Rivaroxaban and Apixaban for DVTVTE Prophylaxis

Home , Apixaban, Rivaroxaban

DATE: September 2016 OREGON HEALTH AND SCIENCE UNIVERSITY OFFICE OF CLINICAL INTEGRATION AND EVIDENCE-BASED PRACTICE Evidence-Based Practice Summary Rivaroxaban and Apixaban for DVT/VTE Prophylaxis

Prepared for: Stephanie Halvorson, MD Authors: Tovah Kohl, MA

BACKGROUND

Total hip (THA) and total knee arthroplasty (TKA) are two of the most commonly performed operations in orthopedic surgery. The most common serious complication after THA and TKA is venous thromboembolism (VTE). Without efficacious anticoagulant prophylaxis, symptomatic deep venous thrombosis (DVT) may occur in 15%–30% and fatal pulmonary embolism may occur in 0.5%–2% of the patients undergoing THAs or TKAs. With modern surgical techniques and methods of preventing VTE including earlier mobilization and chemoprophylaxis, the rate of VTE has decreased over time. Currently in the United States, any VTE after THA and TKA is considered a preventable complication. Developing a VTE prophylaxis regimen with optimal efficacy and safety profiles is essential. However, the use of potent anticoagulation has been associated with higher rates of complications, such a bleeding. The most commonly used chemoprophylaxis after THAs and TKAs include low-molecular-weight heparin (LMWH), adjusted-dose warfarin, enoxaparin, and aspirin. However, due to the limitations of these drugs, new oral anticoagulants have been developed. Rivaroxaban and apixaban are both direct factor Xa (FXa) inhibitors. Rivaroxaban and Apixaban are currently approved in the United States for VTE prophylaxis after THAs and TKAs (Russell 2012). ASK THE QUESTION

Question 1: In patients who have undergone total hip arthroplasty (THA) or total knee arthroplasty (TKA) does a prophylactic oral anticoagulant (rivaroxaban and apixaban) post-operatively prevent deep vein thrombosis (DVT)/ pulmonary embolism (PE)?

DATE: September 2016

SEARCH FOR EVIDENCE

Databases included Ovid MEDLINE, Cochrane Database of Systematic Reviews, PsycINFO, and National Guideline Clearinghouse, also looked at references and citing articles

Search strategy included: 1 exp arthroplasty, replacement, hip/ or exp hip prosthesis/ or exp arthroplasty, replacement, knee/ or exp knee prosthesis/ (53884) 2 exp Anticoagulants/ad, ae, ct, tu, to [Administration & Dosage, Adverse Effects, Contraindications, Therapeutic Use, Toxicity] (88894) 3 exp Blood Coagulation Factors/ai (14279) 4 2 or 3 (101886) 5 exp Thrombosis/pc [Prevention & Control] (17816) 6 exp Pulmonary Embolism/pc [Prevention & Control] (4687) 7 exp "embolism and thrombosis"/ (203421) 8 exp Preventive Health Services/ (519938) 9 7 and 8 (2306) 10 5 or 6 or 9 (22223) 11 1 and 4 and 10 (787) 12 ((rivaroxaban or aspirin or lovenox or warfarin or anti-coag* or anticoag* or ((factor or coagulat*) adj2 (inhibit* or block or antagon*))) adj10 (prevent* or prophyla*) adj5 (embol* or thrombo* or clot or clots)).mp. [mp=title, abstract, original title, name of substance word, subject heading word, keyword heading word, protocol supplementary concept word, rare disease supplementary concept word, unique identifier, synonyms] (3926) 13 1 and 12 (269) 14 ((thromboprophyl* or ((prevent* or prophyla*) adj5 (embol* or thrombo* or clot or clots))) adj10 ((hip or hips or knee* or joint* or arthroplas*) adj3 replac*)).mp. (610) 15 4 and 14 (484) 16 ((rivaroxaban or aspirin or lovenox or warfarin or anti-coag* or anticoag* or ((factor or coagulat*) adj2 (inhibit* or block or antagon*))) adj10 ((hip or hips or knee* or joint* or arthroplas*) adj3 replac*)).mp. [mp=title, abstract, original title, name of substance word, subject heading word, keyword heading word, protocol supplementary concept word, rare disease supplementary concept word, unique identifier, synonyms] (1093) 17 10 and 16 (537)

DATE: September 2016 18 12 and 14 and 16 (100) 19 11 or 13 or 15 or 17 or 18 (1219) 20 remove duplicates from 19 (1194) 21 limit 20 to english language (1066) 22 limit 20 to abstracts (988) 23 21 or 22 (1164) 24 limit 23 to (comparative study or controlled clinical trial or guideline or meta analysis or randomized controlled trial or systematic reviews) (504) 25 exp Epidemiologic Studies/ (2091730) 26 23 and 25 (346) 27 24 or 26 (664) 28 23 not 27 (500)

Filters/limits included systematic reviews published in English in the last 3 years.

CRITICALLY ANALYZE THE EVIDENCE

The literature search resulted in more than 600 articles that analyzed oral anticoagulants (DOACs) after THA and TKA. We narrowed the search to include systematic reviews and relevant observational studies from 2013-2017. We identified nine studies that analyzed the effects of prophylactic DOACs in the prevention of VTE/DVT and included the outcome of major bleeding. In order to simplify the review process, we grouped the evidence into DOAC with outcomes: (1) VTE/DVT Prophylaxis with Rivaroxaban; (2) Major Bleeding with Rivaroxaban Use; (3) VTE/DVT Prophylaxis with Apixaban; (4) Major Bleeding with Apixaban Use; (5) Pooled Studies that included Rivaroxaban and/or Apixaban for DVT/VTE Prophylaxis, and (6) Pooled Studies of Major Bleeding with Rivaroxaban and/or Apixaban use:

1. VTE/DVT Prophylaxis with Rivaroxaban: Five studies, including four systematic reviews and one observational study, examined rivaroxaban use for VTE/DVT prophylaxis. One study compared rivaroxaban with apixaban and found that rivaroxaban use was associated with 4 fewer VTEs than apixaban (95% CI 9 fewer to 1 more) per 1000 patients (RR, 0.59 [95% CI 0.26-1.33]) (Adam 2013). Feng (2015) conducted a systematic review to analyze the efficacy of factor Xa inhibitors for thomboprophylaxis and demonstrated a lower occurrence of total VTE when the intervention drug was rivaroxaban (RR 0.70, 95%CI 0.60 to 0.81). An observational study observed the circulating concentrations of rivaroxaban and apixaban in patients to improve the knowledge of coagulation with these drugs (Freyburger 2015). The samples from T1 to T4 exhibiting rivaroxaban plasma concentrations higher

