Ticagrelor Loading Dose Provides Faster Platelet Inhibition Than Clopidogrel in Ad Hoc PCI

In patients with troponin-negative ACS undergoing ad hoc PCI, ticagrelor given prior to the procedure results in more prompt and more potent platelet inhibition than clopidogrel, a small study suggests. The findings raise questions about current guidelines governing the management of stable CAD.  

The Ad-Hoc PCI Study, published in the February 16 issue of the Journal of the American College of Cardiology, was initially presented in 2015 at the Society for Cardiovascular Angiography and Interventions Scientific Sessions.

“These results support that ticagrelor [loading dose] is more effective than clopidogrel [loading dose] for inhibition of platelet reactivity in the peri-intervention period in low-risk, troponin-negative ACS patients undergoing ad hoc PCI,” according to senior author Roxana Mehran, MD, of Mount Sinai Hospital (New York, NY), and colleagues.

Clinical practice guidelines emphasize the importance of early initiation of potent P2Y12 inhibitors for patients with moderate-to-high-risk ACS. How to manage lower risk ACS patients in whom the decision to proceed with PCI is only made after the diagnostic angiogram—so called “ad hoc” PCI—is less well established. European guidelines recommend clopidogrel but not ticagrelor in this setting, and the most recent American College of Cardiology/American Heart Association guidelines are less certain about the benefits of pretreatment with the agents. No prior study has specifically addressed the question of ticagrelor vs clopidogrel in patients with low-risk, troponin-negative ACS.

For the Ad-Hoc PCI Study, Mehran and colleagues, including lead author Dominick J. Angiolillo, MD, of the University of Florida College of Medicine in Jacksonville, looked at 100 P2Y12 inhibitor-naive, troponin-negative ACS patients from 15 centers. Patients were randomized to a 180-mg loading dose of ticagrelor (n = 51) or a 600-mg loading dose of clopidogrel (n = 49) between July 2012 and June 2014. Ticagrelor patients received an additional 90-mg dose 12 hours after the loading dose, and patients in both groups received a 160- to 500-mg loading dose of aspirin, followed by 75 to 100 mg daily.

Platelet function testing with the VerifyNow assay (Accriva; San Diego, CA) was performed at 5 time points: before the loading dose; at the end of PCI; and at 30 minutes, 2 hours, and 8 hours.

Despite patients being considered low-risk, there was a high rate of pre-existing cardiovascular risk factors and history of MI or prior PCI in both groups.  

Faster Platelet Inhibition With Ticagrelor

Compared with clopidogrel, the primary endpoint of P2Y12 reactivity unit (PRU) levels at 2 hours was lower in the ticagrelor group (98.4 ± 95.4 vs 257.5 ± 74.5; P < 0.001). This observation was seen across time points, and it emerged as early as 36 minutes after the loading dose and was maintained out to 8 hours.

Mean percentage change from baseline in PRU and mean percent inhibition of P2Y12 receptor from BASE channel also were greater with ticagrelor than clopidogrel at the 2-hour and 8-hour time points.

In exploratory analysis, the percentage of patients with high on-treatment platelet reactivity—which was about 90% of patients in both groups— was reduced with ticagrelor compared with clopidogrel immediately after PCI, and at 2 hours and 8 hours post-procedure. Importantly, 53.3% of clopidogrel-treated patients still had high on-treatment platelet reactivity at 8 hours vs only 2.4% of ticagrelor-treated patients (P < .001).

No deaths or other adverse events were reported. Bleeding events considered related to study drug occurred in 4 ticagrelor-treated patients and in no clopidogrel-treated patients. Of these, 2 were classified as minor and 2 as minimal.

Angiolillo et al note that practice patterns with regard to early initiation of P2Y12 inhibitors “vary across the globe, with patients in the United States less likely to be pretreated compared with those in Europe.” Although the study was not powered to assess clinical events, the findings are of considerable clinical relevance, they add, especially since high on-platelet reactivity status has been linked to increased risk of stent thrombosis and MI.

Eye on Improving Outcomes for Elective Patients

Writing in an accompanying editorial, Gilles Montalescot, MD, PhD, of Pitié-Salpêtrière University Hospital (Paris, France), and colleagues note the increasing off-label use of prasugrel and ticagrelor in elective PCI, particularly for high-risk elective procedures such as left main and bifurcation stenting and those involving multiple stents, as well as in patients who have high-risk features for ischemic events.

“Elective PCI performed in stable CAD patients looks like a new potential indication for ticagrelor,” they conclude. “There is a medical demand from physicians for intuitive protection when complex revascularization procedures are performed, a strategy somewhat supported by guidelines. Whether a medical need exists for patients will be known only after the results of the ongoing trials are published.”

Two ongoing studies, TWILIGHT and ALPHEUS, will further explore how ticagrelor may improve outcomes in stable CAD patients. In ALPHEUS, crushed tablets are being used in an attempt to improve the drug’s onset of action for platelet inhibition compared with clopidogrel. TWILIGHT is evaluating ticagrelor alone compared with the combination of aspirin and ticagrelor during the post-PCI period (3 to 15 months).

Note: Mehran is a faculty member of the Cardiovascular Research Foundation, which owns and operates TCTMD.  

Sources: 
1. Angiolillo DJ, Franchi F, Waksman R, et al. Effects of ticagrelor versus clopidogrel in troponin-negative patients with low-risk ACS undergoing ad hoc PCI. J Am Coll Cardiol. 2016;67:603-613.
2. Silvain J, Kerneis M, Montalescot G. Potent P2Y12 inhibitors in low-risk patients: is there a medical need [editorial]? J Am Coll Cardiol. 2016;67:614-617. 

Disclosures:

• The study was funded by AstraZeneca. Angiolillo reports received consulting fees or honorarium from Abbott Vascular, AstraZeneca, Daiichi-Sankyo, Eli Lilly, Merck, PLx Pharma, Sanofi, and The Medicines Company; participating in review activities from CeloNova, Johnson & Johnson, and St. Jude Medical; and receiving institutional payments for grants from AstraZeneca, CSL Behring, Daiichi-Sankyo, Eli Lilly, Gilead, GlaxoSmithKline, Janssen Pharmaceuticals, Novartis, Osprey Medical, and The Medicines Company. 
• Mehran reports receiving research grants from AstraZeneca, Bristol-Myers Squibb/Sanofi-Aventis, DSI/Eli Lilly, and The Medicines Company as well as consulting or advisory board fees from AstraZeneca, CSL Behring, Janssen Pharmaceuticals, and Osprey Medical. 
• Montalescot reports research grants or consulting/lecture fees from multiple companies, including the Cardiovascular Research Foundation. 

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