Safety and Efficacy of Anticoagulation Regimens in COVID-19

By John Love, Pharm.D, MBA

Program Number : 

Approved Dates:   April 1, 2022-October 1, 2022        

Approved Contact Hours:  One Hour(s) (1) CE(s) per session

Learning Objectives

1. Identify different dosage strategies for prophylactic anticoagulation in the setting of COVID-19.
2. Summarize available data regarding different anticoagulation strategies in COVID-19.
3. Recommend when therapeutic anticoagulation is appropriate in the setting of COVID-19.

Background

Medically ill patients are at an increased risk of development of venous thromboembolism (VTE). Guidelines have historically made recommendations for prophylactic anticoagulation when patients are acutely ill¹ and therapeutic anticoagulation when there is confirmation of deep venous thrombosis or in select situations, such as in atrial fibrillation². Anticoagulant options include low molecular weight heparin (LMWH), unfractionated heparin (UFH), fondaparinux, direct oral anticoagulants (DOACs) such as apixaban or rivaroxaban, argatroban, or bivalirudin.

In 2019, a novel coronavirus (COVID-19) was discovered which has since become a global pandemic. Early in the pandemic, it was observed that patients acutely ill with COVID-19 were at increased risk of development of VTE.  Patients that are hospitalized with COVID-19³ are thought to be in a pro-thrombotic state due to increased fibrin deposits, reduced natural anticoagulation (or maximal anticoagulation being reached), an increase in interleukin 1-b and interleukin 18. A recent meta-analysis found that the incidence rate of VTE among COVID positive pateints to be 14.7%⁴. Unsurprisingly, administration of anticoagulant medications was associated with improved mortality⁵. However, the optimal regimen for prophylactic anticoagulation was unknown and has since been the objective of many studies.

Guidelines

The International Society of Thrombosis and Hemostasis (ISTH)⁶, the American Society of Hematologists (ASH)⁷, and the National Institute of Health (NIH)⁸ have each produced guidelines that reviewed anticoagulation research in COVID-19. Both ISTH and ASH recommend the use of prophylactic anticoagulation over therapeutic or intermediate dose anticoagulation due to limited data. However, both of these guidelines were published before larger, randomized clinical trials were published that have provided more insight.

The NIH guidelines initially made a similar recommendation but were updated as more data was published. The NIH guidelines currently recommend therapeutic anticoagulation in patients who are hospitalized, require low-flow oxygen, and do not require intensive care unit level of care and have an elevated D-dimer level above the upper limit of normal. Therapy should continue for fourteen days or until discharge, whichever comes first. Based on the results of more recent studies, the NIH recommends against the use of therapeutic anticoagulation in patients requiring intensive care unit level of care or high-flow oxygen. It should be noted that this recommendation is without confirmation of DVT or PE. The NIH does not recommend routine imaging for DVT or PE unless the patient is experiencing symptoms consistent with those conditions. Unless a contraindication exists, the NIH recommends prophylactic dosage anticoagulation in all patients who are not receiving therapeutic anticoagulation.

The NIH identifies contraindications to therapeutic anticoagulation as those with platelet counts < 50 x 10⁹/L, hemoglobin < 8g/dL, requiring dual antiplatelet therapy, major bleeding within 30 days that required a visit to an emergency department or hospitalization, history of a bleeding disorder, or an inherited or active acquired bleeding disorder. This list of contraindications was developed based upon exclusion criteria from the major studies that evaluated the use of therapeutic anticoagulation.

The NIH guidelines also recommend the use of LMWH as first line therapy, UFH as second line, and recommends against the use of direct oral anticoagulants. This recommendation stems from the shorter half-lives of these agents, the relative ease of bleeding reversal, that these agents have intravenous and subcutaneous administration methods (which may be beneficial in patients who are unable to tolerate oral medications due to oxygen requirements), and are noted to have less drug-drug interactions compared to direct oral agents.

Regimens

The ASH⁷ guidelines proposed dosage regimens identified as prophylactic, intermediate, and therapeutic dosages. Approved indications and historical use do not match all of the dosages outlined in these guidelines. Many of these regimens have not been explicitly studied but were suggested as potential options. Examples of each of these regimens are below.

