The Right Anticoagulation Dose in COVID-19? Final Answer Remains Elusive

Early on in the COVID-19 pandemic, patient presentations and autopsy reports made it abundantly clear that abnormal coagulation and multiorgan clotting were key signatures of this disease. Interim results from an eagerly awaited international, multiplatform randomized trial were released recently, suggesting that moderately ill patients—but not those who require ICU-level care—can benefit from therapeutic-dose anticoagulation. Yet it remains unclear whether that’s the right approach to take as a routine strategy.

That’s a critical question as the number of cases caused by more-infectious SARS-CoV-2 variants continue to mount around the world and asymptomatic spread continues. When can an anticoagulant help and who might it harm?

How frontline physicians and clinical trialists have come together to get an answer as quickly as possible to make informed decisions and—hopefully—save lives is a story of collaboration and agility not usually seen in the competitive arena of anticoagulant research.

Needing Definitive Answers

The earliest reports came out of China, pointing to an increase in thrombosis, both arterial and venous, associated with the disease. Shortly after, European researchers confirmed the findings.

Erik Klok, MD, PhD (Leiden University Medical Center, the Netherlands), was the lead author of two early studies conducted at three Dutch hospitals—one published on April 10 and the other on April 30, both in Thrombosis Research—affirming the high rates of thrombotic complications among COVID-19 patients who require ICU-level care.

Speaking to TCTMD more than 9 months later, Klok said his hospital acted on that early data. “We decided based on these observations that all patients in the Netherlands hospitalized for COVID-19 should receive thromboprophylaxis in usual doses,” Klok told TCTMD, adding that physicians are allowed to make the decision to go to higher doses. However, he said, “we advise against therapeutic doses of anticoagulation because, of course, of the risk of major bleeding.”

Observations by Klok and colleagues, as well as by Chinese investigators early on, proved to be just the tip of the iceberg. What really raised concerns among clinicians, according to Jeffrey Berger, MD (NYU Langone Health, New York, NY), were autopsy studies showing that in addition to thromboses in large arteries or veins, patients with COVID-19 also had a lot of microthrombosis that could be contributing to the poor outcomes of those infected with the virus.

These findings, repeated again and again as the pandemic wore on, led some to advocate for—and start using—higher doses of anticoagulation in patients with COVID-19, rather than the standard thromboprophylaxis given to hospitalized patients. Observational studies, including one conducted among Mount Sinai hospitals in New York City, suggested therapeutic-dose anticoagulation might improve survival, without a significant increase in major bleeding.

But those studies—often retrospective and conducted at single centers—could not provide definitive answers, and without randomized trials, physicians couldn’t be sure about what to do. Several randomized studies were launched, including a local trial at NYU called PROTECT, which served as the platform for the larger ACTIV-4a trial in hospitalized patients, according to Berger, co-principal investigator (PI) of the trial.

Insights From a Multiplatform RCT

To get to an answer more quickly, leaders of three trials—ATTACC, REMAP-CAP, and ACTIV-4a—joined forces. Together, the trials were conducted at several hundred sites across five continents. Adults hospitalized with COVID-19 were stratified by the severity of their illness—either requiring ICU-level care or not—and then randomized to receive therapeutic-dose heparin or usual prophylaxis for venous thromboembolism (VTE), all according to local hospital policy. Patients were treated for 14 days or until hospital discharge, whichever came first.

The primary outcome was the number of days free from the need for organ support (ICU-level care or a requirement for mechanical ventilation, extracorporeal membrane oxygenation, vasopressors, or high-flow nasal oxygen) through day 21, which also incorporated in-hospital mortality.

The last 2 months have seen the fruits of that collaboration.

A press release from the US National Institutes of Health (NIH), which coordinates the ACTIV program, announced on December 22, 2020, that enrollment into the ICU stratum had been paused based on futility. Therapeutic anticoagulation did not reduce the need for organ support, and there was potential harm. The trial continued in the moderately ill patients.

