2Hendrick Medical Center, Abilene, Texas, USA
3Texas Tech University Health Sciences Center School of Pharmacy, Abilene, Texas, USA
Summary: A 46-year-old female was admitted with bilateral PE and Deep Venous Thromboembolism (DVT) of the left lower extremity. She was treated and discharged on rivaroxaban (Xarelto®) 15mg twice daily for three weeks then 20mg daily. Five weeks later, she presented to the emergency department with dyspnea, chest pain, tachycardia and hypoxia. CT angiogram showed a new saddle pulmonary embolism. She was admitted and started on a heparin drip that was later switched to enoxaparin and warfarin. The decision was made to discontinue rivaroxaban and begin long-term treatment with warfarin.
Discussion: It has been reported that extremes of body weight do not alter rivaroxaban exposure, but the EINSTEIN-PE trial showed a trend of worse outcome with rivaroxaban in patients weighing > 90 kg. The etiology of saddle PE of this case may include not only obesity and previous DVT, but also possible inadequate rivaroxaban concentration.
Conclusion: This patient developed a saddle pulmonary embolism while receiving anticoagulation with rivaroxaban. Although she had previously been diagnosed with a PE and is morbidly obese, possible failure of Xarelto® may not be disregarded.
Key words: Xarelto®; Rivaroxaban; Obese; Venous Thromboembolism; Deep Vein Thrombosis; Pulmonary Embolism; Prophylaxis
Rivaroxaban (Xarelto®) is an oral factor Xa inhibitor which inhibits platelet activation and fibrin clot formation through a direct, selective, and reversible inhibition of factor Xa in both the intrinsic and extrinsic coagulation pathways [2]. Xarelto® was first approved in July 2011 for prevention of DVT and PE following knee or hip replacement surgery [3]. The trials that led to the approval of Xarelto® were the RECORD 1, 2, and 3 trials [3]. In November of 2011, Xarelto® was approved for the prevention of stroke in patients with non-valvular atrial fibrillation following the results of the ROCKET AF trial [4]. Xarelto® was then approved for the treatment and prevention of recurrent blood clots in November 2012 [5]. The dose for this indication is 15 mg twice daily with food for 3 weeks followed by 20 mg daily with food based on the EINSTEIN-DVT and EINSTEIN-PE trials [5].
Xarelto® use should be avoided in patients with renal impairment (CrCl < 30 mL/min) being treated for a DVT/PE [2]. Previous studies have shown that body weight > 120 kg did not significantly influence Xarelto® exposure, and postoperative thromboprophylaxis trials were not affected by weight up to 190 kg, so no dosage adjustment is recommended at this time [2]. DOACs such as Pradaxa® (dabigatran), Eliquis® (apixaban) and Xarelto® (rivaroxaban) have been approved for various indications to give patients an alternative to warfarin therapy. There are no case reports at this time involving possible Xarelto® failure in obese populations.
Vital signs at admission are available in Table 1. Laboratory results at admission can be found in Table 2. Upon admission, physical exam revealed bilateral edema in the left lower extremity greater than the right. Chest x-ray revealed mild to moderate vascular congestion. CT angiogram of the chest showed multiple pulmonary artery filling defects including a saddle embolus. The patient received oxygen at 4 L/min via nasal cannula, and unfractionated heparin drip per hospital protocol for Venous Thrombo Embolism (VTE) and was admitted to the intensive care unit. A venous doppler that afternoon revealed a DVT of the left popliteal vein.
Heart rate |
104 bpm |
Blood pressure |
122/95 mmHg |
Respiratory rate |
20 - 33 breaths/min |
O2 saturation |
87% on room air |
Temperature |
97.9°F |
Height |
165.1 cm |
Weight |
149.5 kg |
BMI |
54.8 kg/m2 |
Glucose |
363 mg/dL |
T-Bili |
0.68 mg/dL |
Troponin |
0.01 mcg/L |
ALP |
133 U/L |
D-dimer |
2.66 mcg/L |
ALT |
28 U/L |
BUN |
16 mg/dL |
AST |
15 U/L |
SCr |
1.0 mg/dL |
PT |
14.1 sec |
Na |
141 mmol/L |
INR |
1.1 |
K |
4.2 mmol/L |
Hemoglobin |
14.6 g/dL |
Cl |
106 mmol/L |
Hematocrit |
42.9% |
CO2 |
23 mmol/L |
Platelets |
131 X 109/L |
On day six the patient was discharged on warfarin 12.5 mg by mouth daily and enoxaparin 150 mg (1 mg/kg) subcutaneously twice daily. The patient was to follow up with the Coumadin clinic 2 days after discharge. At a follow-up visit six months later, warfarin dose was 20 mg on Monday, Tuesday and Wednesday and 15 mg on Thursday, Friday, Saturday and Sunday (total 120 mg/week) and a chest CT did not identify any remaining thrombus.
