The art of delivering evidence-based dual antiplatelet therapy

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Applied Evidence

The art of delivering evidence-based dual antiplatelet therapy

J Fam Pract. 2018 December;67(12):758-766

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References

1. Schömig A, Neumann FJ, Kastrati A, et al. A randomized comparison of antiplatelet and anticoagulant therapy after the placement of coronary-artery stents. N Engl J Med. 1996;334:1084-1089.

2. Ducrocq G, Serebruany V, Tanguay J. Antiplatelet therapy in the era of drug-eluting stents: current and future perspectives. Expert Rev Cardiovasc Ther. 2007;5:939-953.

3. Capodanno D, Angiolillo DJ. Management of antiplatelet therapy in patients with coronary artery disease requiring cardiac and noncardiac surgery. Circulation. 2013;128:2785-2798.

4. Bonaca MP, Bhatt DL, Cohen M, et al. Long-term use of ticagrelor in patients with prior myocardial infarction. N Engl J Med. 2015;372:1791-1800.

5. Damman P, Woudstra P, Kuijt WJ, et al. P2Y12 platelet inhibition in clinical practice. J Thromb Thrombolysis. 2012;33:143-153.

6. Steinhubl SR, Bhatt DL, Brennan DM, et al; CHARISMA Investigators. Aspirin to prevent cardiovascular disease: the association of aspirin dose and clopidogrel with thrombosis and bleeding. Ann Intern Med. 2009;150:379-386.

7. Mehta SR, Tanguay JF, Eikelboom JW, et al. Double-dose versus standard-dose clopidogrel and high-dose versus low-dose aspirin in individuals undergoing percutaneous coronary intervention for acute coronary syndromes (CURRENT-OASIS 7): a randomised factorial trial. Lancet. 2010;376:1233-1243.

8. Mahaffey KW, Wojdyla DM, Carroll K, et al. Ticagrelor compared with clopidogrel by geographic region in the Platelet Inhibition and Patient Outcomes (PLATO) trial. Circulation. 2011;124:544-554.

9. Xian Y, Wang TY, McCoy LA, et al. Association of discharge aspirin dose with outcomes after acute myocardial infarction: insights from the Treatment with ADP Receptor Inhibitors: Longitudinal Assessment of Treatment Patterns and Events after Acute Coronary Syndrome (TRANSLATE-ACS) Study. Circulation. 2015;132:174-181.

10. Patrono C, Baigent C, Hirsh J, et al. Antiplatelet drugs: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest. 2008;133:199S-233S.

11. Wenaweser P, Dörffler-Melly J, Imboden K, et al. Stent thrombosis is associated with an impaired response to antiplatelet therapy. J Am Coll Cardiol. 2005;45:1748-1752.

12. Farid NA, Kurihara A, Wrighton SA. Metabolism and disposition of the thienopyridine antiplatelet drugs ticlopidine, clopidogrel, and prasugrel in humans. J Clin Pharmacol. 2010;50:126-142.

13. Valgimigli M, Bueno H, Byrne RA, et al. 2017 ESC focused update on dual antiplatelet therapy in coronary artery disease developed in collaboration with EACTS: The Task Force for dual antiplatelet therapy in coronary artery disease of the European Society of Cardiology (ESC) and of the European Association for Cardio-Thoracic Surgery (EACTS). Euro Heart J. 2017;39:213-260.

14. Levine GN, Bates ER, Bittl JA, et al. 2016 ACC/AHA guideline focused update on duration of dual antiplatelet therapy in patients with coronary artery disease. J Am Coll Cardiol. 2016;68:1082-1115.

15. Jernberg T, Payne CD, Winters KJ, et al. Prasugrel achieves greater inhibition of platelet aggregation and a lower rate of non-responders compared with clopidogrel in aspirin-treated patients with stable coronary artery disease. Eur Heart J. 2006;27:1166-1173.

16. Wiviott SD, Braunwald E, McCabe CH, et al. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2007;357:2001-2015.

17. Debesh PP, Oestreich JH. Ticagrelor: pharmacokinetics, pharmacodynamics, clinical efficacy, and safety. Pharmacotherapy. 2014;34:1077-1090.