A month later, on January 22, 2021, the NIH issued another press release, this time with positive news: therapeutic-dose anticoagulation decreased the need for organ support in patients who did not require ICU-level care when they entered the study, regardless of D-dimer level, with a trend toward less mortality.

The contradictory results in the two patient groups were fleshed out a bit in a slide set released by trial investigators a week later, which had a warning emblazoned on the title slide: “Results are prepublication, not from locked databases, and not peer-reviewed.” The presented results confirm that therapeutic-dose anticoagulation was superior to standard thromboprophylaxis on the primary outcome in the non-ICU patients, and inferior in the ICU patients. For mortality, a secondary outcome, therapeutic-dose anticoagulation was associated with a numerically lower rate in the non-ICU group (5.7% vs 7.7%) but a higher rate in the sicker patients (35.3% vs 32.6%).

For composite thrombotic events (deep vein thrombosis, pulmonary embolism, MI, ischemic stroke, and other thrombotic events), rates were lower with therapeutic-dose heparin in both the moderate group (1.9% vs 5.3%) and the ICU group (6.7% vs 11.8%).

In terms of major bleeding, the rate was numerically higher with full-dose anticoagulation in both groups, although the researchers note that the rate remained below 2% (1.6% to be exact) in the moderately ill patients and—at 3.7%—in the predicted range for critically ill patients receiving therapeutic-dose heparin in the ICU group.

“It’s been nice to see that in a very short period of time, when people work together, we get answers to some really serious and fundamental questions,” Berger said.

Discrepant Results

It’s not clear why full-dose anticoagulation would be beneficial in patients who are only moderately ill with COVID-19 and potentially harmful in those who are already in the ICU, though it could have to do with the timing of treatment.

Jean Connors, MD (Brigham and Women’s Hospital, Boston, MA), said the trial “suggests that, in my mind, it may be too late to intervene to prevent pulmonary microvascular thrombosis in patients who reach the ICU because they’re so sick. They already have thrombosis and the heparin will prevent new thrombosis but doesn’t change the course of their illness.”

It’s been nice to see that in a very short period of time, when people work together, we get answers to some really serious and fundamental questions. Jeffrey Berger

In patients who have less-severe disease, on the other hand, “you can intervene with anticoagulation and prevent them from getting more ill because they’re not making all that microvascular thrombosis,” she speculated. “So it suggests maybe there’s a window of opportunity [where you can] intervene with anticoagulation to prevent organ support and possibly mortality.”

Berger agreed with the thrust of that argument. “I think that for patients who are in the severe state, it may just be too late,” he said. “They already have so much inflammation, immune dysfunction, maybe microthrombosis, that sort of the cat is out of the bag, that it’s a little bit too late to just be able to use a high-dose blood thinner to help them. I think for patients who are not there yet, these data suggest there is less requirement of ICU level of care. I think this would suggest that we need to start using these types of therapies earlier.”

Berger noted that the ongoing ACTIV-4b trial, for which Connors is the national PI, is evaluating whether starting antithrombotic therapies earlier in outpatients with COVID-19 will prevent hospitalization and thrombotic events.

Klok said, if anything, he would have expected to see a beneficial effect in the ICU-level patients, and he could not explain why the trial results worked out the way they did. It’s possible, he suggested, that use of unfractionated versus low-molecular-weight heparin could have influenced the findings. Unfractionated heparin is difficult to keep in the correct therapeutic range, he explained, especially in the setting of COVID-19, which is accompanied by high levels of inflammation and factor VIII activity. Additional trial details are needed to determine whether this played a role in the findings, Klok said.

Time to Change Practice?

The physicians interviewed by TCTMD differed in how the results should be interpreted and put into practice.

Connors said starting early on in the pandemic she was an advocate for bumping up anticoagulation to an intermediate dose for COVID-19 patients in the ICU based on the reports of increased thrombosis. Before responding to these new trial results, however, the community needs to see more data in a final, peer-reviewed publication. “How we apply this interim knowledge to our patients is not yet clear,” she said, noting that numbers in interim analyses can change when events are adjudicated.

