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Orthopaedic Surgery
Rivaroxaban – A Novel, Oral Anticoagulant for Thromboprophylaxis
After Major Orthopaedic Surgery
a report by
Louis M Kwong
Department of Orthopaedic Surgery, Harbor-UCLA Medical Center
Rivaroxaban is a novel, oral, direct Factor Xa (FXa) inhibitor in advanced and all-cause mortality. The secondary efficacy end-point was the
clinical development for the prophylaxis and treatment of incidence of major VTE, defined as the composite of proximal DVT, PE
thromboembolic disorders.
1
By acting at the pivotal point of the and VTE-related death.
coagulation cascade, where inhibition of one molecule of FXa prevents
the generation of approximately 1,000 thrombin molecules,
2
rivaroxaban The primary safety end-point was the incidence of major post-operative
effectively reduces the risk of thrombus formation. Rivaroxaban is a bleeding – defined as bleeding starting more than six hours after surgery,
promising alternative to the pharmacological strategies currently available or after the first post-operative dose of study drug (whichever came first),
for prophylaxis against venous thromboembolism (VTE) manifesting as but no later than two days after the last administration of study drug. Major
deep vein thrombosis (DVT) or pulmonary embolism (PE). VTE is a well- post-operative bleeding included fatal bleeding; bleeding into a critical
recognised serious risk after major orthopaedic surgery.
3
organ; bleeding leading to re-operation; bleeding warranting treatment
cessation; and clinically overt bleeding (above expected levels) leading to a
Low molecular weight heparins (LMWHs) are the standard of care for ≥2g/dl fall in haemoglobin, or transfusion of >2 units of blood.
thromboprophylaxis after major orthopaedic surgery in Europe. Although
these are effective, they must be administered subcutaneously, making Proof-of-principle Study
them inconvenient and costly for extended prophylaxis in the out-patient The first of these phase II trials was an open-label, phase IIa, proof-of-
setting.
4
Rivaroxaban is anticipated to overcome these limitations by principle study of rivaroxaban conducted in patients undergoing THR.
12
providing effective oral thromboprophylaxis after elective surgical The efficacy and safety of oral rivaroxaban (2.5–30mg twice daily (bid)
procedures, such as total hip replacement (THR) or total knee and 30mg once daily (od)) initiated post-operatively were compared with
replacement (TKR). Furthermore, rivaroxaban has a predictable the subcutaneous LMWH enoxaparin (40mg od initiated the evening
pharmacological profile allowing fixed dosing, like LMWHs, without before surgery). Standardised, mandatory bilateral venography was
requiring monitoring. performed after patients had received study drugs for five to nine days.
Rivaroxaban reduced the incidence of the primary efficacy end-point, and
This review discusses phase II findings of rivaroxaban for prophylaxis against there was a dose trend with increasing rivaroxaban doses (p=0.0504).
VTE after major orthopaedic surgery. These findings have resulted in the Furthermore, a significant dose–response relationship was observed for
initiation of an extensive phase III programme in this indication, and suggest major VTE (p=0.0108). As would be expected, the incidence of major
that welcome advances in anti-thrombotic therapy may be on the horizon. post-operative bleeding increased dose dependently with rivaroxaban
(p=0.0008). Results with rivaroxaban 30mg od were consistent with the
Clinical Studies – Prophylaxis Against Venous dose–response relationships between the bid doses and all end-points,
Thromboembolism After Major Orthopaedic Surgery
In early clinical studies in healthy subjects, rivaroxaban was consistently
well tolerated, with a rapid onset of action as well as predictable Louis M Kwong, MD is the Vice Chairman of the
pharmacokinetics and pharmacodynamics. It has a half-life of five to nine
Department of Othopaedic Surgery at the Harbor-UCLA
Medical Center, where he is also Medical Director of the
hours in healthy young subjects,
5,6
increasing to 12 hours in elderly
Orthopaedic Clinics, Chief of the Orthopaedic Arthritis
subjects.
7
After multiple rivaroxaban doses, no clinically relevant changes
Service, and Program Director of Orthopaedic Residency
Training. He is an Associate Clinical Professor of
in bleeding time, blood pressure, heart rate, electrocardiogram (ECG) or
Orthopaedic Surgery in the David Geffen School of Medicine
vital signs were observed.
6
In addition, rivaroxaban did not prolong the at UCLA. A recipient of the John Charnley Award for
QTc interval.
8
Rivaroxaban also demonstrated a low propensity for
contributions in the field of hip surgery, he is also involved
in orthopaedic instrument and implant design, and holds a patent for a debris-isolating
interactions with commonly used medications, including aspirin and non-
prosthetic hip joint. Dr Kwong has served as a rescue physician in the Los Angeles County
steroidal anti-inflammatory drugs (NSAIDs).
9,10
Furthermore, it is likely
Sheriff’s Department (LASD) Air 5 helicopter program for over 12 years. He is the Medical
that fixed doses of rivaroxaban may be given to patients irrespective of
Director of the LASD Reserve Forces Emergency Medical Technician Training Program. With
the Department of Homeland Security, Dr Kwong is a medical officer on the National Medical
age, gender or body weight.
7,11
Response Team – Western Region for Weapons of Mass Destruction response. Additionally,
he is a Medical Officer on Disaster Medical Assistance Team California-9. Dr Kwong travels
extensively internationally for research and the teaching of orthopaedic surgery. He has
Results of phase I studies confirmed that rivaroxaban was suitable for
provided humanitarian surgery in various parts of the world, from the treatment of gunshot
further investigation, and led to four large, phase II, dose-finding clinical and blast injuries in Bosnia during the Balkan War to his recent deployment to New Orleans
trials being conducted in over 4,000 patients undergoing elective THR or
following Hurricane Katrina for three medical strike team missions for the Department of
Homeland Security.
TKR worldwide.
12–15
In all of these studies, the primary efficacy end-point
was defined as the composite of any DVT, non-fatal, symptomatic PE
© TOUCH BRIEFINGS 2007 41
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