TRANSPARENCY COMMITTEE OPINION. 29 April 2009

Transcription

1 The legally binding text is the original French version TRANSPARENCY COMMITTEE OPINION 29 April 2009 ANGIOX 250 mg, powder for concentrate for solution for injection or infusion by the intravenous route Box of 2 (glass) vials (CIP: ) Box of 10 (glass) vials (CIP: ) Applicant: THE MEDICINES COMPANY Bivalirudin ATC code: B01AE06 List I Medicinal product reserved for hospital use Date of first Marketing Authorisation: 20 September 2004(centralised procedure) Extension of indication: Marketing authorisation amendment of 10 January 2008 Reason for request: Inclusion on the list of medicines approved for use by hospitals in the extension of indication: Treatment of patients with acute coronary syndrome (unstable angina/non-st segment elevation myocardial infarction (UA/NSTEMI)) planned for urgent or early intervention. ANGIOX should be administered with aspirin and clopidogrel. Medical, Economic, and Public Health Assessment Division 1

2 1. CHARACTERISTICS OF THE MEDICINAL PRODUCT 1.1 Active ingredient Bivalirudin 1.2. Indications - Treatment of patients with acute coronary syndrome (ACS; unstable angina/non-st segment elevation myocardial infarction (UA/NSTEMI)) planned for urgent or early intervention. ANGIOX should be administered with aspirin and clopidogrel (extension of indication) - Anticoagulant in patients undergoing percutaneous coronary intervention (PCI) Dosage ANGIOX should be administered intravenously (i.v.), by a physician who is a specialist in the treatment of acute coronary syndrome or in coronary intervention procedures. The bivalirudin dose should be body weight adjusted in mg/kg. Patients treated for ACS planned for urgent or early intervention The recommended starting dose is an intravenous bolus of 0.1 mg/kg followed by an infusion of 0.25 mg/kg/h. Patients receiving conservative medical therapy may continue the infusion of 0.25 mg/kg/h for 72 h. - If the patient proceeds to PCI, an additional bolus of 0.5 mg/kg should be administered and the infusion increased to 1.75 mg/kg/h for the duration of the procedure. Following PCI, the infusion, reduced to 0.25 mg/kg/h, may be continued for 4 to 12 h if clinically necessary. - For patients who proceed to coronary artery bypass graft (CABG) surgery off pump, the infusion of bivalirudin should be continued until the time of surgery. Just prior to surgery, an intravenous bolus of 0.5 mg/kg should be administered followed by an infusion of 1.75 mg/kg/h for the duration of the surgery. For those who proceed to CABG surgery on pump, the infusion of bivalirudin should be continued until 1 h prior to surgery, after which the infusion should be discontinued and the patient treated with unfractionated heparin. Patients undergoing PCI The recommended dose is an intravenous bolus of 0.75 mg/kg body weight followed immediately by an intravenous infusion at a rate of 1.75 mg/kg body weight/h for at least the duration of the procedure. The infusion may be continued for up to 4 h post-pci if clinically necessary. The safety and efficacy of a single bolus have not been evaluated. Consequently, administration of a single bolus of ANGIOX is not recommended, even if a short PCI procedure is planned. Monitoring of coagulation parameters - in the context of a PCI: the activated clotting time (ACT) may be used to assess bivalirudin activity. ACT values 5 min after the bivalirudin bolus average 365 +/- 100 sec. If the ACT is less than 225 sec, a second bolus dose of 0.3 mg/kg should be administered. - Monitoring of the coagulation time is recommended during PCI in patients with renal impairment. The ACT should be checked 5 min after the bolus. If the ACT is less than 225 sec, a second bolus dose of 0.3 mg/kg should be administered and the ACT re-checked 5 min after the administration of the second bolus. In the patients with moderate renal impairment included in the pivotal phase III study in angioplasty (REPLACE-2), the ACT values measured 5 min after a bolus of bivalirudin were 2

