Dabigatran vs rivaroxaban for thromboprophylaxis

Dabigatran vs rivaroxaban for thromboprophylaxis Dabigatran etexilate and rivaroxaban were both licensed recently for thromboprophylaxis following hip or knee surgery. In this article, the North Central London Formulary and Medicines Management Group review the evidence for the efficacy and safety of both drugs. Venous thromboembolism is the most serious and frequent complication of total hip and knee replacement surgery and hip fracture surgery. 1 In the absence of thromboprophylaxis, venous thromboembolism will develop in approximately 50% of patients who have undergone total hip replacement (THR) and hip fracture surgery, and in approximately 0% of patients who have undergone total knee replacement (TKR) surgery. 2 Thromboprophylaxis is therefore essential (see background box). Recently, dabigatran etexilate (Pradaxa; Boehringer Ingelheim) and rivaroxaban (Xarelto; Bayer) have been licensed for extended thromboprophylaxis after THR and TKR surgery, and the National Institute for Health and Clinical Excellence has published two technology appraisals NICE recommends that patients undergoing elective total hip (THR) or knee replacement (TKR) surgery should receive post-operative prophylaxis with either subcutaneous low molecular weight heparin (such as enoxaparin) or fondaparinux. This is given for 7 10 days after TKR surgery and for an average of 28 days after THR surgery. 3 Patients with poor renal function or at high risk of bleeding or thrombosis should receive unfractionated heparin. The value of thromboprophylaxis with unfractionated heparin (UFH) in orthopaedic surgery has been well established. Use of UFH use reduces hard primary clinical efficacy outcomes (subclinical and clinical deep vein thrombosis [DVT], clinical pulmonary embolism [PE] and fatal PE) by two-thirds. 4 Background endorsing their use for this indication. 10,11 Dabigatran is a univalent, oral, competitive, reversible, direct thrombin inhibitor which inhibits free and fibrinbound thrombin and thrombin-induced platelet aggregation. 12 It is administered as the oral prodrug dabigatran etexilate. Rivaroxaban is an oxazolidinone derivative that is an inhibitor of factor Xa. 13 By directly inhibiting factor Xa, rivaroxaban blocks both intrinsic and extrinsic pathways in the clotting process. It is also taken orally. Dabigatran efficacy The efficacy of dabigatran was assessed in two pivotal, randomised, multicentre, double-blind, double-dummy, noninferiority, phase III studies of similar design; one in patients undergoing TKR surgery (RE-MODEL) 14 and one in More recently, data has shown that the use of low molecular weight heparin (LMWH) injections have at least equivalent efficacy to UFH. 5 The incidence of DVT associated with 5 11 days of LMWH has been reported to occur in as many as 20% of patients, leading to the prescribing of extended duration prophylaxis. 7 The use of extended duration prophylaxis has reduced the incidence of asymptomatic, total and proximal DVT and symptomatic DVT by at least 50%. 8 Heparin-induced thrombocytopenia is a risk in orthopaedic patients given subcutaneous prophylactic heparin. The incidence is approximately 5% with UFH and 0.5% with LMWH 9 and is a major disadvantage associated with the use of these drugs. To receive your free copy of The British Journal of Clinical Pharmacy please return to clinicalpharmacy.org.uk and complete a subscriptions form. patients undergoing THR (RE-NOVATE). 15 The objective of these studies was to prove the non-inferiority of dabigatran to the established intervention, LMWH (enoxaparin). A non-inferiority margin of 7.7% and 9.2% was established a priori for THR and TKR surgery, respectively. If the upper limit of the 95% confidence interval for the absolute difference (with respect to the primary outcome) between dabigatran and enoxaparin did not exceed this margin, dabigatran would be regarded as noninferior, having preserved two-thirds of the 95% confidence interval difference between enoxaparin and placebo. Of the 5,595 patients randomised to either dabigatran or enoxaparin, 5,540 went on to undergo primary TKR surgery (n=2,07) or primary THR surgery (n=3,44). They were given either dabigatran etexilate (75mg or 110mg within one to four hours of completion of surgery, provided there was good haemostasis, followed by 150mg or 220mg once daily) or enoxaparin (40mg 240

