key: cord-0950069-ukrqnn76
authors: Spyropoulos, Alex C.; Lopes, Renato D.
title: Commissioned Commentary on the 2021 American Society of Hematology Guidelines on use of anticoagulation in patients with COVID-19 being discharged from the hospital
date: 2022-03-08
journal: Blood Adv
DOI: 10.1182/bloodadvances.2021006871
sha: 8c7b931c287afba4e7c578a02b36a6ff1fad14d0
doc_id: 950069
cord_uid: ukrqnn76

nan

The COVID-19 pandemic has fundamentally changed the way we practice medicine , conduct clinical trials, , and rapidly gather, generate, and evaluate high quality evidence to guide clinical practice. This is clearly apparent in the accelerated process of assessing and formulating clinical practice guidelines in order for them to be clinically meaningful during the compressed time frame of a pandemic. A good example of the natural tension that exists between methodological purity and clinical relevance of COVID-19 associated guidelines lies with the 2021 American Society of Hematology (ASH) Guidelines on use of anticoagulation in patients with COVID-19 being discharged from the hospital ( Table 1) 1 .

The authors issued a conditional recommendation against the use of outpatient anticoagulant prophyalxis in patients with COVID-19 being discharged from the hospital 1 However, as the authors themselves suggest, the overall low quality of evidence on the topic of post-discharge thromboprophylaxis of hospitalized COVID-19 patients requires both careful interpretation and judgment of both direct evidence in this population as well as indirect evidence from non-COVID-19 hospitalized medically ill populations, and it is here that the authors' interpretations are subject to some bias or not entirely based on a holistic or complete interpretation of the available clinical data. Importantly, three main issues stand out: 1) definition of the relevant hospitalized COVID-19 patient population at high thrombotic risk post-discharge, 2) choice of relevant outcomes, including balancing desirable versus undesirable effects of a thromboprophylactic strategy, and 3) methods of incorporating high quality evidence in a timely fashion.

With regards to the first issue, the definition of which hospitalized COVID-19 patients would benefit from a post-discharge thromboprophylactic strategy is critical to assess potential benefits of such a strategy. From a clinical perspective, the authors' recommendation that suggested against using anticoagulant thromboprophylaxis in patients with being discharged from the hospital should reflect the fact that routine use of such a strategy should be avoided in hospitalized COVID-19 patients, but this begs the question of which patient profiles at high thrombotic risk might benefit from this strategy. This was indeed the key issue with similar recommendations from the 2018 ASH Guidelines on post-discharge thromboprophylaxis in non-COVID 19 medically ill patients, which failed to incorporate clinical datawhich supported medically ill patient profiles at high thrombotic risk and low bleed risk (including those with pneumonia and sepsis) who clearly benefited from extended postdischarge thromboprophylaxis and which led to regulatory approval of 2 direct oral anticoagulants (DOACs) -betrixaban and rivaroxaban -for this indication [2] [3] [4] . The authors state that no (thrombotic) risk assessment models (RAMs) have been specifically derived or prospectively validated in COVID-19 patients. In addition, they include the IMPROVE-DD VTE RAM (which is a refinement of the well-validated IMPROVE VTE RAM that incorporates elevated D-dimers) in hospitalized medical patients as a "non-COVID" RAM that has been externally validated in COVID-19 patients 1 external validation studies in nearly 19,000 hospitalized COVID-19 patients using the original model cut-offs, with a score of 4 or more predicting a high VTE risk COVID-19 inpatient group, and has shown reasonable discrimination with an area under the curve of ~0.70 8, 9 . In another external validation study, the RAM was a strong and independent predictor of thrombosis and mortality in those patients classified as "high risk" 10 . In the largest prospective post-discharge registry encompassing nearly 5,000 hospitalized COVID-19 patients -the IMPROVE-DD VTE model using a cut-off score of 4 was an independent predictor of postdischarge thromboembolic outcomes and mortality (OR, 1.51; 95% CI, 1.06-2.14) 11 . Most importantly, the IMPROVE VTE RAM using a cut-off score of 4 or more or a score of 2 or 3 with elevated Dd was used prospectively in the seminal extended post-discharge clinical randomized trial of hospitalized COVID-19 inpatients -the MICHELLE trial -to select a high risk COVID-19 inpatient group for thromboembolism and cardiovascular mortality 12, 13 . It is clear from this data that the IMPROVE VTE RAM or its derivative incorporating elevated Dd is not only the most extensively validated thrombotic tool in hospitalized COVID-19 patients, but is able to be used prospectively to identify a high thrombotic risk group of COVID-19 inpatients that benefited from extended post-hospital discharge thromboprophylaxis ( Table 2) .

