Efficacy and safety of prasugrel in acute coronary syndrome patients.

Clinical Biochemistry 47 (2014) 516–528

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Clinical Biochemistry journal homepage: www.elsevier.com/locate/clinbiochem

Review

Efficacy and safety of prasugrel in acute coronary syndrome patients Radu M. Nanau a,b, Faustine Delzor a,c, Manuela G. Neuman a,b,⁎ a b c

In Vitro Drug Safety and Biotechnology, Toronto, ON, Canada Department of Pharmacology and Toxicology, Faculty of Medicine, University of Toronto, Toronto, ON, Canada Faculty of Pharmacy, University Paul Sabatier, Toulouse, France

a r t i c l e

i n f o

Article history: Received 22 August 2013 Received in revised form 9 March 2014 Accepted 13 March 2014 Available online 21 March 2014 Keywords: Acute coronary syndrome Clopidogrel Hypersensitivity syndrome reaction Light transmission aggregometry Pharmacovigilance Prasugrel Vasodilatator stimulated phosphoprotein

a b s t r a c t Ischemic heart disease is the primary cause of death worldwide. The pathophysiological process of cardiovascular diseases is linked to atheromatous plaque formation, while plaque rupture releases thrombogenic elements, which lead to activation of platelets, blood clotting and formation of thrombi. Platelet inhibitors are used to prevent thrombosis. The present systematic review discusses the efficacy of prasugrel in terms of platelet inhibition potential and clinical prevention of cardiovascular outcomes. The balance between reduction of ischemic events as a measure of drug efficacy and the risk of bleeding is reviewed. Other adverse events observed in patients treated with this platelet inhibitor are discussed, including hematological complications, and cutaneous and hepatic idiosyncratic reactions. The complex relationship between prasugrel use and cancer promotion is also described. © 2014 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.

Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . Materials and methods . . . . . . . . . . . . . . . . . . . . Cardiovascular complications . . . . . . . . . . . . . . . . . Bleeding . . . . . . . . . . . . . . . . . . . . . . . . . . . Assays measuring response variability to platelet inhibitors . . . . Hematologic complications . . . . . . . . . . . . . . . . . . Dermatotoxicity and cutaneous hypersensitivity syndrome reactions Hepatotoxicity and drug-induced liver injury . . . . . . . . . . Endocrine and metabolic disturbances . . . . . . . . . . . . . Infection . . . . . . . . . . . . . . . . . . . . . . . . . . . Other adverse events . . . . . . . . . . . . . . . . . . . . . Drug–drug interactions . . . . . . . . . . . . . . . . . . . . Prasugrel and cancer . . . . . . . . . . . . . . . . . . . . . Which P2Y12 inhibitor is preferred? . . . . . . . . . . . . . . Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . .

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Abbreviations: ACS, acute coronary syndrome; ADP, adenosine diphosphate; ADR, adverse drug reaction; CABG, coronary artery bypass surgery; CI, confidence interval; CV, cardiovascular; CYP, cytochrome p450; HOPR, high on-treatment platelet reactivity; HR, hazard ratio; HSR, hypersensitivity syndrome reaction; LD, loading dose; LTA, light transmission aggregometry; MD, maintenance dose; MFI, mean fluorescence intensity; MI, myocardial infarction; MPA, maximum platelet aggregation; NSTEMI, non-ST segment elevation myocardial infarction; PCI, percutaneous coronary intervention; PGE1, prostaglandin E1; PI %, P2Y12 inhibition percentage; PPI, proton pump inhibitor; PPP, platelet poor plasma; PRI, platelet reactivity index; PRP, platelet rich plasma; PRU, P2Y12 reaction unit; RANNTES, regulated on activation, normal T cell expressed and secreted; STEMI, ST segment elevation myocardial infarction; UA, unstable angina; VASP, vasodilatator associated stimulated phospho-protein. ⁎ Corresponding author at: Department of Pharmacology and Toxicology, In Vitro Drug Safety and Biotechnology, Banting Institute, 100 College Street, Lab 217, Toronto, ON M5G 0A3, Canada. E-mail address: [email protected] (M.G. Neuman). URL: http://www.marsdd.com/tenantdirectory/invitro.html (M.G. Neuman).

http://dx.doi.org/10.1016/j.clinbiochem.2014.03.005 0009-9120/© 2014 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.

