COVID Clot Prevention Evidence Starts to Emerge

 Clotting problems with severe COVID-19 became clear in the early days of the pandemic; now at around the 1-year mark of the first cases, research is just beginning to reveal what prophylactic strategies are best.

By March, Chinese clinicians treating the initial onslaught of cases there pointed to endothelial damage and clotting in not only the lungs but also the heart and other organs. They argued for prophylactic anticoagulation of all these patients with severe disease regardless of meeting typical hospital criteria for it.

Case reports described pervasive clots in the lungs on autopsy; breakthrough clotting clogging dialysis lines despite antithrombotic medication; and even clots forming in real-time during mechanical thrombectomy for ischemic stroke.

Observational studies came swiftly, too, and have gradually clarified the prevalence of venous thromboembolic and other clotting complications.

"It is still presumably one of the important features of the disease; that I don't think we were far off from what we were thinking back in April and May," said Behnood Bikdeli, MD, of Brigham and Women's Hospital and Harvard Medical School in Boston.

Consensus guidelines emerged from the International Society on Thrombosis and Haemostasis (ISTH) plus other professional societies in April and from the American Society of Hematology in October.

However, clinical trials aimed at preventing these clots struggled. "I would have wished we had the results by now; part of the challenge is the disease came in waves," Bikdeli noted.

The small phase II HESA COVID trial made it through, finding that therapeutic-level dosing of enoxaparin (Lovenox) improved respiratory outcomes in severe COVID-19. Some other trials with even modestly larger samples weren't so lucky against rapidly shifting surges.

"We went from a blank piece of paper to our first patient randomized who had COVID in a little over 2 weeks. Those timelines are almost impossible," said Alex Spyropoulos, MD, primary investigator on the HEP-COVID trial, which compared anticoagulation dose strategies at Northwell Health's Feinstein Institutes for Medical Research in New York City.

"Northwell touched over 100,000 COVID-positive patients. And yet despite being in the epicenter of the epicenter, the pandemic passed us and we were only able to get few patients into our randomized trials," he told MedPage Today in June. The completion date for that trial was recently pushed back from October 2020 to April 2021.

Interim analysis of only the largest randomized trial platforms have started to yield results on antithrombotic use for COVID-19 now in December.

Three adaptive platform partner trials -- ACTIV-4, REMAP-CAP, and ATTACC -- just halted therapeutic anticoagulation for prophylactic use in ICU patients after interim data showed futility in seeking a reduction in need for organ support and possible safety concern.

"It is terrific gain of knowledge to have results from randomized trials, even if they have to be stopped early," said Stephan Moll, MD, a hematologist-oncologist involved in setting the prophylaxis protocols for the University of North Carolina at Chapel Hill. "This is refreshing news after all the retrospective, limited data of the first 9 months of the COVID-19 pandemic."

ACTIV-4, REMAP-CAP, and ATTACC data are "urgently" undergoing additional analyses to be made available as soon as possible, according to trial leadership. Non-ICU subgroups, and a range of other treatment arms in those trials, are also ongoing.

In November, the pragmatic, adaptive RECOVERY trial, which brought us dexamethasone for COVID-19, added an aspirin arm for 2,000 people hospitalized with the virus to see if it improves survival.

"Before COVID-19, we had seen the adaptive design more so in oncology. As of late, it has resurfaced in cardiovascular diseases as well, because during the pandemic obviously we need quick answers to several questions and they're testing multiple hypotheses," noted Bikdeli, who was involved with the ISTH consensus document and a primary investigator on the international INSPIRATION trial. The latter is testing intermediate-dose versus standard prophylactic anticoagulation in ICU patients with COVID-19. Enrollment in that two-by-two factorial design trial also looking at statins has completed, and results are expected soon.

The next few months should bring results from multiple outpatient antithrombotic trials, Bikdeli noted. For example, the ACTIV-4 trial also is studying aspirin in newly diagnosed ambulatory cases, while lower doses of direct oral anticoagulants, including apixaban (Eliquis) and rivaroxaban (Xarelto), are being investigated in this setting.

"To me, the lesson from all that has happened in the last several months is despite the best of our intent, just thinking physiologically and thinking what mechanisms make sense, might fall short of being the truth," Bikdeli said. "We should be cautious, wait for the data, and let the data inform our practice."

https://www.medpagetoday.com/infectiousdisease/covid19/90438