Heparin's COVID-19 Benefit Greatest in Moderately Ill Patients

Richard Mark Kirkner

August 16, 2021

Editor's note: Find the latest COVID-19 news and guidance in Medscape's Coronavirus Resource Center.

Therapeutic levels of heparin can have widely varying effects on COVID-19 patients depending on the severity of their disease, according to a multiplatform clinical trial that analyzed patient data from three international trials.

COVID-19 patients in the ICU, or at least receiving ICU-level care, derived no benefit from anticoagulation with heparin, while non–critically ill COVID-19 patients – those who were hospitalized but not receiving ICU-level care – on the same anticoagulation were less likely to progress to need respiratory or cardiovascular organ support despite a slightly heightened risk of bleeding events.

Reporting in two articles published online in the New England Journal of Medicine, authors of three international trials combined their data into one multiplatform trial that makes a strong case for prescribing therapeutic levels of heparin in hospitalized patients not receiving ICU-level care were non–critically ill and critically ill.

"I think this is going to be a game changer," said Jeffrey S. Berger, MD, ACTIV-4a co–principal investigator and co–first author of the study of non–critically ill patients. "I think that using therapeutic-dose anticoagulation should improve outcomes in the tens of thousands of patients worldwide. I hope our data can have a global impact."

Outcomes Based on Disease Severity

The multiplatform trial analyzed data from the Antithrombotic Therapy to Ameliorate Complications of COVID-19 (ATTACC); A Multicenter, Adaptive, Randomized Controlled Platform Trial of the Safety and Efficacy of Antithrombotic Strategies in Hospitalized Adults with COVID-19 (ACTIV-4a); and Randomized, Embedded, Multifactorial Adaptive Platform Trial for Community-Acquired Pneumonia (REMAP-CAP).

The trial evaluated 2,219 non–critically ill hospitalized patients, 1,181 of whom were randomized to therapeutic-dose anticoagulation; and 1,098 critically ill patients, 534 of whom were prescribed therapeutic levels of heparin.

In the critically ill patients, those on heparin were no more likely to get discharged or spend fewer days on respiratory or CV organ support – oxygen, mechanical ventilation, life support, vasopressors or inotropes – than were those on usual-care thromboprophylaxis. The investigators stopped the trial in both patient populations: in critically ill patients when it became obvious therapeutic-dose anticoagulation was having no impact; and in moderately ill patients when the trial met the prespecified criteria for the superiority of therapeutic-dose anticoagulation.

ICU patients on therapeutic-level heparin spent an average of 1 day free of organ support vs. 4 for patients on usual-care prophylactic antithrombotic drugs. The percentage of patients who survived to hospital discharge was similar in the therapeutic-level and usual-care critically ill patients: 62.7% and 64.5%, respectively. Major bleeding occurred in 3.8% and 2.8%, respectively. Demographic and clinical characteristics were similar between both patient groups.

However, in non–critically ill patients, therapeutic levels of heparin resulted in a marked improvement in outcomes. The researchers estimated that, for every 1,000 hospitalized patients with what they labeled moderate disease, an initial treatment with therapeutic-dose heparin resulted in 40 additional patients surviving compared to usual-care thromboprophylaxis.

The percentages of patients not needing organ support before hospital discharge was 80.2% on therapeutic-dose heparin and 76.4% on usual-care therapy. In terms of adjusted odds ratio, the anticoagulation group had a 27% improved chance of not needing daily organ support.

Those improvements came with an additional seven major bleeding events per 1,000 patients. That broke down to a rate of 1.9% in the therapeutic-dose and 0.9% in the usual-care patients.

As the Delta variant of COVID-19 spreads, Patrick R. Lawler, MD, MPH, principal investigator of the ATTACC trial, said there's no reason these findings shouldn't apply for all variants of the disease.Lawler, a physician-scientist at Peter Munk Cardiac Centre at Toronto General Hospital, noted that the multiplatform study did not account for disease variant. "Ongoing clinical trials are tracking the variant patients have or the variants that are most prevalent in an area at that time," he said. "It may be easier in future trials to look at that question."

Explaining Heparin's Varying Effects

The study did not specifically sort out why moderately ill patients fared better on heparin than their critically ill counterparts, but Lawler speculated on possible reasons. "One might be that the extent of illness severity is too extreme in the ICU-level population for heparin to have a beneficial extent," he said.

He acknowledged that higher rates of macrovascular thrombosis, such as venous thromboembolism, in ICU patients would suggest that heparin would have a greater beneficial effect, but, he added, "it may also suggest how advanced that process is, and perhaps heparin is not adequate to reverse the course at that point given relatively extensive thrombosis and associate organ failure."

As clinicians have gained experience dealing with COVID-19, they've learned that infected patients carry a high burden of macro- and microthrombosis, Berger said, which may explain why critically ill patients didn't respond as well to therapeutic levels of heparin. "I think the cat is out of the bag; patients who are severe are too ill to benefit," he said. "I would think there's too much microthrombosis that is already in their bodies."

However, this doesn't completely rule out therapeutic levels of heparin in critically ill COVID-19 patients. There are some scenarios where it's needed, said Berger, associate professor of medicine and surgery and director of the Center for the Prevention of Cardiovascular Disease at New York University Langone Health. "Anyone who has a known clot already, like a known macrothrombosis in their leg or lung, needs to be on full-dose heparin," he said.

That rationale can help reconcile the different outcomes in the critically and non–critically ill COVID-19 patients, wrote Hugo ten Cate, MD, PhD, of Maastricht University in the Netherlands, wrote in an accompanying editorial. But differences in the study populations may also explain the divergent outcomes, ten Cate noted.

The studies suggest that critically ill patients may need hon-heparin antithrombotic approaches "or even profibrinolytic strategies," Cate wrote, and that the safety and effectiveness of thromboprophylaxis "remains an important question." Nonetheless, he added, treating physicians must deal with the bleeding risk when using heparin or low-molecular-weight heparin in moderately ill COVID-19 patients.

Deepak L. Bhatt MD, MPH, of Brigham and Women's Hospital Heart & Vascular Center, Boston, said in an interview that reconciling the two studies was "a bit challenging," because effective therapies tend to have a greater impact in sicker patients.

"Of course, with antithrombotic therapies, bleeding side effects can sometimes overwhelm benefits in patients who are at high risk of both bleeding and ischemic complications, though that does not seem to be the explanation here," Bhatt said. "I do think we need more data to clarify exactly which COVID patients benefit from various antithrombotic regimens, and fortunately, there are other ongoing studies, some of which will report relatively soon."

He concurred with Berger that patients who need anticoagulation should receive it "apart from their COVID status," Bhatt said. "Sick, hospitalized patients with or without COVID should receive appropriate prophylactic doses of anticoagulation." However, he added, "Whether we should routinely go beyond that in COVID-positive inpatients, I think we need more data."

The ATTACC platform received grants from the Canadian Institutes of Health Research and several other research foundations. The ACTIV-4a platform received funding from the National Heart, Lung, and Blood Institute. REMAP-CAP received funding from the European Union and several international research foundations, as well as Amgen and Eisai.

Lawler had no relationships to disclose. Berger disclosed receiving grants from the NHLBI, and financial relationships with AstraZeneca, Janssen, and Amgen outside the submitted work. ten Cate reported relationships with Alveron, Coagulation Profile, Portola/Alexion, Bayer, Pfizer, Stago, Leo Pharma, Daiichi, and Gilead/Galapagos. Bhatt is chair of the data safety and monitoring board of the FREEDOM COVID anticoagulation clinical trial.

This article originally appeared on MDedge.com, part of the Medscape Professional Network.

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