By: Michael A. Kutcher, MD, FSCAI and Kalon K.L. Ho, MD, FSCAI

General principles regarding a switch from one P2Y12 agent to another to avoid a gap in effective anti-platelet inhibition coverage:

Patient Issues

• Before starting dual anti-platelet therapy (DAPT) with aspirin and deciding on the initial P2Y12 agent: A review of the indications, risks and benefits for the individual patient should also include potential compliance and socioeconomic issues.

• Once the patient is on a P2Y12 agent maintenance dose schedule: Follow-up with the patient while in the hospital to assure they have no side effects and they can be compliant with no economic issues.

• Consult social service and pharmacy to assist if there are identified economic issues. Most of the pharmaceutical companies offer some type of voucher or financial assistance for qualified patients.

• Double-check prior to discharge to make sure the patient has an adequate P2Y12 supply and resources to comply with uninterrupted DAPT.

• Make sure the patient is discharged with a clearly identified access number to speak to a health care professional if side-effects, compliance or economic issues preclude continuing with the specific P2Y12 agent.

• Be aware of the “Bewitching Hour”: 30 days after discharge when the first P2Y12 prescription needs to be renewed or the voucher runs out.

 
Pharmacologic Issues

• Weigh the indications and the risk/benefit of a switching strategy to another P2Y12 agent. The risk of bleeding due to an overlap if a new loading dose is given should be weighed against the higher risk of a serious gap in adequate anti-platelet inhibition if just a new maintenance dose is used.

• The oral thienopyridines, clopidogrel and prasugrel, are nondirect agents that irreversibly block the platelet ADP P2Y12 receptor:  Whereas ticagrelor is a cyclopentyltriazolopyrimidine that directly and reversibly inhibits through allosteric modulation the platelet ADP P2Y12 receptor [1]. Because of this reversible binding and plasma half-life of 8 to 12 hours, twice-a-day dosing is necessary. Therefore, the switch from ticagrelor to a thienopyridine theoretically would be best done with a loading dose followed by a maintenance dose to avoid a gap in anti-platelet coverage [2,3,4,5].

• There may be logistical prescription dose issues in stable outpatients if a switch from one P2Y12 agent to another is indicated. There are some reports that suggest a loading dose may not be required in the switch from clopidogrel to prasugrel [6,7,8]; clopidogrel to ticagrelor [6,9]; and prasugrel to clopidogrel [10]. A switch strategy from prasugrel to ticagrelor is currently being evaluated in an ongoing trial [11]. But these reports are early small trials, pharmacodynamic studies or ongoing trials. More prospective larger trials of loading dose versus no loading dose, powered to thoroughly assess clinical outcomes, are necessary before there can be a clear mandate to recommend these strategies.

• In summary, based on currently available (but still incomplete) data and absent a severe bleeding issue:  An acceptable P2Y12 switching strategy, in nearly all clinical situations, would consist of a loading dose of the new P2Y12 agent followed by a maintenance dose regimen to avoid any gap in adequate anti-platelet inhibition [2].

• Keep in mind that the medical literature is still in evolution regarding the best strategy for switching between the various P2Y12 agents. Clinical judgment and the analysis of risk/benefit tailored to each individual patient will take precedence. There will be further updates on this issue as more published information is forthcoming.

References

1. Ferreiro JL, Angiolillo DJ. New directions in antiplatelet therapy. Circ Cardiovasc Interv 2012;5:433-445. Click here for PDF.

2. Bagai A, Chua D, Cohen EA, Saw J, Verma S, Vijayaraghavan R, Welsh R, Finchett D. Pharmacodynamic and clinical implications of switching between P2Y12 receptor antagonists: Considerations for practice. Crit Pathways in Cardiol 2014;13:156-58. Click here for PDF.

3. Derek So - Principal Investigator. Transition from ticagrelor to clopidogrel following acute coronary syndrome: To bolus or not? The CAPITAL OPTI-CROSS Study. Sponsor: Ottawa Heart Institute Research Corporation. ClinicalTrials.gov Identifier: NCT02054663. The present proposal will evaluate the pharmacodynamics of 2 strategies with specialized platelet function testing. The investigators hypothesize that a bolus dose of clopidogrel during the switch will confer better ischemic protection without increasing bleeding risk for patients undergoing a switch in therapy. Estimated study completion date: March 2015.