18. Fihn SD, Blankenship JC, Alexander KP, et al. 2014 ACC/AHA/AATS/PCNA/SCAI/STS focused update of the guideline for the diagnosis and management of patients with stable ischemic heart disease. Circulation. 2014;130:1749-1767.

19. Benedetto U, Altman DG, Gerry S, et al. Impact of dual antiplatelet therapy after coronary artery bypass surgery on 1-year outcomes in the Arterial Revascularization Trial. Eur J Cardiothorac Surg. 2017;52:456-461.

20. Toyota T, Shiomi H, Morimoto T, et al. Short versus prolonged dual antiplatelet therapy (DAPT) duration after coronary stent implantation: a comparison between the DAPT study and 9 other trials evaluating DAPT duration. PLoS One. 2017;12:e0174502.

21. Costa F, van Klaveren D, James S, et al. Derivation and validation of the predicting bleeding complications in patients undergoing stent implantation and subsequent dual antiplatelet therapy (PRECISE-DAPT) score: a pooled analysis of individual-patient datasets from clinical trials. Lancet. 2017;389:1025-1034.

22. PREdicting bleeding Complications In patients undergoing Stent implantation and subsEquent Dual Anti Platelet Therapy (PRECISE-DAPT) WebCalculator. www.precisedaptscore.com/predapt/webcalculator.html. Accessed October 21, 2018.

23. Yeh RW, Secemsky EA, Kereiakes DJ, et al; DAPT Study Investigators. Development and validation of a prediction rule for benefit and harm of dual antiplatelet therapy beyond 1 year after percutaneous coronary intervention. JAMA. 2016;315:1735-1749.

24. American College of Cardiology. DAPT Risk Calculator. http://tools.acc.org/DAPTriskapp/#!/content/calculator/. Accessed October 21, 2018.

25. Johnston SC, Amarenco P, Albers GW, et al. Ticagrelor versus aspirin in acute stroke or transient ischemic attack. N Engl J Med. 2016;375:35-43.

26. Cannon CP, Bhatt DL, Oldgren J, et al. Dual antithrombotic therapy with dabigatran after PCI in atrial fibrillation. N Engl J Med. 2017;377:1513-1524.

27. Abraham NS, Hlatky MA, Antman EM, et al; ACCF/ACG/AHA. ACCF/ACG/AHA 2010 Expert Consensus Document on the concomitant use of proton pump inhibitors and thienopyridines: a focused update of the ACCF/ACG/AHA 2008 Expert Consensus Document on reducing the gastrointestinal risks of antiplatelet therapy and NSAID use: a report of the American College of Cardiology Foundation Task Force on Expert Consensus Documents. Circulation. 2010;122:2619-2633.

28. Levine GN, Bates ER, Blankenship JC, et al. 2011 ACCF/AHA/SCAI guideline for percutaneous coronary intervention: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines and the Society for Cardiovascular Angiography and Interventions. Circulation. 2011;124:e574-e651.

29. Fleisher LA, Fleischmann KE, Auerbach AD, et al; American College of Cardiology; American Heart Association. 2014 ACC/AHA Guideline on perioperative cardiovascular evaluation and management of patients undergoing noncardiac surgery. A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2014;64:e77-e137.

30. Kristensen SD, Knuuti J, Saraste A, et al; Authors/Task Force Members. 2014 ESC/ESA Guidelines on non-cardiac surgery: cardiovascular assessment and management: The Joint Task Force on non-cardiac surgery: cardiovascular assessment and management of the European Society of Cardiology (ESC) and the European Society of Anesthesiology (ESA). Euro Heart J. 2014;35:2383-2431.

31. Wong KS, Chen C, Fu J, et al; CLAIR study investigators. Clopidogrel plus aspirin versus aspirin alone for reducing embolisation in patients with acute symptomatic cerebral or carotid artery stenosis (CLAIR study): a randomised, open-label, blinded-endpoint trial. Lancet Neurol. 2010:9:489-497.

32. SPS3 Investigators; Benavente OR, Hart RG, McClure LA, et al. Effects of clopidogrel added to aspirin in patients with recent lacunar stroke. N Engl J Med. 2012;367:817-825.

