The legally binding text is the original French version TRANSPARENCY COMMITTEE OPINION. 18 January 2012

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1 The legally binding text is the original French version TRANSPARENCY COMMITTEE OPINION 18 January 2012 ELIQUIS 2.5 mg, film-coated tablets B/10 (CIP code: ) B/20 (CIP code: ) B/60 (CIP code: ) B/60x1 (CIP code: ) Applicant: BRISTOL-MYERS SQUIBB apixaban ATC code: B01AF02 List I Date of Marketing Authorisation: 18 May 2011 Reason for request: Inclusion on the list of medicines refundable by National Health Insurance (B/10, B/20 and B/60) and approved for hospital use (B/60x1). Medical, Economic and Public Health Assessment Division 1/29

2 1. CHARACTERISTICS OF THE MEDICINAL PRODUCT 1.1. Active ingredient Indications Prevention of venous thromboembolic events (VTE) in adult patients who have undergone elective hip or knee replacement surgery Dosage The recommended dose is 2.5 mg taken orally twice daily. The initial dose should be taken 12 to 24 hours after surgery. Physicians may consider the potential benefits of earlier anticoagulation for VTE prophylaxis as well as the risks of post-surgical bleeding in deciding on the time of administration within this time window. In patients undergoing total hip replacement surgery, the recommended duration of treatment is 32 to 38 days. In patients undergoing total knee replacement surgery, the recommended duration of treatment is 10 to 14 days. If a dose of ELIQUIS is missed, the patient should immediately take the missed tablet and then continue with twice daily intake as before. Switching treatment from parenteral anticoagulants to apixaban (and vice versa) can be done at the next scheduled dose. Special populations/situations: - Body weight: no dose adjustment is required. - Gender: no dose adjustment is required. - Elderly subjects: no dose adjustment is required. - Paediatric population: the safety and efficacy of ELIQUIS in children below age 18 have not been established. - Renal impairment: because there is no clinical experience in patients with creatinine clearance < 15 ml/min or in patients undergoing dialysis, apixaban is not recommended in these patients. Limited clinical data in patients with severe renal impairment (creatinine clearance ml/min) indicate that apixaban plasma concentrations are increased in this population, therefore, apixaban is to be used with caution in these patients. No dose adjustment is necessary in patients with mild or moderate renal impairment. - Hepatic impairment: ELIQUIS is contraindicated in patients with hepatic disease associated with coagulopathy and clinically relevant bleeding risk. It is not recommended in patients with severe hepatic impairment. It should be used with caution in patients with mild or moderate hepatic impairment (Child-Pugh A or B). No dose adjustment is required in patients with mild or moderate hepatic impairment. Patients with elevated liver enzymes (ALT/AST > 2 ULN) or total bilirubin level 1.5 ULN were excluded in clinical trials. Therefore ELIQUIS should be used with caution in this population. ALT should be measured as part of the standard pre-operative assessment. - Epidural/spinal anaesthesia or lumbar puncture: When spinal/epidural anaesthesia or lumbar/epidural puncture is employed in patients treated with antithrombotic agents for prevention of thromboembolic complications could risk the appearance of an epidural or 1 is the second oral anticoagulant in the class of reversible direct factor Xa inhibitors. Its metabolism seems relatively uninfluenced by the state of kidney and liver function, even in cases of moderate impairment. 2/29

3 spinal haematoma, which can result in long-term or permanent paralysis. The risk of these events may be increased by the postoperative use of indwelling epidural catheters or the concomitant use of medicinal products affecting haemostasis. Indwelling epidural or intrathecal catheters must be removed at least 5 hours prior to the first dose of ELIQUIS. The risk may also be increased by traumatic or repeated epidural or spinal puncture. Patients are to be frequently monitored for signs and symptoms of neurological impairment (e.g. numbness or weakness of the legs, bowel or bladder dysfunction). If neurological compromise is noted, urgent diagnosis and treatment is necessary. Before embarking on any cerebrospinal surgery, the physician should consider the potential benefit versus risk in anticoagulant patients or in patients to be anticoagulated for thromboprophylaxis. There is no clinical experience with the use of apixaban with indwelling intrathecal or epidural catheters. In case there is such need and based on the pharmacokinetic data, a time interval of hours (i.e. 2 half-life) between the last dose of apixaban and catheter withdrawal should elapse, and at least one dose should be omitted before catheter withdrawal. The next dose of apixaban may be given at least 5 hours after catheter withdrawal. As with all new anticoagulant drugs, clinical experience with neuraxial anaesthesia is limited, and extreme caution is therefore recommended when using apixaban in the presence of this type of anaesthesia. 3/29

4 2. SIMILAR MEDICINAL PRODUCTS 2.1. ATC Classification B01A B01AF B01AF02 Antithrombotic agents Direct factor Xa inhibitors 2.2. Medicines in the same therapeutic category Other direct factor Xa inhibitors (administered orally): - rivaroxaban (XARELTO 10 mg, tablets) (substantial AB, IAB IV in terms of efficacy in comparison to LOVENOX) 2.3. Medicines with a similar therapeutic aim (antithrombotic agents) These medicinal products have a substantial clinical effectiveness. Direct thrombin inhibitors Oral route: - dabigatran etexilate: PRADAXA 75 mg and 110 mg, capsules (IAB V in comparison to LOVENOX) Parenteral route: desirudin: REVASC 15 mg/0.5 ml powder and solvent for solution for injection Indication: Prevention of deep venous thrombosis after elective orthopaedic surgery (hip or knee replacement). lepirudin: REFLUDAN 50 mg lyophilisate for solution for injection Indication: Inhibition of coagulation in adult patients with heparin-induced thrombocytopenia (HIT) type II and thromboembolic disease requiring parenteral antithrombotic therapy. The diagnosis should be confirmed by means of the heparin-induced platelet activation test or an equivalent test. Indirect thrombin and factor Xa inhibitors: For initial thromboprophylaxis in major orthopaedic surgery on the lower limb: Unfractionated heparins: SUBCUTANEOUS CALCIPARINE Indication: This heparin is a classic, so-called unfractionated heparin. Prevention of venous thromboembolic accidents: - in a surgical setting; - in bed-ridden patients presenting an acute medical condition (including in post-infarction status, in cases of heart failure, after ischemic stroke with paralysis of the lower limbs). In this case use is reserved for severe renal impairment (creatinine clearance of the order of less than 30 ml/min according to estimates based on the Cockroft formula) as a possible alternative to prescribing a low-molecular-weight heparin. 4/29

