This month, Tzu-Fei Wang, MD, and Marc Carrier, MD, MSc, reviewed anticoagulation strategies for patients who are obese and therefore at risk of venous thromboembolism, atrial fibrillation, and cardiovascular diseases. Below, we summarize their approach.
This material is repurposed from "How I treat obese patients with oral anticoagulants," published in the March 19, 2020 edition of Blood.
- Obesity is a known risk factor for VTE, AF, and cardiovascular diseases.
- The use of DOACs should be avoided in patients after bariatric surgery,
pending further clinical trials. - Standard VTE prevention doses of DOACs can be used in patients who are morbidly obese and require thromboprophylaxis after surgery.
- Outside of clinical trials, DOAC levels in the morbidly obese population are not routinely monitored.
- Standard treatment doses of DOACs can be used in patients with VTE or AF and who have a body weight greater than 120 kg or BMI greater than 40 kg/m2 as long as there is shared decision-making after an informed discussion of available evidence
Obesity is rapidly increasing worldwide, with a prevalence of 39.8% and 30% among U.S. and Canadian adults, respectively, in 2015 to 2016. In 2016, it was estimated that, globally, more than 1.9 billion adults were overweight and more than 650 million were obese. Obesity is a known risk factor for new and recurrent venous thromboembolism (VTE), atrial fibrillation (AF), and cardiovascular diseases. The mechanisms by which obesity and VTE might be connected include increased plasma levels of procoagulant factors, platelet and endothelial dysfunction, hypofibrinolysis, venous stasis, and increased inflammation. Furthermore, adipose tissue secretes hormones such as leptin, resistin, and various cytokines that upregulate the expression of tissue factor, resulting in a prothrombotic state. Obesity is strongly associated with nonalcoholic fatty liver disease, which is linked to increased levels of many prothrombotic factors and increased incidence of cardiovascular diseases and VTE.
Explanations for the link between obesity and AF may include the increased left atrial volume and size and increased left ventricle diastolic dysfunction.
Obesity can affect drug pharmacokinetics by increasing volume of distribution and altering
drug clearance as well as other pharmacodynamic effects. Traditional anticoagulants are dosed either based on laboratory testing (as is the case for vitamin K antagonists [VKAs]) or by weight (as is the case for heparin or low-molecular-weight heparin [LMWH]). Thus, when fixed-dose direct oral anticoagulants (DOACs) became the mainstay of anticoagulation, many clinicians were concerned about their efficacy and safety in patients who are obese, since dosing is not weight-based and laboratory monitoring is not commonly performed.
Case 1: Anticoagulation for acute VTE in a patient who is morbidly obese
A 48-year-old man presented with new-onset right lower extremity pain and swelling. A Doppler ultra-sound showed an acute deep vein thrombosis (DVT) involving the right common femoral, femoral, popliteal, and posterior tibial veins. The patient had not experienced recent surgery, long travel, immobilization, or trauma. His medical history included morbid obesity (weight = 140 kg, body mass index [BMI] = 48 kg/m2), hypertension, hyperlipidemia, and type 2 diabetes. Kidney function was normal with an estimated creatinine clearance of 90 mL/min by Cockcroft-Gault formula. What type of anticoagulant should be recommended for this individual?
Case 1 Commentary: After reviewing the risks and benefits of anticoagulant options, including evidence for the use of DOACs in patients who are morbidly obese, the patient preferred a DOAC over warfarin. He was started on standard-dose rivaroxaban for his acute DVT. At a 3-month follow-up, he was doing well with resolution of symptoms from the DVT and showed no evidence of bleeding. The rationale for the use of DOACs in patients who are obese comes from pharmacokinetic studies that included a small number of obese participants, showing that body weight or BMI had either modest or no effects on DOAC concentration and anti-Xa levels. For VTE, data from the EINSTEIN rivaroxaban study showed no association between weight or BMI and thrombotic or bleeding outcomes in patients on rivaroxaban among 303 patients (3.7%) with a weight of 120 kg or more in the trial. Other VTE DOAC trials with dabigatran, apixaban, and edoxaban showed similar efficacy and safety outcomes for the obese patient subpopulation. An additional seven recent retrospective studies showed no significant differences for BMI groups or between DOAC and warfarin treatment, although five of these studies did not adjust for confounder effects and should be interpreted with caution. DOAC monitoring is not routine for patients as anti-Xa drug levels and correlations with clinical outcomes are not known. Using a large health-care claims database to identify morbidly obese patients by ICD-9 codes, two studies have shown that the risks of thrombosis and major bleeding were comparable in patients receiving rivaroxaban versus warfarin for either AF or VTE. The use of health-care resources, including hospitalization rate, length of stay, and outpatient visits were significantly lower with rivaroxaban than with warfarin. Taken together, all of these studies provide evidence that even in patients with morbid obesity (weight of greater than 120 kg and/or BMI greater than 40 kg/m2), there are no differences in the risks of thrombosis or major bleeding between DOACs and VKAs.
