Randomized Trial Comparing the Effects of Ticagrelor Versus Clopidogrel on Myocardial Perfusion in Patients With Coronary Artery Disease

Matthieu Pelletier-Galarneau, Chad R R N Hunter, Kathryn J Ascah, Rob S B Beanlands, Girish Dwivedi, Robert A deKemp, Benjamin J W Chow, Terrence D Ruddy, Matthieu Pelletier-Galarneau, Chad R R N Hunter, Kathryn J Ascah, Rob S B Beanlands, Girish Dwivedi, Robert A deKemp, Benjamin J W Chow, Terrence D Ruddy

Abstract

Background: Ticagrelor is a P2Y12 receptor inhibitor used in acute coronary syndromes to reduce platelet activity and to decrease thrombus formation. Ticagrelor is associated with a reduction in mortality incremental to that observed with clopidogrel, potentially related to its non-antiplatelet effects. Evidence from animal models indicates that ticagrelor potentiates adenosine-induced myocardial blood flow (MBF) increases. We investigated MBF at rest and during adenosine-induced hyperemia in patients with stable coronary artery disease treated with ticagrelor versus clopidogrel.

Methods and results: This randomized double-blinded crossover study included 22 patients who received therapeutic interventions of ticagrelor 90 mg orally twice a day for 10 days and clopidogrel 75 mg orally once a day for 10 days, with a washout period of at least 10 days between the treatments. Global and regional MBF and myocardial flow reserve were measured using rubidium 82 positron emission tomography/computed tomography at baseline and during intermediate- and high-dose adenosine. Global MBF was significantly greater with ticagrelor versus clopidogrel (1.28±0.55 versus 1.13±0.47 mL/min per gram, P=0.002) at intermediate-dose adenosine and not different at baseline (0.65±0.19 versus 0.60±0.15 mL/min per gram, P=0.084) and at high-dose adenosine (1.64±0.40 versus 1.61±0.19 mL/min per gram, P=0.53). In regions with impaired myocardial flow reserve (<2.5), MBF was greater with ticagrelor compared with clopidogrel during intermediate and high doses of adenosine (P<0.0001), whereas the differences were not significant at baseline.

Conclusions: Ticagrelor potentiates global and regional adenosine-induced MBF increases in patients with stable coronary artery disease. This effect may contribute to the incremental mortality benefit compared with clopidogrel.

Clinical trial registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01894789.

Keywords: adenosine; clopidogrel; myocardial blood flow; positron emission tomography; ticagrelor.

© 2017 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.

Figures

Figure 1
Figure 1
Schematic representation of randomized crossover design. BID indicates twice a day; OD, once daily; PET, positron emission tomography.
Figure 2
Figure 2
Myocardial blood flow (MBF) polar maps of a representative patient with global MBF presented for clopidogrel and ticagrelor at baseline and during intermediate and high adenosine doses. Global MBF was not different at baseline and high‐dose adenosine, whereas it was greater at intermediate adenosine dose with ticagrelor compared with clopidogrel.
Figure 3
Figure 3
Global (A) myocardial blood flow (MBF) and (B) myocardial flow reserve (MFR) at baseline and during intermediate and high adenosine. **P<0.01. ns indicates not significant.
Figure 4
Figure 4
Regional myocardial blood flow (MBF) at baseline and during intermediate and high adenosine of regions with myocardial flow reserve (MFR)

Figure 5

Regional myocardial flow reserve (MFR)…

Figure 5

Regional myocardial flow reserve (MFR) during intermediate and high adenosine of regions with…

Figure 5
Regional myocardial flow reserve (MFR) during intermediate and high adenosine of regions with MFR <1.5 (A), ≥1.5 and <2.0 (B), ≥2.0 and <2.5 (C), ≥2.5 and <3.0 (D), ≥3.0 and <3.5 (E), and ≥3.5 (F).
Figure 5
Figure 5
Regional myocardial flow reserve (MFR) during intermediate and high adenosine of regions with MFR <1.5 (A), ≥1.5 and <2.0 (B), ≥2.0 and <2.5 (C), ≥2.5 and <3.0 (D), ≥3.0 and <3.5 (E), and ≥3.5 (F).