5 Low-molecular-weight heparin (LMWH): - dalteparin: FRAGMIN 0.2 ml - enoxaparin: LOVENOX 0.4 ml - nadroparin: FRAXIPARINE - tinzaparin: INNOHEP 10,000 IU anti-xa/1 ml Fondaparinux sodium: ARIXTRA 2.5 mg/0.5 ml solution for injection in prefilled syringe (substantial AB) Indication: Prevention of venous thromboembolic events in major orthopaedic surgery of the lower limb in adults, such as hip fracture, hip replacement or major knee surgery. For prolonged thromboprophylaxis in major orthopaedic surgery on the lower limb: the value of postoperative prophylactic treatment in orthopaedic hip surgery was established for enoxaparin lasting 4 to 5 weeks (LOVENOX) and for dalteparin (FRAGMIN) lasting up to 35 days. With the other LMWHs, the recommended treatment duration in the majority of cases is 10 days, after which follow-on treatment with a vitamin K antagonist (VKA) should be considered. Danaparoid: ORGARAN 750 IU anti-xa/0.6 ml solution for injection Indication: Prophylactic treatment of thromboembolic disease in orthopaedic and cancer surgery. Prophylactic treatment of thromboembolic events in patients with: - acute heparin-induced thrombocytopenia (HIT) type II without thromboembolic complications; - or documented history of HIT type II and requiring preventive antithrombotic therapy by the parenteral route. Vitamin K antagonists Administered orally: - Warfarin: COUMADINE 2 mg and 5 mg - Acenocoumarol: SINTROM 4 mg and MINISINTROM 1 mg - Fluindione: PREVISCAN 20 mg Indication: Treatment of deep vein thrombosis and pulmonary embolism, and prevention of recurrence of these conditions, as a follow-on treatment from heparin. 5/29

6 3. ANALYSIS OF AVAILABLE DATA The assessment of the clinical effectiveness of apixaban (ELIQUIS) in preventing venous thromboembolic disease (VTED) after total hip replacement (THR) surgery or total knee replacement (TKR) surgery is based essentially on the results of two European double-blind phase III non-inferiority clinical studies comparing the efficacy and the adverse effects of apixaban with those of enoxaparin in patients undergoing total knee replacement surgery (ADVANCE 2 2 or CV studies) or total hip replacement surgery (ADVANCE 3 3 ; study CV185035). An indirect comparison of the efficacy and adverse effects of apixaban, dabigatran etexilate and rivaroxaban in the prevention of VTED after THR or TKR surgery is also presented. A third, North American, phase III study (ADVANCE 1) compared the efficacy and tolerance of thromboprophylaxis with apixaban 2.5 mg p.o. 2 /day with that of 30 mg of enoxaparin 2 /day subcutaneously after total knee replacement surgery. In this North American study (ADVANCE 1 4 ), the pre-specified non-inferiority criteria were not achieved. But these results are not taken into account in this opinion owing to the fact that enoxaparin was not administered in accordance with the dosage scheme recommended in France (40 mg 1 /day) Methodology of studies ADVANCE 2 (TKR) and ADVANCE 3 (THR) Aims and objectives of the two studies: To demonstrate the non-inferiority of apixaban in comparison to enoxaparin in preventing the onset of venous thromboembolic events and death from all causes in adult patients and secondarily, if this hypothesis is validated, its superiority. Figure: Scheme of ADVANCE 2 study (TKR) 9-15 h preoperatively 1 st oral dose of enoxaparin/placebo h postoperatively 1 st oral dose of study product/placebo 2.5 mg 2 /day Treatment period 12 (± 2) days - TKR Follow-up period 60 days Enoxaparin 40 mg 1 /day Screening 14 days Randomisation 1-4 days D 1 Surgery Bilateral ascending venography 2 Lassen MR, Raskob GE, Pineo G, et al. versus enoxaparin for thromboprophylaxis after knee replacement (ADVANCE-2): a randomized double-blind trial. Lancet 2010; 375: Lassen MR, Gallus A, Raskob GE, et al. versus Enoxaparin for Thromboprophylaxis after Hip Replacement (ADVANCE-3). N Engl J Med 2010; 363: Lassen MR, Raskob GE, Gallus A, et al. or enoxaparin for Thromboprophylaxis after knee replacement (ADVANCE 1). N Engl J Med 2009; 361: /29

7 Figure: Scheme of ADVANCE 3 study (THR) 9-15 h preoperatively 1 st dose of enoxaparin/placebo h postoperatively 1 st dose of study product/placebo 2.5 mg 2 /day Treatment period 35 (± 3) days - THR Follow-up period 60 days Enoxaparin 40 mg 1 /day Screening 14 days Randomisation 1-4 days D 1 Surgery Bilateral ascending venography These two were multicentre studies: - ADVANCE 2 (TKR): 125 centres (6 in France) in 27 countries enrolled patients between June 2007 and January ADVANCE 3 (THR): 160 centres (6 in France) in 21 countries enrolled patients between March 2007 and September Inclusion criteria: Adults (at least 18 years) due to undergo elective surgery for: - Unilateral or bilateral TKR on the same day or repair of one or more components of a TKR (ADVANCE 2) - Unilateral THR or repair of one or more components of a THR (ADVANCE 3) These patients agreed to have bilateral ascending venography carried out. Among the non-inclusion criteria: - High risk of bleeding - Active hepatobiliary disease or liver enzyme levels (alanine-aminotransferase: ALT) or aspartate-aminotranferase: AST) > 2 times the upper limit of the usual normal range (ULN) or the total bilirubin level 1.5 ULN; - Impaired kidney function with a creatinine clearance (Cr Cl) < 30 ml/min. Dosage of the medicines assessed: - : 2.5 mg 2 /day p.o. starting 12 to 24 hours after the end of surgery; - Enoxaparin: 40 mg 1 /day s.c. starting 9 to 15 hours before surgery and repeated after surgery, according to the investigator s practice. Treatment duration: - 10 to 14 days for TKR: (ADVANCE 2) - 32 to 38 days for THR (ADVANCE 3) Primary endpoint: An efficacy criterion combining total VTEs 5 and deaths from all causes occurring during the treatment period (from the first day of taking the treatment until 2 days after the last intake). Secondary efficacy criteria: - criterion combining major VTEs 6 and deaths associated with a VTE occurring during the treatment period ( major efficacy criterion, being more clinically relevant). - And also: - each of the events of the various composite criteria taken individually - criterion combining symptomatic VTEs and deaths associated with a VTE (combining symptomatic DVTs and fatal and non-fatal PEs) - criterion combining symptomatic and asymptomatic proximal DVTs. 5 The total VTEs were defined by the proximal and distal DVTs, either asymptomatic detected by bilateral phlebography, or confirmed symptomatic VTEs and the non-fatal PEs. 6 The major VTEs have been defined by symptomatic or asymptomatic proximal DVTs and non-fatal PEs. 7/29

