Robert Storey. Sheffield, United Kingdom

Transcription

1 Breakthrough Antiplatelets and Anticoagulants: Focus on brand new drugs Robert Storey Professor of Cardiology, Department of Cardiovascular Science, University of Sheffield and Academic Director and Honorary Consultant Cardiologist, Cardiology and Cardiothoracic Surgery Directorate, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, United Kingdom 1

2 My Conflicts of Interest Are: Company Name Relationship AstraZeneca Research grant, honoraria, consultant Eli Lilly / Daiichi Sankyo Research/educational grants, honoraria, consultant The Medicines Company Consultant Merck Research grant, consultant Novartis Consultant Sanofi aventis /BMS Consultant Eisai Consultant Medscape Honoraria Accumetrics Educational grant, research consumables, consultant Iroko Honorarium

3 HEPARINS FONDAPARINUX BIVALIRUDIN RIVAROXABAN APIXABAN DABIGATRAN VORAPAXAR ATOPAXAR Thrombin generation Antithrombotic mechanisms Coagulation Thromboxane A 2 x ASPIRIN 5HT Collagen ADP x GPVI 5HT Thrombin 2A P2Y 1 TPα PAR-4 x PAR-1 ATP P2X 1 5HT ADP ATP Dense granule ADP x TICAGRELOR P2Y 12 PLATELET P2Y 12 ACTIVATION TICLOPIDINE CLOPIDOGREL PRASUGREL ACTIVE METABOLITE CANGRELOR Shape change Alpha granule Coagulation factors Inflammatory mediators Amplification α IIb β 3 α IIb β 3 Fibrinogen x Aggregation α IIb β 3 GP IIb/IIIa ANTAGONISTS

4 Oral reversibly-binding binding P2Y 12 inhibition: PLATO study Ticagrelor vs clopidogrel 4

5 Ticagrelor: CPTP (Cyclo-Pentyl-Triazolo-Pyrimidine) HO HO O OH N N N S N N H N F F 5 van Giezen JJJ, Humphries RG. Semin Thromb Hemost. 2005;31:

6 ONSET/OFFSET Study IPA with ADP 5uM (final extent) 100 Ticagrelor 180mg LD /90mgbd(n=54) * * * * * 90 Clopidogrel 600mg LD / 75 mg od (n=50) * * // * I PA % * // 10 0 Onset Maintenance Offset Gurbel PA et al. Circulation 2009 Time (hours) // weeks

7 PLATO PLATELET: VerifyNow P2Y 12 Assay Comparing Maintenance Therapy with Clopidogrel vs Ticagrelor 500 **** **** tion Unit ts Platel let Reac PRU ***P< Clopidogrel Ticagrelor Clopidogrel Ticagrelor Trough Peak Storey RF et al. J Am Coll Cardiol

8 Ticagrelor and adenosine uptake Coronary artery flow response to adenosine 30 μg/min intra-arterial arterial infusion (mean ± SEM) Jan-Arne Björkman, Ian Kirk, JJJ van Giezen. AHA

9 Secondary efficacy endpoints over time Myocardial infarction Cardiovascular death 7 Clopidogrel Ticagrelor Clopidogrel 5.1 Cumu ulative incid dence (%) HR 0.84 (95% CI ), p=0.005 Cumu ulative incid dence (%) Ticagrelor HR 0.79 (95% CI ), p=0.001 No. at risk Days after randomisation Days after randomisation Ticagrelor 9,333 8,678 8,520 8,279 6,796 5,210 4,191 9,333 8,294 8,822 8, ,482 4,419 Clopidogrel 9,291 8,560 8,405 8,177 6,703 5,136 4,109 9,291 8,865 8,780 8, ,441 4,364

10 PLATO Invasive Definite it Stent t Thrombosis 2 tent throm mbosis, % 1 Clopidogrel, 600 mg Clopidogrel, <600 mg Ticagrelor, 600 mg clopidogrel Ticagrelor, <600 mg clopidogrel Definite st Days Since PCI Cannon CP, et al. Lancet. 2010;375:

11 PLATO All-cause mortality planned invasive vs non-invasive strategy All-ca ause mor rtality (% %) Non-invasive HR, 0.75, 95% CI: ( ) Invasive HR, 0.81, 95% CI: ( ) 8.2% 6.1% Number at risk Invasive Days after randomization Ticagrelor Clopidogrel Non-invasive Ticagrelor Clopidogrel James S et al. Brit Med J 2011

12 Time to major bleeding primary safety event 15 (% per year) Ticagrelor 10 Clopidogrel l K-M estima ated rate 5 HR 1.04 (95% CI ), p= Days from first IP dose No. at risk Ticagrelor 9,235 7,246 6,826 6,545 5,129 3,783 3,433 Clopidogrel 9,186 7,305 6,930 6,670 5,209 3,841 3,479

13 PLATO Non-CABG and CABG-related major bleeding 9 8 NS Ticagrelor Clopidogrel % per ye ear) p= NS K-M estimate ed rate ( p= Non-CABG PLATO major bleeding Non-CABG TIMI major bleeding CABG PLATO major bleeding CABG TIMI major bleeding

14 Primary Efficacy Outcome US and Non-US and by ASA Dose *Hazard ratio not calculated due to small number of events.

15 A PLATO: Any dyspnoea AE ( 30 days) ntage (% %) Kap plan Mei ier perce 9 Ticagrelor (T) (742/9235) 8.29% 8 Clopidogrel (C) (339/9186) % HR 95% CI P-value T vs. C < Days from first IP dose n at risk T C Storey RF et al. Eur Heart J AE = adverse event; CI = confidence interval; HR = hazard ratio; IP = investigational product.

16 Death following on-treatment pulmonary AE Ticagrelor Clopidogrel Clopidogrel Ticagrelor %) incidence (%) Incidence( Cumulative Cumulative C T vs C: HR 0.46 (95% CI: ); P < Time Time after after randomisation randomization (months) Number at risk T C No. at Risk T 9235 C Storey RF et al. Presented at ACC 2012

17 Factor Xa antagonism in ACS: ATLAS studies Rivaroxaban vs placebo 17

18 Antithrombotic action of rivaroxaban Coagulation Thromboxane A 2 x ASPIRIN 5HT Collagen ADP RIVAROXABAN x GPVI 5HT 2A P2Y1 Thrombin generation Thrombin PAR-1 PAR-4 TPα ATP P2X 1 5HT ADP ATP Dense granule ADP x TICAGRELOR P2Y 12 PLATELET P2Y 12 ACTIVATION CLOPIDOGREL PRASUGREL ACTIVE METABOLITE Shape change Alpha granule Coagulation factors Inflammatory mediators Amplification α IIb β 3 α IIb β 3 Fibrinogen x Aggregation α IIb β 3 GP IIb/IIIa ANTAGONISTS

19 ding (%) nt Bleed Significan nically S Clin PRIMARY SAFETY ENDPOINT: CLINICALLY SIGNIFICANT BLEEDING Total Daily Dose: (= TIMI Major, TIMI Minor, Bleed Req. Med. Attn.) Rivaroxaban 20 mg ---- Rivaroxaban 15 mg ---- Rivaroxaban 10 mg % 12.7% HR 5.1 ( ) 3.6 ( ) Rivaroxaban 5 mg ---- Placebo % 3.4 ( ) 6.1% 3.3% 2.2 ( ) *p<0.01 for placebo Vs Riva 5mg. p<0.001 for Riva 10,15,20mg, vs placebo Days After Start of Treatment Kaplan-Meier estimates for cumulative events, HR(CI), for bleeding rates during the 180 day period ; HR=Hazard Ratio; CI=Confidence Interval Gibson CM, AHA 2008

