BRUCEFINAL2

Running head: PREVENTION OF VENOUS THROMBOEMBOLISM 1

Prevention of Venous Thromboembolism After Hip or Knee Replacement

Molly P. Bruce

Georgetown University School of Nursing and Health Studies

NURO540

PREVENTION OF VENOUS THROMBOEMBOLISM 2

Prevention of Venous Thromboembolism After Hip or Knee Replacement

Total hip and knee replacements are surgical procedures that are frequently performed in

healthcare. According to the Centers for Disease Control and Prevention (2014), there are

approximately 719,000 total knee replacements and 332,000 total hip replacements performed in

the United States each year. Hip and knee replacements are performed for various reasons

including development of osteoarthritis, rheumatoid arthritis, osteonecrosis, or fractures, among

many other factors (National Institute of Arthritis and Musculoskeletal and Skin Diseases, 2010).

Patients undergoing these procedures are at an increased risk for the development of venous

thromboembolisms (VTE), which is a potentially fatal complication occurring after major

orthopedic surgeries. Therefore, it is standard practice to place patients on prophylactic

anticoagulants for a minimum of ten days, though extended use of up to five weeks has been

found to be most effective (Eriksson et al., 2008).

Two anticoagulant agents currently available for the prevention of VTE include

rivaroxaban (Xarelto) and enoxaparin (Lovenox). Rivaroxaban is the newest oral anticoagulant

agent introduced for the purpose of reducing the risk of VTE in patients with atrial fibrillation or

patients who have just had knee or hip replacement surgery. Enoxaparin is a low molecular

weight heparin (LMWH) given subcutaneously and has been the standard of care in recent years

for treating hip and knee replacement patients prophylactically (Westendorf et al., 2013). Some

studies have shown rivaroxaban to be as effective as enoxaparin in the prevention of VTE, which

could be useful for prescribing physicians to consider since rivaroxaban may be more preferred

by patients due to administration route.

The purpose of this paper is to present a summary of existing literature comparing the

effectiveness of rivaroxaban to enoxaparin in the prevention of VTE. This will be done by

completing a critical appraisal of the literature including a conceptualization the problem, review

of findings, methodological rigor, strengths and limitations, and an appraisal of the strength of

evidence from included studies in order to develop an evidence-based solution to the below

PICOT question.

PICOT Question

The PICOT question being appraised is, “In adult patients who have undergone hip or

knee replacement, is rivaroxaban more effective than enoxaparin for the prevention of VTE, over


the course of a month?” The population under investigation has undergone either hip or knee

replacement, also known as arthroplasty, and has started rivaroxaban or enoxaparin either prior

to or shortly after the completion of surgery. The age of adults included ranges from 19 to 65.

The intervention under study is the use of oral rivaroxaban and it is being compared to

subcutaneous enoxaparin. Both rivaroxaban and enoxaparin are medications used to prevent the

patient from developing a VTE, or blood clot. Other terms used to describe these medications

are blood thinners or anticoagulants. Specifically, rivaroxaban is a direct factor Xa inhibitor that

interrupts intrinsic and extrinsic pathways during the coagulation cascade, thereby blocking the

formation of blood clots (U.S. National Library of Medicine, 2014). Enoxaparin is a LWMH

that binds to antithrombin III, which inactivates factor Xa and thrombin, inhibiting clot

formation (U.S. National Library of Medicine, 2014). The outcome under study includes

prevention of VTE. Venous thromboembolism includes the development of a deep vein

thrombosis (DVT) or pulmonary embolism (PE). Key words used for VTE might include blood

clot, DVT, pulmonary embolism (PE), or thromboembolism. The timing component of the

PICOT question is over the course of one month.

Significance of the Problem

Venous thromboembolisms occur in approximately 85% of patients who have undergone

major orthopedic surgery without the use of post-pharmacological prophylaxis (Westendorf et

al., 2013). Despite evidence provided in several meta-analysis studies indicating the need for

pharmacological prophylaxis after hip and knee replacement, nearly 50% of patients do not

receive extended prophylaxis after discharge (Kakkar et al., 2008). It is important for patients to

receive prophylactic anticoagulant medications to lessen the risk of VTE development, since this

is a potentially fatal complication. Without VTE prophylaxis after hip and knee replacement,

length of stay, readmission, and mortality will be negatively impacted and financial implications

will result due to the severity of VTE.

Enoxaparin and rivaroxaban are both options that have been explored for prophylaxis in

past years. While enoxaparin has been around longer, rivaroxaban has been receiving more

attention due to its route of administration and potential to be more effective at preventing VTEs.

The required length of time to take prophylactic anticoagulants most always extends past the

patient’s discharge date, given that the minimum recommended length for prophylaxis after hip

or knee replacement is ten days. Therefore, when patients are prescribed daily subcutaneous


enoxaparin, an additional responsibility is put on the patient and family to understand the

importance of administering subcutaneous enoxaparin correctly and consistently. Though it is

important for patient’s to approach rivaroxaban in the same manner, the route of administration

is by mouth, thereby not necessitating family cooperation.

Among other considerations, a study conducted by Duran et al. (2012) found rivaroxaban

to be more cost efficient than enoxaparin. According to Duran et al. (2012), rivaroxaban has a

cost savings of $511.93 per patient when compared to enoxaparin. In addition to being cost

efficient, a study completed by Lassen et al. (2008) found that gastrointestinal side effects were

mostly experienced by patients on these medications and that similar occurrence rates were

found between enoxaparin and rivaroxaban, with the greatest being 13% in patient’s taking

enoxaparin and 12% in those taking rivaroxaban (Lassen et. al, 2008). However, side effects

such as bleeding were found to be greater in rivaroxaban. Given these statistics and the

possibility of rivaroxaban being more efficacious at preventing VTEs than enoxaparin, it is

important for physicians to highly consider rivaroxaban over enoxaparin, while also taking into

consideration risks versus benefits when prescribing prophylaxis for these patients.