8 The net clinical benefit was evaluated with a criterion combining total VTEs, major bleeding events and deaths from all causes during the treatment period. Method and strategy for analysing the results: The non-inferiority and superiority tests were pre-specified for the two efficacy criteria, primary and secondary. Non-inferiority hypothesis: - as regards the primary efficacy criterion, the non-inferiority of apixaban was demonstrated if the upper limit of the 95% confidence interval (95% CI) for the relative risk (RR) was below As regards ADVANCE 2, the upper limit of the 95% CI for the difference between the two treatments needed moreover to be below 5.6%. - as regards the secondary major efficacy criterion, the non-inferiority of apixaban was demonstrated if the upper limit of the 95% CI for RR was below 1.5. Superiority hypothesis: as regards the primary and major secondary efficacy criteria, the superiority of apixaban was demonstrated if the upper limit of the 95% CI for RR was below 1. Statistical tests were performed with a unilateral α-risk of At the request of the health authorities, the tests were also performed with a bilateral α-risk of Calculation of the number of subjects necessary for the detection of asymptomatic DVTs reckoned on a percentage of venograms not done or non-evaluable proximally or distally of 30%, and proximally alone of 20%. These percentages are those which as a rule have been considered and found in recent trials of this type (Re-model, Renovate, Record 1 and Record 3). The ADVANCE 2 and ADVANCE 3 study protocols took this into account in calculating the number of subjects necessary to obtain adequate statistical power on the primary and secondary efficacy criteria. Four populations were defined for the analysis of the results: - Primary analysis population (mitt): randomised patients operated with an evaluable adjudicated venogram or an adjudicated thromboembolic event or patients who had died during the treatment period. - Per protocol population (PP): patients from the primary analysis population, excluding those with major protocol violations. - Secondary analysis population: patients from the primary analysis population, supplemented by those whose venograms are evaluable in the proximal venous segments. - Tolerance population: patients who have received at least one dose of treatment Efficacy results from the ADVANCE 2 study (TKR) Characteristics of the evaluated population In all, 3057 patients were randomised. More than 98% of them have received at least one dose of the study treatment and the same proportion of patients (i.e. 91.1%) completed the treatment period, both groups adhering to the protocol. The demographic characteristics of the patients on inclusion were similar in the two treatment groups, with a mean age of 66 years (over 60% were aged under 65 and 20% were aged at least 75 years), and the majority of the patients were female (72%), Caucasian (79%), with a mean weight of 78.5 kg with 36% of patients being overweight and 22% obese. Of the 43% of patients with impaired kidney function, 35% had mild renal impairment (Cr Cl between 51 and 80 ml/min) and 6% had moderate renal impairment(cr Cl between 30 and 50 ml/min). Finally, one patient in four had at least one thromboembolic risk factor. The patient populations evaluated are presented in the table below. The proportion of patients in each of them was similar in both treatment groups: 8/29

9 Table: Populations defined for analysis ADVANCE 2 Study (TKR) 2.5 mg 2 /day Enoxaparin 40 mg 1 /day Randomised patients, n Tolerance population, n (%) 1501 (98.2) 1508 (98.6) Primary analysis population (mitt*), n (%) 976 (63.9) 997 (65.2) Secondary analysis population, n (%) 1195 (78.2) 1199 (78.4) Per protocol efficacy population (PP), n (%) 907 (59.4) 921 (60.2) *mitt: intention-to-treat population The mean time between the first preoperative dose of enoxaparin and the start of the surgery was 13.1 hours in the enoxaparin group patients. The first postoperative dose was administered 12 to 24 hours after surgery in 88.6% of the patients in the apixaban group and 89.8% of those in the enoxaparin group. On average, patients received their first postoperative dose of treatment 19 hours after surgery, i.e. on the following morning in both treatment groups. The mean treatment duration was 12.1 ± 3.2 days for apixaban and 12.1 ± 2.8 days for enoxaparin. Results Primary efficacy endpoint: more than a third of patients (36% in the apixaban group and 35% in the enoxaparin group) was excluded from the primary efficacy analysis on account of a venogram not being done or non-evaluable. Table: Results for the primary efficacy endpoint in the PP and mitt populations ADVANCE 2 Study (TKR) PP population mitt population Enoxaparin Enoxaparin 2.5 mg 2 /day 40 mg 1 /day 2.5 mg 2 /day 40 mg 1 /day N Incidence, n (%) 135 (14.88) 228 (24.76) 147 (15.06) 243 (24.37) 95% CI [12.71; 17.36] [22.07; 27.66] [12.95; 17.46] [21.81; 27.14] Reduction in the relative risk versus enoxaparin 40% 38% 95% CI [27; 50]** [26; 49]** Bilateral test (p value) superiority - < *** Reduction in the absolute risk versus enoxaparin 9.83% 9.27% 95% CI [6.21; 13.45]** [5.79; 12.74]** Bilateral test (p value) non-inferiority < < NNT* - 11 * NNT: number needed to treat **: non-inferiority was demonstrated if the upper limit of the 95% CI of the difference in risk between the two treatments was < 5.6% (lower limit of the reduction in the relative risk > than -5.6%) and if the upper limit of the 95% CI of the relative risk was < 1.25 (lower limit of the reduction in the relative risk > than -25%) ***: superiority was demonstrated if the upper limit of the 95% CI of the RR was < 1 or p < /29

10 Sub-group analyses: the incidence of primary efficacy endpoint events was evaluated in various predetermined patient sub-populations (age, weight, BMI, renal impairment, number of thromboembolic risk factors); a post-hoc analysis was also performed on an exploratory basis in so-called fragile patients, defined as having at least one of the following three risk factors: weight < 50 kg, age 75 years or creatinine clearance < 50 ml/min. From these analyses it emerges that the effect on the reduction in primary efficacy endpoint events observed in the overall study population was uniform regardless of the predetermined patient sub-population. Major secondary efficacy endpoint: Regarding the criterion combining major VTEs + VTE-related deaths, the percentages of venograms not done or not evaluable on proximal segments was 20% in both groups. Table: Results for the secondary efficacy endpoint in the ADVANCE 2 Study (TKR), secondary analysis population 2.5 mg 2 /day Enoxaparin 40 mg 1 /day N Incidence, n (%) 13 (1.09) 26 (2.17) 95% CI [0.62; 1.88] [1.47; 3.18] Reduction in the relative risk versus enoxaparin 50% 95% CI [3; 74]** Bilateral test (p value) non-inferiority Bilateral test (p value) superiority *** Reduction in the absolute risk versus enoxaparin 1,04% 95% CI [0,05; 2,03] NNT* 96 * NNT: number needed to treat **: Non-inferiority was demonstrated if the upper limit of the 95% CI of the RR was < 1.5 (lower limit of the reduction in the relative risk > -50%) ***: Superiority was demonstrated if the upper limit of the 95% CI of the RR was < 1 or p < /29

11 - Other secondary efficacy endpoints: Table: Results for the other secondary efficacy endpoints in the ADVANCE 2 Study (TKR) 2.5 mg 2 /day Enoxaparin 40 mg 1 /day Events during the course of the treatment period Death from all causes, n/n a (%) 2/1528 (0.13) 0/1529 (0.00) VTE-related deaths, n/n a (%) 1/1528 (0.07) 0/1529 (0.00) Symptomatic VTEs and VTE-related deaths, n/n a (%) 7/1528 (0.46) 7/1529 (0.46) PEs (fatal or non-fatal), n/n a (%) 4/1528 (0.26) 0/1529 (0.00) Non-fatal PEs, n/n a (%) 3/1528 (0.20) 0/1529 (0.00) Total DVTs, n/n b (%) 142/971 (14.62) 243/997 (24.37) Symptomatic DVTs, n/n a (%) 3/1528 (0.2) 7/1529 (0.46) Symptomatic and asymptomatic proximal DVTs n/n c (%) Events during the course of the follow-up period 9/1192 (0.76) 26/1199 (2.17) Deaths from all causes, n/n d (%) 1/1458 (0.07) 1/1469 (0.07) VTE-related deaths, n/n d (%) 1/1458 (0.07) 0/1469 (0.00) Symptomatic VTEs and VTE-related deaths, n/n d (%) 5/1458 (0.34) 2/1469 (0.14) PEs (fatal or non-fatal), n/n d (%) 3/1458 (0.21) 1/1469 (0.07) Non-fatal PEs, n/n d (%) 2/1 458 (0.14) 1/1469 (0.07) Symptomatic DVTs, n/n d (%) 2/1458 (0.14) 1/1469 (0.07) Proximal symptomatic DVTs, n/n d (%) 2/1458 (0.14) 1/1469 (0.07) A patient could present more than one event. VTE: Venous Thromboembolic Event DVT: Deep Vein Thrombosis PE: Pulmonary Embolism a Population analysed: randomised patients b Population analysed: randomised patients operated on with an evaluable adjudicated venogram or an adjudicated event forming part of the criterion during the treatment period c Population analysed: randomised patients operated on with an evaluable and adjudicated bilateral proximal venogram or an adjudicated event forming part of the criterion during the treatment period d Population analysed: randomised patients included in the follow-up period 11/29

