The Ontario Drug Benefit (ODB) Program provides drug coverage for eligible recipients, which includes residents of long-term care homes. One class of drugs covered under the ODB formulary are low molecular weight heparins (LMWHs), which are anticoagulants (blood thinners) that treat and prevent abnormal blood clots. LMWHs are used both for treatment and prophylaxis of various thromboembolic disorders such as deep vein thrombosis, pulmonary embolism, and post-hip or knee replacement surgery. Other off-label indications are considered for funding under the Exceptional Access Program (EAP) on a case-by-case basis.

Research suggests that COVID-19 is associated with significant inflammation and clinical and pathologic evidence of widespread blood clots. According to the National Institutes of Health in the United States, clinical trials to test the effects of full doses of anticoagulants in COVID-19 patients were launched because clinicians have observed that many patients ill with COVID-19, including those who have died from the disease, formed blood clots throughout their bodies, even in their smallest blood vessels. This unusual clotting can cause multiple health complications, including lung failure, heart attack, and stroke. Moreover, guidance by the Government of Canada on the care of long-term care home residents during the COVID-19 pandemic noted that residents with COVID-19 are at risk for coagulopathy and this appears to be correlated with disease severity.

This section describes scientific evidence and jurisdictional guidance on the role of LMWH for thromboprophylaxis of COVID-19-positive long-term care home residents. All of the information presented was identified and provided by members of the COVID-19 Evidence Synthesis Network. The majority of the information presented is taken directly from these sources.

• Limited information was identified from the long-term care sector. Information from the hospital and community sectors, as well as non-COVID-19 settings, was included where available.
• The majority of the information contains clinical guidance; these recommendations are those of the authors of the original sources and the Research, Analysis, and Evaluation Branch does not have the expertise to evaluate such recommendations.
• The methodological quality of most of the sources identified are unclear as they have not been assessed.

Scientific Evidence

• A rapid review by Ontario Health (February 11, 2021) did not identify any studies on the effectiveness and safety of thromboprophylaxis with LMWH for long-term care residents with COVID-19. The importance of individual risk assessment for venous thromboembolism and decisions on thromboprophylaxis are emphasized in the scientific literature.
  • Hospital Setting: The rapid review identified two systematic reviews and 26 primary studies that examined the use of thromboprophylaxis with LWMH for hospitalized patients with COVID-19 and found the following:
    • In the two systematic reviews, substantial heterogeneity was observed in the incidence of venous thromboembolism and mortality of hospitalized COVID-19 patients treated with LMWH. The authors stated heterogeneity was not mitigated by stratification of clinical setting (e.g., ward, intensive care unit) and may be related to different venous thromboembolism risk profiles and clinical severity of patients as well as differences in the methods used to identify venous thromboembolism across studies (e.g., clinical parameters, laboratory assessment, diagnostic imaging).
    • In the primary studies (which were not included in the above-mentioned systematic reviews), prophylactic dose LMWH was most often compared with different doses of the same LMWH. Other comparators included other types of anticoagulants (e.g., fondaparinux) or no control group. Overall, the studies have variable direction of results and it is unclear how outcomes may have been affected by different thromboprophylaxis dosing regimens.
    • Several factors limit the ability to draw conclusions from these studies, including: study design (most were observational, retrospective studies), small sample sizes, short follow-up periods, and lack of random assignment of dosing regimens.
    • See Table 2 and 3 in the Appendix for further details about the findings on LMWH thromboprophylaxis in hospitalized patients with COVID-19 reported in each of the systematic reviews and primary studies, respectively.
  • Non-Hospital Setting: In the ClinicalTrials.gov database, the rapid review did not identify any ongoing studies on LMWH within the long-term care population; however, the following ongoing randomized controlled trials within a non-hospitalized setting were identified:
    • NCT04400799 (Switzerland): Enoxaparin vs. no enoxaparin in COVID-19 patients ≥50 years eligible for ambulatory treatment. Estimated completion date is April 2021.
    • NCT04416048 (Germany): Rivaroxaban vs. standard of care (LMWH or unfractionated heparin) in moderate or severe COVID-19 patients >18 years. Estimated completion date is May 2021.
    • NCT04492254 (United Kingdom): Enoxaparin vs. standard of care (no enoxaparin) in confirmed COVID-19 patients ≥55 years with at least two additional risk factors. Estimated completion date is July 2021.

