Thromboprophylaxis in Patients Undergoing Orthopedic Surgeries; Focus on Cost-effective Analysis and Safety Comparison Between Rivaroxaban and Enoxaparin
Phase: PHASE3
Conditions: Thromboses, Deep Vein, Surgery--Complications
Sponsor: Ahmed AbdelMoneim Hassan Ali

Thromboprophylaxis in Patients undergoing Orthopedic 
Surgeries; Focus on cost-effective analysis and safety 
comparison between Rivaroxaban and Enoxaparin.
 
 
 
 
2016 
Faculty of Pharmacy, Beni-Suef University-  20th December 2016 
Protocol study 
Submitted for partial fulfillment of Doctorate of Philosophy in 
Clinical pharmacy by: Ahmed A H Ali 
                                      MSc, BCPS, BCACP 
Under supervision of: 
Prof. Hesham Boshra Al Said Mahmoud 
           Professor of Cardiology, Faculty of Medicine, Beni-Suef University. 
Dr. Ahmed Abdullah Hassan Elberry 
        Associate Professor of Clinical Pharmacology, Faculty of Medicine, Beni-Suef University. 
Dr. Emad Gaber Kamel Elbana 
        Associate Professor of orthopedic surgery, Faculty of Medicine, Beni-Suef University. 
Dr. Raghda Roshdy Sayed Hussein 
        Lecturer of Clinical Pharmacy, Faculty of Pharmacy, Beni-Suef University. 
 

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Introduction  
           In general, many surgeries put patients at a great risk for venous 
thromboembolism (VTE) and potential fatal consequences, including pulmonary 
embolism. Despite significant advances in the pharmacotherapy of prevention and 
treatment of VTE, pulmonary embolism still remains a common preventable cause 
of death in hospitals. Therefore, efforts vitally should be continued to pursue 
advances toward the safest and most effective means of preventing and managing 
VTE.  
There is a Today consensus that patients undergoing high-risk surgery should 
receive prophylaxis against postoperative venous thromboembolism (VTE). A good 
example of that could be orthopedic surgeries which place patients at unnecessary 
increased risk of fatal pulmonary embolism. For many years, pharmacotherapy 
options have been recommended by the American College of Chest Physicians 
(ACCP) for postoperative thromboprophylaxis were low-molecular-weight heparins 
(LMWHs), fondaparinux, and warfarin. However, their limitations have been 
repeatedly demonstrated in a huge number of randomized controlled trials (RCTs). 
[1,2] 
Since its introduction, low-molecular-weight heparins (LMWHs) are still common 
used in practice as thromboprophylactic agent. But, they require subcutaneous 
administration which making it challenging for use in settings other than the 
inpatient one. Despite the lower incidence of low-molecular-weight heparins 
(LMWHs) induced heparin-induced thrombocytopenia (HIT) compared with 
unfractionated heparins (UFH) in the postoperative setting, the risk of LMWH 
induced HIT in patients treated for VTE still concerns many clinicians. In addition 
to its subcutaneous administration, fondaparinux is contraindicated in severe renal 
impairment patients (with creatinine clearance (CrCl) <30 milliliter/minute) and 
those who have low body weight (<50 kg; VTE prophylaxis only). While available 
orally, Vitamin K antagonists (VKAs) like Warfarin have unpredictable 
pharmacologic effects requiring a wakeful monitoring. Warfarin is also a remarkable 
source of food and drug interactions. As a result, it is mandatory to search for novel 
drugs or at least to search for new indications of really existing drugs. [2] 
In July 2011, the Food and Drug Administration (FDA) approved an orally 
administered selective factor Xa inhibitor called Rivaroxaban for the prevention of 
deep vein thrombosis (DVT) after total hip replacement (THR) or total knee 

