New Guidance on Switching Between P2Y12 Inhibitors

DECEMBER 18, 2017
According to the CDC's National Center for Health Statistics, cardiovascular disease remains the No. 1 cause of death in the United States. Contributing to this statistic is heart failure, sudden cardiac death, acute coronary syndrome (ACS) and corresponding coronary artery disease. One of the main treatment modalities in patients with ACS and for those undergoing percutaneous coronary intervention (PCI) are P2Y12 inhibitors. Five of these agents are on the market in the United States: ticlopidine; clopidogrel; prasugrel; ticagrelor; and the newest agent, cangrelor, which is the first intravenous (IV) P2Y12 inhibitor approved. Ticlopidine is not used often clinically and is not advocated for in the guidelines. Instead prasugrel and ticagrelor are recommended as first-line agents for ACS. However, clopidogrel remains the most prescribed of the P2Y12 inhibitors.1,2

With the introduction of more agents, the prospect of switching between them has become a reality for clinicians, though the evidence behind these switches continues to be limited. Reasons for switching may include adherence, adverse effects, cost, drug interactions, and patient-specific characteristics.3 Although switching therapies is feasible, concerns remain regarding the safety of such switches, leaving patients at risk for bleeding or thrombosis. Clinical practice guidelines have yet to include specific information on how to switch between P2Y12 inhibitors, leaving clinicians asking serious questions regarding the practice. Luckily, in November 2017, a consensus document was published that gives clinicians the first set of viable guidelines to follow when switching P2Y12 inhibitor therapy.4

Several definitions are given for switches between oral P2Y12 inhibitors based on antiplatelet activity.4 First, time is defined based on the index event that led to the initiation of the P2Y12 inhibitor. Acute events occur within 24 hours of initiation, early from 1 to 30 days, late is 30 days to 1 year, and very late after 1 year. These definitions mirror the Academic Research Consortium definition for stent thrombosis.5 Moving from clopidogrel to prasugrel or ticagrelor is deemed escalation, because of more potent platelet inhibition with these agents.4 Conversely, moving from either prasugrel or ticagrelor to clopidogrel is defined as de-escalation. Switches between prasugrel and ticagrelor are called changes. Of all those modifications, only the switch from ticagrelor to prasugrel and from ticagrelor to clopidogrel have the potential for a drug-drug interaction, which may cause thrombotic or safety concerns. For switches involving cangrelor, going from oral to IV P2Y12 inhibitors is deemed bridging and from IV to oral is called transition. Drug-drug interactions involving cangrelor may occur with transition to clopidogrel or prasugrel.

Recommendations are made for every feasible switch between P2Y12 inhibitors, including oral and IV formulations and stratified according to time for oral switches. The recommendations include whether a loading dose would be necessary and how long after the last dose of a P2Y12 inhibitor should the loading or maintenance dose be administered. Transitioning from cangrelor to oral P2Y12 inhibitors is often a practice after PCI, whereas bridging from oral P2Y12 inhibitors to cangrelor occurs mostly in patients needing to undergo procedures, which require discontinuation of oral P2Y12 inhibitor therapy. A synopsis of the recommendations is presented in Tables 1 and 2.
 

Table 1. Recommendations on Switching Between Oral P2Y12 Inhibitors
P2Y12 Inhibitor
Patient Is Stopping
P2Y12 Inhibitor
to Be Started
Recommendation
                                 Acute/Early Phase
Clopidogrel Prasugrel 60 mg LD, irrespective of last clopidogrel dose; MD can be started ~24 hours after last clopidogrel dose
Clopidogrel Ticagrelor 180 mg LD, irrespective of last clopidogrel dose; MD can be started ~24 hours after last clopidogrel dose
Prasugrel Clopidogrel 600 mg LD 24 hours after last prasugrel dose†
Prasugrel Ticagrelor 180 mg LD 24 hours after last prasugrel dose
Ticagrelor Clopidogrel 600 mg LD 24 hours after last ticagrelor dose†
Ticagrelor Prasugrel 60 mg LD 24 hours after last ticagrelor dose
                             Late/Very Late Phase
Clopidogrel Prasugrel 10 mg MD 24 hours after last clopidogrel dose
Clopidogrel Ticagrelor 90 mg MD 24 hours after last clopidogrel dose
Prasugrel Clopidogrel 75 mg MD 24 hours after last prasugrel dose
Prasugrel Ticagrelor 90 mg MD 24 hours after last prasugrel dose
Ticagrelor Clopidogrel 600 mg LD 90 mg MD 24 hours after last ticagrelor dose†
Ticagrelor Prasugrel 60 mg LD 24 hours after last ticagrelor dose
LD indicates Loading dose; MD, Maintenance dose

†Consider using 75 mg dose without loading in patients who are bleeding or have bleeding concerns.

