Drug Evaluation
Ticagrelor for the treatment of peripheral arterial disease Aun-Yeong Chong & Derek Y So† 1.
Introduction
2.
Current recommended antithrombotic treatment in
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PAD 3.
Introduction to the compound
4.
Pharmacodynamics
5.
Pharmacokinetics and metabolism
6.
Clinical efficacy
7.
Safety and tolerability
8.
Conclusion
9.
Expert opinion
University of Ottawa Heart Institute, Division of Cardiology, Department of Medicine, Ontario, Canada
Introduction: Peripheral arterial disease (PAD) is a manifestation, and marker of severity, of a generalized atherosclerotic process. Antiplatelet therapy is recommended to prevent cardiovascular events but much of the evidence to support this is drawn from studies on older drugs. Areas covered: In this review, the authors discuss the available evidence for the basis of current recommendations and review the data from Phase I to III trials on ticagrelor as a potential future treatment. This paper also reviews the properties of ticagrelor, its adverse effects, and how it differs from current recommended antiplatelet agents. As it is also more potent, a personalized approach to antiplatelet therapy may prove useful. It further highlights the additional effects of ticagrelor mediated by adenosine and their potential benefits, which may provide an explanation to its superior outcomes in trials comparing it with clopidogrel. Expert opinion: Although there is a current lack of evidence to support the use of ticagrelor in patients with PAD, its unique pleomorphic properties make it attractive for future investigations and development of similar drugs. Keywords: adenosine, antiplatelet, atherosclerosis, peripheral arterial disease, ticagrelor Expert Opin. Investig. Drugs (2014) 23(12):1737-1743
1.
Introduction
Peripheral arterial disease (PAD), coronary artery disease (CAD) and cerebrovascular disease (CVD) are predominantly manifestations of atherosclerosis, a systemic process beginning in the second decade of life. Early studies such as the international REduction of Atherothrombosis for Continued Health (REACH) Registry and Clopidogrel and Aspirin versus Aspirin Alone for the Prevention of Atherothrombotic Events (CHARISMA) show that the presence of PAD, among patients with CAD, CVD or multiple risk factors, is associated with a worse outcome [1,2]. Conversely, the presence of PAD per se in patients is associated with a > 50% chance of myocardial ischemia [3,4], thereby reflecting PAD as a marker for severity of coronary atherosclerosis. Of note, even in the absence of other established cardiovascular disease, patients with PAD remain at higher risk of all-cause mortality [5]. In this review, the authors will discuss the current evidence for the use of the more established antiplatelets in PAD and explore the potential role for the novel antiplatelet agent, ticagrelor. 2.
Current recommended antithrombotic treatment in PAD
The ACC/AHA guidelines for the management of patients with PAD focused recommendations to the abdominal aorta, renal and mesenteric arteries and lower extremity arteries based on the robust evidence. Due to the nature of the disease process, the pharmacological management of PAD expectedly targets risk factor management and progression of atherosclerosis, with clinical impact upon cardiovascular ischemic events such as myocardial infarction (MI), ischemic stroke and 10.1517/13543784.2014.974803 © 2014 Informa UK, Ltd. ISSN 1354-3784, e-ISSN 1744-7658 All rights reserved: reproduction in whole or in part not permitted
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Box 1. Drug Summary. Drug name Phase Indication
Route of administration Chemical structure
Ticagrelor III Reduction of cardiovascular events in patients with peripheral arterial disease Oral Cyclopentyl-triazolopyrimidine F HN N
N
N
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HO
O
HO
Pivotal trial(s)
N
N
F S
OH
[25,26]
death [6,7]. Indeed, the 2011 ACCF/AHA focused update recommends antiplatelet therapy to patients with symptomatic atherosclerotic lower extremity PAD to reduce the risk of MI, stroke and vascular death. The recommendation specifies aspirin at doses of 75 -- 325 mg daily, or clopidogrel 75 mg daily as alternative for patients contraindicated to aspirin therapy. The guidelines also supported the possible use of dual antiplatelet therapy with aspirin and clopidogrel for patients at high perceived cardiovascular risk who have low risk for bleeding, with a weaker recommendation [7,8]. Antiplatelet therapy may also be considered in asymptomatic patients with an ankle-brachial index (ABI) £ 0.90 [7,8]. With the absence of robust data, novel antiplatelet agents, such as prasugrel or ticagrelor, were not recommended in these PAD guidelines. PAD should be regarded as a marker of the severity of atherosclerosis and increased risk for atherosclerotic plaque rupture. Therefore, the aim for antithrombotic treatment in PAD is focused on the reduction of thrombotic events in predominantly, the coronary and cerebrovascular beds. Accordingly, almost all published studies of antithrombotic therapy in PAD define outcome measures as a combination of coronary and cerebrovascular-related mortality and morbidity. Few studies of antiplatelet in PAD actually specify the development of critical limb ischemia, peripheral arterial revascularization or amputation as components of the primary endpoint, except for studies on endovascular treatment. Aspirin in PAD The early Antithrombotic Trialists’ Collaboration metaanalysis in 2002 of antiplatelet therapy in high-risk patients demonstrated a 23% reduction in serious vascular events in the subgroup of patients with PAD [9]. This served as the basis for routine use of aspirin in patients with PAD. However, more recent meta-analyses on the role of aspirin in PAD have called into question its perceived benefit [5,10]. The 2.1
1738
Prevention of Progression of Asymptomatic Diabetic Arterial Disease and Aspirin for Asymptomatic Atherosclerosis trials enrolled asymptomatic patients from population screening using ABI thresholds of 0.99 and 0.95, respectively, drawing criticism that only low-risk patients were recruited, despite the presence of diabetes mellitus [5]. Therefore it should not be surprising, that in these lower risk cohorts with preclinical PAD, that aspirin did not show a significant reduction in vascular events. This is also consistent with recent findings on patients with asymptomatic CAD. Similarly, in the JPAD study (Japanese Primary Prevention of Atherosclerosis with Aspirin for Diabetes), treatment with aspirin did not prevent vascular events over a 5-year follow-up period [11]. On the contrary, the small Critical Leg Ischemia Prevention Study, which enrolled high-risk patients defined by the symptomatic or asymptomatic with ABI < 0.85, showed a significant reduction in major vascular events and critical leg ischemia with low-dose aspirin (100 mg daily) compared to antioxidant vitamins. However, the study was prematurely terminated due to poor recruitment, with only 366 patients randomized out of the planned sample size of 2000 [12]. The small