RE-MODEL [TKR] 14 RE-NOVATE [THR] 15 DE-220 DE-150 ENX DE-220 DE-150 ENX mitt primary efficacy population (n) 503 52 512 880 874 897 Total VTE and all-cause mortality [n (%)] 183 (3.4%) 213 (40.5%) 193 (37.7%) 53 (.0%) 75 (8.%) 0 (.7%) Absolute risk difference: DE versus enoxaparin [% (95% CI)] -1.3% (-7.3 to 4.) +2.8% (-3.1 to 8.7) -0.7% (-2.9 to 1.) +0.9% (-0. to 4.4) p-value 0.0003 0.017 <0.0001 <0.0001 NNT (number needed to treat) 77 143 mitt secondary efficacy population (n) 50 527 511 909 888 917 Major VTE and VTE-related mortality 13 (2.%) 20 (3.8%) 18 (3.5%) 28 (3.1%) 38(4.3%) 3 (3.9%) [n (%)] Absolute risk difference: DE versus enoxaparin [% (95% CI)] -1.0% (-3.1 to 1.2) +0.3% (-2.0 to 2.) -0.8% (-2.5 to 0.8) +0.4% (-1.5 to 2.2) p-value 0.38 0.82 0.33 0.71 NNT 100 125 Safety population (n) 79 703 94 114 113 1154 Major bleeding events [n (%)] 10 (1.5%) 9 (1.3%) 9 (1.3%) 23 (2.0%) 15 (1.3%) 18(1.%) Absolute risk difference versus enoxaparin (%) +0.2% 0% +0.4% -0.3% p-value 0.82 1.0 0.44 0.0 NNH (number needed to harm) 500 250 DE-220 = dabigatran etexilate 220mg daily; DE-150 = dabigatran etexilate 150mg daily; ENX = enoxaparin 40mg daily; mitt = modified intention-to-treat Table 1: Summary of trials of dabigatran etexilate (DE) versus enoxaparin (ENX) following total hip or knee replacement surgery subcutaneously daily, beginning the evening before surgery). Both drugs were given for six to ten days for TKR surgery and 28 to 35 days for THR. Dabigatran was initiated after a mean of 3.4 hours after surgery, with an overall median treatment duration of eight days for TKR and 33 days for THR. Concomitant treatment with low dose aspirin ( 10mg) and selective cyclooxygenase-2 inhibitors was allowed during treatment, but use of long-acting nonsteroidal anti-inflammatory drugs was not. The use of elastic compression stockings was permitted. Women of childbearing potential were excluded from the study. The primary efficacy outcome was a composite endpoint of the incidence of total venous thromboembolic events (VTE defined as venographic or symptomatic deep vein thrombosis or symptomatic pulmonary embolism) and all-cause mortality during the treatment period. Secondary efficacy endpoints included a composite of major VTE (defined as proximal deep vein thrombosis [DVT] and pulmonary embolism [PE]) and VTE-related mortality, proximal DVT, total DVT, symptomatic DVT, symptomatic PE and death during the treatment period. A bilateral venographic assessment was undertaken within 24 hours of the last oral dose and patients were followed up for three months. Sample size calculations assumed that 25% of patients would have a nonevaluable venogram in the TKR study and 35% in the THR study (the basis of these assumptions were not reported). The primary analysis set (modified intention-to-treat population) included all randomised patients who had received at least one dose of study medication, had undergone surgery and had evaluable VTE data during the treatment period, or who died during treatment. Both doses of dabigatran in both the THR and TKR studies demonstrated the non-inferiority of dabigatran with regard to the primary efficacy outcome compared with enoxaparin (see Table 1). Of the components that contributed towards the primary efficacy outcome, the largest difference was seen in the rate of asymptomatic DVT. A third, double-blind, randomised, phase