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replacement (TKR) surgeries. According to the Regulation of Coagulation in 
Orthopedic Surgery to Prevent Deep Vein Thrombosis and Pulmonary Embolism 
(RECORD) trials, rivaroxaban demonstrated superiority to enoxaparin in reducing 
venous thromboembolism without significant increase of bleeding risk. Rivaroxaban 
is recommended to be used at a fixed dose of 10 mg daily, with or without food, for 
35 days following THR or 12 days following TKR. [3]  
Although the US Food and Drug Administration (FDA) advisory committee has 
recommended approval of rivaroxaban, many questions have been raised on the 
Regulation of Coagulation in Orthopedic Surgery to Prevent Deep Vein Thrombosis 
and Pulmonary Embolism (RECORD) trials of rivaroxaban. Some may argue that 
dosing was inconsistent with the recommendations. Others went far to say that the 
duration of treatment was inconsistent and did vary with enoxaparin. In other words, 
it was somewhat short. 
Results from the ORTHO-TEP registry on joint replacement arthroplasty (hip and 
knee) from Dresden, Germany and Xarelto® in the Prophylaxis of Postsurgical 
Venous Throboembolism after Elective Major Orthopaedic Surgery of the Hip or 
Knee (XAMOS) study are in accordance with the conclusion of Regulation of 
Coagulation in Major Orthopedic surgery reducing the Risk of DVT and PE 
(RECORD) trials. A subset of countries that participated in XAMOS also included 
patients undergoing fracture-related orthopedic surgery. [1,3,4] 
Surgery as a therapy for cancer may double the risk of venous thromboembolism. 
However, results from studies including SAVE-ONCO, PROTECHT, and 
FRAGEM have been used as a backbone of recommendation for VTE prophylaxis 
in cancer patient, no controlled one has compared the new anticoagulant like 
Rivaroxaban with the standard of care therapy drugs [6]. All these new drugs 
including rivaroxaban have not been intensively studied in patients undergoing day-
surgery. High risk VTE ambulatory surgical patients such as patients with a previous 
episode of VTE or with additive risk factors may benefit from rivaroxaban. [7]. 
It is a hot topic of debate to accept standard method of VTE prevention in plastic 
surgery. In a retrospective experience of 2 surgical centers that use rivaroxaban for 
routine VTE prophylaxis for patients undergoing abdominoplasty, Oral rivaroxaban 
administration for chemoprophylaxis in abdominoplasty patients is safe, with low 

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rates of symptomatic VTE and hematoma formation. The authors recommended 
routine use of the medication for patients at increased risk for VTE events. 
Regarding other trials that compare rivaroxaban by standard of care drugs, we can’t 
find direct comparison between the two regimens. [8]  
Similarly, no controlled trials have evaluated the role of rivaroxaban as a new oral 
anticoagulant in Venous thromboembolism (VTE) prophylaxis for other 
nonorthopedic surgical patients. According to American College of Chest 
Physicians (ACCP), 2012 recommendation for thromboprophylaxis for general, 
abdominal-pelvic surgery, thoracic, cardiac surgery and Gynecological surgery, it is 
recommended to weigh the risk of thrombosis against the bleeding risk before adding 
LMWH or unfractionated heparin. 
Moreover, very few randomized clinical trials (RCTs) are powered to study side 
effects when comparing substances, and even large RCTs may be too small to reveal 
rare side effects. It seems difficult to compare safety data from trial to trial because 
there is no standardized definition of bleeding. One prospective study collecting data 
from the electronic health record at two institutions concluded that using of 
enoxaparin for VTE prophylaxis following THA and TKA was associated with a 
lower rate of the primary outcome (any postoperative bleeding) compared with the 
use of rivaroxaban in a similar cohort of patients. However, it was a retrospective 
investigation with many limitations can be argued with regard to selection and 
change in practice guideline during the study period. 
Finally, there is lack of literature data that define rivaroxaban as orthopedic 
postoperative thromboprophylactic agent rather than well-known indications (hip 
and knee replacements). It also is not plausible to accurately compare safety data 
with other injectable anticoagulants. 
 
