Do blood thinners prevent people who are hospitalised with COVID-19 from developing blood clots?

COVID-19 typically affects the lungs and airways, however, in addition to respiratory problems, about 16% of people hospitalised with COVID-19 experience problems with their blood and blood vessels, leading to blood clots forming in the arteries, veins and lungs. These blood clots can break loose and travel to other parts of the body, where they may cause blockages leading to heart attacks or strokes. Nearly half of all people with severe COVID-19, in intensive care units, may develop clots in their veins or arteries.

What are blood thinners?

Blood thinners are medicines that prevent harmful blood clots from forming. However, they may cause unwanted effects such as bleeding. Some guidelines recommend giving blood thinners when people are first admitted to hospital with COVID-19, to prevent blood clots from developing, rather than waiting to see if blood clots develop and then treating them with blood thinners.

What did we want to find out?

We wanted to know whether giving people hospitalised with COVID-19 blood thinners as a preventive measure, reduced the number of deaths compared to people who received no treatment or who received a placebo treatment. We also wanted to know whether these people needed less support with breathing, whether they still developed harmful blood clots, whether they experienced bleeding and whether they experienced any other unwanted events (for example, nausea, vomiting, kidney problems and amputations).

What did we do?

We searched for studies that assessed blood thinners given to people hospitalised with COVID-19 to prevent blood clots. Studies could be of any design as long as they compared a blood thinner with another blood thinner, no treatment or a placebo (sham). Studies could take place anywhere in the world and participants could be any age as long as they were in hospital with confirmed COVID-19 disease.

Search date: 20 June 2020

What we found

We hoped to find randomised controlled trials (RCTs). RCTs allocate participants at random to receive either the treatment under investigation or the comparison treatment (another treatment, no treatment or placebo). RCTs give the best evidence.

We did not find any RCTs, so we included seven non-randomised ‘retrospective’ studies that looked back at treatments given to 5929 people. These studies took place in intensive care units, hospital wards and emergency departments in China, Italy, Spain and the USA. They provided evidence on deaths and bleeding but no evidence on respiratory support, blood clotting and other unwanted effects. The studies were very different from each other, so we were not able to pool their results.

Blood thinners compared with no treatment (6 studies)
- One study reported a reduction in mortality and another study reported a reduction in mortality in severely ill people only. Three studies reported no difference in mortality and the remaining study reported no deaths in either group.
- One study reported major bleeding in 3% of participants who received blood thinners and 1.9% of participants who did not receive blood thinners.

Treatment dose of blood thinners compared with preventive dose (1 study)
All the participants were in the intensive care unit on mechanical ventilators. They may or may not have had blood clots but were given either blood thinners in a dose usually used to treat clots (higher dose), or a dose used to prevent clots (lower dose).
- This study reported a lower rate of death in people who received the treatment dose (34.2%) compared with the preventive dose (53%).
- This study reported major bleeding in 31.7% of participants who received the treatment dose compared with 20.5% of those who received the preventive dose.

Reliability of the evidence

We do not know whether blood thinners are a useful preventive treatment for people with COVID-19 because we are very uncertain about the evidence. None of the studies randomised participants and all were retrospective. Also, they reported different results from each other and did not report their methods fully. This means our confidence (certainty) in the evidence is very low.

What happens next?

Our searches found 22 ongoing studies, 20 of which are RCTs, with 14,730 people. We plan to add the results of these studies to our review when they are published. We hope that these better quality studies will provide a conclusive answer to our review question.

Authors' conclusions: 

There is currently insufficient evidence to determine the risks and benefits of prophylactic anticoagulants for people hospitalised with COVID-19. Since there are 22 ongoing studies that plan to evaluate more than 15,000 participants in this setting, we will add more robust evidence to this review in future updates.

Read the full abstract...
Background: 

Coronavirus disease 2019 (COVID-19) is a serious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The primary manifestation is respiratory insufficiency that can also be related to diffuse pulmonary microthrombosis in people with COVID-19. This disease also causes thromboembolic events, such as pulmonary embolism, deep venous thrombosis, arterial thrombosis, catheter thrombosis, and disseminated intravascular coagulopathy. Recent studies have indicated a worse prognosis for people with COVID-19 who developed thromboembolism.

