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Medical experts are recommending for patients prescribed anticoagulants to receive the COVID-19 vaccine. Many of these patients have underlying health conditions putting them at increased risk for serious illness if infected with COVID-19. There are no known pharmacological interactions between components of the vaccine and oral or parenteral anticoagulants. There is a risk of light bleeding, bruising, or hematoma at the injection site but the vaccine is not associated with a serious risk of bleeding. For patients taking warfarin, there is guidance to suggest that the INR should be below 4.0 or below the upper threshold of a person’s therapeutic range prior to receiving the COVID-19 vaccine to reduce risk of bleeding complications.

Patients receiving the COVID-19 vaccine should make the vaccinator aware they are taking an anticoagulant. Anticoagulated patients should be vaccinated with a fine-gauge needle (23-gauge or smaller caliber) followed by firm pressure on the injection site for 2-5 minutes.

Resources

• Vaccine Administration: Intramuscular (IM) injections: Adults 19 years of age and older (cdc.gov)
• COVID-19 and Blood Clotting | Blood Clots (stoptheclot.org)
• COVID-19 Vaccination While on a Blood Thinner (wpcomstaging.com)

The COVID-19 pandemic poses unprecedented challenges to the health care community. The Anticoagulation Forum is fully committed to providing clinicians with the most current, relevant, and actionable information available. This AC Forum notice has been produced to provide time- sensitive information important to COVID-19 response efforts.

Following six reported cases of cerebral venous sinus thrombosis (CVST) in individuals after receiving the Johnson & Johnson (J&J) COVID-19 vaccine in the US, the CDC and FDA are recommending a pause in the use of the J&J COVID-19 vaccine pending further review.

Per the CDC Health Alert April 13, 2021 1pm:

• As of April 12, 2021, approximately 6.85 million doses of the J&J COVID-19 vaccine have been administered in the US
• The CDC and FDA are reviewing data six US cases of CVST in individuals after receiving the J&J COVID-19 vaccine. One patient died.
• In these cases, CVST was seen in combination with thrombocytopenia
• All six cases occurred among women aged 18–48 years
• The interval from vaccine receipt to symptom onset ranged from 6-13 days
• Providers should maintain a high index of suspension for symptoms that might represent serious thrombotic events or thrombocytopenia in patients who have recently received the J&J COVID-19 vaccine
• Based on studies conducted among the patients diagnosed with immune thrombotic thrombocytopenia after the AstraZeneca COVID-19 vaccine in Europe, the pathogenesis of these rare and unusual adverse events after vaccination may be associated with platelet-activating antibodies against platelet factor-4 (PF4)
• In this setting, the use of heparin may be harmful, and alternative treatments need to be given (see links to clinical pathways below in ‘Information for Clinicians’)
• On April 13, 2021, the CDC and FDA recommend a pause in the use of the J&J COVID- 19 vaccine out of an abundance of caution.
• The CDC’s Advisory Committee on Immunization Practices (ACIP) has suggested extension of this pause for at least another week as they continue review the data.

To access the complete CDC Health Alert visit: https://emergency.cdc.gov/han/2021/han00442.asp

Additional CDC COVID-19 resources are available at: https://www.cdc.gov/coronavirus/2019-ncov/index.html

INFORMATION FOR CLINICIANS
While evidence regarding the incidence and treatment of thrombosis associated with the J&J COVID-19 vaccine is still preliminary and the situation continues to be quite fluid, similarities exist between reports of thrombosis with the Astra Zeneca COVID-19 vaccine currently in use outside of the US. Clinical recommendations for the identification and treatment of such cases may therefore be informative for clinicians until more definitive guidance becomes available. Available resources include, but are not limited to:

Interim guidance from ISTH for the Diagnosis and Treatment on Vaccine Induced Immune Thrombotic Thrombocytopenia (Updated 20 April, 2021) including diagnostic flow chart:
https://cdn.ymaws.com/www.isth.org/resource/resmgr/ISTH_VITT_Guidance_2.pdf 
https://cdn.ymaws.com/www.isth.org/resource/resmgr/news/ISTH_VITT_Flow_Chart_Final.pdf