DATE: September 2016 than 100 ng/ml testified to a mean antithrombin increase of 24% when compared to the pretreatment T0 samples (P = 0.007), whereas the 39 samples exhibiting apixaban plasma concentrations higher than 100 ng/ml demonstrated a mean antithrombin increase of 18% (P = 0.007 and 0.0002, respectively). Hamidi (2013) conducted a systematic review to assess the efficacy of rivaroxaban relative to enoxaparin. There was a statistically significant decrease in DVTs compared to enoxaparin in THA and TKAs (RR 0.21 [95%CI 0.14-0.32] and RR 0.62 [95%CI 0.51-0.75], respectively). Ma (2015) also conducted a systematic review to compare rivaroxaban with enoxaparin in total knee replacements. Their findings were similar and found a statistically significant decrease in DVTs with rivaroxaban use (RR = 0.59 [95% CI: 0.48-0.72, P< 0.01]). Overall Level of Evidence: Moderate

2. Major Bleeding with Rivaroxaban Use: Five studies, including four systematic reviews and one retrospective cohort study, examined the risk of major bleeding with rivaroxaban use for VTE/DVT prophylaxis. The first systematic review (Adam 2013) compared the risk and benefits of DOACs versus standard prophylaxis. Their review found that rivaroxaban resulted in more clinically relevant bleeding events than apixaban (RR, 1.52 [CI, 1.19 to 1.95]), and the risk for major bleeding was also increased with rivaroxaban compared with apixaban (RR, 1.59 [CI, 0.84 to 3.02]). Feng (2015) conducted a systematic review to analyze the efficacy of factor Xa inhibitors for thomboprophylaxis and found a higher occurrence of bleeding complications when the intervention drug was rivaroxaban (RR 1.52, 1.14 to 2.02, P=0.004; Q=34.80, P=0.041; I2=36.8%). When reviewing the relationship between rivaroxaban dosing and a complication rate they found for rivaroxaban, there was a linear relationship between the treatment dose of rivaroxaban and the bleeding complication rate (RR:1.031, 1.018 to 1.044, P = 0.000). Higher rivaroxaban doses were associated with more major bleeding or clinically relevant non-major bleeding. A 5 mg increase of treatment dose was associated with a 13% increase of bleeding risk (RR: 1.168, 1.098 to 1.243, P =0.000). Hamidi (2013) conducted a systematic review to assess the efficacy of rivaroxaban relative to enoxaparin. There was a statistically significant increased risk of major bleeding with rivaroxaban compared to enoxaparin in THAs and TKAs (RR 2.23 [95%CI 1.06-4.67] and RR 1.61 [95%CI 0.80-3.24], respectively). A retrospective cohort study (Ricket 2016) evaluated the bleeding events between patients who received enoxaparin or rivaroxaban for prevention of venous thromboembolism (VTE) following total hip arthroplasty (THA) or total knee arthroplasty (TKA). Postoperative bleeding, defined in this study as a composite of major bleeding and clinically relevant non-major bleeding, was lower in the enoxaparin group compared to the rivaroxaban group (2.2% vs 6.3%, P < 0.01). In another systematic review, Russell et al (2013) analyzed the data from the new oral direct Factor Xa inhibitors including rivaroxaban for VTE and DVT prophylaxis. They found a trend for an increased risk of major bleeding in patients taking rivaroxaban (OR 1.81, 95% CI 0.91–3.62, p =0.09). Overall Level of Evidence: Moderate

DATE: September 2016 3. VTE/DVT Prophylaxis with Apixaban: Four studies, including three systematic reviews and one observational study, examined apixaban use for VTE/DVT prophylaxis.The first systematic review (Adam 2013) compared rivaroxaban with apixaban and found that rivaroxaban was associated with 4 fewer VTEs than apixaban (95% CI 9 fewer to 1 more) per 1000 patients (RR, 0.59 [95% CI 0.26-1.33]). Feng (2015) conducted a systematic review to analyze the efficacy of factor Xa inhibitors for thomboprophylaxis and demonstrated a lower occurrence of total VTE when the intervention drug was apixaban (RR 0.62, 0.47 to 0.81, P=0.001) compared to enoxaparin. An observational study observed the circulating concentrations of rivaroxaban and apixaban in patients to improve the knowledge of coagulation with these drugs (Freyburger 2015). The samples from T1 to T4 exhibiting rivaroxaban plasma concentrations higher than 100 ng/ml testified to a mean antithrombin increase of 24% when compared to the pretreatment T0 samples (P = 0.007), whereas the 39 samples exhibiting apixaban plasma concentrations higher than 100 ng/ml demonstrated a mean antithrombin increase of 18% (P = 0.007 and 0.0002, respectively). Ma (2015) also conducted a systematic review to compare apixaban with enoxaparin in total knee replacements. The subgroup analysis of apixaban studies found that apixaban lowered the risk of DVTs compared to enoxaparin (RR = 0.68, 95% CI: 0.59-0.79, P < 0.01). However, further analysis stratified by the regimen of enoxaparin did not find a significant difference between apixaban and 30 mg b.i.d dose of enoxaparin (RR = 0.85, 95% CI: 0.66-1.10, P < 0.01). Overall Level of Evidence: Moderate