33. Diener HC, Bogousslavsky J, Brass LM, et al; MATCH investigators. Aspirin and clopidogrel compared to clopidogrel alone after recent ischaemic stroke or transient ischaemic attack in high-risk patients (MATCH): randomised, double-blind, placebo-controlled trial. Lancet. 2004;364:331-337.

34. NIH Stroke Scale. National Institute of Neurological Disorders and Stroke. https://www.ninds.nih.gov/sites/default/files/NIH_Stroke_Scale_Booklet.pdf. Accessed November 14, 2018.

35. Wang Y, Wang Y, Zhao X, et al; CHANCE Investigators. Clopidogrel with aspirin in acute minor stroke or transient ischemic attack. N Engl J Med. 2013;369:11-19.

36. Johnston SC, Easton JD, Farrant M, et al. Clopidogrel and aspirin in acute ischemic stroke and high-risk TIA. N Engl J Med. 2018;379:215-225.

37. CAPRIE Steering Committee. A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). CAPRIE Steering Committee. Lancet. 1996:16;348:1329-1339.

38. Johnson SC, Amarenco P, Albers GW, et al; SOCRATES Steering Committee and Investigators. Ticagrelor versus aspirin in acute stroke or transient ischemic attack. N Engl J Med. 2016;375:35-43.

39. Hansen ML, Sørensen R, Clausen MT, et al. Risk of bleeding with single, dual, or triple therapy with warfarin, aspirin, and clopidogrel in patients with atrial fibrillation. Arch Intern Med. 2010;170:1433-1441.

ASA, as a component of DAPT, is recommended at a dosage of 81 mg/d. In trials of ASA plus clopidogrel, lower ASA dosages had comparable ischemic event rates compared to higher ASA dosages.^6,7 Patients given higher ASA dosages with ticagrelor had poorer outcomes when compared with low-dosage ASA.⁸ Higher dosages of ASA, alone or with DAPT, increase the risk of bleeding complications.^9,10

Clopidogrel is the only P2Y12 inhibitor available as a generic medication in the United States. As a pro-drug, clopidogrel requires 2 metabolic transformations to its active metabolite after being hydrolyzed in the gut, which delays onset of platelet inhibition for several hours after ingestion.¹¹ Furthermore, individual genetic variation in cytochrome P450 (CYP) 2C19 (CYP2C19), one of the hepatic enzymes in this metabolic process, may lead to less alteration of clinical platelet aggregation response, and increased drug interactions.¹²Methods to assess platelet function have shown decreased inhibition of platelet aggregation for some CYP2C19 polymorphisms, although consistent clinical effects of this inhibition have not been identified to date; genetic testing for these polymorphisms is, therefore, not recommended routinely.¹³

Indications for DAPT treatment with clopidogrel are unstable angina or non-ST-segment elevation acute coronary syndrome (NSTE-ACS), whether planned treatment is medical or coronary revascularization. Other indications include acute ST-segment elevation MI (STEMI) with planned medical treatment, and recent MI, stroke, or established peripheral arterial disease.^13,14

Prasugrel has faster onset of action and greater and more consistent P2Y12 inhibition than clopidogrel. After prasugrel is hydrolyzed in the gut, an intermediary metabolite is activated in the liver. Peak serum concentration is reached within 30 minutes.¹² Unlike the case with clopidogrel, genetic variation in the CYP gene does not impart significant impact on forming the active metabolite.¹⁵

Longer duration of DAPT reduces stroke incidence and the long-term risk of myocardial infarction—unrelated to stent thrombosis.

Indication for the use of prasugrel is ACS that is managed with percutaneous coronary intervention (PCI). Dual antiplatelet therapy with prasugrel results in reduced risk of cardiovascular death, nonfatal MI, and stroke, compared with ASA plus clopidogrel, with an increase in bleeding events.¹⁶ Thrombolysis patients and those who have a history of stroke had a greater risk of hemorrhage complications with prasugrel treatment, compared with clopidogrel. Prasugrel offered no benefit to patients older than 75 years or those who weigh <60 kg. If used in patients who weigh <60 kg, however, dosage reduction is recommended.¹⁶

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