A 51-year-old obese woman with a history of hypertension, hyperlipidemia, and bipolar disorder presented to the emergency department with shortness of breath and sudden onset of dyspnea. She was given a diagnosis of bilateral submassive pulmonary embolisms (PEs) as seen on a computed tomography scan. She denied having a history of thromboembolism in the past, but her sister has a history of deep vein thrombosis (DVT). She denies smoking, use of oral contraceptives, and recent travel or surgery.

The patient’s pertinent examination results follow:

Weight: 124 kg
Body mass index (BMI): 53 kg/m2
Serum creatinine: 0.93 mg/dL
D-dimer: >4000 ng/mL
 
Pulmonary Vascular Service was consulted, and the patient was admitted to medicine service and started on unfractionated heparin infusion (goal partial thromboplastin time: 60-80 seconds). The consult team was concerned that direct oral anticoagulation (DOAC) medications would be ineffective due to the patient’s obesity. She was started on warfarin instead, in addition to parenteral therapy for acute PE.
 
Discussion
Venous thromboembolism (VTE) is defined by the diagnosis of DVT, PE, or both. In the United States, as many as 900,000 individuals (1 or 2 per 1000) are affected by VTE each year. VTE is the third leading cardiovascular cause of death, affecting up to 100,000 people per year. The risk of death is especially higher within 1 month after diagnosis, and one-third of people given the diagnosis have a VTE recurrence within 10 years.1
 
Patients at risk for thromboembolism are those who have undergone recent surgery or trauma, have had prolonged immobility, are of increased age, or have active cancer.2 Patients should be evaluated for thrombosis risk and provided with prophylaxis therapy to prevent blood clots from forming. However, these are not the only patients at risk. Many lifestyle factors can also increase the risk of blood clots; examples include smoking, hypertension, metabolic syndrome, hyperlipidemia, and obesity.3 As seen in the patient case here, obesity was a contributing factor in developing VTE.
 
Obesity in the United States has become a public health problem. Between 2011 and 2012, an estimated 35% of adults 20 years or older were obese.4 There was no change in prevalence of obesity in this population from the previous decade. Estimates indicate that by 2030, more than 50% of the adult US population will be considered obese, and 10% will be considered morbidly obese (BMI >40 kg/m2).5 Obesity not only increases the risk of VTE but also is associated with other cardiovascular conditions, such as myocardial infarction, congestive heart failure, atrial fibrillation, and stroke. Obesity can also affect the treatments used to manage these conditions because pharmacokinetic parameters, such as volume of distribution, half-life, and drug elimination, can be altered in obese patients. Changes in pharmacokinetic parameters in obese patients may be seen in any of the various classes of anticoagulants.6
 
According to guidelines published in February 2016,7 the DOACs dabigatran, rivaroxaban, apixaban, and edoxaban are recommended as first-line therapy over vitamin K antagonists (VKA), such as warfarin, for DVT of the leg or PE without cancer for the first 3 months of treatment. In patients who are not started on a DOAC, VKA therapy is recommended as an alternative to treatment with low molecular weight heparin. Parenteral therapy must be given for at least 5 days prior to initiation of dabigatran and edoxaban treatment, and it must be overlapped with VKA therapy. No parenteral therapy is recommended prior to treatment with the DOACs rivaroxaban or apixaban. After the first 3 months of therapy, the patient should be evaluated to determine if extended treatment is warranted.
 
Despite the recommendations in the treatment guidelines, there is still concern regarding the use of anticoagulant medications in patients who are obese, as shown by the medical team’s decision in the case presented here. This concern stems from the low number of patients enrolled in DOAC studies. Reviews of DOAC studies evaluating efficacy and safety in treatment and prevention of VTE and stroke prophylaxis in atrial fibrillation found that the frequencies of patients with a body weight >100 kg ranged from 14% to 19%, and the percentages were even lower for participants who were obese or morbidly obese.8 A meta-analysis published in 2015 evaluated 6 randomized controlled trials (27,000 participants) comparing DOACs to warfarin in VTE treatment, and concluded that there was similar efficacy and safety at various levels of body weight (ie, low, medium, and high).9 However, the authors concluded that more studies with larger study populations should be performed to confirm these findings. At present, there are no recommendations to adjust doses of DOACs for patients who are obese, but in underweight patients with body weight <60 kg, an adjusted dose may be needed if other factors are present.10,11 As stated in the treatment guidelines, DOAC therapy should be considered first-line therapy for acute VTE, but if treatment with DOACs is not started due to patient characteristics, as in the patient case here, then VKA treatment, overlapped with parenteral therapy, should be started to reduce mortality and prevent recurrence. 


Nicholas Feola, PharmD, is an advanced practice clinical pharmacist who works in the Collaborative Drug Therapy Management clinics, specifically in Infectious Disease and Anticoagulation, at the Brigham and Women’s Hospital in Boston, Massachusetts.

References
  1. Beckman MG, Hooper WC, Critchley SE, Ortel TL. Venous thromboembolism: a public health concern. Am J Prev Med. 2010;38(4 suppl):S495-S501. doi: 10.1016/j.amepre.2009.12.017.
  2. Heit JA, Spencer FA, White RH. The epidemiology of venous thromboembolism. J Thromb Thrombolysis. 2016;41(1):3-14. doi: 10.1007/s11239-015-1311-6.
  3. Goldhaber SZ. Risk factors for venous thromboembolism. J Am Coll Cardiol. 2010;29:56(1):1-7. doi: 10.1016/j.jacc.2010.01.057.
  4. Ogden CL, Carroll MD, Kit BK, Flegal KM. Prevalence of childhood and adult obesity in the United States, 2011-2012. JAMA. 2014;311(8):806-814. doi: 10.1001/jama.2014.732.
  5. Kelly T, Yang W, Chen CS, Reynolds K, He J. Global burden of obesity in 2005 and projections to 2030. Int J Obes (Lond). 2008;32(9):1431-1437. doi: 10.1038/ijo.2008.102.
  6. Domienik-Karlowicz J, Pruszczyk P. The use of anticoagulants in morbidly obese patients. Cardiol J. 2016;23(1):12-16. doi: 10.5603/CJ.a2015.0054.
  7. Kearon C, Akl EA, Ornelas J, et al. Antithrombotic therapy for VTE disease: CHEST Guideline and Expert Panel Report. Chest. 2016;149(2):315-352. doi: 10.1016/j.chest.2015.11.026.
  8. Di Minno MN, Lupoli Roberta, Di Minno A, Ambrosino P, Scalera A, Dentali F. Effect of body weight on efficacy and safety of direct oral anticoagulants in the treatment of patients with acute venous thromboembolism: a meta-analysis of randomized controlled trials. Ann Med. 2015;47(1):61-68. doi: 10.3109/07853890.2014.982064.
  9. GÏ‹ler E, Babur GÏ‹ler G, Demir GG, HatipoÄŸlu S. A review of the fixed dose use of new oral anticoagulants in obese patients: is it really enough? Anatol J Cardiol. 2015;15(12):1020-1029. doi: 10.5152/AnatolJCardiol.2015.6532.
  10. Eliquis [package insert]. Princeton, NJ: Bristol-Myers Squibb Company; 2012.
  11. Savaysa [package insert]. Parsippany, NJ: Daiichi Sankyo, Inc; 2015.