4. Major Bleeding with Apixaban Use: Two systematic reviews examined the risk of major bleeding with apixaban use for VTE/DVT prophylaxis.Feng (2015) conducted a systematic review to analyze the efficacy of factor Xa inhibitors for thomboprophylaxis and did not find a higher occurrence of bleeding complications when the intervention drug was apixaban (RR 0.88, 0.73 to 1.06). For apixaban, major bleeding did not show linear relationship with the treatment dose (RR: 1.027, 0.968 to 1.090) nor a nonlinear relationship (RR at 50% percentile: 1.032, 0.871 to 1.223). In another systematic review, Russell et al (2013) analyzed the data from the new oral direct Factor Xa inhibitors including rivaroxaban for VTE and DVT prophylaxis. There was a trend for an increased risk of major bleeding in patients taking rivaroxaban (OR 1.81, 95% CI 0.91–3.62, p =0.09), but not with apixaban (p = 0.33). There was no difference between the oral FXa inhibitors and enoxaparinin the rates of major plus clinically relevant non- major bleeding (p = 0.91). However, there was a trend toward fewer events in the patients taking apixaban (OR 0.8, 95% CI 0.64–1.01, p = 0.06). Overall Level of Evidence: Moderate 5. Pooled Studies that included Rivaroxaban and/or Apixaban for DVT/VTE Prophylaxis: Three systematic reviews combined the results of multiple DOACs to assess their effectiveness for VTE/DVT prophylaxis. One systematic review (Forster 2016) assessed the effects of extended-duration anticoagulant thromboprophylaxis for the prevention of VTE in people undergoing elective THA or TKA by pooling multiple studies that investigated various Direct Oral Anticoagulants (DOACs). For symptomatic VTEs compared to placebo, DOACs decreased odds of a symptomatic VTE (OR 0.20 [95% CI 0.06-0.68]). DOACs did not © Office of Clinical Integration and EBP, 2016 5 Oregon Health and Science University

DATE: September 2016 significantly decrease the odds of symptomatic VTEs compared to heparin (OR 0.70 [95% CI 0.28-1.70]). Another systematic review (Russell 2013) analyzed the data from the new oral direct Factor Xa inhibitors for VTE and DVT prophylaxis. The pooled analysis revealed that Factor Xa inhibitors decreased the odds for total VTE and death as well as DVT (OR 0.38 [95%CI 0.23– 0.61] p < 0.0001 and OR 0.36 [95% CI 0.2–0.62] p= 0.0003, respectively). The third systematic (Squizzato 2015) review sought to determine the incidence of post-operative arterial thrombosis is patients treated with DOACs and heparin undergoing TKA and THA. The combined data from THR and TKR studies, showed that DOACs and enoxaparin were associated with similar risks for both total arterial thrombosis (OR 0.86 [95 %CI, 0.53-1.40] I²=11), and major vascular events (OR 0.97 [95 %CI, 0.69-1.36] I²=0). 6. Pooled Studies of Major Bleeding with Rivaroxaban and/or Apixaban use: Three systematic reviews combined the results of multiple DOACs to assess their risk of major bleeding. One systematic review (Forster 2016) assessed the effects of extended- duration anticoagulant thromboprophylaxis for the prevention of VTE in people undergoing elective THA or TKA by pooling multiple studies that investigated various DOACs. There were no major differences in major bleeding between DOACs and placebo (OR 1.00 [95% CI 0.06-16.02]) or clinically relevant bleeding (OR 1.22 [95% CI 0.76-1.95]). Ma (2015) also conducted a systematic review to compare rivaroxaban with enoxaparin in total knee replacements. The pooled analysis revealed no major difference between rivaroxaban/apixaban and enoxaparin in terms of risk of major bleeding (RR 0.72 [95% CI: 0.44-1.17]). A third systematic review (Squizzato 2015) sought to determine the incidence of post-operative arterial thrombosis is patients treated with DOAC and heparin undergoing TKA and THA. DOACs and enoxaparin were similar at the fixed-effect model in the risk of major bleeding plus clinically relevant bleeding (OR 1.03; 95 %CI, 0.92, 1.15; I²=38).

Conclusion: Overall, there is moderate quality evidence to show that prophylactic use of both apixaban and rivaroxaban decreases the risk of DVT after a TKA or THA. There is moderate quality evidence that suggests a minor increased risk of major bleeding with the use of rivaroxaban, but not with apixaban.

PICO Question: In patients who have undergone total hip arthroplasty (THA) or total knee arthroplasty (TKA) does a prophylactic direct oral Lower Quality Rating anticoagulant (rivaroxaban and apixaban) post-operatively) prevent deep vein thrombosis (DVT)/ pulmonary embolism (PE)? if: Outcome: VTE/ DVT Prophylaxis Studies inconsistent Modality: Rivaroxaban (wide variation of treatment effect across Author/Date Purpose Study Design & Sample Outcomes Design Limitations studies, populations, of Study Methods interventions, or Total # of Studies: 8 # of Systematic Reviews: 7 # of Non-Randomized Studies: 1 outcomes varied)

Adam, S. S., et al. To compare Systematic review with meta- 16 studies, 38, 747 Rivaroxaban vs dabigatran Study Limitations = Studies are indirect None (2013). Annals of the benefits analysis participants RR, 0.68 (95% CI 0.21-2.23) (PICO question is quite and risks of RD, 3 fewer ( 11 fewer to 4 more) events Systematic Review Review did not address different from the © Office of Clinical Integration and EBP, 2016 6 Oregon Health and Science University

DATE: September 2016 Internal Medicine new oral per 1000 pts focused clinical question available evidence in anticoagulants Search was not detailed or regard to population, (NOACs) vs Rivaroxaban vs apixaban exhaustive intervention, Quality of the studies was not standard RR, 0.59 (95% CI 0.26-1.33) comparison, or RD, 4 fewer ( 9 fewer to 1 more)per 1000 appraised or studies were of low thromboproph quality outcome) ylaxis. pts Methods and/or results were inconsistent across studies Studies are imprecise (When studies include few patients and Feng, W., et al. To analyze Systemic review, traditional meta- 7 studies, 5429 Lower occurrence of total VTE was shown Study Limitations = few events and thus (2015). the efficacy analysis, dose-response meta- participants when the intervention drug was None have wide confidence Thrombosis and safety of analysis and network meta-analysis rivaroxaban (RR 0.70, 0.60 to 0.81, Systematic Review intervals and the results Review did not address Research direct factor P=0.000; P=0.035; I2=37.4%) are uncertain) focused clinical question Xa inhibitors Search was not detailed or for exhaustive Publication Bias thromboproph Quality of the studies was not (e.g. pharmaceutical ylaxis after appraised or studies were of low company sponsors study total hip or quality on effectiveness of drug, knee Methods and/or results were only small, positive inconsistent across studies replacement. studies found)

