Rivaroxaban is an oral anticoagulant that works by directly inhibiting Factor Xa and so interrupting both the intrinsic and extrinsic pathway of the coagulation cascade and subsequent thrombus formation. It is the first orally active direct Factor Xa inhibitor and was granted marketing authorization in 2008 by both the European Commission and Health Canada for the prevention of venous thromboembolism in patients who have undergone elective total hip replacement and total knee replacement surgery. Rivaroxaban’s authorization comes as a result of the recent RECORD 1–4 Trials, which looked at its efficacy versus subcutaneous enoxaparin as a thromboprophylaxis in patients undergoing THA and total knee arthroplasty [1–4]. In the RECORD 1 trial, a randomized double-blinded study, 4,518 patients were assigned to receive 10 mg daily of oral rivaroxaban immediately after THA or 40 mg once daily of subcutaneous heparin beginning the same evening after THA . The primary efficacy outcome was the composite of deep venous thrombosis, nonfatal pulmonary embolism or death after 36 days and, significantly, the major safety outcome was major bleeding. The primary efficacy outcome occurred in 18 of 1,595 patients (1.1%) in the rivaroxaban group and in 58 of 1,558 patients (3.7%) in the enoxaparin group (absolute risk reduction, 2.6%; 95% confidence interval, 1.5 to 3.7; P < 0.001). Major bleeding occurred in 6 of 2,209 patients (0.3%) in the rivaroxaban group and in 2 of 2,224 patients (0.1%) in the enoxaparin group (P = 0.18). The authors concluded that a once daily oral dose of rivaroxaban was more effective for extended thromboprophylaxis than a once daily subcutaneous dose of enoxaparin in patients undergoing elective THA, with the two drugs having similar safety profiles. The manufacturers recommend that rivaroxaban only needs be taken for 35 days postoperatively, after which the risk of such a thrombotic event decreases hugely. Although six cases of major bleeding were reported in the RECORD 1 trial, we could find no available case reports in the literature regarding this side effect.
The circumstances of our patient’s case demonstrated very clearly both the obvious advantages and yet the severe disadvantages of rivaroxaban. Upon its formulation, the immediate appeal of this drug was three-fold. First, it was more efficacious in preventing deep venous thrombosis or pulmonary embolisms compared to other anticoagulants, as shown in the RECORD trials. Second, it could be taken orally, negating the need for daily subcutaneous injections that patients experience if taking heparin or a low-molecular-weight heparin, most notably in the immediate days after surgery. Third, and perhaps most significantly from a socioeconomic perspective, regular visits to general practitioners or outpatient clinics for international normalized ratio monitoring when taking warfarin are also unnecessary when taking rivaroxaban. Interestingly, rivaroxaban is the first oral Factor Xa inhibitor licensed for this purpose in Ireland. It will most likely set a trend for a class of oral anticoagulants that will see the end of subcutaneous anticoagulation as well as oral anticoagulants that require continuous blood level monitoring. Although only currently licensed for orthopedic surgery, more recent studies have shown that rivaroxaban is as effective as enoxaparin when treating symptomatic venous thromboembolism. In addition, a Phase III study of low-dose rivaroxaban in patients with acute coronary syndrome is also underway after a recent Phase II study showed that it may reduce major ischemic events [5, 6].
In this case, the fact that our patient had no history of hemorrhage in the past and that the organ and associated system involved, the rectum and gastrointestinal tract, had never caused him medical problems prior to this makes the magnitude of the PR bleeding more noteworthy. The absence of any risk factors would have placed him in a low-risk category for side effects. The RECORD 1 trial found reports of major bleeds in only six patients and this case demonstrates that these side effects, though rare, do occur in supposedly low-risk patients, with serious and potentially fatal complications.
The treatment of such a severe side effect includes transfusion with PRBCs based on regularly observed Hb levels. One could consider the role of radiological embolization if a source is found but this was not an option in our case. The most important learning point, however, is that the offending agent is discontinued as quickly as possible. This relies on a detailed history with specific focus on recent pharmacological treatments. Rivaroxaban has a mean terminal half-life of seven to eleven hours, which should be taken into account along with other medications that the patient is taking, such as antimycotics or human immunodeficiency virus protease inhibitors, which can potentiate bleeding. Once the agent is discontinued, bridging the patient through the period of hemorrhage safely is the primary goal. The lack of any obvious antidote to reverse the effects of the drug is an aspect that needs further research. Early studies have shown that prothrombin complex concentrate may be useful in reversing the effects of rivaroxaban . Other possible measures include the use of recombinant Factor VIIa to reduce bleeding or the use of activated charcoal to reduce absorption in cases of overdose.