20 Recent ACS: STEMI, NSTEMI, UA No increased bleeding risk, No warfarin, No ICH, No prior stroke if on ASA + Thienopyridine Stabilized 1-7 Days Post-Index Event Stratified by Thienopyridine use at MD Discretion + ASA 75 to 100 mg/day Placebo N=5,176 ASA + Thieno, n=4,821 ASA, n=355 RIVAROXABAN 2.5 mg BID n=5,174 ASA + Thieno, n=4,825 ASA, n=349 RIVAROXABAN 5.0 mg BID N=5,176 ASA + Thieno, n=4,827 ASA, n=349 PRIMARY ENDPOINT: EFFICACY: CV Death, MI, Stroke* (Ischemic + Hemg.) SAFETY: TIMI major bleeding not associated with CABG Event driven trial of 1,002 events in 15,342 patients** * Stroke includes ischemic stroke, hemorrhagic stroke, and uncertain stroke ** 184 subjects were excluded from the efficacy analyses prior to unblinding

21 PRIMARY EFFICACY ENDPOINT: RIVAROXABAN 5.0 mg BID CV Death / MI / Stroke* Estimate ed Cumula ative incide ence (%) 10 5 Placebo Rivaroxaban 5mgBID 10.7% 8.8% HR 0.85 mitt p=0.028 ITT P= Months Rivaroxaban at 5 mg PO BID was associated with a numerical but not statistically significant reduction in mortality. * First occurrence of cardiovascular death, MI, stroke (ischemic, hemorrhagic, and uncertain) as adjudicated by the CEC Two year Kaplan-Meier estimates, HR and 95% confidence interval estimates from Cox model stratified by thienopyridine use are provided per mitt approach; Stratified log-rank p-values are provided for both mitt and ITT approaches.

22 EFFICACY ENDPOINTS: RIVAROXABAN 2.5 mg PO BID 12% ve inciden nce (%) Estimated Cumulati CV Death / MI / Stroke* HR 0.84 mitt p=0.020 ITT p=0.007 Cardiovascular Death 5% 5% Placebo HR 0.66 HR 0.68 Rivaroxaban 2.5 mg BID NNT = % 9.1% mitt p=0.002 ITT p=0.005 Placebo Rivaroxaban 2.5 mg BID NNT = % 2.7% All Cause Death mitt p= ITT p=0.004 Placebo Rivaroxaban 2.5 mg BID NNT = Months Months Months 4.5% 2.9% * First occurrence of cardiovascular death, MI, stroke (ischemic, hemorrhagic, and uncertain) as adjudicated by the CEC across thienopyridine use strata Two year Kaplan-Meier estimates, HR and 95% confidence interval estimates from Cox model stratified by thienopyridine use are provided per mitt approach; Stratified log-rank p-values are provided for both mitt and ITT approaches; NNT=Number needed to treat.

23 12% Cumulativ ve incidenc ce (%) Estimated EFFICACY ENDPOINTS: RIVAROXABAN 2.5 mg PO BID In Patients Treated with ASA + Thienopyridine CV Death / MI / Stroke* HR 0.85 mitt p= ITT p=0.011 Cardiovascular Death 5% 5% Placebo HR 0.62 Placebo HR % 9.0% mitt p< ITT p<0.001 Rivaroxaban Rivaroxaban 2.5 mg BID 2.5 mg BID NNT = 71 NNT = % 2.5% All Cause Death mitt p< ITT p<0.001 Placebo Rivaroxaban 2.5 mg BID NNT = Months Months Months 4.5% 2.7% *: First occurrence of cardiovascular death, MI, stroke (ischemic, hemorrhagic, and uncertain) as adjudicated by the CEC Two year Kaplan-Meier estimates, HR and 95% confidence interval estimates from Cox model stratified by thienopyridine use are provided per mitt approach; Stratified log-rank p-values are provided for both mitt and ITT approaches; NNT=Number needed to treat.