With regards to the second issue, we have clear evidence at this point that COVID-19 in hospitalized patients produces a severe COVID-19 specific coagulopathy manifested by dysregulated thrombin generation, much more than a bleeding diathesis 14 . A review of the evidence tables for the document reveals an overall low certainty in the evidence, which is consistent from data coming mostly from observational studies 1 . However, the evidence tables reveal in absolute terms benefits of 5 fewer deaths and 4 fewer VTE events per 1,000 COVID-19 inpatients with a post-discharge antithrombotic strategy versus 1 more major bleed per 1,000 patients 1 . The panel judged that both benefits and harms of post-discharge thromboprohylaxis was trivial, based on a defined estimated incidence of fewer than 5 events per 1,000 patients.

However, the clinical severity of efficacy and safety pairings should be taken into account when evaluating an overall antithrombotic strategy in guidelines development. Indeed, in previous antithrombotic guidelines, 5 fewer deaths per 1,000 patients from an antithrombotic strategy have not only been judged as non-trivial and clinically meaningful, but form the entire basis of why we give in-hospital thromboprophylaxis 15, 16 .

The third issue however, is paramount on how present guideline panels are able to incorporate rapidly evolving high quality data in the setting of the COVID-19 pandemic.

Randomized clinical trials conducted during a pandemic should follow the general high quality standards used in clinical research. However, the urgent need for assessing new treatments requires leveraging more efficient and innovative research processes to address new challenges in conducting clinical research. In the light of these principles, the MICHELLE trial was conducted in 14 centers in Brazil in approximately 9 months and showed the patients at high risk for thrombotic complications (defined as an IMPROVE VTE score of 4 or more or a score of 2 or 3 with elevated Dd) and low risk of bleeding who received thrombophylaxis with rivaroxaban 10 mg daily for 35 days versus no anticoagulation had a 67% relative risk reduction in the primary outcome, which included a composite of major thromboembolic events and cardiovascular death 12 . Importantly, no major bleeding events were seen with this strategy 12 .

Therefore, these results illustrate that despite the relatively small sample size, through the right study design, careful selection of the population, and appropriate choice of the antithrombotic regimen, the antithrombotic sweet-spot for post-discharge thromboprophylaxis in COVID-19 patients was found. Given this contemporary and randomized evidence to guide the care of patients with COVID-19, it is surprising to see that this background work in identifying a high thrombotic risk population using a validated VTE RAM and primary results of the MICHELLE trial not incorporated into the 2021 ASH guidelines for post-discharge extended anticoagulation in COVID-19 patients, especially during a pandemic where high quality evidence is desperately needed. Recommendation. The ASH guideline panel suggets against using outpatient anticoagulant thromboprophylaxis in patients with COVID-19 who are being discharged from the hospital and who do have suspected or confirmed VTE or another indication for anticoagulation (conditional recommendation based on very low certainty in the evidence about effects)

 An individualized assessment of the patient's risk of thrombosis and bleeding and shared decision-making are important when deciding on whether to use post-discarge thromboprohylaxis. Prospectively validated risk assessment models to estimate thrombotic and bleeding risk in COVID-19 patients following hospital discharge are not available  The panel acknowledged that post-discharge thromboprophylaxis may be reasonable in patients judged to be at high thrombotic risk and low bleed risk

The panel judged both the benefits and hars of post-discharge thromboprphylaxis to be trival in terms of absolute effects. While there was a trivial mortality benefit (5 fewer deaths [from 7 fewer to 2 fewer deats] per 1,000 patients and reduction in VTE (4 fewer [from 9 fewer to 4 more] per 1,000 patients, this evidence was of very low certainty. 

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IMPROVE -The International Medical Prevention Registry on Venous Thromboembolism

ULN -upper limit of normal

AUC ROC -area under the receiver operator curve