 
 

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Aim of the work 
The main objective is to reduce the incidence of venous thromboembolism (VTE) in 
orthopedic postoperative patients based on the potential benefit of using rivaroxaban 
as a monotherapy. 
It is around efficacy and safety evaluation of using rivaroxaban as a monotherapy 
prophylactic agent in patients undergoing orthopedic surgeries taking into the 
account the reliable selection of patients most benefit. 
Answering questions about additional cost benefit from the perceptive of the cost-
effective analysis on extrapolating the results emerged to our university teaching 
hospital setting are going to be evaluating as well. 
Methodology 
Study design and randomization  
It is proposed to randomly assign at least 100 patients sequentially based on 
admission; in a single blind, interventional trial, to two separate groups. Patients are 
going to be selected from our university teaching hospital. patients were randomly 
assigned to a study group with the use of permuted blocks and stratification using 
well trusted randomization websites or software programs (SAS). Permuted block 
randomization list will be transferred from alphabetic symbol by the competent 
orthopedic supervisor and coded based on the randomization order by manual coding 
preset by orthopedic supervisor [5]. Double dummy technique may be feasible here 
as long as we tackled difficulty of providing syringes containing saline. However, 
the risk of injecting a saline solution subcutaneously (i.e. bleeding complications 
may develop in persons taking an anticoagulant agent plus unnecessary injections) 
may outweigh the benefit. Since the investigator do not know which therapy is 
administrated, the potential for the results to be biased is minimized [6]. 
The first group is to be on rivaroxaban with dosage according to the orthopedic 
approved regimen (10 mg once daily 6-10 hours after the surgery; recommended 
total duration of therapy: 12 to 14 days; ACCP recommendation: Minimum of 10 to 
14 days; extended duration of up to 35 days suggested (Guyatt 2012)
 [
3
].
 

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The other group will be administered the standard of care (SOC) enoxaparin. Dosage 
and duration of therapy are illustrated in Table 1 [2]. 
Drug  
Dosage and Duration 
Enoxaparin  
Once-daily dosing: 40 mg once daily, with initial dose within 9 to 15 hours before surgery, 
and daily for at least 10 days (or up to 35 days postoperatively) or until risk of DVT has 
diminished or the patient is adequately anticoagulated on warfarin. The American College 
of Chest Physicians recommends initiation ≥12 hours preoperatively or ≥12 hours 
postoperatively; extended duration of up to 35 days suggested (Guyatt, 2012). 
 
Table 1: Dosing of SOC drugs used in throbmoprophylaxis after orthopedic surgery. 
It is expected here that all medication will be taken for a duration of 10 days after 
surgery. The type, duration and dose of the thromboprophylactic agents will be  
discussed with and determined by the competent physician before saying a particular 
patient can be enrolled.  
Study population  
         The Patients >18 years who are going to be scheduled to undergo orthopedic 
surgery in whom decision of thromboprophylaxis taken will be enrolled for 
inclusion. 
Exclusion criteria are based on the approved contraindication listed, for all drugs 
used, in the drug’s labels and supplemented by data from well trusted compendia 
like Lexi comp® or Micromedex®. The exclusion criteria are as follows, but not 
limed to: 
I. 
Severe hypersensitivity to drugs or any component of the formulation. 
II. 
Planned intermittent pneumatic compression 
III. 
A requirement for anticoagulant therapy that could not be stopped 
IV. 
Severe hypersensitivity reaction (eg, anaphylaxis) to rivaroxaban or 
enoxaparin. 
V. 
Received another anticoagulant for more than 24 hours 
VI. 
Active bleeding or a high risk of bleeding 
VII. Thrombocytopenia associated with a positive test for antiplatelet antibody. 
VIII. Warfarin associated INR more than 1.5 on the day of the surgery 
IX. 
Conditions preventing bilateral venography 
X. 
ICU stay after surgery 
XI. 
Pregnant or breast-feeding 

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XII. Creatinine clearance less than 30 ml per minute or acute renal failure 
before the surgery or at any point during the study period. 
XIII. Moderate or Severe (Child Pugh B or C) hepatic Impairment or in patients 
with any hepatic disease associated with coagulopathy. 
XIV. Concomitant use of drugs that are both p-glycoprotein inhibitors and 
moderate to strong cyp3a4 (ketoconazole, itraconazole, lopinavir/ritonavir, 
ritonavir, indinavir/ritonavir & conivaptan) 
XV. CrCl 15 to 80 mL/min PLUS both P-glycoprotein inhibitors and moderate 
CYP3A4 inhibitors (eg, abiraterone acetate, diltiazem, dronedarone, 
erythromycin, verapamil) 
The study draft will be summited to our ethics committee attached to the hospital 
administration board before enrollment of patients. 
 
