The legally binding text is the original French version TRANSPARENCY COMMITTEE OPINION. 14 March 2012

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1 The legally binding text is the original French version TRANSPARENCY COMMITTEE OPINION 14 March 2012 XARELTO 15 mg film-coated tablets B/14 (CIP code: ) B/28 (CIP code: ) B/42 (CIP code: ) B/10 (CIP code: ) B/100 (CIP code: ) XARELTO 20 mg film-coated tablets B/14 (CIP code: ) B/28 (CIP code: ) B/10 (CIP code: ) B/100 (CIP code: ) Applicant: BAYER SANTE ATC code: B01AX06 List I Date of Marketing Authorisation (centralised European): 09 December 2011 (Rapporteur country: Sweden) Reason for request: Inclusion on the list of medicines refundable by National Health Insurance (B/14, B/28 and B/42 for the 15 mg/tablet dosage and B/14 and B/28 for the 20 mg/tablet dosage) and approved for hospital use (B/10 and B/100 for both dosages) in the extension of indication: Treatment of deep venous thrombosis (DVP) and prevention of recurrent DVT and pulmonary embolism (PE) following an acute DVP in adults. Medical, Economic and Public Health Assessment Division 1/25

2 1. CHARACTERISTICS OF THE MEDICINAL PRODUCT 1.1. Active ingredient Indication Prevention of stroke and systemic embolism in adult patients with non-valvular atrial fibrillation with one or more risk factors, such as congestive heart failure, hypertension, age 75 years, diabetes mellitus, prior stroke or transient ischaemic attack. This extension of the indication was also the subject of a request for inclusion. Treatment of deep venous thrombosis (DVP) and prevention of recurrent DVT and pulmonary embolism (PE) following an acute DVP in adults. NB: XARELTO 10 mg tablets are indicated for Prevention of venous thromboembolism (VTE) in adult patients undergoing elective hip or knee replacement surgery Dosage The recommended dose for the initial treatment of acute DVT is 15 mg twice daily for the first three weeks followed by 20 mg once daily for the continued treatment and prevention of recurrent DVT and PE. Dosing schedule Maximum daily dose Day mg twice daily 30 mg Day 22 and onwards 20 mg once daily 20 mg The duration of therapy should be individualised after careful assessment of the treatment benefit against the risk for bleeding (see section 4.4). Short duration of therapy (3 months) should be based on transient risk factors (e.g. recent surgery, trauma, immobilisation) and longer durations should be based on permanent risk factors or idiopathic DVT. Experience with XARELTO in this indication for more than 12 months is limited. If a dose is missed during the 15 mg twice daily treatment phase (day 1-21), the patient should take XARELTO immediately to ensure intake of 30 mg XARELTO per day. In this case two 15 mg tablets may be taken at once. The patient should continue with the regular 15 mg twice daily intake as recommended on the following day. If a dose is missed during the 20mg once daily treatment phase (day 22 and onwards), the patient should take XARELTO immediately, and continue on the following day with the once daily intake as recommended. The dose should not be doubled within the same day to make up for a missed dose. Converting from Vitamin K Antagonists (VKA) to XARELTO For patients treated for DVT and prevention of recurrent DVT and PE, VKA treatment should be stopped and XARELTO therapy should be initiated once the INR is 2.5. When converting patients from VKAs to XARELTO, INR values will be falsely elevated after the intake of XARELTO. The INR is not valid to measure the anticoagulant activity of XARELTO, and therefore should not be used. 1 is an anticoagulant that is a direct (does not act via antithrombin), competitive, reversible and specific inhibitor of factor Xa. It is active following oral administration. 2/25

3 Converting from XARELTO to Vitamin K Antagonists (VKA) There is a potential for inadequate anticoagulation during the transition from XARELTO to VKA. Continuous adequate anticoagulation should be ensured during any transition to an alternate anticoagulant. It should be noted that XARELTO can contribute to an elevated INR. In patients converting from XARELTO to VKA, VKA should be given concurrently until the INR is 2.0. For the first two days of the conversion period, standard initial dosing of VKA should be used followed by VKA dosing guided by INR testing. While patients are on both XARELTO and VKA the INR should not be tested earlier than 24 hours after the previous dose but prior to the next dose of XARELTO. Once XARELTO is discontinued INR testing may be done reliably at least 24 hours after the last dose. Converting from parenteral anticoagulants to XARELTO For patients currently receiving a parenteral anticoagulant, XARELTO should be started 0 to 2 hours before the time of the next scheduled administration of the parenteral medicinal product (e.g. LMWH) or at the time of discontinuation of a continuously administered parenteral medicinal product (e.g. intravenous unfractionated heparin). Converting from XARELTO to parenteral anticoagulants Give the first dose of parenteral anticoagulant at the time the next XARELTO dose would be taken. Special populations: Renal impairment: No dose adjustment is necessary in patients with mild renal impairment (creatinine clearance ml/min). In patients with moderate (creatinine clearance ml/min) or severe (creatinine clearance ml/min) renal impairment the following dosage recommendations apply for the treatment of DVT and prevention of recurrent DVT and PE: Patients should be treated with 15 mg twice daily for the first 3 weeks. Thereafter, the recommended dose is 15 mg once daily based on PK modelling. Limited clinical data for patients with severe renal impairment (creatinine clearance ml/min) indicate that rivaroxaban plasma concentrations are significantly increased, therefore, XARELTO is to be used with caution in these patients. Use is not recommended in patients with creatinine clearance < 15 ml/min. Hepatic impairment: XARELTO is contraindicated in patients with hepatic disease associated with coagulopathy and clinically relevant bleeding risk including cirrhotic patients with Child Pugh B and C. Elderly population: No dose adjustment. Body weight/gender: No dose adjustment. Dosing recommendations before and after invasive procedures and surgical intervention: If an invasive procedure or surgical intervention is required, XARELTO should be stopped at least 24 hours before the intervention, if possible and based on the clinical judgement of the physician. If the procedure cannot be delayed the increased risk of bleeding should be assessed against the urgency of the intervention. XARELTO should be restarted after the invasive procedure or surgical intervention as soon as possible provided the clinical situation allows and adequate haemostasis has been established.» 3/25

