Platelet Inhibition, Endothelial Function, and Clinical Outcome in Patients Presenting With ST-Segment-Elevation Myocardial Infarction Randomized to Ticagrelor Versus Prasugrel Maintenance Therapy: Long-Term Follow-Up of the REDUCE-MVI Trial

Nina W van der Hoeven, Gladys N Janssens, Henk Everaars, Alexander Nap, Jorrit S Lemkes, Guus A de Waard, Peter M van de Ven, Albert C van Rossum, Javier Escaned, Hernan Mejia-Renteria, Tim J F Ten Cate, Jan J Piek, Clemens von Birgelen, Marco Valgimigli, Roberto Diletti, Niels P Riksen, Nicolas M Van Mieghem, Robin Nijveldt, Maarten A H van Leeuwen, Niels van Royen, Nina W van der Hoeven, Gladys N Janssens, Henk Everaars, Alexander Nap, Jorrit S Lemkes, Guus A de Waard, Peter M van de Ven, Albert C van Rossum, Javier Escaned, Hernan Mejia-Renteria, Tim J F Ten Cate, Jan J Piek, Clemens von Birgelen, Marco Valgimigli, Roberto Diletti, Niels P Riksen, Nicolas M Van Mieghem, Robin Nijveldt, Maarten A H van Leeuwen, Niels van Royen

Abstract

Background Off-target properties of ticagrelor might reduce microvascular injury and improve clinical outcome in patients with ST-segment-elevation myocardial infarction. The REDUCE-MVI (Evaluation of Microvascular Injury in Revascularized Patients with ST-Segment-Elevation Myocardial Infarction Treated With Ticagrelor Versus Prasugrel) trial reported no benefit of ticagrelor regarding microvascular function at 1 month. We now present the follow-up data up to 1.5 years. Methods and Results We randomized 110 patients with ST-segment-elevation myocardial infarction to either ticagrelor 90 mg twice daily or prasugrel 10 mg once a day. Platelet inhibition and peripheral endothelial function measurements including calculation of the reactive hyperemia index and clinical follow-up were obtained up to 1.5 years. Major adverse clinical events and bleedings were scored. An intention to treat and a per-protocol analysis were performed. There were no between-group differences in platelet inhibition and endothelial function. At 1 year the reactive hyperemia index in the ticagrelor group was 0.66±0.26 versus 0.61±0.28 in the prasugrel group (P=0.31). Platelet inhibition was lower at 1 month versus 1 year in the total study population (61% [42%-81%] versus 83% [61%-95%]; P<0.001), and per-protocol platelet inhibition was higher in patients randomized to ticagrelor versus prasugrel at 1 year (91% [83%-97%] versus 82% [65%-92%]; P=0.002). There was an improvement in intention to treat endothelial function in patients randomized to ticagrelor (P=0.03) but not in patients randomized to prasugrel (P=0.88). Major adverse clinical events (10% versus 14%; P=0.54) and bleedings (47% versus 63%; P=0.10) were similar in the intention-to-treat analysis in both groups. Conclusions Platelet inhibition at 1 year was higher in the ticagrelor group, without an accompanying increase in bleedings. Endothelial function improved over time in ticagrelor patients, while it did not change in the prasugrel group. Clinical Trial Registration URL: https://www.clinicaltrials.gov/. Unique Identifier: NCT02422888.

Keywords: ST‐segment‐elevation myocardial infarction; endothelial function; microvascular injury; platelet inhibition; prasugrel; ticagrelor.

Figures

Figure 1
Figure 1
Study enrollment and participation flowchart. *In these patients we did retrieve the survival status at 1.5‐year follow‐up, and we therefore also included them in the final analysis.
Figure 2
Figure 2
Platelet inhibition and reactivity in patients randomized to ticagrelor vs prasugrel. In the intention to treat analysis (A and B), we included the total study population of 108 patients. The per‐protocol analysis (C and D) was performed in 84 patients who did not switch or stop their randomized P2Y12 therapy before 1‐year follow‐up. 3A (ITT) and C (PP) indicate the platelet inhibition, and 3B (ITT) and D (PP) indicate the platelet reactivity in patients randomized to ticagrelor vs prasugrel maintenance therapy at 3 different time points. The line in the boxplots indicates the median, and the cross indicates the mean. PP indicates per‐protocol; PRU, platelet reactivity unit; ITT, intention to treat.
Figure 3
Figure 3
Platelet inhibition and reactivity in the total study population. In the intention‐to‐treat analysis (A and B), we included the total study population of 108 patients. The per‐protocol analysis (C and D) was performed in 84 patients who did not switch or stop their randomized P2Y12 therapy before 1‐year follow‐up. A‐C indicates the platelet inhibition, and B‐D indicates the platelet reactivity in the total study population at 3 different time points. The line in the boxplots indicates the median, and the cross indicates the mean. PRU indicates platelet reactivity unit.
Figure 4
Figure 4
Peripheral endothelial function and improvement in peripheral endothelial function in patients randomized to ticagrelor vs. prasugrel maintenance therapy. The dashed line represents the established cutoff value for decreased peripheral endothelial function (RHI <1.67 equals the natural logarithm RHI <0.51). The line in the boxplots indicates the median and the cross indicates the mean. The increase in RHI over time was calculated using a mixed‐model analysis including time as main effect. RHI indicates reactive hyperemia index.
Figure 5
Figure 5
Kaplan–Meier curve for the occurrence of MACE at 1.5‐year follow‐up. The Kaplan–Meier curve of the MACE‐free survival at 1.5‐year follow‐up in patients randomized to ticagrelor vs. prasugrel maintenance therapy. The hazard ratio with the 95% CI is for the occurrence of MACE, with prasugrel as reference. There is no significant between‐group difference in MACE. FU indicates follow‐up; MACE, major adverse clinical events.

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