R.M. Nanau et al. / Clinical Biochemistry 47 (2014) 516–528

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consideration of benefits and risks based on a detailed medical history and known underlying diseases in each individual.

Introduction Ischemic heart disease is the primary cause of death worldwide [1]. The pathophysiological process of cardiovascular (CV) diseases is linked to atheromatous plaque formation, fibrogenesis and inflammation. This process is reviewed in detail by Binazon et al. [2]. Myocardial infarction (MI), with or without ST segment elevation, is the main subtype of acute coronary syndrome (ACS). ACS describes the sudden interruption of blood flow to the heart, characterized by the partial or complete obstruction of coronary arteries. ACS can result from the erosion and rupture of an atheromatous coronary plaque [3]. Atheromatous plaque rupture releases thrombogenic elements, which lead to platelet activation, blood clotting, and thrombi formation. Thrombus formation can prevent the flow of oxygen to the heart and can thus be responsible for myocardial ischemia and necrosis [2]. The platelet aggregation pathway is mediated by collagen, thrombin, and the binding of adenosine diphosphate (ADP) to the purinergic P2Y12 receptor on platelets. The interaction between ADP and P2Y12 leads to adenylate cyclase inhibition. Platelets are responsible for vessel occlusion, and platelet aggregation can thus lead to ischemic heart conditions. P2Y12 receptor antagonists inhibit platelet activation by ADP [2, 4]. As such, antiplatelet therapy is administered in ACS patients. The two types of P2Y12 receptor antagonists currently in use are the members of the thienopyridine family ticlopidine, clopidogrel and prasugrel, and the newer cyclopentyl triazolopyrimidine ticagrelor. Thienopyridines are irreversible P2Y12 receptor antagonists while ticagrelor binds the P2Y12 receptor reversibly. Aspirin (75–162 mg/day) in combination with clopidogrel (75 mg/day) is the current gold standard treatment in patients who underwent a CV event. Ticlopidine has been largely replaced by other platelet inhibitors due to an unfavorable safety profile [5]. Recent clinical trials have shown superior antiplatelet effects in ACS patients treated with prasugrel or ticagrelor, compared to clopidogrel. Furthermore, prasugrel and ticagrelor significantly reduce the rates of clinical end points such as CV death, nonfatal MI or nonfatal stroke. These differences were particularly evident in patients with a planned invasive strategy such as percutaneous coronary intervention (PCI) [6, 7]. This systematic review aims to present the current knowledge regarding the efficacy and the known adverse events of prasugrel (Effient®, Eli Lilly and Company) in ACS patients. Treatment strategies in patients are decided by their respective physicians after a careful

Materials and methods Efficacy was assessed in clinical trials comparing prasugrel and clopidogrel. The Effient product information and various Food and Drug Administration documents were consulted in order to identify adverse events and adverse drug reactions (ADR) associated with prasugrel use. A comprehensive PubMed and Google Scholar literature search was performed using the terms “prasugrel”, “P2Y12”, “assay”, “adverse event”, “adverse reactions”, as well as the name of each individual adverse event included in the Effient product information and the Food and Drug Administration documents, using articles indexed between 2005 and 2014 (Fig. 1). Each author read the publications separately and the results were discussed. We have used the data from case reports and from five major clinical trials, namely JUMBO-TIMI 26 [8], TRITON-TIMI 38 [6], PRINCIPLE-TIMI 44 [9], TRIGGER-PCI [10] and TRILOGY ACS [11]. The characteristics and main findings of these clinical trials are summarized in Table 1. Our main focus was to compare prasugrel with clopidogrel based on the balance between superior efficacy and higher risk of bleeding, especially life-threatening or fatal bleeding. Cardiovascular complications CV complications often define the primary efficacy end points in acute or stable coronary disease patients treated with prasugrel. These include death from CV causes, nonfatal MI and/or nonfatal stroke in the TRITON-TIMI 38 [6], TRILOGY ACS [11] and TRIGGER-PCI trials [10], while MI, recurrent ischemia and thrombosis represented the secondary end points of the JUMBO-TIMI 26 trial [8]. In contrast to clinical end points, the PRINCIPLE-TIMI 44 trial used in vitro assays to measure inhibition of platelet aggregation (IPA) after administration of either loading dose (LD) or maintenance dose (MD) prasugrel in PCI patients [9]. These trials compared prasugrel with clopidogrel, with concomitant aspirin use. Prasugrel was associated with significantly lower rates of reaching the primary end point (p b 0.001), owing particularly to lower odds of nonfatal MI (p b 0.001) as well as lower odds of stent thrombosis (p b 0.001) compared to clopidogrel in the TRITON-TIMI

