Rivaroxaban for treatment of symptomatic pulmonary embolism: exploring new territories

Dr. Jason Hart (biography and disclosure) and Dr. Neda Amiri (biography and disclosure)

What I did before
In the US, more than 200,000 patients are diagnosed with venous thromboembolism (VTE) events annually (1). Up to 30% of these patients die within 30 days (1). I manage all cases of diagnosed pulmonary embolism (PE) by initiating low molecular weight heparin (LMWH) (Dalteparin 200 IU/kg SC QD) or IV unfractionated heparin (UFH) (in patients with renal failure). Thereafter, following the CHEST guidelines (2), I start Warfarin on the second day, and ensure that the patient has at least 5 days of treatment with heparin, and their INR is in the 2-3 range for at least 2 days before continuing management with Warfarin alone.
There are challenges with use of Warfarin for treatment of VTE. The narrow therapeutic target may be difficult to achieve in some patients. Even within the same patient, depending on the diet and use of other concomitant drugs, there may be big swings in the weekly INR values. Patients, often limited by mobility and access to transportation, have challenges going to laboratory facilities for having their INR checked. There is also significant variability in physician comfort level for adjusting warfarin dosing leading to difficulties in maintaining therapeutic window.
However, the advent of new anticoagulation drugs is revolutionizing conventional treatment methods. One of these new anticoagulants is Rivaroxaban. Rivaroxaban is a potent Factor Xa inhibitor (3). With a rapid oral absorption profile, the drug reaches peak plasma concentration in 2.5-4 hours (4). Its half-life is 5-9 hours in healthy individuals and 9-13 hours in those older than 65 years old (5).

What changed my practice
In April 2012, NEJM published “The EINSTEIN-PE” (6) study, which looked at the use of oral Rivaroxaban for the treatment of symptomatic pulmonary embolism in 4833 patients. In a randomised, open-label, multicentre, non-inferiority international study with funding from Bayer Health-Care and Janssen Pharmaceuticals, study authors recruited patients with symptomatic PE with or without documented DVT. They excluded patients who were treated with LMWH or UFH for more than 48 hours, received fibrinolytics, had a thrombectomy, or placement of a IVC filter. Furthermore, they excluded patients with Creatinine Clearance of less than 30 ml/min or those who had liver impairment. Pregnant or breastfeeding women were also excluded from the study.
Patients in the study arm were randomized to receive Rivaroxaban 15mg BID for three weeks, and then to be switched to 20 mg daily. The control arm of the study treated patients with the “conventional method” of Enoxaparin 1 mg/kg BID with subsequent bridging to Vitamin K antagonists (VKA, Warfarin/Acenocoumarol) according to the CHEST guidelines. The period of anticoagulation was determined by the treating physician before randomization. Patients were followed up for the intended treatment period (3, 6 or 12 months).
Baseline characteristics of the study patients including extent of pulmonary embolism, cause of pulmonary embolism (provoked vs. unprovoked) and history of thromboembolism were similar between the two groups. The pulmonary embolism was thought to be unprovoked in approximately 64% of patients in both groups. Similar number of patients had active cancer in both arms (4.7% in Rivaroxaban arm vs. 4.5% in Standard treatment arm). Most patients in both groups were anticoagulated for 6 months (57.3% in the Rivaroxaban arm vs. 57.5% in the Standard therapy group). Furthermore, approximately 37% of patients in both arms received 12 months of anticoagulation treatment. Patients were followed for the length of the treatment. The primary outcome of the study was symptomatic recurrent VTE. The primary safety outcome was measured as clinically relevant (major and non major bleeding) bleeding.
In the 2419 patients who were assigned to receive Rivaroxaban, 50 (2.1%) patients had recurrent VTE when compared to 44/2413 (1.8%) who were treated with standard therapy (Hazard ratio 1.12, 95% confidence interval of 0.75-1.668; P=0.003 for one-sided non-inferiority margin of 2 and P=0.57 for superiority). There was no statistically significant difference between the two groups in terms of first episode of major or clinically relevant non major bleeding (10.3% in Rivaroxaban arm vs. 11.4% in standard treatment arm, hazard ratio, 0.9; 95% CI 0.76-1.07;P=0.23). However, there were 26 (1.1%) episodes of major bleeding in patients treated with Rivaroxaban compared with 52 (2.2%) in the standard treatment arm (hazard ratio, 0.49; CI 0.31-0.79, P=0.003).
Authors concluded that in patients with symptomatic PE, oral Rivaroxaban alone is non-inferior to Warfarin for preventing reoccurrence of VTE, with the possibility of an improved safety profile.