Table 2. Recommendations on Bridging or Transitioning Between IV and Oral P2Y12 Inhibitors
P2Y12 Inhibitor
Patient Is Stopping
P2Y12 Inhibitor
to Be Started
Days to Hold P2Y12 Inhibitor Prior to Procedure Recommendation
Clopidogrel Cangrelor 5 Initiate cangrelor 0.75 mcg/kg/min without bolus 2 to 3 days after stopping clopidogrel; platelet function testing can be considered to guide therapy.†
Prasugrel Cangrelor 7 Initiate cangrelor 0.75 mcg/kg/min without bolus 3 to 4 days after stopping prasugrel; platelet function testing can be considered to guide therapy.†
Ticagrelor Cangrelor 5 Initiate cangrelor 0.75 mcg/kg/min without bolus 2 to 3 days after stopping ticagrelor; platelet function testing can be considered to guide therapy.†
Cangrelor Clopidogrel N/A 600 mg LD can be given immediately after cangrelor infusion is discontinued.
Cangrelor Prasugrel N/A 60 mg LD can be given immediately after cangrelor infusion is discontinued.
Cangrelor Ticagrelor N/A 180 mg LD may be given at the start of cangrelor infusion (ideal) or up to infusion discontinuation.
† Stop cangrelor 1 to 6 hours prior to scheduled procedure; may restart oral therapy 1 to 6 hours post-procedure;
   Clopidogrel is recommended oral therapy for restarting, regardless of previous P2Y12 inhibitor used
 
For clinicians practicing in cardiac and other settings, reading this new consensus document will provide a wealth of information about switching between P2Y12 inhibitors. Until new clinical or pharmacokinetic/pharmacodynamics data are released on this topic, this document serves as the best guidance for clinicians and is a welcome addition to the clinical repertoire as the use of these agents continues to increase in practice.

 
References
1.       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(23):e574–651. doi: 10.1161/CIR.0b013e31823ba622.
2.       Sherwood MW, Wiviott SD, Peng SA, et al. Early clopidogrel versus prasugrel use among contemporary STEMI and NSTEMI patients in the US: insights from the National Cardiovascular Data Registry. J Am Heart Assoc. 2014;3:e000849. doi: 10.1161/JAHA.114.000849.
3.       Rollini F, Franchi F, Angiolillo DJ. Switching P2Y12-receptor inhibitors in patients with coronary artery disease. Nat Rev Cardiol. 2016;13:11–27. doi: 10.1038/nrcardio.2015.113. 
4.       Angiolillo DJ, Rollini F, Storey RF, et al. International expert consensus on switching platelet P2Y12 receptor-inhibiting therapies. Circulation. 2017;136(20):1955-1975. doi: 10.1161/CIRCULATIONAHA.117.031164.
5.       Cutlip DE, Windecker S, Mehran R, et al. Clinical end points in coronary stent trials: a case for standardized definitions. Circulation. 2007;115(17):2344–51.


Alexander Kantorovich, PharmD, BCPS
Alexander Kantorovich, PharmD, BCPS, is a Clinical Assistant Professor of Pharmacy Practice at Chicago State University College of Pharmacy and Clinical Pharmacy Specialist in the area of Internal Medicine at Advocate Christ Medical Center in Oak Lawn, Illinois. Dr. Kantorovich earned his Associate of Science degree with an emphasis in chemistry from William Rainey Harper College in 2008 and received his Doctor of Pharmacy degree in 2012 from the University of Illinois at Chicago College of Pharmacy. He went on to complete a 2-year pharmacotherapy residency with an emphasis in cardiology and critical care at the Cleveland Clinic and earned board certification in pharmacotherapy in 2014. His research interests center around cardiovascular pharmacotherapy, anticoagulation, and anticoagulation reversal.
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