PubMed and Google Scholar Search Effient product information “prasugrel” “P2Y12” “assay” “clinical trial” “adverse event” “adverse reaction” 2005 to 2014

1000 results returned

200 articles published in English and French were downloaded and read by all authors Inclusion criteria: papers looking at ACS patients treated with prasugrel, in vitro studies analyzing platelet inhibition by prasugrel Exclusion criteria: main drug tested was not prasugrel, animal studies

5 clinical trials measured efficacy and bleeding events: JUMBO-TIMI 26, TRITONTIMI 38, PRINCIPLE-TIMI 44, TRIGGER-PCI and TRILOGY ACS

data from real-life cohorts and case reports presenting complications of the primary disease and adverse events which rely on spontaneous reporting by investigators

120 publications were included Fig. 1. Prasugrel therapy in acute coronary syndrome.

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Table 1 Characteristics and main findings of clinical trials comparing prasugrel and clopidogrel. Study and patient demographics

Treatment regimens

PRINCIPLE-TIMI 44 [9] Randomized, double-blind, 2-phase crossover study of prasugrel vs. high-dose clopidogrel 201 ACS patients scheduled to undergo cardiac catheterization with planned PCI TRIGGER-PCI [10] Blinded, randomized study of prasugrel vs. highdose clopidogrel 423 patients with high on-treatment platelet reactivity following elective PCI TRILOGY ACS [11] Double-blind randomized trial 9326 ACS patients with UA/NSTEMI treated without PCI and exposed to study medication within 10 days of event 7243 patients b75 years of age treated with normal dose prasugrel vs. clopidogrel 2083 patients ≥75 years of age treated with lowdose prasugrel (5 mg/day) vs. clopidogrel

102 prasugrel and 99 clopidogrel LD: 60 mg prasugrel or 600 mg clopidogrel MD: 10 mg prasugrel or 150 mg clopidogrel Cross-over to other treatment regimen after mean 14 days 212 prasugrel and 211 clopidogrel Clopidogrel pre-treatment, followed by study drug LD: 60 mg prasugrel or placebo MD: daily prasugrel 10 mg or clopidogrel 75 mg LD: prasugrel 30 mg or clopidogrel 300 mg MD: prasugrel 10 mg in subjects b75 years of age, prasugrel 5 mg in subjects ≥75 years of age or ≤60 kg in weight or clopidogrel 75 mg

Efficacy data

Safety data

Any of death (all-cause mortality), MI, stroke, recurrent MI requiring hospitalization or clinical target vessel thrombosis (any PCI or CABG): 47 of 650 (7.2%) in prasugrel vs. 24 of 254 (9.4%) in clopidogrel (HR 0.76, 95% CI 0.46-1.24, p = 0.260)

Primary: non-CABG-related significant hemorrhage at 30 days [composite of TIMI major (hemoglobin drop N5 g/dL) or minor (hemoglobin drop between 3 and 5 g/dL) hemorrhage]: 11 of 650 (1.7%) in prasugrel vs. 3 of 254 (1.2%) in clopidogrel (HR 1.42, 95% CI 0.40–5.08, p = 0.590)