It suggests maybe there’s a window of opportunity [where you can] intervene with anticoagulation to prevent organ support and possibly mortality. Jean Connors

“We are not changing our practice at the Brigham,” Connors said. “We are still using intermediate-dose heparin in our ICU patients—the goal is to prevent VTE. We’re not sure that it does that, but we’re a little leery of changing things right now.”

As for ramping up anticoagulation in less-sick patients, she added, “we’re not ready to change our practice. We’re not ready to give everybody that’s moderately ill therapeutic-dose heparin simply because they have COVID.”

Klok agreed that the interim results of the multiplatform trial, in which his center participated as part of REMAP-CAP, are not enough to shift practice around anticoagulation in COVID-19, stressing, too, that the final publication is needed before that can happen. He bemoaned the fact that study results have been increasingly released in preliminary form throughout the pandemic. “We do not change guideline recommendations based on press releases,” he said.

Especially because the multiplatform results are contradictory in the moderate and severe groups, there is a need to see the final published data as well as the findings from other ongoing randomized trials, of which there are several, Klok said. “We need detailed results of the ongoing randomized controlled trials to make an evidence-based recommendation. Until then, we should stick to what we know and what we do routinely.”

For his part, Berger sees results that can be acted upon now. He pointed out that before the results of the multiplatform RCT were released, some physicians were in the full-dose anticoagulation camp, others were in the lower-dose camp, and most realized there was sufficient equipoise to justify participation in the ongoing trials. The end result was that how anticoagulation was being used was all over the place. “Unfortunately, when you leave medical decisions to people’s opinions you see great differences in care around by location,” Berger said.

Now, with the interim results of the multiplatform trial available, “I think that has led to basically putting the brake on using, as a strategy, therapeutic anticoagulation in all patients receiving ICU-level of care,” he said.

As for the positive findings in the hospitalized patients who aren’t that sick, Berger said, “I personally think this is a game changer. I think this is what the medical community has been waiting for.”

Asked whether practice will start changing now or whether physicians will wait for the peer-reviewed publication of the results, Berger said, “I think that we have to remember that we are not in a normal era where we have the luxury of waiting for the data and evaluating it—meaning, we’re in a pandemic where every single day more patients are dying from this horrible disease. And I think that people are beginning to change their practice.”

The released data, though not final, are important because they will help clinicians as they weigh the risks and benefits of increasing anticoagulation dose in an individual patient, Berger said. “We were comforted by the fact that major bleeding was quite uncommon, and I think that is reassuring.”

He acknowledged, however, that even if individual centers decide to act on these findings, as NYU has, a full publication of the results will likely be needed to change practice guidelines in the United States.

Major Remaining Questions

Even after the multiplatform RCT results go through peer review and get published, there will still be a number of crucial questions that remain to be answered.

For instance, Berger said, it’s unknown how to handle moderately ill patients who are started on therapeutic-dose anticoagulation and then deteriorate. In ACTIV-4a, it was suggested that these patients remain on their assigned therapy unless there was a reason for switching, but it’s not clear that that’s the right approach.

We do not change guideline recommendations based on press releases. Erik Klok

In addition, he said, it’s unknown whether a patient who remains in the hospital beyond 14 days should continue on full-dose anticoagulation.

Moreover, there are emerging data that platelets are involved in COVID-19 as well, and the ACTIV-4a researchers—likely in collaboration with the REMAP-CAP and ATTACC groups—are planning another arm of the trial to investigate the safety and efficacy of platelet inhibitors.

For Klok, there are no definitive answers around anticoagulation in COVID-19 yet, “so all questions are still open.” He added, though, that “I think everybody agrees that we should give some form of anticoagulant treatment to all.”

In the “unprecedented and uncertain times” of the pandemic, Connors underscored, “everybody is trying to do the right thing, but we don’t know yet what the best approach is for these patients.”