sample size, with only 210 patients completing follow-up at 2 years, therefore precludes definitive conclusions on its true influence on cardiovascular outcomes. Hence, the 2011 updated ACCF/AHA guidelines continue to recommend the use of aspirin only in symptomatic PAD. Clopidogrel in PAD The evidence for the use of clopidogrel in patients with PAD stems from subgroup analyses of two early trials -- Clopidogrel versus Aspirin in Patients at Risk of Ischemic Events (CAPRIE) and CHARISMA. In CAPRIE, approximately a third of the patients had PAD and clopidogrel use in this subgroup was associated with a statistically significant 23.8% relative reduction in the combined endpoint of ischemic stroke, MI, or vascular death compared to aspirin. Subsequent to this, CHARISMA studied patients at high risk for atherothrombotic events and compared dual antiplatelet therapy with aspirin and clopidogrel versus aspirin alone. The study showed an overall non-significant 7.1% relative risk reduction in MI, stroke or cardiovascular death. However, a post hoc analysis of higher risk patients, with documented prior MI, ischemic stroke or symptomatic PAD, suggested potential clinical benefit of dual antiplatelet therapy in this group [13]. A subsequent subgroup analysis of 3096, symptomatic and asymptomatic, PAD patients included in CHARISMA showed that dual antiplatelet therapy reduced the rate of MI and hospitalization for ischemic events at the risk of increased minor bleeding [14]. As the overall evidence for dual antiplatelet therapy is underwhelming, current recommendations from the American College of Chest Physicians Evidence-Based Clinical Practice Guidelines still favor single antiplatelet therapy for primary and secondary prevention of cardiovascular 2.2
Expert Opin. Investig. Drugs (2014) 23(12)
Ticagrelor
events in patients with asymptomatic or symptomatic PAD, even for patients undergoing peripheral artery percutaneous transluminal angioplasty with stenting [15]; the last recommendation is in contradistinction to coronary artery stenting, where dual antiplatelet therapy is recommended.
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3.
Introduction to the compound
Ticagrelor (Box 1), a cyclopentyltriazolopyrimidine, is a novel class of platelet P2Y12 receptor inhibitor, with proven clinical efficacy in patients with CAD, presenting with acute coronary syndromes (ACS). Ticagrelor also inhibits adenosine reuptake by erythrocytes and increases the plasma level of adenosine [16]. Adenosine-mediated effects of ticagrelor may confer additional benefits (and adverse effects) beyond that of P2Y12 inhibition alone. 4.
Pharmacodynamics
Ticagrelor has a theoretical advantage over thienopyridines, as it does not require biotransformation to an active metabolite and thus achieve a more rapid onset of action. The ONSET--OFFSET study confirmed that a loading dose of 180 mg ticagrelor had more rapid platelet inhibition compared to 600 mg clopidogrel with 41% inhibition versus 8% inhibition respectively at 30 min [17]. This trend continues to 2 h with 90% of patients receiving ticagrelor achieving > 70% platelet inhibition compared to just 16% of patients receiving clopidogrel. Following the last dose, the antiplatelet effect of ticagrelor also declined more rapidly compared to clopidogrel. As it does not require any biotransformation, it is also less susceptible to interactions with other drugs dependent on CYP metabolism. Of note, pharmacodynamic response to clopidogrel among carriers of the common CYP2C19 loss-of-function alleles can be blunted [18]. Carriers of these alleles have increased cardiovascular events compared to non-carriers when treated with clopidogrel [19]. In contrast, ticagrelor’s effects are independent of the influence of CYP2C19 loss-of-function alleles [20], thereby suggesting applicability for clinical use on a more universal basis. There were concerns in the PLatelet inhibition And patienT Outcomes (PLATO) trial that the effects observed in North Americans were divergent compared to others around the world [21]. In PLATO, a prespecified subgroup analysis showed a significant interaction between treatment and region (p = -0.045), with less effect of ticagrelor in North America than in the rest of the world. Two independently performed analyses identified a statistical interaction with aspirin maintenance dose as a possible explanation for the regional difference. The lowest risk of cardiovascular death, MI, or stroke was associated with a low maintenance dose of concomitant aspirin [21].
5.
Pharmacokinetics and metabolism
Ticagrelor is an oral, direct acting, reversible inhibitor of the ADP P2Y12 receptor with unique pharmacokinetic properties. It has rapid onset and offset, while at the same time conferring increased potency compared to clopidogrel. The Tmax of ticagrelor is ~ 2 h [22] with a plasma half life of ~ 8 h [23]. It is metabolized in the liver by CYP3A4 enzyme to produce the equally active metabolite AR-C124910XX. At steady state, this metabolite is present at ~ 1/3 of the concentration of the parent drug in the circulation. No dose adjustment is necessary for patients with renal failure as elimination of both ticagrelor and AR-C124910XX occurs primarily via hepatic metabolism and biliary excretion [24]. 6.
Clinical efficacy
The PLATO trial recruited 18624 patients with ACS and showed that compared to clopidogrel, ticagrelor significantly reduced the composite endpoint of vascular mortality, MI, or stroke [25]. Of particular interest for clinicians was the surprising significant reduction in overall mortality observed in the study. Overall major bleeding was not significantly different when compared to clopidogrel, but there was an increase in the rate of major bleeding among patients treated medically or those who underwent percutaneous coronary interventions [25]. This overall absence in increased major bleeding observed in the PLATO study was likely attributed to the lack of increased bleeding for patients undergoing coronary artery bypass graft surgery (CABG) as the majority of these patients had cessation of ticagrelor days before undergoing CABG. This may be especially relevant in PAD patients, who are already at increased risk of bleeding. Indeed, in a post-hoc analysis of PLATO, patients with PAD (n = 1144) were shown to have significantly higher rates of death from vascular cause, MI or stroke (19.3 vs 10.2%) and major bleeding compared to patients without PAD [26]. Within the PAD group, death from vascular cause, MI or stroke was numerically lower in the ticagrelor group compared to clopidogrel, with numerically lower risk in major bleeding [26]. These key findings were consistent with the overall trial results but did not reach statistical significance as the subgroup analysis was too small. However, it would appear reassuring that despite the significantly higher risk of bleeding in PAD patients, ticagrelor, being the more potent P2Y12 inhibitor, reduced the cardiovascular events without concurrently increasing the risk of major bleeding. If confirmed in prospective future studies, this would result in a very favorable risk:benefit ratio. 7.