• Three international partners, spanning four continents (e.g., Canada, the United States, Australia, Mexico, Brazil) are collaborating in a multiple platform randomized controlled trial: the Randomized, Embedded, Multi-factorial Adaptive Platform Trial for Community-Acquired Pneumonia (REMAP-CAP) Therapeutic Anticoagulation; Accelerating COVID-19 Therapeutic Interventions and Vaccines-4 (ACTIV-4) Antithrombotics Inpatient; and Antithrombotic Therapy to Ameliorate Complications of COVID-19 (ATTACC). The trials have the common goal of assessing the benefit of full doses of blood thinners, including LMWH, to treat moderately ill or critically ill adults hospitalized for COVID-19, compared to a lower dose often used to prevent blood clots in hospitalized patients. For example:
  • The results of the ATTACC trial will soon be publicly available. This randomized controlled trial is sponsored by the University of Manitoba, and the University Health Network in Toronto is a collaborator. There are 60 study locations across Canada, the United States, Mexico, and Brazil. This trial will determine whether therapeutic anticoagulation with heparin (subcutaneous LMWH or intravenous unfractionated heparin) versus usual care reduces the need for intubation or death in hospitalized patients with COVID-19 (n=1,203). The period covered by the study was May 20, 2020 to January 2021.

• A research article discussed whether aspirin can be used for prophylaxis of COVID-19-induced coagulopathy. The article discusses the mechanism of aspirin action, the current evidence of use of aspirin in COVID-19, and limitations of aspirin use in COVID-19. The article concluded that given many clinicians are already using aspirin and nonsteroidal anti-inflammatory drugs (NSAIDs) to treat viral infections including COVID-19 off-label, without recourse to robust evidence of safety or effectiveness, there is an urgent need for well-conducted, randomized clinical trials in this area. The results of such studies will help to guide clinical practice during this pandemic.
• Dr. Brian Hutton (Ottawa Hospital Research Institute) is leading a review on the incidence of thrombotic events and related risk factors for COVID-19. Results will be available soon.
• A clinical review (December 2016) by the University of Ottawa Heart Institute assessed the comparative efficacy and safety of LMWH compared to unfractionated heparin (UFH) in medical and non-orthopedic surgical adult patients based on findings from randomized controlled trials published in or after 1995. The review found that:
  • Among medical patients, prophylaxis with LMWH reduced the risk of venous thromboembolism and deep vein thrombosis with no increased risk of bleeding or death, compared with UFH. There may be differences in the risk of an event between stroke and no stroke populations.
  • Among non-orthopedic surgical patients, prophylaxis with LMWH may increase the risk of bleeding, but not major bleeding, compared with UFH. There were no differences in the odds of venous thromboembolism, deep vein thrombosis, or pulmonary embolism. This finding was based on one trial and should be interpreted with caution.

International Scan

• The rapid review by Ontario Health (February 11, 2021) identified limited guidance or information pertaining to thromboprophylaxis in long-term care residents with COVID-19 or non-hospitalized patients from international health authorities, organizations, and grey literature. The importance of individual risk assessment for venous thromboembolism and decisions on thromboprophylaxis are emphasized in the available guidance.
  • Long-Term Care Setting: See Table 4 in the Appendix for further details.
    • United Kingdom: The British Geriatrics Society’s guidance (November 16, 2020) recommended the consideration of tailored thromboprophylaxis for residents of care homes.
    • France: The High Council for Public Health’s guidance (April 8, 2020) recommended the consideration of thromboprophylaxis with LMWH for bedridden patients in residential facilities for the elderly.
  • Hospital Setting:
    • World Health Organization: The COVID-19 Clinical Management: Living Guidance (January 25, 2021) makes a conditional recommendation in favour of standard thromboprophylaxis dosing of anticoagulation, rather than intermediate or therapeutic dosing, in hospitalized patients with COVID-19 who do not have an established indication for higher dose anticoagulation.
    • Canadian Agency of Drugs and Technologies in Health (CADTH): According to a CADTH report (June 11, 2020) on the state of the evidence for the use of LMWH prophylaxis in hospitalized COVID-19 patients, there is an increased risk of venous thromboembolism among hospitalized COVID-19 patients, especially those in intensive care units.
      • Most international guidance suggests using prophylactic dosing of pharmacologic thromboprophylaxis to prevent venous thromboembolism in patients who have been hospitalized with COVID-19.
      • International guidance does not suggest the routine use of extended-duration pharmacologic thromboprophylaxis. The use of extended-duration pharmacologic thromboprophylaxis in patients with COVID-19 who are being discharged from hospital may be considered based on the risk of venous thromboembolism and the risk of bleed.
      • The report also included a list of ongoing clinical trials assessing the effectiveness and safety of pharmacologic thromboprophylaxis to prevent venous thromboembolism.
  • Non-Hospital Setting: Guidance from the United States, Australia, Norway, and the United Kingdom recommends considering thromboprophylaxis with LMWH in COVID-19 patients under specific circumstances. See Table 5 in the Appendix for further details. For example:
    • United States: The National Institutes of Health’s recommendations (December 17, 2020) state that anticoagulants and antiplatelet therapy should not be initiated in non-hospitalized patients with COVID-19 for the prevention of venous thromboembolism or arterial thrombosis unless the patient has other indications for the therapy or is participating in a clinical trial.
    • Australia: The National COVID-19 Clinical Evidence Taskforce’s guidelines (February 4, 2021) recommend using prophylactic doses of anticoagulants, preferably LMWH, in adults with moderate COVID-19 or other indications, unless there is a contraindication (e.g., risk for major bleeding).