To delineate the dose Increase Quality Rating response if: effect of Large Effect direct factor Dose-response Xa inhibitors. gradient To compare Plausible the efficacy confounders or other between any biases increase certainty two direct of effect factor Xa inhibitors. Quality (certainty) of evidence for studies as a Forster, R. and M. To assess the Systematic review with meta- 4 studies, 9639 DOAC vs placebo: Study Limitations = whole: Stewart (2016). effects of analysis participants (DOACs Symptomatic VTE: OR 0.20 (95% CI 0.06- None High Cochrane extended- investigated included 0.68) Systematic Review Moderate Review did not address Database of duration rivaroxaban) Low DOAC vs heparin: focused clinical question Systematic anticoagulant Search was not detailed or Very Low Reviews thromboproph Symptomatic VTE: OR 0.70 (95%CI 0.28-1.70) exhaustive ylaxis for the Quality of the studies was not prevention of appraised or studies were of low venous quality thromboembo Methods and/or results were inconsistent across studies © Office of Clinical Integration and EBP, 2016 7 Oregon Health and Science University

DATE: September 2016 lism (VTE) in people undergoing elective hip or knee replacement surgery or hip fracture repair.

Freyburger, G., et The aim of observational, nonrandomized, one- 102 patients ( 51 After 1 week of treatment, the drugs Study Limitations = al. (2015). Blood this study was period comparison study on behalf received rivaroxaban differed: Cmax and Ctrough were closer None Coagulation & to improve of the Committee for Health and 51 received when apixaban was taken twice daily Non-Randomized Studies Fibrinolysis knowledge of Products and Therapeutic Innovation apixaban) (83 ± 39 and 58 ± 17 ng/ml) than with Failure to develop and apply what happens of the University Hospital of rivaroxaban taken once a day (113 ± 67 and appropriate eligibility criteria in the Bordeaux 13 ± 20 ng/ml). Flawed measurement of both coagulation of exposure and outcome orthopaedic The 53 samples from T1 to T4 exhibiting Failure to adequately control patients under rivaroxaban plasma concentrations higher confounding rivaroxaban than 100 ng/ml testify to a mean Incomplete or inadequately and apixaban, antithrombin increase of 24% when short follow-up in order to compared to the 51 pretreatment T0 Differences in important finalize and samples (P = 0.007), whereas the 39 prognostic factors at baseline cross-validate samples exhibiting apixaban plasma effective concentrations higher than 100 ng/ml measurement demonstrate a mean antithrombin increase methods and of 18% (P = 0.007 and 0.0002, respectively) to provide arguments for Although rivaroxaban and apixaban present helping to apparently similar constant rates, they reference one exhibit significant differences in their or the other concentrations and anticoagulant effects drug. when studied ex vivo in orthopedic patients. Hamidi, V., et al. To assess the Systematic Review with meta- 5 studies, 8878 DVT-Total Hip replacement: Study Limitations = (2013). relative analysis participants RR 0.21 (95%CI 0.14-0.32) None International efficacy and Systematic Review Journal of cost- DVT-Total knee replacement: Review did not address Technology effectiveness RR 0.62 (95%CI 0.51-0.75) focused clinical question Assessment in of two new Search was not detailed or Health Care oral exhaustive anticoagulants Quality of the studies was not , rivaroxaban appraised or studies were of low and quality dabigatran, Methods and/or results were relative to inconsistent across studies subcutaneous enoxaparin

DATE: September 2016 for the prevention of thromboembo lism after total hip replacement (THR) and total knee replacement surgery (TKR) Ma, G., et al. To compare Systematic Review 2 studies, 5679 DVT: Study Limitations = (2015). the efficacy participants RR = 0.59 (95% CI: 0.48-0.72, None Thrombosis and P< 0.01; P heterogeneity = 0.17, I2=47%) Systematic Review Research safety of Review did not address direct factor focused clinical question Xa inhibitors Search was not detailed or (rivaroxaban exhaustive and apixaban) Quality of the studies was not with appraised or studies were of low enoxaparin quality for the Methods and/or results were prevention of inconsistent across studies venous thromboembo lism (VTE) after total knee replacement. Russell, R. D. and To analyze Systematic Review 4 studies, 12,726 VTE + death Study Limitations = M. H. Huo (2013). data from all patients OR 0.38 ( 95%CI 0.23–0.61) p < 0.0001 None Journal of of the phase DVT Systematic Review Arthroplasty III clinical OR 0.36 ( 95% CI 0.2–0.62) p= 0.0003 Review did not address trials for both focused clinical question newer oral Search was not detailed or direct FXa exhaustive inhibitors for Quality of the studies was not VTE appraised or studies were of low prophylaxis in quality patients Methods and/or results were undergoing inconsistent across studies THAs and TKAs Squizzato, A., et the aim of Systematic Review 4 studies, 12,726 THR Study Limitations = al. (2015). determining: patients NOACs and enoxaparin were similar at the None Thrombosis & 1) the fixed-effect model in Systematic Review Haemostasis incidence of the risk of pulmonary embolism (OR 0.94; Review did not address postoperative 95 %CI, 0.47,1.85; focused clinical question arterial I²=23), major vascular events (OR 0.97; 95 Search was not detailed or thrombosis %CI, 0.61,1.55; I²=0) exhaustive © Office of Clinical Integration and EBP, 2016 9 Oregon Health and Science University

DATE: September 2016 (AT) in Quality of the studies was not NOACs- TKR arterial thrombosis: appraised or studies were of low treated and NOACs and enoxaparin were similar at the quality LMWH- fixed-effect model in Methods and/or results were treated the risk of pulmonary embolism (OR 1.27; inconsistent across studies patients 95 %CI, 0.76, 2.11; undergoing I²=40), major vascular events (OR 1.06; 95 elective TKR %CI, 0.66, 1.71; I²=51), or THR during active The combined data from THR and TKR treatment and studies, NOACs and during enoxaparin were similar at fixed-effect follow-up;2) model in the risk of major the incidence efficacy and safety outcomes, in particular of patient- in the risk of total arterial relevant thrombosis (OR 0.86; 95 %CI, 0.53, 1.40; outcomes (i. I²=11), major vascular e. events (OR 0.97; 95 %CI, 0.69, 1.36; I²=0) prevention of major symptomatic thrombotic events and/or total mortality with minimal risk of major bleeding) with NOACs compared with standard therapy. The GRADE criteria were used to evaluate the quality of evidence presented in research articles reviewed during the development of this guideline. For more detailed information, see Appendix A.

