Doctors treating patients with a new disease face uncertainties. Will the treatment benefit or harm the patient or make no measurable difference. The results of controlled clinical trials and the difference between treatment and placebo, provide the guideposts for decisions. What must doctors do when the results of early clinical trials are ambiguous or contradictory as they often are for a new disease such as Covid-19.
Here I describe just such an example. Should patients hospitalized for Covid-19 be treated with anticoagulants as early as possible, or should treatment be delayed until clinical signs indicate that hyper-coagulation is likely? This is just one of the many judgments caregivers must make in facing a new complex disease such as Covid-19.
Hyper-coagulation (excessive blood-clotting) is a cause of death and disability facing patients hospitalized for severe Covid-19. Anticoagulants (blood thinners) have been reported to reduce in-hospital deaths. The question then becomes how early should anticoagulation therapy begin upon hospitalization. Here I review two studies that reach different conclusions.
The use of Heparin-based anticoagulants (blood-thinners) as a therapy for COVID-19 was initially put forward by a study of 449 patients with COVID-19 from Wuhan, China. The results concluded that no difference in 28‐day mortality was found between heparin users and nonusers. But patient subgroups at-risk of sepsis and coagulation dysfunction who had received low-dose prophylactic doses of heparin had approximately 20% lower mortality than patients who had not.
This study has some limitations as it did not control for medical or symptom history. The study was also conducted from January 1 to February 13, 2020 when there were still insufficient medical resources in Wuhan, China and the influence of other therapies on these patients has not been evaluated. However, the study still used a large patient population and due to the lack of treatment options for Covid-19 at the time, all patients received relatively similar supportive care.
A different US-based study demonstrates a link between the early initiation of preventative (prophylactic) anticoagulation in newly admitted COVID-19 patients lowers coronavirus disease mortality, compared with no treatment. The study examined 4297 patients (median age, 68 years; 93% men) who were admitted to Department of Veterans Affairs hospitals from March 1 to July 31, 2020 with laboratory-confirmed COVID-19 infection, and no history of anticoagulation. Those who received anticoagulation in the first 24 hours after hospital admission had a 27% lower risk for 30-day mortality than patients who received no anticoagulation therapy. The early onset of prophylactic anticoagulation was also not associated with an increased risk of transfusion-related bleeding.
In contrast to these two studies, a study from Northwestern University showed that patients who were newly started on therapeutic anticoagulation in the hospital had worse clinical outcomes. The study looked at 1716 adults hospitalized with COVID-19 of whom 372 were on therapeutic anticoagulation during their admission. After adjusting for controlled variables, there was no difference in death, critical illness or mechanical ventilation among patients who continued on therapeutic anticoagulation prescribed prior to admission when compared to patients who received preventative (prophylactic) anticoagulation. Patients who were newly started on therapeutic anticoagulation for COVID-19 infection, in the hospital had worse clinical outcomes; there was an increased risk of overall death, critical illness, mechanical ventilation, and death in critical illness. However, it is worth noting that 85.9% of these subjects who newly received therapeutic anticoagulation for COVID-19 infection had a critical illness status. The study concluded that they did not find any benefit of therapeutic anticoagulation in patients with COVID-19.
Based on these studies, it is currently too soon to broadly recommend the early use of low-dose anticoagulants to reduce Covid-19 related mortality rates. More research is needed to determine whether the apparent benefit of heparins could be related to their anti-inflammatory and antiviral effects, not just to their anticoagulant effect. We also need further research to investigate how the disease stage impacts the use of anticoagulants and what other subgroups would benefit most from this treatment. For now please sympathize with the doctors who must make this and other life and death decisions based on insufficient data several times a day as the pandemic rolls on.