Key messages
- High-dose blood thinners result in little or no difference in death rate and increase minor bleeding compared to low-dose blood thinners for people hospitalised with COVID-19. Giving blood thinners compared to not giving blood thinners might reduce the death rate.
- It is very likely that new studies will not change the evidence about the effects of different doses of blood thinners on death rate and minor bleeding. High-quality studies are still needed to analyse the need for additional respiratory support, giving blood thinners compared to no blood thinners, comparing different blood thinners, and giving blood thinners for extended periods.
What is COVID-19?
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 vessels, leading to blood clots forming in the arteries, veins and lungs. Nearly half of all people with severe COVID-19 in intensive care units develop clots in their veins or arteries.
What are blood thinners?
Blood thinners are medicines that prevent harmful blood clots from forming (deep vein thrombosis). However, they can 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 whether blood clots develop and then treating them with blood thinners.
What did we want to find out?
We wanted to know whether giving blood thinners to people hospitalised with COVID-19 as a preventive measure reduced the number of deaths compared to people who received no treatment or those who received a placebo treatment (an identical-seeming treatment but with no active ingredient). We also wanted to determine whether these individuals needed less support with breathing, whether they still developed harmful blood clots, whether they experienced bleeding and whether they experienced any other unwanted events.
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. 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. We pooled the results when appropriate.
What did we find?
We included seven studies with 16,185 people hospitalised with COVID-19 in either intensive care units, hospital wards or emergency departments. Studies were from Brazil (2), Iran (1), Italy (1), and the USA (1), and two involved more than country. People in the studies were aged from 55 to 68 years on average. Studies lasted from 15 to 90 days and provided evidence on deaths, bleeding, blood clotting, length of hospital stay and unwanted effects. There was little or no evidence on need for respiratory support (help with breathing), deaths related to COVID-19, and quality of life.
Higher-dose of blood thinners compared with lower-dose (4 studies, 4647 people)
In people who received higher compared to lower doses of blood thinners there was little to no difference in death rate. However, people on higher doses were more likely to experience minor bleeding compared to in those on lower doses. People who received higher doses of blood thinners likely had reduced pulmonary embolism (blood clot in the lung or blood vessel leading to the lung), slightly increased major (more severe) bleeding, and probably had little to no difference in time spent in hospital compared to those who received the lower doses of blood thinners. In people who received higher doses of blood thinners, there was little to no difference in the rate of deep vein thrombosis, and other unwanted events compared to those who received the lower dose of blood thinners.
Blood thinners compared with no treatment (3 studies, 11,538 people)
People who received blood thinners had a reduced death rate compared to those who did not receive blood thinners, but the evidence is very uncertain.
What are the limitations of the evidence?
We are very confident that higher doses of blood thinners do not change the risk of death but do increase the risk of bleeding in people hospitalised with COVID-19.
Although our confidence in the evidence is very limited, people who receive blood thinners may have a lower death rate compared to those who did not receive any blood thinners.
What happens next?
Our searches found 62 ongoing studies with 35,470 people. We plan to add the results of these studies to our review when they are published.
How up to date is this evidence?
The evidence is up to date to 14 April 2021.
When compared to a lower-dose regimen, higher-dose anticoagulants result in little to no difference in all-cause mortality and increase minor bleeding in people hospitalised with COVID-19 up to 30 days. Higher-dose anticoagulants possibly reduce pulmonary embolism, slightly increase major bleeding, may result in little to no difference in hospitalisation time, and may result in little to no difference in deep vein thrombosis, stroke, major adverse limb events, myocardial infarction, atrial fibrillation, or thrombocytopenia.
Compared with no treatment, anticoagulants may reduce all-cause mortality but the evidence comes from non-randomised studies and is very uncertain. It is unclear whether anticoagulants have any effect on the remaining outcomes compared to no anticoagulants (very low-certainty evidence or no data).
Although we are very confident that new RCTs will not change the effects of different doses of anticoagulants on mortality and minor bleeding, high-quality RCTs are still needed, mainly for the other primary outcome (necessity for additional respiratory support), the comparison with no anticoagulation, when comparing the types of anticoagulants and giving anticoagulants for a prolonged period of time.
The primary manifestation of coronavirus disease 2019 (COVID-19) is respiratory insufficiency that can also be related to diffuse pulmonary microthrombosis and thromboembolic events, such as pulmonary embolism, deep vein thrombosis, or arterial thrombosis. People with COVID-19 who develop thromboembolism have a worse prognosis.
Anticoagulants such as heparinoids (heparins or pentasaccharides), vitamin K antagonists and direct anticoagulants are used for the prevention and treatment of venous or arterial thromboembolism. Besides their anticoagulant properties, heparinoids have an additional anti-inflammatory potential. However, the benefit of anticoagulants for people with COVID-19 is still under debate.
