Is the role of bivalirudin established?

Transcription

1 Is the role of bivalirudin established? Rob Henderson Consultant Cardiologist Trent Cardiac Centre Nottingham University Hospitals Conflicts of Interest: None Declarations: Member NICE Unstable Angina & NSTEMI Guideline Development Group Clinical Adviser NICE Stable Angina Guideline Development Group Deputy Chair NICE STEMI Guideline Development Group BCIS Clinical Standards Lead

2 Bivalirudin 20-amino acid synthetic polypeptide analogue of hirudin C 98 H 138 N 24 O 33 direct inhibitor of soluble and clotbound thrombin rapid onset with t½ of 25 mins given as an iv infusion cleared principally by proteolytic cleavage & by renal excretion

3 Bivalirudin site of action Coagula)on cascade Xa Bivalirudin Prothrombin Thrombin Fibrinogen Fibrin

4 NICE CG94 bivalirudin for non-st elevation ACS Guidance: Consider bivalirudin as an alternative to the combination of a heparin plus a GPI for patients who: are at intermediate or higher risk of adverse cardiovascular events (predicted 6-month mortality >3%) and are not already receiving a GPI or fondaparinux and are scheduled to undergo angiography (with follow-on PCI if indicated) within 24 hours of admission (ACUITY, cost effective with high uncertainty) NICE CG

5 ACUITY bivalirudin in non-st elevation ACS scheduled for invasive strategy 13,819 Patients with moderate or high risk NSTE-ACS undergoing early (<72h) invasive strategy Angiography performed Median time to angiography (h) Unfractionated heparin* Low-molecularweight heparin* UFH/LMWH +GPI (N = 4603) Bivalirudin +GPI (N = 4604) Bivalirudin (N = 4612) 99.2% 98.8% 98.9% % 40.4% 40.5% 26.3% 24.8% 25.4% GPI during PCI 96.6% 96.7% 9.1% *before randomisation eptifibatide 62%, abciximab 19%, tirofiban 19% Stone NEJM 2006;355:2203

6 ACUITY - bivalirudin in non-st-elevation ACS scheduled for invasive strategy Net Clinical Outcome* (%) Primary outcome at 30 days Death, MI, revasc for ischaemia, major bleeding Heparin+GPI (n=4603) Bivalirudin+GPI (n=4604) Bivalirudin alone (n=4612) 11.9% 11.9% P= % P= Days From Randomization Stone et al, NEJM 2006;355:2203

7 ACUITY - bivalirudin in non-st elevation ACS scheduled for invasive strategy Events at 30 days 14% 12% 10% UFH/Enox & GPI (n=4603) Bivalirudin & GPI (n=4604) Bivalirudin (n=4612) 11.7% 11.8% 10.1% 8% 7.3% 7.7% 7.8% 6% 5.7% 5.3% 4% 2% 0% 3.0% NS NS NS P<0.001 NS P=0.015 MACE* Major bleed Net clinical outcome All patients scheduled for coronary arteriography/pci *Death, MI, revasc for ischaemia Stone, NEJM 2006;355:2203

8 Influence of timing of clopidogrel on bivalirudin treatment in non- ST elevation ACS ACUITY sub-study Death, MI, revasc for ischaemia at 30 days P=0.08 Peri-PCI=after angio or <30 mins after PCI Post-PCI=>30 mins after PCI Timing of Clopidogrel Exposure Lincoff JACC Intv 2008;1:639

9 Influence of timing of clopidogrel on bivalirudin treatment in non- ST elevation ACS ACUITY sub-study Death, MI, revasc for ischaemia at 30 days P=0.08 EMEA licence states that bivalirudin should be administered with aspirin and clopidogrel Peri-PCI=after angio or <30 mins after PCI Post-PCI=>30 mins after PCI Timing of Clopidogrel Exposure Lincoff JACC Intv 2008;1:639

10 ACUITY bivalirudin in non-st elevation ACS scheduled for invasive strategy Events at one year All differences non-significant Stone, JAMA 2007;298:2497

11 ACUITY and NICE guidance NICE guidance Consider bivalirudin in patients at intermediate or higher risk and not already receiving fondaparinux or GPI and scheduled to undergo angio/pci<24 hours Cost-effective with high degree of uncertainty ACUITY data Recruited moderate/high risk NSTE-ACS no patients pre-treated with fondaparinux or GPI no evidence for switch angio/pci done median 20 hrs after randomisation short-term reduction in bleeding did not translate to longer-term benefit

12 NICE TA230 bivalirudin for the treatment of STEMI Guidance: Bivalirudin in combination with aspirin and clopidogrel is recommended for the treatment of adults with ST-segment-elevation myocardial infarction undergoing primary percutaneous coronary intervention (HORIZONS-AMI, bivalirudin dominant in CE analysis - greater efficacy & less cost)