3 on average 366 ± 89 sec without dose adjustment. At the end of the PCI procedure, in these same patients, the ACT values were on average 355 ± 81 sec. - Concomitant administration of bivalirudin with platelet inhibitors or anticoagulants can increase the risk of bleeding; clinical and biological parameters of haemostasis should be regularly monitored. In patients taking warfarin who are treated with bivalirudin, monitoring of the INR should be undertaken, after the end of the bivalirudin therapy, to make sure that it returns to pre-treatment levels. Special situations - Renal insufficiency: the systemic clearance of bivalirudin decreases with glomerular filtration rate (GFR). The clearance of bivalirudin is similar in patients with normal renal function and those with mild renal impairment. Clearance is reduced by approximately 20% in patients with moderate or severe renal impairment, and 80% in dialysis-dependent patients (cf. Table 11 of the SPC: Pharmacokinetic parameters for bivalirudin in patients with normal and impaired renal function). ANGIOX is contraindicated in patients with severe renal insufficiency (GFR < 30 ml/min) and also in dialysis-dependent patients. In patients with renal insufficiency, it is not necessary to adjust the ACS dose (bolus of 0.1 mg/kg; infusion of 0.25 mg/kg/h). Patients with moderate renal impairment (GFR ml/min) undergoing PCI (whether being treated with bivalirudin for ACS or not) should receive a lower infusion rate of 1.4 mg/kg/h. The bolus dose should not be changed from the posology described under ACS or PCI above. - Elderly persons: the pharmacokinetics were evaluated in elderly patients in the renal pharmacokinetics study. The dose adjustments in this age group should be based on renal function. - Children and adolescents: no relevant data concerning the use of ANGIOX in children. 2. SIMILAR MEDICINAL PRODUCTS 2.1 ATC Classification (2009) B Blood and blood forming organs B01A Antithrombotic agents B01AE Direct thrombin inhibitors B01AE06 Bivalirudin 2.2 Medicines in the same therapeutic category Other antithrombotic direct thrombin inhibitors: none. Note: The other proprietary direct thrombin inhibitors marketed in France have a different indication: REFLUDAN (lepirudin) has the following indication: Anticoagulation in adult patients with heparin-induced thrombocytopenia (HIT) type II and thromboembolic disease mandating parenteral antithrombotic therapy and REVASC (desirudin) has the following indication: Prevention of deep venous thrombosis in patients undergoing elective hip or knee replacement surgery.. 3

4 2.3 Medicines with a similar therapeutic aim (antithrombotics) Antithrombotic anticoagulants - Low molecular weight heparins (LMWH): Indication: treatment of unstable angina and non-q-wave myocardial infarction in the acute phase, in combination with aspirin enoxaparin: LOVENOX (sol for inj containing 6000 IU anti-xa/0.6 ml, 8000 IU anti- Xa/0.8 ml, 10,000 IU anti-xa/1 ml, and 30,000 IU anti-xa/3 ml) dalteparin: FRAGMIN (sol for inj containing 7500 IU anti-xa/0.75 ml and 10,000 IU anti-xa/1 ml) nadroparin: FRAXIPARINE - Unfractionated heparins (UFH): CALCIPARINE and Héparine CHOAY. Indication: treatment of Q-wave and non-q-wave myocardial infarction and of unstable angina, in the acute phase. - Fondaparinux sodium: ARIXTRA 2.5 mg Indication: Treatment of unstable angina or non-st segment elevation myocardial infarction (UA/NSTEMI) in patients in whom management by an invasive strategy (percutaneous coronary intervention: PCI) on an emergency basis (< 120 min) is not indicated Antithrombotic platelet aggregation inhibitors - Proprietary products based on aspirin 75 to 325 mg/day - Clopidogrel: PLAVIX Reminder of the indication of PLAVIX: prevention of atherothrombotic events in patients suffering from myocardial infarction (from a few days until less than 35 days),... In patients suffering from acute coronary syndrome: non-st segment elevation acute coronary syndrome (unstable angina or non-q-wave myocardial infarction), including patients undergoing a stent placement following percutaneous coronary intervention, in combination with acetylsalicylic acid (ASA). - Glycoprotein IIb/IIIa inhibitors ( GPIIb/IIIa inhibitors ): Abciximab: REOPRO Indication: Is indicated as an adjunct to heparin and acetylsalicylic acid for: - Percutaneous Coronary Intervention: The prevention of ischaemic cardiac complications in patients undergoing percutaneous coronary intervention (balloon angioplasty, atherectomy, and stent). - Unstable angina: The short-term (1-month) reduction of the risk of myocardial infarction, in patients with unstable angina, not responding to full conventional therapy who have been scheduled for percutaneous coronary intervention. Eptifibatide: INTEGRILIN Indication Integrilin is intended for use with acetylsalicylic acid and unfractionated heparin. Integrilin is indicated for the prevention of early myocardial infarction in adults presenting with unstable angina or non-q-wave myocardial infarction, with the last episode of chest pain occurring within 24 hours and with electrocardiogram changes and/or elevated cardiac enzymes. Patients most likely to benefit from the treatment are those at high risk of developing myocardial infarction within the first 3-4 days after onset of acute angina symptoms including for instance those that are likely to undergo an early PTCA (Percutaneous Transluminal Coronary Angioplasty). Tirofiban: AGRASTAT Indication Prevention of early myocardial infarction in patients presenting with unstable angina or non-q-wave myocardial infarction with the last episode of chest pain occurring within 12 hours and with ECG changes and/or elevated cardiac enzymes. Patients most likely to benefit from the treatment are those at high risk of developing myocardial infarction within the first 3-4 days after onset of acute angina symptoms including for instance those that are likely to undergo an early PTCA. Aggrastat is intended for use with acetylsalicylic acid and unfractionated heparin. 4

