Rivaroxaban (Xarelto ) in patients following acute coronary syndrome with raised biomarkers. Dr Luke Roberts Senior Medical Advisor Bayer PLC

Transcription

1 Rivaroxaban (Xarelto ) in patients following acute coronary syndrome with raised biomarkers Dr Luke Roberts Senior Medical Advisor Bayer PLC Date of prep: Jan 2015

2 Conflicts of interest: Salaried employee of Bayer PLC

3 Rationale for the use of rivaroxaban in ACS Mechanisms of platelet activation and coagulation are highly interdependent, thrombin plays a central role in both 1,2 Excess thrombin generation persists in ACS patients for at least 6 12 months beyond the acute presentation, 3,4 providing a rationale for a dual pathway strategy (long-term antiplatelet and oral anticoagulant therapy) Anticoagulant therapy combined with antiplatelet therapy may target complementary mechanisms associated with thrombus formation in patients with ACS 1. Monroe and Hoffmann. Arterioscler Thromb Vasc Biol 2006; 2. Mackman. Nature 2008; 3. Merlini et al. Circulation 1994; 4. Ardissino et al. Blood 2003.

4 Mortality rate after hospital discharge for ACS remains high 10 Death from hospital discharge to 6 months Mortality (%) STEMI NSTEMI Unstable angina Days GRACE, Global Registry of Acute Coronary Events Fox et al. BMJ 2006;333:1091.

5 ATLAS ACS 2 TIMI 51: a randomized, double-blind, event-driven phase III trial in patients hospitalized with ACS NO Stratum 1: ASA alone (7%) N=15,526* Physician's decision whether or not to add thienopyridine YES Stratum 2: ASA + thienopyridine (93%) Placebo (n=355) Rivaroxaban 2.5 mg bid (n=349) Rivaroxaban 5 mg bid (n=349) Placebo (n=4821) Rivaroxaba n 2.5 mg bid (n=4825) Rivaroxaban 5 mg bid (n=4827) Event-driven study 983 events ASA dose: mg 1. Gibson et al. Am Heart J 2011;161: e6; 2. Mega et al. N Engl J Med 2012;366:9 19.

6 Study endpoints Primary efficacy endpoint: composite of cardiovascular death, MI and stroke (ischaemic, haemorrhagic or uncertain) Secondary efficacy endpoint: composite of all-cause death, MI or stroke Main safety endpoint: incidence of major bleeding not associated with CABG surgery (according to TIMI bleeding definition)

7 Inclusion and Exclusion criteria Inclusion criteria Diagnosis of STEMI, NSTEMI, or UA with at least one of the following: 0.1 mv ST-segment deviation TIMI risk score 4 Patients aged 18 years - 54 years in addition to primary ACS event with either: Diabetes mellitus or Prior MI Patients received ASA mg/day alone or ASA plus a thienopyridine Based on national/local dosing guidelines Exclusion criteria Increased bleeding risk, e.g. Low platelet count History of intracranial haemorrhage Active internal bleeding Prior stroke or TIA in stratum 2 patients Atrial fibrillation Except single episodes >2 years previously in patients aged <60 years with no evidence of cardiopulmonary disease Severe concomitant condition or disease at time of randomisation. Known significant liver disease or liver function abnormalities Anaemia History of HIV at screening Substance abuse Life expectancy <6month

8 ATLAS ACS 2 TIMI 51: rivaroxaban 2.5 mg bid significantly reduced CV events and death 13 Cumulative incidence (%) CV death/mi/stroke (primary efficacy endpoint) HR=0.84 (95% CI ) Placebo 10.7% 9.1% Rivaroxaban 2.5 mg bid 5 Cardiovascular death HR=0.66 (95% CI ) 4.1% 2.7% 5 All-cause death HR=0.68 (95% CI ) 4.5% 2.9% Months Months Both strata. Months 1. Mega et al. N Engl J Med 2012;366:9 19; 2. Gibson et al. AHA 2011 (