Guidance produced from the Expert Haematology Panel (EHP, UK) focused on COVID-19 Vaccine induced Thrombosis and Thrombocytopenia (VITT) (Version 1.3; April 7, 2021; Document updated frequently)

https://b-s-h.org.uk/media/19530/guidance-version-13-on-mngmt-of-thrombosis-with- thrombocytopenia-occurring-after-c-19-vaccine_20210407.pdf

https://thrombosiscanada.ca/wp-uploads/uploads/2021/04/51.-Vaccine-induced-prothrobotic-immune-thrombcytopenia_02April2021-1.pdf

It should first be noted that in the large pivotal trials that brought the DOACs to market, enrolled patients were assigned a dose based on renal function at study randomization without changes during the study period. Subgroup analyses of the ARISTOTLE and ROCKET-AF trials demonstrated that – in patients experiencing worsening renal function during the study period - apixaban and rivaroxaban maintained their efficacy and safety benefits as compared to warfarin. It should also be noted that studies have identified off-label DOAC dosing (including under- and over-dosing for renal function) as a common problem that significantly increases the risk of major bleeding, thromboembolic events, and all-cause mortality. As such, guidelines and experts note that patients prescribed DOACs require regular monitoring of renal function to ensure their safe and effective use – with dose adjustments made according to the renal dosing parameters for each DOAC agent. However, it may be impractical and unnecessary to frequently adjust the dose when a patient’s renal function is slightly fluctuating across parameter endpoints. DOAC dosing decisions should be based on factors such as the extent of creatinine change, the overall trend in renal function, and the clinical plan in response to the changing renal function (i.e., repeat labs, work-up, adjustments to medications which may be causative, etc). Other considerations that may sway a decision include (but are not limited to), drug-drug interactions, perceived bleeding/thrombotic risk, and patient preference. An approach that limits frequent dose changes and promotes shared decision-making between the patient and prescriber is recommended.

Resources

• JAMA Cardiol. 2016;1:451-460
• Circulation. 2016;134:37-47
• J Am Coll Cardiol. 2016;68(24);2597-604
• J Am Coll Cardiol. 2017 Jun 13;69(23):2779-2790

As of this writing, there exists no prospective AF nor VTE trial data involving patients with ESRD prescribed any of the direct-acting oral anticoagulants (DOACs). Such patients were excluded from the large randomized controlled trials of DOACs vs. warfarin for these conditions. Further, none of the DOACs have FDA approval for use in this specific population. Both apixaban and rivaroxaban include language in their prescribing information about use in these populations that is based on pharmacokinetic modeling data involving a SINGLE DOSE of the respective agents administered to eight study subjects. A steady state pharmacokinetic modeling study published in 2017 found that apixaban 2.5mg twice daily given to patients on hemodialysis (HD) resulted in drug exposure comparable to that of apixaban 5mg twice daily given to pts with preserved renal function. It concluded that apixaban 5mg twice daily resulted in supratherapeutic levels and should be avoided in the HD population. However, a more recent retrospective outcomes study evaluating the use of apixaban in patients with AF and ESRD concluded that "apixaban may be associated with a lower risk of major bleeding compared with warfarin, with a standard 5mg twice a day dose also associated with reductions in thromboembolic and mortality risk."" As this likely represents the best available data, it would appear that following the AF dosing recommendations in the prescribing information represents the best approach.

As for VTE, there exists no available data to inform decisions.

Resources

• Eliquis (apixaban) prescribing Information
• Xarelto (rivaroxaban) prescribing information
• J Am Soc Nephrol 2017. 28: 2241–2248
• Circulation. 2018 Oct 9;138(15):1519-1529

In 2016, the International Society on Thrombosis and Haemostasis published guidance advising caution when using DOACs in morbidly obese patients (>120 kg or BMI >40 kg/m2) due to the limited efficacy and safety data in this patient population. Some pharmacokinetic and pharmacodynamic data have found modest effects of body weight extremes on DOAC exposure, but the clinical relevance is not well known. The published literature on this topic is predominantly limited to case reports, retrospective cohort analyses, and post hoc analysis of RCTs.