5 3. ANALYSIS OF AVAILABLE DATA The extension of the indication of ANGIOX to the treatment of unstable angina or non-st segment elevation myocardial infarction (UA/NSTEMI) in patients planned for urgent or early intervention, in combination with aspirin and clopidogrel, is based on the results of a comparative clinical study (ACUITY/TMC-BIV-02-08). 3.1 ACUITY (acute catheterisation urgent intervention triage strategy) study The study had two objectives: - To compare the efficacy and safety of two antithrombotic treatments in medium to high risk non-st segment elevation ACS patients undergoing early angiography followed by medical treatment, percutaneous coronary intervention (PCI), or a coronary bypass (first randomisation). - To evaluate the clinical impact of the time of administration of the GpIIb/IIIa platelet aggregation inhibitor before or during PCI, the drug having been prescribed either in all cases or in cases of need (second randomisation; ACUITY timing trial). Study design This was a multicentre, randomised, open, parallel-group, non-inferiority study. The patients were randomised to one of the following three groups: heparin + GPIIB/IIIA inhibitor (group A); bivalirudin + GPIIB/IIIA inhibitor (group B), or bivalirudin (group C). Inclusion criteria: patients aged 18 years or over with angina pain lasting at least 10 min associated with the diagnosis of ACS and who met at least 1 of the following 4 criteria: - 1 st criterion: age 65 years, aspirin in the last 7 days, > 2 angina episodes in the previous 24 h and > 3 of the following risk factors: hypertension, hypercholesterolaemia, familial history, diabetes, smoking - 2 nd criterion: ST segment depression 1mm or ST segment elevation 30 min - 3 rd criterion: elevation of troponins I, T, or of CK-MB in the 24 h before inclusion - 4 th criterion: history of documented coronary disease (coronary stenosis > 50% on angiography; PCI or coronary bypass, myocardial infarction) Non-inclusion criterion: severe renal impairment (creatinine clearance < 30 ml/min). Dosage of evaluated treatments: - Antithrombotic agents: heparin (UFH or LMWH, group A) was administered according to the recommendations applicable to the treatment of non-st segment elevation ACS 4. Enoxaparin was administered to 47.5% of the patients and UFH to 52.5%. The bivalirudin dose (groups B and C) was an initial bolus of 0.10 mg/kg followed by an infusion of 0.25 mg/kg/h during the angiography. For the patients having a PCI, an additional bolus of 0.5 mg/kg was administered and the infusion was increased to 1.75 mg/kg/h during the intervention. - Platelet aggregation inhibitors: The patients undergoing angiography received aspirin, and a thienopyridine (clopidogrel) was recommended; 1 Stone GW, Bertrand ME, Lincoff AM, et al. A Prospective, Randomized Trial of Bivalirudin in Acute Coronary Syndromes: One Year Results from the ACUITY Trial. JACC 2007;49: 10B. 2 Stone GW. Bivalirudin for Patients with Acute Coronary Syndromes. N Engl J Med 2006;355: Stone GW. Antithrombotic Strategies in Patients With Acute Coronary Syndrome Undergoing Early Invasive Management One-Year Results From the ACUITY Trial. JAMA 2007;298: Dosage of heparin in ACUITY: UFH: bolus of 60 IU/kg, then intravenous infusion of 12 IU/kg/h until a kaolin-activated PTT of 50 to 75 sec prior to angiography and an ACT of 200 to 250 sec during the PCI. Enoxaparin: prior to angiography, a subcutaneous dose of 1.0 mg/kg every 12 h. An additional intravenous bolus of 0.3 mg/kg was administered before the PCI if the last subcutaneous dose was over 8 h ago or of 0.75 mg/kg if it was over 16 h ago. 5