Primary: composite of rate of death from CV causes, nonfatal MI or nonfatal stroke during the follow-up period: 643 of 6813 (9.9%) in prasugrel vs. 781 of 6795 (12.1%) in clopidogrel (HR 0.81, 95% CI 0.73–0.90, p b 0.001) Secondary: primary composite end point and a composite of death from CV causes, nonfatal MI or urgent target-vessel revascularization at day 30 or day 90: 652 of 6813 (10.0%) in prasugrel vs. 798 of 6795 (12.3%) in clopidogrel (HR 0.81, 95% CI 0.73-0.89, p b 0.001) Secondary: stent thrombosis and a composite of death from CV causes, nonfatal MI, nonfatal stroke or re-hospitalization due to a cardiac ischemic event during the follow-up period: 797 of 6813 (12.3%) in prasugrel vs. 938 of 6795 (14.6%) in clopidogrel (HR 0.84, 95% CI 0.76–0.92, p b 0.001) Major cardiac adverse events end points: MI in 1 of 99 (1.0%) clopidogrel patients and 2 of 102 (2.0%) prasugrel patients prior to day 14

TIMI major bleeding not related to CABG: 146 of 6741 (2.4%) in prasugrel vs. 111 of 6716 (1.8%) in clopidogrel (HR 1.32, 95% 1.03–1.68, p = 0.03) TIMI life-threatening bleeding not related to CABG: 85 of 6741 (1.4%) in prasugrel vs. 56 of 6716 (0.9%) in clopidogrel (HR 1.52, 95% CI 1.08–2.13, p = 0.01) TIMI major or minor bleeding: 303 of 6741 (5.0%) in prasugrel vs. 231 of 6716 (3.8%) in clopidogrel (HR 1.31, 95% CI 1.11–1.56, p = 0.002)

Primary: composite of rate of death from CV causes, nonfatal MI or nonfatal stroke during the follow-up period among patients b75 years of age: 364 of 3620 (10.0%) in prasugrel vs. 397 of 3623 (11.0%) in clopidogrel (HR 0.91, 95% CI 0.79-1.05, p = 0.21) Composite of rate of death from CV causes, nonfatal MI or nonfatal stroke during the follow-up period in overall population: 621 of 4663 (13.3%) in prasugrel vs. 648 of 4663 (13.9%) in clopidogrel (HR 0.96, 95% CI 0.86–1.07, p = 0.45)

GUSTO severe or life-threatening bleeding not related to CABG among patients b75 years or age: 13 of 3590 (0.4%) in prasugrel vs. 14 of 3590 (0.4%) in clopidogrel (HR 0.94, 95% CI 0.44-1.99, p = 0.87) GUSTO severe or life-threatening bleeding not related to CABG in overall population: 22 of 4623 (0.5%) in prasugrel vs. 27 of 4617 (0.6%) in clopidogrel (HR 0.83, 95% CI 0.48–1.46, p = 0.53) TIMI major bleeding not related to CABG among patients b75 years or age: 39 of 3590 (1.1%) in prasugrel vs. 30 of 3590 (0.8%) in clopidogrel (HR 1.31, 95% CI 0.81–2.11, p = 0.27) TIMI major bleeding not related to CABG in overall population: 58 of 4623 (1.3%) in prasugrel vs. 48 of 4617 (1.0%) in clopidogrel (HR 1.23, 95% CI 0.84–1.81, p = 0.29)

No TIMI major bleeding events prior to day 14 Any bleeding events: 19 of 102 (18.6%) in prasugrel and 14 of 99 (14.1%) in clopidogrel prior to day 14 After cross-over, 4 of 99 (4.0%) clopidogrel patients who switched to prasugrel experiences a hemorrhagic adverse event Primary: composite of CV death or MI: 0 of 212 (0.0%) in prasugrel TIMI major bleeding not related to CABG: 3 of 210 (1.4%) in vs. 1 of 211 (0.5%) in clopidogrel prasugrel vs. 2 of 210 (1.0%) in clopidogrel

ACS — acute coronary syndrome; CABG — coronary artery bypass surgery; CI — confidence interval; CV — cardiovascular; HR — hazard ratio; LD — loading dose; MD — maintenance dose; MI — myocardial infarction; NSTEMI — non-ST segment elevation myocardial infarction; PCI — percutaneous coronary intervention; STEMI — ST segment elevation myocardial infarction; UA — unstable angina.