4 2. SIMILAR MEDICINAL PRODUCTS 2.1. ATC Classification (2009) B B01 B01A B01AX B01AX06 Blood and haematopoietic organs Antithrombotic agents Antithrombotic agents Other antithrombotic agents 2.2. Medicines in the same therapeutic category - Other direct inhibitors of factor Xa: none Medicines with a similar therapeutic aim (antithrombotic agents) - Medicines indicated in the curative treatment of deep venous thrombosis (DVT) in the acute phase: Low molecular weight heparins (subcutaneous administration) INN dalteparin enoxaparin nadroparin tinzaparin Fondaparinux sodium (SC administration) Unfractionated heparins PROPRIETARY MEDICINAL PRODUCT FRAGMINE (x2/day) LOVENOX (x2/day) FRAXODI: (x1/day) FRAXIPARIN (x2/day) INNOHEP (x1/day) ARIXTRA (x1/day) SUBCUTANEOUS CALCIPARINE (x 2 to 3/day) HEPARIN SODIUM CHOAY (IV administration) DOSAGES 7,500 IU AXa/0.75 ml, 10,000 IU AXa/1 ml, 6,000 IU AXa/0.6 ml, 8,000 IU AXa/0.8 ml, 10,000 IU AXa/1 ml, 30,000 IU AXa/3 ml, 11,400 IU AXa/0.6 ml, 15,200 IU AXa/0.8 ml, 19,000 IU AXa/1 ml, 1,900 IU AXa/0.2ml, 2,850 IU AXa/0.3 ml, 3,800 IU AXa/0.4 ml, 5,700 IU AXa/0.6 ml, 7,600 IU AXa/0.8 ml, 9,500 IU AXa/1 ml, 10,000 IU AXa/0.5ml, 14,000 IU AXa/0.7 ml, 18,000 IU AXa/0.9 ml, 40,000 IU AXa/2 ml, 5 mg/0.4 ml 7.5 mg/0.6 ml 10 mg/0.8 ml 4/25

5 - Medicines indicated in the treatment of acute pulmonary embolism (PE), with the exception of patients who are haemodynamically unstable or who require thrombolysis or pulmonary embolectomy: - enoxaparin: LOVENOX; tinzaparin: INNOHEP These two low molecular weight heparins have a limited in indication in pulmonary embolism: without serious signs, in the absence of pre-existing cardiopulmonary pathology and with the exclusion of those likely to undergo thrombolytic treatment or surgery. LOVENOX (6,000 IU anti-xa/0.6 ml; 8,000 IU/anti-Xa/0.8 ml; 10,000 IU anti-xa/1 ml ; 30,000 IU anti-xa/3 ml) had IAB V in the curative treatment of deep venous thrombosis with or without pulmonary embolism, without serious clinical signs and with the exclusion of pulmonary embolism likely to undergo thrombolytic treatment or surgery (opinion of 6 July 2005). INNOHEP had a minor IAB (IV) in the curative treatment of deep venous thrombosis, due to convenience of use (one injection per day) compared to other LMW heparins, which require two injections per day (opinion of 14 February 1996). The Committee has confirmed this level of IAB in the extension of the indication curative treatment of pulmonary embolism without serious signs, in the absence of pre-existing cardiopulmonary pathology and with the exclusion of those likely to undergo thrombolytic treatment or surgery ; The level of benefit is considerable (opinion of 28 March 2001). - Fondaparinux sodium, SC administration ARIXTRA ARIXTRA had a minor IAB (IV) with respect to safety compared to routine management in the treatment of DVT and acute PE, with the exclusion of patients who are haemodynamically unstable or who require thrombolysis or pulmonary embolectomy (opinion of 6 July 2005). - Unfractionated heparins: SUBCUTANEOUS CALCIPARINE; HEPARIN SODIUM CHOAY - Vitamin K antagonists (oral preparations): These are indicated in the treatment of deep venous thrombosis and pulmonary embolism, and in the prevention of recurrence of these conditions, as a follow-on treatment from heparin. - acenocoumarol: SINTROM 4 mg and MINISINTROM 1 mg - fluindione: PREVISCAN 20 mg - Warfarin: COUMADIN 2 mg and 5 mg NB: All the medicines listed above have a substantial AB. 5/25

6 3. ANALYSIS OF AVAILABLE DATA Evaluation of the clinical benefit of rivaroxaban (XARELTO) in the treatment of deep venous thrombosis (DVT) and prevention of recurrent DVT and pulmonary embolism (PE) following an acute DVT in adults is fundamentally based on the results of a phase III clinical study of non-inferiority (EINSTEIN-DVT; study 11702a), which compared the efficacy and adverse effects of rivaroxaban with those of enoxaparin treatment followed by a vitamin K antagonist (enoxaparin/vka). A second phase III study (EINSTEIN-EP; study 11702b) had the objective of evaluating the clinical benefit of rivaroxaban in the treatment of symptomatic pulmonary embolism. The results of this study are still being analysed and are not yet available. One phase III extension study (EINSTEIN-EXTENSION; study 11899) compared, in a double-blind manner, the efficacy and safety of rivaroxaban treatment for 6 to 12 months with placebo in patients who had already been treated with an anticoagulant for DVT or PE for a period of 6 to 14 months. This study included patients from the EINSTEIN-DVT and EINSTEIN-EP studies. It provides information on the safety profile of rivaroxaban prescribed over the long term (up to 2 years). Efficacy results are presented for information only, since the duration of prolonged treatment with rivaroxaban has not been validated through an MA Efficacy Einstein-DVT study Objectives of the Einstein-DVT study: The objective of this randomised, open-label study was to demonstrate the non-inferiority (and in the second place, the superiority) of rivaroxaban compared to treatment with enoxaparin followed by a vitamin K antagonist (warfarin or acenocoumarol) in the acute phase of symptomatic deep venous thrombosis (DVT) without symptomatic pulmonary embolism (PE) and in the prevention of recurrences of DVT or PE. Furthermore, this study had the objective of comparing the risk of bleeding with these two medicines with respect to the incidence of major or non-major but clinically significant bleeding (primary safety endpoint). Study design Figure 1: Methodology of the Einstein-DVT study Treatment duration of 3, 6 or 12 months DVT without symptomatic PE confirmed objectively 15 mg 2x/day 20 mg 1x/day Enoxaparin 1.0 mg/kg 2x/day for 5 days, followed by VKA starting 48 hr, target INR 2.5 (range 2-3) ] D1 D21 30-day observation period 6/25