III, non-inferiority study (RE-MOBILIZE) has been conducted comparing the safety and efficacy of dabigatran (dosed as above) versus enoxaparin (30mg twice daily) in reducing the risk of VTE following TKR. 1 The inclusion criteria and the primary and secondary efficacy outcomes were defined as for the RE-MODEL and RE-NOVATE trials. In this trial however, in the 1,89 patients analysed, both doses of dabigatran failed to meet the pre-defined criteria to demonstrate non-inferior efficacy to enoxaparin (composite of total VTE was 31% for dabigatran 220mg daily [p=0.02]; 34% for dabigatran 150mg daily [p<0.001]; and 25% for enoxaparin). Rivaroxaban efficacy Four large phase III randomised, doubleblind, double-dummy studies of similar design have compared rivaroxaban with enoxaparin for the prevention of VTE after THR surgery (RECORD-1 17 & RECORD-2 18 ) or TKR (RECORD-3 19 & RECORD-4 20 ) surgery. As with the RE-MODEL and RE-NOVATE studies, September 2009 Vol. 1 The British Journal of Clinical Pharmacy 241

RECORD-1 [THR] 17 RECORD-2 [THR] 18 RECORD-3 [TKR] 19 RECORD-4 [TKR] 20 RVB ENX RVB ENX RVB ENX RVB ENX mitt primary efficacy population (n) 1595 1558 84 89 824 878 95 959 Any DVT, non-fatal PE, or death [n (%)] Weighted absolute risk difference versus enoxaparin [% (95% CI)] 18 (1.1%) 58 (3.7%) 17 (2.0%) 81 (9.3%) -2.% (-1.5 to -3.7) -7.3% (-5.2 to -9.4) 79 (9.%) 1 (18.9%) -9.2% (-12.4 to -5.9) 7 (.9%) 97 (10.1%) -3.2% (-5.7 to -0.7) p-value <0.001 <0.001 <0.001 0.012 NNT (number needed to treat) 38 14 11 31 Pooled (weighted) NNT 20 1 mitt secondary efficacy population (n) 18 178 91 92 908 925 1122 1112 Major VTE [n (%)] 4 (0.2%) 33 (2.0%) (0.%) 49 (5.1%) 9 (1.0%) 24 (2.%) 13 (1.2%) 22 (2.0%) Weighted absolute risk difference versus -1.7% (-2.5 to -1.0) -4.5% (-.0 to -3.0) -1.% (-2.8 to -0.4) -0.8% (-1.82 to 0.22) enoxaparin [% (95% CI)] p-value <0.001 <0.001 0.01 0.124 NNT 0 22 3 125 Pooled (weighted) NNT 32 83 Safety population (n) 2209 2224 1228 1229 1220 1239 152 1508 Major bleeding events [n (%)] (0.3%) 2 (0.1%) 1 (<0.1%) 1 (<0.1%) 7 (0.%) (0.5%) 0.7% 0.3% Absolute risk difference versus enoxaparin (%) +0.2% +0.1% +0.4% p-value 0.18 0.77 NNH (number needed to harm) 500 1000 250 Pooled (weighted) NNH 500 400 Table 2: Summary of trials of rivaroxaban (RVB) versus enoxaparin (ENX) following total hip or knee replacement surgery the objective was to demonstrate the noninferiority of rivaroxaban to the established intervention, LMWH (enoxaparin). The non-inferiority margin established a priori for the primary efficacy endpoint was 3.5%, 4.4%, 4% and 4% for RECORD-1, 2, 3 and 4, respectively. All patients underwent mandatory bilateral venography on the day after the last dose of study medication. The primary endpoint in all studies was the composite of any DVT (symptomatic or asymptomatic, as detected by venography), non-fatal PE, or death from any cause. The main secondary endpoint was major VTE defined as the composite of proximal DVT, non-fatal PE, or VTE-related death. RECORD 1 3 Patients were randomised to receive rivaroxaban (10mg orally once daily, starting six to eight hours after wound closure) plus placebo injections or enoxaparin (40mg subcutaneously once daily, starting 12 hours pre-operatively and restarted six to eight hours after wound closure) plus placebo tablets. The duration of active study medication was as follows: RECORD-1 (THR): rivaroxaban and enoxaparin were continued for 35±4 days RECORD-2 (THR): rivaroxaban was continued for 35±4 days and enoxaparin for 12±2 days RECORD-3 (TKR): rivaroxaban and enoxaparin were continued for 12±2 days RECORD-4 Patients were randomised to receive either rivaroxaban (10mg orally, once daily) plus placebo injections or enoxaparin (30mg subcutaneously, twice daily) plus placebo tablets, starting six to eight hours and 12 to 24 hours after wound closure, respectively. Rivaroxaban