L'aspirina è diventata obsoleta nell'era dei nuovi inbitori P2Y12? Leonardo Bolognese MD, FESC, FACC Cardiovascular Department, Arezzo, Italy ISO 9001

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1 L'aspirina è diventata obsoleta nell'era dei nuovi inbitori P2Y12? Leonardo Bolognese MD, FESC, FACC Cardiovascular Department, Arezzo, Italy

2 Scientific Advances and Cardiovascular Mortality Nabel and Braunwald. N Engl J Med 2012;366: GISSI and ISIS-2

3 Randomised Trial of Intravenous Streptokinase, Oral Aspirin, Both, or Neither among Cases of Suspected Acute Myocardial Infarction: ISIS-2 Cumulative number of vascular deaths Placebo infusion: 1029 vascular deaths (12.0%) Streptokinase: 791 vascular deaths (9.2%) Days of randomisation Cumulative number of vascular deaths Placebo tablets: 1016 vascular deaths (11.8%) Aspirin: 804 vascular deaths (9.4%) Days of randomisation Cumulative number of vascular deaths Placebo infusion and tablets: 568 vascular deaths (13.2%) Streptokinase and Aspirin: 343 vascular deaths (8.0%) Days of randomisation ISIS-2 Collaborative Group, Lancet 1988; II:

4 Aspirin in Secondary Prevention Antithrombotic Trialists Collaboration. Lancet 2009; 373: Limited Data on Aspirin After PCI With Stent Implantation! 16 Secondary Prevention Trials 43,000 Patient-Years

5 Risk of Bleeding With Aspirin Antithrombotic Trialists Collaboration. Lancet 2009; 373: Extracranial Bleeding Hemorrhagic Stroke PRIMARY PREVENTION HR (95% CI) 1.54 ( ) P-Heter = 0.20 HR (95% CI) 1.32 ( ) P-Heter = 0.40 SECONDARY PREVENTION 2.69 ( ) 1.67 ( )

6 Clinical Issues With Aspirin - Treatment Failure ( Aspirin Resistance ) - Aspirin preparation (ie, enteric coated formulations) - Drug-drug interactions (ie, NSAIDs) - COX-1 related pathways - Medication noncompliance - Premature discontinuation - Irreversible platelet inhibition - Bleeding risk - Gastrotoxicity

7 Bimodal response to aspirin loading and effects on tissue perfusion in STEMI Fefer et al. Platelets 2013; 24:

8 Why has the role of aspirin as an inevitable component of antiplatelet therapy never been seriously challenged? Aspirin is established in clinical practice as the default antiplatelet therapy in cardiovascular disease. Aspirin alone has not been found sufficient to reduce ischaemic events in several clinical settings. As a result, the concept of dual antiplatelet therapy has become established. Studies of newer and stronger P2Y12 receptor inhib. have all been conducted in the presence of aspirin Unethical for aspirin not to be included In some clinical settings such as in patients receiving coronary stents previous studies suggested that antiplatelet monotherapy without aspirin was ineffective

9 What is the net clinical effect of aspirin in patients receiving newer and more potent P2Y12 receptor antagonists?

10 Effects of aspirin and P2Y12 receptor antagonists on platelet pathways Berger JS Am J Cardiol 2013;112:

11 The Asprin Paradox

12 In the presence of strong P2Y12 receptor blockade, aspirin provides little additional inhibition of platelet aggregation Armstrong PCJ et al. J Thromb Haemost 2011; 9:

13 Antiplatelet effects of aspirin vary with level of P2Y12 receptor blockade supplied by ticagrelor Kirkby NS et al. Journal of Thrombosis and Haemostasis 2011; 9:

14 Aspirin in dogs increases vascular resistance with limited additional anti-platelet effect when combined with potent P2Y12 inhibition Björkman JA et al. Thrombosis Research 131;2013:

15 Is there an opportunity to reconsider the unchallenged role of aspirin in this clinical context? Aspirin key role as an inhibitor of arachidonic acidstimulated clotting may by mimeked by P2Y12 inhib. The anti-platelet benefit of aspirin and P2Y12 antagonists may not be additive, as inhibition of P2Y12 can also effectively inhibit the TXA2 pathway of platelet activation in the absence of aspirin An aspirin-mediated reduction in PGI2 production might oppose the effect achieved by aspirin-mediated inhibition of platelet TXA2 formation

16 Does aspirin increase clinical risk in the presence of potent P2Y12 receptor antagonists? Warner TD et al. Heart 2010;96:1693e1694

17 MATCH study 7,599 pts with recent stroke or TIA. All on clopidogrel. Randomization to receive ASA or Placebo on top. Vascular death, stroke, MI, rehosp for ACS Intracranial bleeding Lancet 2004; 364:

18 Rates of the composite end point by open-label median maintenance aspirin dose in patients enrolled in the PLATO trial Mahaffey KW et al. Circulation 2011;124:544e554

19 Aspirin dose and ticagrelor benefit in PLATO:fact or fiction?? Source:

20 The WOEST Trial: First randomised trial comparing two regimens with and without aspirin in patients on oral anticoagulant therapy undergoing coronary stenting Paradigm Shift in Interventional Pharmacology: Is it time to drop aspirin? Dewilde WJ et al. Lancet. 2013;381(9872):

21 Paradigm Shift: Is it time to drop aspirin? Ongoing Clinical Trials 1. GLOBAL LEADERS - Ticagrelor monotherapy in PCI with bioabsorbable stents (n=16,000) 2. ABSORB-OAC - Clopidogre/Ticagrelor monotherapy in PCI with BVS 3. COMPASS - Rivaroxiban monotherapy for 2 o prevention post-mi & PAD (n=19,500) 4. PIONEER - Rivaroxiban + clopidogrel post-pci with AFib (n=2,100) 5. RE-DUAL PCI - Dabigatran + clopidogrel/ticagrelor post-pci with Afib (n=8520) 6. TRIPLE A Study - Apixaban moniotherapy +/- aspirin

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23 ABSORB-OAC Trial

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25 XARELTO (rivaroxaban) Use in Patients With AF Undergoing PCI: PIONEER AF-PCI End of treatment at 12 months 2100 patients with NVAF No prior stroke/tia PCI with stent placement 72 hours After Sheath removal R A N D O M I Z E 1,6, or 12 months XARELTO 2.5 mg bid Clopidogrel 75 mg qd Aspirin mg qd 1,6, or 12 months VKA (target INR ) Clopidogrel 75 mg qd Aspirin mg qd XARELTO 15mg QD Aspirin mg qd VKA (target INR ) Aspirin mg qd Primary endpoint: TIMI major, minor, and bleeding requiring medical attention Secondary endpoint: CV death, MI, stroke, and stent thrombosis *XARELTO dosed at 10 mg once daily in patients with CrCl of 30 to <50 ml/min. Alternative P2Y 12 inhibitors: 10 mg once-daily prasugrel or 90 mg twice-daily ticagrelor. Low-dose aspirin ( mg/d). Data on File. Janssen Pharmaceuticals, Inc.

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27 Apixaban in AF/ACS: The TRIPLE A Trial Design

28 CONCLUSIONS With the arrival of the potent P2Y12 antagonists, ticagrelor and prasugrel, the need for cotreatment with aspirin in acute coronary syndromes must be re-examined So far, no information exists on the effect of the more potent P2Y12 antagonists as monotherapy Landmark randomized studies investigating these issues are ongoing

29 Thank You