Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.
ADVANCED SEARCH
Log in
Top
Trials
Published in: Trials 1/2020

01-12-2020 | Ticagrelor | Study protocol

Ticagrelor and preconditioning in patients with stable coronary artery disease (TAPER-S): a randomized pilot clinical trial

Authors: D. D’Amario, A. Restivo, A. M. Leone, R. Vergallo, S. Migliaro, F. Canonico, M. Galli, C. Trani, F. Burzotta, C. Aurigemma, G. Niccoli, A. Buffon, R. A. Montone, A. Flex, F. Franceschi, G. Tinelli, U. Limbruno, F. Francese, I. Ceccarelli, J. A. Borovac, I. Porto, F. Crea

Published in: Trials | Issue 1/2020

Login to get access

Abstract

Background

Ticagrelor is a reversibly binding, direct-acting, oral, P2Y12 antagonist used for the prevention of atherothrombotic events in patients with coronary artery disease (CAD). Ticagrelor blocks adenosine reuptake through the inhibition of equilibrative nucleoside transporter 1 (ENT-1) on erythrocytes and platelets, thereby facilitating adenosine-induced physiological responses such as an increase in coronary blood flow velocity. Meanwhile, adenosine plays an important role in triggering ischemic preconditioning through the activation of the A1 receptor. Therefore, an increase in ticagrelor-enhanced adenosine bioavailability may confer beneficial effects through mechanisms related to preconditioning activation and improvement of coronary microvascular dysfunction.

Methods

To determine whether ticagrelor can trigger ischemic preconditioning and influence microvascular function, we designed this prospective, open-label, pilot study that enrolled patients with stable multivessel CAD requiring staged, fractional flow reserve (FFR)-guided percutaneous coronary intervention (PCI). Participants will be randomized in 1:1 ratios either to ticagrelor (loading dose (LD) 180 mg, maintenance dose (MD) 90 mg bid) or to clopidogrel (LD 600 mg, MD 75 mg) from 3 to 1 days before the scheduled PCI. The PCI operators will be blinded to the randomization arm. The primary endpoint is the delta (difference) between ST segment elevations (in millimeters, mm) as assessed by intracoronary electrocardiogram (ECG) during the two-step sequential coronary balloon inflation in the culprit vessel. Secondary endpoints are 1) changes in coronary flow reserve (CFR), index of microvascular resistance (IMR), and FFR measured in the culprit vessel and reference vessel at the end of PCI, and 2) angina score during inflations. This study started in 2018 with the aim of enrolling 100 patients. Based on the rate of negative FFR up to 30% and a drop-out rate up to 10%, we expect to detect an absolute difference of 4 mm among the study arms in the mean change of ST elevation following repeated balloon inflations. All study procedures were reviewed and approved by the Ethical Committee of the Catholic University of Sacred Heart.

Discussion

Ticagrelor might improve ischemia tolerance and microvascular function compared to clopidogrel, and these effects might translate to better long-term clinical outcomes.

Trial registration

EudraCT No. 2016–004746-28. No. NCT02701140. 

Trial status

Information provided in this manuscript refers to the definitive version (n. 3.0) of the study protocol, dated 31 October 2017, and includes all protocol amendments. Recruitment started on 18 September 2018 and is currently ongoing. The enrollment is expected to be completed by the end of 2019.