Search Strategy and Results

The databases used to search for articles related to the topic included CINAHL and

PubMed. Search terms used included hip or knee arthroplasty or replacement and enoxaparin

and rivaroxaban. The terms hip or knee arthroplasty or replacement were used before adding

another Boolean operator, AND, between enoxaparin and rivaroxaban to further narrow results.

Inclusion criteria included adults, English language, humans, within ten years, aged 19-65+,

rivaroxaban and enoxaparin or LMWH had to be included, and studies had to be done on patients

who underwent hip or knee replacement. Studies were excluded if inclusion criteria were not

met.

After entering appropriate keywords, Boolean operators, and inclusion/exclusion criteria,

there were 26 results on PubMed and four results on CINAHL (Figure 1). Of these results, each

article was screened for overall appropriateness and relativeness to the topic, and a total of

eleven were utilized for this article. These articles consist of eight randomized controlled trials

(RCTs) of which four were pooled-analyses, two cohort studies, and one meta-analysis. Articles


were evaluated and graded using the Rating system for the Hierarchy of Evidence for

Intervention/Treatment Questions (Figure 2).

Critical Appraisal of the Literature

Conceptualization of the Problem

The conceptual framework of the literature that was reviewed for the PICOT question

consisted of making a determination as to whether enoxaparin or rivaroxaban is more effective at

preventing VTE in hip and knee replacement patients. For these studies, each concept was

appropriately and consistently defined by detailing the differences between enoxaparin and

rivaroxaban. The doses of medications used in the studies varied in milligrams (mg) and

frequency of administration. Enoxaparin was administered in either 40mg daily or 30mg twice a

day. Rivaroxaban doses varied from 5-60mg, with the majority of studies administering 10mg

daily. The length of administration time also varied between studies, from ten to 35 days. In

addition to differentiating rivaroxaban from enoxaparin, each study also clearly defined the

concept of VTE.

It is important to note that while concepts were consistent across the majority of studies,

two of these only examined LMWH as a group, instead of enoxaparin alone. The author of one

of these studies explained that they utilized various LMWHs because hospital recommendations

were altered during the study period based on national prophylaxis guidelines for hip or knee

replacement patients (Westendorf et al., 2013). The second study included all LMWH so that

physicians could prescribe based on their preference instead of being limited to one option

(Turpie et al., 2013).

Findings

Findings from the eleven research articles that were utilized were all consistent. There

were no conflicting findings reported on development of VTE. All studies provided statistically

significant results that reported subcutaneous enoxaparin, or LMWH in general, to be associated

with higher rates of VTE when compared to oral rivaroxaban. This stayed true at varying doses

and frequencies of administration (Appendix A).

In addition to researching VTE rates with the administration of rivaroxaban and

enoxaparin, it is relevant to mention that all of the included studies also looked at safety, and

specifically rates of bleeding, for each drug. All but one of these studies reported a minimal to

moderate increase in bleeding with rivaroxaban than with enoxaparin. Fisher et al. (2007) found


that there was a dose-dependent response for bleeding with rivaroxaban (p<0.001), by showing

that in a population of 1,317 patients, bleeding occurred in “0.9%, 1.3%, 2.1%, 3.9%, and 7.0%

of patients receiving rivaroxaban total daily doses of 5, 10, 20, 40, and 60mg, respectively,

versus 1.7% of patients receiving enoxaparin (p. 931).” Westendorf et al. (2013) was the only

study that found rivaroxaban (10mg) to have a lower risk of bleeding when compared with

LMWH, 2.9% versus 7.0% (p<0.001) for 2,538 patients.

Methodological Rigor

Both experimental and nonexperimental research designs were utilized in the appraised

studies. The experimental studies consisted of eight RCTs of which four were pooled analyses,

while the two nonexperimental studies were cohort studies. In addition, a meta-analysis was

included. Of the studies included, the majority of samples were obtained internationally. The

research samples also included all appropriate candidates undergoing hip or knee replacement

being treating prophylactically for VTE, increasing representativeness and external validity of

the population under study.

A factor found in many of the research studies that negatively affected the measurement

of study variables, was the recurring incidence of inadequate venograms obtained to assess for

the development of VTE. To resolve this issue, most of the studies were able to increase the

recruitment of patients to meet the statistical power of their trials. All but two studies were

randomized and blinded, minimizing confounding variables and increasing internal validity. The

two studies that were not randomized were cohort studies, which could have negatively impacted

the internal validity of results obtained.

Strengths and Limitations

The strengths of the overall body of evidence include similarity in study populations,

inclusion of RCTs, and the utilization of ethical guidelines. The PICOT question under appraisal

specifically targets an adult population who has undergone either hip or knee replacement

surgery. These inclusion criteria were all met in the appraised research articles, which increased

the chances of determining an appropriate answer to the PICOT question. In addition, the

majority of studies included were either RCTs or pooled analyses of multiple RCTs. These

studies were not only randomized, but also double-blinded lessening the chances of bias. The

RCTs included also had large sample sizes, with the majority meeting their calculated power

analysis, increasing generalizability. Lastly, the majority of included studies mentioned


appropriate ethical considerations including the obtainment of informed consent and approval

from ethics committees.

The limitations of the body of evidence include the utilization of multiple doses and

frequencies of administration for each drug, use of LMWH instead of enoxaparin in two studies,

the inclusion of two cohort studies, and risks of bias due to connections to sponsors. The studies

under investigation included a variety of drug dosages and frequencies in administration. As

mentioned earlier, enoxaparin dosages ranged from 40mg daily to 30mg twice a day, while

rivaroxaban dosages varied from 5-60mg, with the majority of studies administering 10mg daily.

