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Anticoagulants may be ineffective in severe cases

Severe cases of COVID-19 result in uncontrolled inflammation leading to thrombosis (formation of blood clots) in several organs. These risks are generally assessed by levels of specific circulating biomarkers, such as C-reactive protein or D-dimer. As a precaution, patients may be given preventative treatments based on heparin and low molecular weight derivatives (pharmacological thromboprophylaxis), in order to avoid secondary hemostasis (formation of clots) or to reduce inflammation. But observations have suggested that administering these anticoagulants in therapeutic doses (higher, and for longer, and sometimes using a different means of administration) may help patients. But the effects are still uncertain.

Researchers and Canadian doctors (in a consortium of universities, including Manitoba) carried out an international clinical trial (393 hospitals involved) in order to determine if heparin-based anticoagulants (in therapeutic doses) would be beneficial for critically ill patients. Three clinical trials began in April 2020 and were specifically adapted, with harmonisation of procedures and strategies (REMAP -CAP, ACTIV-4a, ATTACC). These trials received support from the National Institute of Health (NIH) and the American defence department. The symptomatic COVID-19 patients were classified according to the severity of their cases (particularly concerning the necessity of respiratory or cardiac assistance) and according to their blood levels of D-dimer. The anticoagulants were given randomly (564 patients, with 41% given standard doses and 51% higher doses, via centralised computer systems. Unless they left the emergency services before the end, patients were studied for almost a month, and precise measures were planned in advance to deal with organ failure.

What were the results of this study? On the one hand, the treatments were comparable. On the other, the anticoagulants are more dangerous.

Surprisingly, in the two groups, the problems of bleeding were rare and levels were only slightly higher with therapeutic doses (3,8% vs 2,3%). In both cases, thrombotic events and deaths reached 40%.  

However, treatment with anticoagulants is risky with higher doses: compared to standard thromboprophylactic treatments, therapeutic doses of anticoagulants (heparin) do not increase the probability of patient survival and do not reduce the number of days involving respiratory or cardiac assistance. The trial was even stopped in December 2020. In fact, anticoagulants turn out to be less effective than other treatments for critically ill patients.

The authors of the study suggest that the effects of this treatment can depend on the time of administration: once a severe state has been declared, it could be ineffective and would probably aggravate the alveolar haemorrhages frequently observed in the lungs of critically ill patients.

Another part of this study (also published in NEJM) shows, however, that therapeutic doses do increase survival of non-critical patients. Since this study was carried out in 10 different countries, its results are now applied in all COVID-19 treatment centres.

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