Trial sponsor

Fondazione Policlinico Universitario A. Gemelli – Roma, Polo di Scienze Cardiovascolari e Toraciche, Largo Agostino Gemelli 8, 00168 Rome, Italy.
Appendix
Available only for authorised users
Literature
1.
Wallentin L, Becker RC, Budaj A, Cannon CP, Emanuelsson H, Held C, et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2009;361(11):1045–57.PubMed
2.
Storey RF, Bliden KP, Patil SB, Karunakaran A, Ecob R, Butler K, et al. Incidence of dyspnea and assessment of cardiac and pulmonary function in patients with stable coronary artery disease receiving ticagrelor, clopidogrel, or placebo in the ONSET/OFFSET study. J Am Coll Cardiol. 2010;56(3):185–93.PubMed
3.
Storey RF, Becker RC, Harrington RA, Husted S, James SK, Cools F, et al. Pulmonary function in patients with acute coronary syndrome treated with ticagrelor or clopidogrel (from the Platelet Inhibition and Patient Outcomes [PLATO] pulmonary function substudy). Am J Cardiol. 2011;108(11):1542–6.PubMed
4.
van Giezen JJ, Sidaway J, Glaves P, Kirk I, Bjorkman JA. Ticagrelor inhibits adenosine uptake in vitro and enhances adenosine-mediated hyperemia responses in a canine model. J Cardiovasc Pharmacol Ther. 2012;17(2):164–72.PubMed
5.
Burki NK, Dale WJ, Lee LY. Intravenous adenosine and dyspnea in humans. J Appl Physiol (1985). 2005;98(1):180–5.
6.
Ohman J, Kudira R, Albinsson S, Olde B, Erlinge D. Ticagrelor induces adenosine triphosphate release from human red blood cells. Biochem Biophys Res Commun. 2012;418(4):754–8.PubMed
7.
Hale SL, Kloner RA. Cardioprotection with adenosine-regulating agent, GP531: effects on no-reflow, infarct size, and blood flow following ischemia/ reperfusion in the rabbit. J Cardiovasc Pharmacol Ther. 2010;15(1):60–7.PubMed
8.
Wittfeldt A, Emanuelsson H, Brandrup-Wognsen G, van Giezen JJ, Jonasson J, Nylander S, et al. Ticagrelor enhances adenosine-induced coronary vasodilatory responses in humans. J Am Coll Cardiol. 2013;61(7):723–7.PubMed
9.
Alexopoulos D, Moulias A, Koutsogiannis N, Xanthopoulou I, Kakkavas A, Mavronasiou E, et al. Differential effect of ticagrelor versus prasugrel on coronary blood flow velocity in patients with non-ST-elevation acute coronary syndrome undergoing percutaneous coronary intervention: an exploratory study. Circ Cardiovasc Interv. 2013;6(3):277–83.PubMed
10.
Tomai F, Crea F, Chiariello L, Gioffre PA. Ischemic preconditioning in humans: models, mediators, and clinical relevance. Circulation. 1999;100(5):559–63.PubMed
11.
Layland J, Carrick D, Lee M, Oldroyd K, Berry C. Adenosine: physiology, pharmacology, and clinical applications. J Am Coll Cardiol. 2014;7(6):581–91.
12.
Kloner RA, Rezkalla SH. Preconditioning, postconditioning and their application to clinical cardiology. Cardiovasc Res. 2006;70(2):297–307.PubMed
13.
Floyd JS, Maynard C, Weston P, Johanson P, Jennings RB, Wagner GS. Effects of ischemic preconditioning and arterial collateral flow on ST-segment elevation and QRS complex prolongation in a canine model of acute coronary occlusion. J Electrocardiol. 2009;42(1):19–26.PubMed
14.
Tomai F, Crea F, Gioffre PA. Preconditioning, collateral recruitment and adenosine. J Am Coll Cardiol. 2000;35(1):259–60.PubMed
15.
Yang XM, Liu Y, Cui L, Yang X, Liu Y, Tandon N, et al. Platelet P2Y(1)(2) blockers confer direct postconditioning-like protection in reperfused rabbit hearts. J Cardiovasc Pharmacol Ther. 2013;18(3):251–62.PubMed
16.
Tissier R, Cohen MV, Downey JM. Protecting the acutely ischemic myocardium beyond reperfusion therapies: Are we any closer to realizing the dream of infarct size elimination? Arch Mal Coeur Vaiss. 2007;100(9):794–802.PubMed
17.
Yang XM, Liu Y, Cui L, Yang X, Liu Y, Tandon N, et al. Two classes of anti-platelet drugs reduce anatomical infarct size in monkey hearts. Cardiovasc Drugs Ther. 2013;27(2):109–15.PubMed
18.
Furber AP, Prunier F, Nguyen HC, Boulet S, Delepine S, Geslin P. Coronary blood flow assessment after successful angioplasty for acute myocardial infarction predicts the risk of long-term cardiac events. Circulation. 2004;110(23):3527–33.PubMed
19.
Takahashi T, Hiasa Y, Ohara Y, Miyazaki S, Ogura R, Miyajima H, et al. Usefulness of coronary flow reserve immediately after primary coronary angioplasty for acute myocardial infarction in predicting long-term adverse cardiac events. Am J Cardiol. 2007;100(5):806–11.PubMed
