Blood and Clots Series: Which antithrombotic therapy should I start for my patient with acute VTE?

In Blood & Clots, Medical Concepts by Eric Tseng7 Comments

All the content from the Blood & Clots series can be found here.

CanMEDS Roles addressed: Expert

Case Description

You diagnose an 83 year old female patient with an acute DVT. Her comorbidities include hypertension, diabetes, mild chronic kidney disease  (CrCL 55), osteoarthritis, and early mild cognitive impairment for which she is taking Ramipril 10 mg daily, Hydrochlorothiazide 25 mg daily, Metformin 500 mg TID, Donepezil 10 mg daily, and Ibuprofen 200 mg BID. She has no history of coronary artery disease or atrial fibrillation. You feel she can be discharged home safely if you can sort out a treatment plan. Which anticoagulant should you choose for this patient?

Main Text

What are the options?

For stable outpatients starting anticoagulant therapy, the two most common options for oral therapy would be Warfarin (bridged with 5-7 days of Low Molecular Weight Heparin subcutaneous injections) or a Direct Oral Anticoagulant (Dabigatran, Rivaroxaban, or Apixaban). Most articles written about oral anticoagulant therapy for VTE over the past 5 years have some iteration of a table describing the properties of the DOACs (this is a good example here) 1.

A few other factors help determine whether your patient is a good candidate for a DOAC 2:

  1. Is there a contraindication to a DOAC? Individuals who are breastfeeding or pregnant should not be using DOACs as there is insufficient safety data and they were excluded from clinical trials. Patients with mechanical heart valves should be on Warfarin, not a DOAC 3.
  2. Are there any significant drug-drug interactions? Drugs that induce/inhibit p-glycoprotein may interact with Dabigatran, and drugs that induce/inhibit both p-glycoprotein and CYP3A4 may interact with Rivaroxaban and Apixaban. A table of common interactions can be found here 1. A few common drugs to look out for: some Antifungals (particularly Ketoconazole and Voriconazole) increase DOAC effect, Antiepileptics (particularly Phenytoin, Carbamazepine, Phenobarbitol) reduce DOAC effect, and tuberculosis medications (Rifampin) reduce DOAC effect.
  3. Is there sufficient renal and hepatic function? The DOACs are reliant to a variable extent on renal clearance. These drugs should also be avoided in moderate to severe renal dysfunction (CrCL < 25-30) as there is a risk of drug accumulation. These patients were excluded in clinical trials. For the same reasons, DOACs should be avoided in patients with acute hepatitis, chronic active hepatitis, or cirrhosis associated with coagulopathy (Childs-Pugh B or C).
  4. Can your patient pay for the drug? The costs of DOACs will vary depending on whether the patient has private insurance, or whether regional government drug plans cover these drugs. This should be discussed openly with patients before therapy is started.
  5. Is frequent laboratory access difficult? Initiation of Warfarin requires frequent INR checks (approximately weekly) until stable INRs are achieved. Meanwhile, DOACs require lab work infrequently (creatinine clearance every 6-12 months).

Here are some other advantages and disadvantages of DOACs as compared with Warfarin (Adapted from 2):

Advantages Disadvantages
  • No routine monitoring
  • Overall better safety profile (less major bleeding, less intracranial hemorrhage)
  • Rapid onset (can avoid injections if using Rivaroxaban or Apixaban)
  • Short half-life (periprocedural management)
  • Improved quality of life
  • Fewer drug and dietary interactions
  • Assays to measure DOAC anticoagulant activity are not widely available
  • Contraindicated in severe renal or liver dysfunction
  • only Dabigatran has a complete reversal agent (Idarucizumab)
  • Their short half-life makes adherence important
  • If no insurance coverage is available, they are expensive

You have decided to start a DOAC. Which one should you choose?

Dabigatran, Rivaroxaban, and Apixaban have all been compared with Warfarin in large phase 3 clinical trials and have similar efficacy for preventing VTE recurrence, while reducing the risk of major bleeding (especially reduction in ICH) 4. As they are all effective treatments for VTE, a few additional considerations impact the choice of therapy.