PICO Question: In patients who have undergone total hip arthroplasty (THA) or total knee arthroplasty (TKA) does a prophylactic direct Lower Quality Rating if: oral anticoagulant (rivaroxaban and apixaban) post-operatively) prevent deep vein thrombosis (DVT)/ pulmonary embolism (PE)? Studies inconsistent Outcome: Major Bleeding (wide variation of treatment Modality: Rivaroxaban effect across studies, populations, interventions, Author/Date Purpose Study Design & Sample Outcomes Design Limitations or outcomes varied) of Study Methods Total # of Studies: 8 # of Systematic Reviews: 7 # of Non-Randomized Studies: 1 Studies are indirect (PICO question is quite Adam, S. S., et al. To compare Systematic review with meta- 16 studies, 38, 747 Rivaroxaban resulted in more clinically Study Limitations = different from the available None (2013). Annals of the benefits analysis participants relevant bleeding events than apixaban evidence in regard to and risks of (RR, 1.52 [CI, 1.19 co 1.95]). Systematic Review Review did not address population, intervention, © Office of Clinical Integration and EBP, 2016 10 Oregon Health and Science University

DATE: September 2016 Internal Medicine new oral focused clinical question comparison, or outcome) anticoagulants Risk for major bleeding was also increased Search was not detailed (NOACs) vs with rivaroxaban compared with apixaban or exhaustive Studies are imprecise Quality of the studies standard (RR, 1.59 [CI, 0.84 to 3.02]) (When studies include few was not appraised or studies thromboproph were of low quality patients and few events and ylaxis. Methods and/or results thus have wide confidence were inconsistent across intervals and the results are studies uncertain)

Publication Bias Feng, W., et al. To analyze Systemic review, traditional meta- 7 studies, 5429 Higher occurrence of bleeding Study Limitations = (e.g. pharmaceutical (2015). the efficacy analysis, dose-response meta- participants complication was shown when None company sponsors study on the intervention drug was rivaroxaban (RR Systematic Review Thrombosis and safety of analysis and network meta-analysis effectiveness of drug, only 1.52, 1.14 to 2.02, P = Review did not address Research direct factor small, positive studies found) 0.004; Q=34.80, P=0.041; I2=36.8%) focused clinical question Xa inhibitors Search was not detailed for For rivaroxaban, there was a linear or exhaustive Increase Quality Rating if: thromboproph relationship between the treatment Quality of the studies Large Effect ylaxis after dose of rivaroxaban and the bleeding was not appraised or studies Dose-response gradient total hip or complication rate (RR: were of low quality Plausible confounders or knee 1.031, 1.018 to 1.044, P = 0.000). Higher Methods and/or results were inconsistent across other biases increase replacement. rivaroxaban doses studies certainty of effect To delineate were associated with more major bleeding or clinically relevant but the dose non-major bleeding. A 5 mg increase of Quality (certainty) of response treatment dose was associated evidence for studies as a effect of with a 13% increase of bleeding risk (RR: whole: direct factor 1.168, 1.098 to 1.243, P = High Xa inhibitors. 0.000). Moderate To compare Low the efficacy Very Low between any two direct factor Xa inhibitors.

Forster, R. and M. To assess the Systematic review with meta- 4 studies, 9639 DOAC vs placebo: Study Limitations = Stewart (2016). effects of analysis participants (DOACs Major Bleeding: OR 1.00 (95% CI 0.06- None Cochrane extended- investigated included 16.02) Systematic Review Review did not address Database of duration rivaroxaban) Clinically relevant bleeding: OR 1.22 (95% focused clinical question Systematic anticoagulant CI 0.76-1.95) Search was not detailed Reviews thromboproph or exhaustive ylaxis for the Quality of the studies prevention of was not appraised or studies venous were of low quality thromboembo Methods and/or results © Office of Clinical Integration and EBP, 2016 11 Oregon Health and Science University

DATE: September 2016 lism (VTE) in were inconsistent across people studies undergoing elective hip or knee replacement surgery or hip fracture repair.

Hamidi, V., et al. To assess the Systematic Review with meta- 5 studies, 8878 Major Bleeding-Total Hip replacement: Study Limitations = (2013). relative analysis participants RR 2.23 (95%CI 1.06-4.67) None International efficacy and Systematic Review Journal of cost- Major Bleeding-Total knee replacement: Review did not address Technology effectiveness RR 1.61 (95%CI 0.80-3.24) focused clinical question Assessment in of two new Search was not detailed Health Care oral or exhaustive anticoagulants Quality of the studies , rivaroxaban was not appraised or studies and were of low quality dabigatran, Methods and/or results relative to were inconsistent across subcutaneous studies enoxaparin for the prevention of thromboembo lism after total hip replacement (THR) and total knee replacement surgery (TKR) Ma, G., et al. To compare Systematic Review 2 studies, 5679 Major Bleeding: Study Limitations = (2015). the efficacy participants Pooled RR( rivaroxaban/ apixaban) = 0.72 None Thrombosis and (95% CI: 0.44-1.17, Systematic Review Research safety of Review did not address direct factor focused clinical question Xa inhibitors Search was not detailed (rivaroxaban or exhaustive and apixaban) Quality of the studies with was not appraised or studies enoxaparin were of low quality for the Methods and/or results prevention of were inconsistent across venous studies