and enoxaparin were continued for 12±2 days. All studies demonstrated superiority of rivaroxaban with regards to the primary efficacy endpoint, compared to enoxaparin (see Table 2). Of the components that contributed towards the primary efficacy endpoint, the largest difference was seen in the rate of asymptomatic DVT. Although all studies included an a priori statistical analysis to recruit enough patients to account for a 25% dropout rate (as a result of the inability to obtain valid venograms), the actual non-evaluable rate was slightly higher (2 30%). RECORD-1 and RECORD-3 recruited extra patients to compensate for this and thus maintain statistical power. However, this was not done in RECORD-2 or RECORD-4 and therefore has implications for the validity of the final results; although sensitivity analyses suggest that the missing data did not affect the power of the study or bias the outcome. 242

Safety Dabigatran The primary safety outcome in RE-MODEL and RE-NOVATE was the occurrence of bleeding events (major bleeding events, clinically relevant non-major bleeding events and minor bleeding events) during study treatment. An experienced and independent committee of experts, blinded to all treatment allocations, adjudicated all bleeding events centrally, using pre-defined and detailed rules. There was no significant difference in bleeding events between either dose of dabigatran and enoxaparin. Most major bleeding events were at the surgical wound site (89% in the TKR study and 91% in the THR study). There were no fatal bleeding events in the TKR study and two in the THR study (0.09%; one in each of the dabigatran groups). The incidence of hepatotoxicity and cardiac events was low in both studies and comparable to enoxaparin. The most common reason for treatment discontinuation was gastrointestinal disorders (nausea, vomiting and constipation) in the THR study and acute coronary events (unstable angina, myocardial infarction and cardiac death) in the TKR study, although these events were comparable between all three arms of the studies (DE-220, DE-150 and ENX). Rivaroxaban The main safety outcome of the four RECORD studies was the incidence of major bleeding, defined as bleeding that was fatal, bleeding that occurred in a critical organ or required re-operation, or sitebleeding with a fall in haemoglobin level of >2g/dL, requiring blood transfusion. The incidence of major bleeding across all studies was low (<0.1% to 0.7%) and did not differ significantly between rivaroxaban and enoxaparin. The incidences of ontreatment bleeding and non-major bleeding were not significantly different between the two treatment groups. Since different criteria were used to assess bleeding events in the RECORD (rivaroxaban) and RE-MODEL/RE- NOVATE (dabigatran) studies, it is not possible to directly compare their safety profiles (bleeding risk). However, no significant differences were observed. No differences were reported between rivaroxaban and enoxaparin in liver function test results. In the RECORD 2 study, an apparent excess of cardiovascular adverse events was noted after discontinuation of rivaroxaban (five patients [0.4%], including two deaths of cardiovascular origin). No cardiovascular adverse events were noted after discontinuation of enoxaparin. Although this trend was not observed in the other three studies, the reporting of these events raises concern about the potential for rebound activation of coagulation following discontinuation of rivaroxaban. The number of patients treated in the trials may be too few to realise the true incidence in clinical practice. A prospective, randomised, doubleblind, double-dummy, crossover study investigating the potential for rivaroxaban to cause QTc prolongation in healthy subjects (n=50; age 50) concluded that rivaroxaban does not prolong the QTc interval. 