Safety and tolerability
The safety and tolerability of ticagrelor was tested in various Phase I and II trials. In Phase I trials, ticagrelor was tested
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Table 1. Relevant studies of ticagrelor. Study PLATO*
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PLATO subgroup analysisz
EUCLID
DISPERSE
DISPERSE-2
Design Randomized double blind prospective study; ticagrelor 180 mg bolus followed by 90 mg b.i.d. vs clopidogrel 300 mg bolus followed by 75 mg daily Subgroup analysis of patients with PAD -- self-reported or captured on eCRF but not confirmed by objective testing at the time of enrolment Randomized double-blind prospective study; ticagrelor 90 mg b.i.d. vs clopidogrel 75 mg daily Randomized double-blind prospective study; ticagrelor 50 mg b.i.d. vs 100 mg b.i.d. vs 200 mg b.i.d. vs 400 mg daily vs clopidogrel 75 mg daily for 28 days in addition to aspirin 75 -- 100 mg daily Randomized double-blind prospective study; ticagrelor 90 mg b.i.d. vs ticagrelor 180 mg b.i.d. vs copidogrel 300 mg bolus followed by 75 mg daily
n
Patient population
Primary measures
18624
ACS
Composite of death from vascular causes, MI or stroke
1144
ACS and PAD
Composite of death from vascular causes, MI or stroke
13500
PAD
Cardiovascular death, MI and ischemic stroke (results awaited)
200
Atherosclerosis
Final extent and maximal extent of platelet aggregation at multiple time points
990
Non-ST elevation acute coronary syndrome
Major and minor bleeding through 4 weeks
*Landmark study as in bibliography. z Subgroup analysis as in bibliography. ACS: Acute coronary syndrome; b.i.d.: Twice daily; MI: Myocardial infarction; PAD: Peripheral arterial disease; PLATO: PLatelet inhibition And patienT Outcomes.
in healthy volunteers in dosage of 50 -- 600 mg daily or 50 -- 300 mg twice daily (b.i.d.). This showed that the pharmacokinetics of ticagrelor is predictable and is associated with consistent platelet inhibition. However, twice daily administration achieved greater platelet inhibition than once daily (q.d.) [27]. The Phase II DISPERSE study evaluated 50, 100, 200 mg b.i.d. or 400 mg q.d. administration of ticagrelor and demonstrated the safety and tolerability profile, with superior efficacy to clopidogrel 75 mg daily [28]. This was then followed by DISPERSE (Dose confIrmation Study assessing anti-Platelet Effects of AZD6140 vs. clopidogRel in non-ST-segment Elevation MI)-2, a dose confirmation study in non-ST-elevation MI patients. This study showed that ticagrelor 180 mg b.i.d. was associated with increased minor bleeds compared to ticagrelor 90 mg b.i.d. and clopidogrel 75 mg daily [29]. The latter dose was then tested in the seminal Phase III PLATO trial [25]. In PLATO, dyspnea was observed in 13.8% of patients receiving ticagrelor compared to 7.8% of patients receiving clopidogrel [25]. This resulted in 0.9% of patients discontinuing ticagrelor compared to 0.1% of patients discontinuing clopidogrel. For patients with PAD, many of whom have longstanding smoking history and pre-existing chronic airways disease, the effects of the ticagrelor-mediated dyspnea may make 1740
tolerability of the drug different compared to those presenting with ACS in PLATO. Accordingly, the true effects of these potential side effects will require ratification as Phase III studies on ticagrelor among PAD patients are carried out. Other adverse events observed in the PLATO study included a higher incidence of ventricular pauses in the first week but not at day 30 in the ticagrelor group. These pauses were rarely associated with symptoms and there was no significant difference with respect to syncope or pacemaker implantation. The levels of creatinine and uric acid also increased slightly more during the treatment period with ticagrelor versus clopidogrel. 8.
Conclusion
All the relevant clinical studies can be found in Table 1. There has been no prospective randomized data investigating ticagrelor in patients with PAD. The large randomized, doubleblind, parallel group, multicentre Phase IIIb study, Examining Use of tiCagreLor In paD (EUCLID) has recently completed its enrolment of > 13,500 patients with established PAD to compare ticagrelor monotherapy against clopidogrel monotherapy for the reduction of cardiovascular death, MI and ischemic stroke (NCT01732822), and its results are eagerly awaited.
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Ticagrelor
Of interest also, vorapaxar, which belongs to another class of drug that inhibits the protease-activated receptor 1, and therefore, thrombin-induced platelet activation was demonstrated to reduce ischemic complications among patients with atherothrombotic disease (including PAD) [30]. In that study, ~ 37% of patients with PAD were concurrently treated with a P2Y12 inhibitor, of which most commonly used was clopidogrel. Of concern, there was a significant increase in moderate and severe bleeding, including intracranial bleeding. However, in a subgroup analysis of patients with PAD, vorapaxar did not reduce the risk of cardiovascular death, MI or stroke (the primary endpoint) but significantly reduced acute limb ischemia and peripheral revascularization at the expense of increased bleeding [31]. Ticagrelor, a more potent P2Y12 receptor inhibitor may emulate the benefits of vorapaxar among PAD patients if used alone; however, its concurrent use with vorapaxar may trigger concerns for increase bleeding risks. Therefore, the future role of ticagrelor in PAD patients will need to be taken in context of the uptake of vorapaxar into clinical practice. 9.