There was also not a consistent timeframe for the length of administration, ranging from ten to

35 days. These factors combined could lead to inconsistent results that are difficult to compare

to studies with varying dosages, frequencies, and timeframes. In addition, two of the studies

examined LMWH as a group instead of enoxaparin alone, which could also alter the comparison

of findings. Another limitation of the obtained body of evidence includes the utilization of two

cohort studies. Without randomization and blinding, the risk of bias is increased. Lastly, in one

of these cohort studies, Bayer Pharmaceuticals was a sponsor, and this company manufactures

rivaroxaban (Turpie et al., 2013). Many of the involved researchers had connections with Bayer

including employment, stockholders, consultants, and some obtained grants from the company,

further increasing the risk of bias in the included study. This was the same case for the meta-

analysis conducted by Nieto, Espada, Merino, and Gonzalez (2012).

Summary Statement Regarding Strength of the Evidence

After reviewing the body of existing literature, it was found that oral rivaroxaban is

superior to subcutaneous enoxaparin for preventing VTE after total hip or knee replacement. In

order to support this statement, it is important to note that the eleven studies incorporated in this

literature review each included quality, quantity, and consistency of varying degrees. The

majority of the included studies were of high quality, minimizing biases and increasing internal

validity through randomization and blinding. However, two studies were cohort studies and

were not randomized, thereby affecting quality. In addition, the majority of included studies had

a level II rating with the Rating system for the Hierarchy of Evidence for Intervention/Treatment

Questions. Quantity was appropriately addressed in each study since all studies had large sample

sizes with strong magnitude of effects. Power analyses were conducted in the majority of studies

and most of these met their calculated analysis, with the exception of the study conducted by


Kakkar et al. (2008). Relative risk and odds ratios were utilized in the majority of the studies.

Lastly, all studies were consistent since they yielded statistically significant results showing

evidence that rivaroxaban was more efficacious at preventing VTE after total hip or knee

replacement when compared with enoxaparin.

The Rating system for the Hierarchy of Evidence for Intervention/Treatment Questions

(Figure 2) was used to rate evidence obtained from the included research studies. Of these

studies, one was rated a level one, eight were rated a level two, and two were rated as a level

four. Levels are ranked from highest evidence as level one to lowest evidence as level seven.

The average grade of all studies included combined is a level two, suggesting a fairly high level

of evidence, collectively.

Based on the review of literature and overall soundness of evidence obtained, it is

suggested that physicians consider prescribing low-dose rivaroxaban over enoxaparin for

prevention of VTE after total hip or knee replacement based on the patient and their overall risk

factors. However, it is of upmost importance that other considerations not included in the

proposed PICOT question be considered before prescribing rivaroxaban over enoxaparin due to

greater risks of bleeding while on rivaroxaban, especially with higher doses. Fisher et al. (2007)

concluded that daily doses of 5-20mg of rivaroxaban was found to be most effective at

preventing VTE and had a favorable safety balance, relative to enoxaparin. At a dose of 10mg of

rivaroxaban, Huisman et al. (2010) found that bleeding risks were 2.5% compared to 3.1% in

enoxaparin, but there was a 2-fold higher risk of developing VTE with enoxaparin compared

with rivaroxaban. Given the comparison of the nearly similar risks of bleeding to the benefit of

greater protection from VTE with low-dose rivaroxaban, it might be realistic to prescribe low-

dose rivaroxaban over enoxaparin when applicable. Regardless of the provider’s decision to

prescribe rivaroxaban over enoxaparin, patient risks versus benefits must always be taken into

consideration so that the patient can obtain the best results with the least adverse effects possible.

Clinical Recommendations

As mentioned above, it is recommended that low-dose rivaroxaban be prescribed over

enoxaparin for the prevention of venous thromboembolism after hip or knee replacement.

Venous thromboembolism development was shown to be less likely with rivaroxaban than with

enoxaparin. However, it is important to weigh patient risks versus benefits before prescribing


low-dose rivaroxaban due to higher risks of bleeding, especially with higher doses. Due to

theses risks of bleeding, certain factors should be taken into consideration before prescribing

rivaroxaban over enoxaparin. One of these considerations would be to determine whether or not

the patient has had a history of bleeding. For these patients, it might be best to prescribe

enoxaparin rather than low-dose rivaroxaban, even though the bleeding risks were shown to be

only slightly more elevated in rivaroxaban than enoxaparin. Other factors taken into

consideration should include patient preference, likeliness of compliance, and probabilities of

VTE development.

Prescription for Change

The change model used to implement the above clinical recommendations for

organizational change is the ACE Star Model of Knowledge Transformation. This model was

chosen since it includes the utilization of both old and new concepts for improving patient care.

It also is a continuous model, suggesting that knowledge transformation is a constant, endless

process (Stevens, 2004). Medications for VTE prevention are continually developed and

studied, and practice guidelines will always be evolving based on evidence-based practice, just

as the ACE Star Model suggests. This model also incorporate clinical practice guidelines that

disclose risks and benefits of different evidence-based options, which would be beneficial for the

evidence obtained in this paper. The steps applied in this model include discovering a research

question, summarizing the evidence, translating findings, integrating findings into practice, and

evaluating the overall outcomes.

Discovering Research

As mentioned previously, this topic was thoroughly researched using two databases,

PubMed and CINAHL, in order to generate knowledge on the proposed PICOT question.

Articles with various research designs including RCTs, cohort studies, and a meta-analysis were

incorporated in the search to gather evidence on the topic. This stage of discovering existing

research is necessary in order to rectify the need for change in current clinical practice (Stevens,

2004).

Summarizing the Evidence

Stevens (2004) mentions that summarizing the evidence is the first step in evidenced-

based practice, since it encompasses research findings into one meaningful statement. By


combining findings from various studies, the risk of overall findings occurring based on chance

diminishes, and reliability and reproducibility of findings is increased (Stevens, 2004). The

evidence obtained on the proposed PICOT question in this paper, suggested that VTE rates were

lessened with rivaroxaban than with enoxaparin prophylaxis. This held true for every study that

was included.