12 3.3. Efficacy results from the ADVANCE 3 Study (THR) Characteristics of the evaluated population In all, 5407 patients were randomised. More than 98% of the randomised patients received at least one dose of the study treatment in the two groups. A total of 91.7% in the apixaban group and 90.7% in the enoxaparin group completed the treatment period. The characteristics of the enrolled patients were similar in both treatment groups, with a mean age of 61 years (about 12% were aged 75 or over), 53% were women and 90% Caucasian, their mean weight was 79 kg, with 32% of the patients being overweight and 15% obese. The majority of the patients had normal (65%) or slightly impaired (29.5%) kidney function. More than one patient in four had at least one associated thromboembolic risk factor. The patient populations included in the analysis are presented in the table below. The proportion of patients in each of them was similar in both treatment groups: Table: Populations defined for analysis ADVANCE 3 Study (THR) 2.5 mg 2 /day Enoxaparin 40 mg 1 /day Randomised patients, n Tolerance population, n (%) 2673 (98.7) 2659 (98.5) Primary analysis population (mitt*), n (%) 1949 (72.0) 1917 (71.0) Secondary analysis population, n (%) 2199 (81.2) 2195 (81.3) Per protocol population (PP), n (%) 1850 (68.3) 1829 (67.8) *mitt: intention-to-treat population The mean time between the first preoperative dose of enoxaparin and the start of the surgery was 13.6 hours, in conformity with the protocol. The first postoperative dose was administered 12 to 24 hours after surgery in 86.5% of the patients in the apixaban group and 86.2% of those in the enoxaparin group. On average, patients received their first postoperative dose of treatment 19 hours after surgery, i.e. on the following morning in both treatment groups. The mean treatment duration was 34.0 ± 7.7 days for apixaban and 33.9 ± 7.8 days for enoxaparin. Results Primary efficacy endpoint: almost 30% of the patients (28% in the apixaban group and 29% in the enoxaparin group) were excluded from the primary efficacy analysis on account of a venogram not being done or non-evaluable. 12/29

13 Table: Results for the primary efficacy endpoint in the PP and mitt populations ADVANCE 3 Study (THR) PP population mitt population 2.5 mg 2 /day Enoxaparin 40 mg 1 /day 2.5 mg 2 /day Enoxaparin 40 mg 1 /day N Incidence, n (%) 24 (1.30) 68 (3.72) 27 (1.39) 74 (3.86) 95% CI [0.87; 1.94] [2.94; 4.70] [0.95; 2.02] [3.08; 4.83] Reduction in the relative risk versus enoxaparin 65% 64% 95% CI [46; 80]** [46; 78]** Bilateral test (p value) non-inferiority - < Bilateral test (p value) superiority - < *** Reduction in the absolute risk versus enoxaparin 2.42% 2.47% 95% CI [1.44; 3.49] [1.50; 3.54] NNT* - 40 *NNT: number needed to treat **: Non-inferiority is demonstrated if the upper limit of the 95% CI of the RR was < 1.25 (i.e. the lower limit of the reduction in the relative risk is > -25%) ***: Superiority is demonstrated if the upper limit of the 95% CI of the RR was < 1 or the p value of the superiority test is < 0.05 Sub-group analyses: the effect on the reduction in primary efficacy endpoint events observed in the overall ADVANCE 3 study population was uniform regardless of the predetermined patient sub-population (age, weight, BMI, renal impairment, number of thromboembolic risk factors, fragile patients). Major secondary efficacy endpoint: Regarding the criterion combining major VTEs and VTE-related deaths: the percentage of venograms not done or not evaluable on the proximal segments was 20% in both groups. Table: Results for the secondary efficacy endpoint in the ADVANCE 3 Study (THR), secondary analysis population 2.5 mg 2 /day n = 2199 Enoxaparin 40 mg 1 /day n = 2195 Incidence, n (%) 10 (0.45) 25 (1.14) 95% CI [0.24; 0.85] [0.77; 1.69] Reduction in the relative risk versus enoxaparin 60% 95% CI [20; 85]** Bilateral test (p value) non-inferiority Bilateral test (p value) superiority *** Reduction in the absolute risk versus enoxaparin 0.68% 95% CI [0.17; 1.27] Bilateral test (p value) superiority NNT* 147 *NNT: number needed to treat **: non-inferiority was demonstrated if the upper limit of the 95% CI of the RR was < 1.5 (i.e. the lower limit of the reduction in the relative risk was > -50%) ***: superiority was demonstrated if the upper limit of the 95% CI of the RR was < 1 or if the p value for the superiority test was < /29

14 Other secondary efficacy endpoints Table: Results for the other secondary efficacy endpoints ADVANCE 3 Study (THR) 2.5 mg 2 /day Enoxaparin 40 mg 1 /day Events during the course of the treatment period Death from all causes, n/n a (%) 3/2708 (0.11) 1/2699 (0.04) VTE-related deaths, n/n a (%) 1/2708 (0.04) 0/2699 (0.00) Symptomatic VTEs and VTE-related deaths, n/n a (%) 4/2708 (0.15) 10/2699 (0.37) PEs (fatal or non-fatal), n/n a (%) 3/2708 (0.11) 5/2699 (0.19) Non-fatal PEs, n/n a (%) 2/2708 (0.07) 5/2699 (0.19) Total DVTs, n/n b (%) 22/1944 (1.13) 68/1911 (3.56) Symptomatic DVTs, n/n a (%) 1/2708 (0.04) 5/2699 (0.19) Symptomatic and asymptomatic proximal DVTs n/n c (%) 7/2196 (0.32) 20/2190 (0.91) Events during the course of the follow-up period Deaths from all causes, n/n d (%) 2/2 598 (0.08) 1/2577 (0.04) VTE-related deaths, n/n d (%) 0 0 Symptomatic VTEs and VTE-related deaths, n/n d (%) 0 6/2577 (0.23) PEs (fatal or non-fatal), n/n d (%) 0 4/2577 (0.16) Non-fatal PEs, n/n d (%) 0 4/2577 (0.16) Symptomatic DVTs, n/n d (%) 0 3/2577 (0.12) Proximal symptomatic DVTs, n/n d (%) 0 3/2577 (0.12) A patient could present more than one event. a Population analysed: randomised patients b Population analysed: randomised patients operated on with an evaluable adjudicated venogram or an adjudicated event forming part of the criterion during the treatment period c Population analysed: randomised patients operated on with an evaluable and adjudicated bilateral proximal venogram or an adjudicated event forming part of the criterion during the treatment period d Population analysed: randomised patients included in the follow-up period 14/29

