Jeroen De HaesPromotor: Dr. Poortmans

The use of aspirin and clopidogrel in cardiac surgery

Antiplatelet Therapy and Cardiac Surgery: A Challenge?

� Indications of DAPT

� Pharmacology� Aspirin

� P2Y12 Receptor blockers

� Perioperative use� Benefit

� Risk

� Practical Recommendations

Overview

� CHARISMA Trial:

� No benefit in primary prevention

� No benefit in stable CAD

� CURE trial:

� Benefit for NSTEMI or Unstable Angina without PCI

� CLARITY-TIMI 28 trial:

� Benefit of DAPT auxiliary to thrombolytics

� PCI-CURE trial/ CREDO trial:

� Benefit of DAPT for STEMI

� Multiple Trials/ FDA:

� BMS 1 years or at least 1 month

� DES: at least 1 year

Indications for DAPT

Pharmacology: ASPIRIN

Aspirin inhibition of COX-1 decreases TXA2 production. Source: Gasparyan, A. Y. et al. J Am Coll Cardiol 2008;51:1829-1843

� COX- 1 inhibition� Preventing platelet activation and

aggregation

� Impair Secondary Haemostasis

� Influences interaction between platelets, neutrophils and erythrocytes

� Augments endothelial functions

Pharmacology: P2Y12 Receptor Inhibitors

� General� Preventing ADP binding to P2Y12 Receptor

� Inhibition of activation, aggregation and thrombin generation

� Inhibition of CRP and TNF release

� Inhibition of platelet-neutrophil aggregates

� Clopidogrel� Prodrug

� Slow onset and variable inhibition

� Prasugrel� Prodrug� More rapid and less variable inhibition� Higher risk for bleeding

� Ticagrelor� Reversible� Fast onset and off-set� More consistent inhibition

Mahla E, Metzler H, Tantry U et al. Controversies in oral antiplatelet therapy in patients undergoing aortocoronary bypass surgery. The Annals of Thoracic Surgery 2010; 90(3): 1040-1051

� Rebound Phenomenon� Bieving et al./ Vial et al.: Dose dependent

� Increased risk of cardiovascular events

� O’Riodan et al: Cessation has gloomy prognosis

� Increased bleeding risk� POISE-2: 23% relative increase

� Burger et al: Increase bleeding complications, not severity

RISKS

� Lower all cause mortality in secondary prevention� Sung et al.

� Decrease in post-op MI after cardiac surgery and in-hospital mortality

� Hastings et al

� Cardioprotective effect immediately post-op in CABG setting

BENEFITS

Perioperative use of Aspirin: Benefits vs Risk

� Increased bleeding risk� ACUITY trialDependent on timing of last

dose

� CURRENT-OASIS 7:Effect of loading dose

� Increased Mortality and Post-op MI� Siller-Matula et al: related to increased

bleeding

� Vorobcsuk et al: similar results

� Miceli et al: cessation less then 5 days

RISKS

�Reduction of cardiovascular ischemic events� ACUITY trial: stopping clopidogrel 5 days

before surgery

� Miceli et al: Time frame of 5 days

BENEFITS

Perioperative use of Clopidogrel: Benefits vs Risk

Miceli A, Duggan SMJ, Aresu G, de Siena PM, Romeo F, Glauber M, et al. Combined clopidogrel and aspirin treatment up to surgery increases the risk of postoperative myocardial infarction, blood loss and reoperation for bleeding in patients undergoing coronary artery bypass grafting. Eur J Cardiothorac Surg [Internet]. 2013;43(June 2012):722–8

Miceli A, Duggan SMJ, Aresu G, de Siena PM, Romeo F, Glauber M, et al. Combined clopidogrel and aspirin treatment up to surgery increases the risk of postoperative myocardial infarction, blood loss and reoperation for bleeding in patients undergoing coronary artery bypass grafting. Eur J Cardiothorac Surg [Internet]. 2013;43(June 2012):722–8

� PLATO trial:

� no raise in CABG related bleeding

� Lower rate of post CABG mortality

Ticagrelor� TRITON-TIMI 38:

� greater bleeding risk than clopidogrel group

� Lower 13 month mortality

Prasugrel

Perioperative use of Prasugrel and Ticagrelor

Siller-Matula JM, Petre a., Delle-Karth G, Huber K, Ay C, Lordkipanidze M, et al. Impact of preoperative use of P2Y12 receptor inhibitors on clinical outcomes in cardiac and non-cardiac surgery: A systematic review and meta-analysis. Eur Hear J Acute Cardiovasc Care [Internet]. 2015

Practical recommendations: Cessation of drugs

� Aspirin:� Continued in perioperative surgery except for high-bleeding risk surgeries� ACC/AHA guideline: stop Aspirin 7-10days before cardiac surgery� Guideline by European Journal of Cardio-Thoracic surgery:

� Stop aspirin 2-10 days before elective cardiac surgery� Urgent cardiac surgery: continue aspirin up to the day of surgery