20.
Bax M, de Winter RJ, Koch KT, Schotborgh CE, Tijssen JG, Piek JJ. Time course of microvascular resistance of the infarct and noninfarct coronary artery following an anterior wall acute myocardial infarction. Am J Cardiol. 2006;97(8):1131–6.PubMed
21.
van de Hoef TP, Bax M, Meuwissen M, Damman P, Delewi R, de Winter RJ, et al. Impact of coronary microvascular function on long-term cardiac mortality in patients with acute ST-segment-elevation myocardial infarction. Circ Cardiovasc Interv. 2013;6(3):207–15.PubMed
22.
Held EP, Henry TD. When small vessels become big problems! Microvascular dysfunction in NSTEMI. Catheter Cardiovasc Interv. 2018;92(6):1075–6.PubMed
23.
Marzilli M, Sambuceti G, Testa R, Fedele S. Platelet glycoprotein IIb/IIIa receptor blockade and coronary resistance in unstable angina. J Am Coll Cardiol. 2002;40(12):2102–9.PubMed
24.
Uren NG, Crake T, Lefroy DC, de Silva R, Davies GJ, Maseri A. Delayed recovery of coronary resistive vessel function after coronary angioplasty. J Am Coll Cardiol. 1993;21(3):612–21.PubMed
25.
Pepine CJ, Anderson RD, Sharaf BL, Reis SE, Smith KM, Handberg EM, et al. Coronary microvascular reactivity to adenosine predicts adverse outcome in women evaluated for suspected ischemia results from the National Heart, Lung and Blood Institute WISE (Women’s Ischemia Syndrome Evaluation) study. J Am Coll Cardiol. 2010;55(25):2825–32.PubMedPubMedCentral
26.
Rognoni A, Cavallino C, Lupi A, Secco GG, Veia A, Bacchini S, et al. Ticagrelor: a novel drug for an old problem. Recent Pat Cardiovasc Drug Discov. 2014;9(1):51–7.PubMed
27.
Papapanagiotou A, Daskalakis G, Siasos G, Gargalionis A, Papavassiliou AG. role of platelets in cardiovascular disease: molecular mechanisms. Curr Pharm Des. 2016;22(29):4493–505.PubMed
28.
Kubisa MJ, Jezewski MP, Gasecka A, Siller-Matula JM, Postuła M. Ticagrelor - toward more efficient platelet inhibition and beyond. Ther Clin Risk Manag. 2018;14:129–40.PubMedPubMedCentral
29.
Danielak D, Karazniewicz-Lada M, Glowka F. Ticagrelor in modern cardiology - an up-to-date review of most important aspects of ticagrelor pharmacotherapy. Expert Opin Pharmacother. 2018;19(2):103–12.PubMed
30.
Mustafa SJ, Morrison RR, Teng B, Pelleg A. Adenosine receptors and the heart: role in regulation of coronary blood flow and cardiac electrophysiology. Handb Exp Pharmacol. 2009;193:161–88.
31.
Hakeem A, Edupuganti MM, Almomani A, Pothineni NV, Payne J, Abualsuod AM, et al. Long-term prognosis of deferred acute coronary syndrome lesions based on nonischemic fractional flow reserve. J Am Coll Cardiol. 2016;68(11):1181–91.PubMed
32.
Thabane L, Ma J, Chu R, Cheng J, Ismaila A, Rios LP, et al. A tutorial on pilot studies: the what, why and how. BMC Med Res Methodol. 2010;10:1.PubMedPubMedCentral
33.
Niccoli G, Altamura L, Fabretti A, Lanza GA, Biasucci LM, Rebuzzi AG, et al. Ethanol abolishes ischemic preconditioning in humans. J Am Coll Cardiol. 2008;51(3):271–5.PubMed
34.
De Bruyne B, Pijls NHJ, Kalesan B, Barbato E, Tonino PAL, Piroth Z, et al. Fractional flow reserve–guided pci versus medical therapy in stable coronary disease. N Engl J Med. 2012;367(11):991–1001.PubMed
35.
De Luca L, Capranzano P, Patti G, Parodi G. Switching of platelet P2Y12 receptor inhibitors in patients with acute coronary syndromes undergoing percutaneous coronary intervention: Review of the literature and practical considerations. Am Heart J. 2016;176:44–52.PubMed
36.
Rollini F, Franchi F, Angiolillo DJ. Switching P2Y12-receptor inhibitors in patients with coronary artery disease. Nat Rev Cardiol. 2016;13(1):11–27.PubMed
37.
Rollini F, Franchi F, Singh K, Cho JR, Bhatti M, DeGroat C, et al. Impact of timing from blood sampling to pharmacodynamic assessment on measures of platelet reactivity in patients treated with P2Y12 receptor inhibitors. Thromb Haemost. 2016;116(6):1060–9.PubMed
38.
Park Y, Franchi F, Rollini F, Angiolillo DJ. Dual antiplatelet therapy after coronary stenting. Expert Opin Pharmacother. 2016;17(13):1775–87.PubMed
39.
Stenton C. The MRC breathlessness scale. Occup Med. 2008;58(3):226–7.
40.