6 - Aspirin: 300 to 325 mg p.o. or 250 to 500 mg i.v. during the hospital stay, then 75 to 325 mg/day after the hospital stay. - Clopidogrel: a loading dose of 300 mg or more was recommended in the 2 h following the PCI. A dose of 75 mg/day was recommended for 1 year in patients with coronary disease. The patients in groups A and B were also randomized to receive a GPIIB/IIIA inhibitor, either before the angiography or during the angioplasty. Only eptifibatide or tirofiban could be prescribed when the GPIIb/IIIa inhibitor was administered prior to the angiography. Eptifibatide or abciximab could be used in the catheterisation laboratory. - Abciximab (started in the catheterisation laboratory): bolus of 0.25 mg/kg, then infusion of µg/kg/min, 12 h. - Eptifibatide: bolus of 180 µg/kg, then 2 µg/kg/min, for 18 h. If eptifibatide is started in the catheterisation laboratory, a second bolus is administered after 10 min. - Tirofiban: 0.4 µg/kg/min for 30 min, then 0.1 µg/kg/min by infusion, 12 to 18 h. Three primary endpoints and two comparisons: - Any clinical event endpoint covering death from any cause, myocardial infarction, revascularisation, major bleeding. Note: This endpoint was not taken into account by the EMEA in the analysis of the results. - Ischaemic endpoint covering death from any cause, myocardial infarction, unplanned revascularisation carried out because of ischaemic syndrome. - Major bleeding. Among the secondary endpoints: - Each component of the ischaemic endpoint (death from any cause, myocardial infarction, revascularisation) - Incidence of thrombocytopenia 5 - Rehospitalisation. - Duration of hospitalisation. Strategy used to analyse the results at 30 days: Two comparisons were made: - Bivalirudin on its own versus heparin + GP IIb/IIIa inhibitor: - hypothesis of superiority in regard to haemorrhagic events, - hypothesis of non-inferiority (could be switched to superiority) in regard to ischaemic events. - Bivalirudin + GP IIb/IIIa inhibitor versus heparin + GP IIb/IIIa inhibitor: - hypothesis of non-inferiority (could be changed to superiority) in regard to the events of a composite net benefit endpoint (ischaemic and haemorrhagic events). - A non-inferiority margin of 25% of the event rate observed in group A was chosen. Comment: the arguments in favour of this choice were not specified and reasoning based on relative risk would have been preferable for establishing non-inferiority 6. Three types of analysis were defined, including ITT and PP. The results were analysed on an intent-to-treat basis (ITT: randomised patients); per-protocol analysis (PP: randomised patients who received at least one dose of the study treatment) was used for confirmation purposes. An analysis of the patients who received at least one dose of the assigned treatment no matter what that treatment was (so-called ATP) was also used for the safety results. 5 Thrombocytopenia was defined as a platelet count below 150,000/mm 3 in patients who had had a platelet count above 150,000/mm 3 on inclusion. 6 The non-inferiority limit was set on the basis of the absolute risk of ischaemic events in the control group such that the maximum increase in the risk of events does not exceed 25% of the frequency observed in the control group. Reasoning based on relative risk would have been preferable for establishing non-inferiority. 6

7 Results: Characteristics of the evaluated population For the 13,819 randomised patients: - The mean age of the patients was 63 years; approximately 45% were at least 65 years of age. 70% were men. - Less than 20% of the patients had a creatinine clearance < 60 ml/min. The population included was at intermediate to high risk of ischaemic complications and eligible for early invasive management (within 72 h): 77% had recurrent ischaemia, 70% had ECG changes or elevation of cardiac biomarkers, 28% had diabetes, and 41% had unstable angina. Angiography was performed within 72 h in 99% of the patients. Efficacy results The results in the population defined by the description of the indication for ANGIOX are those observed in the patient subgroup that received aspirin and clopidogrel, which was 63% of the ACUITY study population. Analysis of this subgroup at 30 days and at 1 year was undertaken at the EMEA's request in order to ascertain the population deriving greatest benefit from the treatment. The results at 30 days and 1 year for the whole of the population (ITT) and for the patients that received aspirin and clopidogrel prior to angiography or prior to PCI (PP) are thus presented below: Differences in risk for the composite ischaemic endpoint and its components at 30 days and 1 year (ITT population): 7

8 Group A Group B B A Group C C A Endpoint N UFH/enoxaparin + GPIIB/IIIA inhibitor N=4603 bivalirudin + GPIIB/IIIA inhibitor N=4604 difference in risk (95% CI) bivalirudin on its own N=4612 difference in risk (95% CI) (%) 30 days Composite ischaemic 334 (7.3) 356 (7.7) 0.48 (-0.60, 1.55) 360 (7.8) 0.55 (-0.53, 1.63) Death (1.3) (1.5) (-0.31, 0.66) (1.6) (-0.23, 0.75) MI (4.9) (5.0) (-0.84, 0.93) (5.4) (-0.46, 1.35) Unplanned revascularisation 105 (2.3) 123 (2.7) 0.39 (-0.24, 1.03) 110 (2.4) 0.10 (-0.51, 0.72) 1 year Composite ischaemic 702 (15.3) 732 (15.9) 0.65 (-0.83, 2.13) 736 (16.0) 0.71 (-0.77, 2.19) Death (3.9) (3.8) (-0.83, 0.74) (3.7) (-.96, 0.60) MI (6.8) (7.0) (-0.84, 1.23) (7.6) (-0.22, 1.89) Unplanned revascularisation 371 (8.1) 407 (8.8) 0.78 (-0.36, 1.92) 389 (8.4) 0.37 (-0.75, 1.50) 8