Prescribed co-medication of interest. 
       Because of the well documented effect of drugs affecting CYP3A4 co-
prescribed 
with 
rivaroxaban, 
strong 
inhibitor 
and inducers listed on 
http://medicine.iupui.edu/clinpharm/ddis/clinical-table/  under the guidance of US 
Food and Drugs Adminerstration(FDA) are contraindicate with rivaroxaban. Patient 
on these interacting drugs will be excluded.   
Outcome measure and follow up. 
       The primary efficacy outcomes are the composite of any deep-vein thrombosis, 
nonfatal pulmonary embolism, or death up to 30 days. The main secondary efficacy 
outcome is major venous thromboembolism, which is defined as the composite of 
proximal deep-vein thrombosis, nonfatal pulmonary embolism, or death from 
venous thromboembolism.  
The main safety outcome is the incidence of major bleeding beginning after the first 
dose of the study drug and up to 2 days after the last dose of the study drug (on-
treatment period). Major bleeding is defined as bleeding that is fatal, occurs in a 
critical organ (e.g., retroperitoneal, intracranial, intraocular, and intraspinal 
bleeding), or requires reoperation or extra surgical-site bleeding that was clinically 
overt and is associated with a fall in the hemoglobin level of at least 2 g per deciliter 
or that requires transfusion of 2 or more units of whole blood or packed cells. Other 
safety outcomes include any on-treatment bleeding, any on-treatment non- major 

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bleeding, hemorrhagic wound complications (a composite of excessive wound 
hematoma and reported surgical-site bleeding), any bleeding that starts after the first 
oral dose of rivaroxaban and ended up to 2 days after the last dose is administered, 
adverse events, and death.  
Validated clinical prediction rule is recommended to estimate pretest probability of 
venous thromboembolism. Duplex ultrasonography is the preferred test to diagnose 
DVT [7]. Many prediction scales are available like Wells Clinical Models for 
Evaluating the Pretest Probability of VTE. 
Symptoms and signs of DVT may include unilateral leg swelling, pain in the affected 
leg, calf tenderness in affected leg, increased leg warmth, erythema of affected leg, 
or a “palpable cord” may be felt in the affected leg. 
Regarding PE, diagnosis is suspected in patients with dyspnea, tachypnea, pleuritic 
chest pain, cough, and/or fever. Diagnosis begins with initial risk stratification based 
on presence of shock or persistent hypotension to identify patients at high risk of 
early mortality. 
For patients with suspected high-risk PE with shock or hypotension, emergency 
computed tomography(CT) angiography beside transthoracic echocardiography is 
recommended depending availability and clinical circumstances. While for patients not 
suspected of having high-risk PE, clinical assessment of likelihood of PE using validated 
prediction rules and clinical judgement to distinguish between low and high-risk PE may 
use [8].  However, PE can be diagnosed based on computed tomography pulmonary 
angiography (CTPA). CT pulmonary angiography is preferred method when available.  
It is recommended to have baseline Scr and platelets count. Based on Heparin 
induced thrombocytopenia, it is advisable to monitor platelets count beginning of 
the fourth day and every three days until discontinue of Heparins. 
Data analysis 
        The patients in the two groups will be matched in advance for the difference in 
Patients’ characteristics, VTE risk factors, history of VTE, types of surgery, types 
of anesthesia and duration of surgery. This ensures fair randomization between 
groups. Statistical analysis will be performed at an overall significance level of 0.05, 
adjusted for the primary and secondary end points using non- independent t-test 

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(SPSS software). Comparisons of the primary end points between treatment groups 
were performed by means of a log-rank test. To estimate the size of the effect, we 
will use a Cox regression model. On the other hand, the cost-effective analysis 
(CEA) will be based mainly on estimating the average cost-effective ratio(ACER) 
and the incremental cost for each additional cure. 
 

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