A 2017 meta-analysis of phase III RCTs evaluated DOAC safety and efficacy in high body weight (>100 kg) and obese patients (BMI >30 kg/m2). No significant difference in thromboembolic or bleeding outcomes was found regardless of indication of therapy (atrial fibrillation or VTE).² There were very few patients included with extremely high body weights (>120 kg or BMI >40 kg/m2) therefore a separate analysis of this patient population could not be conducted. Since this publication, there has been additional yet limited evidence evaluating those with extremely high body weights.

A recent meta-analysis evaluating high body weight adults (>100 kg but <300 kg) with acute VTE found no significant difference in recurrent VTE or bleeding events at 12 months between DOACs and VKAs.³ In the DOAC arm (n=632), 41.8% of patients were >120 kg and 43.6% had a BMI >40 kg/m2. Of note, ~92% of those in the DOAC arm were prescribed rivaroxaban. Another retrospective study looking at atrial fibrillation/flutter patients with BMI >40 kg/m2 or weight >120 kg concluded that apixaban or rivaroxaban may be considered safe and effective alternatives to warfarin, with caution given to dabigatran until further studies are conducted.⁴ A single-center, retrospective analysis of nearly 800 patients compared apixaban and rivaroxaban to warfarin in those with a BMI of at least 40 kg/m2 for indications of both atrial fibrillation and VTE. No significant differences among recurrent VTEs and strokes were found between apixaban, rivaroxaban, and warfarin. An additional subgroup analysis of those with a BMI of at least 50 kg/m2 also did not find any significant differences in efficacy outcomes.⁵

Although there is limited guidance on DOAC use within an obese population, current available evidence suggests that it can be considered a comparable alternative to warfarin. Shared decision-making remains essential to ensure risks vs benefits are discussed and that a collective decision is made regarding therapy selection.

*Of note, the safety and efficacy of dosing for secondary prevention of VTE (apixaban 2.5mg BID and rivaroxaban 10mg daily) is not well known in those with extremely high body weights. While there was no exclusion criteria in AMPLIFY-EXT or EINSTEIN CHOICE based on weight or BMI, it would be reasonable to continue these patients on therapeutic dosing until more data is known.

Resources:

1. Sebaaly J, Kelley D. Direct Oral Anticoagulants in Obesity: An Updated Literature Review. Ann Pharmacother. 2020 Nov;54(11):1144-1158. 

2. Boonyawat K, Caron F, Li A, et al. Association of body weight with efficacy and safety outcomes in phase III randomized controlled trials of direct oral anticoagulants: a systematic review and meta-analysis. J Thromb Haemost. 2017;15:1322-1333.

3. Coons JC, Albert L, Bejjani A, Iasella CJ. Effectiveness and Safety of Direct Oral Anticoagulants versus Warfarin in Obese Patients with Acute Venous Thromboembolism. Pharmacotherapy. 2020 Mar;40(3):204-210.

4. Kido K, Ngorsuraches S. Comparing the Efficacy and Safety of Direct Oral Anticoagulants With Warfarin in the Morbidly Obese Population With Atrial Fibrillation. Ann Pharmacother. 2019 Feb;53(2):165-170. doi: 10.1177/1060028018796604. Epub 2018 Aug 22. PMID: 30130979.

5. Kushnir M, Choi Y, Eisenberg R, et al. Efficacy and safety of direct oral factor Xa inhibitors compared with warfarin in patients with morbid obesity: a single-centre, retrospective analysis of chart data. Lancet Haematol. 2019;6:e359-e365.

Patients with low body weight (≤60 kg) and extremely low body weight (<50 kg) were under-represented in pivotal DOAC RCTs. There is currently no direct societal guidance on use of DOACs in those with low body weight. Pharmacokinetic data suggests only a modest increase in Cmax and AUC in those with low body weight, but this has not consistently correlated with worsening clinical outcomes. A 2017 meta-analysis of phase III RCTs evaluated DOAC safety and efficacy in those with low body weight (≤60 kg). The study concluded that dose adjustment of DOACs outside of that recommended by package inserts is unlikely to improve safety or efficacy.¹ A 2019 retrospective cohort study of more than 14,000 low body weight (≤60kg) Asian patients treated with DOACs for atrial fibrillation found that regular doses of DOACs showed comparable results as reduced dosages in both efficacy and safety.² It also showed DOACs were safer and more effective than warfarin. The benefits were consistent in those <50 kg as well except for hospitalization for GIB.

