International Journal of Cardiology 192 (2015) 1113

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International Journal of Cardiology

journal homepage: www.elsevier.com/locate/ijcard

Letter to the Editor

Ticagrelor-related gout: An underestimated side effect

Nixiao Zhang, Zhiwei Zhang, Yajuan Yang, Yanmin Xu, Guangping Li, Tong Liu
Tianjin Key Laboratory of Ionic-Molecular Function of Cardiovascular disease, Department of Cardiology, Tianjin Institute of Cardiology, Second Hospital of Tianjin Medical University,
Tianjin 300211, People's Republic of China

a r t i c l e

i n f o

Article history:
Received 4 May 2015
Accepted 6 May 2015
Available online 8 May 2015
Keywords:
Ticagrelor
Gout
Hyperuricemia
Uric acid
Side effect

Dual antiplatelet therapy with aspirin and a P2Y12 receptor blocker,

has been recognized as the standard therapy in patients with acute
coronary syndrome (ACS) and following percutaneous coronary intervention. Ticagrelor, a novel direct, reversibly binding P2Y12 antagonist,
has better pharmacodynamic effects and improves clinical outcomes
compared with clopidogrel in the setting of ACS [1,2]. However,
ticagrelor-related dyspnea [35] and bradyarrhythmias have been observed in the PLATO trial [6] and real world ACS patients, and may
lead to drug discontinuation. Gaubert et al. [7] demonstrated that
ticagrelor-related dyspnea is a major cause of drug discontinuation during one-month follow-up period. In addition, re-hospitalization because
of drug-correlated dyspnea accounts for 2% of the study population.
Adenosine concentration levels or this reversible P2Y12 antagonist
acting on sensory neurons may play a signicant role in ticagrelorrelated dyspnea. Besides, ticagrelor may cause bradyarrhythmias in
the PLATO trial [8] and may induce complete atrioventricular block [9]
and sinus node dysfunction [10] in some case reports. However, no
difference in terms of incidence of clinically bradycardia events (syncope, sudden death, cardiac arrest or pacemaker placement) was observed
in the PLATO trial [8].
Very recent published data from the PEGASUS-TIMI54 trial [11]
indicates that long term use of ticagrelor may increase the incidence
of gout in patients with prior myocardial infarction. The PEGASUS-

Corresponding author at: Department of Cardiology, Tianjin Institute of Cardiology,

Second Hospital of Tianjin Medical University, Tianjin 300211, People's Republic of China.
E-mail address: liutongdoc@126.com (T. Liu).

http://dx.doi.org/10.1016/j.ijcard.2015.05.023
0167-5273/ 2015 Elsevier Ireland Ltd. All rights reserved.