Aleil B, Ravanat C, Cazenave JP, Rochoux G, Heitz A, Gachet C. Flow cytometric analysis of intraplatelet VASP phosphorylation for the detection of clopidogrel resistance in patients with ischemic cardiovascular diseases. J Thromb Haemost. 2005;3(1):85–92.PubMed
41.
Bonello L, Paganelli F, Arpin-Bornet M, Auquier P, Sampol J, Dignat-George F, et al. Vasodilator-stimulated phosphoprotein phosphorylation analysis prior to percutaneous coronary intervention for exclusion of postprocedural major adverse cardiovascular events. J Thromb Haemost. 2007;5(8):1630–6.PubMed
42.
Campo G, Valgimigli M, Frangione A, Luccarelli S, Cangiano E, Cavazza C, et al. Evaluation of platelet inhibition by tirofiban in patients stratified according to aspirin and clopidogrel responsiveness: the 3T/2R (Tailoring treatment with tirofiban in patients showing resistance to aspirin and/or resistance to clopidogrel). J Am Coll Cardiol. 2010;55(3):255–6.PubMed
43.
Friedman PL, Shook TL, Kirshenbaum JM, Selwyn AP, Ganz P. Value of the intracoronary electrocardiogram to monitor myocardial ischemia during percutaneous transluminal coronary angioplasty. Circulation. 1986;74(2):330–9.PubMed
44.
Tomai F, Crea F, Danesi A, Perino M, Gaspardone A, Ghini AS, Ruggeri G, Chiariello L, Gioffrè PA. Effects of A1 adenosine receptor blockade on the warm-up phenomenon. Cardiologia. 1997;42(4):385–92.PubMed
45.
Tomai F, Crea F, Gaspardone A, Versaci F, De Paulis R, Polisca P, Chiariello L, Gioffrè PA. Effects of A1 adenosine receptor blockade by bamiphylline on ischaemic preconditioning during coronary angioplasty. Eur Heart J. 1996;17(6):846–53.PubMed
46.
47.
De Bruyne B, Pijls NH, Smith L, Wievegg M, Heyndrickx GR. Coronary thermodilution to assess flow reserve: experimental validation. Circulation. 2001;104(17):2003–6.PubMed
48.
Pijls NH, De Bruyne B, Smith L, Aarnoudse W, Barbato E, Bartunek J, et al. Coronary thermodilution to assess flow reserve: validation in humans. Circulation. 2002;105(21):2482–6.PubMed
49.
Fearon WF, Farouque HM, Balsam LB, Caffarelli AD, Cooke DT, Robbins RC, et al. Comparison of coronary thermodilution and Doppler velocity for assessing coronary flow reserve. Circulation. 2003;108(18):2198–200.PubMed
50.
Fearon WF, Balsam LB, Farouque HM, Caffarelli AD, Robbins RC, Fitzgerald PJ, et al. Novel index for invasively assessing the coronary microcirculation. Circulation. 2003;107(25):3129–32.PubMed
51.
Layland J, Carrick D, McEntegart M, Ahmed N, Payne A, McClure J, et al. Vasodilatory capacity of the coronary microcirculation is preserved in selected patients with non-ST-segment-elevation myocardial infarction. Circ Cardiovasc Interv. 2013;6(3):231–6.PubMed
Metadata
Title
Ticagrelor and preconditioning in patients with stable coronary artery disease (TAPER-S): a randomized pilot clinical trial
Authors
D. D’Amario
A. Restivo
A. M. Leone
R. Vergallo
S. Migliaro
F. Canonico
M. Galli
C. Trani
F. Burzotta
C. Aurigemma
G. Niccoli
A. Buffon
R. A. Montone
A. Flex
F. Franceschi
G. Tinelli
U. Limbruno
F. Francese
I. Ceccarelli
J. A. Borovac
I. Porto
F. Crea
Publication date
01-12-2020
Publisher
BioMed Central
Published in
Trials / Issue 1/2020
Electronic ISSN: 1745-6215
DOI
https://doi.org/10.1186/s13063-020-4116-7

Other articles of this Issue 1/2020

Trials 1/2020 Go to the issue

Commentary

Designing process evaluations using case study to explore the context of complex interventions evaluated in trials

Study protocol

Postoperative analgesia of scalp nerve block with ropivacaine in pediatric craniotomy patients: a protocol for a prospective, randomized, placebo-controlled, double-blinded trial

Study protocol

Stuck-moving needle acupuncture myofascial trigger point to treat idiopathic frozen shoulder: study protocol for a randomized controlled trial

Study protocol

Overall adjustment acupuncture for postmenopausal osteoporosis (PMOP): a study protocol for a randomized sham-controlled trial

Study protocol

Implementing complaint-directed mini-interventions for depressive complaints in primary care to increase participation among patients with a lower socioeconomic status: design of a cluster randomised controlled trial

Study protocol

Reach out behavioral intervention for hypertension initiated in the emergency department connecting multiple health systems: study protocol for a randomized control trial