Although there is limited guidance on DOAC use within a low body weight population, current available evidence suggests that it can be considered a comparable alternative to warfarin. Additionally, evidence suggests that dosage adjustments outside of those recommended by package inserts is unlikely to improve efficacy or safety.

1. Boonyawat K, Caron F, Li A, et al. Association of body weight with efficacy and safety outcomes in phase III randomized controlled trials of direct oral anticoagulants: a systematic review and meta-analysis. J Thromb Haemost. 2017;15:1322-1333.

2. Lee S, Choi E, Park C, et al. Direct Oral Anticoagulants in Patients With Nonvalvular Atrial Fibrillation and Low Body Weight. J Am Coll Cardiol. 2019 Mar, 73 (8) 919–931.

Recent publications have highlighted that “off-label” DOAC dose reductions correspond with higher incidence of thromboembolic events. Presently, “off-label” dose reductions should be avoided.

Resources

• Off-Label Dosing of Non-Vitamin K Antagonist Oral Anticoagulants and Adverse Outcomes
• Non-Vitamin K Anticoagulant Dose Selection: It’s Best to Read and Follow the Directions

Since DOACs exhibit a similar pharmacokinetic profile as LMWH, the use of parenteral bridging is generally not a recommended strategy for perioperative management. For high risk procedures, it is recommended that DOACs be held 3-5 half-lives to achieve maximal drug clearance.

Resources

• ASRA Guidelines
• AC Forum Guidance - DOAC Management

Recent literature has shifted the landscape on how perioperative bridging should be approached. In most cases bridging with LMWH is associated with more risk of bleeding than prevention of VTE. Instances where bridging could be considered are:

1. Active cancer
2. Recent VTE (within 3 months)
3. Strong Thrombophilia (APS, protein C/S def or antithrombin deficiency)
4. Previous therapeutic failure or VTE during short term interruption
5. Patient undergoing procedure with high thrombotic risk

Resources

• A Call to Reduce the use of Bridging Anticoagulation
• American College of Cardiology Periprocedural Guidance

Recent studies such as the BRIDGE trial have demonstrated that there is a net harm associated with LMWH bridging. Consideration for bridging should be reserved for patients who are at high risk for thromboembolism such as:

1. Patients with any thromboembolism during past interruptions of anticoagulation, or while on therapeutic anticoagulation
2. Patients with a cerebrovascular accident or transient ischemic attack in the past 3 months
3. Patients with recent (within 1 month) evidence of mural thrombus or left atrial appendage clot
4. Patients with a mitral mechanical valve
5. Patients with older caged ball or tilting disc mechanical valves
6. Patients with VTE in the past 3 months
7. Patients with VTE and a properly diagnosed hypercoagulable state, including antiphospholipid antibody syndrome,
8. Protein C or Protein S deficiency, or antithrombin3 deficiency.
9. CHADS2 score of 5-6 or CHADS2VASc score of 7-9

Additional guidance is available from the American College of Cardiology at:
American College of Cardiology Periprocedural Guidance

In patients undergoing major orthopedic surgeries who do not require bridging, it is still necessary to consider post-operative VTE prophylaxis, due to the high risk of thromboembolism associated with major orthopedic surgeries, until full dose anticoagulation is cleared by the orthopedic surgeon.

In very high risk patients in whom full dose bridging is deemed necessary, it is recommended risks and benefits be discussed with the proceduralist to determine the best course of action for the patient.

Resources

• A Call to Reduce the use of Bridging Anticoagulation
• Prevention of VTE in orthopedic surgery patients - Article 1
• Prevention of VTE in Orthopedic Surgery Patients - Article 2

The concomitant use of dexamethasone and direct-acting oral anticoagulants (DOACs) therapy is not a clinically significant issue. There are limited human/in vivo studies investigating the interaction between DOACs and dexamethasone. COVID-19 patients are at a higher risk of thrombotic events and frequently receive extended courses of dexamethasone, however, the use of dexamethasone is reserved for the critically ill COVID-19 patients requiring oxygen supplementation.¹ Some institutions may use DOAC therapy to prevent VTE in acutely-ill patients while many patients are already taking DOAC therapy for concomitant conditions like prior venous thromboembolism (VTE) or atrial fibrillation (Afib). Because corticosteroids increase the risk of gastrointestinal bleeding or perforation by forty percent,² monitoring serum concentrations of DOACs may be warranted if concomitant use is unavoidable.³