References

    1. Wallentin L, Becker RC, Budaj A, Cannon CP, Emanuelsson H, Held C, Horrow J, Husted S, James S, Katus H, Mahaffey KW, Scirica BM, Skene A, Steg PG, Storey RF, Harrington RA, Freij A, Thorsén M. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2009;361:1045–1057.
    1. Bonaca MP, Bhatt DL, Cohen M, Steg PG, Storey RF, Jensen EC, Magnani G, Bansilal S, Fish MP, Im K, Bengtsson O, Oude Ophuis T, Budaj A, Theroux P, Ruda M, Hamm C, Goto S, Spinar J, Nicolau JC, Kiss RG, Murphy SA, Wiviott SD, Held P, Braunwald E, Sabatine MS; PEGASUS‐TIMI 54 Steering Committee and Investigators . Long‐term use of ticagrelor in patients with prior myocardial infarction. N Engl J Med. 2015;372:1791–1800.
    1. Bonaca MP, Goto S, Bhatt DL, Steg PG, Storey RF, Cohen M, Goodrich E, Mauri L, Ophuis TO, Ruda M, Špinar J, Seung K‐B, Hu D, Dalby AJ, Jensen E, Held P, Morrow DA, Braunwald E, Sabatine MS. Prevention of stroke with ticagrelor in patients with prior myocardial infarction: insights from PEGASUS‐TIMI 54 (Prevention of Cardiovascular Events in Patients With Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin‐Thrombolysis in Myocardial Infarction 54). Circulation. 2016;134:861–871.
    1. Cannon CP, Husted S, Harrington RA, Scirica BM, Emanuelsson H, Peters G, Storey RF. Safety, tolerability, and initial efficacy of AZD6140, the first reversible oral adenosine diphosphate receptor antagonist, compared with clopidogrel, in patients with non‐ST‐segment elevation acute coronary syndrome: primary results of the DISPERSE‐2 trial. J Am Coll Cardiol. 2007;50:1844–1851.
    1. Waksman R, Maya J, Angiolillo DJ, Carlson GF, Teng R, Caplan RJ, Ferdinand KC. Ticagrelor versus clopidogrel in black patients with stable coronary artery disease. Circ Cardiovasc Interv. 2015;8:e002232.
    1. Clavijo LC, Maya J, Carlson G, Angiolillo DJ, Teng R, Caplan R, Price MJ. Platelet inhibition with ticagrelor versus clopidogrel in Hispanic patients with stable coronary artery disease with or without diabetes mellitus. Cardiovasc Revasc Med. 2015;16:450–454.
    1. Wiviott SD, Braunwald E, McCabe CH, Montalescot G, Ruzyllo W, Gottlieb S, Neumann F‐J, Ardissino D, De Servi S, Murphy SA, Riesmeyer J, Weerakkody G, Gibson CM, Antman EM. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2007;357:2001–2015.
    1. Aït Mokhtar O, Gaubert M, Laine M, Bonello L, Guieu R, Cautela J, Peyrol M, Barraud J, Thuny F, Dignat‐Georges F, Sabatier F, Fromonot J, Rossi P, Paganelli F. Pleiotropic effects of ticagrelor: myth or reality? Arch Cardiovasc Dis. 2016;109:445–448.
    1. van Giezen JJJ, Sidaway J, Glaves P, Kirk I, Björkman J‐A. Ticagrelor inhibits adenosine uptake in vitro and enhances adenosine‐mediated hyperemia responses in a canine model. J Cardiovasc Pharmacol Ther. 2012;17:164–172.
    1. Wittfeldt A, Emanuelsson H, Brandrup‐Wognsen G, van Giezen JJJ, Jonasson J, Nylander S, Gan L‐M. Ticagrelor enhances adenosine‐induced coronary vasodilatory responses in humans. J Am Coll Cardiol. 2013;61:723–727.
    1. Alexopoulos D, Moulias A, Koutsogiannis N, Xanthopoulou I, Kakkavas A, Mavronasiou E, Davlouros P, Hahalis G. 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;6:277–283.
