COVID-19 Anticoagulation Trials 'Paused' for Futility, Safety

December 22, 2020

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Parts of three linked studies investigating increased levels of anticoagulation in hospitalized COVID-19 patients have been "paused" because of futility and safety concerns, a statement from the US National Heart, Lung, and Blood Institute (NHLBI) confirms.

The trials involved are the REMAP-CAP, ACTIV-4, and ATTACC studies.

All three trials have paused enrollment of critically ill COVID-19 patients requiring intensive care unit support for whom therapeutic doses of anticoagulation drugs did not reduce the need for organ support, the NHLBI statement notes.

The statement also says that a potential for harm in this subgroup could not be excluded, noting that increased bleeding is a known complication of full-dose anticoagulation. The trials are working urgently to undertake additional analyses, which will be made available as soon as possible.   

The three clinical trial platforms are working together to test the effects of full therapeutic doses of anticoagulants vs lower prophylactic doses in COVID-19 patients.

Informed by the deliberations of the data safety monitoring boards of these trials, all of the trial sites have paused enrollment of the most critically ill hospitalized patients with COVID-19. 

Enrollment continues in the trials for moderately ill hospitalized COVID-19 patients, the statement notes.  

"Whether the use of full-dose compared to low-dose anticoagulants leads to better outcomes in hospitalized patients with less COVID-19 severe disease remains a very important question," the NHLBI statement says.

Patients who require full dose anticoagulants for another medical indication are not included in these trials.

The statement explains that COVID-19 is associated with significant inflammation and clinical and pathologic evidence of widespread blood clots. These trials were launched because clinicians have observed that many patients ill with COVID-19, including those who have died from the disease, formed blood clots throughout their bodies, even in their smallest blood vessels. This unusual clotting can cause multiple health complications, including lung failure, myocardial infarction, and stroke. 

The three trials are the result of a collaboration between major international partners. The trials include: the Randomized, Embedded, Multi-factorial Adaptive Platform Trial for Community-Acquired Pneumonia (REMAP-CAP) Therapeutic Anticoagulation; Accelerating COVID-19 Therapeutic Interventions and Vaccines-4 (ACTIV-4) Antithrombotics Inpatient; and Antithrombotic Therapy to Ameliorate Complications of COVID-19 (ATTACC).

The trials, which span four continents, have the common goal of assessing the benefit of full doses of anticoagulants to treat moderately ill or critically ill adults hospitalized for COVID-19, compared with a lower dose often used to prevent blood clots in hospitalized patients.

In the United States, the ACTIV-4 trial is being led by a collaborative effort involving a number of universities, including the University of Pittsburgh and New York University.  

The trials are supported by multiple international funding organizations including the National Institutes of Health, Canadian Institutes of Health Research, the National Institute for Health Research (UK), the National Health and Medical Research Council (Australia), and the PREPARE and RECOVER consortia (European Union).

Risk-Benefit Ratio 'Not Favorable'

Judith Hochman, MD, director of the Clinical Cardiovascular Research Center at NYU Langone, who is principal investigator of the ACTIV-4 trial, explained to Medscape Medical News that all three trials are looking at the same question — whether full-dose therapeutic anticoagulation is superior to low-dose prophylactic anticoagulation with heparin or low molecular weight heparin in patients hospitalized with COVID-19.

The three trials started off slightly differently: REMAP began with only ICU patients but has broadened to include non-ICU patients as well, ATTACC started off with only non-ICU patients but has broadened to include ICU patients as well, and ACTIV-4 enrolled both ICU and non-ICU patients from the beginning.

The NHLBI is funding ACTIV-4, but the three trials are harmonizing the collection and review of data so they have greater power to show a result. "The vast majority of COVID trials are underpowered to come to any conclusions, so it is important to collaborate in this way," Hochman noted.

Elaborating on the reasons for pausing enrolment in the ICU cohort, she said, "We know full dose anticoagulation increases the risk of bleeding — that would be expected. But what we didn't know was whether it would have a greater efficacy compared to low-prophylactic doses in reducing critical illness. The primary endpoint of these trials in this ICU group was the number of organ support-free days — the number of days patients do not require vasopressor support, mechanical ventilation or high flow oxygen. Results so far show that the chance of seeing a difference in this outcome is very small if we continue," she said.    