15 3.4. Adverse effects The assessment of the adverse effects of apixaban (ELIQUIS) is based on the data from four clinical studies (11,828 patients): one phase II study (APROPOS) and three phase III studies (ADVANCE 1, ADVANCE 2 and ADVANCE 3). The enoxaparin dosage was 30 mg 2 /day in the APROPOS and ADVANCE 1 studies, and 40 mg 1 /day in the ADVANCE 2 and ADVANCE 3 studies. The mean duration of exposure was 12 days in the TKR studies (APROPOS, ADVANCE 1 and ADVANCE 2) and 35 days in the THR study (ADVANCE 3). There were 5924 patients exposed to 2.5 mg apixaban 2 /day. In all, 11% of these patients had adverse effects. They should be interpreted taking the surgical context into account. A summary of the adverse events that occurred during the treatment period is presented in Appendix 2 to this opinion. Table: Events reported with a frequency > 5% during the course of the treatment period APROPOS (TKR), ADVANCE 1 (TKR), ADVANCE 2 (TKR), ADVANCE 3 (THR) studies n = 5924 Enoxaparin n = 5904 Total number of patients with at least one adverse event, n (%) 3812 (64.3) 3936 (66.7) Nausea, n (%) 821 (13.9) 916 (15.5) Constipation, n (%) 632 (10.7) 708 (12.0) Fever, n (%) 470 (7.9) 487 (8.2) Treatment-induced pain, n (%) 463 (7.8) 476 (8.1) Vomiting, n (%) 398 (6.7) 464 (7.9) Peripheral oedema, n (%) 372 (6.3) 381 (6.5) Hypotension, n (%) 340 (5.7) 338 (5.7) Dizziness, n (%) 321 (5.4) 275 (4.7) Deep vein thrombosis, n (%) 291 (4.9) 352 (6.0) The frequency of serious adverse effects was similar in the apixaban and enoxaparin groups for each of the periods (treatment and follow-up) and for each of the four studies. The most common adverse effects were: anaemia, bleeding, bruising and nausea. The percentage of adverse event-related treatment withdrawals was similar in both apixaban and enoxaparin arms and affected fewer than 3% of the patients. Risk of bleeding The incidence of major bleeding measured on the basis of the composite criteria containing data on major bleeding, clinically-relevant non-major bleeding and all bleeding were similar for patients treated with apixaban 2.5 mg or with enoxaparin 40 mg. All bleeding criteria included bleeding at the site of surgery. During the ADVANCE 2 Study (TKR), major bleeding or clinically-relevant non-major bleeding was reported over the course of the treatment period in 3.5% of patients in the apixaban group and in 4.8% of those in the enoxaparin group. Bleeding was observed in particular at the surgical site (62 patients (4.1%) under apixaban and 80 patients (5.3%) under enoxaparin) and at the gastrointestinal level (6 patients (0.4%) for each of the groups). No bleeding with a fatal outcome was reported. During the follow-up period, major bleeding was observed only in the enoxaparin group. Bleeding tolerance was assessed in several predetermined patient sub-populations: according to age, weight, BMI, renal impairment, the number of thromboembolic risk factors and fragile patients. The results in these various sub-groups are consistent with those in the overall population as regards major bleeding and clinically-relevant non-major bleeding. 15/29

16 During the ADVANCE 3 Study (THR), major bleeding or clinically-relevant non-major bleeding was reported over the course of the treatment period in 4.8% of patients in the apixaban group and in 5.0% of those in the enoxaparin group. Bleeding was observed principally at the surgical site (177 patients (6.6%) on apixaban and 173 patients (6.5%) on enoxaparin), at the gastrointestinal level (19 patients (0.7%) on apixaban) and 5 patients (0.2%) on enoxaparin) and due to haemarthrosis (3 patients (0.1%) on apixaban and 5 patients (0.2%) on enoxaparin). No bleeding with a fatal outcome was reported. During the follow-up period, two cases of major or clinically-relevant bleeding were observed on apixaban as against nine in the enoxaparin group. Irrespective of the patient sub-population studied, no significant difference was observed between the two arms as regards major or clinically-relevant non-major bleeding. The SPC states that as with anticoagulants, patients treated with ELIQUIS are to be carefully observed for signs of bleeding. It is recommended to be used with caution in conditions with increased risk of haemorrhage, such as: congenital or acquired coagulation disorders; active ulcerative gastrointestinal disease; bacterial endocarditis, thrombocytopenia; platelet disorders; history of haemorrhagic stroke; severe uncontrolled hypertension; and recent brain, spinal or ophthalmological surgery. ELIQUIS administration should be discontinued if severe haemorrhage occurs. In the event of overdose, there is no antidote to apixaban (ELIQUIS). Risk management plan accompanying the granting of Marketing Authorisation The medicinal product is covered by a risk management plan that mentions bleeding as an identified risk, and as a potential risk, the increases in the liver function parameters. Other data The aim of one study (APPRAISE II) was to assess the efficacy and tolerance of apixaban 5 mg 2 /day in comparison to placebo in acute coronary syndrome patients. Most of the patients (about 80%) had been receiving apixaban as an adjunct to antiplatelet monotherapy or dual therapy with aspirin and clopidogrel. The study was suspended early on the advice of the independent data monitoring committee owing to the increased bleeding encountered in the apixaban group in comparison to the placebo group (all bleeding: 17.4% vs. 7.6%), possibly explainable by the inclusion of apixaban in the antiplatelet dual or triple therapy, in contrast to the placebo group. Renal impairment (SPC) Because there is no clinical experience in patients with creatinine clearance < 15 ml/min or in patients undergoing dialysis, apixaban is not recommended in these patients. Limited clinical data in patients with severe renal impairment (creatinine clearance ml/min) indicate that apixaban plasma concentrations are increased in this population, therefore, apixaban is to be used with caution in these patients. No dose adjustment is necessary in patients with mild or moderate renal impairment. 16/29