24 TIMI Major non-cabg bleeding Analysis Treatment-Emergent Non CABG TIMI Major Bleeding* Placebo 2.5 mg Rivaroxaban 2 Yr KM Estimate 0.6% 1.8% HR 3.46 p<0.001 p< mg Rivaroxaban 2.4% HR 4.47 *: First occurrence of Non-CABG TIMI major bleeding events occurred between first dose to 2 days post last dose as adjudicated by the CEC across thienopyridine use strata; Two year Kaplan-Meier estimates, HR and 95% confidence interval estimates from Cox model stratified by thienopyridine are provided; Stratified log-rank p-values are provided; #: Raw percentage for CV death/mi/stroke (ischemic, hemorrhagic, uncertain) ; ##: Raw percentage of subjects with abnormal value measured between first dose to 2 days post last dose among subjects with normal baseline measurement.

25 p=ns for Riva vs Placebo p=0.044 for 2.5 mg vs 5.0 mg TREATMENT-EMERGENT EMERGENT FATAL BLEEDS AND ICH 0.4 p=0.009 Riva Vs Placebo Placebo 2.5 mg Rivaroxaban 5.0 mg Rivaroxaban p=ns for Riva vs Placebo * n=9 n=6 n=15 n=5 n=14 n=18 Fatal ICH Fatal ICH 0.2 n=4 n=5 n=8 *Among patients treated with aspirin + thienopyridine, there was an increase in fatal bleeding among patients treated with 5.0 mg of Rivaroxaban (15/5110) vs 2.5 mg of Rivaroxaban (5/5115) (p=0.02)

26 Thrombin receptor antagonism in ACS: TRACER study Vorapaxar vs placebo 26

27 Antithrombotic action of vorapaxar VORAPAXAR Thrombin generation Coagulation Thrombin xpar-1 Thromboxane A 2 PAR-4 TPα x ASPIRIN 5HT Collagen GPVI 5HT 2A ADP P2Y 1 ATP P2X 1 5HT ADP ATP Dense granule ADP x TICAGRELOR P2Y 12 PLATELET P2Y 12 ACTIVATION TICLOPIDINE CLOPIDOGREL PRASUGREL ACTIVE METABOLITE Shape change Alpha granule Coagulation factors Inflammatory mediators Amplification α IIb β 3 α IIb β 3 Fibrinogen x Aggregation α IIb β 3 GP IIb/IIIa ANTAGONISTS

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31 Morrow et al. ACC 2012, Chicago, March 24, 2012

32 Morrow et al. ACC 2012, Chicago, March 24, 2012

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34 SUMMARY Ticagrelor: novel mechanism of P2Y 12 inhibition, also an adenosine reuptake inhibitor, progressive mortality reduction over 12 months in ACS patients at expense of more dyspnoea and spontaneous bleeding Rivaroxaban: oral factor Xa inhibitor, net clinical benefit with mortality reduction at very low dose at expense of increased major bleeding? patient selection, safety in combination with ticagrelor unknown Vorapaxar: thrombin receptor (PAR-1) antagonist, missed primary endpoint in ACS study, evidence of reduced MI at expense of increased major bleeding / ICH? secondary prevention role in low bleeding risk subgroups FUTURE STUDIES NEED TO ADDRESS IDEAL COMBINATIONS AND LONGTERM PROPHYLAXIS POST ACS

35 Thank you for listening! HEPARINS FONDAPARINUX BIVALIRUDIN RIVAROXABAN APIXABAN DABIGATRAN VORAPAXAR ATOPAXAR Thrombin generation Coagulation Thromboxane A 2 x ASPIRIN 5HT Collagen ADP x GPVI 5HT Thrombin 2A P2Y 1 TPα PAR-4 x PAR-1 ATP P2X 1 5HT ADP ATP Dense granule ADP x TICAGRELOR P2Y 12 TICLOPIDINE CLOPIDOGREL PRASUGREL ACTIVE METABOLITE CANGRELOR Shape change Alpha granule Coagulation factors Inflammatory mediators Amplification α IIb β 3 α IIb β 3 Fibrinogen x Aggregation α IIb β 3 GP IIb/IIIa ANTAGONISTS