21 A study published in abstract form only (in vitro analysis) has indicated that recombinant factor VIIa can be used to partially reverse the effects of rivaroxaban (reverse the inhibition of thrombin generated). 22 Convenience Dabigatran and rivaroxaban offer the advantage of being oral preparations that do not require regular platelet monitoring, dose adjustment, or daily subcutaneous injections. Rivaroxaban has an advantage over dabigatran since it can be used in patients with a creatinine clearance of Drug appraisal articles University College London Hospitals NHS Foundation Trust, Royal Free Hampstead NHS Trust and The Whittington Hospital NHS Trust operate a centralised medication review scheme for assessing formulary applications to their Use of Medicine and Drugs and Therapeutics Committees. A review of selected formulary applications are published regularly in The British Journal of Clinical Pharmacy. These reviews are intended to inform readers about the individual merits and limitations of the drugs in question, and to provide examples of in-depth, critical reviewing which can be adapted and used in all areas of evidence-based medicine. 15 30 ml/minute (with caution, based on limited clinical data). Moreover, the dosing schedule for rivaroxaban is more simple than that of dabigatran and is more appropriate for patients undergoing surgery with an epidural. When epidural anaesthesia is used, concomitant use of anti-thrombotic drugs can increase the risk of developing a haematoma, which can result in longterm or permanent paralysis. Dabigatran is licensed to be given one to four hours post surgery. In practice this is likely to be given later in patients who have had epidural anaesthesia, so the drug will effectively be used off-label. Rivaroxaban is licensed for administration six to eight hours post surgery. Since rivaroxaban is a substrate for the hepatic enzyme CYP3A4, concomitant administration with drugs that are known inhibitors of this enzyme is not recommended. Dabigatran is not metabolised by the cytochrome P450 system so may be a more appropriate choice for patients on potentially interacting medication. However, since dabigatran is a substrate for the efflux transporter P-glycoprotein, its plasma level is noted to increase by up to 50% with the co-administration of medicines that are inhibitors of this transporter, notably amiodarone. This interaction (increased risk of bleeding) may be of greater relevance in practice when considering the target population elderly people who are more likely to have a co-existing cardiovascular condition requiring treatment with amiodarone. The clinical significance of these interactions in clinical practice are yet to be determined. Cost One month s supply of rivaroxaban costs approximately 135 and one month s supply of dabigatran costs approximately 125. Although prescribing of these oral agents will result in a cost burden with regard to drug acquisition costs, this should offset the indirect costs associated with the use of LMWH, such as nursing time for administration (both in hospital and in the community), sharps bins, swabs, delayed discharges, laboratory monitoring costs, and increased GP visits or outpatient clinic appointments. Cost-utility analyses conducted by NICE concluded that both dabigatran September 2009 Vol. 1 The British Journal of Clinical Pharmacy 243