Prasugrel low dose: 40 mg LD followed by 7.5 mg MD (n = 199) Prasugrel normal dose: 60 mg LD followed by 10 mg MD (n = 200) Prasugrel high dose: 60 mg LD followed by 15 mg MD (n = 251) Clopidogrel normal dose: 300 mg LD followed by 75 mg MD (n = 254) 6813 prasugrel and 6795 clopidogrel TRITON-TIMI 38 [6] Double-blind phase 3 trial of prasugrel vs. clopidogrel 13608 ACS patients with LD: prasugrel 60 mg or clopidogrel 300 mg scheduled PCI (10074 with UA/NSTEMI and 3534 MD: prasugrel 10 mgor clopidogrel 75 mg daily Aspirin 75–162 mg daily with STEMI) Coronary anatomy known

JUMBO-TIMI 26 [8] Phase 2, randomized, doseranging, double-blind safety trial of prasugrel vs. clopidogrel 904 ACS patients undergoing elective or urgent PCI


38 trial [6]. These differences were not significant in the JUMBO-TIMI 26 [8] and TRILOGY ACS trials [11], while the small sample size and low incidence of the primary efficacy end points did not allow for statistical comparison between prasugrel and clopidogrel in the TRIGGER-PCI trial [10]. IPA was superior beginning 30 min after the administration of prasugrel LD and remained significant throughout the MD phase, compared to clopidogrel [9]. The Effient product information warns against other CV complications such as hypertension, hypotension, atrial fibrillation, bradycardia and chest pain. However, there are no reports detailing these findings [12,13]. Heart failure, especially right ventricular failure, can lead to peripheral edema. Ventricular systolic or diastolic dysfunction increases capillary hydrostatic pressure. Edema ensues when fluid extravasation outweighs the ability of the lymphatic system to return it to the vascular space [14]. Drugs are one of the causes of peripheral edema. Although the involvement of platelet inhibitors is unknown, peripheral edema was identified as a treatment-emergent adverse event in the TRILOGY trial. At the same time, the rate of peripheral edema was significantly lower in the prasugrel group (1.9%) compared to the clopidogrel group (2.7%) (p = 0.012) [11]. A possible explanation for this difference is the superior efficacy of prasugrel, leading to lower rates of heart failure. Bleeding Bruising and bleeding were the major ADRs of prasugrel identified in clinical trials [6,8,10,11,15–17]. Bleeding (major, life-threatening or minor) not related to coronary artery bypass grafting represents the key safety data point of the TRITON-TIMI 38 trial [18]. Prasugrel treatment was associated with a higher rate of non-coronary artery bypass grafting-related major bleeding (2.4% vs. 1.8%, hazard ratio (HR) 1.32, 95% confidence interval (CI) 1.03–1.68, p = 0.03), spontaneous major bleeding (1.6% vs. 1.1%, HR 1.51, 95% CI 1.09–2.08, p = 0.01), life-threatening major bleeding (1.4% vs. 0.9%, HR 1.52, 95% CI 1.08–2.13, p = 0.01), as well as fatal major bleeding (0.4% vs. 0.1%, HR 4.19, 95% CI 1.58–11.11, p = 0.002) compared to clopidogrel [6]. Yet, differences between prasugrel and clopidogrel were not significant in the smaller samples of the JUMBO-TIMI 26, PRINCIPLE-TIMI 44 and TRIGGER-PCI trials [8–10]. When taking into account both major and minor bleeding, prasugrel was associated with a higher incidence compared to clopidogrel in the TRITON-TIMI 38 trial (5.0% vs. 3.8%, HR 1.31, 95% CI 1.11–1.56, p = 0.002) but not in the TRILOGY trial (p = 0.11) [6,11]. Table 1 summarizes the efficacy and safety end points in ACS patients treated with prasugrel and clopidogrel in randomized trials. Based on these data, no differences were found between different prasugrel dosing regimens in individuals ≥18 and ≤75 years of age in JUMBO-TIMI 26. Furthermore, a non-significant trend towards lower incidence of major adverse cardiac events and higher risk of non-coronary artery bypass surgery-related significant hemorrhage was observed in prasugrel-treated patients. These differences became significant in the larger samples of the TRITON-TIMI 38 trial. No differences between prasugrel and clopidogrel were observed in ACS patients treated without PCI in TRILOGY ACS [6,8,11]. Old age (≥75 years) and low body weight (b60 kg) are risk factors for bleeding [13]. Both prasugrel (10 mg/day) and clopidogrel (75 mg/day) were associated with an increase in minor and major bleeding in the older age subsample (≥ 75 years) of the TRITON-TIMI 38 trial (3.8% in prasugrel and 2.9% in clopidogrel in patients b75 years vs. 9.0% and 6.9%, respectively, in patients ≥ 75 years). Prasugrel is associated with more severe outcomes in patients ≥ 75 years compared to clopidogrel, such as intracranial (7 prasugrel vs. 3 clopidogrel patients) and fatal hemorrhage (9 vs. 1, respectively) [19]. These results could mean that prasugrel is a risk factor for the severity of bleeding in old patients, which led to a warning against prasugrel use in this age group [13]. Data from the TRILOGY trial show