Translation of Evidence

After a summary of existing evidence is developed, it is important to translate this into a

clinical practice guideline (CPG) so that providers can easily become informed on the overall

body of evidence (Stevens, 2004). Clinical practice guidelines help assist providers in

determining the best clinical decisions for their patients by including risks, benefits, and costs.

These guidelines also clearly explain clinical recommendations and link these recommendations

to evidence obtained during research (Stevens, 2004). The CPG for the evidence obtained on the

proposed PICOT question in this review, will include the recommendation to prescribe low-dose

rivaroxaban over enoxaparin for VTE prevention. It also will include the findings of higher

bleeding rates with rivaroxaban and the importance to weigh risks versus benefits for each

patient.

Integration of Evidence into Practice

In order to integrate evidence into practice, it is important to identify key stakeholders,

barriers, and facilitators for change. Key stakeholders included in this recommendation of

implementing low-dose rivaroxaban over enoxaparin for VTE prevention in hip and knee

replacement patients, encompasses the surgeons who are completing the surgery, nurses

providing care after the procedures, and the patients and outpatient providers after discharge.

These are the main individuals who will be affected by the change, and therefore need to be

involved in the decision making process. A major barrier to change for the recommendations

made would be non-adherence to change by these providers and noncompliance by the patient.

Providers may be most comfortable with their previous standard of practice and become resistant

to change. In addition, patients may not be compliant with medication administration, and in the

case of prescribing enoxaparin, may not be adequately administering their medication as

prescribed. Lastly, the major facilitators of change would be the inpatient and outpatient


providers caring for these patients, since they have authoritative privileges for prescribing these

medications.

It is also important to have a strategy for implementing change. Lewin’s Model of

Change incorporates three steps to implement change including unfreezing, changing, and

refreezing. In the first step, the stakeholders will be recognized and pursued. A summary of the

obtained evidence will be presented to them in order to increase motivation for change. At this

time, it is important to address all questions and concerns so that the stakeholders are well

informed on the new evidence. The next step is incorporating the change itself by facilitating

and integrating the developed CPGs into practice. Lastly, the change is made permanent and

overall health outcomes, efficacy, and patient and provider satisfaction are evaluated.

Evaluating Outcomes

The last step in the ACE Star Model of Knowledge Transformation is evaluating

outcomes. To evaluate patient outcomes for VTE prevention after hip or knee replacement, both

formative and summative criteria will be included. The formative criteria to be evaluated

include medication compliance and appropriate administration by nurses and patients, number of

providers who adopt the change, and overall feasibility of recommendations made. Summative

criteria will include the occurrence of VTE with rivaroxaban as compared to enoxaparin,

bleeding rates with each drug, a cost summary, and unintended consequences. Time points for

these evaluations will take place on the day of medication course completion and subsequently

one month after this date. Venous thromboembolism development will be evaluated with

venograms. Evaluation results will be disseminated to the aforementioned key stakeholders so

that the clinical practice change can be reevaluated for effectiveness.

Conclusion

The intention of this paper was to determine a solution to the proposed PICOT question

regarding the effectiveness of rivaroxaban compared to enoxaparin for the prevention of VTE

after total hip or knee replacement surgery. This was achieved by reviewing multiple studies

completed on the topic with overall high levels of evidence. This paper included an explanation

of the PICOT question, significance of the problem, search strategy and results, critical appraisal

of the literature, conceptualization of the problem including findings, methodological rigor,

strengths and limitations, and a summary statement regarding strength of evidence from the


articles included in this review. By evaluating these criterions, it was concluded that rivaroxaban

is superior in preventing VTE after hip or knee replacement when compared with enoxaparin,

suggesting that prescribing providers should closely consider their options based on the patient

and their risk factors when interacting with this patient population.


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Appendix ASummary of Primary Sources of Evidence

Citation of Evidence Eriksson, B.I., Borris, L.C., Friedman, R.J., Haas, S., Huisman, M.V., Kakkar, A.K.,… Bandel, T.J. (2008).

Study Question or Hypothesis Null hypothesis: “The efficacy of rivaroxaban is inferior to that of enoxaparin in the per-protocol population.”

Study Design RCT; double-blinded; between February 2006-March 2007

Sample Setting Sample size: 4,541 Setting: None given Location: 27 countries worldwide

Interventions & Outcomes Independent variables: Rivaroxaban 10mg once daily

PO or Enoxaparin 40mg once daily SC in addition to either a PO or SC placebo

Dependent variable: development of VTE

Data Collection & Analysis Data collection methods: bilateral venography done at last dose of study drug & at 36 days to screen for VTE; laboratory tests

Data analysis methods: Analysis of variance with two-sided P values, with a type I error of 5%; Mantel-Haenszel weighting with corresponding asymptotic two-sided 95% CI used to estimate difference between incidence rates in rivaroxaban group and enoxaparin group that was estimated by stratification according to country

Findings & Conclusions VTE occurred in 4/1696 (0.2%) in those taking Rivaroxaban and in 33/1678 (2.0%) in the Enoxaparin group (absolute risk reduction, 1.7%; 95% CI, 1.0 to 2.5; P<0.001) (p. 2768)

Strengths & Limitations Strengths: Trial performed under Declaration of Helsinki; protocol approved by institutional review board; informed consent obtained from patients; power analysis; adequate follow-up (only 1 patient withdrew)

Limitations: Number of valid venograms was lower than expected- more patients recruited than planned for; no information given on setting of drug administration

Implications for Practice & Research

Taking Rivaroxaban 10mg daily PO was significantly more effective than Enoxaparin 40mg SC daily for the prevention of VTE after hip arthroplasty.