TIMI54 trial randomly assigned 21,162 patients who had a prior myocardial infarction 1 to 3 years earlier to ticagrelor at a dose of 90 mg
twice daily, ticagrelor at a dose of 60 mg twice daily, or placebo. All
the patients were to receive low-dose aspirin and were followed up
for a median of 33 months. The results showed that ticagrelor signicantly decreased the risk of cardiovascular death, myocardial infarction
or stroke during a 33-month follow-up. Besides, the investigators also
found that the long term use of ticagrelor was associated with dosedependent 1.481.77 fold increased risk of gout compared with placebo.
Actually, the previous PLATO trial has also shown that the increases of
mean serum uric acid levels from baseline values were 14% and 15% at
1 and 12 months respectively following the ticagrelor treatment compared with clopidogrel, but there was no difference regarding the incidence of gout/gouty arthritis over time between the two groups [6].
To the best of our knowledge, ticagrelor-related gout was not systematically reviewed in the literature. In this letter to the editor, we intend to
discuss the potential mechanisms regarding ticagrelor-related gout and
propose some suggestions for the prevention of this underestimated
side effect during long term use of ticagrelor.
Gout is termed as hyperuricemia accompanied with acute arthritis,
tophus, chronic arthritis, joint deformity, chronic interstitial nephritis
and uric acid stones, which is more prevalent in males more than
40 years old and goes through three stages (asymptomatic period,
acute arthritis period, tophus/chronic arthritis) [12,13]. Purine or adenosine is converted to hypoxanthine, then is metabolized to xanthine and
ultimately uric acid. The normal value of serum uric acid is 149
416 mol/L in males and 89357 mol/L in females. Exceeding this
level may result in uric acid crystallization and clinical symptoms, just
like gout/gouty arthritis. Sudden onset of gouty arthritis mainly results
from a rapid rise or fall in serum uric acid, as well as inammation
caused by uric acid crystallization.
Ticagrelor, as a reversibly binding P2Y12 receptor antagonist, is
rapidly absorbed [14] and metabolized [15]. AR-C124910XX, the major
metabolite which it rapidly formed, has a potency approximately
equal to that of ticagrelor [16], but with a little difference existing as
well. Ticagrelor is not required for hepatic metabolization [17], it is
often metabolized in the kidneys. Therefore, the high renal serum
drug concentration may inuence the renal function so as to interfere
with the ltration, absorption, uptake and secretion of uric acid. Several
renal urate transporters are involved in this process [18] (Fig. 1).
Ticagrelor and its metabolite AR-C124910XX have weak inhibitory
effects on urate transporter 1 (URAT1), while AR-C124910XX alone is
reported to restrain Xenopus oocytes expressing organic ion transporter
(OAT)1 but not ticagrelor [16]. Importantly, OAT3 expressed in Xenopus

12

N. Zhang et al. / International Journal of Cardiology 192 (2015) 1113

Fig. 1. Uric acid metabolism in proximal tubules. URAT1: urate transporter 1; OAT4: organic ion transporter 4; MRP4: adenosine-5-triphosphate-dependent urate export transporter;
OAT1: organic ion transporter 1; OAT3: organic ion transporter 3.

oocytes is conrmed to be inhibited by both ticagrelor and ARC124910XX. Therefore, it is reasonable to assume that OAT3 is a probable transporter involved in hyperuricemia and gout related to ticagrelor.
Reabsorption of uric acid is regulated by urate transporter 1 (URAT1)
[19] and organic ion transporter (OAT)4 [20] in the apical membrane
of proximal tubules. The uptake of blood urate into proximal tubules
goes through OAT1 [21] and OAT3 [22] in the basolateral membrane.
Moreover, the secretion of uric acid lies on an adenosine-5-triphosphate-dependent urate export transporter (MRP4) [23] in the apical
membrane (Fig. 1). The decline in renal urate clearance cannot be
neglected as well [24]. On the other hand, when uric acid synthesis increases, the incidence of gout changes correspondingly. Under normal
circumstances, adenosine can be transported into erythrocytes or
other cells by plasma membrane nucleoside transporters to form hypoxanthine or adenosine triphosphate (ATP) [25,26] (Fig. 2). Ticagrelor
and its metabolite have negative effects on such transporters, with the
adenosine from extracellular/blood vessels increasing in response to ischemia, hypoxia and inammation. The inhibitory effects of ticagrelor
on the cellular uptake of adenosine, in addition to antagonizing the
P2Y12 receptor, is sufcient to increase the circulating levels of adenosine in patients with ACS, which may partly explain its advantageous effects in clinical outcomes compared with other P2Y12 receptor blockers
[27]. Consequently, the elevated level of adenosine in extracellular/
blood vessels may further increase uric acid synthesis, which was fortied by tissue with high levels of xanthine oxidase, such as those from
the liver, kidney and small intestines [28].
In conclusion, ticagrelor-related gout is an underestimated side
effect during long term use of ticagrelor. We recommend that clinicians
assess serum uric acid levels regularly and pay more attention to
the possible symptoms of gout during long term administration of
ticagrelor, especially in patients with hyperuricemia. Also, we need to
educate our patients on ticagrelor to avoid a number of foodstuffs
which are risk factors for gout, including sugar sweetened beverages,
alcohol, red meat, seafood, and fruit juice [12].