17 Hepatic impairment (SPC) ELIQUIS is contraindicated in patients with hepatic disease associated with coagulopathy and clinically relevant bleeding risk. It is not recommended in patients with severe hepatic impairment. It should be used with caution in patients with mild or moderate hepatic impairment (Child-Pugh A or B). No dose adjustment is required in patients with mild or moderate hepatic impairment. Patients with elevated liver enzymes (ALT/AST > 2 ULN) or total bilirubin level 1.5 ULN were excluded from clinical trials. Therefore ELIQUIS should be used with caution in this population. ALT should be measured as part of the standard pre-operative assessment Indirect comparisons Following elective hip (THR) or knee (TKR) replacement surgery, there are no studies available that offer a direct comparison of the efficacy and adverse effects of thromboprophylaxis with apixaban (ELIQUIS) and those with dabigatran etexilate (PRADAXA) or with rivaroxaban (XARELTO) on account of concomitant development. An indirect comparison was however carried out by the applicant. The following endpoints were taken into consideration: Efficacy criteria: - Total VTEs and deaths from all causes: composite criterion combining proximal or distal DVTs (detected or confirmed by venography), non-fatal pulmonary embolisms and deaths from all causes. This is the primary endpoint in these studies. - Total deep vein thromboses (DVTs) - Major VTEs and VTE-related deaths: composite criterion combining proximal DVTs (detected or confirmed by venography), non-fatal pulmonary embolisms and VTE-related deaths. Tolerancecriteria: - Major bleeding - Clinically-relevant non-major bleeding (CRNM) - Composite criterion combining clinically-relevant major and non-major bleeding (CRNM) - All bleeding The hypothesis of exchangeability (according to which trials are similar enough and/or the effects of drugs versus their common comparison drug are sufficiently stable irrespective of patient characteristics to guarantee reproducibility of the results) seems plausible: there are contemporary trials (published between 2007 and 2010 for phase III trials), conducted in accordance with similar experimental designs and with enrolled patients of a similar profile: 17/29

18 Table: Description of the main characteristics of the patients enrolled in these trials Trial Mean age (years) Weight (kg) BMI (kg/m 2 ) Duration of surgery (min) Creatinine clearance > 60 ml/min Women (%) History of venous thrombo embolis m (%) History of orthopaedic surgery (%) THR trials ADVANCE % RECORD ODIXa-HIP mg RECORD RE-NOVATE (mean ml/min) TKR trials ADVANCE % 72 2 (DVT) 27 ADVANCE % APROPOS mg RECORD RECORD RE-NOVATE RE-MODEL RE- MOBILIZE (mean 82.9 ml/min) Methodology of indirect comparisons These were carried out using the method of adjusted indirect comparisons from the synthesis by meta-analysis of the results of the direct comparisons available. As regards enoxaparin, the clinical trials at a dosage of 30 mg 2 /day (North American Scheme) and 40 mg 1 /day (European Scheme) were the ones considered. A systematic review of the randomised trials evaluating one of the three medicinal products (dabigatran, rivaroxaban and apixaban) was conducted on 8 July 2010 in the Cochrane Library, Medline and Embase databases, as well in the abstracts of the discipline s main congresses. The results of the trials were combined using a method of combining odds ratios with a random model. Results Thirteen trials (29,957 patients) were taken into consideration: four assessed apixaban (three in TKR and one in THR; 11,946 patients), five rivaroxaban (two in TKR and three in THR; 10,519 patients) and four dabigatran (two in TKR and two in THR; 7,492 patients). Two doses of dabigatran, 150 mg and 220 mg, were investigated in all the trials except one (the RENOVATE 2 trial in hip replacement surgery where only the 220 mg dose was investigated). The durations of thromboprophylaxis varied depending on the type of surgery: between 28 and 35 days for the hip and between 10 and 15 days for the knee. One trial with dabigatran in the knee (REMODEL) tested a shorter duration of 6 to 10 days. It emerges from the indirect comparisons (cf. the more detailed presentation in Appendix 1) that apixaban does not appear to be inferior to dabigatran etexilate or to rivaroxaban, and this applies to any of the efficacy or bleeding tolerance criteria used. These comparisons suggest that apixaban and dabigatran etexilate 220 mg have a similar effectiveness after a total hip or knee replacement (in terms of major VTEs + VTE-related deaths). Rivaroxaban could be more effective than apixaban, but at the price of a higher risk of bleeding. 7 Lassen MR, Davidson BL, Gallus A, et al. The efficacy and safety of apixaban, an oral, direct factor Xa inhibitor, as thromboprophylaxis in patients following total knee replacement (APROPOS). J Thromb Haemost 2007; 5: /29

19 3.6. Other data The MA, granted in accordance with the European centralised registration procedure, was accompanied by a request for follow-up studies. Two use studies will assess, retrospectively and descriptively, the use of ELIQUIS in the indication and outside the indication from insurance databases (Germany) and from a Register (National Patient Register in Sweden). A Paediatric Investigation Plan, comprising a pharmacokinetic study and a clinical study into the prevention of venous thromboembolic events versus placebo in children, has been approved by EMEA. The medicinal product is currently undergoing phase III studies that are likely to lead to a request to extend the indication within the next three years: in the prevention of venous thromboembolic events in medically hospitalised patients, in the treatment of venous thromboembolic events (VTEs) and in the prevention of stroke and systemic embolisms in patients with atrial fibrillation Discussion Interpreting the results of the ADVANCE 2 and 3 studies gives rise to a number of comments: To appreciate what apixaban has to offer in comparison to enoxaparin, it is right and proper to seek to assess the clinical effectiveness taking into account the risk of bleeding. Based on the incidence of total VTEs, major bleeding and deaths from all causes occurring during the treatment period, the clinical benefit of apixaban in comparison to enoxaparin is in favour of apixaban in both the ADVANCE 2 and ADVANCE 3 studies. In the ADVANCE 2 Study: 16% (95% CI: [13.74; 18.34]) in the apixaban group versus 26% (95% CI: [23.04; 28.45]), in the enoxaparin group, i.e. a reduction in the relative risk versus enoxaparin of 38% (95% CI [26%; 48%]) and in the absolute risk of 9.71% (95% CI [6.17; 13.25]). In the ADVANCE 3 Study: 2.5% (95% CI [1.89; 3.30]) in the apixaban group versus 4.72% (95% CI [3.86; 5.78]) in the enoxaparin group, or a reduction in the relative risk of 47% (95% CI [26; 63] and in the absolute risk of 2.22% (95% CI [1.06; 3.44]). However, the clinical benefit was evaluated on the basis of a scarcely clinically-relevant primary endpoint, combining events of different degrees of seriousness: death, pulmonary embolism, symptomatic VTEs which were mainly proximal and asymptomatic VTEs which were mainly distal. This composite criterion, while common to all comparators, does not permit a proper assessment of the magnitude of the clinical benefit in favour of apixaban, especially as the events that have occurred have been mainly asymptomatic and distal. Moreover, the results as regards the primary endpoint are not available in almost 30% of the patients. The fact of having started enoxaparin before the surgical operation may also have an impact on the occurrence of bleeding. 19/29