Level of Evidence Level II, Rating System for the Hierarchy of Evidence for Intervention/Treatment Questions (Melnyk & Fineout-Overholt, 2011)


Citation of Evidence Fisher, W.D., Eriksson, B.I., Bauer, K.A., Borris, L., Dahl, O.E. Gent, M.,… Haas, S. (2007).

Study Question or Hypothesis Is Rivaroxaban as effective as enoxaparin at preventing VTE in patients undergoing knee or hip replacement?

Study Design Pool-analysis of 2 RCTs that were both double-blinded

Sample Setting Sample size: Hip study 722; Knee study 621 Setting: Not given Location: Hip study in Europe; Knee study in North

AmericaInterventions & Outcomes Independent variables: Rivaroxaban given at 2.5, 5, 10,

20, or 30mg BID or enoxaparin 30-40mg daily; hip or knee replacement

Dependent variable: development of VTEData Collection & Analysis Data collection methods: bilateral venography 5-9 days

after surgery

Data analysis methods: Logistic regression used to analyze dose response relationship of rivaroxaban; 95% CI used to derive patient population of mean age so equal that there were equal numbers of patients in each study and equivalent numbers of male and female patients; Regression model used to rest differences in dose response relationships with rivaroxaban between hip and knee replacement groups; common odds ratio used for enoxaparin versus rivaroxaban

Findings & Conclusions VTE occurred in 16.1-24.4% of patients receiving rivaroxaban 5-60mg, and 27.8% receiving enoxaparin.

VTE with rivaroxaban occurred in 6.9-18.2% of patients in the hip study, compared to 23.3-40.4% in the knee study.

There was a flat dose response relationship with rivaroxaban for total VTE, p=0.39 (pp. 934-935)

Strengths & Limitations Strengths: Studies performed under Declaration of Helsinki and Good Clinical Practice guidelines; received consent from local ethic review committees; informed consent obtained from patients before participation; independent Data and Safety Monitoring Board monitored safety and efficacy throughout study

Limitations: Studies were not powered to detect differences between separate rivaroxaban and enoxaparin doses; specific setting of drug administration not acknowledged


Rivaroxaban was found to be more effective at daily doses of 5-20mg than enoxaparin, for the prevention of VTE after a hip or knee replacement.


Citation of Evidence Huisman, M.V., Quinlan, D.J., Dahl, O.E., & Schulman, S. (2010).

Study Question or Hypothesis Are PO dabigatran and rivaroxaban as effective as enoxaparin at preventing VTE after hip or knee arthroplasty?


Study Design Pooled-analysis of 6 RCTs; double-blinded

Sample Setting Sample size: 18,405 total (10,220 in enoxaparin vs. rivaroxaban group from a total of 3 studies)

Setting: Not given Location(s): Not given

Interventions & Outcomes Independent variables: Enoxaparin SC 40mg once daily or 30mg BID; rivaroxaban 10mg PO daily (10-15 days in knee study and 28-35 days in hip study); hip or knee arthroplasty

Dependent variables: VTE developmentData Collection & Analysis Data collection methods: lower limb venography

Data analysis methods: Odds ratios for individual outcomes were done for each study and pooled using Mantel-Haenszel method; 95% CI; statistical calculations done with Review Manager

Findings & Conclusions When compared to rivaroxaban, enoxaparin showed a 2-fold higher risk of VTE development (1.2% versus 0.6%; OR, 2.04; 95% CI, 1.32 to 3.17; P<0.001; number needed to treat, 167)

When compared to dabigatran (220mg daily), enoxaparin had similar risks of VTE development (0.9% versus 1.1%; OR, 0.76; 95% confidence interval [CI], 0.44 to 1.31) (pp. 654-655)

Strengths & Limitations Strengths: All studies were approved by local research ethics boards; all provided informed consent; follow-up >99% in all 3 trials for enoxaparin vs. rivaroxaban group

Limitations: Study-level data used instead of patient-level data; patients were excluded if they had impaired renal function or were very old, which could decrease generalizability


Enoxaparin and dabigatran had similar efficacy rates. However, when compared to rivaroxaban, enoxaparin had a significant increase in risk of VTE development. Implications were made to balance risks of bleeding with risks of VTE events when choosing prophylactic therapy after orthopedic surgery.


Citation of Evidence Kakkar, A.K., Brenner, B., Dahl, O.E., Eriksson, B.I., Mouret, P., Muntz, J.,… Soglian, A.G. (2008).

Study Question or Hypothesis Is 5 weeks of PO Ribaroxaban more effective than 2 weeks of SC Enoxaparin for preventing the development of VTE after hip arthroplasty?

Study Design RCT; double-blinded; from February 2006 to April 2007

Sample Setting Sample size: 2,509 Setting: Not given Location(s): 123 centers across 21 countries


Interventions & Outcomes Independent variables: Ribaroxaban PO daily for 31-39 days (with placebo injection for 10-14) or enoxaparin SC for 10-14 days (with placebo pill for 31-39 days)

Dependent variables: development of VTE

Data Collection & Analysis Data collection methods: Bilateral venography done to detect VTE day after last dose of medication

Data analysis methods: Used SAS version 8.2; Mantel-Haenszel weighting with corresponding asymptotic two-sided 95% CI and two-sided p value; Fisher’s exact test

Findings & Conclusions VTE occurred in 17/864 (2.0%) patients receiving rivaroxaban and in 81/869 (9.3%) in the enoxaparin group (absolute risk reduction 7.3%, 95% CI 5.2-9.4; p<0.0001) (p. 34)

Strengths & Limitations Strengths: Trial performed under Declaration of Helsinki; protocol approved by institutional review board; informed consent obtained from patients

Limitations: Adequate sample size was estimated to be 2500 patients. Of the 2,509 sampled, 776 were excluded for various reasons as shown in the article on Table 1 (no intake of study medication, indeterminate venography, no planned surgery, incorrect time interval between end of surgery and first dose of medication, etc.). In addition, 348 patients in the rivaroxaban group and 338 in the enoxaparin group did not have a venography done. However, sensitivity analyses were done.