DATE: September 2016 thromboembo lism (VTE) after total knee replacement. Ricket, A. L., et al. To evaluate Retrospective cohort study 3 cohorts, 878 Major bleeding Study Limitations = (2016). Annals of bleeding participants Any postoperative bleeding, defined in this None Pharmacotherapy events study as a composite of major bleeding and Non-Randomized Studies between clinically relevant non-major Failure to develop and patients who bleeding, was lower in the enoxaparin apply appropriate eligibility received group compared to the rivaroxaban group criteria enoxaparin or (2.2% vs 6.3%, P < 0.01). Flawed measurement of rivaroxaban both exposure and outcome for prevention Failure to adequately of venous control confounding thromboembo Incomplete or lism (VTE) inadequately short follow-up following Differences in important total hip prognostic factors at arthroplasty baseline (THA) or total knee arthroplasty (TKA). Russell, R. D. and To analyze Systematic Review 4 studies, 12,726 There was a trend for an increased risk of Study Limitations = M. H. Huo (2013). data from all patients major bleeding None Journal of of the phase in patients taking rivaroxaban (OR 1.81, Systematic Review Arthroplasty III clinical 95% CI 0.91–3.62, p =0.09) Review did not address trials for both focused clinical question newer oral Search was not detailed direct FXa or exhaustive inhibitors for Quality of the studies VTE was not appraised or studies prophylaxis in were of low quality patients Methods and/or results undergoing were inconsistent across THAs and studies TKAs Squizzato, A., et the aim of Systematic Review 4 studies, 12,726 NOACs and enoxaparin were similar at the Study Limitations = al. (2015). determining: patients fixed-effect model in None Thrombosis & 1) the the risk of major bleeding + clinically Systematic Review Haemostasis incidence of relevant bleeding (OR 1.03; 95 %CI, 0.92, Review did not address postoperative 1.15; I²=38) focused clinical question arterial Search was not detailed thrombosis or exhaustive (AT) in Quality of the studies NOACs- was not appraised or studies treated and were of low quality LMWH- Methods and/or results treated were inconsistent across © Office of Clinical Integration and EBP, 2016 13 Oregon Health and Science University

DATE: September 2016 patients studies undergoing elective TKR or THR during active treatment and during follow-up;2) the incidence of patient- relevant outcomes (i. e. prevention of major symptomatic thrombotic events and/or total mortality with minimal risk of major bleeding) with NOACs compared with standard therapy.

The GRADE criteria were used to evaluate the quality of evidence presented in research articles reviewed during the development of this guideline. For more detailed information, see Appendix A.

PICO Question: In patients who have undergone total hip arthroplasty (THA) or total knee arthroplasty (TKA) does a prophylactic direct oral Lower Quality Rating anticoagulant (rivaroxaban and apixaban) post-operatively) prevent deep vein thrombosis (DVT)/ pulmonary embolism (PE)? if: Outcome: VTE/ DVT Prophylaxis Studies inconsistent Modality: Apixaban (wide variation of treatment effect across Author/Dat Purpose Study Design & Sample Outcomes Design Limitations studies, populations, e of Study Methods interventions, or Total # of Studies: 7# of Systematic Reviews: 6 # of Non-Randomized Studies: 1 outcomes varied)

Adam, S. S., et To compare the Systematic review with meta- 16 studies, 38, 747 Rivaroxaban vs apixaban Study Limitations = Studies are indirect None al. (2013). benefits and analysis participants RR, 0.59 (95% CI 0.26-1.33) (PICO question is quite RD, 4 fewer ( 9 fewer to 1 more)per 1000 Systematic Review Annals of risks of new different from the pts Review did not address Internal oral available evidence in focused clinical question Medicine anticoagulants Search was not detailed or regard to population, (NOACs) vs Apixaban vs. dabigatran RR, 1.16 (0.31-4.28) exhaustive intervention, © Office of Clinical Integration and EBP, 2016 14 Oregon Health and Science University

DATE: September 2016 standard RD 1 more (7 fewer to 8 more) per 1000 Quality of the studies was not comparison, or thromboprophyl pts appraised or studies were of low outcome) axis. quality Methods and/or results were Studies are inconsistent across studies imprecise (When studies include few patients and Feng, W., et al. To analyze the Systemic review, traditional meta- 7 studies, 5429 Lower occurrence of total VTE was shown Study Limitations = few events and thus (2015). efficacy and analysis, dose-response meta- participants when the intervention drug was apixaban None have wide confidence Thrombosis safety of direct analysis and network meta-analysis (RR 0.62, 0.47 to 0.81, P=0.001; Q=20.88, Systematic Review intervals and the results Review did not address Research factor Xa P=0.007; I2=61.7%) compared to are uncertain) focused clinical question inhibitors for enoxaparin. Search was not detailed or Publication Bias thromboprophyl exhaustive (e.g. pharmaceutical axis after total Quality of the studies was not hip or knee appraised or studies were of low company sponsors study replacement. To quality on effectiveness of drug, delineate the Methods and/or results were only small, positive inconsistent across studies dose response studies found)

effect of direct factor Xa Increase Quality Rating inhibitors. To if: compare the Large Effect efficacy Dose-response between any gradient two direct Plausible factor Xa confounders or other inhibitors. biases increase certainty of effect Forster, R. and To assess the Systematic review with meta- 4 studies, 9639 Study Limitations = M. Stewart effects of analysis participants (DOACs DOAC vs heparin: None Quality (certainty) of (2016). extended- investigated included Symptomatic VTE: OR 0.70 Systematic Review evidence for studies as a Review did not address Cochrane duration apixaban) (95%CI 0.28-1.70) whole: focused clinical question Database of anticoagulant High Search was not detailed or Moderate Systematic thromboprophyl exhaustive Low Reviews axis for the Quality of the studies was not prevention of appraised or studies were of low Very Low venous quality thromboemboli Methods and/or results were inconsistent across studies sm (VTE) in

people undergoing elective hip or knee replacement

DATE: September 2016 surgery or hip fracture repair.