7 Course of the study: This was a multicentre study: 253 centres in 32 countries enrolled patients between March 2007 and April In France, 28 centres enrolled 245 patients. The protocol authorised administration of treatment with LMWH, UFH or fondaparinux (for a maximum period of 48 hours) prior to randomisation. During the study, use of acetylsalicylic acid (<100 mg/day) or clopidogrel (75 mg/day) was permitted. Inclusion criteria: Adults with confirmed symptomatic acute proximal DVT without symptomatic PE. Exclusion criteria included: - severe renal impairment with creatinine clearance (Cr Cl) < 30 ml/min, - active bleeding or high risk of bleeding, which contraindicated treatment with enoxaparin or VKA - severe liver disease (e.g. acute hepatitis, active chronic hepatitis, cirrhosis) or ALT >3x the upper limit of normal (ULN). - concomitant use of inhibitors or strong inducers of CYP3A4. Dosage of the medicines evaluated: - : 15 mg x2/day for 3 weeks then 20 mg/day in one daily dose; - Enoxaparin: 1 mg/kg x2/day for at least 5 days combined with a VKA (warfarin or acenocoumarol) (overlap of 4 to 5 days) then treatment with VKA alone until two consecutive INR spaced at an interval of 24 hr were 2. The target INR was 2.5 (range: ). The duration of treatment could be 3 months following the first episode of DVT with transient or reversible risk factors, or 6 or 12 months in cases of idiopathic DVT or cases with persistent risk factors or where there was a history of DVT or PE. Patients were stratified into three subgroups according to treatment duration (3, 6 or 12 months). The planned follow-up period was 30 days. Primary efficacy endpoint: The primary endpoint was recurrence in the form of DVT or PE (whether fatal 2 or not). The occurrence of the first of these events was taken into account when evaluating this endpoint. Secondary endpoints: - Each of the component events of the primary efficacy endpoint (recurrence in the form of DVT or PE) - All-cause mortality: - Recurrence of DVT (DVT, PE) or all-cause mortality - The net clinical benefit was estimated on the basis of the composite endpoint, which combined recurrence in the form of DVT or PE (whether fatal or not) and major bleeding. - One criterion combining major bleeding 3 and bleeding which was not major, but clinically significant 4, which was the primary safety endpoint. - Incidence of vascular events 2 Fatal pulmonary embolism was defined as either pulmonary embolism, which had been confirmed by diagnostic tests or by autopsy, or death of unknown cause and/or where DVT/PE could not be excluded. 3 Major bleeding was defined as all fatal bleeding, any obvious bleeding associated with a loss of haemoglobin 2 g/dl or requiring transfusion of 2 units of blood or more, any bleeding involving a critical organ (intracranial, intraspinal, intraocular, pericardial, intramuscular with compartment syndrome, retroperitoneal). 4 Bleeding that is not major but is clinically significant is defined as any excessive bleeding, which does not fit the definition of a major bleeding event, but which is associated with medical intervention or with non-scheduled contact with a doctor or with a (temporary) interruption of treatment, or with problems for the patient (such as pain) or with changes in the activities of daily life. 7/25

8 - Method and strategy for the analysis of the results: Three populations were defined for the analysis of the results: - ITT population: all randomised patients. - Per protocol population (PP): patients from the ITT population, excluding those with at least one major protocol violation. - Safety population (treated population): randomised patients, who received at least one dose of anticoagulant (enoxaparin, warfarin, acenocoumarol, rivaroxaban). The mean incidence of the occurrence of DVT or PE was expected to be 3% for the two treatment groups. The null hypothesis was that rivaroxaban is equivalent to the reference treatment. In order to refute this with a statistical power of 90%, an α risk of 5% and a noninferiority margin of 2, a sample size of at least 1465 patients per group was judged to be needed in order to have the number of events reach 88. The protocol anticipated that recruitment could be interrupted if the steering committee estimated that the total number of at least 88 recurrent thromboembolic events could be achieved. In such a case, the patients had to complete the scheduled duration of treatment, with the exception of patients in the 12-month cohort, who had completed at least 6 months of treatment. The time elapsed between randomisation and the occurrence of the first event for the primary efficacy endpoint was analysed using the Cox proportional risk model, stratified by the planned duration of treatment (3, 6 or 12 months) and adjusted for the presence of cancer at the time of enrolment. The hazard ratio for rivaroxaban/comparator was calculated with a two-sided confidence interval of 95%. On the basis of this model, rivaroxaban was considered to be at least as effective as the comparator if the upper limit of the confidence interval was below 2.0. Similar limit values were obtained in recent clinical trials (limit = 2 in the Van Gogh (2007) and Thrive 3 (2005) studies; limit = 1.7 in the Matisse (2004) study. If non-inferiority was demonstrated with respect to the primary efficacy endpoint, superiority was tested (in the ITT and PP populations). Furthermore, if non-inferiority was established with respect to the primary efficacy endpoint, the safety population was subjected to a procedure of sequential tests as follows: a) test of superiority for the primary safety endpoint (major bleeding and clinically significant but not major bleeding), b) test of superiority for the major bleeding alone. Analyses of the primary efficacy endpoint, which had been planned a priori, and of the primary safety endpoint were performed within the various subgroups; they measured the influence of the following covariables: active cancer, idiopathic DVT, history of DVT or PE, known thrombophilia, gender (male vs female), age (<60 vs >60 years and <65 years vs years vs >75 years), weight (<90 kg vs >90 kg), renal function (creatinine clearance <50 ml/min, between 50 and 80 ml/min or >80 ml/min), presence or absence of lung disease, heart disease, presence or absence of immobilisation at the moment of randomisation, location of the DVT (femoral or proximal vs popliteal or distal). Results according to treatment duration (3, 6 or 12 months) and, in the enoxaparin/vka arm, as a function of INR were also analysed. Results for the population of vulnerable patients 5 were subjected to post-hoc analysis. 5 Vulnerable patients were defined as those with at least one of the following characteristics: age >75 years or weight <50 kg or creatinine clearance <50 ml/min. 8/25