Extended use of rivaroxaban was significantly more effective than short-term use of enoxaparin in the prevention of VTE after hip arthroplasty.


Citation of Evidence Lassen, M.R., Ageno, W., Borris, L.C., Lieberman, J.R., Rosencher, N., Bandel, T.J., Misselwitz, F. (2008).

Study Question or Hypothesis Is oral rivaroxaban as efficient as subcutaneous enoxaparin for preventing VTE after total knee arthroplasty?

Study Design RCT; double-blinded; from February 2006 to November 2006

Sample Setting Sample size: 2,531 Setting: 147 centers Location: 19 countries

Interventions & Outcomes Independent variables: PO rivaroxaban 10mg daily after knee arthroplasty or SC enoxaparin 40mg daily after knee arthroplasty both for 10-14 days

Dependent variable: development of DVT


Data Collection & Analysis Data collection methods: bilateral venography between day 11-15

Data analysis methods: Mantel-Haenszel weighting used to estimate difference between incidences in rivaroxaban group and enoxaparin group; 95% CI; statistical power of 90% used with a two-sided type I error rate of 5%

Findings & Conclusions VTE occurred in 79/824 patients (9.6%) receiving rivaroxaban and in 166/878 patients (18.9%) receiving enoxaparin (absolute risk reduction, 9.2%; 95% confidence interval [CI], 5.9 to 12.4; P<0.001)

Major VTE events occurred in 9/908 patients (1.0%) in rivaroxaban group and 24/925 (2.6%) in enoxaparin group (weighted absolute risk reduction, 1.6%; 95% CI, 0.4 to 2.8; P = 0.01; relative risk reduction, 62%; 95% CI, 18 to 82; P=0.02) (p. 2779)

Strengths & Limitations Strengths: Trial performed under Declaration of Helsinki; protocol approved by institutional review board; informed consent obtained from patients; power analysis

Limitations: There were a low number of valid venograms obtained. Therefore, recruitment was increased from 2300 to 2500+ patients to meet statistical power of the trial. Comparison groups were well-balanced increasing generalizability, other than females>males in rivaroxaban group (P=0.03).


Rivroxaban given in a fixed daily dose is superior to enoxaparin in preventing VTE in postop knee arthroplasty patients.


Citation of Evidence Levitan, B., Yuan, Z., Turpie, A.G., Friedman, R.J., Homering, M., Berlin, J.A.,… Berkowitz, S.D. (2014).

Study Question or Hypothesis What is the benefit-risk profile for rivaroxaban versus enoxaparin in patients who had total hip or knee arthroplasty?

Study Design Pooled-analysis of RCTs; from February 7,2006 to January 31, 2008

Sample Setting Sample size: 12,729 Setting: Not given Location(s): Not given

Interventions & Outcomes Independent variables: Rivaroxaban 10mg PO or 40mg SC enoxaparin


Data Collection & Analysis Data collection methods: chart review

Data analysis methods: Post-hoc analysis; Kaplan-Meier rates


Findings & Conclusions Out of 10,000 patients, compared to enoxaparin, rivaroxaban was expected to be associated with 38 fewer symptomatic VTE events (95% CI: -6 to 82)

In 10,000 patients, compared with enoxaparin, rivaroxaban was associated with 98 (95% CI: 27 to 169) fewer symptomatic VTE.

The median time to onset for symptomatic VTE was 18 days for hip arthroplasty and 5 days for knee arthroplasty.

After both hip or knee arthroplasty, rivaroxaban prevented more harmful events than enoxaparin. (pp. 161-162)

Strengths & Limitations Strengths: Randomization in studies; groups under study were well-balanced with similar surgical and demographic characteristics

Limitations: Different durations of anticoagulant use were used in the four studies which could obscure results; 95% CI overlaps in the study for the hip and knee rate differences


Rivaroxaban administration resulted in greater benefits than harm when compared with enoxaparin after total hip or knee arthroplasty.


Citation of Evidence Turpie, A.G., Lassen, M.R., Davidson, B.L., Bauer, K.A., Gent, M., Kwong, L.M.,… Cushner, F.D. (2009).

Study Question or Hypothesis Is rivaroxaban as effective as enoxaparin for thromboprophylaxis after total knee arthroplasty?

Study Design RCT; double-blinded; from June 2006 to October 2007

Sample Setting Sample size: 3,148 Setting: 131 centers; patient’s home after discharge Location(s): 12 countries

Interventions & Outcomes Independent variables: Rivaroxaban 10mg once daily with SC placebo or SC enoxaparin 30mg BID with PO placebo

Dependent variables: Development of VTE

Data Collection & Analysis Data collection methods: bilateral venography between days 11 and 15

Data analysis methods: Mantel-Haenszel weighting used to analyze the difference in the primary efficacy outcome between rivaroxaban and enoxaparin with corresponding asymptotic two-sided 95% CI; age, weight, and BMI were analyzed with two-way ANOVA, with georgraphical region and treatment group as fixed effects; statistical tests were done with a two-sided type I error rate of 5%


Findings & Conclusions In the modified intention-to-treat population, VTE occurred in 67/965 (6.9%) of patients who received rivaroxaban and in 97/959 (10.1%) of patients who received enoxaparin (absolute risk reduction 3·19%, 95% CI 0·71–5·67; p=0·0118)

In per-protocol population, VTE occurred in 58/864 (6.7%) patients receiving rivaroxaban and 82/878 (9.3%) patients receiving enoxaparin (weighted absolute risk reduction 2·71%, 95% CI 0·17–5·25), indicating superiority of rivaroxaban over enoxaparin (p=0.0362) (p. 1676)

Strengths & Limitations Strengths: Study done in accordance with Declaration of Helsinki & local regulations; independent ethics committees or institutional review boards approved the protocol for each center; informed consent obtained from patients before randomization; randomized; adequate power analysis

Limitations: Inadequate venograms to assess for VTEs was higher than expected in study


Rivaroxaban PO 10mg was significantly superior to SC enoxaparin 30mg BID for preventing VTE after total knee arthroplasty.