519

that a lower dose of prasugrel (5 mg/day) in individuals ≥75 years is associated with a similar rate of major and minor bleeding compared to clopidogrel (75 mg/day) [11]. Dose adjustments are also required as body weight decreases. Compared to patients weighing ≥ 85 kg (mean weight of patients in the TRITON-TIMI 38 trial), patients weighing b60 kg were exposed to 1.5 times more drug for the same prasugrel dose [19]. Higher major bleeding rates in prasugrel patients compared to clopidogrel patients were observed in the entire TRITONTIMI 38 sample, as well as a similar trend in the b 60 kg subsample. Statistical significance between the drugs was not achieved owing to the small size of sample (p = 0.089) [6]. A post hoc evaluation of the unpublished TRITON-TIMI 38 data performed by the Food and Drug Administration Cardiovascular and Renal Drugs Advisory Committee revealed that prasugrel no longer provides net clinical benefits compared to clopidogrel in patients ≥ 75 years old and weighing b60 kg, due to a loss of superior efficacy and an increased risk of fatal bleeding [19]. Hemorrhage, particularly intracranial hemorrhage, was also reported [6,20–22]. Due to its increased risk of intracranial hemorrhage, prasugrel is not recommended in patients with a history of cerebrovascular diseases such as stroke [21]. No intracranial hemorrhage was reported in another study [23]. Gastrointestinal hemorrhage [24–26] and peptic ulcer [27] were reported in other studies. Minor bleeding events, defined by Armero et al. as nuisance bleeding and internal bleeding, were common following PCI [28]. Epistaxis was identified as the main minor bleeding event associated with prasugrel use [29]. The initial major bleeding event is an important determinant of prasugrel discontinuation [30]. Prasugrel is associated with a higher bleeding risk at the approved dose (10 mg/day) than clopidogrel as it has an up to 2.7 times more potent platelet aggregation inhibition potential compared to the standard clopidogrel dose (75 mg/day) [31]. Assays measuring response variability to platelet inhibitors Cui et al. used liquid chromatography with tandem mass spectrometric detection in order to measure the levels of prasugrel's active metabolite R-138727 in a small sample of 36 healthy Chinese volunteers [32]. Blood samples were reacted with 3′-methoxyphenacyl bromide in acetonitrile within 30 s of collection to derivatize and stabilize the active metabolite (Table 2). These results were consistent with previously reported values in a Chinese population (320 ng/mL prasugrel active metabolite concentration after a 30 mg LD) [33]. Similar results are described in a Korean population [34]. Median Tmax is 0.5 h (range 0.25–1 h), regardless of ethnicity [32,33]. However, Chinese individuals experience more rapid exposure to the active metabolite of prasugrel compared to Caucasian individuals, accompanied by a greater degree of platelet inhibition. While Tmax remained constant between Chinese and Caucasians, both Cmax and AUC0–t were higher in the former. In these pharmacokinetic studies (Table 2), a high degree of platelet inhibition was observed following the 60 mg and 30 mg LD (94–98%), measured by VerifyNow P2Y12 assay (explained in subsequent paragraphs on assays). The high degree of platelet inhibition was maintained during the 10 mg MD (87%–90%) with lower results in the 7.5 mg and 5 mg MD group (79%–83% and 64%–67%, respectively). These data show that the degree of platelet inhibition is proportional to the amount of active metabolite generated [32]. By quantifying platelet reactivity, laboratory assays are used to objectively assess the variability in antiplatelet responses among patients. Resistance to standard doses of platelet inhibitors in ACS patients leads to higher rates of thrombotic events and poor clinical outcomes, especially in patients undergoing PCI [35]. High on-treatment platelet reactivity (HOPR) while on clopidogrel is defined as higher than expected platelet response to ADP [36]. The reasons may be pharmacokinetic (poor absorption or metabolism of the drug to its active metabolite, higher clearance) or due to a pre-existent platelet hyper-reactivity

