CME INDIA Presentation by Dr Awanindra Kumar Singh, MD Physician, PGDCC. Working as Attending consultant in Non Invasive Cardiology with Artemis Cardiac care unit at Raj Hospital Ranchi, Previously associated with Delhi Heart and Lung institute, Forties Escorts & Paras Hospital Gurgaon. Working for last 11 years in Non Invasive Cardiology.

Lots of cases are CORAD-5, symptomatic, not going for COVID test has become problematic, want prescription from physician, early steroids and anticoagulants are being used, how justified is another issue. Many times, demand oral drugs at remote places, as no one available to inject LMWH at home. Pathetic scenario….

Even Post COVID use of oral anti coagulants for prolonged period is a new entity. At this hour, a basic knowledge of oral anti coagulants is needed.

Why Oral Anticoagulants are in Focus?

The Year 2020 is going down in history as the year of SARS-COV 2 or COVID 19 pandemic. COVID 19 has & continues to be a source of an unprecedented suffering & loss of life throughout the world principally by causing systemic inflammation, cytokine storm & thromboembolic events in the victims.

The pathogenesis of hypercoagulability in COVID-19 is incompletely understood. 

Many but not all laboratory findings in COVID 19 are similar to DIC, including a marked increase in D-dimer and in some cases, mild thrombocytopenia. However, other coagulation parameters in COVID-19 are distinct from DIC. In COVID-19, the typical findings include high fibrinogen and high factor VIII activity, suggesting that major consumption of coagulation factors is not occurring & that COVID 19 induced coagulopathy is more Prothrombotic than Haemorrhagic.

What is the Evidence?

• A study led by Girish N. Nadkarni, MD, MPH, CPH and Anuradha Lala, MD, FACC, and colleagues at Mount Sinai in New York, examined the electronic health records of 4,389 adult patients confirmed COVID-19 positive and admitted between March 1 and April 30 to five New York City hospitals in the Mount Sinai system. This retrospective observational study of in-hospital anticoagulation at therapeutic and prophylactic doses, vs. no anticoagulation, concluded that all regimens of anticoagulation {therapeutic (full dose) and prophylactic (less than therapeutic dose)} was far superior to no anticoagulation in COVID-19 patients & showed about 50% higher chance of survival & roughly 30% less chance of intubation than those not on anticoagulants.
• The researchers also reviewed data from the first consecutive autopsies of COVID-19 patients performed at their institution and found that 11 of 26 patients (42%) had thromboembolic disease that was not suspected clinically. Of these, 3 patients (27%) were on therapeutic anticoagulation.
• Based on the observations of this study another researcher Valentin Fuster, MD, PhD, MACC designed a large-scale international randomized trial focusing on three antithrombotic regimens, therapeutic and prophylactic subcutaneous low-molecular weight heparin and therapeutic oral apixaban, to determine the type, duration and doses for improved treatment and outcomes for patients with COVID-19.
• Another early study out of the Hubei Province in China suggests that in absence of VTE prophylaxis, 25% of COVID-19 patients developed lower extremity DVT as assessed by surveillance doppler ultrasound. Which is higher than the 5 to 15% incidence seen in the placebo arms of early studies of VTE prevention. In these early studies, use of pharmacologic VTE prophylaxis reduced the incidence of VTE by up to 60% without an increase in major bleeding.
• A second study from the Netherlands found pulmonary embolism (PE) in25 of 184 ICU patients with COVID-19 (13.6%), 72% of which were in central, lobar, or segmental pulmonary arteries, which occurred despite standard dose pharmacologicprophylaxis.
• A third study from Italy identified thromboembolic events (venous and arterial) in 7.7% of patients admitted with COVID-19, estimating a cumulative rate of21%.

While each of these studies are limited in their design, data collection, and/or statistical methodology, the importance of VTE prophylaxis cannot be understated for hospitalized patients with this illness.

Despite the lack of quality published evidence, many institutional protocols have adopted an intermediate-intensity (i.e., administering the usual daily LMWH dose twice daily) or even a therapeutic-intensity dose strategy for thromboprophylaxis based on local experience.

VTE Prophylaxis with DOACs(direct oral anticoagulant)

DOACs are approved for VTE treatment & prophylaxis however DOACs are not indicated in several circumstances, including people with mechanical valves or moderate-to-severe mitral stenosis; antiphospholipid syndrome; pregnancy or lactation.

DOACs are prone to Drug interactions

Multiple drugs have been repurposed against COVID {Antibiotics like Azithromycin, Doxycycline, Anti-malarial (HCQs), Anti Helminthics (Ivermectin), Steroids, Anti-viral drugs, Immunomodulators etc}. Treatment of COVID-19 infection is currently based on antiviral and immunosuppressive drugs. Several drugs, particularly those that strongly interact with P-glycoprotein and/or cytochrome P450-based metabolic pathways, such as antiviral agents, can modify DOAC pharmacokinetic and pharmacodynamic profiles, consequently changing their plasma anticoagulant activity.