To assess the benefits and harms of anticoagulants versus active comparator, placebo or no intervention in people hospitalised with COVID-19.
We searched the CENTRAL, MEDLINE, Embase, LILACS and IBECS databases, the Cochrane COVID-19 Study Register and medRxiv preprint database from their inception to 14 April 2021. We also checked the reference lists of any relevant systematic reviews identified, and contacted specialists in the field for additional references to trials.
Eligible studies were randomised controlled trials (RCTs), quasi-RCTs, cluster-RCTs and cohort studies that compared prophylactic anticoagulants versus active comparator, placebo or no intervention for the management of people hospitalised with COVID-19. We excluded studies without a comparator group and with a retrospective design (all previously included studies) as we were able to include better study designs. Primary outcomes were all-cause mortality and necessity for additional respiratory support. Secondary outcomes were mortality related to COVID-19, deep vein thrombosis, pulmonary embolism, major bleeding, adverse events, length of hospital stay and quality of life.
We used standard Cochrane methodological procedures. We used Cochrane RoB 1 to assess the risk of bias for RCTs, ROBINS-I to assess risk of bias for non-randomised studies (NRS) and GRADE to assess the certainty of evidence. We meta-analysed data when appropriate.
We included seven studies (16,185 participants) with participants hospitalised with COVID-19, in either intensive care units, hospital wards or emergency departments. Studies were from Brazil (2), Iran (1), Italy (1), and the USA (1), and two involved more than country. The mean age of participants was 55 to 68 years and the follow-up period ranged from 15 to 90 days. The studies assessed the effects of heparinoids, direct anticoagulants or vitamin K antagonists, and reported sparse data or did not report some of our outcomes of interest: necessity for additional respiratory support, mortality related to COVID-19, and quality of life.
Higher-dose versus lower-dose anticoagulants (4 RCTs, 4647 participants)
Higher-dose anticoagulants result in little or no difference in all-cause mortality (risk ratio (RR) 1.03, 95% CI 0.92 to 1.16, 4489 participants; 4 RCTs) and increase minor bleeding (RR 3.28, 95% CI 1.75 to 6.14, 1196 participants; 3 RCTs) compared to lower-dose anticoagulants up to 30 days (high-certainty evidence). Higher-dose anticoagulants probably reduce pulmonary embolism (RR 0.46, 95% CI 0.31 to 0.70, 4360 participants; 4 RCTs), and slightly increase major bleeding (RR 1.78, 95% CI 1.13 to 2.80, 4400 participants; 4 RCTs) compared to lower-dose anticoagulants up to 30 days (moderate-certainty evidence). Higher-dose anticoagulants may result in little or no difference in deep vein thrombosis (RR 1.08, 95% CI 0.57 to 2.03, 3422 participants; 4 RCTs), stroke (RR 0.91, 95% CI 0.40 to 2.03, 4349 participants; 3 RCTs), major adverse limb events (RR 0.33, 95% CI 0.01 to 7.99, 1176 participants; 2 RCTs), myocardial infarction (RR 0.86, 95% CI 0.48 to 1.55, 4349 participants; 3 RCTs), atrial fibrillation (RR 0.35, 95% CI 0.07 to 1.70, 562 participants; 1 study), or thrombocytopenia (RR 0.94, 95% CI 0.71 to 1.24, 2789 participants; 2 RCTs) compared to lower-dose anticoagulants up to 30 days (low-certainty evidence). It is unclear whether higher-dose anticoagulants have any effect on necessity for additional respiratory support, mortality related to COVID-19, and quality of life (very low-certainty evidence or no data).
Anticoagulants versus no treatment (3 prospective NRS, 11,538 participants)
Anticoagulants may reduce all-cause mortality but the evidence is very uncertain due to two study results being at critical and serious risk of bias (RR 0.64, 95% CI 0.55 to 0.74, 8395 participants; 3 NRS; very low-certainty evidence). It is uncertain if anticoagulants have any effect on necessity for additional respiratory support, mortality related to COVID-19, deep vein thrombosis, pulmonary embolism, major bleeding, stroke, myocardial infarction and quality of life (very low-certainty evidence or no data).
Ongoing studies
We found 62 ongoing studies in hospital settings (60 RCTs, 35,470 participants; 2 prospective NRS, 120 participants) in 20 different countries. Thirty-five ongoing studies plan to report mortality and 26 plan to report necessity for additional respiratory support. We expect 58 studies to be completed in December 2021, and four in July 2022. From 60 RCTs, 28 are comparing different doses of anticoagulants, 24 are comparing anticoagulants versus no anticoagulants, seven are comparing different types of anticoagulants, and one did not report detail of the comparator group.