4. Angiolillo DJ – Principal Investigator. Switching From Ticagrelor to Clopidogrel in Patients With Coronary Artery Disease (SWAP-4). Sponsor: University of Florida. ClinicalTrials.gov Identifier: NCT02287909. It is common in clinical practice to switch patients while on maintenance dosing (MD) with ticagrelor to treatment with clopidogrel. However, the pharmacodynamic (PD) effects of switching from ticagrelor to clopidogrel remain unknown. In addition, it is unknown whether switching from ticagrelor to clopidogrel should occur with or without a loading dose (LD). Therefore, the aim of this investigation is to evaluate the PD effects of switching from ticagrelor to clopidogrel with and without a LD. The present study has a prospective, randomized, open-label design, in which patients will be treated with 4 different strategies to assess PD profiling after switching. This study will provide important insights on PD effects of switching from ticagrelor to clopidogrel. Estimated study completion date: March 2016.

5. Angiolillo DJ, Curzen N, Gurbel P, Vaitkus P, Lipkin F, Li W, Jakubowski JA, Zettler M, Effron MB, Trenk D. Pharmacodynamic evaluation of switching from ticagrelor to prasugrel in patients with stable coronary artery disease. Results of the SWAP-2 Study (Switching Anti Platelet-2). J Am Coll Cardiol 2014;63:1500-9.

6. Alexopoulos D, Galati A, Xanthopoulou I, Mavronasiou E, Kassimis G, Theodoropoulos KC,  Makris G, Damelou A, Tsigkas G, Hahalis G, Davlouros P. Ticagrelor versus prasugrel in acute coronary syndrome patients with high on-clopidogrel platelet reactivity following percutaneous coronary intervention: A pharmacodynamic study. J Am Coll Cardiol 2012;60:193-9.

7. Bagai A, Wang Y, Wang TY, Curtis JP, Gurm HS, Shah B, Cheema AN, Peterson EP, Saucedo JF, Granger CB, Roe MT, Bhatt DL, McNamara RL, Alexander KP. In-hospital switching between clopidogrel and prasugrel among patients with acute myocardial infarction treated with percutaneous coronary intervention: Insights into contemporary practice from the National Cardiovascular Data Registry. Circ Cardiovasc Interv 2014;7:585-593.

8. Angiolillo DJ, Saucedo JE, DeRaad R, Frelinger AL, Gurbel PA,  Costigan TM, Jakubowski JA, Ojeh CK, Effron MB for the SWAP Investigators. Increased platelet inhibition after switching from maintenance clopidogrel to prasugrel in patients with acute coronary syndromes. Results of the SWAP (SWitching Anti Platelet) Study. J Am Coll Cardiol 2010;56:1017-23.

9. Caiazzo G, De Rosa S, Torella D, Spaccarotella C, Mongiardo A, Giampà S, Micieli M, Palella E, Gulletta E, Indolfi C. Administration of a loading dose has no additive effect on platelet aggregation during the switch from ongoing clopidogrel treatment to ticagrelor in patients with acute coronary syndrome. Circ Cardiovasc Interv 2014;7:104-112.

10. Kerneis M, Silvain J, Abtan J, MD, Cayla G, O’Connor SA, Barthélémy O, MD, Vignalou JB, Beygui F, Brugier D, Martin R, Collet JP, Montalescot G. Switching acute coronary syndrome patients from prasugrel to clopidogrel. J Am Coll Cardiol Intv 2013;6:158-165.

11. Dominick Angiolillo – Principal Investigator. Pharmadynamic evaluation of switching from prasugrel to ticagrelor. The SWAP (SWitching Anti Platelet)-3 Study. Sponsor: University of Florida. ClinicalTrials.gov Identifier: NCT02016170. The proposed  pharmadynamic (PD) investigation will have a prospective, randomized, parallel design aimed to show that switching patients from maintenance prasugrel to ticagrelor with or without a loading dose provides similar levels of platelet inhibition. This study will provide insights on the PD effects of switching and will help clinicians to choose the most appropriate schema to avoid complications related to inadequate antiplatelet therapy in patients with coronary artery disease if switching from prasugrel to ticagrelor is desired. Estimated study completion date: March 2016.

Questions or Comments? Contact:

Michael A. Kutcher, MD, FSCAI
Director, Interventional Cardiology
Wake Forest School of Medicine
1 Medical Center Blvd.
Winston-Salem, NC  27157
Office: 336-716-2960
Fax: 336-716-9188
E-mail: [email protected]

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• "New Directions in Antiplatelet Therapy"

• "Pharmacodynamic and Clinical Implications of Switching Between P2Y12 Receptor Antagonists: Considerations for Practice"