Authors: Kelly Knauer, PharmD; Ulyana Kucherepa, PharmD
PGY-1 Pharmacy Practice Residents
Mentor: Davina Dell-Steinbeck, PharmD, BCPS
Program Number: 2022-05-04
Approved Dates: June 1, 2022-December 1, 2022 Approved Contact Hours: One Hour(s) (1) CE(s) per session
2016 ACC/AHA guidelines recommend a minimum one month of DAPT in patients with stable ischemic heart disease (SIHD) receiving a bare metal stent (BMS) since the risk of BMS thrombosis is highest during the initial time after the stent placement. Bare metal stents can be considered for patients who cannot tolerate DAPT (i.e. high bleeding risk, planned major surgery, medication non-adherence).2 However, in most patients with SIHD, drug-eluting stents (DES) are used for the purposes of coronary stenosis prevention. Patients receiving first generation DES (paclitaxel or tacrolimus) should receive at least 12 months of DAPT [2,3]. Newer generation DES (everolimus-, zotarolimus-, ridaforolimus-eluting stents and bioresorbable polymer) showed lower restenosis and thrombosis risk.2,3 With respect to such evidence, 2016 ACC/AHA and 2017 ESC guidelines recommendations on DAPT in SIHD post-percutaneous coronary intervention (PCI) have been shortened from 12 to 6 months (or 3 months if high bleeding risk).2,4 Suggested duration of DAPT in patient with acute coronary syndrome (ACS) post-PCI is at least 12 months (or 6 months if high bleeding risk) per 2016 AHA/ACC and 2017 ESC guidelines2,4.
P2Y12 inhibitors are an integral part of antithrombosis due to their role in interruption of platelet aggregation. In typical physiology, platelets patch vessel wall injuries by attaching to an exposed extracellular matrix in the subendothelium through a series of actions. First, platelets interact with the adhesive protein von Willebrand factor by using the glycoprotein (GP) Ib-IX-V receptor complex located on its membrane, and also attach to collagen using GP Ia/IIa and GP VI receptors. Once the platelet is bound, it activates, alters shape, and stimulates degranulation to release soluble platelet agonists including thromboxane and adenosine diphosphate (ADP). These platelet agonists amplify platelet response and aggregation. ADP binds to P2Y1 and P2Y12 G-protein coupled receptors on platelets to activate the GP IIb/IIIa receptor, which results in further platelet degranulation, thromboxane production, and platelet aggregation. P2Y12 inhibitors prevent the activation of GP IIb/IIIa receptor and resulting platelet aggregation by interfering with the binding of ADP to the P2Y12 receptor. 5,6
Several P2Y12 inhibitors are available on the market with each having their own considerations. Clopidogrel is a prodrug, and requires metabolism to its active form carboxylesterase-1 through CYP2C19. Poor and intermediate metabolizers of this enzyme may not have the same efficacy as a result, and an alternate P2Y12 inhibitor might be a better choice. Poor metabolizers include genotypes *2/*2, *2/*3, *3/*3, which are more commonly found in patients of Asian descent, and intermediate genotypes include *1/*2, *1/*3, and *2/*17. Prasugrel is also a prodrug, however it is converted to its active metabolite by several pathways and is less affected by variations in metabolism. Notably, it should be avoided in patients who have a history of stroke or transient ischemic attack. Prasugrel is found on the Beers list and is generally not recommended for use in patients over the age of 75 due to bleeding risks. Additionally, dose reductions are recommended for patients with a body weight of less than 60 kg. Ticagrelor is a reversible P2Y12 inhibitor, and is the only one that requires twice daily dosing. It is recommended to avoid aspirin doses of more than 100 mg daily while using ticagrelor due to reduced efficacy. Cangrelor is an intravenous option for patients who are unable to take oral agents. It is a reversible inhibitor with a rapid onset of action and a short half-life. As a result, normal platelet function returns within an hour of treatment discontinuation. Table 1 provides a guide for recommended dosing of the different P2Y12 options. 5,6
Clinical Trial Review
There has been increased recent interest in the question of DAPT duration of therapy for patients following PCI, with many studies having been published in this area. Table 2 gives a summary of some of the more current individual studies that have been completed on this topic including the studied population and the conclusions that were drawn. Additionally, there have been several meta-analyses and systematic reviews conducted to investigate the most optimal duration of DAPT in patients undergoing PCI that are discussed further. Cumulatively, the results of these studies demonstrate the complexity of the topic and the need for patient specific considerations in therapy recommendations.