� Restart Aspirin as soon as possible post-operative

� Clopidogrel/Ticagrelor: � Stop 5-7 days before elective cardiac surgery� Urgent CAGB: stop 24hours if possible� Bridging therapy with GP IIb/IIIa receptor inhibitors: requires further research

� Prasugrel:� Stop 7-10 days before elective cardiac surgery

Practical recommendations: Reduction of blood loss

� Prophylatic Platelet transfusion� Rapid reversal

� Risk of reversal of clinical benefit

� Use of Antifibrinolytics� Aprotinin: renal dysfunction and end-organ damage

� Tranexamic acid: � reduces blood loss, need for transfusion and re-operation

� Can be used safely

� In vitro platelet function testing: Additional studies recommended� Recognizing patients had higher bleeding risk

� Fixing optimal window for surgery

� Predictive value and guide for transfusion

Cannon CP, Mehta SR, Aranki SF. Balancing the benefit and risk of oral antiplatelet agents in coronary artery bypass surgery. Ann Thorac Surg [Internet]. 2005;80:768–79.

Questions & Discussion

� 10. Hastings S, Myles P, McIlroy D. Aspirin and coronary artery surgery: a systematic review and meta-analysis. Br J Anaesth [Internet]. 2015;115:376–85. Available from: http://bja.oxfordjournals.org/lookup/doi/10.1093/bja/aev164

� 11. Cannon CP, Mehta SR, Aranki SF. Balancing the benefit and risk of oral antiplatelet agents in coronary artery bypass surgery. Ann Thorac Surg [Internet]. 2005;80:768–79. Available from: http://www.sciencedirect.com.kuleuven.ezproxy.kuleuven.be/science/article/pii/S0003497504020041#

� 12. Dunning J, Versteegh M, Fabbri A, Pavie A, Kolh P, Lockowandt U, et al. Guideline on antiplatelet and anticoagulation management in cardiac surgery. Eur J Cardio-thoracic Surg. 2008;34:73–92.

� 13. Miceli A, Duggan SMJ, Aresu G, de Siena PM, Romeo F, Glauber M, et al. Combined clopidogrel and aspirin treatment up to surgery increases the risk of postoperative myocardial infarction, blood loss and reoperation for bleeding in patients undergoing coronary artery bypass grafting. Eur J Cardiothorac Surg [Internet]. 2013;43(June 2012):722–8. Available from: http://www.ncbi.nlm.nih.gov/pubmed/22733842

� 14. Vorobcsuk A, Aradi D, Farkasfalvi K, Horváth IG, Komócsi A. Outcomes of patients receiving clopidogrel prior to cardiac surgery. Int J Cardiol [Internet]. Elsevier Ireland Ltd; 2012;156(1):34–40. Available from: http://dx.doi.org/10.1016/j.ijcard.2010.10.034

� 15. Bellemain-Appaix A, O’Connor S a, Silvain J, Cucherat M, Beygui F, Barthélémy O, et al. Association of clopidogrel pretreatment with mortality, cardiovascular events, and major bleeding among patients undergoing percutaneous coronary intervention: a systematic review and meta-analysis. JAMA [Internet]. 2012;308(23):2507–16. Available from: http://www.ncbi.nlm.nih.gov/pubmed/23287889

� 16. Fox K a a, Mehta SR, Peters R, Zhao F, Lakkis N, Gersh BJ, et al. Benefits and risks of the combination of clopidogrel and aspirin in patients undergoing surgical revascularization for non- ST-elevation acute coronary syndrome: The clopidogrel in unstable angina to prevent recurrent ischemic events (CURE) trial. Circulation. 2004;110:1202–8.

� 17. Kapetanakis EI, Medlam D a., Petro KR, Haile E, Hill PC, Dullum MKC, et al. Effect of clopidogrel premedication in off-pump cardiac surgery: Are we forfeiting the benefits of reduced hemorrhagic sequelae? Circulation. 2006;113:1667–74.

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� 7. Cao C, Indraratna P, Ang SC, Manganas C, Park J, Bannon PG, et al. Should clopidogrel be discontinued before coronary artery bypass grafting for patients with acute coronary syndrome? A systematic review and meta-analysis. J Thorac Cardiovasc Surg [Internet]. Elsevier Inc.; 2014;148(6):3092–8. Available from: http://www.sciencedirect.com/science/article/pii/S0022522314006011

� 8. Fitchett D, Mazer CD, Eikelboom J, Verma S. Antiplatelet therapy and cardiac surgery: Review of recent evidence and clinical implications. Can J Cardiol [Internet]. Canadian Cardiovascular Society; 2013;29(9):1042–7. Available from: http://dx.doi.org/10.1016/j.cjca.2013.02.014

� 9. Ma X, Ma C, Yan Y, Qian Z, Zheng X. Safety and efficacy outcomes of preoperative aspirin in patients undergoing coronary artery bypass grafting: a systematic review and meta-analysis. J Cardiovasc Pharmacol Ther [Internet]. 2014;19(324):97–113. Available from: http://www.ncbi.nlm.nih.gov/pubmed/24212980

References