Conicts of interest
None.
Financial disclosures
None.
Acknowledgment
The authors of this manuscript have certied that they comply with
the Principles of Ethical Publishing in the International Journal of
Cardiology.
References
[1] S. De Servi, C. Cavallini, S. Leonardi, M. Ferlini, Prasugrel and ticagrelor compared to
clopidogrel in non-st-segment elevation acute coronary syndromes undergoing percutaneous coronary interventions: certainties and uncertainties, Int. J. Cardiol. 181
(2015) 443445.
[2] L. Bonello, C. Frere, S. Cointe, M. Laine, J. Mancini, F. Thuny, et al., Ticagrelor increases
endothelial progenitor cell level compared to clopidogrel in acute coronary
syndromes: a prospective randomized study, Int. J. Cardiol. 187 (2015) 502507.
[3] M.J. Sanchez-Galian, P.J. Flores-Blanco, A. Lopez-Cuenca, M. Gomez-Molina, E.
Guerrero-Perez, F. Cambronero-Sanchez, et al., Ticagrelor related dyspnea in patients with acute coronary syndromes: incidence and implication on ticagrelor
withdrawn, Int. J. Cardiol. 187 (2015) 517518.
[4] N. Lombardi, M.C. Lenti, R. Matucci, A. Mugelli, A. Vannacci, Ticagrelor-related
dyspnea: an underestimated and poorly managed event? Int. J. Cardiol. 179
(2015) 238239.
[5] H. Wu, Q. Wang, J. Zhou, J. Qian, J. Ge, First report of stent thrombosis after a switch
therapy resulting from ticagrelor-related dyspnea, Int. J. Cardiol. 176 (2014)
e127e128.
[6] L. Wallentin, R.C. Becker, A. Budaj, C.P. Cannon, H. Emanuelsson, C. Held, et al.,
Ticagrelor versus clopidogrel in patients with acute coronary syndromes, N. Engl.
J. Med. 361 (2009) 10451057.
[7] M. Gaubert, M. Laine, T. Richard, N. Fournier, C. Gramond, J. Bessereau, et al., Effect of
ticagrelor-related dyspnea on compliance with therapy in acute coronary syndrome
patients, Int. J. Cardiol. 173 (2014) 120121.

Fig. 2. Adenosine transformation. Plasma membrane nucleoside transporter; AMP: adenosine monophosphate; ATP: adenosine triphosphate.

N. Zhang et al. / International Journal of Cardiology 192 (2015) 1113

[8] B.M. Scirica, C.P. Cannon, H. Emanuelsson, E.L. Michelson, R.A. Harrington, S. Husted,
et al., The incidence of bradyarrhythmias and clinical bradyarrhythmic events in
patients with acute coronary syndromes treated with ticagrelor or clopidogrel in
the PLATO (platelet inhibition and patient outcomes) trial: results of the continuous
electrocardiographic assessment substudy, J. Am. Coll. Cardiol. 57 (2011)
19081916.
[9] A. Goldberg, I. Rosenfeld, I. Nordkin, M. Halabi, Life-threatening complete atrioventricular block associated with ticagrelor therapy, Int. J. Cardiol. 182 (2015) 379380.
[10] M. Nicol, J. Deblaise, R. Choussat, O. Dubourg, N. Mansencal, Side effects of ticagrelor:
sinus node dysfunction with ventricular pause, Int. J. Cardiol. (2015) (Epub ahead of
print).
[11] M.P. Bonaca, D.L. Bhatt, M. Cohen, P.G. Steg, R.F. Storey, E.C. Jensen, et al., Long-term
use of ticagrelor in patients with prior myocardial infarction, N. Engl. J. Med. 372
(2015) 17911800.
[12] P.C. Robinson, Horsburgh S. Gout, Joints and beyond, epidemiology, clinical features,
treatment and co-morbidities, Maturitas 78 (2014) 245251.
[13] J. He, Y. Yang, D.Q. Peng, Monosodium urate (MSU) crystals increase gout associated
coronary heart disease (CHD) risk through the activation of nlrp3 inammasome,
Int. J. Cardiol. 160 (2012) 7273.
[14] R.F. Storey, S. Husted, R.A. Harrington, S. Heptinstall, R.G. Wilcox, G. Peters, et al.,
Inhibition of platelet aggregation by azd6140, a reversible oral P2Y12 receptor
antagonist, compared with clopidogrel in patients with acute coronary syndromes,
J. Am. Coll. Cardiol. 50 (2007) 18521856.
[15] R. Teng, S. Oliver, M.A. Hayes, K. Butler, Absorption, distribution, metabolism, and
excretion of ticagrelor in healthy subjects, Drug Metab. Dispos. 38 (2010)
15141521.
[16] K. Butler, R. Teng, Evaluation and characterization of the effects of ticagrelor on
serum and urinary uric acid in healthy volunteers, Clin. Pharmacol. Ther. 91
(2012) 264271.
[17] S. Husted, H. Emanuelsson, S. Heptinstall, P.M. Sandset, M. Wickens, G. Peters, Pharmacodynamics, pharmacokinetics, and safety of the oral reversible P2Y12 antagonist
azd6140 with aspirin in patients with atherosclerosis: a double-blind comparison to
clopidogrel with aspirin, Eur. Heart J. 27 (2006) 10381047.