"Given that the trial is unlikely to show a benefit and we know these full therapeutic doses of anticoagulation cause an increased bleeding risk, then there will not be a favorable risk-benefit."

The trial also has a key secondary endpoint of thrombotic events but that has not been analyzed and is not part of the current decision.

All three trials are continuing in the non-ICU patient group. These non-ICU patients make up 80% of the ACTIV-4 trial, more in the ATTACC trial, and less in the REMAP trial, Hochman reported. 

"It is very important to stress that these results do not apply to patients already on full dose anticoagulants for an approved indication," she cautioned. "We already know these patients with an approved indication for full dose anticoagulation have a positive risk benefit ratio, and they should not be concerned about the current findings. These trials are trying to prevent clots in critically ill patients who do not have an approved indication for full dose anticoagulation."

Asked how she recommends clinicians now treat these critically ill COVID patients in the ICU in terms of anticoagulation, Hochman said they have to use their clinical judgement. "Prophylactic doses of heparin/low molecular weight heparin are still indicated," she said. "Some centers are trying a slightly higher prophylactic dose but we don't have data on that yet."

Speculating on why the full dose anticoagulation did not show benefit, she suggested it might be too late in the course of the disease to make any difference. "What we've observed at autopsy is thrombi in the microcirculation as well as the large vessels. It may be too late to treat all those thrombi," she said. "We are still hopeful that higher doses of anticoagulation may show benefit earlier in the course of the disease."

The ACTIV-4 trial is actually made up of three different studies of anticoagulation in COVID-19 patients. ACTIV-4a is this study in hospitalized patients randomized to full-dose versus prophylactic-dose anticoagulation with heparin/LMW heparin.

The ACTIV-4b study is being conducted in nonhospitalized COVID patients looking at outpatient use of antithrombotic medication (aspirin or apixaban), and ACTIV-4c includes COVID-19 patients after they have been discharged from hospital and is testing low dose apixaban or placebo.

"The current announcement has no effect on ACTIV-4b or ACTIV-4c," Hochman noted.

Many Questions Remain

Commenting for Medscape Medical News, Gregg Stone, MD, Mount Sinai Heart Health System, New York, explained that autopsies in patients who have died of COVID-19 have shown widespread arterial and venous thrombosis, often not clinically evident, raising the hypothesis that anticoagulation might benefit such patients.

"Several questions arise," Stone said, including 1) whether any prophylactic anticoagulation is better than none; 2) whether full-dose anticoagulation is better than prophylactic-dose anticoagulation; 3) whether a new oral anticoagulant is more or less safe and/or efficacious than a heparin formulation; 4) whether anticoagulation is more likely to have a favorable safety and effectiveness endpoint in the early or late stages of the disease, he said.

"ACTIV-4 is addressing issues 2 and 4, but not issues 1 and 3," Stone said. "The [Data and Safety Monitoring Board (DSMB)] has now recommended pausing enrolment of those patients ill enough to be admitted to an ICU, but not earlier, suggesting that once the disease has progressed to a severe stage, full-dose anticoagulation is not beneficial (and may be harmful). Perhaps this is not a surprising finding."

But he says there is still a great deal that is not known. "Questions remaining include: What are the event rates that led to this pause? How ill were these patients? Were most intubated already with [acute respiratory distress syndrome] or was there similar lack of efficacy and possible harm in those not yet intubated, and/or with lesser radiographic abnormalities? What were the bleeding complications and the profile of the patients in whom bleeding occurred? And more."

Stone is part of a Mount Sinai group conducting the Freedom COVID-19 Anticoagulation trial in which 3600 hospitalized but less critically ill patients who are not intubated are randomized 1:1:1 to prophylactic-dose enoxaparin, full-dose enoxaparin, or apixaban.

"Given the different enrolment criteria and the fact that ACTIV-4 is continuing enrolment into the less severe strata, I don't anticipate major changes to our trial," he commented.

Similarly, other ongoing trials investigating different regimens of anticoagulation in COVID-19 patients will need to consider whether their studies need modification based on enrolment criteria and DSMB guidance, he said.

As to advice for practitioners, Stone recommends that they offer their patients participation in one of the ongoing randomized trials so these questions can be expeditiously answered. For those not within a randomized trial, because COVID-19 patients are at increased risk for bleeding, he recommends prophylactic-dose (and not full-dose) anticoagulation for those not at excessive risk for and without a definite indication for full-dose anticoagulation.

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