20 3.8. Conclusion (ELIQUIS) in thromboprophylaxis was evaluated in two studies (ADVANCE-2 and 3), comparing in double-blind mode 2.5 mg apixaban 2 /day orally with 40 mg enoxaparin 1 /day subcutaneously. One of these studies involved 5407 patients scheduled for total hip replacement (THR) and 3057 patients scheduled for total knee replacement (TKR). The first dose was administered 12 to 24 hours after surgery in the case of apixaban and 9 to 15 hours before surgery in the case of enoxaparin. The medicinal products were administered for 10 to 14 days in the TKR study and for 32 to 38 days in the THR study. These two studies set out to test the non-inferiority of apixaban by comparison with enoxaparin and, secondarily, if non-inferiority was assured, the superiority of apixaban with respect to enoxaparin was tested. The primary endpoint was the occurrence of VTEs and/or overall death. This criterion is not the most clinically relevant as it mixes together, in addition to death from all causes, both asymptomatic VTEs detected by bilateral venography and confirmed symptomatic VTEs and non-fatal PEs. Efficacy results: In both studies apixaban was more effective than enoxaparin in reducing the onset of the following events: VTEs and/or overall death (primary endpoint), major VTEs and/or VTE-related deaths (secondary endpoint). Effect size: After TKR (ADVANCE 2): - the incidence of total VTEs and/or overall death in the mitt population was 15.06% with apixaban and 24.37% with enoxaparin, i.e. an absolute reduction in favour of apixaban of 9.27%. On average, therefore, 11 patients (NNT) have to be treated with apixaban, as opposed to enoxaparin, to avoid one venous thromboembolic event or one death. - the incidence of major VTEs and/or VTE-related deaths in the so-called secondary analysis population was 1.09% with apixaban and 2.17% with enoxaparin, i.e. an absolute reduction in favour of apixaban of 1.04%. On average, 96 patients (NNT) have to be treated with apixaban, as opposed to enoxaparin, to avoid one major venous thromboembolic event or one VTE-related death. - There were seven pulmonary embolisms, two of which were fatal, with apixaban as against just one with enoxaparin during the course of treatment and then of the follow-up. After THR (ADVANCE 3): - the incidence of total VTEs and/or global death in the mitt population was 1.39% with apixaban and 3.86% with enoxaparin, i.e. an absolute risk reduction in favour of apixaban of 2.47% (NNT = 40). - the incidence of major VTEs and/or VTE-related deaths in the so-called secondary analysis population was 0.45% with apixaban and 1.14% with enoxaparin, i.e. an absolute risk reduction of 0.68% (NNT = 147). - there were three pulmonary embolisms, one of which was fatal, with apixaban as against nine with enoxaparin during the course of treatment and then of the follow-up. The clinical benefit of apixaban in comparison to enoxaparin is slight and relates essentially to the occurrence of asymptomatic VTEs. No explanation can be given for the higher number of PEs observed with apixaban after TKR. An indirect comparison of good methodological quality tends to show that apixaban (ELIQUIS) is at least as effective in these two indications as rivaroxaban (XARELTO) and dabigatran (PRADAXA). 20/29

21 Adverse effects: The incidence of certain adverse events such as bleeding, anaemia and abnormal aminotransferase levels was lower with apixaban than with enoxaparin in the phase II and III studies of total hip or knee replacement. As regards the bleeding risk, there was no difference between apixaban and enoxaparin: TKR: major bleeding or clinically-relevant non-major bleeding (3.5% with apixaban vs 4.8% with enoxaparin). This was observed in particular at the surgical site (4.1% vs 5.3%) and gastrointestinally (0.4% in both groups). THR: major bleeding or clinically-relevant non-major bleeding (4.8% with apixaban vs 5.0% with enoxaparin). This was observed in particular at the surgical site (6.6% vs 6.5%) and gastrointestinally (0.7% vs 0.2%). In these two studies, 415 patients (including 203 in the apixaban group) had moderate renal impairmentwhich, according to the SPC, does not require any dosage adjustment (no more than weight or age). should be used with caution in cases of severe renal impairment owing to the lack of clinical data. When the creatinine clearance is below 15 ml/min or in the case of dialysis, its use is not recommended owing to the lack of clinical experience. Transferability The clinical studies were performed in patient populations whose mean age was 61 years after THR and 66 years after TKR. Patients aged over 75 years represented 12% (THR) to 20% (TKR) of the patient populations. According to the data from PMSI (2006), patients aged over 80 years account for 20% of patients having a THR and 17% of those having a TKR. Clinical data on patients with moderate renal insufficiency are limited. 21/29

22 4. TRANSPARENCY COMMITTEE CONCLUSIONS 4.1. Actual benefit Venous thromboembolic disease is one of the primary causes of cardiovascular death (along with myocardial infarction and stroke): it is a serious and potentially life-threatening condition (potentially fatal pulmonary embolism) or else it can have significant sequelae (post-thrombotic syndrome). Patients undergoing major orthopaedic surgery for elective total hip or knee replacement represent a population at high thromboembolic risk under thromboprophylaxis. In these patients ELIQUIS (apixaban) is a front-line treatment for the primary prevention of venous thromboembolic events. (ELIQUIS) has a high efficacy/adverse effects ratio. Public health benefit The public health burden of venous thromboembolic disease (VTED) is considerable. In the prophylaxis of venous thromboembolic events, to have available effective and well-tolerated treatments to control bleeding, especially in at-risk subjects, does constitute a public health need that is an established priority (objectives 69 and 72 of the Law of 9 August 2004 relating to Public Health policy). Based on the available data, ELIQUIS can be expected to have a minor additional impact compared to current therapeutic management, in terms of reducing the morbidity and mortality associated with the complications of VTED or with major bleeding induced by antithrombotic treatments in patients who have undergone elective total hip or knee replacement surgery. There is no guarantee that the experimental data can be transferred into real life (attrition bias, composite assessment criterion that includes asymptomatic non-clinical events, venographic confirmation not used routinely), and this will depend in particular on the profile of the patients treated and on compliance, which are liable to be different in real life than in trial patients. A positive impact of ELIQUIS on the organisation of care could be expected owing to the lack of necessity for specific biological monitoring and to its oral administration. However, the relatively short treatment duration and the usual approach to managing these patients (in rehabilitation centres in particular), could limit this impact. Moreover, the lack of an antidote in a bleeding situation, possibly necessitating plasma exchange, could have a negative impact. It is therefore difficult to assess the impact that this proprietary medicinal product will have on the organisation of healthcare services. All things considered, ELIQUIS should be able to contribute to the response to an identified public health need. ELIQUIS is therefore expected to be of benefit to public health. This benefit is low. There are medicinal alternatives to apixaban (ELIQUIS) by the oral route (dabigatran etexilate; rivaroxaban (XARELTO); vitamin K antagonists) and administered by injection (LMWH, UFH and fondaparinux sodium, among others). In conclusion, the actual benefit of ELIQUIS is substantial Improvement in actual benefit (IAB) ELIQUIS offers a level IV improvement in actual benefit (minor IAB) compared to enoxaparin in terms of efficacy for thromboprophylaxis following total knee or hip replacement surgery. 22/29