Case 2: Anticoagulation for AF in a patient who is morbidly obese
A 76-year-old woman with hypertension and diabetes was brought to the emergency room with palpitations, bilateral lower-extremity swelling, and shortness of breath. Upon evaluation, she was found to have a new onset of AF with rapid ventricular rate, as well as congestive heart failure with an ejection fraction of 35%. Her estimated creatinine clearance was 50 mL/min by Cockcroft-Gault formula. Multiple medical interventions were initiated, and anticoagulation was recommended, given her high CHADS -VASc score of 6. Her weight is 125 kg and her BMI is 41 kg/m2. Which anticoagulant would be recommended for this patient?
Case 2 Commentary: The patient was discharged with apixaban 5 mg twice daily for stroke prevention and was doing well without evidence of thromboembolicevents or bleeding at 6 month follow-up. Post hoc analysis of prospective AF studies with more than 2,000 patients with AF who had a BMI of greater than 40 kg/m2 showed no evidence of inferior efficacy or safety with DOACs compared with VKAs. In the ARISTOTLE trial, among 982 patients with a weight of 120 kg or greater, risk of stroke, systemic embolism, and major bleeding were comparable among patients receiving apixaban and VKAs. Among the 258 patients with a weight greater than 140 kg, the risk was numerically higher but not statistically significant.
Case 3: Anticoagulation after bariatric surgery
A 49-year-old woman presented with chest pain and shortness of breath 10 days after a spine fusion surgery and was found to have an acute pulmonary embolism (PE) on a computed tomography (CT) scan. The patient had a history of morbid obesity and underwent sleeve gastrectomy 5 years ago. She had lost 50 kg since the surgery. Her current weight is 121 kg and her BMI is 39 kg/m2. What anticoagulant option would be recommended for her?
Case 3 Commentary: There is little evidence on the efficacy and safety of DOACs in patients who have had bariatric surgery. Different types of bariatric surgeries lead to various effects on drug absorption, depending on the gastrointestinal bypass site and the main sites of absorption of the DOAC. With the rationale of altered absorption of DOACs in patients after bariatric surgery, limited evidence supporting that this might be true, and lack of studies reporting clinical outcomes in this population, we avoid DOAC use after bariatric sugeries. Use of either VKA where international normalized ratio can be monitored or LMWH that avoids the gastrointestinal system remains our preferred choice in this population. The patient in this case agreed with warfarin treatment, completed 3 months of anticoagulation without bleeding events for her provoked PE, stopped anticoagulation, and had no evidence of VTE recurrence at 1 year.
Case 4: Anticoagulation as VTE prophylaxis in morbidly obese patients
A 60-year-old man presents for a total hip replacement for chronic osteoarthritis of the right knee. His medical history includes obesity with a weight of 130 kg and a BMI of 45 kg/m2, hypertension, hyperlipidemia, and a history of a postoperative DVT 3 years ago after left knee replacement. His orthopedic surgeon is requesting recommendations for perioperative thromboprophylaxis. What regimen should be used?
Case 4 Commentary: This patient can be given the standard prophylactic dose of either dabigatran, rivaroxaban, or apixaban for 10 to 14 days after his knee replacement. Obesity is a risk factor for osteoarthritis and the need of joint replacement. Effective thromboprophylaxis is essential in the prevention of surgery-related VTE. Post hoc analyses on the effect of BMI among 5,686 patients across three randomized controlled trials of thromboprophylaxis with dabigatran or enoxaparin for total hip or knee replacement surgery showed no differences in the rate of VTE or major hemorrhage between dabigatran and enoxaparin in patients with a BMI of 30 kg/m2 or higher. Similarly, post hoc analyses of thromboprophylaxis after total hip or knee replacement with either apixaban or rivaroxaban showed no significant differences in the incidence of VTE or bleeding events in patients with BMI of 40 kg/m2 or greater compared with those with a BMI or less than 40 kg/m2. A meta-analysis including studies on apixabanand dabigatran in postarthroplasty patients showed that the efficacy and safety of DOACs were comparable to enoxaparin for VTE prevention in patients who are obese. These data support the use of standard prophylactic dose of DOACs for patients who are obese.
Future Directions
In obese patients with a weight below 120 kg or BMI of less than 40 kg/m2, data from large randomized controlled trials have been reassuring for the efficacy and safety of DOACs, and we use them as in nonobese adults. Yet, evidence of DOAC use in the morbidly obese population remains limited (but is accumulating), particularly in the VTE population, and there are no randomized controlled trials to date. Future studies should focus on evaluating the efficacy and safety of DOACs in the morbidly obese population, especially with VTE. Different DOAC agents could have different pharmacokinetic profiles and should be investigated individually. Dedicated studies in obese and morbidly obese patients are needed to address this knowledge gap and determine the optimal care of these patients. Until then, an informed discussion should be carried out with patients to allow individualized decision-making.
Reference
Wang T, Carrier C. How I treat obese patients with oral anticoagulants. Blood. 2019;135(12):904–911.