A recent systematic review and individual level meta-analysis of randomized controlled trials by Valgimili et al. assessed the risks and benefits of P2Y12 inhibitor monotherapy compared with DAPT and whether these associations were modified by patient characteristics . Trials including patients with concomitant indications for anticoagulation were excluded. The investigators censored ischemic and bleeding events in the initial phase of treatment (1 month after coronary revascularization) as the rates of stent thrombosis are known to be highest approximately 1 month after coronary revascularization . The findings showed that aspirin withdrawal 1-3 months after PCI and continuation with monotherapy conserved ischemic protection compared with DAPT with effects irrespective of the choice of P2Y12 inhibitor. 
Another recent meta analysis by Xu et al. assessed randomized controlled trials that included adults with coronary artery disease who received DAPT after PCI with implantation of drug eluting stents. Any studies utilizing bare metal stents were excluded, as well as studies with a crossover design. In total, 24 trials with a total of 81,339 participants overall were reviewed. Five trials compared DAPT for 12 months to durations longer than a year, seven trials compared DAPT for 12 months to 6 months, three trials compared DAPT 12 months to DAPT for 3 months followed by aspirin monotherapy, three trials compared DAPT for 12 months to DAPT for 3 months followed by P2Y12 monotherapy, four trials compared DAPT for 6 months to DAPT for longer than a year, and two trials compared DAPT for 12 months to DAPT for one month followed by P2Y12 monotherapy. 
The findings demonstrated no statistical differences in mortality and cardiac death risk between DAPT for 3 months followed by P2Y12 monotherapy when compared to the other DAPT durations. Unsurprisingly, DAPT for longer than one year was associated with more risks for major bleeding. Studies with shorter durations of DAPT of 3 months or less were associated with reduced risks of bleeding. Interestingly, when assessing ischemic endpoints it was found that DAPT for 3 months followed by P2Y12 monotherapy, DAPT for 3 months followed by aspirin monotherapy, and DAPT for 1 month followed by P2Y12 monotherapy were not significantly different from DAPT for longer than one year, however DAPT for 6 months and DAPT for 12 months were shown to have an increased risk of myocardial infarction compared to DAPT for longer than 12 months. Ultimately, the conclusion was drawn that DAPT for 3 months followed by either P2Y12 or aspirin monotherapy, or DAPT for 1 month followed by P2Y12 monotherapy have a balanced risk of hemorrhage and ischemia, with no clear higher benefit of one strategy out of the three. 
Takeaways and Recommendations
When reviewing that data from the recent literature, there are a few points that are important to consider. First of all, most of the studies were conducted in Asia. This may be a confounding factor, especially in considering the trials that included clopidogrel due to the increased likelihood of genetic differences in metabolism. Secondly, there was an overrepresentation of ticagrelor compared to prasugrel in the studies utilizing newer P2Y12 inhibitors, which may limit the generalizability of the results to prasugrel. Overall, there are several important aspects that are worth investigating to further define the most optimal DAPT duration including the choice of P2Y12 inhibitor, patient demographics (ethnicity), and degree of vessel occlusion.
In the current practice guidelines, short-term DAPT duration has not been clearly outlined.
Nevertheless, a paradigm shift in DAPT duration in patients post-PCI is obviously emerging. A short-term DAPT in patients post-PCI may be an attractive option to mitigate the bleeding risks associated with antiplatelet agents. Long-term duration of DAPT was correlated with increased incidence of bleeding events in comparison to one to three months of P2Y12 monotherapy in patients undergoing percutaneous coronary revascularization with drug-eluting stents [5-9]. Recent meta-analyses have not shown significant differences in major ischemic events in 1-3 months of DAPT in comparison to standard 12-month therapy in patients with CAD after DES implantation [10-11]. This emerging evidence offers a short-term duration of DAPT followed by P2Y12 inhibitor monotherapy as a reasonable choice, particularly in high-bleeding risk patients.