23 4.3. Therapeutic use The aim of preventing venous thromboembolic disease is to avoid the two complications of pulmonary embolism and post-thrombotic syndrome; it is usually pursued until the patient is able to walk freely. After major orthopaedic surgery of the lower limb for a total hip or knee replacement, the thromboembolic risk is high and requires the routine prescription of prophylactic measures. In this case, short-term thromboprophylaxis (for 10 days after surgery) is therefore recommended: the first-line anticoagulant prescribed may be a low-molecular-weight heparin (LMWH non-inferiority in comparison to UFH) or fondaparinux 2.5 mg (ARIXTRA 2.5 mg). An unfractionated heparin (UFH; morbidity/mortality data available for UFHs) is recommended in cases of severe renal insufficiency. In cases of total hip replacement surgery it is recommended to continue with the thromboprophylaxis. Only UFHs and two LMWHs enoxaparin (LOVENOX) and dalteparin (FRAGMIN) are indicated in prevention for up to 35 days. Alternating thromboprophylaxis in the short term with an oral anticoagulant (VKA) could also be considered. PRADAXA (dabigatran etexilate) and XARELTO (rivaroxaban) are active oral antithrombotics that can be prescribed as first-line drugs. Their efficacy and tolerance when used for short-term (after knee replacement) and longer-term (after hip replacement) prophylaxis have been compared with those of enoxaparin (LOVENOX): - PRADAXA has demonstrated its non-inferiority with respect to enoxaparin (LOVENOX) on a composite criterion (combining total VTE incidence and deaths from all causes) with a similar bleeding risk. - XARELTO (rivaroxaban) has demonstrated a slightly superior efficacy with a daily dose of 10 mg/day in adults in comparison to enoxaparin (LOVENOX) on a composite criterion without any increased bleeding risk. This clinical effectiveness was established correctly. It is not known to what extent this additional effectiveness is accompanied by a reduction in the clinical events that one tries to avoid (death, pulmonary embolisms, symptomatic venous thromboses and their complications). According to the SPC, XARELTO may be prescribed to elderly patients aged over 65 without any need to adjust the dosage, as well as to overweight (> 120 kg) or underweight (< 50 kg) adults. However, the clinical data are limited (few patients have been assessed) and an increased risk of bleeding cannot be ruled out, in light of the increased bleeding risk observed in the RECORD studies). In patients with moderate or severe renal impairment, the reference treatment is UFH; the use of LMWHs is not recommended (and contraindicated if Cr Cl < 20 ml/min). In some patients (those with moderate renal impairment, subjects over 75 years of age), PRADAXA is recommended at a dosage of 150 mg/day for thromboprophylaxis, but clinical data are limited in these patients. The administration of 2.5 mg s.c. of fondaparinux sodium (ARIXTRA) seems to put these patients more at risk. Fondaparinux sodium is contraindicated if Cr Cl < 30 ml/min, the data are limited when 20 < Cr Cl < 30 ml/min. Rivaroxaban (XARELTO) may be prescribed, without any need for dosage adjustment, in cases of severe renal insufficiency when the Cr Cl > 15 ml/min). It should be prescribed with caution when 15 < Cr Cl < 30 ml/min. Clinical data are however limited in these patients. Fondaparinux (ARIXTRA 2.5 mg s.c.), dabigatran etexilate (PRADAXA per os) and rivaroxaban (XARELTO per os) do not require routine monitoring of the coagulation parameters. Place of apixaban in the thromboprophylaxis of VTED ELIQUIS (apixaban) is a new antithrombotic also active orally and which may be prescribed as a first-line drug. It represents an alternative to enoxaparin (s.c. route), over which it has a slight superiority in efficacy without any obvious increased bleeding risk. It seems to have an antithrombotic efficacy/bleeding risk ratio of the same order as that of dabigatran etexilate and of rivaroxaban. Like dabigatran and rivaroxaban, there is no antidote in the event of overexposure to apixaban, especially in the presence of peri- or postoperative bleeding. 23/29

24 The assessment of apixaban in current practice will be useful in order to be better able to estimate, among other things, the incidence and impact of bleeding and the efficacy of the thromboprophylaxis, especially as regards compliance (two intakes per day)., dabigatran etexilate and rivaroxaban are not recommended in patients undergoing hip fracture surgery in the absence of clinical data. During the course of the surgical operation there may be a reduction in the glomerular filtration rate. Because of its metabolism, the risk of apixaban accumulation in moderate renal impairment cases could be less than with rivaroxaban and dabigatran etexilate (dialysable). However, its potential value in renal impairment cases, on account of its low kidney excretion rate was not demonstrated, as patients with severe renal impairment had been excluded from the studies Target population The target population is defined as adult patients operated on for total hip or knee replacement. Quantitative assessment: according to data from the PMSI (programme for the medicalisation of information systems) database Medicine Surgery Obstetrics in 2010, there were 200,562 admissions involving knee or hip replacement surgery. Note: This estimate tends to exaggerate the target population likely to benefit from apixaban thromboprophylaxis given the prevalence of severe renal impairment in the elderly population Transparency Committee recommendations The transparency Committee recommends inclusion on the list of medicines refundable by National Health Insurance and on the list of medicines approved for hospitals use and various public services. Request for a study: The Transparency Committee would like to set up a cohort study following up patients treated with ELIQUIS in France in order to determine the following: - characteristics of the patients treated (age, type of surgery, type of anaesthesia, comorbidities, etc.); - actual conditions of use of ELIQUIS (dosage, treatment duration, adherence to the dosage regimen, compliance, concomitant treatments, etc.); - frequency of occurrence of clinical venous thromboembolic events; - tolerancein terms of major bleeds; - impact on the organisation of healthcare (less recourse to biological monitoring and to nursing procedures and movements, management of major bleeds, etc.). The duration of the study will need to be justified by an independent scientific committee. If scheduled or ongoing studies, in particular within the remit of the European Risk Management plan, fail to answer all the questions raised by the Transparency Committee, a specific study will need to be conducted. The protocol will be examined in conjunction with Afssaps as regards the objectives about which the latter is, in particular, tolerance. 24/29

25 Reasons for requesting POST-REGISTRATION data The results of studies that have assessed the efficacy and tolerance of apixaban rely essentially on demonstrating a benefit based on a primary endpoint combining clinical events with asymptomatic events diagnosed by a venographic examination that is little used in practice. These results, moreover, are only available in the per protocol or mitt population, excluding 30% of the enrolled population. Besides, the treatment persistence and compliance of patients treated with apixaban (two oral intakes a day) is not guaranteed in current practice and managing a bleed under treatment is complicated by the lack of any antidote. The transferability of the data presented to current practice is also debatable, and it would be necessary to provide additional data, under actual conditions of use, comparing apixaban with the usual management of adult patients undergoing elective surgery, so as to be able to document the following points: - conditions of use of the treatments employed in managing the patient; - characteristics of the patients treated; - treatment compliance; - impact on morbidity/mortality (occurrence of clinical venous thromboembolic events, major bleeds) Packaging: Appropriate for the prescription conditions Reimbursement rate: 65%. 25/29

26 APPENDIX 1 Results of indirect comparisons of apixaban, dabigatran etexilate and rivaroxaban - Thromboprophylaxis after knee replacement surgery (TKR): Figures: Efficacy and tolerance results of the indirect comparisons in TKR Efficacy Total VTEs + deaths from all causes Odds ratio (95% CI) Major VTEs + VTE-related deaths DVTs In favour of apaxiban In favour of the control Bleeding tolerance 26/29

27 Major bleeding Odds ratio (95% CI) CRNM bleeding Major or CRNM bleeding All bleeding In favour of apaxiban In favour of the control - Thromboprophylaxis after hip surgery (THR): Figures: Efficacy and tolerance results of the indirect comparisons in THR Efficacy Total VTEs + deaths from all causes Odds ratio (95% CI) Major VTEs + VTE-related deaths DVTs In favour of apaxiban In favour of the control Bleeding tolerance 27/29