9 Results: Populations analysed Table 1: Numbers of patients in the different analysis populations Enoxaparin/VKA Total Randomised ITT population Safety population Per protocol population (PP) Characteristics of the evaluated population In all, 3,449 patients were randomised. The demographic characteristics of the patients at baseline were similar in the two treatment groups, with a mean age of 56 years (30% were aged between 60 and 75 years and 15% were older than 75 years), mean weight of 82 kg (BMI 28 kg/m 2 ), with the majority being male (57%) and Caucasian (77%). Of the 31% of patients with impaired kidney function, 23 % had mild renal impairment (Cr Cl between 50 and 80 ml/min) and 7% had moderate renal impairment (Cr Cl between 30 and 50 ml/min), while less that 1% had severe renal impairment (Cr Cl < 30 ml/min). The distribution of patients as a function of the treatment duration predetermined by the investigator is presented in Table 2. Table 2: distribution of patients as a function of treatment duration N = 1731 (100%) Enoxaparin/VKA N = 1718 (100%) Total N = 3449 (100%) 3 months 208 (12.0%) 203 (11.8%) 411 (11.9%) 6 months 1083 (62.6%) 1083 (63.0%) 2166 (62.8%) 12 months 440 (25.4%) 432 (25.1%) 872 (25.3%) The patients demographic characteristics were comparable between the two treatment arms for the same predetermined treatment period of 3, 6 or 12 months. At baseline, the diagnosis of symptomatic proximal DVT was confirmed in 99% of patients (ITT population), with DVT being considered as secondary 6 in approximately 38% of patients. The two groups were comparable both with respect to the spontaneous nature or otherwise of the DVT and with respect to the trigger factor (Table 3). Table 3. Classification of DVT ITT population N = 1731 (100%) Enoxaparin/VKA N = 1718 (100%) Spontaneous DVT 1055 (60,9%) 1083 (63,0%) Secondary DVT 676 (39.1%) 635 (37.0%) Recent surgery or injury 338 (19.5%) 335 (19.5%) Immobilisation 265 (15.3%) 260 (15.1%) Use of medicines containing oestrogens 140 (8.1%) 115 (6.7%) Post-partum 6 (0.3%) 11 (0.6%) Active cancer 118 (6.8%) 89 (5.2%) 6 DVT is considered as being secondary if at least one of the following factors is present at the time of diagnosis: recent surgery or injury, immobilisation, oestrogen treatment, post-partum period, active cancer. 9/25

10 Table 4: thromboembolic risk factors ITT population (N=1731) Enoxaparin/VKA (N=1718) Idiopathic DVT/PE 807 (46.6%) 862 (50.2%) Recent surgery or injury 338 (19.5%) 335 (19.5%) History of DVT/PE 336 (19.4%) 330 (19.2%) Immobilisation 265 (15.3%) 260 (15.1%) Use of medicines containing oestrogens 140 (8.1%) 115 (6.7%) Known constitutional thrombophilic status 107 (6.2%) 116 (6.8%) Active cancer 118 (6.8%) 89 (5.2%) Family history of VTE; 35 (2.0%) 18 (1.0%) Post-partum 6 (0.3%) 11 (0.6%) The profile of the patients, with respect to risk factors, differed between the groups given 3, 6 or 12 months of treatment. In the 3-month subgroup, the patients most commonly had a temporary, reversible risk factor (recent surgery or injury, immobilisation, use of medicines containing oestrogens). In the 6-month subgroup, the most common diagnosis was idiopathic DVT. In the 12-month subgroup, the two most common characteristics were idiopathic DVT and history of DVT/PE. Duration of treatment: This was 6 months for the majority of patients. Table 5: thromboembolic risk factors according to treatment duration ITT population Enoxaparin/VKA Planned duration of treatment = 3 months (n=208) (n=203) Recent surgery or injury 102 (49.0%) 104 (51.2%) Immobilisation 71 (34.1%) 54 (26.6%) Idiopathic DVT 49 (23.6%) 54 (26.6%) Use of medicines containing oestrogens 24 (11.5%) 22 (10.8%) History of DVT/PE 6 (2.9%) 14 (6.9%) Active cancer 9 (4.3%) 6 (3.0%) Planned duration of treatment = 6 months (n=1 083) (n=1 083) Idiopathic DVT 571 (52.7%) 597 (55.1%) Recent surgery or injury 187 (17.3%) 196 (18.1%) Immobilisation 164 (15.1%) 166 (15.3%) History of DVT/PE 142 (13.1%) 135 (12.5%) Use of medicines containing oestrogens 102 (9.4%) 77 (7.1%) Active cancer 83 (7.7%) 63 (5.8%) Known thrombophilic status 49 (4.5%) 62 (5.7%) Planned duration of treatment = 12 months (n=440) (n=432) Idiopathic DVT 187 (42.5%) 211 (48.8%) History of DVT/PE 188 (42.7%) 181 (41.9%) Known thrombophilic status 56 (12.7%) 52 (12.0%) Recent surgery or injury 49 (11.1%) 35 (8.1%) Immobilisation 30 (6.8%) 40 (9.3%) Active cancer 26 (5.9%) 20 (4.6%) Family history of VTE; 21 (4.8%) 12 (2.8%) Use of medicines containing oestrogens 14 (3.2%) 16 (3.7%) 10/25