Expert opinion
As a molecule in a novel class of drugs, ticagrelor may be very different in its effects on PAD compared to aspirin and the thienopyridines (ticlopidine, clopidogrel and prasugrel). Unlike clopidogrel, which has until recently been the mainstay P2Y12 inhibitor, ticagrelor is a cyclopentyl-triazolopyrimidine that does not require biotransformation. Hence, its activity is not susceptible to genetic variants that are relevant to clopidogrel and prasugrel. Studies in PAD patients to substantiate potential benefits of ticagrelor among carriers of these common genetic variants would be important, especially as ticagrelor was proven to have efficacy irrespective of CYP2C19 loss-of-function carrier status in PLATO [20]. In one previous study, patients who carry CYP2C19 loss of function alleles were shown to have higher risk of in-stent restenosis after endovascular treatment of lower limb PAD when treated with clopidogrel [32]. To overcome this, the use of ticagrelor instead has been proposed and preliminary data has proven its safety [33]. However, as ticagrelor is significantly more potent than clopidogrel, one would expect that the incidence of bleeding due to drug use would compound on the already higher risk of bleeding in patients with PAD. Perhaps here, the role of tailored personalized therapy based on genetic variation could be central to guiding the choice of therapy, limiting ticagrelor use to non-responders of clopidogrel. Studies on tailored therapy are ongoing in patients with ACS and whereas the concept is intellectually (and economically) appealing, it remains to be proven before entering clinical practice. Ticagrelor has been shown to inhibit the equilibrative nucleoside transporter-1, which is responsible for transporting adenosine intracellularly to be metabolised [34]. In addition, in vitro studies using human erythrocytes show that ticagrelor
induces ATP release, which is subsequently converted to adenosine [35]. These combined processes, with the former being the predominant contributor, raise the plasma level of adenosine, and its effect on the A2A, A2B and A3 receptors are believed to mediate the pleomorphic effects of ticagrelor independent of P2Y12 platelet inhibition. The putative effects of ticagrelor may be of particular importance to the management of patients with obstructive arterial disease, including PAD when compared to previously studied antiplatelet drugs. Adenosine stimulates the mobilization of stem cells in animals via the A2A and A3 receptors. In addition, a rat model utilizing human endothelial progenitor cells (EPCs), adenosine was shown to facilitate the migration of EPCs to the infarcted rat heart by increasing the expression of CXCR-4 and decreasing the expression of micro RNA-150 via the A2B receptor [36]. Adenosine is also known to cause vasodilation and increase blood flow in the heart, skeletal muscle, brain and other tissue beds. Data supports that it mediates the process of angiogenesis at physiological concentrations, by stimulating the proliferation and migration of endothelial cells [37,38]. Animal models have been used to demonstrate that A2A receptor activation increases both EPC recruitment and local vessel sprouting in the early stages of wound healing [39]. In vitro, concentrations as low as 1 µmol has been shown to increase VEGF expression in dog myocardial vascular smooth muscle cells [40]. Similar plasma concentrations of adenosine have already been measured in patients taking ticagrelor compared to clopidogrel [16]. Greater understanding of the mechanisms involved in angiogenesis and the role of bone-marrow-derived EPCs in the repair process is paramount, as angiogenesis lies at the heart of two major disease processes, cancer and cardiovascular disease, albeit at opposite extremes. It may involve adenosine as shown in animal studies and although it has not been demonstrated in humans, it is tempting to speculate that the same may occur. Finally, ticagrelor has also been shown in comparison to clopidogrel and prasugrel to improve peripheral arterial endothelial function as measured by tonometry after forearm ischemia, a method validated against flow-mediated dilatation (FMD) [41]. Endothelial dysfunction is associated with worse outcomes in cardiovascular disease, but the effect of restoration of endothelial function as measured by biomarkers or FMD on the progression of atherosclerosis and/or thrombosis is currently unknown. The role of antiplatelet therapy in PAD is mainly to reduce overall cardiovascular events and as a consequence, mortality. The direct treatment of PAD in itself has not been associated with mortality benefit. With the on-going controversy on the lack of benefit from aspirin in primary prevention of cardiovascular events due to the risk of bleeding, one may reach the same conclusion with the more potent ticagrelor. Until robust evidence from the EUCLID study of its use in PAD is available or its hypothetical pleomorphic effects are proven, ticagrelor has a limited role in the present management of PAD. However, the wealth of data from mechanistic studies
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derived from predominantly animal studies on the pleomorphic effects of adenosine in cardiovascular disease, if proven, would make ticagrelor a very promising therapy indeed.
Declaration of interest AY Chong is supported by the Division of Cardiology Research and the Education Development Fund. DY So has also received grant support from the Canadian Institute of
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Husted S, Emanuelsson H, Heptinstall S, et al. 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 2006;27:1038-47 Cannon CP, Husted S, Harrington RA, et al. 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;50:1844-51 Morrow DA, Braunwald E, Bonaca MP, et al. Vorapaxar in the secondary prevention of atherothrombotic events. N Engl J Med 2012;366:1404-13 Bonaca MP, Scirica BM, Creager MA, et al. Vorapaxar in patients with peripheral artery disease: results from TRA2{degrees}P-TIMI 50. Circulation 2013;127:1522-6 Guo B, Tan Q, Guo D, et al. Patients carrying CYP2C19 loss of function alleles have a reduced response to clopidogrel therapy and a greater risk of in-stent restenosis after endovascular treatment of lower extremity peripheral arterial disease. J Vasc Surg 2014;60(4):993-1001 Spiliopoulos S, Katsanos K, Pastromas G, et al. Initial experience with ticagrelor in patients with critical limb ischemia and high on-clopidogrel platelet reactivity undergoing complex peripheral endovascular procedures. Cardiovasc Intervent Radiol 2014. [Epub ahead of print] Armstrong D, Summers C, Ewart L, et al. Characterization of the adenosine pharmacology of ticagrelor reveals therapeutically relevant inhibition of equilibrative nucleoside transporter 1.