9 12,626 patients had cardiac biomarker elevation. In the overall population rivaroxaban reduced the CV death, MI and stroke. HR 0.81 ( ) P=0.003 In those patients without cardiac biomarker elevation rivaroxaban vs placebo there was not a reduction in the primary efficacy endpoint. HR 1.06 ( ) P= ,353 patients had cardiac biomarker elevation and no prior stroke or TIA (both doses). Rivaroxaban reduced CV death, MI or stroke. HR 0.79 ( ) P=0.001 Mega et al. European Heart Journal (2014) 35 (Abstract Supplement), 992

10 Rivaroxaban 2.5mg bd reduces Cardiovascular death, MI or stroke among patients with elevated biomarkers and no prior stroke or TIA Cumulative incidence (%) Mega et al. European Heart Journal (2014) 35 (Abstract Supplement), 992

11 Rivaroxaban 2.5mg bd reduces Cardiovascular death and all cause death among patients with elevated biomarkers and no prior stroke or TIA Cumulative incidence (%) 5% 4% 3% 2% 1% 0% CV Death HR 0.55 ( ) P< Days NNT = 50 NNT = 49 Placebo Rivaroxaban All cause death HR 0.58 ( ) P<0.001 Days Mega et al. European Heart Journal ( 2014 ) 35 ( Abstract Supplement ), 992

12 Bleeding events in patients with biomarker elevation and no prior stroke/ TIA population Among patients with cardiac biomarker elevation and no prior stroke or TIA, rivaroxaban 2.5 mg twice daily as compared with placebo increased the rates of non-cabg TIMI major bleeding without an increase in fatal bleeding Mega et al. European Heart Journal ( 2014 ) 35 ( Abstract Supplement ), 992

13 Summary Among patients with a recent ACS with cardiac biomarker elevation and no prior stroke or TIA, rivaroxaban 2.5 mg twice daily as compared with placebo: Reduces CV death, MI, or stroke Reduces CV death and all-cause death Increases non-cabg TIMI major bleeding, without an increase in fatal bleeding Mega et al. European Heart Journal ( 2014 ) 35 ( Abstract Supplement ), 992