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Table 2 Pharmacokinetic parameters of the active metabolite of prasugrel in healthy volunteers. Ethnicity

Parameters

60 mg LD

30 mg LD

10 mg MD

7.5 mg MD

5 mg MD

Chinese [32]

Cmax (ng/mL) AUC0–tlast (ng × h/mL) Cmax (ng/mL) AUC0–tlast (ng × h/mL)

631.0 649.0 498 600

307.0 309.0 271 283

106.0 95.9 92.3 78.1

71.1 58.3 61.9 58.4

42.5 40.1 41.0 38.3

Korean [34]

phenomenon [35,37]. HOPR can be estimated by an array of established assays meant to measure platelet reactivity in the presence of a platelet agonist such as ADP, thrombin or arachidonic acid. Light transmission aggregometry (LTA) is an in vitro assay based on the increase in light transmission following GPIIb/IIIa-dependent platelet aggregation [38]. The change of GPIIb/IIIa to its active conformation follows activation by platelet agonists such as ADP. ADP acts via P2Y12 and P2Y1 receptors, and is commonly used for testing thienopyridines. Centrifugation separates red cells from platelet rich plasma (PRP). PRP blocks light and thus stands for 0% light transmission, while platelet poor plasma (PPP) stands for 100%. When a platelet agonist is added, formation of platelet aggregates allows more light to go through and light transmission increases [39]. In the presence of a platelet inhibitor, platelet aggregates form to a lesser degree and light transmission is lower. Results are given in maximum platelet aggregation (MPA) percentages: MPA% = (X/Y), where X = light transmission measured in the presence of an agonist and Y = 100% light transmission. Alternatively, results are expressed in %IPA, defined as the reverse of MPA [9]. The VerifyNow P2Y12 assay also relies on GPIIb/IIIa-dependent aggregation and light transmission measurements. Fibrinogen-coated beads are added in order to amplify the aggregation and draw the aggregates to the bottom of the tube. Prostaglandin E1 (PGE1) is used to reduce the unwanted effects of ADP on the P2Y1 receptor [40], and thus increase the test sensitivity to the ADP-P2Y12 aggregation pathway [41]. Results are read directly in P2Y12 reaction units (PRU). A P2Y12 inhibition percentage (%PI) can also be calculated as follows: 100 × (P2Y12 reaction units) / [thrombin receptor activating peptidestimulated aggregation (base)] [9]. The vasodilatator associated stimulated phosphoprotein (VASP) phosphorylation assay uses the high correlation between VASP dephosphorylation and P2Y12 receptor state of activation. The level of P2Y12 receptor inhibition (i.e. with prasugrel) is directly proportional to VASP phosphorylation, which is analyzed by flow cytometry and measured by fluorescence, using antibodies targeting phosphorylated VASP [40]. PGE1, through an adenylate cyclase-dependent pathway, has similar effects on VASP [42]. Results of the VASP assay are given in platelet reactivity index (PRI) percentage: %PRI = 100 × [MFI (PGE1) − MFI (PGE1 + ADP)] / MFI (PGE1), where MFI is the mean fluorescence intensity [9,42]. VASP has a good predictive value for bleeding and ischemic events [43]. VASP is also more discriminant than other assays in low %PRI values and could thus be successfully used with the most potent platelet inhibitors, such as prasugrel [43]. VASP is the