9 Differences in risk for the composite ischaemic endpoint at 30 days and 1 year in the patient subgroup that received aspirin and clopidogrel administered prior to angiography or prior to PCI (PP population). Endpoint N (%) Group A UFH/enoxaparin + GPIIB/IIIA inhibitor (N=2842) Group B bivalirudin + GPIIB/IIIA inhibitor (N=2924) B A difference in risk (95% CI) Group C bivalirudin on its own (N=2911) C A difference in risk (95% CI) Composite ischaemic 210 (7.4) Death 39 (1.4) MI 137 (4.8) Unplanned revascularisation Composite ischaemic 74 (2.6) 458 (16.1) 30 days (1.4) 142 ( 4.9) 83 (2.8) 1 year 491 (16.8) 0.03 (-1.32, 1.38) (-0.60, 0.60) 0.04 (-1.07, 1.14) 0.23 (-0.61, 1.08) 0.68 (-1.24, 2.59) 205 (7.0) 36 (1.2) 138 ( 4.7) 64 (2.2) 459 (15.8) (-1.68, 0.99) (-0.72, 0.45) (-1.18, 1.02) (-1.20, 0.39) (-2.24, 1.54) Death 105 (3.7) 114 (3.9) 0.20 (-0.78, 1.19) 97 (3.3) (-1.31, 0.59) MI 189 (6.7) 212 (7.3) 0.60 (-0.71, 1.91) 199 (6.8) 0.19 (-1.11, 1.48) Unplanned revascularisation 268 (9.4) 293 (10.0) 0.59 (-0.94, 2.12) 259 (8.9) (-2.02, 0.96) - In this study (2 nd randomisation), the results in terms of major bleeding and for the ischaemic endpoint were not affected by the time of administration of the GPIIb/IIIa inhibitor, at 30 days or at 1 year. No interaction between the time of GPIIb/IIIa inhibitor administration and bivalirudin therapy was observed 7. The decrease in the incidence of bleeding in the bivalirudin group (group C) was not affected by the time of GPIIB/IIIa inhibitor administration. Comments - As the study was an open study and as one of the components of one of its endpoints was subjective (unplanned revascularisation), it is not possible to exclude measurement bias and follow-up bias. - Following a protocol amendment, the choice of heparin (UFH or enoxaparin) and that of possible prescription of thienopyridine (clopidogrel) depended on the practice of the study centre. The percentages using UFH and enoxaparin were similar (47.9% versus 47.4%) in the control group after randomisation and before angiography. As randomisation was not undertaken according to the choice between UFH and LMWH (enoxaparin) in the reference comparison group (group A), no conclusions can be drawn regarding the respective efficacy of these two anticoagulants compared to bivalirudin. 7 Table 5, ACUITY timing trial day 30 and 1 year results, including Arm C, p12, scientific discussion, EPAR. 9

10 - The patients all received a GPIIB/IIIA inhibitor, except in the bivalirudin-only group (group C): a GPIIB/IIIA inhibitor in addition to aspirin and clopidogrel is in practice prescribed to about 30% of patients only (cf. estimation of the target population); however, the risk of haemorrhage is increased if a GPIIB/IIIA inhibitor is prescribed. - At 30 days, more deaths, MIs, and unplanned revascularisations were observed in the groups given bivalirudin than in the reference group (group A). There were also more deaths in group C (bivalirudin on its own). In view of these worrying results, the EMEA called for an additional analysis on the basis of the ischaemic endpoint at 1 year. The tendency towards less favourable results in the bivalirudin groups which was observed at 30 days was not found after 1 year's follow-up; in particular, mortality was not increased under bivalirudin. This raises the question of the role of either the anticoagulant regimen during the angioplasty or the interventions after the angioplasty (aspirin and/ clopidogrel, ACE inhibitor, etc.). - To better define the patients in whom the efficacy/adverse effects ratio of bivalirudin was favourable, an analysis of the results for the composite ischaemic endpoint was carried out at the EMEA s request in the subgroup of patients that received aspirin + clopidogrel (which was administered prior to angiography or prior to angioplasty). The results (Table 6, page 13, EPAR) showed that the incidence of the events of the composite endpoint was similar in the three groups (A, B, and C), with a reduction of the risk of bleeding in the bivalirudin-only patients (group C) in this subgroup. The level of evidence of this analysis is reduced by reason of the methodology employed to obtain it: a posteriori multiple, subgroup analysis to define the MA population. - The tests for superiority, based on the ischaemic endpoint at 30 days and 1 year, comparing the bivalirudin groups (groups B and C) and the reference group (group A) are not conclusive. It is not known whether the acknowledged decrease in efficacy is offset by a tangible clinical benefit. The expected benefit of a reduction of (major) haemorrhagic risk by bivalirudin must be put into perspective (cf. section 3.2). Bleeding at the femoral puncture sites can be reduced by using radial access 8, which is common in France; this strategy was employed in only 13% of the patients, however. Using the radial rather than the femoral route significantly reduced the risk of haemorrhage in ACUITY Incidence of adverse effects In the ACUITY study, the adverse effects were more frequent in women and in patients over 65 years of age than in males or younger patients in the two bivalirudin groups and the heparin comparator group. Nearly 2.1% of the patients given bivalirudin experienced an adverse effect with the drug. Haemorrhage In the ACUITY study, major bleeding was defined as one of the following: intracranial haemorrhage, retroperitoneal haemorrhage, intraocular haemorrhage, haemorrhage necessitating a radiological or surgical intervention to access the site, haematoma 5 cm at the puncture site, a drop in the haemoglobin concentration 4 g/dl without any obvious source of bleeding, a drop in the haemoglobin concentration 3 g/dl with an obvious source of bleeding, reintervention because of bleeding, bleeding necessitating a transfusion of blood or a blood product. Minor bleeding was defined as any observed haemorrhagic event not meeting the criteria for major bleeding. 8 Sanmartin M. Bivalirudin in acute coronary syndromes. N Engl J Med 2007;356(10): Hamon M. et al. Choice of arterial access site and outcomes in patients with acute coronary syndromes managed with an early invasive strategy: the ACUITY trial. EuroInterv.2009;4:

11 Minor bleeding was reported very frequently ( 1/10), and major bleeding frequently ( 1/100 and < 1/10). A significant decrease in the frequency of major and minor bleeding was seen in the patients in the bivalirudin-only group in comparison with the patients in the heparin + GPIIB/IIIA inhibitor and bivalirudin + GPIIB/IIIA inhibitor groups. Major haemorrhages at the puncture site were the most frequent. Radial access would have enabled this risk to be reduced 10. A similar decrease in the frequency of bleeding was observed in the patients in the bivalirudin-only group who received heparin prior to randomisation (2078 patients) (SPC). ACUITY study: incidence of bleeding at 30 days (intent-to-treat population) Bivalirudin Bivalirudin + GPIIB/IIIA UFH/enoxaparin 4612 patients inhibitor + GPIIB/IIIA inhibitor 4604 patients 4603 patients Major bleeding. 3.0% 5.3% 5.7% ACUITY criteria Intracranial 0.9% 1.7% 1.9% haemorrhage or a drop in the haemoglobin concentration 5 g/dl Haematoma at the 4.5% 7.4% 7.5% puncture site Oozing of blood at the puncture site 3.8% 7.7% 8.5% A beneficial effect in terms of a reduction of bleeding relative to the comparator UFH/enoxaparin combined with a GP IIb/IIIa inhibitor was observed solely in the bivalirudin-only group. Potentially fatal severe bleeding (intracranial haemorrhage in particular) has been reported in the course of postmarketing experience of bivalirudin. In the event of major bleeding, the treatment must be halted. No antidote exists, but bivalirudin is haemodialysable. Risk of thrombocytopenia In the ACUITY study, thrombocytopenia was reported in 10 patients treated with bivalirudin (0.1%). Most of these patients received concomitant treatment with acetylsalicylic acid and clopidogrel, and six of them also received GPIIB/IIIA inhibitors. There was no death in this group. 3.3 Conclusion The ACUITY study was an open randomised non-inferiority study. Three antithrombotic agents were compared in nearly 14,000 patients with unstable angina or non-st segment elevation myocardial infarction (UA/NSTEMI): bivalirudin + GPIIB/IIIA inhibitor (group B) versus bivalirudin (group C) versus the reference treatment combining heparin (UFH/enoxaparin) + GPIIB/IIIA inhibitor. The distribution of care was as follows: 99% underwent angiography within 72 h, then 56% received angioplasty, 11% an aortocoronary bypass, and 33% medical treatment only. Around 55% were under 65 years of age and less than 20% had renal impairment (creatinine clearance < 60 ml/min). The non-inferiority margin used was 25% of the ischaemic event rate observed in the reference group A. Major haemorrhage was also an endpoint. 10 Jolly SS et al. Radial versus femoral access for coronary angiography or intervention and the impact on major bleeding and ischemic events: a systematic review and meta-analysis of randomized trials. Am Heart J 2009;157:

12 Non-inferiority of the bivalirudin groups to the control group in terms of the incidence of the composite ischaemic endpoint (death, MI, and unplanned revascularisation carried out because of ischaemic syndrome) was observed after 30 days and 1 year. After 30 days, there were more deaths, MIs, and unplanned revascularisations in the two bivalirudin groups (B and C) than in the reference group. An additional analysis at 1 year tends to confirm non-inferiority in regard to the incidence of deaths, however. The patients who seem to benefit from bivalirudin therapy are those who have received aspirin and clopidogrel, according to an ACUITY study subgroup analysis; all the patients received aspirin and 63% received clopidogrel. This was the population accepted for the granting of MA in this clinical situation. However, the level of evidence of this result is limited by the methodology, which was more exploratory than demonstrative (a posteriori subgroup analysis). The acknowledged decrease in efficacy in ACUITY as a result of bivalirudin therapy in comparison with the reference therapy of heparin + GPIIB/IIIA inhibitor (the principle of a non-inferiority study) should be offset by a clinical benefit: and indeed, a reduction of haemorrhagic risk was observed in the bivalirudin-only group (group C). Bleeding at the puncture site occurred in numerous instances (nearly 50% of haemorrhages), given that the preferred route of access in the catheterisation laboratory was femoral and not radial for the patients in this study. However, it is an established fact that the risk of haemorrhagic complications is higher with the femoral route than with the radial route (ref. 9 and ref. 10). It is thus not possible to quantify the possible clinical benefit (size of the effect) due to bivalirudin on its own. It has not been established that the results of the ACUITY study can be carried over into the clinical practice of French cardiologists (who prefer enoxaparin as an anticoagulant and, in particular, prefer to use the radial route). It should be noted that methods of administration of ANGIOX can be sources of error (cf. dosage recommended in the SPC, expert opinion). Furthermore, most of these patients are treated before they reach cardiology departments and are given heparin among other things. Should heparin be replaced by bivalirudin in these patients? The validity of this strategy is not well supported 11. To conclude, bivalirudin as monotherapy is an alternative to prescription of the combination of heparin + GPIIB/IIIA inhibitor in cases of catheterisation by the femoral route. 4. TRANSPARENCY COMMITTEE CONCLUSIONS 4.1 Actual benefit All acute coronary syndromes (with or without ST segment elevation) call for treatment by a specialist team. The immediate seriousness of coronary syndromes without ST segment elevation (unstable angina, NSTE myocardial infarction) depends on the clinical situation (stable or unstable), whether or not there is a threat to life in the short term, and risk factors. It determines the patients' management. Two methods of treatment are possible: medical treatment only and, in some patients, an invasive approach with coronary angiography and revascularisation by means of an angioplasty (PCI) or an aortocoronary bypass (ACB). The invasive approach is implemented within 120 min (emergency) or, more often, within 24 to 11 According to the SPC, a switch to ANGIOX can be carried out as follows: 30 min after UFH administered by the intravenous route or 8 h after discontinuation of a LMWH administered by the subcutaneous route. 12

13 72 h because although there is an acute risk of complications there is not an immediate threat to life. Anticoagulants are recommended in combination with platelet aggregation inhibitors in these patients. Several anticoagulants have been evaluated: unfractionated heparin (UFH), enoxaparin (LOVENOX), bivalirudin (ANGIOX), and fondaparinux (ARIXTRA 2.5 mg). ARIXTRA 2.5 mg is indicated in patients in whom an invasive approach (percutaneous coronary intervention: PCI) performed as an emergency (within 120 min) is not indicated. It is thus a first-line medicinal product. ANGIOX is indicated in patients planned for urgent or early intervention, in combination with aspirin and clopidogrel. It is a first-line treatment. Public health benefit In terms of public health, ischaemic heart diseases represent a major burden. That of non-st segment elevation acute coronary syndromes (unstable angina or myocardial infarction (MI) without ST segment elevation) necessitating urgent or early intervention (PCI*) is considered substantial. Improving the secondary prevention of these clinical situations continues to be a public-health need. On the basis of the data from the ACUITY study versus heparin** + GPIIB/IIIA inhibitor (non-inferiority in terms of ischaemic efficacy, reduction of haemorrhagic risk in the ANGIOX-only group), it is not expected that ANGIOX will have an additional impact on morbidity/mortality in comparison with existing therapies. Furthermore, there is no guarantee that the results of the ACUITY study can be carried over into actual practice in France because: - it is an international study (global data) that does not necessarily reflect French practice: the organisation of emergency care, greater use of radial access with less risk of a haemorrhage, more infrequent use of GPIIB/IIIA inhibitor therapy. - there is uncertainty over the regimen for the administration of ANGIOX [probably little use by prehospital emergency services, switching to ANGIOX on arrival at hospital may well complicate management] Aside from cases where there is a history of heparin-induced thrombocytopenia (less than 1% of angioplasty patients), it is not thought that the proprietary product ANGIOX can make an additional contribution towards meeting the identified public-health need. Consequently, in the current state of knowledge and in view of the treatments available at present, it is not expected that ANGIOX will benefit public health in this indication. * Percutaneous coronary intervention ** UFH or LOVENOX The efficacy/adverse effects ratio of ANGIOX bivalirudin is high. Conclusion: The actual benefit of ANGIOX in this indication is substantial. 4.2 Improvement in actual benefit in the extension of the indication (NSTE ACS) ANGIOX does not bring an improvement in actual benefit (IAB V) in the strategy for the management of non-st segment elevation acute coronary syndromes. 4.3 Therapeutic use of ANGIOX in non-st segment elevation acute coronary syndromes The aim of treatment is to prevent death and the onset of a transmural myocardial infarction. Three clinical situations may be distinguished: - There is an immediate threat to life: emergency use of an immediate invasive strategy (within 120 min) is justified in such instances. 13