Therapeutic Dosages

The NIH guidelines are based on four randomized trials that together helped identify which patients would benefit most from therapeutic anticoagulation. The ATTACC, ACTIV-4a, and REMAP-CAP investigators combined their results for publication in two of these studies. One study of these studies reviewed non-critically ill patients (defined as those not requiring intensive level care or high-flow oxygen), while the other looked at critically ill patients.  The HEP-COVID trial evaluated critical and non-critically ill patients, while the RAPID trial evaluated patients who were started upon anticoagulation shortly after admission.

Therapeutic Anticoagulation with Heparin in Critically Ill Patients with COVID-19⁹
               Of the studies that current NIH guidelines are based on, this study was the first that was published and is one of two studies that is a combination of data from the ATTACC, ACTIV-4a, and REMAP-CAP investigations. The aim of this study was to evaluate whether therapeutic dose anticoagulation reduced the number of days requiring organ support in critically ill patients.  Patients were considered critically ill if they were receiving ICU-level respiratory or cardiovascular organ support (high-flow oxygen, noninvasive or invasive mechanical ventilation, extracorporeal life support, vasopressors, or inotropes) in an ICU. Results are listed below. This study was larger than previously published research with 1098 patients included. Ultimately, this study was stopped early due to meeting pre-defined criterion for futility and failing to reach significance on organ support free-days, survival to discharge, and thrombotic event or death.  The authors theorized that COVID-19 causes micro and macrovascular damage in lung tissue, but that patients who are critically ill have already experienced this damage and thus unable to benefit from therapeutic dose anticoagulation.  The authors suggested that earlier initiation of therapeutic anticoagulation could benefit patients by preventing progression of damage caused by the disease.

Therapeutic Anticoagulation with Heparin in Non-Critically Ill Patients with COVID-19¹⁰
               This is the comparison study published by the ATTACC, ACTIV-4a, and REMAP-CAP investigators that focused on patients who were not yet critically ill. This study included many patients, with a population size of 2219 patients. The included patients were considered non-critically ill, which was defined as being hospitalized without requiring ICU level care (including high-flow oxygen) at enrollment. Again, this study aimed to evaluate the impact on organ support-free days, but also included a stratification based upon D-dimer level at two times the local upper limit of normal for each institution. The primary outcome was designed to analyze the number of days without requiring critical care level organ support.

The final results are included below with a comparison to the data found in critically ill patients, as well as reporting the d-dimer stratification. This study was stopped early due to meeting predefined criterion for superiority for therapeutic anticoagulation, but it is important to note that the pre-defined primary outcome of organ support-free days up to day 21 had to be changed to survival to discharge without requiring intensive care level of organ support as the average organ support-free days in both groups was 22 days (and the outcome was designed to stop counting at 21 days). The authors calculated that for every 1000 patients that received initial treatment with therapeutic anticoagulation, 40 additional patients would not require organ support from addition to discharge. This would come at the expense of 7 additional major bleeds.

There are several important takeaways from this study.  The first is that the benefit shown is prevention of escalation of care. The study did not find a statistical significance in mortality between the two groups. However, if mortality was combined with major thrombotic events a statistical difference was found. This is expected to occur, however, because administering higher dose anticoagulation should prevent thrombotic events from occurring in any patient population. Second, when stratified by D-Dimer, the difference in the primary outcome was found in patients with elevated or unknown D-Dimer, but was not found in the low level D-Dimer group.

RAPID¹¹

               The RAPID trial was a multicenter trial that was evaluating the impact of therapeutic dose anticoagulation compared to prophylactic dose when therapy is started early in the disease course, which the study defined as within five days of admission. The RAPID trial only evaluated UFH and LMWH. The primary outcome was a composite outcome defined as death, invasive mechanical ventilation, non-invasive mechanical ventilation, or ICU admission and was not statistically significant. However, this study did not meet power. Unlike the other trials included in this review, this study did not find a benefit in escalation of care but did find a mortality benefit when the composite outcome was broken out into individual components.