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Ohman J, Kudira R, Albinsson S, et al. Ticagrelor induces adenosine triphosphate release from human red blood cells. Biochem Biophys Res Commun 2012;418:754-8
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Rolland-Turner M, Goretti E, Bousquenaud M, et al. Adenosine stimulates the migration of human endothelial progenitor cells. Role of CXCR4 and microRNA-150. PLoS One 2013;8:e54135
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Adair TH. Growth regulation of the vascular system: an emerging role for adenosine. Am J Physiol Regul Integr Comp Physiol 2005;289:R283-96
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Adair TH. An emerging role for adenosine in angiogenesis. Hypertension 2004;44:618-20
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Montesinos MC, Shaw JP, Yee H, et al. Adenosine A(2A) receptor activation promotes wound neovascularization by stimulating angiogenesis and vasculogenesis. Am J Pathol 2004;164:1887-92
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Gu JW, Brady AL, Anand V, et al. Adenosine upregulates VEGF expression in cultured myocardial vascular smooth muscle cells. Am J Physiol 1999;277:H595-602
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Torngren K, Ohman J, Salmi H, et al. Ticagrelor improves peripheral arterial function in patients with a previous acute coronary syndrome. Cardiology 2013;124:252-8
Affiliation Aun-Yeong Chong MD MRCP(UK) MBBS BSc(Med) & Derek Y So† MD FRCPC † Author for correspondence University of Ottawa Heart Institute, Division of Cardiology, Department of Medicine, 40 Ruskin Street, Ottawa K1Y 4W7, Ontario, Canada Tel: +1 613 761 5387; Fax: +1 613 761 4338; E-mail: [email protected]
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Ticagrelor for the treatment of peripheral arterial disease Aun-Yeong Chong & Derek Y So† 1.
Introduction
2.
Current recommended antithrombotic treatment in
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PAD 3.
Introduction to the compound
4.
Pharmacodynamics
5.
Pharmacokinetics and metabolism
6.
Clinical efficacy
7.
Safety and tolerability
8.
Conclusion
9.
Expert opinion
University of Ottawa Heart Institute, Division of Cardiology, Department of Medicine, Ontario, Canada
Introduction: Peripheral arterial disease (PAD) is a manifestation, and marker of severity, of a generalized atherosclerotic process. Antiplatelet therapy is recommended to prevent cardiovascular events but much of the evidence to support this is drawn from studies on older drugs. Areas covered: In this review, the authors discuss the available evidence for the basis of current recommendations and review the data from Phase I to III trials on ticagrelor as a potential future treatment. This paper also reviews the properties of ticagrelor, its adverse effects, and how it differs from current recommended antiplatelet agents. As it is also more potent, a personalized approach to antiplatelet therapy may prove useful. It further highlights the additional effects of ticagrelor mediated by adenosine and their potential benefits, which may provide an explanation to its superior outcomes in trials comparing it with clopidogrel. Expert opinion: Although there is a current lack of evidence to support the use of ticagrelor in patients with PAD, its unique pleomorphic properties make it attractive for future investigations and development of similar drugs. Keywords: adenosine, antiplatelet, atherosclerosis, peripheral arterial disease, ticagrelor Expert Opin. Investig. Drugs (2014) 23(12):1737-1743
1.
Introduction
Peripheral arterial disease (PAD), coronary artery disease (CAD) and cerebrovascular disease (CVD) are predominantly manifestations of atherosclerosis, a systemic process beginning in the second decade of life. Early studies such as the international REduction of Atherothrombosis for Continued Health (REACH) Registry and Clopidogrel and Aspirin versus Aspirin Alone for the Prevention of Atherothrombotic Events (CHARISMA) show that the presence of PAD, among patients with CAD, CVD or multiple risk factors, is associated with a worse outcome [1,2]. Conversely, the presence of PAD per se in patients is associated with a > 50% chance of myocardial ischemia [3,4], thereby reflecting PAD as a marker for severity of coronary atherosclerosis. Of note, even in the absence of other established cardiovascular disease, patients with PAD remain at higher risk of all-cause mortality [5]. In this review, the authors will discuss the current evidence for the use of the more established antiplatelets in PAD and explore the potential role for the novel antiplatelet agent, ticagrelor. 2.
Current recommended antithrombotic treatment in PAD
The ACC/AHA guidelines for the management of patients with PAD focused recommendations to the abdominal aorta, renal and mesenteric arteries and lower extremity arteries based on the robust evidence. Due to the nature of the disease process, the pharmacological management of PAD expectedly targets risk factor management and progression of atherosclerosis, with clinical impact upon cardiovascular ischemic events such as myocardial infarction (MI), ischemic stroke and 10.1517/13543784.2014.974803 © 2014 Informa UK, Ltd. ISSN 1354-3784, e-ISSN 1744-7658 All rights reserved: reproduction in whole or in part not permitted
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Box 1. Drug Summary. Drug name Phase Indication
Route of administration Chemical structure
Ticagrelor III Reduction of cardiovascular events in patients with peripheral arterial disease Oral Cyclopentyl-triazolopyrimidine F HN N
N
N
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HO
O
HO
Pivotal trial(s)
N
N
F S
OH
[25,26]
death [6,7]. Indeed, the 2011 ACCF/AHA focused update recommends antiplatelet therapy to patients with symptomatic atherosclerotic lower extremity PAD to reduce the risk of MI, stroke and vascular death. The recommendation specifies aspirin at doses of 75 -- 325 mg daily, or clopidogrel 75 mg daily as alternative for patients contraindicated to aspirin therapy. The guidelines also supported the possible use of dual antiplatelet therapy with aspirin and clopidogrel for patients at high perceived cardiovascular risk who have low risk for bleeding, with a weaker recommendation [7,8]. Antiplatelet therapy may also be considered in asymptomatic patients with an ankle-brachial index (ABI) £ 0.90 [7,8]. With the absence of robust data, novel antiplatelet agents, such as prasugrel or ticagrelor, were not recommended in these PAD guidelines. PAD should be regarded as a marker of the severity of atherosclerosis and increased risk for atherosclerotic plaque rupture. Therefore, the aim for antithrombotic treatment in PAD is focused on the reduction of thrombotic events in predominantly, the coronary and cerebrovascular beds. Accordingly, almost all published studies of antithrombotic therapy in PAD define outcome measures as a combination of coronary and cerebrovascular-related mortality and morbidity. Few studies of antiplatelet in PAD actually specify the development of critical limb ischemia, peripheral arterial revascularization or amputation as components of the primary endpoint, except for studies on endovascular treatment. Aspirin in PAD The early Antithrombotic Trialists’ Collaboration metaanalysis in 2002 of antiplatelet therapy in high-risk patients demonstrated a 23% reduction in serious vascular events in the subgroup of patients with PAD [9]. This served as the basis for routine use of aspirin in patients with PAD. However, more recent meta-analyses on the role of aspirin in PAD have called into question its perceived benefit [5,10]. The 2.1
