Drug interaction studies found that the concomitant use of rivaroxaban with drugs that are combined P-glycoprotein (P-gp) and CYP3A4 inhibitors led to increased rivaroxaban exposure and PD effects (ie, Factor Xa inhibition and prolonged prothrombin time). Rivaroxaban exposure was increased significantly when the drug was administered with combined P-gp and strong CYP3A4 inhibitors (eg, azole antifungal agents and protease inhibitors). Therefore, coadministration of rivaroxaban with these agents should be avoided, particularly in patients with any degree of renal impairment, because bleeding risk may increase. In cases where a change in exposure is considered unlikely to affect bleeding risk (ie, coadministration of weaker combined P-gp and CYP3A4 inhibitors, such as clarithromycin and erythromycin), no precautions are necessary.
If bleeding occurs during treatment with rivaroxaban, it may be appropriate to temporarily discontinue the drug and start supportive care. Rivaroxaban has a relatively short half-life (5-9 hours in healthy subjects aged 20-45 years and 11-13 hours in the elderly), meaning that drug effect decreases relatively quickly compared with warfarin. There is currently no direct antidote for rivaroxaban, but a study in healthy human subjects demonstrated that administration of prothrombin complex concentrates may be a potential option.34 Absolute contraindications to rivaroxaban treatment include patients with active pathological bleeding and those with severe hypersensitivity to the drug.
RIVAROXABAN ECONOMICS
Despite its high cost, economic analyses indicate that enoxaparin is a cost-effective agent for VTE prophylaxis compared with warfarin, which is well known to be inexpensive.35 An economic analysis that took into account prophylaxis failures and treatment complications as well as the direct costs associated with medical services, drugs, and laboratory tests showed a cost advantage for enoxaparin over warfarin that lasted for a substantial amount of time (19-31 days after hospital discharge).35
An economic model that followed patients for 1 year postsurgery specifically evaluated the costs associated with symptomatic VTE and major bleeding events in the RECORD trials, assuming the cost of rivaroxaban to be similar to that of enoxaparin 40 mg.36 Cost savings for rivaroxaban over enoxaparin were $82 to $291 per patient, depending on the indication (TKR or THR) and regimen, with cost savings increasing further if the costs of home nursing or training patients to self-administer enoxaparin are included.36 This economic model was also applied to THR and TKR figures from 2005 to show the global cost-effectiveness of rivaroxaban.37 This analysis showed that based on RECORD1, the use of rivaroxaban was associated with an average cost savings of $82 per patient and a reduction of 6 symptomatic events per 1,000 patients undergoing THR. Based on RECORD3, the use of rivaroxaban was associated with a cost savings of $284 per patient and a reduction of 18 symptomatic events per 1,000 patients undergoing TKR.
A later cost-effectiveness analysis by Duran and colleagues, published after FDA approval, included U.S. pricing information.38 In patients receiving extended-duration prophylaxis (35 days) following THR, rivaroxaban was associated with a cost savings of $695 per patient compared with enoxaparin. Compared with 14 days of enoxaparin, extended-duration rivaroxaban (35 days) prevented about 10 additional symptomatic VTE events per 1,000 patients and saved $244 per patient. In patients undergoing TKR, short-duration rivaroxaban
(10-14 days) prevented about 13 additional symptomatic VTE events per 1,000 patients while saving $411 per patient compared with short-duration enoxaparin (10-14 days). It should be noted that statistically significant differences were detected only in the base-case economic analysis, and differences in PE and bleeding events were not captured.
Conclusion
The prevalence of VTE after total joint replacement continues to pose a significant burden to our health care system in terms of morbidity, mortality, and health care costs. Novel anticoagulants such as rivaroxaban, which is now FDA-approved, represent promising alternatives to the traditional agents used for VTE prophylaxis. In addition to its superior efficacy and comparable safety profile to enoxaparin, rivaroxaban’s oral route of administration and straightforward management make it a promising alternative. In particular, the lack of a requirement for routine coagulation monitoring or dose adjustment should simplify treatment with the potential to improve compliance and adherence.
Some questions remain unanswered, such as lack of a direct antidote or widely accepted reversibility technique and how to monitor or assess anticoagulation status in emergency situations, such as overdose or pathologic bleeding. Importantly, early cost-effectiveness analyses indicate that rivaroxaban is cost-effective and potentially even cost-saving compared with enoxaparin and warfarin.Careful postmarketing surveillance will need to be conducted to establish its safety in real-world settings.
Acknowledgments
The authors would like to acknowledge Matthew Romo, PharmD, who provided editorial support with funding from Janssen Scientific Affairs, LLC.