Freyburger, G., The aim of this observational, nonrandomized, one- 102 patients ( 51 received After 1 week of treatment, the drugs Study Limitations = et al. (2015). study was to period comparison study on behalf rivaroxaban and 51 differed: Cmax and Ctrough were closer None Blood improve of the Committee for Health received apixaban) when apixaban was taken twice daily Non-Randomized Studies Coagulation & knowledge of Products and Therapeutic Innovation (83 ± 39 and 58 ± 17 ng/ml) than with Failure to develop and apply Fibrinolysis what happens in of the University Hospital of rivaroxaban taken once a day (113 ± 67 and appropriate eligibility criteria the coagulation Bordeaux 13 ± 20 ng/ml). Flawed measurement of both of orthopaedic exposure and outcome patients under The 53 samples from T1 to T4 exhibiting Failure to adequately control rivaroxaban and rivaroxaban plasma concentrations higher confounding apixaban, in than 100 ng/ml testify to a mean Incomplete or inadequately order to finalize antithrombin increase of 24% when short follow-up and cross- compared to the 51 pretreatment T0 Differences in important validate samples (P = 0.007), whereas the 39 prognostic factors at baseline effective samples exhibiting apixaban plasma measurement concentrations higher than 100 ng/ml methods and to demonstrate a mean antithrombin increase provide of 18% (P = 0.007 and 0.0002, arguments for respectively) helping to reference one or Although rivaroxaban and apixaban the other drug. present apparently similar constant rates, they exhibit significant differences in their concentrations and anticoagulant effects when studied ex vivo in orthopedic patients. Ma, G., et al. To compare the Systematic Review 3 studies, 6380 DVT: Study Limitations = (2015). efficacy and participants Subgroup analysis of apixaban studies None Thrombosis safety of direct (RR = 0.68, 95% CI: 0.59-0.79, P < 0.01; Systematic Review Research factor Xa P heterogeneity = 0.01, Review did not address inhibitors I2 = 78%). focused clinical question (rivaroxaban Search was not detailed or and apixaban) However, further analysis stratified by the exhaustive with enoxaparin regime of enoxaparin did not find a Quality of the studies was not for the significant difference between apixaban appraised or studies were of low prevention of and 30 mg b.i.d dose of enoxaparin (RR = quality venous 0.85, 95% CI: 0.66-1.10, P < 0.01; Methods and/or results were thromboemboli P heterogeneity = 0.03, I2 = 78%) inconsistent across studies sm (VTE) after total knee replacement. Russell, R. D. To analyze data Systematic Review 11,659 participants VTE + death Study Limitations = and M. H. Huo from all of the Pooled data demonstrated that apixaban None (2013). Journal phase had a trend Systematic Review of Arthroplasty III clinical trials toward decreased events compared to Review did not address for both newer enoxaparin (OR 0.59, 95% CI focused clinical question oral direct FXa 0.34–1.02, p = 0.06) Search was not detailed or

DATE: September 2016 inhibitors for exhaustive VTE DVT Quality of the studies was not prophylaxis in OR 0.55 (95% CI 0.32–0.95) p< 0.03 appraised or studies were of low patients quality undergoing Methods and/or results were THAs and inconsistent across studies TKAs Squizzato, A., et the aim of Systematic Review 3 studies, 2673 TKR arterial thrombosis Study Limitations = al. (2015). determining: 1) participants OR 0.43 (95 %CI 0.08-2.37) None Thrombosis & the incidence of Systematic Review Haemostasis postoperative THR arterial thrombosis: Review did not address arterial OR 1.66 (95 %CI 0.40- 6.95) focused clinical question thrombosis Search was not detailed or (AT) in exhaustive NOACs-treated Quality of the studies was not and LMWH- appraised or studies were of low treated patients quality undergoing Methods and/or results were elective TKR or inconsistent across studies THR during active treatment and during follow-up;2) the incidence of patient-relevant outcomes (i. e. prevention of major symptomatic thrombotic events and/or total mortality with minimal risk of major bleeding) with NOACs compared with standard therapy.

The GRADE criteria were used to evaluate the quality of evidence presented in research articles reviewed during the development of this guideline. For more detailed information, see Appendix A.

PICO Question: In patients who have undergone total hip arthroplasty (THA) or total knee arthroplasty (TKA) does a prophylactic direct Lower Quality Rating if:

DATE: September 2016 oral anticoagulant (rivaroxaban and apixaban) post-operatively) prevent deep vein thrombosis (DVT)/ pulmonary embolism (PE)? Studies inconsistent Outcome: Major Bleeding (wide variation of treatment Modality: Apixaban effect across studies, populations, interventions, Author/Dat Purpose Study Design & Sample Outcomes Design Limitations or outcomes varied) e of Study Methods Total # of Studies: 6# of Systematic Reviews: 6 Studies are indirect (PICO question is quite Adam, S. S., et To compare the Systematic review with meta- 16 studies, 38, 747 Study Limitations = The risk for major bleeding was lower with different from the available al. (2013). benefits and analysis participants apixaban than with enoxaparin in TKR (RR None evidence in regard to Annals of risks of new 0.56, 95%CI 0.32-0.96) but not in THR (RR Systematic Review Review did not address population, intervention, Internal oral 1.22, 95%CI 0.65-2.26) focused clinical question comparison, or outcome) Medicine anticoagulants Search was not detailed (NOACs) vs Risk for major bleeding was increased with rivaroxaban compared with apixaban (RR, or exhaustive Studies are imprecise standard Quality of the studies 1.59 [CI, 0.84 to 3.02]) (When studies include few thromboprophyl was not appraised or studies patients and few events and axis. were of low quality Methods and/or results thus have wide confidence were inconsistent across intervals and the results are studies uncertain)

DATE: September 2016 Feng, W., et al. To analyze the Systemic review, traditional meta- 2 studies, 5052 Study Limitations = Publication Bias (2015). efficacy and analysis, dose-response meta- participants None (e.g. pharmaceutical Thrombosis safety of direct analysis and network meta-analysis Systematic Review company sponsors study on Review did not address Research factor Xa effectiveness of drug, only focused clinical question inhibitors for Search was not detailed small, positive studies found) thromboprophyl or exhaustive axis after total Quality of the studies Increase Quality Rating if: hip or knee was not appraised or studies Large Effect replacement. To were of low quality Dose-response gradient delineate the Methods and/or results Plausible confounders or were inconsistent across dose response other biases increase studies effect of direct certainty of effect factor Xa inhibitors. To Quality (certainty) of compare the evidence for studies as a efficacy whole: between any High two direct Moderate factor Xa Low inhibitors. Very Low

For apixaban, its primary safety outcomes (major bleeding) did not show linear relationship with the treatment dose (RR: 1.027, 0.968 to 1.090, P = 0.371) nor non linear relationship as well (RR at 50% percentile: 1.032, 0.871 to 1.223, P = 0.708; RR at 95 percentile: 0.989, 0.729 to 1.342, P=0.948)

Forster, R. and To assess the Systematic review with meta- 5 studies,16199 Study Limitations = M. Stewart effects of analysis participants (DOACs DOAC vs heparin: None (2016). extended- investigated included Bleeding events: OR 1.11 Systematic Review Review did not address Cochrane duration apixaban) (95%CI 0.79-1.54) focused clinical question Database of anticoagulant Search was not detailed Systematic thromboprophyl or exhaustive

DATE: September 2016 Reviews axis for the Quality of the studies prevention of was not appraised or studies venous were of low quality Methods and/or results thromboemboli were inconsistent across sm (VTE) in studies people undergoing elective hip or knee replacement surgery or hip fracture repair.