14 - There is no immediate threat to life, although there is an acute risk of complications: in this case, the invasive strategy (coronary angiography, and a reperfusion intervention if necessary) may be postponed until up to 72 h after diagnosis. - The patient s clinical status does not necessitate the use of an invasive strategy. ANGIOX represents an alternative to prescription of (unfractionated or low-molecular-weight) heparin in cases where patients with NSTE ACS are managed invasively within 72 h of the onset of the first symptoms and where the patient's clinical situation warrants combining a GPIIB/IIIA inhibitor with the antithrombotic agent and with the platelet aggregation inhibitors aspirin + clopidogrel. In this case and in combination with these two platelet aggregation inhibitors, ANGIOX is an alternative to the combination of heparin (UFH or LMWH) + GPIIB/IIIA inhibitor for the purpose of preventing major haemorrhages, though the occurrence of these can be reduced effectively by using radial access in the catheterisation laboratory. Revascularisation by aortocoronary bypass and not by angioplasty is also a treatment option of choice. 4.4 Target population in the extension of the indication (UA/NSTEMI) The target population is defined as patients with acute coronary syndrome (unstable angina/non-st segment elevation myocardial infarction (UA/NSTEMI)) planned for urgent or early intervention who are simultaneously treated with aspirin and clopidogrel. Quantitative estimation of the target population: - The population of patients planned for urgent or early intervention is defined on the basis of the recommendations of the European Society of Cardiology (ESC) and the Haute Autorité de Santé (section 4.4). They are patients in whom the risk justifies angioplasty within 48 to 72 h. This population may be estimated at between 30,000 and 50,000 patients: The FAST-MI registry (French registry of ST or non-st segment elevation acute coronary syndromes) 12 evaluated the management of myocardial infarcts in real life and measured its impact on patient outcome in the medium and long term. It was a prospective multicentre study (223 centres) carried out over a period of one month (November) in 2005 in Cardiological Intensive Care Units (CICUs). This registry included 3059 patients, with 60% of the French CICUs taking part and a homogeneous geographic distribution. On discharge from hospital, 53% of the patients were classed as having a STEMI and 47% as having a diagnosis of NSTEMI; this corresponds to an annual CICU ACS total of 61,180 (3059 x 12 x 100/60 = 61,180), 47% of them with UA/NSTEMI = 28,754, with a risk high enough to be admitted to a CICU. In a different approach, based on PMSI (2006) data, the number of UA/NSTEMI cases can be estimated at 127,000, though it should be noted that the data represent hospital admissions and not necessarily the number of new patients. The FAST-MI registry shows that 78% of the NSTEMI patients in CICUs underwent coronary angiography and 50.5% had a percutaneous coronary intervention. On this basis, extrapolation to the French population may suggest a maximum of 50,000 patients with UA/NSTEMI undergoing PCI. - A reduction of the risk of haemorrhage with ANGIOX is possible (cf. discussion of the ACUITY results) in NSTE ACS patients treated with heparin and a GPIIB/IIIA inhibitor; this subpopulation is between 17% (according to the GRACE registry 13 ) and 25% (2003 to 2007 period, ARH [regional hospital agency] registry of coronary angiographies and angioplasties of Ile-de-France). On the basis of these data, the population of patients for whom ANGIOX constitutes an alternative to prescription of a heparin + GPIIB/IIIA inhibitor would be around 15, Cambou J-P, Simon T., Mulak G., Bataille V. et Danchin N., for the FAST MI investigators, The French registry of acute ST elevation or non-st elevation Myocardial Infarction (FAST MI) : Study design and baseline characteristics. Archives des maladies du Cœur ; 100: Fox KA et al. Management of acute coronary syndromes. Variations in practice and outcome; findings from the Global Registry of Acute Coronary Events (GRACE). Eur Heart J 2002 ;23 :

15 4.5. Conclusion The Transparency Committee recommends inclusion on the list of medicines approved for use by hospitals and various public services in the extension of indication. 15