For VTE treatment, the International Society on Thrombosis and Haemostasis (ISTH) recommends standard dosing in patients with a body weight ≤ 120 kg and BMI of ≤ 40 kg/m2 [8]. They also suggest avoidance of newer oral anticoagulants with a body weight > 120 kg and BMI > 40 kg/m2 due to lack of clinical data for use in this population [8]. If the agents are used in these patients, the ISTH recommends monitoring anti-Xa levels or mass spectrometry for efficacy. When the level falls below the expected range for the drug in use, they suggest changing therapy to a vitamin K antagonist rather than dose adjusting the agent [8].
The results of the EINSTEIN-PE trial are available in Table 3 [9]. Xarelto® was non-inferior to warfarin in recurrent VTE and superior to standard therapy with regard to major bleeding (NNT=91) [9]. The subgroup analysis looked at efficacy in BMI ≥ 30 kg/m2 and weight > 90 kg and found no statistically significant difference between groups; however, BMI > 30 kg/m2 is not morbidly obese [10]. The trend was in favor of enoxaparin plus warfarin rather than rivaroxaban in patients > 90 kg. With low power in the subgroup analysis, true difference between standard therapy and rivaroxaban cannot be indisputable [10]. The EINSTEIN-DVT trial was similar comparing Xarelto® to VKA bridged with subcutaneous enoxaparin in patients with symptomatic DVT. The results of this trial were similar to the EINSTEIN-PE trial, detailed results are available in Table 4 [11]. Due to the small number of obese patients in each of these studies, it may not be easy to extrapolate the results of this study to an obese population.
EINSTEIN-PE9 (n=4832) |
Recurrence on rivaroxaban |
Recurrence on enoxaparin +VKA (n=2413) |
P value |
Total patient population |
2.1% |
1.8% |
|
≤ 70kg |
2.6% |
1.6% |
> 0.05 |
> 70-90kg |
1.9% |
2.1% |
> 0.05 |
> 90kg |
1.9% |
1.5% |
> 0.05 |
BMI < 30 kg/m2 |
2.3% |
1.9% |
> 0.05 |
BMI ≥ 30 kg/m2 |
1.5% |
1.5% |
> 0.05 |
EINSTEIN-DVT11 (n=3449) |
Recurrence on rivaroxaban |
Recurrence on enoxaparin +VKA (n=1718) |
Total patient population |
2.1% |
3.0% |
≤ 70kg |
2.4% |
4.0% |
> 70-90kg |
1.8% |
2.7% |
> 90kg |
2.2% |
2.3% |
Kubitza, et al. 12 |
Max pharmacodynamic effect of the dose |
Patient population |
|
≤ 50kg |
46.80 |
> 70-80kg |
45.80 |
> 120kg |
41.70 |
Given that DOACs do not require monitoring, it is difficult to assess if the levels of rivaroxaban were actually subtherapeutic due to increased BMI or if there was another cause to this patient’s recurrent VTE. Based on Kubitza’s trial, the 12 patients > 120 kg on rivaroxaban showed a slight decrease in the maximum anti-Xa activity [12] (Table 5). The maximum pharmacodynamics effect results demonstrate that it is theoretically possible to have subtherapeutic activity in morbidly obese patients, especially with a BMI greater than 50 kg/m2. The patient was morbidly obese as well, which is itself an independent predictor of VTE and VTE recurrence [16, 17]. Based on the Padua VTE Prediction Score, this patient had a total score of 4 from previous VTE history and obesity which led to a high risk for VTE [18, 19].
When warfarin education was delivered, the patient’s compliance to Xarelto® was assessed. It seems the patient was compliant with her regimen. Possible drug interactions between the patient’s home meds and Xarelto® were assessed and no significant interactions were found. The initial PE was not a saddle embolism; the different placement could mean this is not the same PE. However, her previous DVT could have migrated and led to her saddle embolism. Her initial therapy was in line with 2016 CHEST guidelines, which states that rivaroxaban is appropriate for the treatment of acute PE [1]. There were no hypercoagulability test results available for review. Despite the limitations of this case report, there remains a high possibility of treatment failure being the cause of her saddle embolus.