1738
Prevention of Progression of Asymptomatic Diabetic Arterial Disease and Aspirin for Asymptomatic Atherosclerosis trials enrolled asymptomatic patients from population screening using ABI thresholds of 0.99 and 0.95, respectively, drawing criticism that only low-risk patients were recruited, despite the presence of diabetes mellitus [5]. Therefore it should not be surprising, that in these lower risk cohorts with preclinical PAD, that aspirin did not show a significant reduction in vascular events. This is also consistent with recent findings on patients with asymptomatic CAD. Similarly, in the JPAD study (Japanese Primary Prevention of Atherosclerosis with Aspirin for Diabetes), treatment with aspirin did not prevent vascular events over a 5-year follow-up period [11]. On the contrary, the small Critical Leg Ischemia Prevention Study, which enrolled high-risk patients defined by the symptomatic or asymptomatic with ABI < 0.85, showed a significant reduction in major vascular events and critical leg ischemia with low-dose aspirin (100 mg daily) compared to antioxidant vitamins. However, the study was prematurely terminated due to poor recruitment, with only 366 patients randomized out of the planned sample size of 2000 [12]. The small sample size, with only 210 patients completing follow-up at 2 years, therefore precludes definitive conclusions on its true influence on cardiovascular outcomes. Hence, the 2011 updated ACCF/AHA guidelines continue to recommend the use of aspirin only in symptomatic PAD. Clopidogrel in PAD The evidence for the use of clopidogrel in patients with PAD stems from subgroup analyses of two early trials -- Clopidogrel versus Aspirin in Patients at Risk of Ischemic Events (CAPRIE) and CHARISMA. In CAPRIE, approximately a third of the patients had PAD and clopidogrel use in this subgroup was associated with a statistically significant 23.8% relative reduction in the combined endpoint of ischemic stroke, MI, or vascular death compared to aspirin. Subsequent to this, CHARISMA studied patients at high risk for atherothrombotic events and compared dual antiplatelet therapy with aspirin and clopidogrel versus aspirin alone. The study showed an overall non-significant 7.1% relative risk reduction in MI, stroke or cardiovascular death. However, a post hoc analysis of higher risk patients, with documented prior MI, ischemic stroke or symptomatic PAD, suggested potential clinical benefit of dual antiplatelet therapy in this group [13]. A subsequent subgroup analysis of 3096, symptomatic and asymptomatic, PAD patients included in CHARISMA showed that dual antiplatelet therapy reduced the rate of MI and hospitalization for ischemic events at the risk of increased minor bleeding [14]. As the overall evidence for dual antiplatelet therapy is underwhelming, current recommendations from the American College of Chest Physicians Evidence-Based Clinical Practice Guidelines still favor single antiplatelet therapy for primary and secondary prevention of cardiovascular 2.2
Expert Opin. Investig. Drugs (2014) 23(12)
Ticagrelor
events in patients with asymptomatic or symptomatic PAD, even for patients undergoing peripheral artery percutaneous transluminal angioplasty with stenting [15]; the last recommendation is in contradistinction to coronary artery stenting, where dual antiplatelet therapy is recommended.
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3.
Introduction to the compound
Ticagrelor (Box 1), a cyclopentyltriazolopyrimidine, is a novel class of platelet P2Y12 receptor inhibitor, with proven clinical efficacy in patients with CAD, presenting with acute coronary syndromes (ACS). Ticagrelor also inhibits adenosine reuptake by erythrocytes and increases the plasma level of adenosine [16]. Adenosine-mediated effects of ticagrelor may confer additional benefits (and adverse effects) beyond that of P2Y12 inhibition alone. 4.
Pharmacodynamics
Ticagrelor has a theoretical advantage over thienopyridines, as it does not require biotransformation to an active metabolite and thus achieve a more rapid onset of action. The ONSET--OFFSET study confirmed that a loading dose of 180 mg ticagrelor had more rapid platelet inhibition compared to 600 mg clopidogrel with 41% inhibition versus 8% inhibition respectively at 30 min [17]. This trend continues to 2 h with 90% of patients receiving ticagrelor achieving > 70% platelet inhibition compared to just 16% of patients receiving clopidogrel. Following the last dose, the antiplatelet effect of ticagrelor also declined more rapidly compared to clopidogrel. As it does not require any biotransformation, it is also less susceptible to interactions with other drugs dependent on CYP metabolism. Of note, pharmacodynamic response to clopidogrel among carriers of the common CYP2C19 loss-of-function alleles can be blunted [18]. Carriers of these alleles have increased cardiovascular events compared to non-carriers when treated with clopidogrel [19]. In contrast, ticagrelor’s effects are independent of the influence of CYP2C19 loss-of-function alleles [20], thereby suggesting applicability for clinical use on a more universal basis. There were concerns in the PLatelet inhibition And patienT Outcomes (PLATO) trial that the effects observed in North Americans were divergent compared to others around the world [21]. In PLATO, a prespecified subgroup analysis showed a significant interaction between treatment and region (p = -0.045), with less effect of ticagrelor in North America than in the rest of the world. Two independently performed analyses identified a statistical interaction with aspirin maintenance dose as a possible explanation for the regional difference. The lowest risk of cardiovascular death, MI, or stroke was associated with a low maintenance dose of concomitant aspirin [21].
5.
Pharmacokinetics and metabolism
Ticagrelor is an oral, direct acting, reversible inhibitor of the ADP P2Y12 receptor with unique pharmacokinetic properties. It has rapid onset and offset, while at the same time conferring increased potency compared to clopidogrel. The Tmax of ticagrelor is ~ 2 h [22] with a plasma half life of ~ 8 h [23]. It is metabolized in the liver by CYP3A4 enzyme to produce the equally active metabolite AR-C124910XX. At steady state, this metabolite is present at ~ 1/3 of the concentration of the parent drug in the circulation. No dose adjustment is necessary for patients with renal failure as elimination of both ticagrelor and AR-C124910XX occurs primarily via hepatic metabolism and biliary excretion [24]. 6.