11 Other medicines received Within the ITT population, 73% of patients in the rivaroxaban group and 71% in the enoxaparin/vka group had already received an LMWH, a UFH or fondaparinux before being randomised for treatment of their DVT. After the randomisation, 21% of patients in the rivaroxaban group and 28% in the enoxaparin/vka group had received other antithrombotic agents. The most commonly used was enoxaparin (rivaroxaban group: 5%; enoxaparin/vka group: 12%) and warfarin (rivaroxaban and enoxaparin/vka groups: 3%). An anti-platelet aggregation agent was administered to 11.6% of patients in the rivaroxaban group and 10.6% in the enoxaparin/vka group (10% of patients in each group received salicylic acid). Monitoring of INR The mean percentage of time spent within the target therapeutic period was 57.7% of the total study duration. According to a cross-sectional study conducted in France by the Medical Service of the Health Insurance for the Limousin-Poitou-Charentes region in , this percentage would be 54%. Table 6: percentage of time spent outside the therapeutic period, group of patients from the enoxaparin/vka group safety population Time spent outside the target INR of between 2 and 3 (%) INR < 2,0 24.4% INR > % Data lacking 1.8% Premature discontinuation of treatment: Table 7: main reasons for early discontinuation of treatment ITT population N=1731 Enoxaparin/VKA N=1718 Patients having completed the treatment period 1426 (82.4%) 1367 (79.6%) Patient not having received the treatment 7 (0.4%) 13 (0.8%) Of patients discontinuing treatment prematurely: 298 (17.2%) 338 (19.7%) Study terminated by the sponsor a 102 (5.9%) 94 (5.5%) Endpoint of clinical efficacy achieved b 28 (1.6%) 25 (1.5%) Withdrawal of consent 36 (2.1%) 77 (4.5%) Adverse effect (AE) 74 (4.3%) 67 (3.9%) Death 19 (1.1%) 22 (1.3%) Lost from sight 12 (0.7%) 18 (1.0%) Non-compliance 8 (0.5%) 15 (0.9%) a following achievement of the planned number of events b following achievement of the clinical endpoint, the decision to continue or discontinue the treatment is left to the discretion of the investigator Patients who were lost to view or withdrew their consent have been censored in the analyses. 7 Chastagner M, Gault M, Aboyans V, Lacroix P. A long-term follow-up quality evaluation of patients taking oral anticoagulant therapy. Arch Mal Coeur Vaiss 2005; 98: /25

12 Primary efficacy endpoint: The incidence of recurrent DVT and PE, with or without a fatal outcome, was 2.1% in the rivaroxaban group and 2.9% in the enoxaparin/vka group, HR 0.70 (95% CI: [ ] in the PP population. Since the upper limit of the confidence interval was lower than the predefined non-inferiority margin of 2.0, the non-inferiority of rivaroxaban compared to treatment with enoxaparin/vka has been demonstrated, p < The results in the ITT population were similar, with the incidence of the primary efficacy endpoint being 2.1% in the rivaroxaban group and 3.0% in the enoxaparin/vka group, HR = 0.68 (95% CI: ), p< NB: The limit for non-inferiority was calculated to guarantee the preservation of 66% of the efficacy of the standard treatment (enoxaparin+vka). The upper limit of the confidence interval observed was 1.097, which corresponds to a preservation of 96.8% of the efficacy of the comparator (1 + ( )*(1/0.25-1) = 1.097). Superiority of rivaroxaban over treatment with enoxaparin/vka has not been demonstrated in the ITT population (p = ) nor in the per protocol population (p = ). Table 8: summary of results for the primary efficacy endpoint Population ITT a PP b Enoxaparin/VKA 36/1731 (2.1%) 51/1718 (3.0%) 32/1525 (2.1%) 46/1571 (2.9%) Cox proportional risk model for rivaroxaban vs. enoxaparin/vka Hazard ratio Confidence interval. p non-inferiority p superiority < < a events until the end of the planned treatment period, regardless of whether the medicine was taken (for the ITT population) b events during treatment, until the last documented dose of the medicine + 2 days (for the PP population) NB: Non-inferiority with respect to the primary efficacy endpoint having been established, in accordance with the protocol, tests for superiority with respect to safety endpoints were performed. Refer to the section on adverse effects. Analysis in sub-groups (ITT population) of the primary efficacy endpoint: The results were uniform in the various pre-specified sub-groups, particularly in terms of treatment duration (3, 6 or 12 months) and in vulnerable patients: Table 9: incidence of the primary efficacy endpoint according to predetermined duration of treatment Duration of Enoxaparin/VKA treatment n/n (%) n/n (%) Hazard ratio (95% CI) 3 months 5/208 (2.4%) 3/203 (1.5%) months ( ) 25/1083 (2.3%) 29/1083 (2.7%) months ( ) 6/440 (1.4%) 19/432 (4.4%) ( ) Value of p for the interaction test /25

13 Table 10: incidence of the primary efficacy endpoint in the sub-group of vulnerable patients Enoxaparin/VKA Hazard ratio 95% CI Vulnerable patients 2.5% 4.3% Non-vulnerable 2.0% 2.7% patients Likewise, with respect to the age factor, the incidence of the primary efficacy endpoint was similar in the rivaroxaban arm for the three age groups: younger than 65 years (2.3%), between 65 and 75 years (1.6%) and older than 75 years (1.9%) Secondary efficacy endpoints: Events of the primary efficacy endpoint: Table 11: incidence of each of the events of the primary efficacy endpoint ITT population N=1731 ITT population Enox./VKA N=1718 N=1525 PP population Enox./VKA N=1571 Primary efficacy endpoint 36 (2.1%) 51 (3.0%) 32 (2.1%) 46 (2.9%) Death (PE) 1 (<0.1%) Death (PE cannot be excluded) 3 (0.2%) 6 (0.3%) 2 (0.1%) 5 (0.3%) PE and symptomatic DVT 1 (<0.1%) 0 1 (<0.1%) 0 Symptomatic, recurrent PE alone 20 (1.2%) 18 (1.0%) 17 (1.1%) 16 (1.0%) Symptomatic, recurrent DVT alone 14 (0.8%) 28 (1.6%) 13 (0.9%) 26 (1.7%) All-cause mortality: In total, 93 deaths (rivaroxaban: 41 [2.4%]; enoxaparin/vka: 52 [3.0%]) were reported in the safety population. The four most commonly reported causes of death in the two treatment groups were: cancer (rivaroxaban: 1.6%; enoxaparin/vka: 1.2%), unexplained death for which PE cannot be excluded (rivaroxaban: 0.2%; enoxaparin/vka: 0.4%), infectious disease (rivaroxaban: 0.2%; enoxaparin/vka: 0.5%) and bleeding (rivaroxaban: 0.1%; enoxaparin/vka: 0.3%). Endpoint combining recurrence of DVT, fatal or non-fatal PE and all-cause mortality: the results are in favour of rivaroxaban, with an incidence of 4.0% (69/1731) in the rivaroxaban groups and 5.1% (87/1718) in the enoxaparin/vka group within the ITT population, HR (95% CI: to 0.991) within the ITT population according to the Cox proportional risks model. The results for the PP population are similar: incidence of 2.8% (42/1525) in the rivaroxaban group and 3.7% (58/1571) in the enoxaparin/vka group. Table 12: incidence rates for secondary endpoint events ITT population N=1731 Enox./VKA N=1718 N=1525 PP population Enox./VKA N=1571 Endpoint combining recurrence of 69 (4.0%) 87 (5.1%) 42 (2.8%) 58 (3.7%) DVT or PE and all-cause mortality Death (PE) 1 (<0.1%) Death (PE cannot be excluded) 3 (0.2%) 6 (0.3%) 2 (0.1%) 5 (0.3%) Death (bleeding) 1 (<0.1%) 5 (0.3%) 1 (<0.1%) 3 (0.2%) Death (cardiovascular) 2 (0.1%) 4 (0.2%) 1 (<0.1%) 0 13/25