13 HORIZONS AMI bivalirudin in STEMI scheduled for PPCI 3602 patients with STEMI presenting within 12h of symptom onset and who were undergoing primary PCI UFH & GPI Bivalirudin N Heparin pre-procedure 76.3% 65.8% Heparin during procedure 98.9% 2.6% Bivalirudin 0.2% 96.9% GPI 97.7% 7.5% Abciximab 52.0% 4.3% Eptifibatide 45.6% 3.2% Clopidogrel 98.2% 98.7% Open label (blinded event adjudication) Radial in 6% Stone NEJM 2008;358:2218

14 HORIZONS AMI bivalirudin in STEMI scheduled for PPCI 14% 12% UFH & GPI (n=1802) Bivalirudin (n=1800) 30 d outcomes 12.1% 10% 8% 8.3% 9.2% 6% 5.5% 5.4% 4.9% 4% 2% 0% P=0.95 P<0.001 P=0.005 MACE* Major bleed Net clinical outcome STEMI with intention to treat by PPCI *Death, re-mi, ischaemic TVR, CVA Stone NEJM 2008;358:2218

15 Interaction between treatment assignment & pre-procedural unfractionated heparin - HORIZONS-AMI Major adverse cardiovascular events at 30 days 10% 8% Interaction P value 0.08 Pre-procedural UFH 7.2% No pre-procedural UFH 6% 4.6% 5.6% 5.2% 4% 2% 0% Bivalirudin (n=1797) UFH+GPI (n=1798) Death, reinfarction, target vessel revascularization for ischaemia, and stroke Stone NEJM 2008;358:2218

16 HORIZONS AMI - acute stent thrombosis (<24h) Def/prob stent thrombosis (%) No pre-randomisation heparin Pre-randomisation heparin Time in hours Bivalirudin 2.6% Bivalirudin 0.9% UFH+GPI 0.8% UFH+GPI 0.1% Dangas Circulation 2011;123:1745

17 HORIZONS AMI 3 year stent thrombosis (ARC definite/probable) Stent Thrombosis (%) Bivalirudin alone (n=1611) Heparin + GPIIb/IIIa (n=1591) 3.5% 3.0% HR 0.89; 95%CI 0.65 to 1.23; p= % 4.5% Months ARC= Academic Research Consortium Stone Lancet 2011;37:2193

18 HORIZONS AMI 3 year major bleeding (non-cabg) Major Bleeding (%) Bivalirudin alone (n=1800) Heparin + GPIIb/IIIa (n=1802) 9.4% 6.0% 10.5% 6.9% 2 HR 0.64; 95%CI 0.51 to 0.80; P= Months Intracranial, intraocular, retroperitoneal, access site bleed requiring intervention/surgery, hematoma 5 cm, Hb 3g/dL with or 4g/dL w/o overt source; reoperation for bleeding; or blood product transfusion Stone Lancet 2011;37:2193

19 HORIZONS AMI 3 year cardiac mortality Time in Months Cardiac Mortality (%) yr HR (95%CI) 0.56 (0.40, 0.80) P= % 2.1% Heparin + GPIIb/IIIa (n=1802) Bivalirudin alone (n=1800) Months 5.1% 2.9% Δ2.2% Stone Lancet 2011;37:2193

20 HORIZONS-AMI - some questions Is the effect of bivalirudin on late mortality (44% reduction in hazard) biologically plausible? All due to reduced bleeding? If bleeding is important, why did reduced bleeding in ACUITY not reduce late mortality? Why is pre-procedural heparin necessary to prevent thrombotic events? Would greater use of radial route (6% in HORIZONS AMI) reduce major bleeding and decrease late mortality benefit?

21 HORIZONS AMI and NICE guidance NICE Bivalirudin in combination with aspirin and clopidogrel is recommended for the treatment of adults with ST-segmentelevation myocardial infarction undergoing primary percutaneous coronary intervention The Committee was satisfied that treatment with bivalirudin in combination with aspirin and prasugrel is outside the marketing authorisation for bivalirudin and therefore beyond the remit of this appraisal HORIZONS-AMI Relevance to UK limited by: UFH+GPI as comparator (30% PPCI in UK do not get GPI) Pre-procedural heparin (not routine in UK) Clopidogrel use (but TA182 recommends prasugrel as an option) Femoral access (in RIVAL radial use in STEMI reduced mortality) Open label design (possibility of bias)

22 What NICE should have said NICE Bivalirudin in combination with aspirin and clopidogrel is an option for the treatment of adults with ST-segment-elevation myocardial infarction undergoing primary percutaneous coronary intervention The Committee was satisfied that treatment with bivalirudin in combination with aspirin and prasugrel is outside the marketing authorisation for bivalirudin and therefore beyond the remit of this appraisal HORIZONS-AMI Relevance to UK limited by: UFH+GPI as comparator (30% PPCI in UK do not get GPI) Pre-procedural heparin (not routine in UK) Clopidogrel use (but TA182 recommends prasugrel as an option) Femoral access (in RIVAL radial use in STEMI reduced mortality) Open label design (possibility of bias) Alternative option: aspirin, prasugrel, heparin±gpi, radial route