Clinical efficacy
The PLATO trial recruited 18624 patients with ACS and showed that compared to clopidogrel, ticagrelor significantly reduced the composite endpoint of vascular mortality, MI, or stroke [25]. Of particular interest for clinicians was the surprising significant reduction in overall mortality observed in the study. Overall major bleeding was not significantly different when compared to clopidogrel, but there was an increase in the rate of major bleeding among patients treated medically or those who underwent percutaneous coronary interventions [25]. This overall absence in increased major bleeding observed in the PLATO study was likely attributed to the lack of increased bleeding for patients undergoing coronary artery bypass graft surgery (CABG) as the majority of these patients had cessation of ticagrelor days before undergoing CABG. This may be especially relevant in PAD patients, who are already at increased risk of bleeding. Indeed, in a post-hoc analysis of PLATO, patients with PAD (n = 1144) were shown to have significantly higher rates of death from vascular cause, MI or stroke (19.3 vs 10.2%) and major bleeding compared to patients without PAD [26]. Within the PAD group, death from vascular cause, MI or stroke was numerically lower in the ticagrelor group compared to clopidogrel, with numerically lower risk in major bleeding [26]. These key findings were consistent with the overall trial results but did not reach statistical significance as the subgroup analysis was too small. However, it would appear reassuring that despite the significantly higher risk of bleeding in PAD patients, ticagrelor, being the more potent P2Y12 inhibitor, reduced the cardiovascular events without concurrently increasing the risk of major bleeding. If confirmed in prospective future studies, this would result in a very favorable risk:benefit ratio. 7.
Safety and tolerability
The safety and tolerability of ticagrelor was tested in various Phase I and II trials. In Phase I trials, ticagrelor was tested
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Table 1. Relevant studies of ticagrelor. Study PLATO*
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PLATO subgroup analysisz
EUCLID
DISPERSE
DISPERSE-2
Design Randomized double blind prospective study; ticagrelor 180 mg bolus followed by 90 mg b.i.d. vs clopidogrel 300 mg bolus followed by 75 mg daily Subgroup analysis of patients with PAD -- self-reported or captured on eCRF but not confirmed by objective testing at the time of enrolment Randomized double-blind prospective study; ticagrelor 90 mg b.i.d. vs clopidogrel 75 mg daily Randomized double-blind prospective study; ticagrelor 50 mg b.i.d. vs 100 mg b.i.d. vs 200 mg b.i.d. vs 400 mg daily vs clopidogrel 75 mg daily for 28 days in addition to aspirin 75 -- 100 mg daily Randomized double-blind prospective study; ticagrelor 90 mg b.i.d. vs ticagrelor 180 mg b.i.d. vs copidogrel 300 mg bolus followed by 75 mg daily
n
Patient population
Primary measures
18624
ACS
Composite of death from vascular causes, MI or stroke
1144
ACS and PAD
Composite of death from vascular causes, MI or stroke
13500
PAD
Cardiovascular death, MI and ischemic stroke (results awaited)
200
Atherosclerosis
Final extent and maximal extent of platelet aggregation at multiple time points
990
Non-ST elevation acute coronary syndrome
Major and minor bleeding through 4 weeks
*Landmark study as in bibliography. z Subgroup analysis as in bibliography. ACS: Acute coronary syndrome; b.i.d.: Twice daily; MI: Myocardial infarction; PAD: Peripheral arterial disease; PLATO: PLatelet inhibition And patienT Outcomes.
in healthy volunteers in dosage of 50 -- 600 mg daily or 50 -- 300 mg twice daily (b.i.d.). This showed that the pharmacokinetics of ticagrelor is predictable and is associated with consistent platelet inhibition. However, twice daily administration achieved greater platelet inhibition than once daily (q.d.) [27]. The Phase II DISPERSE study evaluated 50, 100, 200 mg b.i.d. or 400 mg q.d. administration of ticagrelor and demonstrated the safety and tolerability profile, with superior efficacy to clopidogrel 75 mg daily [28]. This was then followed by DISPERSE (Dose confIrmation Study assessing anti-Platelet Effects of AZD6140 vs. clopidogRel in non-ST-segment Elevation MI)-2, a dose confirmation study in non-ST-elevation MI patients. This study showed that ticagrelor 180 mg b.i.d. was associated with increased minor bleeds compared to ticagrelor 90 mg b.i.d. and clopidogrel 75 mg daily [29]. The latter dose was then tested in the seminal Phase III PLATO trial [25]. In PLATO, dyspnea was observed in 13.8% of patients receiving ticagrelor compared to 7.8% of patients receiving clopidogrel [25]. This resulted in 0.9% of patients discontinuing ticagrelor compared to 0.1% of patients discontinuing clopidogrel. For patients with PAD, many of whom have longstanding smoking history and pre-existing chronic airways disease, the effects of the ticagrelor-mediated dyspnea may make 1740
tolerability of the drug different compared to those presenting with ACS in PLATO. Accordingly, the true effects of these potential side effects will require ratification as Phase III studies on ticagrelor among PAD patients are carried out. Other adverse events observed in the PLATO study included a higher incidence of ventricular pauses in the first week but not at day 30 in the ticagrelor group. These pauses were rarely associated with symptoms and there was no significant difference with respect to syncope or pacemaker implantation. The levels of creatinine and uric acid also increased slightly more during the treatment period with ticagrelor versus clopidogrel. 8.
Conclusion
All the relevant clinical studies can be found in Table 1. There has been no prospective randomized data investigating ticagrelor in patients with PAD. The large randomized, doubleblind, parallel group, multicentre Phase IIIb study, Examining Use of tiCagreLor In paD (EUCLID) has recently completed its enrolment of > 13,500 patients with established PAD to compare ticagrelor monotherapy against clopidogrel monotherapy for the reduction of cardiovascular death, MI and ischemic stroke (NCT01732822), and its results are eagerly awaited.