14 Death (other) 31 (1.8%) 34 (2.0%) 9 (0.6%) 9 (0.6%) Symptomatic PE and DVT 1 (<0.1%) 0 1 (<0.1%) 0 Symptomatic, recurrent PE alone 20 (1.2%) 18 (1.0%) 17 (1.1%) 16 (1.0%) Symptomatic recurrent DVT alone 14 (0.8%) 28 (1.6%) 13 (0.9%) 26 (1.7%) Estimate of net clinical benefit: the incidence of recurrent DVT or PE and of major bleeding was 2.9% (51/1731) in the rivaroxaban group and 4.2% (73/1718) in the enoxaparin/vka group within the ITT population, HR = (95% CI: to 0.954). In the PP population, the incidence was 2.8% (43/1525) in the rivaroxaban group and 4.1% (64/1571) in the enoxaparin/vka group Einstein-Extension study The patients enrolled into this study between February 2007 and September 2009 were either patients enrolled into the EINSTEIN-DVT or EINSTEIN-PE studies, who had received and anticoagulant (rivaroxaban or enoxaparin/vka) for 6 to 12 months, or patients who had been treated with a VKA for 6 to 14 months. The patients were randomised to receive either 20 mg rivaroxaban daily or placebo. The choice of the treatment duration was made by the investigator and could vary from 6 to 12 months. A further observation period of 30 days was implemented after cessation of treatment. Primary efficacy endpoint: fatal or non-fatal recurrence of DVT or PE. Secondary efficacy endpoints: - non-fatal recurrence of DVT or PE and all-cause mortality (secondary efficacy endpoint no. 1) - non-fatal recurrence of DVT or PE, all-cause mortality, stroke and myocardial infarction (secondary efficacy endpoint no. 2) - fatal or non-fatal recurrence of DVT or PE and major bleeding (net clinical benefit). - all-cause mortality: With respect to safety, the incidence of the following events was measured: - major bleeding - bleeding that was not major, but clinically significant - vascular events Hepatic function was evaluated (laboratory tests). Method and strategy for the analysis of the results: Hypotheses applied: - A relative reduction in expected risk of 70% with rivaroxaban versus placebo, a total of 30 events was calculated to obtain a power of 90%. - an expected mean incidence rate for the primary efficacy endpoint of 3% to 4% with placebo, a sample size of approximately 650 patients per group was selected. The time elapsed between randomisation and the occurrence of the first primary endpoint event was analysed using the Cox proportional risks model stratified by planned duration of treatment and adjusted for the preceding treatment (rivaroxaban vs VKA). 14/25

15 Results Table 13: distribution of patients in the analysis populations Placebo Total Patients randomised ITT population Safety population (treated) Per protocol population (PP) Characteristics of the evaluated population In total, 1197 patients were randomised, 602 in the rivaroxaban group and 595 in the placebo group. Of these patients, 314 (52%) in the rivaroxaban group and 318 (53%) in the placebo group had participated in the EINSTEIN-DVT or EINSTEIN-PE studies (the latter being an off-label study at that time). The planned duration of treatment for approximately 60% of patients was 6 months, while for 40% it was 12 months. Approximately 55% of patients had previously been treated with warfarin, 28% with rivaroxaban and 18% with acenocoumarol. The demographic characteristics of patients were comparable between the two groups: Table 14: characteristics of patients ITT population N=602 (100%) Placebo N=594 (100%) Gender Male 354 (58.8%) 339 (57.1%) Female 248 (41.2%) 255 (42.9%) Age N Mean ± s.d 58.2 ± ± 16.0 Range Age group years 87 (14.5%) 94 (15.8%) >40 - <65 years 273 (45.3%) 280 (47.1%) years 153 (25.4%) 121 (20.4%) > 75 years 89 (14.8%) 99 (16.7%) Weight (kg) N Mean ± s.d ± ± Range Creatinine clearance Data missing 58 (9.6%) 50 (8.4%) < 30 ml/min 0 5 (0.8%) 30 - < 50 ml/min 37 (6.1%) 44 (7.4%) 50 - < 80 ml/min 134 (22.3%) 122 (20.5%) > 80 ml /min 373 (62.0%) 373 (62.8%) The most commonly reported thromboembolic risk factor was idiopathic DVT/PE, which was reported by approximately 60% of patients in the ITT population. The qualifying event was proximal DVT without PE for 63% of patients in the rivaroxaban group and for 59% of patients in the placebo group. PE (with or without symptomatic DVT) was the qualifying event in 35% of patients in the rivaroxaban group and in 39% of patients in the placebo group. The mean period between the qualifying event (onset of symptoms of DVT or PE) and randomisation was approximately 250 days in both groups. 15/25