A series of patients managed in the Cremona Thrombosis Centre were admitted at Cremona Hospital for SARS-CoV-2 and started antiviral drugs without stopping DOAC therapy. DOAC plasma levels were measured in hospital and results compared with those recorded before hospitalization.

In all 12 examined patients, an alarming increase in DOAC plasma levels compared to pre-hospitalization was observed after hospital admission. Although a possible role of concomitant drugs or disease-related organ dysfunctions cannot be excluded, the results were consistent with those coming from several studies addressing interferences between DOAC and antiviral agents.

Dexamethasone is an inducer of CYP3A4 and the extent of the drug interaction with direct oral anticoagulants is unknown. Sarilumab and tocilizumab (ACTEMRA) can increase cytochrome P450 enzyme activity and so they should not be used together with apixaban (Eliquis/Apigat) or rivaroxaban (Xarelto/Ixarola) and may also increase the doses of warfarin required. Atazanavir and lopinavir/ritonavir will increase drug concentrations of apixaban (Eliquis/Apigat) and rivaroxaban and decrease the active metabolite of clopidogrel and prasugrel. Although the potential of antiviral agents and other repurposed drugs against COVID 19 to increase the plasmatic concentration of DOACs, as well as their bleeding risk, is well known there is no agreement on the most appropriate clinical management in these circumstances. Accordingly, LMWH or UFH in hospitalized critically ill patients is preferred because of the shorter half-life and fewer drug-drug interactions compared with direct oral anticoagulants.

DOACs (Factor Xa and direct thrombin inhibitors) along with indications & Uses

Factor Xa inhibitors (e.g.,rivaroxaban, apixaban, edoxaban) and oral direct thrombin inhibitors (dabigatran)–

These oral agents are preferred anticoagulant for most hemodynamically stable, non-pregnant patients who do not have severe renal insufficiency or active cancer. While rivaroxaban and apixaban can be administered as monotherapy, and dabigatran is preferably administered following a five day course of heparin (i.e., as dual therapy; LMW or unfractionated heparin [UFH]).

Manufacturer recommendations on compatibility of direct oral anticoagulants with feeding tube administration vary for each agent. For example, apixaban may be crushed and suspended in water whereas dabigatran capsules should not be opened due to substantial increase in drug exposure.

Regular Vitamin K antagonists (warfarin/Acitrom) users who are unable to get INR monitoring during isolation may be candidates for direct oral anticoagulant therapy, but patients with mechanical heart valves, ventricular assist devices, valvular atrial fibrillation, antiphospholipid antibody syndrome, or lactation should generally continue treatment with warfarin therapy. LMWH or UFH remain the anticoagulants of choice in pregnancy.

Switching to DOAC from Vitamin K Antagonists (Warfarin/Acitrom)

Anticipate a therapeutic INR (range 2.0 to 3.0) to decrease to < 2.0, 2 to 3 days after stopping warfarin.9