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Ticagrelor
Of interest also, vorapaxar, which belongs to another class of drug that inhibits the protease-activated receptor 1, and therefore, thrombin-induced platelet activation was demonstrated to reduce ischemic complications among patients with atherothrombotic disease (including PAD) [30]. In that study, ~ 37% of patients with PAD were concurrently treated with a P2Y12 inhibitor, of which most commonly used was clopidogrel. Of concern, there was a significant increase in moderate and severe bleeding, including intracranial bleeding. However, in a subgroup analysis of patients with PAD, vorapaxar did not reduce the risk of cardiovascular death, MI or stroke (the primary endpoint) but significantly reduced acute limb ischemia and peripheral revascularization at the expense of increased bleeding [31]. Ticagrelor, a more potent P2Y12 receptor inhibitor may emulate the benefits of vorapaxar among PAD patients if used alone; however, its concurrent use with vorapaxar may trigger concerns for increase bleeding risks. Therefore, the future role of ticagrelor in PAD patients will need to be taken in context of the uptake of vorapaxar into clinical practice. 9.
Expert opinion
As a molecule in a novel class of drugs, ticagrelor may be very different in its effects on PAD compared to aspirin and the thienopyridines (ticlopidine, clopidogrel and prasugrel). Unlike clopidogrel, which has until recently been the mainstay P2Y12 inhibitor, ticagrelor is a cyclopentyl-triazolopyrimidine that does not require biotransformation. Hence, its activity is not susceptible to genetic variants that are relevant to clopidogrel and prasugrel. Studies in PAD patients to substantiate potential benefits of ticagrelor among carriers of these common genetic variants would be important, especially as ticagrelor was proven to have efficacy irrespective of CYP2C19 loss-of-function carrier status in PLATO [20]. In one previous study, patients who carry CYP2C19 loss of function alleles were shown to have higher risk of in-stent restenosis after endovascular treatment of lower limb PAD when treated with clopidogrel [32]. To overcome this, the use of ticagrelor instead has been proposed and preliminary data has proven its safety [33]. However, as ticagrelor is significantly more potent than clopidogrel, one would expect that the incidence of bleeding due to drug use would compound on the already higher risk of bleeding in patients with PAD. Perhaps here, the role of tailored personalized therapy based on genetic variation could be central to guiding the choice of therapy, limiting ticagrelor use to non-responders of clopidogrel. Studies on tailored therapy are ongoing in patients with ACS and whereas the concept is intellectually (and economically) appealing, it remains to be proven before entering clinical practice. Ticagrelor has been shown to inhibit the equilibrative nucleoside transporter-1, which is responsible for transporting adenosine intracellularly to be metabolised [34]. In addition, in vitro studies using human erythrocytes show that ticagrelor
induces ATP release, which is subsequently converted to adenosine [35]. These combined processes, with the former being the predominant contributor, raise the plasma level of adenosine, and its effect on the A2A, A2B and A3 receptors are believed to mediate the pleomorphic effects of ticagrelor independent of P2Y12 platelet inhibition. The putative effects of ticagrelor may be of particular importance to the management of patients with obstructive arterial disease, including PAD when compared to previously studied antiplatelet drugs. Adenosine stimulates the mobilization of stem cells in animals via the A2A and A3 receptors. In addition, a rat model utilizing human endothelial progenitor cells (EPCs), adenosine was shown to facilitate the migration of EPCs to the infarcted rat heart by increasing the expression of CXCR-4 and decreasing the expression of micro RNA-150 via the A2B receptor [36]. Adenosine is also known to cause vasodilation and increase blood flow in the heart, skeletal muscle, brain and other tissue beds. Data supports that it mediates the process of angiogenesis at physiological concentrations, by stimulating the proliferation and migration of endothelial cells [37,38]. Animal models have been used to demonstrate that A2A receptor activation increases both EPC recruitment and local vessel sprouting in the early stages of wound healing [39]. In vitro, concentrations as low as 1 µmol has been shown to increase VEGF expression in dog myocardial vascular smooth muscle cells [40]. Similar plasma concentrations of adenosine have already been measured in patients taking ticagrelor compared to clopidogrel [16]. Greater understanding of the mechanisms involved in angiogenesis and the role of bone-marrow-derived EPCs in the repair process is paramount, as angiogenesis lies at the heart of two major disease processes, cancer and cardiovascular disease, albeit at opposite extremes. It may involve adenosine as shown in animal studies and although it has not been demonstrated in humans, it is tempting to speculate that the same may occur. Finally, ticagrelor has also been shown in comparison to clopidogrel and prasugrel to improve peripheral arterial endothelial function as measured by tonometry after forearm ischemia, a method validated against flow-mediated dilatation (FMD) [41]. Endothelial dysfunction is associated with worse outcomes in cardiovascular disease, but the effect of restoration of endothelial function as measured by biomarkers or FMD on the progression of atherosclerosis and/or thrombosis is currently unknown. The role of antiplatelet therapy in PAD is mainly to reduce overall cardiovascular events and as a consequence, mortality. The direct treatment of PAD in itself has not been associated with mortality benefit. With the on-going controversy on the lack of benefit from aspirin in primary prevention of cardiovascular events due to the risk of bleeding, one may reach the same conclusion with the more potent ticagrelor. Until robust evidence from the EUCLID study of its use in PAD is available or its hypothetical pleomorphic effects are proven, ticagrelor has a limited role in the present management of PAD. However, the wealth of data from mechanistic studies
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derived from predominantly animal studies on the pleomorphic effects of adenosine in cardiovascular disease, if proven, would make ticagrelor a very promising therapy indeed.
Declaration of interest AY Chong is supported by the Division of Cardiology Research and the Education Development Fund. DY So has also received grant support from the Canadian Institute of
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Affiliation Aun-Yeong Chong MD MRCP(UK) MBBS BSc(Med) & Derek Y So† MD FRCPC † Author for correspondence University of Ottawa Heart Institute, Division of Cardiology, Department of Medicine, 40 Ruskin Street, Ottawa K1Y 4W7, Ontario, Canada Tel: +1 613 761 5387; Fax: +1 613 761 4338; E-mail: [email protected]
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