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HI-TECH: Ticagrelor does not affect endothelial function vs. other P2Y12 inhibitors

New data from the HI-TECH study presented at EuroPCR indicate that ticagrelor did not improve endothelial function or increase systemic adenosine plasma levels compared with prasugrel and clopidogrel.

The open-label, randomized, crossover study conducted at five centers in Switzerland, the Netherlands, Spain and Italy included 54 stabilized patients who had been treated for ACS. Patients were sequentially exposed to each of the three P2Y12 inhibitors following a three-period balanced Latin square crossover design with 4 weeks per treatment period.

The researchers assessed endothelial function using pulse amplitude tonometry, vascular biomarkers and flow-mediated dilatation of the brachial artery in a subset of patients.

Reactive hyperemia index after maintenance dose assessment — the primary endpoint — did not differ after ticagrelor (Brilinta, AstraZeneca; mean, 1.97) compared with prasugrel (Effient, Daiichi Sankyo/Eli Lilly; mean, 2.007; difference, –0.048; 95% CI, –0.212 to 0.115) and clopidogrel (mean, 2.072; difference, –0.34; 95% CI, –0.2 to 0.132), with identical results observed in a matched and per-protocol analysis.

Additionally, the proportion of patients with on-treatment endothelial dysfunction, defined as a reactive hyperemia index of 1.67 or less, after maintenance dose assessment was similar after ticagrelor (29.4%), prasugrel (22.4%) and clopidogrel (22.4%).

The data were consistent across subgroups, the researchers noted.

Results showed no differences in systemic adenosine plasma levels after ticagrelor compared with prasugrel or clopidogrel, which also remained consistent across subgroups. There was no correlation between adenosine plasma levels and ticagrelor or AR-C124910XX in patients treated with ticagrelor.

Jay Giri, MD, MPH
Jay Giri

After ticagrelor, P2Y12 platelet reactivity units were lower at all time points when compared with clopidogrel, but they were only lower after maintenance dose and not after loading dose when compared with prasugrel.

The researchers also found no differences in any of the vascular biomarkers after ticagrelor when compared with prasugrel or clopidogrel at any time point.

In a subset of nine patients, flow-mediated dilatation of the brachial artery was greater after the maintenance dose of ticagrelor (median, 5%) vs. clopidogrel (median, 3.2%; P = .004) but was not different compared with prasugrel (median, 4.04%; P = .18).

“We found no evidence that ticagrelor exerts measurable adenosine-mediated off-target effects on endothelial function at currently approved regimen in stabilized patients who suffered from an ACS,” the researchers wrote in a simultaneous publication in JACC: Cardiovascular Interventions.

“The investigators should be congratulated on a rigorously performed study. Through the use of a unique translational design, they investigated potential differences in P2Y12 inhibitors, something other investigators have examined through population-based clinical outcome trials,” Jay Giri, MD, MPH, and Ashwin Nathan, MD, both from the Cardiovascular Outcomes, Quality, and Evaluative Research Center, Leonard Davis Institute of Health Economics, Cardiovascular Medicine Division at the University of Pennsylvania, wrote in an accompanying editorial in JACC: Cardiovascular Interventions.

In terms of clinical outcomes, studies have demonstrated comparable safety and efficacy between ticagrelor and prasugrel for patients undergoing PCI for ACS, but selecting the right medication for the right patient may be more complex, they noted. For instance, prasugrel carries an FDA black-box warning for patients with a history of transient ischemic attack or stroke and is not recommended for patients aged older than 75 years or patients weighing less than 60 kg, while prasugrel requires twice-daily dosing, which may affect medication adherence.

Even so, medication costs may be the most important factor, as both ticagrelor and prasugrel are expensive, according to Giri, a Cardiology Today Next Gen Innovator, and Nathan.

“Although studies will attempt to identify nuanced differences among different antiplatelet agents to maximize benefits to patients, the best antiplatelet agent in the current era is likely the one the patient can afford to obtain,” they wrote. – by Melissa Foster

References:

Valgimigli M, et al. Drug-device synergy for improved outcomes: new mechanisms. Presented at: EuroPCR; May 22-25, 2018; Paris.

Ariotti S, et al. JACC Cardiovasc Interv. 2018;doi:10.1016/j.jcin.2018.04.022.

Giri J, et al. JACC Cardiovasc Interv. 2018;doi:10.1016/j.jcin.2018.04.047.

Disclosure: The study was supported by a research grant from AstraZeneca. Please see the study for a full list of the authors’ relevant financial disclosures. Giri and Nathan report no relevant financial disclosures.

New data from the HI-TECH study presented at EuroPCR indicate that ticagrelor did not improve endothelial function or increase systemic adenosine plasma levels compared with prasugrel and clopidogrel.

