Author + information
- Sara Ariotti, MD,
- Maarten van Leeuwen, MD,
- Salvatore Brugaletta, MD, PhD,
- Sergio Leonardi, MD, MHS,
- K. Martijn Akkerhuis, MD, PhD,
- Stefano F. Rimoldi, MD,
- Gladys N. Janssens, MD,
- Luis Ortega-Paz, MD,
- Umberto Gianni, MD,
- Jan C. van den Berge, MD,
- Alexios Karagiannis, PhD,
- Stephan Windecker, MD,
- Marco Valgimigli, MD, PhD∗ (, )
- on behalf of the HI-TECH Investigators
- ↵∗Swiss Cardiovascular Center, University Hospital, Freiburgstrasse 4, CH-3010 Bern, Switzerland
Ticagrelor is a nonthienopyridine direct and reversible P2Y12 platelet receptor antagonist, and unlike prasugrel or clopidogrel inhibits, at least partially, the sodium-independent equilibrative nucleoside transporter 1 (1). This ticagrelor-mediated off-target effect has potential to improve endothelial function (1,2), but the evidence is limited (3,4).
The HI-TECH (Hunting for the off-target propertIes of Ticagrelor on Endothelial function and other Circulating biomarkers in Humans) study (NCT02587260) is a randomized, open-label, multicenter crossover study (5). Eligible patients suffered at least 30 days earlier from an acute coronary syndrome (ACS), were free from ischemic or bleeding complications and reported regular intake of a dual antiplatelet therapy regimen. Each patient was exposed to each of the 3 oral P2Y12 inhibitors following a 3-period balanced Latin square crossover design with 4 weeks per treatment period.
Primary endpoint measurements were performed 30 ± 5 days after the witnessed intake each P2Y12 inhibitor (90 mg twice a day for ticagrelor, 10 mg/day for prasugrel [or 5 mg/day if >75 years of age or weight <60 kg], and 75 mg/day for clopidogrel).
Assessment of endothelial function was obtained using pulse amplitude tonometry, which records digital pulse wave amplitude using fingertip plethysmography (EndoPAT, Itamar Medical, Caesarea, Israel) and quantifies the endothelium-mediated changes in vascular tone, elicited by a 5-min occlusion of the brachial artery. A post-occlusion to pre-occlusion ratio is calculated by the EndoPAT software and expressed as reactive hyperemia index (RHI). Assessment of platelet P2Y12 inhibitor functional assay was performed with VerifyNow system (Accriva Diagnostics, San Diego, California).
The primary endpoint was defined as RHI at treatment steady state, assessed 1 to 2 h after MD (maintenance dose) intake of the 3 P2Y12 inhibitors, and consisted of 2 main comparisons: ticagrelor versus prasugrel difference in RHI and ticagrelor versus clopidogrel difference in RHI. With 36 patients completing all sequences (i.e., 6 patients/sequence) the study provided 90% power to detect a 10% RHI relative change in the ticagrelor group (RHI after ticagrelor MD administration) with a 2-sided alpha level at 5%. A total of 54 patients were allocated to 1 of the 6 randomization sequences in 5 centers. Of these, 50 (92.6%) patients completed the randomized P2Y12 inhibitor sequence and the primary endpoint measure was available for 47 (87.0%) patients.
Mean time from index ACS to baseline visit was 233 ± 189 days, ranging from 38 to 1,023 days. RHI after MD assessment (primary endpoint) did not differ after ticagrelor (n = 51; 1.970 ± 0.535) as compared with prasugrel (n = 50; 2.007 ± 0.64; difference: −0.048; 95% confidence interval: −0.212 to 0.115; p = 0.557) or clopidogrel (n = 49; 2.072 ± 0.646; difference: −0.034; 95% confidence interval: −0.200 to 0.132; p = 0.685) (Figure 1). P2Y12 platelet reactivity units were lower after ticagrelor as compared to clopidogrel as compared with prasugrel after MD (Figure 1). Sequence of P2Y12 did not impact treatment effects (p = 0.492).
Several lines of research have suggested that ticagrelor may exert an adenosine-mediated P2Y12-independent mechanism of action. Ours is the third randomized trial to assess the off-target effects of ticagrelor on vascular function (3,4), yet it is the first extending the comparison of ticagrelor to both prasugrel and clopidogrel and the first multicenter trial being executed in a chronic setting (i.e., focusing on stabilized post-ACS patients).
In prior investigations, the duration of treatment with ticagrelor was either 4 or 5 weeks, and therefore comparable to the 4-week duration of each P2Y12 inhibitor in our study. We recruited patients after a mean time from index ACS of 233 ± 189 days, ranging from 38 to 1,023 days. In both prior studies, patients were recruited at index admission for ACS without prior exposure to dual antiplatelet therapy. Our findings do not prove that ticagrelor exerts measurable off-target effects on endothelial function in stabilized post-ACS patients.
Please note: This study was supported by a research grant from AstraZeneca. The study was designed by the principal investigator (Dr. Valgimigli), sponsored by the Erasmus Medical Center and a nonprofit organization; and received grant support from AstraZeneca. Sponsor and supporting company had no role in study design, data collection, data monitoring, analysis, interpretation, or writing of the report. Dr. van Leeuwen has received an institutional research grant support from AstraZeneca. Dr. Brugaletta has received an institutional research grant from AstraZeneca; and speaker fees from Abbott Vascular and Boston Scientific. Dr. Leonardi has received consulting fees from AstraZeneca, Eli Lilly, The Medicines Company, and Chiesi. Dr. Rimoldi has served on the speakers bureau for Servier and Menarini. Dr. Janssens has received institutional research grant support from AstraZeneca. Dr. Karagiannis is affiliated with CTU Bern, University of Bern, which has a staff policy of not accepting honoraria or consultancy fees; however, CTU Bern is involved in design, conduct, or analysis of clinical studies funded by not-for-profit and for-profit organizations, in particular, pharmaceutical and medical device companies provide direct funding to some of these studies. Dr. Windecker has received institutional grant support from Bracco, Boston Scientific, and Terumo. Dr. Valgimigli has received grant support from AstraZeneca during the conduct of the study; personal fees from AstraZeneca, Abbott Vascular, Bayer, Amgen, Cardinal Health, Biosensors, and Daiichi-Sankyo. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. The authors thank Jurgen Ligthart and Karen Witberg for technical assistance with the EndoPAT measurements. (The HI-TECH [Hunting for the off-target propertIes of Ticagrelor on Endothelial function and other Circulating biomarkers in Humans] study; NCT02587260).
- 2018 American College of Cardiology Foundation
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