What I do now
Based on the data presented above, Rivaroxaban can be considered equivalent to Warfarin for management of patients with a new diagnosis of a VTE. Furthermore, the data suggest there is a lower risk of major bleeding with Rivaroxaban. Consequently, select patient groups can now be offered this treatment option. However, some unanswered questions will need to be addressed before Rivaroxiban completely replaces the older anticoagulants.
The optimal duration of anticoagulation with Rivaroxaban remains unknown. In patients with a first episode of a VTE, current CHEST guidelines (2) recommend anticoagulation of 3 months duration if a reversible cause is attributed to the pulmonary embolism. If there is no obvious cause, the patient should be continued on AC treatment for at least a 3-month period. Beyond this period, the guidelines advocate for a discussion between the patient and the physician in terms of risks of a re-occurrence versus those of bleeding associated with anticoagulant therapy. In case of a recurrent event, long-term anticoagulation is recommended. Certainly, given the ease of administration and dosing of Rivaroxiban, this treatment is an attractive substitute for a vitamin K antagonist. However, this current study only provides safety data for duration up to 12 months. Further studies are necessary to explore the optimal duration and long-term safety for anticoagulation with this drug. Whether the CHEST guidelines can be generalized to include the new oral anticoagulants remains to be seen.
Meanwhile, for patients with a cancer-related VTE, anticoagulation with LMWH remains standard of care. Dalteparin has a lower rate of recurrence compared to warfarin is this patient cohort (7). In this setting, the effectiveness of Rivaroxiban has not been sufficiently studied and consequently, it should not be substituted for LMWH. Similarly, there is no safety data of Rivaroxaban use in pregnancy, and as a result, LMWH remains the treatment of choice in this population. Finally, for patients with limited financial resources, Warfarin offers an inexpensive and equally effective treatment option compared to Rivaroxaban. Provincial funding for this drug is currently under review.
Rivaroxaban is the first oral anti-Xa inhbitor to be approved by Health Canada for the treatment of VTE. It provides a convenient and effective therapy for select patients as a substitute for Warfarin. As with any new drug, many unanswered questions remain. I am optimistic that we are standing at the brink of a new era of anticoagulation management.

References (Note: Article requests might require a login ID with CPSBC or UBC)

1. Rosamond W, Flegal K, Fridaz G, et al. Heart disease and stroke statistics – 2007 update: a report from the American Heart Association Statistics Committee ad Stroke Statistics Subcommittee. Circulation 2007; 115:e69-171 (View article)
2. Kearon C, Akl EA, Comerota AJ, et al; American College of Chest Physicians. Antithrombotic therapy for VTE disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(2):e419S-94S (View article with CPSBC or UBC)
3. Roehrig S, Straub A, Pohlmann J, et al. Discovery of the novel antithrombotic agent 5-chloro-N-({(5S)-2-oxo-3- [4-(3-oxomorpholin-4-yl)phenyl]-1,3-oxazolidin-5-yl}methyl)thiophene- 2-carboxamide (BAY 59-7939): an oral, direct factor Xa inhibitor. J Med Chem. 2005 Sep 22;48(19):5900-8 (View article with CPSBC or UBC)
4. Kubitza D, Becka M, Voith B, et al. Safety, pharmacodynamics and pharmacokinetics of single doses of BAZ 59-7939, an oral, director Factor Xa inhibitor. Clin Pharmacol Ther 2005;78:412-21 (View article with CPSBC or UBC)
5. Kubitza D, Becka M, Wensing G, et al. Safety pharmacodynamics and pharmacokinetics of BAY 59-7939 – an oral, director Factor Xa inhibitor – after multiple dosing in healthy male subjects. Eur J Clin Pharmacol 2005;61:873-80 (View article with CPSBC or UBC)
6. Büller HR, Prins MH, Lensin AW, et al. Oral Rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med. 2012;366(14):1287-97 (View article)
7. Lee AY, Levine MN, Baker RI, et al. Low-molecular-weight heparin versus a coumadin for the prevention of recurrent venous thromboembolism in patients with cancer. N Engl J Med. 2003;349(2):146-53 (View article)

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Rivaroxaban for treatment of symptomatic pulmonary embolism: exploring new territories

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