The open-label, randomized, crossover study conducted at five centers in Switzerland, the Netherlands, Spain and Italy included 54 stabilized patients who had been treated for ACS. Patients were sequentially exposed to each of the three P2Y12 inhibitors following a three-period balanced Latin square crossover design with 4 weeks per treatment period.

The researchers assessed endothelial function using pulse amplitude tonometry, vascular biomarkers and flow-mediated dilatation of the brachial artery in a subset of patients.

Reactive hyperemia index after maintenance dose assessment — the primary endpoint — did not differ after ticagrelor (Brilinta, AstraZeneca; mean, 1.97) compared with prasugrel (Effient, Daiichi Sankyo/Eli Lilly; mean, 2.007; difference, –0.048; 95% CI, –0.212 to 0.115) and clopidogrel (mean, 2.072; difference, –0.34; 95% CI, –0.2 to 0.132), with identical results observed in a matched and per-protocol analysis.

Additionally, the proportion of patients with on-treatment endothelial dysfunction, defined as a reactive hyperemia index of 1.67 or less, after maintenance dose assessment was similar after ticagrelor (29.4%), prasugrel (22.4%) and clopidogrel (22.4%).

The data were consistent across subgroups, the researchers noted.

Results showed no differences in systemic adenosine plasma levels after ticagrelor compared with prasugrel or clopidogrel, which also remained consistent across subgroups. There was no correlation between adenosine plasma levels and ticagrelor or AR-C124910XX in patients treated with ticagrelor.

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Jay Giri, MD, MPH
Jay Giri

After ticagrelor, P2Y12 platelet reactivity units were lower at all time points when compared with clopidogrel, but they were only lower after maintenance dose and not after loading dose when compared with prasugrel.

The researchers also found no differences in any of the vascular biomarkers after ticagrelor when compared with prasugrel or clopidogrel at any time point.

In a subset of nine patients, flow-mediated dilatation of the brachial artery was greater after the maintenance dose of ticagrelor (median, 5%) vs. clopidogrel (median, 3.2%; P = .004) but was not different compared with prasugrel (median, 4.04%; P = .18).

“We found no evidence that ticagrelor exerts measurable adenosine-mediated off-target effects on endothelial function at currently approved regimen in stabilized patients who suffered from an ACS,” the researchers wrote in a simultaneous publication in JACC: Cardiovascular Interventions.

“The investigators should be congratulated on a rigorously performed study. Through the use of a unique translational design, they investigated potential differences in P2Y12 inhibitors, something other investigators have examined through population-based clinical outcome trials,” Jay Giri, MD, MPH, and Ashwin Nathan, MD, both from the Cardiovascular Outcomes, Quality, and Evaluative Research Center, Leonard Davis Institute of Health Economics, Cardiovascular Medicine Division at the University of Pennsylvania, wrote in an accompanying editorial in JACC: Cardiovascular Interventions.

In terms of clinical outcomes, studies have demonstrated comparable safety and efficacy between ticagrelor and prasugrel for patients undergoing PCI for ACS, but selecting the right medication for the right patient may be more complex, they noted. For instance, prasugrel carries an FDA black-box warning for patients with a history of transient ischemic attack or stroke and is not recommended for patients aged older than 75 years or patients weighing less than 60 kg, while prasugrel requires twice-daily dosing, which may affect medication adherence.

Even so, medication costs may be the most important factor, as both ticagrelor and prasugrel are expensive, according to Giri, a Cardiology Today Next Gen Innovator, and Nathan.

“Although studies will attempt to identify nuanced differences among different antiplatelet agents to maximize benefits to patients, the best antiplatelet agent in the current era is likely the one the patient can afford to obtain,” they wrote. – by Melissa Foster

References:

Valgimigli M, et al. Drug-device synergy for improved outcomes: new mechanisms. Presented at: EuroPCR; May 22-25, 2018; Paris.

Ariotti S, et al. JACC Cardiovasc Interv. 2018;doi:10.1016/j.jcin.2018.04.022.

Giri J, et al. JACC Cardiovasc Interv. 2018;doi:10.1016/j.jcin.2018.04.047.

Disclosure: The study was supported by a research grant from AstraZeneca. Please see the study for a full list of the authors’ relevant financial disclosures. Giri and Nathan report no relevant financial disclosures.

    Perspective
    Roxana Mehran

    Roxana Mehran

    I am not particularly surprised or intrigued by this study. There are so many factors that affect endothelial function that it is hard to separate them, especially in such a small cohort. One cannot conclude that there is a lack of effect just because it was not observed in this study.

    • Roxana Mehran, MD, MSCAI, FACC, FAHA, FESC
    • Cardiology Today’s Intervention Associate Medical Editor Icahn School of Medicine at Mount Sinai Cardiovascular Research Foundation

    Disclosures: Mehran reports she has financial ties with multiple pharmaceutical and device companies.

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