  • Preference for once versus twice daily dosing – Given the short half-life of DOACs, it is important that all doses are taken. Many patients prefer once-daily dosing (Rivaroxaban) over BID drugs (Dabigatran, Apixaban).
  • Patients with potential cognitive impairment – Dabigatran cannot be blister-packed so other drugs should be considered in patients who require this aid to ensure appropriate medication utilization.
  • History of GI bleeding, peptic ulcer disease, or dyspepsia – Consider anticoagulants besides Dabigatran or Rivaroxaban in these patients. Dabigatran has been associated with dyspepsia in 5-10% of patients while both Dabigatran and Rivaroxaban may be associated with a higher risk of GI bleeding 5.
  • Active cancer – for the moment, LMWH remains the standard of care for cancer-associated thrombosis 6. However, a recent randomized study showed that Edoxaban (another DOAC) was non-inferior to LMWH for the composite outcome of major bleeding and recurrent VTE. As such Edoxaban would also be a reasonable option in patients with cancer 7. *
  • Severe renal dysfunction – Patients with CrCL < 25-30 were excluded from clinical trials as DOACs rely to a variable extent on renal clearance. Warfarin should be used in such patients. Note: avoid using estimated GFR from the lab; calculate the Cockcroft-Gault creatinine clearance yourself using patient’s age, sex, creatinine and weight. There are many apps or sites to help you including here.
  • Increased body mass index – Only 15% of patients in phase 3 RCTs were of body mass greater than 100 kg. Some authors suggest that DOACs should not be used if weight is greater than 120 kg because the efficacy of standard DOAC doses in obesity has not been established 8.

Further guidance about selection of anticoagulant therapy for VTE can be found here 6.

Case Conclusion

Your patient notes that she has insurance to cover the cost of her medications, prefers to avoid frequent laboratory testing, and would prefer to take a once-daily medication that can be blister-packed. You prescribe Rivaroxaban 15 mg BID x 3 weeks, followed by 20 mg once daily. She agrees to switch her analgesic from Ibuprofen to Tylenol to mitigate the risk of bleeding.

You advise that she follow-up with her primary care provider in 3 months’ time for blood work to ensure that her CrCL remains stable.

Main Messages

  • Both LMWH/Warfarin and DOACs are reasonable first-line treatments for acute VTE.
  • DOACs have similar efficacy to Warfarin in the treatment of VTE, and have a favourable safety profile with less major bleeding and intracranial hemorrhage.
  • Decisions about anticoagulant therapy must take into account efficacy, bleeding risk, comorbidity, patient preference, and cost.

All the content from the Blood & Clots series can be found here.

*The section that addresses the question, Which one should you choose? was revised on January 30, 2018 to reflect evidence that has emerged since the post was first drafted and reviewed.

This post was reviewed by Sean Nugent, Brent Thoma and uploaded by Rebecca Dang.

References

1.
NOACs/DOACs: Comparison and Frequency Asked Questions. Thrombosis Canada. http://thrombosiscanada.ca/wp-content/uploads/2017/05/21_NOACs-DOACs-Comparison-and-FAQs-_2017Mar14.pdf. Accessed July 17, 2017.
2.
Burnett A, Mahan C, Vazquez S, Oertel L, Garcia D, Ansell J. Guidance for the practical management of the direct oral anticoagulants (DOACs) in VTE treatment. J Thromb Thrombolysis. 2016;41(1):206-232. [PubMed]
3.
Eikelboom J, Connolly S, Brueckmann M, et al. Dabigatran versus warfarin in patients with mechanical heart valves. N Engl J Med. 2013;369(13):1206-1214. [PubMed]
4.
van E, Coppens M, Schulman S, Middeldorp S, Büller H. Direct oral anticoagulants compared with vitamin K antagonists for acute venous thromboembolism: evidence from phase 3 trials. Blood. 2014;124(12):1968-1975. [PubMed]
5.
Di M, Spadarella G, Spadarella E, Tremoli E, Di M. Gastrointestinal bleeding in patients receiving oral anticoagulation: Current treatment and pharmacological perspectives. Thromb Res. 2015;136(6):1074-1081. [PubMed]
6.
Kearon C, Akl E, Ornelas J, et al. Antithrombotic Therapy for VTE Disease: CHEST Guideline and Expert Panel Report. Chest. 2016;149(2):315-352. [PubMed]
7.
Raskob GE, van Es N, Verhamme P, et al. Edoxaban for the Treatment of Cancer-Associated Venous Thromboembolism. N. December 2017. doi:10.1056/nejmoa1711948
8.
Martin K, Beyer-Westendorf J, Davidson B, Huisman M, Sandset P, Moll S. Use of the direct oral anticoagulants in obese patients: guidance from the SSC of the ISTH. J Thromb Haemost. 2016;14(6):1308-1313. [PubMed]
(Visited 1,072 times, 10 visits today)
Eric Tseng

Eric Tseng

Dr. Eric Tseng is a hematologist who works at St. Michael’s Hospital and the University of Toronto. His clinical practice is focused on non-cancer hematology and thrombosis medicine. His academic interests are in postgraduate medical education and competency based education.