13

[18] M.A. Hediger, R.J. Johnson, H. Miyazaki, H. Endou, Molecular physiology of urate
transport, Physiology (Bethesda) 20 (2005) 125133.
[19] A. Enomoto, H. Kimura, A. Chairoungdua, Y. Shigeta, P. Jutabha, S.H. Cha, et al.,
Molecular identication of a renal urate anion exchanger that regulates blood
urate levels, Nature 417 (2002) 447452.
[20] Y. Hagos, D. Stein, B. Ugele, G. Burckhardt, A. Bahn, Human renal organic anion
transporter 4 operates as an asymmetric urate transporter, J. Am. Soc. Nephrol. 18
(2007) 430439.
[21] K. Ichida, M. Hosoyamada, H. Kimura, M. Takeda, Y. Utsunomiya, T. Hosoya, et al.,
Urate transport via human PAH transporter HOAT1 and its gene structure, Kidney
Int. 63 (2003) 143155.
[22] A. Bakhiya, A. Bahn, G. Burckhardt, N. Wolff, Human organic anion transporter 3
(HOAT3) can operate as an exchanger and mediate secretory urate ux, Cell.
Physiol. Biochem. 13 (2003) 249256.
[23] R.A. Van Aubel, P.H. Smeets, J.J. van den Heuvel, F.G. Russel, Human organic anion
transporter mrp4 (ABCC4) is an efux pump for the purine end metabolite urate
with multiple allosteric substrate binding sites, Am. J. Physiol. Ren. Physiol. 288
(2005) F327F333.
[24] S. Khamdang, M. Takeda, R. Noshiro, S. Narikawa, A. Enomoto, N. Anzai, et al., Interactions of human organic anion transporters and human organic cation transporters
with nonsteroidal anti-inammatory drugs, J. Pharmacol. Exp. Ther. 303 (2002)
534539.
[25] R.W. Li, C. Yang, A.S. Sit, S.Y. Lin, E.Y. Ho, G.P. Leung, Physiological and pharmacological roles of vascular nucleoside transporters, J. Cardiovasc. Pharmacol. 59 (2012)
1015.
[26] M. Lofer, J.C. Morote-Garcia, S.A. Eltzschig, I.R. Coe, H.K. Eltzschig, Physiological
roles of vascular nucleoside transporters, Arterioscler. Thromb. Vasc. Biol. 27
(2007) 10041013.
[27] M. Cattaneo, R. Schulz, S. Nylander, Adenosine-mediated effects of ticagrelor:
evidence and potential clinical relevance, J. Am. Coll. Cardiol. 63 (2014) 25032509.
[28] R. Harrison, Structure and function of xanthine oxidoreductase: where are we now?
Free Radic. Biol. Med. 33 (2002) 774797.