16 Table 15: qualifying events for this study (ITT population) Placebo N=602 (100%) N=594 (100%) No event 7 (1.2%) 5 (0.8%) Not evaluable 6 (1.0%) 6 (1.0%) Proximal DVT without PE 376 (62.5%) 348 (58.6%) Distal DVT without PE 0 1 (0.2%) PE without symptomatic DVT 163 (27.1%) 181 (30.5%) PE with proximal symptomatic DVT 40 (6.6%) 50 (8.4%) PE with symptomatic, only distal DVT 10 (1.7%) 3 (0.5%) The patient populations included in the analysis are presented in the table below. Efficacy results Primary efficacy endpoint: the incidence of fatal or non-fatal recurrence of DVT or PE within the ITT population was 1.3% (8/602) in the rivaroxaban group and 7.1% (42/594) in the placebo group, HR = (95% CI: ; p<0.0001), this being an 81% decrease in the relative risk of recurrences. Table 16: incidence rate of the primary endpoint up to the planned end of treatment and associated result ITT population Parameters N=602 (100%) Placebo N=594 (100%) Hazard Ratio rivaroxaban/placebo (Cox model) (p< ) Confidence Interval (CI) Primary efficacy endpoint 8 (1.3%) 42 (7.1%) Death (PE) 0 1 (0.2%) - - Death (PE cannot be 1 (0.2%) excluded) Symptomatic, recurrent PE 2 (0.3%) (2.2%) Symptomatic, recurrent DVT 5 (0.8%) (5.2%) Sub-group analyses: the efficacy of treatment with rivaroxaban is the same in all the sub-groups (treatment duration, gender, age, weight, renal function, previous treatment with VKA or rivaroxaban, qualifying event [DVT or PE], history of VTE). The sub-groups studied were identical to those in the EINSTEIN-DVT study. 16/25

17 Secondary efficacy endpoints: Table 17: results of secondary efficacy endpoints: Parameters Endpoint no. 1 Recurrence of DVT, nonfatal recurrence of PE and all-cause mortality Endpoint no. 2 Recurrence of DVT, nonfatal recurrence of PE, all-cause mortality and myocardial infarction Endpoint no. 3 Recurrence of DVT, fatal or non-fatal recurrence of PE and major bleeding N=602 (100%) Placebo N=594 (100%) Hazard Ratio rivaroxaban/placebo (Cox model) 8 (1.3%) 43 (7.2%) (p< ) 9 (1.5%) 44 (7.4%) (p< ) 12 (2.0%) 42 (7.1%) (p< ) Confidence Interval Adverse effects Data from clinical studies In the Einstein-DVT study, adverse effects were evaluated in 3429 patients, of whom 1718 had been treated with rivaroxaban (XARELTO). In the rivaroxaban group, the mean duration of treatment was 194 days and the median was 182 days (188 days and 181 days, respectively in the enoxaparin/vka group). The overall incidence of adverse effects occurring during treatment was similar for both groups (of the order of 23%). The Einstein-Extension study provides safety information over a longer term: it involved 1188 patients, of whom 598 were treated with rivaroxaban. The mean duration of treatment was ± 85.1 days in the rivaroxaban group and ± 86.8 days in the placebo group. The overall incidence of adverse effects occurring during treatment was 16.4% in the rivaroxaban group versus 10.7% in the placebo group. The incidence of serious adverse effects occurring during treatment was also higher in the rivaroxaban group (8.7%) than in the placebo group (7.8%). Risk of bleeding: Data from the Einstein-DVT study: The incidence of the primary safety endpoint, combining major bleeding and bleeding that is not major, but clinically significant was similar in the two treatment groups: 8.1% in both groups (rivaroxaban : 139/1718 vs enoxaparin/vka: 138/1711; HR [0.763 to 1.222]). Half of these occurred during the first month of treatment. The incidence of major bleeding alone was 0.8% (14 events) in the rivaroxaban group and 1.2% (20 events) in the enoxaparin/vka group, with one bleeding event being fatal in the rivaroxaban group versus five in enoxaparin/vka group and three bleeding events involving a critical organ occurring in each group. Four intracranial bleeding events occurred (two in each group). The incidence of bleeding that was not major, but clinically significant was similar in the two treatment groups: 7.3% (126/1718) in the rivaroxaban group and 7.0% (119/1711) in the enoxaparin/vka group. 17/25

18 Several analyses were performed in the sub-groups: - Incidence of bleeding according to treatment duration Table 18: incidence of the primary safety endpoint according to the predetermined treatment duration safety population Enoxaparin/VKA Duration of treatment: 3 months 16/207 (7.7%) 16/201 (8.0%) Duration of treatment: 6 months 90/1074 (8.4%) 78/1079 (7.2%) Duration of treatment: 12 months 33/437 (7.6%) 44/431 (10.2%) - In the sub-group of vulnerable patients (age >75 years and or weight 50 kg and/or creatinine clearance < 50 ml/min), no interaction was established (post-hoc analysis): Table 19: analysis of the primary safety endpoint in the sub-group of vulnerable patients Incidence Enoxaparin/VKA Non-vulnerable 105/ /1397 patients (7.4%) (7.8%) Vulnerable patients 34/301 29/314 (11.3%) (9.2%) Hazard 95% CI p Ratio interaction In this sub-group, fewer major bleeding events occurred in the rivaroxaban group (1.1%) than in the enoxaparin/vka group (3.6%). In a post-hoc analysis of the primary safety endpoint in the sub-group of patients who also received a NSAID or an anti-platelet aggregation agent, a similar increase in the risk of bleeding was observed in both treatment groups. In an analysis of the primary safety endpoint with respect to patient characteristics and the presence of risk factors for bleeding, no interaction was established for the factors age (<65 years or 75 years), presence of cancer or treatment with fondaparinux or heparin prior to randomisation. Data from the Einstein-Extension study: The incidence of major bleeding during treatment (primary safety endpoint) was very low: 0.7% (4/598) in the rivaroxaban group versus 0% with placebo, p = No bleeding with a fatal outcome or involving a critical organ was reported. The incidence of major bleeding and bleeding that was not major but of clinical significance was higher in the rivaroxaban group (6.0%, 35/598) than with placebo (1.2%, 7/590), HR: 5.185, 95% CI Likewise, the incidence of bleeding that was not major but of clinical significance was higher in the rivaroxaban group (5.4%, 32/598) than in the placebo group (1.2%, 7/590). This difference in incidence was mostly due to bleeding of urogenital, nasal and rectal origin. According to the SPC, In the clinical studies mucosal bleedings (i.e. epistaxis, gingival, gastrointestinal, genito-urinary) and anaemia were seen more frequently during long term XARELTO treatment compared with VKA treatment. In the event of overdose: There is no antidote for rivaroxaban (XARELTO). is probably not dialyzable due to its strong binding to plasma proteins. According to the SPC, Rare cases of overdose up to 600 mg have been reported without bleeding complications or other adverse reactions. 18/25