Citation of Evidence Turpie, A.G., Lassen, M.R., Eriksson, B.I., Gent, M., Berkowitz, S.D., Misselwitz, F.,…Kakkar, A.K. (2011).

Study Question or Hypothesis Is enoxaparin more effective than rivaroxaban for thromboprophylaxis after hip or knee replacement surgery?

Study Design Pooled-analysis of four phase III RCT studies; between February 7, 2006 and Jaunary 31, 2008

Sample Setting Sample size: 12,729 Setting: 617 centers Location: 41 countries

Interventions & Outcomes Independent variables: enoxaparin 40mg SC daily or enoxaparin 30mg SC BID daily or rivaroxaban 10mg PO daily



Data analysis methods: 95% CI; Odds Ratio; Cox regression model

Findings & Conclusions 0.5% of patients (26/6183) developed of VTE as compared to 1.0% (60/6200) of patients who received enoxaparin (odds ratio 0.48 [95% CI 0.30–0.76]; p=0.001) (p. 447)


Strengths & Limitations Strengths: Randomization; Studies done under International Conference on Harmonization and Good Clinical Practice, Declaration of Helsinki, and local regulations; institutional review boards and ethics committees approved studies; written informed consent obtained before randomization

Limitations: Different intensities of prophylaxis usedImplications for Practice & Research

Rivaroxaban is more effective than LMWH for VTE prevention in patients who have undergone hip or knee replacement.


Citation of Evidence Turpie, A.G., Haas, S., Kreutz, R., Mantovani, L.G., Pattanayak, C.W., Holberg, G.,… Jamal, W. (2013).

Study Question or Hypothesis Is rivaroxaban as effective as standard-of-care for thromboprophylaxis after hip or knee replacement surgery?

Study Design Non-experimental, cohort study; from February 2009 to June 2011

Sample Setting Sample size: 17,701 Setting: 252 centers Location(s): 37 countries

Interventions & Outcomes Independent variables: Rivaroxaban or LMWH or unfractionated heparin, dabigatran, or vitamin K antagonists; hip or knee replacement surgery

Dependent variables: VTE development


Data analysis methods: Logistic regression model used to estimate propensity score for each patient; Estimated odds ratios and CIs were calculated with a Bayesian method

Findings & Conclusions Symptomatic VTE 3 months after surgery occurred in 0.89% in the rivaroxaban group (n=8,778) and 1.35% in the standard-of-care group (n=8,635; odds ratio [OR] 0.65; 95% confidence interval [CI] 0.49–0.87), and 0.91% and 1.31% (weighted) in the propensity score-adjusted analysis (OR 0.69; 95% CI 0.56–0.85).

In comparison to the standard-of-care group, patients who receiving rivaroxaban had a significantly lower rate of VTE, 0.65% versus 1.02% (OR 0.63; 95% CI 0.45-0.89) in the safety population and 0.65% and 1.03% in the adjusted safety population (PR 0.63; 95% CI 0.49-0.81). (pp. 98-99)


Strengths & Limitations Strengths: Written informed consent obtained in countries where necessary; study approved by European Medicines Agency and independent ethics committee or an independent review board where required; sample size

Limitations: No randomization; Bayer Pharmaceuticals sponsored the study and they manufacture rivaroxaban. Many of the researchers in the study have connections with Bayer (employees, stock holders, receive grants, consultants, etc.) which creates a conflict of interest; confounding variables not measured with propensity score design; reporting bias


In unselected patients who are undergoing knee or hip surgery, oral rivaroxaban should be considered by physicians to help improve prevention of VTE.

Level of Evidence Level IV, Rating System for the Hierarchy of Evidence for Intervention/Treatment Questions (Melnyk & Fineout-Overholt, 2011)

Citation of Evidence Westendorf, J.B., Lutzner, J., Donath, L., Tittl, L., Knoth, H., Radke, O.C.,… Kuhlisch, E. (2013).

Study Question or Hypothesis Is LMWH or rivaroxaban more efficient for thromboprophylaxis in hip and knee replacement surgery?

Study Design Non-experimental retrospective cohort study; from January 2006 to June 2011

Sample Setting Sample size: 5,061 Setting: University Clinic “Carl Gustav Carus” Location: Dresden, Germany

Interventions & Outcomes Independent variables: LMWH (fondaparinux 2.5mg) SC daily or rivaroxaban 10mg PO daily for 35 days postop



Data analysis methods: Fisher’s exact test or Student’s t-test and ANCOVA were used to compare differences in baseline variables; Binary data analyzed using logistic regression models; 95% CI; Length of hospital stay analyzed using Kaplan-Meier estimation; Risk for VTE modeled with Cox proportional hazard models

Findings & Conclusions Symptomatic VTE results occurred in 4.1% of patients taking LMWH and 2.1% taking rivaroxaban (p<0.001).

Patients receiving LMWH had a higher rate of distal DVT than those receiving rivaroxaban (2.5 vs. 1.1%; p=0.011). However, a reduction of VTE with rivaroxaban only found to be significant in hip surgery patients, while reduction of VTE in knee surgery patients failed to reach significance. (pp. 157-158)


Strengths & Limitations Strengths: Sampling size comparable to large RCT studies

Limitations: No randomization; Study completed at one center, decreasing generalizability; patients who were taking rivaroxaban had more risk factors for DVT (older, higher BMI, some with history of VTE) when compared to LMWH group; different LMWH were administered during observational period due to changing protocols; no information was available on development of VTE once patients were discharged; reporting bias


Rivaroxaban is more effective than LMWH for VTE prevention in patients who have undergone hip or knee replacement. Switching from LMWH to rivaroxaban could be beneficial.

