Conditional Recommendation, Ungraded Consensus-Based Statement).
Context: There was no disagreement about the direction of the recommendation. The data supporting thromboprophylaxis for the critically ill are quite robust.
Other than the effect on PE seen in the multiplatform trial, there was insufficient evidence to suggest deviation from standard thromboprophylaxis. When all outcomes in the multiplatform trial, and not just PE, are factored in, the case against therapeutic anticoagulation is quite strong. Furthermore, although the risk of VTE is likely lower on therapeutic anticoagulation (absolute risk reduction, approximately 5%), the risk of major bleeding is higher (absolute risk increase, approximately 1%-2%), and there is no effect on mortality. Considering the risk of ascertainment bias for VTE in these open-label trials, the incomplete reporting of VTE events (no DVTs reported) and the high probability of inferiority of therapeutic anticoagulation compared with usual thromboprophylaxis for OSFDs in the multiplatform trial, the data thus far support continued use of existing guidelines.

# Discussion and limitations
This manuscript serves as a brief update to the original guidance statement. [bib_ref] Prevention, diagnosis, and treatment of VTE in patients with coronavirus disease 2019:..., Moores [/bib_ref] Although we have better quality evidence, many questions remain. Despite this, our panel felt that it was important to share our thoughts regarding the new evidence, especially as one recommendation differs in direction from the original publication, and the others have more evidence to support them. The decision to change the recommendation was not an easy one. While the new trials are higher quality evidence, the interpretation of the results is not without controversy. Progression of respiratory failure due to COVID-19 is a different end point than preventing VTE. In the end, we felt that it was an important end point.
Some may question our decision not to include arterial thrombotic events as a primary outcome. These are clearly important to patients and clinicians. Our original publication, however, was focused on VTE, [bib_ref] Prevention, diagnosis, and treatment of VTE in patients with coronavirus disease 2019:..., Moores [/bib_ref] and this was designed as an update to that publication. In addition, a recent meta-analysis that did include these events would not likely have changed our recommendations. [bib_ref] Safety and efficacy of different prophylactic anticoagulation dosing regimens in critically and..., Ortega-Paz [/bib_ref] Questions remain and should guide further research. Does the timing of heparin administration affect the ultimate outcome? Should patients admitted to the ICU during their admission continue therapeutic heparin?
chestjournal.org Does heparin indeed have antiinflammatory, antiviral, or other pleiotropic effects in COVID-19? Which mechanisms of the prothrombotic state are prominent, and does this influence the optimal approach? Are current standard therapies changing the baseline risk of VTE? Should the approach to vaccinated patients be any different than unvaccinated patients?

## Conclusions and future directions
We have learned quite a bit regarding thrombosis in patients with COVID-19 pneumonia. Although advances in care have improved overall outcomes, current evidence supports that the rates of VTE are higher in these patients, at least in the ICU. [bib_ref] Incidence of VTE and bleeding among hospitalized patients with coronavirus disease 2019:..., Jimenez [/bib_ref] [bib_ref] Venous thromboembolism in COVID-19 compared to non-COVID-19 cohorts: a systematic review with..., Mai [/bib_ref] At this time, we believe critically ill patients should still receive standard thromboprophylaxis for VTE, and moderately ill patients with a low bleeding risk might benefit from therapeutic heparin. We see no role for intermediate dose thromboprophylaxis in either setting. The World Health Organization plans to perform a meta-analysis that includes several small trials along with the studies included here, and their findings may inform practice (PROSPERO registration ID is CRD42020213461). In addition, results from recently published trials examining the effect of pre-and posthospital prophylaxis may lead to additional guideline updates.
[fig] 12: patients were excluded, because they did not have confirmed COVID-19. f In REMAP-CAP, levels of oxygen support (including no support) below the level of high-flow nasal cannula were not reported.g Levels of oxygen support below the level of high-flow nasal cannula were not reported. h Levels of oxygen support other than mechanical ventilation were not reported. At baseline, 107 (62%) patients were admitted to an ICU. i A total of 45 of 253 (18%) patients were on either high-flow or noninvasive positive pressure ventilation. j Not listed are 113 patients who were co-enrolled in the REMAP-CAP Antiplatelet Domain (47 in the therapeutic dose anticoagulation group and 66 in the usual care pharmacologic thromboprophylaxis group). k Not listed are 74 patients who were co-enrolled in the REMAP-CAP Antiplatelet Domain (39 in the therapeutic dose anticoagulation group and 35 in the usual-care pharmacologic thromboprophylaxis group). l Treatment during trial period. [/fig]
[fig] Question 2: Should patients with COVID-19 hospitalized in the ward setting be treated with intermediate dose anticoagulation or thromboprophylaxis? [/fig]
[fig] Figure 2 -: Outcomes in critically ill patients receiving increased-dose anticoagulation vs standard thromboprophylaxis. PPx 14 prophylaxis or thromboprophylaxis. [/fig]
[fig] Figure 3 -: Outcomes in critically ill patients receiving intermediate-dose thromboprophylaxis vs standard thromboprophylaxis. [/fig]
[table] TABLE 1 ]: Early Societal Guidelines Regarding Thromboprophylaxis in COVID-19 [/table]
[table] TABLE 3 ]: High Bleeding Risk Patients [/table]