Anticoagulants are medications used in the prevention and treatment of venous or arterial thromboembolic events. Several drugs are used in the prophylaxis and treatment of thromboembolic events, such as heparinoids (heparins or pentasaccharides), vitamin K antagonists and direct anticoagulants. Besides their anticoagulant properties, heparinoids have an additional anti-inflammatory potential, that may affect the clinical evolution of people with COVID-19. Some practical guidelines address the use of anticoagulants for thromboprophylaxis in people with COVID-19, however, the benefit of anticoagulants for people with COVID-19 is still under debate.

Objectives: 

To assess the effects of prophylactic anticoagulants versus active comparator, placebo or no intervention, on mortality and the need for respiratory support in people hospitalised with COVID-19.

Search strategy: 

We searched CENTRAL, MEDLINE, Embase, LILACS and IBECS databases, the Cochrane COVID-19 Study Register and medRxiv preprint database from their inception to 20 June 2020. We also checked reference lists of any relevant systematic reviews identified and contacted specialists in the field for additional references to trials.

Selection criteria: 

Randomised controlled trials (RCTs), quasi-RCTs, cluster-RCTs and cohort studies that compared prophylactic anticoagulants (heparin, vitamin K antagonists, direct anticoagulants, and pentasaccharides) versus active comparator, placebo or no intervention for the management of people hospitalised with COVID-19. We excluded studies without a comparator group. Primary outcomes were all-cause mortality and need for additional respiratory support. Secondary outcomes were mortality related to COVID-19, deep vein thrombosis (DVT), pulmonary embolism, major bleeding, adverse events, length of hospital stay and quality of life.

Data collection and analysis: 

We used standard Cochrane methodological procedures. We used ROBINS-I to assess risk of bias for non-randomised studies (NRS) and GRADE to assess the certainty of evidence. We reported results narratively.

Main results: 

We identified no RCTs or quasi-RCTs that met the inclusion criteria. We included seven retrospective NRS (5929 participants), three of which were available as preprints. Studies were conducted in China, Italy, Spain and the USA. All of the studies included people hospitalised with COVID-19, in either intensive care units, hospital wards or emergency departments. The mean age of participants (reported in 6 studies) ranged from 59 to 72 years. Only three included studies reported the follow-up period, which varied from 8 to 35 days. The studies did not report on most of our outcomes of interest: need for additional respiratory support, mortality related to COVID-19, DVT, pulmonary embolism, adverse events, and quality of life.

Anticoagulants (all types) versus no treatment (6 retrospective NRS, 5685 participants)

One study reported a reduction in all-cause mortality (adjusted odds ratio (OR) 0.42, 95% confidence interval (CI) 0.26 to 0.66; 2075 participants). One study reported a reduction in mortality only in a subgroup of 395 people who required mechanical ventilation (hazard ratio (HR) 0.86, 95% CI 0.82 to 0.89). Three studies reported no differences in mortality (adjusted OR 1.64, 95% CI 0.92 to 2.92; 449 participants; unadjusted OR 1.66, 95% CI 0.76 to 3.64; 154 participants and adjusted risk ratio (RR) 1.15, 95% CI 0.29 to 2.57; 192 participants). One study reported zero events in both intervention groups (42 participants). The overall risk of bias for all-cause mortality was critical and the certainty of the evidence was very low. One NRS reported bleeding events in 3% of the intervention group and 1.9% of the control group (OR 1.62, 95% CI 0.96 to 2.71; 2773 participants; low-certainty evidence).

Therapeutic-dose anticoagulants versus prophylactic-dose anticoagulants (1 retrospective NRS, 244 participants)

The study reported a reduction in all-cause mortality (adjusted HR 0.21, 95% CI 0.10 to 0.46) and a lower absolute rate of death in the therapeutic group (34.2% versus 53%). The overall risk of bias for all-cause mortality was serious and the certainty of the evidence was low. The study also reported bleeding events in 31.7% of the intervention group and 20.5% of the control group (OR 1.8, 95% CI 0.96 to 3.37; low-certainty evidence).

Ongoing studies

We found 22 ongoing studies in hospital settings (20 RCTs, 14,730 participants; 2 NRS, 997 participants) in 10 different countries (Australia (1), Brazil (1), Canada (2), China (3), France (2), Germany (1), Italy (4), Switzerland (1), UK (1) and USA (6)). Twelve ongoing studies plan to report mortality and six plan to report additional respiratory support. Thirteen studies are expected to be completed in December 2020 (6959 participants), eight in July 2021 (8512 participants), and one in December 2021 (256 participants). Four of the studies plan to include 1000 participants or more.

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