    1. Bonello L, Laine M, Kipson N, Mancini J, Helal O, Fromonot J, Gariboldi V, Condo J, Thuny F, Frere C, Camoin‐Jau L, Paganelli F, Dignat‐George F, Guieu R. Ticagrelor increases adenosine plasma concentration in patients with an acute coronary syndrome. J Am Coll Cardiol. 2014;63:872–877.
    1. Fromonot J, Dignat‐Georges F, Rossi P, Mottola G, Kipson N, Ruf J, Bonello L, Guieu R, Paganelli F. Ticagrelor improves peripheral arterial function in acute coronary syndrome patients relationship with adenosine plasma level. J Am Coll Cardiol. 2016;67:1967–1968.
    1. Gerczuk PZ, Kloner RA. An update on cardioprotection: a review of the latest adjunctive therapies to limit myocardial infarction size in clinical trials. J Am Coll Cardiol. 2012;59:969–978.
    1. Efseaff M, Klein R, Ziadi MC, Beanlands RS, deKemp RA. Short‐term repeatability of resting myocardial blood flow measurements using rubidium‐82 PET imaging. J Nucl Cardiol. 2012;19:997–1006.
    1. deKemp RA, Declerck J, Klein R, Pan X‐B, Nakazato R, Tonge C, Arumugam P, Berman DS, Germano G, Beanlands RS, Slomka PJ. Multisoftware reproducibility study of stress and rest myocardial blood flow assessed with 3D dynamic PET/CT and a 1‐tissue‐compartment model of 82Rb kinetics. J Nucl Med. 2013;54:571–577.
    1. Kaufmann PA, Gnecchi‐Ruscone T, Yap JT, Rimoldi O, Camici PG. Assessment of the reproducibility of baseline and hyperemic myocardial blood flow measurements with 15O‐labeled water and PET. J Nucl Med. 1999;40:1848–1856.
    1. Cerqueira MD, Weissman NJ, Dilsizian V, Jacobs AK, Kaul S, Laskey WK, Pennell DJ, Rumberger JA, Ryan T, Verani MS. Standardized myocardial segmentation and nomenclature for tomographic imaging of the heart. A statement for healthcare professionals from the Cardiac Imaging Committee of the Council on Clinical Cardiology of the American Heart Association. Circulation. 2002;105:539–542.
    1. Altman DG. Practical Statistics for Medical Research. New York: CRC Press; 1990.
    1. Wilson RF, Wyche K, Christensen BV, Zimmer S, Laxson DD. Effects of adenosine on human coronary arterial circulation. Circulation. 1990;82:1595–1606.
    1. Prior JO, Allenbach G, Valenta I, Kosinski M, Burger C, Verdun FR, Bischof Delaloye A, Kaufmann PA. Quantification of myocardial blood flow with 82Rb positron emission tomography: clinical validation with 15O‐water. Eur J Nucl Med Mol Imaging. 2012;39:1037–1047.
    1. Cattaneo M, Schulz R, Nylander S. Adenosine‐mediated effects of ticagrelor: evidence and potential clinical relevance. J Am Coll Cardiol. 2014;63:2503–2509.
    1. Barletta KE, Ley K, Mehrad B. Regulation of neutrophil function by adenosine. Arterioscler Thromb Vasc Biol. 2012;32:856–864.
    1. Johnston‐Cox HA, Yang D, Ravid K. Physiological implications of adenosine receptor‐mediated platelet aggregation. J Cell Physiol. 2011;226:46–51.
    1. Ely SW, Berne RM. Protective effects of adenosine in myocardial ischemia. Circulation. 1992;85:893–904.
    1. Gross GJ, Hardman HF, Warltier DC. Adenosine on myocardial oxygen consumption. Br J Pharmacol. 1976;57:409–412.
    1. Liang BT, Jacobson KA. A physiological role of the adenosine A3 receptor: sustained cardioprotection. Proc Natl Acad Sci USA. 1998;95:6995–6999.
    1. Stoller M, Seiler C. Pathophysiology of Coronary Collaterals. Curr Cardiol Rev. 2014;10:38‐56.

Source: PubMed

Sponsors and Collaborators

Medical Conditions

Drug Interventions

3
Subscribe