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With input from Dr Monica Vasudev
1080: Direct oral anticoagulants (DOACs) widely used among patients requiring both short-and long-term anticoagulation.
DOACs are preferred agents owing to their ease of use, favorable pharmacokinetic profilr with fixed dosing, decreased drug-drug interactions, and the lack of monitoring requirements. With the increasing use of DOACs, physicians must be able to manage patients on these medications in the perioperative period, while balancing the risk of bleeding with that of thromboembolic events.
Coronavirus disease 2019 (COVID-19): Hypercoagulability
Patients discharged from the hospital — Those with documented VTE need at least three months of anticoagulation.
Some individuals who have not had a VTE may also require extended thromboprophylaxis following hospital discharge.
- In individuals with other risk factors for VTE like immobilization, recent surgery, or trauma.
- Older age.
- Bleeding risk must be incorporated into decision-making.
- Options for post-discharge prophylaxis include those used in clinical trials, such as rivaroxaban10 mg daily for 31 to 39 days.
Patients not admitted to the hospital — Outpatient thromboprophylaxis may be appropriate for some individuals with COVID-19 who are not admitted to the hospital, particularly those with other thrombotic risk factors such as prior VTE or recent surgery, trauma, or immobilization. This is based on clinical judgment. If thromboprophylaxis is used in an outpatient, rivaroxaban 10 mg daily for 31 to 39 days may be given. (Uptodate)
Clinical indications for therapeutic anticoagulation
For inpatients, particualrly those who are critically ill, LMWH or UFH for any indication is preferred in place of a DOAC, on account of their shorter half-lives and ability for parenteral administration.
COVID-19 patients tend to have elevated levels of fibrinogen.
The issue of using therapeutic-dose anticoagulation for presumed PE has been encountered in many ICUs across the world owing to the difficulty in moving mechanically ventilated patients to computed tomography scanners and the desire or the need to limit staff exposure to COVID-19 positive patients. D-dimer is often not helpful, on account of the significant baseline elevations in these patients. Sudden respiratory decompensation, evidence of right-heart strain on echocardiography, or DVT evident on lower-extremity ultrasound performed for these reasons have been used to increase to therapeutic-dose anticoagulation. [Connors et al. Blood. 2020 Jun 4; 135(23): 2033–2040.]
Blood thinners may improve survival in hospitalized COVID-19 patients
A study published May 6 in the Journal of the American College of Cardiology found that hospitalized COVID-19 patients treated with anticoagulants had improved outcomes both in and out of the intensive care unit setting.
The study revealed that anticoagulants taken orally, subcutaneously, or intravenously may play a pivotal role in COVID-19 patients, and may prevent possible fatal events associated with COVID-19, including heart attack, stroke, and pulmonary embolism.
Using anticoagulants should be considered when patients get admitted to the ER and have tested positive for COVID-19 in order to improve outcomes. However, each case should be evaluated on an individualized basis to account for potential bleeding risk.
This study follows recent research from the Icahn School of Medicine at Mount Sinai which showed that a large number of patients hospitalized with COVID-19 developed high levels of life-threatening blood clots, leading to potentially deadly thromboembolic events. [Source: https://www.eurekalert.org/pub_releases/2020-05/tmsh-btm050420.php]
The current crisis thus offers several arguments in favour of anticoagulation with DOACs in patients without contraindications.
- For patients in whom oral anticoagulation must be started, it seems appropriate to favor the use of DOACs.
- For patients on long-term VKA, the current crisis seems to be an opportunity to switch them to a DOAC.
- For patients who should remain on VKAs (mechanical cardiac valve, antiphospholipid syndrome, renal impairment depending on it severity, ….), the use of point-of-care (POC) devices for measuring INR should be promoted.
[Impact of the COVID-19 pandemic on therapeutic choices in Thrombosis-Hemostasis. Journal of Thrombosis and Haemostasis. http://www.sah.org.ar/pdf/covid-19/bibliografia_14845.pdf, First published: 15 April 2020]
Dabigatran offers potential advantages over currently available anticoagulants. It excludes the need for parenteral or subcutaneous administration, increasing compliance especially when outpatient antithrombotic treatment is needed following early hospital discharge. [Wurnig C, et al. Thromb J. 2015; 13: 37.]
Rivaroxaban is usually given at a fixed dose without monitoring.
- Venous thromboembolism (VTE) prophylaxis in surgical patients: 10 mg daily; duration (12 days vs. extended to 35 days) depends on the type of surgery.