Ma, G., et al. To compare the Systematic Review 2 studies, 5679 Major Bleeding: Study Limitations = (2015). efficacy and participants Pooled RR( rivaroxaban/ apixaban) = 0.72 None Thrombosis safety of direct (95% CI: 0.44-1.17) Systematic Review Research factor Xa Review did not address inhibitors focused clinical question (rivaroxaban Search was not detailed and apixaban) or exhaustive with enoxaparin Quality of the studies for the was not appraised or studies prevention of were of low quality venous Methods and/or results thromboemboli were inconsistent across sm (VTE) after studies total knee replacement. Russell, R. D. To analyze data Systematic Review 11,659patients There was a trend for an increased risk of Study Limitations = and M. H. Huo from all of the major bleeding in patients taking None (2013). Journal phase rivaroxaban (OR 1.81, 95% CI 0.91–3.62, p Systematic Review of Arthroplasty III clinical trials =0.09), but not with apixaban (p = 0.33) Review did not address for both newer focused clinical question oral direct FXa There was no difference between the oral Search was not detailed inhibitors for FXa inhibitors and enoxaparin in the rates or exhaustive VTE of major plus clinically relevant non-major Quality of the studies prophylaxis in bleeding (p = 0.91). However, there was a was not appraised or studies patients trend toward fewer events in the were of low quality undergoing patients taking apixaban (OR 0.8, 95% Methods and/or results THAs and CI 0.64–1.01, p = 0.06) and were inconsistent across TKAs there were more events in patients taking studies rivaroxaban (OR 1.28, 95% CI 1.04–1.59, p = 0.02). Squizzato, A., et the aim of Systematic Review 4 studies, 12,726 NOACs and enoxaparin were similar at the Study Limitations = al. (2015). determining: 1) patients fixed-effect model in None Thrombosis & the incidence of the risk of major bleeding + clinically Systematic Review Haemostasis postoperative relevant bleeding (OR 1.03; 95 %CI, 0.92, Review did not address arterial 1.15; I²=38) focused clinical question © Office of Clinical Integration and EBP, 2016 20 Oregon Health and Science University

DATE: September 2016 thrombosis Search was not detailed (AT) in or exhaustive NOACs-treated Quality of the studies and LMWH- was not appraised or studies treated patients were of low quality undergoing Methods and/or results elective TKR or were inconsistent across THR during studies active treatment and during follow-up;2) the incidence of patient-relevant outcomes (i. e. prevention of major symptomatic thrombotic events and/or total mortality with minimal risk of major bleeding) with NOACs compared with standard therapy. The GRADE criteria were used to evaluate the quality of evidence presented in research articles reviewed during the development of this guideline. For more detailed information, see Appendix A.

DATE: September 2016 REFERENCES 1. Adam, S. S., et al. (2013). "Comparative effectiveness of new oral anticoagulants and standard thromboprophylaxis in patients having total hip or knee replacement: a systematic review." Annals of Internal Medicine 159(4): 275-284. 2. Feng, W., et al. (2015). "Oral direct factor Xa inhibitor versus enoxaparin for thromboprophylaxis after hip or knee arthroplasty: Systemic review, traditional meta-analysis, dose-response meta-analysis and network meta-analysis." Thrombosis Research 136(6): 1133-1144.3. 3. Forster, R. and M. Stewart (2016). "Anticoagulants (extended duration) for prevention of venous thromboembolism following total hip or knee replacement or hip fracture repair." Cochrane Database of Systematic Reviews 3: CD004179. 4. Freyburger, G., et al. (2015). "Rivaroxaban and apixaban in orthopaedics: is there a difference in their plasma concentrations and anticoagulant effects?" Blood Coagulation & Fibrinolysis 26(8): 925-933. 5. Hamidi, V., et al. (2013). "New anticoagulants as thromboprophylaxis after total hip or knee replacement." International Journal of Technology Assessment in Health Care 29(3): 234-243. 6. Ma, G., et al. (2015). "Direct factor Xa inhibitors (rivaroxaban and apixaban) versus enoxaparin for the prevention of venous thromboembolism after total knee replacement: A meta-analysis of 6 randomized clinical trials." Thrombosis Research 135(5): 816-822. 7. Ricket, A. L., et al. (2016). "Comparison of Postoperative Bleeding in Total Hip and Knee Arthroplasty Patients Receiving Rivaroxaban or Enoxaparin." Annals of Pharmacotherapy 50(4): 270-275. 8. Russell, R. D. and M. H. Huo (2013). "Apixaban and rivaroxaban decrease deep venous thrombosis but not other complications after total hip and total knee arthroplasty." Journal of Arthroplasty 28(9): 1477-1481. 9. Squizzato, A., et al. (2015). "Post-operative arterial thrombosis with non-vitamin K antagonist oral anticoagulants after total hip or knee arthroplasty." Thrombosis & Haemostasis 114(2): 237-244.

DATE: September 2016 Appendix A. GRADE criteria for rating a body of evidence on an intervention Developed by the GRADE Working Group

Grades and interpretations: High: Further research is very unlikely to change our confidence in the estimate of effect. Moderate: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low: Any estimate of effect is very uncertain.

Type of evidence and starting level Randomized trial–high Observational study–low Any other evidence–very low

Criteria for increasing or decreasing level Reductions Study quality has serious (–1) or very serious (–2) problems Important inconsistency in evidence (–1) Directness is somewhat (–1) or seriously (–2) uncertain Sparse or imprecise data (–1) Reporting bias highly probable (–1) Increases Evidence of association† strong (+1) or very strong (+2) †Strong association defined as significant relative risk (factor of 2) based on consistent evidence from two or more studies with no plausible confounders Very strong association defined as significant relative risk (factor of 5) based on direct evidence with no threats to validity.