Apixaban and rivaroxaban exploit CYP3A4 metabolism and all DOACs are substrates of p-gp efflux transporters.⁴ Drugs that are strong modifiers for p-gp or CYP3A4 can have clinically significant reactions with DOACs leading to increased risk of thrombosis or bleeding.⁴ Lexicomp classifies dexamethasone as a weak CYP3A4 inducer with no p-gp induction.⁵ Current recommendations demonstrate that there is no interaction between dexamethasone and DOACs. Most recommendations either do not use dexamethasone and DOACs concomitantly, did not discuss interactions between dexamethasone and DOACs, or are review articles/guidelines that recommend against concomitant use of dexamethasone and DOACs based on a theoretical interaction.⁴ Therefore, given the low quality of the data and uncertainty on the degree or duration of a potential prothrombotic state with COVID-19 patients, the concomitant use of DOACs and dexamethasone is not a clinically significant issue.

Resources

• COVID-19 Treatment Guidelines Panel. Coronavirus Disease 2019 (COVID-19) Treatment Guidelines. National Institutes of Health.
• Narum S, Westergren T, Klemp M. Corticosteroids and risk of gastrointestinal bleeding: a systematic review and meta-analysis. BMJ Open. 2014;4(5):e004587. Published 2014 May 15. doi:10.1136/bmjopen-2013-004587
• Wiggins BS, Dixon DL, Neyens RR, Page RL 2nd, Gluckman TJ. Select Drug-Drug Interactions With Direct Oral Anticoagulants: JACC Review Topic of the Week. J Am Coll Cardiol. 2020;75(11):1341-1350. doi:10.1016/j.jacc.2019.12.068
• Vasquez S, Fleming R. Direct Oral Anticoagulant (DOAC) Drug-Drug Interaction Guidance: Anticoagulation Forum. 2020.
• Lexicomp Online, Lexi-Drugs Online, Hudson, Ohio: Wolters Kluwer Clinical Drug Information, Inc.; 2020; November 17, 2020.

Aspirin is not recommended for the prevention of thromboembolism in NVAF due to decreased efficacy and no difference in bleeding risk compared to anticoagulant therapy. The Garfield-AF registry reports that NVAF patients on antiplatelet monotherapy for stroke prevention tend to have higher HAS-BLED scores suggesting that clinicians may be unfamiliar with guidelines and studies revealing similar bleeding risks of anticoagulants and antiplatelet agents. The AVERROES trial showed no significant difference in bleeding with apixaban vs. aspirin. A recent meta-analysis of 4 randomized controlled trials with greater than 20,000 patients, showed no significant difference in outcomes of major bleeding with therapeutic direct oral anticoagulant (DOAC) dosing vs. aspirin. Guidelines from the United States and Europe (CHEST 2018, ESC 2016 and AHA/ACC/HRS 2019) all recommend anticoagulants over antiplatelets and the ESC recommends against antiplatelet therapy used for stroke prevention in NVAF patients.

Resources

• Verheugt, European Heart Journal. 2018; 39(5):464-473
• Dimitrios Sagris, et al., European Journal of Internal Medicine. https://doi.org/10.1016/j.ejim.2020.05.001
• Connoly, NEJM 2011; 364:806-817.
• Lipp, CHEST 2018;154(5):1121-1201.
• European Society of Cardiology 2016; 37, 2893-2962
• January, Circulation.2019;140:e125–e151.

The 9th edition of the ACCP Antithrombotic guidelines (CHEST 2012) states the following:

For patients with stable therapeutic INRs presenting with a single subtherapeutic INR value, we suggest against routinely administering bridging with heparin (Grade 2C).