- Kearon C, Akl EA, Ornelas J, Blaivas A, Jimenez D, Bounameaux H, 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
- Kubitza D, Becka M, Mueck W, Halabi A, Maatouk H, Klause N, et al. Effects of renal impairment on the pharmacokinetics, pharmacodynamics and safety of rivaroxaban, an oral, direct Factor Xa inhibitor. Br J Clin Pharmacol. 2010;70(5):703-712. doi: 10.1111/j.1365-2125.2010.03753.x
- FDA approves Xarelto to reduce risk of blood clots after hip, knee replacements. U.S. Food and Drug Administration. 2014.
- FDA approves Xarelto to prevent stroke in people with common type of abnormal heart rhythm. U.S. Food and Drug Administration. 2014.
- FDA expands use of Xarelto to treat, reduce recurrence of blood clots. U.S. Food and Drug Administration. 2014.
- Buller HR, Prins MH, Lensin AW, Decousus H, Jacobson BF, Minar E, et al. Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med. 2012;366(14):1287-1297. doi: 10.1056/NEJMoa1113572
- Ansell J. New oral anticoagulants should not be used as first-line agents to prevent thromboembolism in patients with atrial fibrillation. Circulation. 2012;125(1):165-170. doi: 10.1161/CIRCULATIONAHA.111.031153
- Martin K, Beyer-Westendorf J, Davidson BL, Huisman MV, Sandset PM, Moll S. Use of direct oral anticoagulants in obese patients: guidance from the SSC of the ISTH. J Thromb Haemost. 2016;14(6):1308-1313. doi: 10.1111/jth.13323
- The EINSTEIN-PE Investigators. Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med. 2012;366:1287-1297. doi: 10.1056/nejmoa1113572
- Bauersachs R, Berkowitz SD, Brenner B, Buller HR, Decousus H, Gallus AS, et al. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med. 2010;363(26):2499-2510. doi: 10.1056/NEJMoa1007903
- The EINSTEIN Investigators. Oral Rivaroxaban for Symptomatic Venous Thromboembolism. N Engl J Med. 2010;363(26):2499-2510. doi: 10.1056/nejmoa1007903
- Kubitza D, Becka M, Zuehlsdorf M, Mueck W. Body weight has limited influence on the safety, tolerability, pharmacokinetics, or pharmacodynamics of rivaroxaban in healthy subjects. J Clin Pharmacol. 2007;47(2):218-226.
- Mueck W, Lensing AW, Agnelli G, Decousus H, Prandoni P, Misselwitz F. Rivaroxaban: population pharmacokinetic analyses in patients treated for acute deep-vein thrombosis and exposure to simulations in patients with atrial fibrillation treated for stroke prevention. Clin Pharmacokinet. 2011;50(10):675-686. doi: 10.2165/11595320-000000000-00000
- Douketis JD, Crowther MA, Foster GA, Ginsberg JS. Does the location of thrombosis determine the risk of disease recurrence in patients with proximal deep vein thrombosis? Am J Med. 2001;110(7):515-519.
- Hansson PO, Sörbo J, Eriksson H. Recurrent venous thromboembolism after deep vein thrombosis: incidence and risk factors. Arch Intern Med. 2000;160(6):769-774.
- Palareti G. Recurrent venous thromboembolism: what is the risk and how to prevent it. Scientifica (Cairo). 2012;2012:391734. doi: 10.6064/2012/391734
- Patel JP, Roberts LN, Arya R. Anticoagulating obese patients in the modern era. Br J Haematol. 2011;155(2):137-149. doi: 10.1111/j.1365-2141.2011.08826.x
- Eichinger S, Hron G, Bialonczyk C, Hirschl M, Minar E, Wagner O, et al. Overweight, obesity, and the risk of recurrent venous thromboembolism. Arch Intern Med. 2008;168(15):1678-1683. doi: 10.1001/archinte.168.15.1678
- Barbar S, Noventa F, Rossetto V, Ferrari A, Brandolin B, Perlati M, et al. A risk assessment model for the identification of hospitalized medical patients at risk for venous thromboembolism: the Padua Prediction Score. J Thromb Haemost. 2010;8(11):2450-7. doi: 10.1111/j.1538-7836.2010.04044.x