麻豆传媒

Anticoagulation was associated with better survival for certain COVID-19 patients in a large observational study from New York City.

Among 2,773 hospitalized COVID-19 patients treated early in the outbreak, the 28% who received systemic anticoagulation saw a similar in-hospital mortality rate as those who went without (22.5% vs 22.8%). Median survival was 21 versus 14 days.

However, among the 395 mechanically ventilated patients, in-hospital mortality was substantially lower with the therapeutic-dose anticoagulation used in that setting -- 29.1% versus 62.7% -- with a median survival of 21 versus 9 days.

Notably, longer duration of anticoagulation was independently associated with reduced risk of mortality (adjusted HR 0.86 per day, 95% CI 0.82-0.89), Valentin Fuster, MD, PhD, of Icahn School of Medicine at Mount Sinai in New York City, and colleagues reported in the .

"We certainly think these patients should be anticoagulated unless the patients have a tendency for bleeding, so still you have to individualize," Fuster told 麻豆传媒.

Major bleeding didn't differ significantly overall by anticoagulation versus none (3% vs 1.9%, P=0.2).

The findings fit those of in COVID-19 but , commented Stephan Moll, MD, of the University of North Carolina at Chapel Hill.

"Thus, promising as these data from a large patient population are, the issue still has discrepant published data," he told 麻豆传媒. "However, they support the general impression by a number of clinicians and academicians, me included, that a somewhat more aggressive anticoagulation strategy in COVID-19 patients may be warranted."

Despite a well-powered (albeit tragically so) dataset and impressive potential effect size in intubated patients, the study was "significantly hampered by its retrospective nature, particularly by the fact that we do not know what decision led [physicians] to give certain patients full-dose anticoagulation," Moll cautioned.

Indeed, causation is far from clear and more information about baseline characteristics would be desirable, agreed Behnood Bikdeli, MD, of NewYork-Presbyterian Hospital/Columbia University Irving Medical Center in New York City.

"Those who survive (e.g., if they are healthier, or for other reasons) would receive a treatment for a longer period, just because they survive. Now, one hypothesis is that anticoagulation helped. But truthfully, we don't know," he said.

Fuster's study included patients hospitalized with laboratory-confirmed COVID-19 within five hospitals in the Mount Sinai Health System in New York City from March 14 through April 11, 2020.

At that time, the widespread coagulation with severe COVID-19 that has now been consistently observed and linked to strokes, clogged dialysis lines, and other manifestations of the disease was not yet clear.

The hospital system developed an algorithm based on initial data suggesting anticoagulation was working, Fuster noted. It called for subcutaneous enoxaparin at a low, prophylactic dose for those admitted to general wards (40 mg daily) and a full therapeutic dose (1 mg/kg body weight twice daily) in the ICU.

Now armed with the data in this paper, the hospital system has gotten more aggressive over the past 2 weeks, switching to an intermediate dose for patients outside the ICU (30 to 40 mg every 12 hours, depending on BMI), he said.

The policy is still evolving, Fuster said, as his group is now aiming to include 5,000 COVID-19-positive patients in an observational study to compare different strategies -- oral antithrombotic agents, subcutaneous heparin, and IV heparin. Depending on those findings, a randomized clinical trial might be the next step.

Meanwhile, Bikdeli said he stands by his group's recent consensus recommendations, which were supported by the International Society on Thrombosis and Haemostasis and four other professional societies, to consider prophylactic anticoagulation in most cases. "If higher doses are considered, it would be best to use them under prospective study protocols so that our practice today informs the practice for tomorrow," he said.

Patients in Fuster's study who received anticoagulation were more likely to require invasive mechanical ventilation (29.8% vs 8.1%, P<0.001). This "likely reflects reservation of [anticoagulation] for more severe clinical presentations," the researchers pointed out, although the association with improved survival persisted after adjusting for mechanical ventilation.

Anticoagulated patients also had higher risk by other clotting and inflammatory measures, including baseline prothrombin time, activated partial thromboplastin time, lactate dehydrogenase, ferritin, C-reactive protein, and D-dimer values. Among those on mechanical ventilation, these factors didn't differ by anticoagulation status.

A separate noted that coagulation abnormalities, including a prolonged activated partial-thromboplastin time (aPTT), have been reported in COVID-19, which "could be seen as a reason to avoid the use of anticoagulation at both therapeutic and prophylactic doses."

Looking in depth at 216 serum samples from COVID-19 patients with severe acute respiratory distress syndrome, 20% had prolonged aPTT. Fully 91% of the 34 patients tested for lupus anticoagulant were positive, significantly more than seen in historical controls. Factor XII deficiency was also common (50 IU/dL or lower in 16 patients).

While more study is needed to determine if lupus anticoagulant is behind COVID-19 thrombosis, neither it nor factor XII deficiency is associated with increased bleeding risk, K. John Pasi, MBChB, PhD, of Royal London Hospital, and colleagues wrote.

"We suggest that a prolonged aPTT should not be a barrier to the use of anticoagulation therapies in the prevention and treatment of venous thrombosis in patients with COVID-19," they concluded. "In our opinion, clinicians should not withhold use of anticoagulants for thrombosis while awaiting further investigation of a prolonged aPTT, nor should they withhold thrombolytic therapy in the face of a high-risk pulmonary embolism on the basis of a prolonged aPTT alone."

Fuster's group acknowledged the limitations of their observational dataset with potential for unobserved confounding, unknown indication for anticoagulation, lack of metrics to further classify illness severity in the mechanically ventilated subgroup, and indication bias.

Outcomes such as 30- or even 20-day mortality would have been more robust, given that in-hospital mortality could have been affected by factors such as discharge to hospice, Bikdeli noted. "Although some information about multivariable regression is provided, one potential concern is that the patients not receiving therapeutic anticoagulation were sicker. Additional clarifications by the authors could be very helpful."

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