14 q Xarelto 2.5 mg film-coated tablets (rivaroxaban) Prescribing Information (Refer to full Summary of Product Characteristics (SmPC) before prescribing) Presentation: 2.5 mg rivaroxaban tablet. Indication(s): Xarelto, co-administered with acetylsalicylic acid (ASA) alone or with ASA plus clopidogrel or ticlopidine, is indicated for the prevention of atherothrombotic events in adult patients after an acute coronary syndrome (ACS) with elevated cardiac biomarkers. Posology and method of administration: Dosage 2.5 mg rivaroxaban orally twice daily; patients should also take a daily dose of mg ASA or a daily dose of mg ASA in addition to either a daily dose of 75 mg clopidogrel or a standard daily dose of ticlopidine. Start Xarelto as soon as possible after stabilisation, including revascularisation for ACS; at the earliest 24 hours after admission & at discontinuation of parenteral anticoagulation. If dose is missed, take next dose, do not double the dose. Refer to SmPC for full information on duration of therapy & converting to/from Vitamin K antagonists (VKA) or parenteral anticoagulants. For patients who are unable to swallow whole tablets, refer to SmPC for alternative methods of oral administration. Renal impairment: Mild & moderate (creatinine clearance 50-80ml/min & ml/min respectively) no dose adjustment. Severe (creatinine clearance 15-29ml/min) - limited data indicate rivaroxaban concentrations are significantly increased, use with caution. Creatinine clearance < 15ml/min not recommended. Hepatic impairment: Do not use in patients with coagulopathy & clinically relevant bleeding risk including cirrhotic patients with Child Pugh B & C. Paediatrics: Not recommended. Contra-indications: Hypersensitivity to active substance or any excipient; active clinically significant bleeding; lesion or condition considered to confer a significant risk for major bleeding (refer to SmPC); concomitant treatment with any other anticoagulants exceptunder specific circumstances of switching anticoagulant therapy or when unfractionated heparin is given at doses necessary to maintain an open central venous or arterial catheter; concomitant treatment of ACS with antiplatelet therapy in patients with a prior stroke or transient ischaemic attack; hepatic disease associated with coagulopathy & clinically relevant bleeding risk including cirrhotic patients with Child Pugh B & C; pregnancy & breast feeding. Warnings & precautions: Clinical surveillance in line with anticoagulation practice is recommended throughout treatment. Discontinue if severe haemorrhage occurs. In studies mucosal bleedings & anaemia were seen more frequently during long term rivaroxaban treatment on top of single or dual anti-platelet therapy haemoglobin/haematocrit testing may be of value to detect occult bleeding. Use is not recommended in patients: with creatinine clearance <15 ml/min; receiving concomitant systemic treatment with strong concurrent CYP3A4- and P-gpinhibitors, i.e. azoleantimycotics or HIV protease inhibitors; with increased bleeding risk (refer to SmPC); in patients receiving concomitant treatment with strong CYP3A4 inducers unless the patient is closely observed for signs and symptoms of thrombosis; not recommended due to lack of data: treatment in combination with other antiplatelet agents than ASA and clopidogrel/ticlopidine; in patientsconcomitantly treated with dronedarone. Use with caution in patients: with conditions with increased risk of haemorrhage (refer to SmPC); with severe renal impairment; with moderate renal impairment concomitantly receiving other medicines which increase rivaroxaban plasma concentrations; treated concomitantly with medicines affecting haemostasis; in ACS patients > 75 years of age or with low body weight (<60 kg). Patients on treatment with Xarelto & ASA or Xarelto & ASA plus clopidogrel/ticlopidine should only receive concomitant treatment with NSAIDs if the benefit outweighs the bleeding risk. In patients at risk of ulcerative gastrointestinal disease prophylactic treatment may be considered. Although treatment with rivaroxaban does not require routine monitoring of exposure, rivaroxaban levels measured with a calibrated quantitative anti-factor Xa assay may be useful in exceptional situations. Elderly population Increasing age may increase haemorrhagic risk. Xarelto contains lactose. Interactions: cf. Warnings & Precautions. Pregnancy & breast feeding: Contra-indicated. Effects on ability to drive & use machines: syncope (uncommon) & dizziness (common) were reported. Patients experiencing these effects should not drive or use machines. Undesirable effects: Common: anaemia, dizziness, headache, eye haemorrhage, hypotension, haematoma, epistaxis, haemoptysis, gingival bleeding, GI tract haemorrhage, GI & abdominal pains, dyspepsia, nausea, constipation, diarrhoea, vomiting, pruritus, rash, ecchymosis, cutaneous & subcutaneous haemorrhage, pain in extremity, urogenital tract haemorrhage, renal impairment, fever, peripheral oedema, decreased general strength & energy, increase in transaminases, post-procedural haemorrhage, contusion, wound secretion. Serious: cf. CI/Warnings & Precautions in addition: thrombocythemia, angioedema and allergic oedema, occult bleeding/haemorrhage from any tissue (e.g. cerebral & intracranial, haemarthrosis, muscle) which may lead to complications (incl. compartment syndrome, renal failure, fatal outcome), syncope, tachycardia, abnormal hepatic function, hyperbilirubinaemia, jaundice, vascular pseudoaneurysm following percutaneous vascular intervention. Prescribers should consult SmPC in relation to full side effect information. Overdose: No specific antidote is available. Legal Category: POM. Package Quantities & Basic NHS Costs: 56 tablets: & 100 tablets: MA Number(s): EU/1/08/472/ Further information available from: Bayer plc, Bayer House, Strawberry Hill, Newbury, Berkshire RG14 1JA, U.K. Telephone: Date of preparation: August Xarelto is a trademark of the Bayer Group. Adverse eventsshould be reported. Reportingformsand information can be found at Adverse eventsshould also be reported to Bayerplc. Tel.: , Fax.: , phdsguk@bayer.co.uk