My take on anticoagulation for COVID-19

• All non-pregnant patients with COVID 19 should receive LMWH / UFA / Fondaparinaux if admitted in the hospital
• Pharmacologic VTE prophylaxis is recommended for all hospitalized pregnant patients with confirmed or highly suspected COVID-19. Providers can follow guidance recently published by the Royal College of Obstetricians (RCOG) [https ://www.rcog.org.uk/globalassets/documents/guidelines /2020-04-09-coronavirus-COVID -19-infection-in-pregnancy.pdf].
• Close collaboration with obstetric and anaesthesiology colleagues is recommended in the event of delivery and/or need for epidural anaesthesia during hospitalization.
• The role of thromboprophylaxis for quarantined patients with mild COVID-19 but significant comorbidities, or for patients without COVID-19 who are less active because of quarantine is uncertain. These patients should be advised to stay active at home. In the absence of high-quality data, pharmacological prophylaxis should be reserved for those patients at highest risk, including those with limited mobility and history of prior VTE or active malignancy.
• Patients not admitted to the hospital — Thrombotic events have been observed in COVID-19 patients who were not admitted to the hospital, but data on the incidence are not available. There are no trials that address thromboprophylaxis in outpatients with COVID-19.
• If thromboprophylaxis is used in an outpatient, use a regimen such as rivaroxaban (Xarelto/Ixarola) 10 mg daily for 31 to 39 days [https://www.hematology.org/COVID-19/COVID-19-and-vte-anticoagulation]. (Cuker 2020).
• Extended (post-discharge) VTE prophylaxis
• After hospital discharge from acute medical illness, extended prophylaxis with LMWH or direct oral anticoagulants (DOACs)can reduce the risk of VTE, at the cost of increase in bleeding events, including major bleeding. Although no data specific to COVID-19 exist, it is reasonable to employ individualized risk stratification for thrombotic and haemorrhagic risk, followed by consideration of extended prophylaxis (for up to 45 days) for patients with elevated risk of VTE (e.g., reduced mobility, comorbidities such as active cancer, and [according to some authors in the writing group] elevated D-dimer >2 times the upper limit of normal) who have low risk of bleeding.
• A full 3-month course of therapeutic anticoagulation for patients with COVID-19 who are presumed to have a hospital associated VTE event is recommended.
• Patients requiring Antiplatelets in combination with DOAC
• Patients already on antiplatelets who require DOACs should continue with single antiplatelet preferably Clopidogrel along with one of the following DOACs in a dose or doses tested in randomized trials and approved by regulatory agencies. For all agents, attention to dose adjustment based on renal function, weight, and age is important.
• For Dabigatran, this includes both the 150 mg twice daily dose and the 110 mg twice daily dose. However, the 110-mg option is not approved for this indication in the United States but is approved and widely used in other countries. Outside the United States, for patients over the age of 80, the 110 mg twice daily dose is mandated in the label.
• The dose of Apixaban is 5 mg twice daily as studied in the AUGUSTUS trial. Dose reduction of apixaban to 2.5 mg twice daily may be necessary in patients with at least two of the following characteristics: age ≥80 years, body weight ≤60 kg, or serum creatinine ≥1.5 mg/dL.
• For Rivaroxaban, some experts recommend 15 mg daily (the dose tested in the PIONEER-AF PCI trial) while others recommend the full dose of 20 mg daily, as approved for stroke prevention. While a lower dose of rivaroxaban (15 mg once daily) plus a P2Y₁₂ inhibitor appears to be a rational choice, the PIONEER AF-PCI trial was underpowered to exclude an increased risk for stroke. If rivaroxaban 15 mg has been selected as the anticoagulant, it is increased to 20 mg when Clopidogrel is discontinued.

CME INDIA Learning Points:

1. All non-pregnant hospitalized patients should get LMWH/ UFH/Fondaparinaux.
2. Use of DOAC are limited due to drug interactions.
3. Dabigatran needs to be overlooked with Heparin.
4. Apixaban or Rivaroxaban can be given as monotherapy and are preferred.
5. Rivoraxaban 10 mg OD can be given for 31 to 39 days post discharge in COVID 19 for long term prophylaxis of VTE.
6. Apixaban seems promising.

References:

1. Health Canada Product Monograph. Eliquis (apixaban). [Internet]. https://pdf.hres.ca/dpd_pm/00053440.PDF
2. Health Canada Product Monograph. Xarelto (rivaroxaban). [Internet]. https://pdf.hres.ca/dpd_pm/00053267.PDF
3. Health Canada Product Monograph. Lixiana (edoxaban). [Internet]. https://pdf.hres.ca/dpd_pm/00055048.PDF
4. Health Canada Product Monograph. Pradaxa (dabigatran). [Internet]. https://pdf.hres.ca/dpd_pm/00055504.PDF
5. January CT, Wann LS, Calkins H, Chen LY, Cigarroa JE, Cleveland JC, et al. 2019 AHA/ACC/HRS Focused Update of the 2014 AHA/ACC/HRS Guideline for the Management of Patients with Atrial Fibrillation: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society in Collaboration With the Society of Thoracic Surgeons. Circulation. 2019;140:e125– e151.
6. Verma A, Cairns JA, Mitchell LB, Macle L, Stiell IG, Gladstone D, et al. 2014 Focused Update of the Canadian Cardiovascular Society Guidelines for the Management of Atrial Fibrillation. Canadian Journal of Cardiology. 2014 Oct 1;30(10):1114–30.
7. Thrombosis Canada. NOACs/DOAC*s: Practical Issues and Frequently-Asked Questions [Internet]. 2020. https://thrombosiscanada.ca/wp-content/uploads/2020/02/NOACs-DOACs-Comparison-and-FAQs_16Feb2020.pdf
8. Health Canada Product Monograph. Coumadin (warfarin). [Internet]. https://pdf.hres.ca/dpd_pm/00047189.PDF
9. White RH, McKittrick T, Hutchinson R, Twitchell J. Temporary discontinuation of warfarin therapy: changes in the international normalized ratio. Ann Intern Med. 1995 Jan 1;122(1):40–2.
10. BC Provincial Academic Detailing Service. Oral anticoagulants in atrial fibrillation: Update. April 2014. [Internet]. https://www2.gov.bc.ca/assets/gov/health/practitioner-pro/pad-2014-oral-anticoagulant-booklet.pdf

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