• The American Society of Hematology released a clinical guideline (February 8, 2021) on the use of anticoagulation for thromboprophylaxis in patients with COVID-19. A multidisciplinary guideline panel made two conditional recommendations in favour of prophylactic-intensity anticoagulation over intermediate-intensity or therapeutic-intensity anticoagulation for patients with COVID-19-related critical illness or acute illness who do not have confirmed or suspected venous thromboembolism. These recommendations were based on very low certainty in the evidence, underscoring the need for high-quality, randomized controlled trials comparing different intensities of anticoagulation. The recommendations will be updated using a living recommendation approach as new evidence becomes available.

Canadian Scan

• The rapid review by Ontario Health (February 11, 2021) identified limited guidance or information pertaining to thromboprophylaxis in long-term care residents with COVID-19 or non-hospitalized patients from national health authorities, organizations, and grey literature. The importance of individual risk assessment for venous thromboembolism and decisions on thromboprophylaxis are emphasized in the available guidance.
  • Long-Term Care Setting:
    • Government of Canada: According to Interim Guidance: Care of Residents in Long Term Care Homes during the COVID-19 Pandemic (July 17, 2020), medical or mechanical venous thromboembolism prophylaxis can be considered on a case-bycase basis for long-term care residents receiving active medical management, with consideration of disease severity, risks, benefits, goals of care, expressed wishes, and advance care plans.
    • Alberta Health Services: The Calgary Zone Long Term Care Pharmacy and Therapeutics Committee made the decision (December 1, 2020) to expedite coverage for LMWH when determined to be required by the attending physician in alignment with Health Canada interim guidance for long-term care residents with COVID-19. Instead of reviewing LMWH requests for coverage on a case-by-case basis in long-term care in Alberta, orders for LMWH will automatically be approved for coverage when Health Canada guidance is met and documented. See Table 4 in the Appendix for further details.
  • Hospital Setting:
    • CADTH: According to the CADTH report (June 11, 2020) on the state of the evidence for the use of LMWH prophylaxis in hospitalized COVID-19 patients, there is an increased risk of venous thromboembolism among hospitalized COVID-19 patients, especially those in intensive care units.
      • Most Canadian guidance suggests using prophylactic dosing of pharmacologic thromboprophylaxis to prevent venous thromboembolism in patients who have been hospitalized with COVID-19.
      • Canadian guidance does not suggest the routine use of extended-duration pharmacologic thromboprophylaxis. The use of extended-duration pharmacologic thromboprophylaxis in patients with COVID-19 who are being discharged from hospital may be considered based on the risk of venous thromboembolism and the risk of bleed.
      • The report also included a list of ongoing clinical trials assessing the effectiveness and safety of pharmacologic thromboprophylaxis to prevent venous thromboembolism.
    • Alberta Health Services: A rapid evidence brief (January 11, 2021) by the COVID-19 Scientific Advisory Group highlighted an increased risk of venous thromboembolism among hospitalized COVID-19 patients, especially those who are admitted to intensive care and those with severe COVID-19 infection. Recommendations included:
      • COVID-19 patients in hospital should receive the usual preventative blood thinners recommended for hospitalized patients at risk of venous thromboembolism unless there are contraindications (usually once daily low-molecular weight heparin products such as tinzaparin).
      • Further testing should be done if there are signs or symptoms suspicious for venous thromboembolism complications (e.g., unexplained high heart rate, low blood pressure, one sided leg swelling, worsening shortness of breath or low oxygen status) rather than relying on elevation in D-dimer blood tests.
      • Higher than usual preventative doses of blood thinners (which have been suggested to prevent venous thromboembolism in COVID-19 patients) are not recommended as new evidence suggests that this increases bleeding risk without adding much benefit. COVID-19 patients should receive standard dosing for the usual length of therapy. Studies are continuing in this area and recommendations may change in the future.

Ontario Scan

• No information identified.

The COVID-19 Evidence Synthesis Network is comprised of groups specializing in evidence synthesis and knowledge translation. The group has committed to provide their expertise to provide high-quality, relevant, and timely synthesized research evidence about COVID-19 to inform decision makers as the pandemic continues. The following members of the Network provided evidence synthesis products that were used to develop this Evidence Synthesis Briefing Note:

• Cochrane Canada. (February 8, 2021). Email Communications.
• Ontario Health. (February 11, 2021). Low Molecular Weight Heparin Thromboprophylaxis for Long-Term Care Residents With COVID-19: An Expedited Summary of the Evidence and Jurisdictional Scan.
• SPOR Evidence Alliance. (January 26, 2021). Email Communications.