Key messages
‐ When used in the outpatient setting, anticoagulants (blood thinners) probably reduce venous thromboembolism (VTE) and pulmonary embolism (PE) when compared with placebo or no treatment in people with COVID-19. However, these drugs seem to have little or no effect in reducing death, major bleeding, need for hospitalisation, or adverse events.
What is VTE?
Venous thromboembolism, which includes both deep vein thrombosis (DVT) and PE, is a condition where a blood clot forms in a vein and may migrate to another location (e.g. the lung). DVT occurs when a blood clot forms inside a deep vein and blocks the blood flow. PE occurs when (part of) a blood clot detaches from the deep vein and ends up in the lung blood vessels, blocking the blood supply of the lungs.
How are COVID-19 and VTE related?
COVID‐19 typically affects the lungs and airways; however, in addition to respiratory problems, people with COVID‐19 can also experience problems with their blood vessels, leading to blood clots forming in the veins and lungs.
How is VTE treated and how can VTE be prevented in people who are at risk?
The initial treatment includes drugs such as anticoagulants to prevent the formation of further new blood clots. Patients may also receive compression stockings and clinical care (e.g. physical exercise, skin hydration, and physical therapy). Anticoagulants such as rivaroxaban and apixaban act by inhibiting the blood elements involved in the formation of blood clots. For this reason, they are also used to prevent blood clots from forming in people who are considered to be at risk, such as people with COVID-19. This is known as prophylactic treatment. However, the use of anticoagulants can cause side effects such as bleeding.
What did we want to find out?
We wanted to find out whether giving anticoagulants to non-hospitalised people with COVID‐19 reduced the number of deaths or new blood clots compared to people who received placebo (an identical-seeming medicine but with no active properties) or no intervention; a different dose or formulation of the same anticoagulant; antiplatelet agents (medications that prevent blood clots from forming); or non-drug treatments. We also wanted to know the effects of anticoagulants on the need for hospitalisation; major bleeding or adverse events; and quality of life.
What did we do?
We searched for studies, giving preference to randomised controlled trials (studies where participants are randomly assigned to one of two or more treatment groups), that evaluated prophylactic anticoagulants given to people with COVID-19 in the outpatient setting, compared with placebo or no treatment, a different dose of the same anticoagulant, or antiplatelet agents. We pooled the results when appropriate.
What did we find?
The results were based on five studies with a total of 1777 participants from the USA, Switzerland, Germany, Belgium, Brazil, India, South Africa, Spain, and the UK. Two large groups of participants were studied: those with COVID-19 who did not require hospitalisation, and people with COVID-19 who had been discharged from hospital. Five studies compared anticoagulants versus placebo or no treatment, and one study also compared a prophylactic anticoagulant with a different dose of the same anticoagulant as well as versus antiplatelet agents. Each comparison investigated the effects of anticoagulants on death, VTE, major bleeding, need for hospitalisation, and adverse events.
We have low confidence that prophylactic anticoagulants compared with placebo or no treatment for non-hospitalised people with COVID-19 have little or no effect on reducing the risk of death or adverse events. Prophylactic anticoagulants probably decrease the risk of VTE; 50 patients would need to be treated to avoid one VTE event.
There may be little or no difference in hospitalisation rates between people who receive prophylactic anticoagulants and those who receive a different dose of the same anticoagulant. Moreover, prophylactic anticoagulants may lead to little or no difference in reducing VTE when compared with antiplatelet agents.
What are the limitations of the evidence?
We have low confidence in the evidence due to issues with study methods and sizes. In the future, high-quality studies may produce important data, especially regarding outcomes such as death, DVT, and PE.
How up-to-date is this evidence?
The evidence is current as of 18 April 2022.
We found low- to moderate‐certainty evidence from five RCTs that prophylactic anticoagulants result in little or no difference in major bleeding, DVT, need for hospitalisation, or adverse events when compared with placebo or no treatment in non-hospitalised people with COVID-19. Low-certainty evidence indicates that prophylactic anticoagulants may result in little or no difference in all-cause mortality when compared with placebo or no treatment, but moderate-certainty evidence indicates that prophylactic anticoagulants probably reduce the incidence of VTE and PE.
Low-certainty evidence suggests that comparing different doses of the same prophylactic anticoagulant may result in little or no difference in need for hospitalisation or adverse events. Prophylactic anticoagulants may result in little or no difference in risk of VTE, hospitalisation, or adverse events when compared with antiplatelet agents (low-certainty evidence). Given that there were only short-term data from one study, these results should be interpreted with caution.
Additional trials of sufficient duration are needed to clearly determine any effect on clinical outcomes.
