COVID-19 VTE Prevention: The Case for Intermediate and Outpatient Dosing

Should patients hospitalized for COVID-19 routinely receive extra anticoagulation or go home with a course of antithrombotics?

The first randomized controlled trial data are still emerging, leaving those questions to the realm of expert consensus statements with only observational and pre-COVID data from which to extrapolate.

The key fulcrum on which the decision rests is how elevated venous thromboembolism (VTE) risk is versus how much bleeding occurs in COVID-19 patients, noted speakers at a Pulmonary Embolism Response Team Consortium webinar on Wednesday.

A widely cited meta-analysis in CHEST yielded a 17% estimated incidence of VTE across 47 studies in hospitalized COVID-19 patients largely on standard thromboprophylaxis, which individually ranged from 0% to 85%.

But you also can’t ignore the 7.8% rate of bleeds in that meta-analysis, noted Rachel Rosovsky, MD, MPH, of Massachusetts General Hospital and Harvard Medical School in Boston.

Still, the major bleeding rate was a more modest 3.9%, so “using these escalated doses in ward patients is probably something we should be considering” to minimize thrombotic complications that might tip patients into needing ICU care, argued Lana Castellucci, MD, of the University of Ottawa, in her presentation on the webinar.

While her center is giving intermediate-dose prophylaxis both in the wards and ICU, the strongest rationale for boosting the dose from standard prophylaxis to intermediate doses is in ICU patients, in whom the room for benefit is bigger and the tradeoff looks most favorable, she noted.

The CHEST meta-analysis pointed to a VTE rate of 7.1% in the general wards, but a rate of 27.9% in the ICU, whereas the 4.4% major bleed rate in ICU patients was roughly the same as that overall.

On the other hand, the American Heart Association COVID-19 registry turned up a less than 4% deep vein thrombosis (DVT) or pulmonary embolism rate, noted webinar panelist Behnood Bikdeli, MD, of Brigham and Women’s Hospital and Harvard Medical School in Boston.

More importantly, many of the thrombotic events reported have been ones that are not life-threatening, with the VTE rate dropping to around 12% in the ICU after excluding catheter-associated events, sub-segmental pulmonary embolism, and isolated distal DVT in the CHEST meta-analysis, he pointed out.

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Irrespective of the risk, there’s no solid evidence at this point that extra anticoagulation is going to help, Bikdeli argued.

Going full therapeutic dose had been suggested by some observational data and the small phase II HESACOVID trial, but has not panned out in three large randomized trials, which all recently shut down the therapeutic dose arms for ICU patients based on futility in reducing need for organ support and a signal for harm.

More data are coming, though, as four of the 75 ongoing antithrombotic therapy trials in COVID-19 are assessing intermediate-dose low-molecular-weight heparin or unfractionated heparin in the ICU, as Bikdeli’s group recently noted in a systematic review available on the preprint server medRxiv.

Bikdeli’s INSPIRATION trial comparing intermediate and standard prophylaxis in ICU COVID-19 patients should be imminently available, he said.

“Until then, equipoise remains,” he concluded. “I wish our mechanistic thinking would play out,” but history has shown that doesn’t always happen.

Post-discharge is also an elevated-risk period, with a higher risk in COVID-19 patients than seen for other patients, noted Kristen M. Sanfilippo, MD, MPHS, of Washington University School of Medicine in St. Louis, Missouri, during the webinar.

In a nearly 5,000-patient study presented at last year’s American Society of Hematology (ASH) meeting, 1.55% developed VTE in the 90 days post-discharge for COVID-19, with 4% mortality during that period. In the MARINER trial, about 1% of post-discharge patients in the placebo group had symptomatic VTE or related death.

However, a recent population-based study from Denmark did not support any higher post-discharge thrombotic risk in COVID-19 patients compared with non-COVID patients or in a historical influenza cohort.

There haven’t been any studies on whether extended thromboprophylaxis works in the post-COVID population, but a meta-analysis of trials pre-COVID suggested a 39% risk reduction in acutely ill medical patients, despite mixed results in trials like MAGELLAN and MARINER.

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The bleeding risk was higher with post-discharge prophylaxis, but the absolute risk was only about 0.3 percentage points higher in the meta-analysis.

In a study of 447 COVID-19 patients published in Research and Practice in Thrombosis and Haemostasis, the 43% discharged on prophylactic anticoagulants had a 1.1% rate of vascular thromboembolic events compared with 2.7% of those discharged without anticoagulation (adjusted OR 0.52, 95% CI 0.08-2.26).

However, with such a low rate of events, senior author Stephan Moll, MD, of the University of North Carolina at Chapel Hill, and colleagues concluded that their findings “suggest against the routine use of post-discharge thromboprophylaxis in COVID-19 patients.”

There could be implications for outpatient trials like the NIH ACTIV-4c trial randomizing COVID-19 patients to aspirin, apixaban (Eliquis), or placebo: “I am fearful that the ACTIV-4c trial will be futile, like the other ACTIV-4a trial recently stopped,” Moll told MedPage Today.

Meanwhile, expert consensus guidelines do not recommend post-discharge prophylaxis for COVID-19, noted webinar panelist Rushad Patell, MD, of Beth Israel Deaconess Medical Center in Boston.

Sanfilippo argued for individualized decisions weighing patients’ bleeding risk and factors consistently linked to post-discharge VTE, such as obesity, prolonged immobility, and certain pre-existing comorbidities. “We’re not going to have a one-size-fits-all solution,” she said.

For now, any use “should remain in line with the inclusion and exclusion criteria for patients enrolled in the pre-COVID-19 randomized controlled trials,” she added.

Disclosures

The webinar was supported by an educational grant from Janssen.

Rosovsky disclosed financial relationships with BMS, Janssen, and Dova.

Bikdeli disclosed work with the RIETE registry supported by Bayer Pharma and Sanofi Spain, salary support from the NHLBI, and consulting for litigation on IVC filters.

Castellucci disclosed financial relationships with BMS, Pfizer, Amag Pharmaceuticals, and The Academy.

Patell and Sanfilippo disclosed no relevant relationships with industry.


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