Level of Evidence Level IV, Rating System for the Hierarchy of Evidence for Intervention/Treatment Questions (Melnyk & Fineout-Overholt, 2011)

Appendix B

Summary of Secondary Sources of EvidenceCitation of Evidence Nieto, J.A., Espada, N.G., Merino, R.G., & Gonzalez, T.C.

(2012).

Objective, Aim or Purpose “To compare the main efficacy and safety endpoints of the pivotal randomised clinical trials (RCTs) on venous thromboembolism (VTE) prevention after total hip (THR) or knee (TKR) replacement with the new oral anticoagulants (NAs) versus enoxaparin.” (p. 183)

Search Strategy No specific search terms given. Only states that RCTs were obtained from medical literature.


Inclusion & Exclusion Criteria Inclusion: English; patients aged 18 years-old or older; enoxaparin SC 40mg daily or 30mg BID, rivaroxaban PO 10mg daily, apixaban PO 2.5mg BID, or dabigatran PO 220mg daily; hip or knee replacement surgery

Exclusion: active bleeding, high bleeding risk, contraindications for enoxaparin, kidney failure, abnormal liver enzymes, specific medications, pregnancy or breastfeeding, planned intermittent pneumatic compression, need for continued anticoagulation, disorders preventing bilateral venography

Data Extraction & Analysis Data collection methods: review of previous studies, chart review

Data analysis methods: Chi-square test and I2 statistic was used for heterogeneity of data; random-effects model used to obtain risk-ratios and their correspondent 95% CI; funnel plot used to assess publication bias

Results, Recommendations & Implications

When comparing VTE rates to enoxaparin 40mg, rivaroxaban showed superiority (RR 0.50; 95% CI 0.34-0.73), followed by apixaban (RR 0.63; 95% CI 0.36-1.01) and dabigatran, which showed equivalence to enoxaparin (RR 1.02; 95% CI 0.86-1.20).

VTE occurred in 927/10,245 (9.1%) of patients treated with new anticoagulants (rivaroxaban, apixaban, dabigatran) and 1,223/10,276 (11.9%) treated with enoxaparin, favoring new anticoagulants (RR 0.71; 95% CI 0.56-0.90).

In patients receiving anticoagulation after hip arthroplasty, the benefit of new anticoagulants (28-39 days) was significant (RR 0.55; 95% CI 0.32-0.95). In patients who underwent knee arthroplasty (new anticoagulants for 6-14 days), the risk ratio was only slightly reduced (RR 0.80; 95% CI 0.61-1.06).

Significant heterogeneity was analyzed among trials and subgroups (Chi square test, p<0.001). (pp. 186-189)

Recommendations for Practice: Rivaroxaban, apixaban, and dabigatran showed more efficacies when compared to enoxaparin after total hip and knee replacement.

Strengths & Limitations Strengths: 10 phase III RCTs included in meta-analysis

Limitations: Mandatory bilateral venographies 24 hours after last anticoagulant dose were required, however relevant proportion of patients had venographs that were no evaluable or either did not undergo venography (26% to 35% in rivaroxaban group); 2 of the researchers in the study received fees from Bayer, the manufacturer of rivaroxaban. 1 research was an investigator in trials sponsored by Bayer creating conflicts of interest.

Level of Evidence Level I, Rating System for the Hierarchy of Evidence for Intervention/Treatment Questions (Melnyk & Fineout-Overholt, 2011)

Legend


ABBREVIATION DEFINITION

BID Two times daily

BMI Body Mass Index

CI Confidence Interval

DVT Deep Vein Thrombosis

LMWH Low Molecular Weight Heparin

OR Odds Ratio

PO Oral

RCT Randomized Controlled Trial

RR Relative Risk

SAS Statistical Analysis System

SC Subcutaneously

VTE Venous thromboembolism

Appendix C

Figure 2. Levels of Evidence

Rating system for the Hierarchy of Evidence for Intervention/Treatment QuestionsLevel I Evidence from a systematic review or meta

analysis of all relevant RCTs.Level II Evidence obtained from well-designed

RCTs.Level III Evidence obtained from well-designed

controlled trials without randomization.Level IV Evidence from well-designed case control

and cohort studies.Level V Evidence from systematic reviews of

descriptive and qualitative studiesLevel VI Evidence from single descriptive or

qualitative studies.


Level VII Evidence from the opinion of authorities and/or reports of expert committees.

From Melnyk, B.M., & Fineout-Overholt, E. (2011). Evidence-based practice in nursing and

healthcare: A guide to best practice (6 ed.). Philadelphia: Lippincott Williams &

Wilkins.

Appendix D

Figure 1. Search Strategy

Inclusion: within

10 years, human,

English, ages 19-65

"Arthroplasty, Replacement, Knee+" OR "Arthoplasty,

Replacement, Hip+"

Cinahl: 2324 PublicationsPubMed: 12892 Publications

3 Duplicates; 27 Publications Remain

11 studies included

16 articles excluded: 8 did not include both

enoxaparin and rivaroxaban5 not related to VTE

prevention1 looked at

thromboprophylaxis on wound healing

1 did not include pharmacological

prophylaxis1 on cost effectiveness

...AND "Rivaroxaban" AND "Enoxaparin"

Cinahl: 4 PublicationsPubMed: 26 Publications

Running head: PREVENTION OF VENOUS THROMBOEMBOLISMS 28

BRUCEFINAL2

Documents

prevention of vte

knee replacement patients

knee replacement total

hip replacement surgery

knee replacement molly

total knee replacements

total hip replacements

effectiveness of rivaroxaban