The coronavirus disease 2019 (COVID-19) pandemic has impacted healthcare systems worldwide. Multiple reports on thromboembolic complications related to COVID-19 have been published, and researchers have described that people with COVID-19 are at high risk for developing venous thromboembolism (VTE). Anticoagulants have been used as pharmacological interventions to prevent arterial and venous thrombosis, and their use in the outpatient setting could potentially reduce the prevalence of vascular thrombosis and associated mortality in people with COVID-19. However, even lower doses used for a prophylactic purpose may result in adverse events such as bleeding. It is important to consider the evidence for anticoagulant use in non-hospitalised people with COVID-19.
To evaluate the benefits and harms of prophylactic anticoagulants versus active comparators, placebo or no intervention, or non-pharmacological interventions in non-hospitalised people with COVID‐19.
We used standard, extensive Cochrane search methods. The latest search date was 18 April 2022.
We included randomised controlled trials (RCTs) comparing prophylactic anticoagulants with placebo or no treatment, another active comparator, or non-pharmacological interventions in non-hospitalised people with COVID-19. We included studies that compared anticoagulants with a different dose of the same anticoagulant. We excluded studies with a duration of under two weeks.
We used standard Cochrane methodological procedures. Our primary outcomes were all-cause mortality, VTE (deep vein thrombosis (DVT) or pulmonary embolism (PE)), and major bleeding. Our secondary outcomes were DVT, PE, need for hospitalisation, minor bleeding, adverse events, and quality of life. We used GRADE to assess the certainty of the evidence.
We included five RCTs with up to 90 days of follow‐up (short term). Data were available for meta-analysis from 1777 participants.
Anticoagulant compared to placebo or no treatment
Five studies compared anticoagulants with placebo or no treatment and provided data for three of our outcomes of interest (all-cause mortality, major bleeding, and adverse events). The evidence suggests that prophylactic anticoagulants may lead to little or no difference in all-cause mortality (risk ratio (RR) 0.36, 95% confidence interval (CI) 0.04 to 3.61; 5 studies; 1777 participants; low-certainty evidence) and probably reduce VTE from 3% in the placebo group to 1% in the anticoagulant group (RR 0.36, 95% CI 0.16 to 0.85; 4 studies; 1259 participants; number needed to treat for an additional beneficial outcome (NNTB) = 50; moderate-certainty evidence). There may be little to no difference in major bleeding (RR 0.36, 95% CI 0.01 to 8.78; 5 studies; 1777 participants; low-certainty evidence). Anticoagulants probably result in little or no difference in DVT (RR 1.02, 95% CI 0.30 to 3.46; 3 studies; 1009 participants; moderate-certainty evidence), but probably reduce the risk of PE from 2.7% in the placebo group to 0.7% in the anticoagulant group (RR 0.25, 95% CI 0.08 to 0.79; 3 studies; 1009 participants; NNTB 50; moderate-certainty evidence). Anticoagulants probably lead to little or no difference in reducing hospitalisation (RR 1.01, 95% CI 0.59 to 1.75; 4 studies; 1459 participants; moderate-certainty evidence) and may lead to little or no difference in adverse events (minor bleeding, RR 2.46, 95% CI 0.90 to 6.72; 5 studies, 1777 participants; low-certainty evidence).
Anticoagulant compared to a different dose of the same anticoagulant
One study compared anticoagulant (higher-dose apixaban) with a different (standard) dose of the same anticoagulant and reported five relevant outcomes. No cases of all-cause mortality, VTE, or major bleeding occurred in either group during the 45-day follow‐up (moderate-certainty evidence). Higher-dose apixaban compared to standard-dose apixaban may lead to little or no difference in reducing the need for hospitalisation (RR 1.89, 95% CI 0.17 to 20.58; 1 study; 278 participants; low-certainty evidence) or in the number of adverse events (minor bleeding, RR 0.47, 95% CI 0.09 to 2.54; 1 study; 278 participants; low-certainty evidence).
Anticoagulant compared to antiplatelet agent
One study compared anticoagulant (apixaban) with antiplatelet agent (aspirin) and reported five relevant outcomes. No cases of all-cause mortality or major bleeding occurred during the 45-day follow‐up (moderate-certainty evidence). Apixaban may lead to little or no difference in VTE (RR 0.36, 95% CI 0.01 to 8.65; 1 study; 279 participants; low-certainty evidence), need for hospitalisation (RR 3.20, 95% CI 0.13 to 77.85; 1 study; 279 participants; low-certainty evidence), or adverse events (minor bleeding, RR 2.13, 95% CI 0.40 to 11.46; 1 study; 279 participants; low-certainty evidence).
No included studies reported on quality of life or investigated anticoagulants compared to a different anticoagulant, or anticoagulants compared to non‐pharmacological interventions.