It should be noted that this is not specific to MHVs, does not speak to repeatedly subtherapeutic INR, and does not speak specifically to high-risk indications. One could extrapolate from current recommendations about bridging for intentional interruptions, but this does not add much clarity to the issue if the guidelines and available literature are taken in context. First, the annualized stroke risk associated with MHVs has been estimated at 2-4% so one can assume a daily risk of no more than 0.01% - quite low. While some societies still encourage periprocedural bridging for certain patients with MHVs, it should be clear that all available literature would suggest net HARM from bridging in all patient populations represented in studies to date. Across the board, the data demonstrates no significant reduction in the risk of thromboembolic events, with significant increase in the risk of major bleeding. Clear data on the risk and benefit of bridging in the highest risk population (including the highest risk patients with MHVs) are lacking, but the net harm from other populations seems so clear that the likelihood of any population exhibiting net benefit is low. As such, bridging for a single subtherapeutic INR should likely be avoided in most cases. For the highest risk patients and/or those with multiple subtherapeutic INRs, the above should be taken

Resources

• CHEST 2012; 141(2)(Suppl):7S–47S.
• Circulation. 2017;135:e1159–e1195.
• European Heart Journal (2017) 38, 2739–2791.
• J Am Coll Cardiol 2000; 86:1097–101.

The WATCHMAN procedure is indicated for the prevention of stroke in patients with atrial fibrillation (AF) and involves the implantation of an occlusive device in the left atrial appendage (LAA) of the heart.¹ More than 90% of AF-related thrombi originate in the LAA making LAA closure (LAAC) an attractive option. The WATCHMAN is associated with stroke reduction similar to warfarin, but with a long-term major bleeding reduction.^2,3,4 Left atrial appendage closure (LAAC) can also be cost-effective in the long-term.⁵ However, there are risks associated with the WATCHMAN, including the risk of procedure-related major bleeding, and risk of stroke from incomplete LAAC. Some opponents have also raised concerns about insufficient data and lack of compelling evidence supporting the WATCHMAN.⁶ Additionally, the WATCHMAN was compared ONLY to warfarin. For patients who are poor candidates for long-term warfarin therapy, the use of safer, more effective, and more convenient anticoagulants (i.e., Direct-Acting Oral Anticoagulants) should be considered before LAAC with WATCHMAN.⁷

Resources

It is best to avoid the use of DOACs in patients with APLS. Warfarin or LMWH should remain first line options until more data becomes available.

Recommendations from the International congress of Antiphospholipid Antibodies Task Force:

“The taskforce recommends that warfarin or other VKA remains the mainstay of anticoagulation in thrombotic APS. Oral direct inhibitors can be considered in APS patients with a first or recurrent VTE occurring off or on subtherapeutic anticoagulation, only when there is known VKA allergy/intolerance or poor anticoagulant control. There are no data to recommend ODI (oral direct inhibitors) in APS patients with recurrent VTE occurring on therapeutic anticoagulation or with APS-related arterial thrombosis”

Resources

• 14th International Congress on Antiphospholipid Antibodies Task Force Report on Antiphospholipid Syndrome Treatment Trends

The CHEST guidelines provide recommendations for lower extremity SVT (not upper). If the SVT is >5cm, recommendations are to utilize prophylactic dosing of fondaparinux.

Patients with superficial venous thrombosis of the lower limb of at least 5 cm in length. Suggest the use of a prophylactic dose of fondaparinux or LMWH for 45 days over no anticoagulation.

Currently, none of the DOACs have FDA approval to treat SVT, however a recent study showed a 45 day course of rivaroxaban 10mg was noninferior to fondaparinux at preventing serious complications in high risk SVT.

Resources

• CHEST Guidelines
• Prevention of thromboembolic complications in patients with superficial-vein thrombosis given rivaroxaban or fondaparinux.

Literature suggests patients who have experienced warfarin associated GIB, the benefits of resuming anticoagulant therapy will outweigh the risks (RETREAT). While the data varies as to exactly when anticoagulation should be restarted, available evidence indicates that waiting ∼14 days may best balance the risk of recurrent bleeding, thromboembolism, and mortality after gastrointestinal tract bleeding (WITT ASH Education Book December 2, 2016 vol. 2016 no. 1 620-624).

Resources

• Reply to “When to resume anticoagulation after acute gastrointestinal bleeding?”
• Thromboembolic events, recurrent bleeding and mortality after resuming anticoagulant following gastrointestinal bleeding
• What to do after the bleed