and rivaroxaban represent a cost-effective alternative to LMWH in the prophylaxis of VTE associated with THR or TKR. However, given the historical difficulties in implementing extended prophylaxis with a LMWH, it is likely that the initial changeover to an oral agent will result in a more significant initial cost impact than the incremental cost-effectiveness ratios calculated within the NICE technology appraisals. Conclusion Although there are no direct comparative data on the efficacy and safety of rivaroxaban versus dabigatran, rivaroxaban demonstrated superiority over the LMWH enoxaparin, whereas dabigatran trials only demonstrated non-inferiority. In terms of safety, no clear significant differences between dabigatran and rivaroxaban are observed. Since rivaroxaban also appears more convenient in both its administrative schedule (following epidural) and clinical use (in mild/ moderate renal impairment), the University College London Hospitals NHS Foundation Trust Use of Medicines Committee approved the use of rivaroxaban in place of LMWH for extended thromboprophylaxis after THR and TKR surgery. Written by Anthony Grosso, principal pharmacist and Pritesh Bodalia, senior pharmacist, at University College London Hospitals NHS Foundation Trust. Acknowledgement: Carolyn Gates, senior pharmacist, UCLH. Conflicts of interest: none declared. References 1. White RH, Romano PS, Zhou H, Rodrigo J, Bargar W. Incidence and time course of thromboembolic outcomes following total hip or knee arthroplasty. Arch Intern Med 1998;158:525 31. 2. Kwong LM. Venous thromboembolism following major orthopaedic surgery getting the bigger picture. Orthopaedic Surgery: US Musculoskeletal Review 200:47 8. 3. National Institute for Health and Clinical Excellence. Venous thromboembolism Reducing the risk of venous thromboembolism (deep vein thrombosis and pulmonary embolism) in inpatients undergoing surgery. London:NICE;2007. 4. Collins R, Scrimgeour A, Yusuf S, Peto R. Reduction in fatal pulmonary embolism and venous thrombosis by perioperative administration of subcutaneous heparin. Overview of results of randomized trials in general, orthopedic, and urologic surgery. N Engl J Med 1988;318:112 73. 5. Koch A, Bouges S, Ziegler S, Dinkel H, Daures JP, Victor N. Low molecular weight heparin and unfractionated heparin in thrombosis prophylaxis after major surgical intervention: update of previous meta-analyses. Br J Surgery 1997;84:50 9.. Geerts WH, Pineo GF, Heit JA, Bergqvist D, Lassen MR, Colwell C et al. Prevention of venous thromboembolism: the seventh ACCP conference on antithrombotic and thrombolytic therapy. Chest 2004;12:338S 400S. 7. Eikelboom JW, Quinlan DJ, Douketis JD. Extended duration prophylaxis against venous thromboembolism after total hip or knee replacement: a meta-analysis of the randomised trials. Lancet 2001;358:9 15. 8. Cohen AT, Bailey CS, Alikhan R, Cooper DJ. Extended thromboprophylaxis with LMWH reduces symptomatic venous thromboembolism following lower-limb arthroplasty a meta-analysis. Thrombosis and Haemostasis 2001;85:940 1. 9. Warkentin T, Sheppard J, Horsewood P, Simpson PJ, Moore JC, Kelton JG. Impact of the patient population on the risk for heparin-induced thrombocytopenia. Blood 2000;9:1703 8. 10. National Institute for Health and Clinical Excellence. Dabigatran etexilate for the prevention of venous thromboembolism after hip or knee replacement surgery in adults. NICE technology appraisal guidance 157. London: NICE; 2008. 11. National Institute for Health and Clinical Excellence. Rivaroxaban for the prevention of venous thromboembolism after hip or knee replacement surgery in adults. NICE technology appraisal guidance 170. 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Turpie AGG, Lassen MR, Davidson BL, Bauer KA, Gent M, Kwong LM et al, for the RECORD-4 investigators. Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty: A randomised trial. Lancet 2009;373:173 80. 21. Kubitza D, Mueck W, Becka M. Randomised, double-blind, crossover study to investigate the effect of rivaroxaban on QT-interval prolongation. Drug Safety 2008;31:7 77. 22. Perzborn E, Harwardt M. Recombinant factor VIIa partially reverses the effects of the factor Xa inhibitor rivaroxaban on thrombin generation, but not the effects of thrombin inhibitors (in vitro). J Thromb Haemost 2007; 5(Suppl 2): Abstract P-W-40. Commentary article An article on p245 reflects on the increasing use of trials designed as noninferiority studies. 244