19 Renal impairment In the Einstein-DVT and Einstein-Extension studies, patients with moderate renal impairment (creatinine clearance of ml/min) were treated with the same dose as patients whose creatine clearance was above 50 ml/min. In the Einstein-DVT study, the incidence of bleeding that was major or not major but of clinical significance was comparable between the two treatment arms for the various creatinine clearance values. The interaction of this factor could not be demonstrated. Table 20: analysis of the primary safety endpoint in Einstein-DVT according to creatinine clearance Characteristics Enoxaparin Hazard ratio n/n (%) n/n (%) (95% CI) Creatinine clearance 80 ml/min 89/1186 (7.5%) 86/1166 (7.4%) ( ) 50 - < 80 ml/min 36/390 (9.2%) 41/400 (10.3%) ( ) < 50 ml/min 13/120 (10.8%) 10/128 (7.8%) ( ) Value of p for the interaction test According to the SPC, in pharmacokinetic studies, the plasma concentrations of rivaroxaban (AUC) were multiplied by 1.4, 1.5 and 1.6 in cases of mild (CrCl 50 to 80 ml/min), moderate (CrCl 30 to 49 ml/min) or severe (CrCl 15 to 29 ml/min) renal impairment, respectively. The corresponding increases in pharmacodynamic effects were more marked. Overall inhibition of factor Xa activity was increased by a factor of 1.5, 1.9 and 2.0, respectively, compared to healthy volunteers (likewise for prolongation of PT). No data are available concerning patients with a creatinine clearance below 15 ml/min. XARELTO is to be used with caution in patients with creatinine clearance ml/min. Use is not recommended in patients with creatinine clearance < 15 ml/min. XARELTO should be used with caution in patients with renal impairment concomitantly receiving other medicinal products that are potent inhibitors of CYP3A4 (e.g. clarithromycin, telithromycin). Hepatic impairment No signs of hepatotoxicity were noted in the Einstein-DVT study. In the Einstein-Extension study, 11 patients (1.9%) treated with rivaroxaban versus 3 (0.5%) on placebo showed an increase in certain liver enzymes (ALT increased to threefold the upper limit of normal) without clinical consequences. The differences between the treatment groups with respect to adverse effects classed as hepatic disorders (MedDRA classifications) were small (2.5% in the rivaroxaban group vs 1.9% in the placebo group). The majority of these differences were attributed to anomalies in laboratory tests. According to data from pharmacokinetic studies, the bioavailability of rivaroxaban is increased in cirrhotic patients with moderate hepatic impairment (Child Pugh class B) compared to healthy volunteers, and these patients also showed a decreased renal elimination of rivaroxaban, like that in patients with moderate renal impairment. No data are available concerning patients with severe hepatic impairment. Furthermore, inhibition of factor Xa activity was increased by a factor of 2.6 in patients with moderate hepatic impairment compared to healthy volunteers; a similar increase was seen in prolongation of PT. XARELTO is contraindicated in patients with hepatic disease associated with coagulopathy and clinically relevant bleeding risk including cirrhotic patients with Child Pugh B and C. 19/25

20 Pharmacovigilance data (other indications for XARELTO) XARELTO 10 mg has been marketed in France since 2009 in the indication prevention of venous thromboembolism in adult patients undergoing elective hip or knee replacement surgery (total prosthesis of the hip or knee). In this indication, it is the subject of a risk management plan in France, with national monitoring performed by the Regional Pharmacovigilance Centre in Angers. According to the manufacturer s data, XARELTO has been prescribed to approximately 783,750 patients worldwide at a dose of 10 mg/day with an estimated treatment duration of 24.5 days in the periods between 1 st October 2008 (start of marketing) and 15 th March During this period, 2177 new, medically confirmed cases have been reported, corresponding to a notification incidence of 2.77/1000. The incidence of serious adverse effects has been 1.95/1000, with 54 cases with a fatal outcome having been reported. Bleeding has been reported in 1018 patients, corresponding to an incidence of 0.13%. Thrombocytopenia has been reported in 22 patients, corresponding to an incidence of 0.003%, 89 patients have had at least one "hepatobiliary" adverse effect, corresponding to a cumulative incidence of 0.01%; 39 patients have had one renal or urinary adverse effect (with "renal impairment" being mentioned in 24 of these cases) and 438 patients have had a venous thromboembolic event, corresponding to an incidence of 0.06%. In France, the population exposed between 6 May and 15 March 2011 amounted to 89,196 patients: 386 cases with at least one adverse effect have been reported, corresponding to a notification incidence of 4.3/1000. The incidence of serious adverse effects was 3.2/1000. An adverse effect with fatal outcome was reported in 14 patients with cardiovascular risk factors, thus there were 16 deaths per 100,000 treated patients. There are no new data of significance in the population of the most elderly patients and/or those with renal or hepatic impairment. Venous thromboembolic events account for 22% of adverse effects that were not recorded in the regulatory documentation. A Risk Management Plan (RMP) for XARELTO accompanies the extension of the MA in the treatment of DVT. This plan is primarily based on the clinical studies in progress, on a prescription-monitoring study and on usage data from European databases. Bleeding has been identified as a serious risk and increases in liver function parameters as an identified potential risk. The information identified as missing relates in particular to patients with severe renal impairment, corrective pro-coagulant treatment in the case of bleeding complications associated with rivaroxaban overdose and the consequences of concomitant prescription with inhibitors of CYP3A4 and/or glycoprotein P (P-gp). It is also planned to monitor the use of rivaroxaban in long-term treatment in real life. Monitoring of the efficacy of risk minimisation measures (prescribing guide and patient card) has also been established Studies in progress Studies are underway to evaluate the clinical benefit of XARELTO: - in the treatment of pulmonary embolism and prevention of recurrence of deep venous thrombosis and/or pulmonary embolism - as secondary prophylaxis of cardiovascular events after acute coronary syndrome Discussion The interpretation of the results prompts several remarks: Einstein-DVT study No problem arises from the methodology of this study, apart from the absence of double blinding for the comparison with warfarin. In the acute phase of DVT and prevention of 20/25

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