- Treatment and secondary prevention of VTE: 15 mg twice a day (with food) for 21 days, followed by 20 mg once a day (with food). If treatment is continued after six months, the dose can be reduced to 10 mg once daily for selected individuals. For those with an increased risk for VTE beyond six months of anticoagulation (eg, two or more episodes of VTE), the 20 mg once-daily dose should be used.
- Stroke prevention in atrial fibrillation (AF): 20 mg once a day with the evening meal (CrCl >50 mL/minute); or 15 mg once a day with the evening meal (CrCl ≤50 mL/minute).
Rivaroxaban is not recommended for VTE prophylaxis, treatment, or secondary prevention in individuals with a creatinine clearance of <30 mL/minute.
Overview (apixaban) —
- Venous thromboembolism (VTE) prophylaxis in surgical patients: 2.5 mg twice daily; duration (12 days versus extended to 35 days) depends on the type of surgery
- Treatment and secondary prevention of VTE: 10 mg twice daily for 7 days, followed by 5 mg twice daily. If therapy continues beyond six months, the dose is reduced to 2.5 mg twice daily .
- Stroke prevention in atrial fibrillation (AF): 5 mg twice daily (CrCl >50 mL/minute); or 2.5 mg twice daily for those with any two of the following: age ≥80 years, body weight ≤60 kg, or serum creatinine ≥1.5 mg/dL.
- Venous thromboembolism (VTE) primary prophylaxis in surgical patients: 110 mg one to four hours after surgery, followed by 220 mg once daily for 28 to 35 days (hip replacement) or 10 days (knee replacement).
- Treatment and secondary prevention of VTE: 150 mg orally twice daily after 5 to 10 days of parenteral anticoagulation (CrCl >30 mL/minute).
- Stroke prevention in atrial fibrillation (AF): 110 mg orally twice a day or 150 mg orally twice a day (CrCl >30 mL/minute). European labeling suggests dose reduction in patients >75 years of age (for instance, 150 mg orally once a day or 110 mg orally twice a day).
Should seriously ill COVID-19 patients be given therapeutic-intensity anticoagulation empirically (in the absence of confirmed or suspected VTE)?
Microvascular thrombosis is believed to be involved in hypoxemic respiratory failure in some patients with COVID-19. Autopsy studies have been limited but they demonstrate large vessel and microvascular thrombosis, pulmonary hemorrhage and high prevalence of VTE.
Should COVID-19 patients receive post-discharge thromboprophylaxis?
Patients hospitalized for acute medical illness have an increased risk for VTE for up to 90 days following discharge. Whether this risk is sufficiently high in patients with COVID-19 to warrant post-discharge thromboprophylaxis is not clearly known. Non-COVID clinical trials which pointed to a benefit for post-discharge thromboprophylaxis given for up to 42 days enrolled patients with combinations of risk factors, including age, co-morbidities such as active cancer, and elevated D-dimer >2 times the upper normal limit.
The decision to use post-discharge thromboprophylaxis should consider the individual patient’s VTE risk factors at the time of discharge, which should include reduced mobility and bleeding risk, as well as feasibility.
Aspirin has been evaluated for VTE prophylaxis in low-risk patients following hip or knee arthroplasty but has not been assessed for COVID-19 post-discharge thromboprophylaxis. Patients should be educated on the signs and symptoms of VTE at hospital discharge and advised to seek urgent medical attention if any of these develop.
If a patient with COVID-19 requires therapeutic anticoagulation for VTE or AFIB stroke prevention, do we have any special considerations?
Dexamethasone is an inducer of CYP3A4 and the extent of the drug interaction with DOACs is not well understood. Sarilumab and tocilizumab can heighten cytochrome P450 enzyme activity and should not be used in association with apixaban or rivaroxaban and may also increase the doses of warfarin required.
Atazanavir and lopinavir/ritonavir can increase drug concentrations of apixaban and rivaroxaban and reduce the active metabolite of clopidogrel and prasugrel. The University of Liverpool has assembled a list of drug interactions, which can be accessed at covid19-druginteractions.org. LMWH or UFH in hospitalized critically ill patients is preferred because of the shorter half-life and fewer drug-drug interactions compared with DOACs. Regular warfarin users who cannot get INR monitoring during isolation may be candidates for DOAC therapy; however, patients with mechanical heart valves, ventricular assist devices, valvular atrial fibrillation, antiphospholipid antibody syndrome, or lactation should continue treatment with warfarin therapy. LMWH or UFH are the anticoagulants of choice in pregnancy.
Dr KK Aggarwal
President CMAAO, HCFI and Past National President IMA