most specific assay to determine biological efficacy of P2YT12 inhibitors, including prasugrel. Table 3 summarizes the main characteristics of these assays. The LTA has long been the gold standard for clopidogrel and prasugrel [35,40]. Point-of-care testing such as the VerifyNow or the VASP assays have then been developed using lower sample volumes, shorter turnaround time and better reproducibility [40]. However, no consensus about which assay should be used as the standard method has been reached among European or American scientific communities [46]. According to various investigators who performed the LTA, the VerifyNow P2Y12 and the VASP assays, prasugrel consistently proved to be a more potent platelet inhibitor than clopidogrel [9,35,44,45]. The results of these trials are summarized in Table 4. A significant difference emerges as early as 30 min in LTA [9] or 2 h in VASP [9,35] after the drug is taken (60 mg LD), and is maintained beyond the 30th month of treatment (10 mg/day MD) [44]. The effect of prasugrel is dosedependent [32]. Nonetheless, even at low doses (5 mg/day), prasugrel remains more potent than clopidogrel (75 mg/day) [44,45]. The cut-off values chosen to assess HOPR are assay-dependent. Until recently, cut-off values for each assay further differed from trial to trial, as shown in Table 5. An example of this is the VerifyNow P2Y12 assay. While cut-off values of PRU N 230 and PRU N208 were previously used, Gurbel et al. suggested that a PRU N 178 would be more appropriate to predict CV death, MI or death, based on a receiver operating characteristic curve compiled from a patient subsample of the TRILOGY trial [44]. For VASP, a PRI cut-off of N50% is generally accepted. Whatever PRU limit is established, HOPR is less likely to occur with prasugrel (10 mg/day) than with clopidogrel (75 mg/day) [44,45]. Table 6 summarizes the results of these trials. In the TRITON-TIMI 38 substudy, the percentages of patients with PRI b20%, PRI b 50% and PRI b 80% at 1–2 h (during LD) were 24% for prasugrel and 2% for clopidogrel (p = 0.0019), 43% for prasugrel and 4% for clopidogrel (p = 0.0001), and 71% for prasugrel and 31% for clopidogrel (p = 0.0001), respectively. The corresponding values at 30 days (during MD) were 29% for prasugrel and 4% for clopidogrel (p = 0.0009), and 76% for prasugrel and 57% for clopidogrel (p = 0.0335), for PRI b20% and PRI b50%, respectively. A greater proportion of patients responded to prasugrel than to clopidogrel during both LD and MD at the PRI b50% cut-off (96% vs. 57%, p b 0.001 at 1–2 h, and 43% vs. 24%, p = 0.033 at 30 days). These findings clearly demonstrate the quicker onset of platelet inhibition with prasugrel during LD and the lower likelihood of HOPR with prasugrel than with clopidogrel during MD. [35].

Table 3 Main characteristics of the assays used to measure response variability to platelet inhibitors. Parameter

Light transmission aggregometry assay

VerifyNow P2Y12 assay

VASP assay

Units ADP concentrations used (μM) Variation after addition of ADP

%MPA, %IPA 5 or 20a [9,35,44,45] %MPA: increases %IPA: decreases Poor High Long [40] No

PRU, %PI 20 [40] PRU: increases %PI: decreases High Low Short [40] Yes

%PRI 5 or 10 [42,43] %PRI: increases

Reproducibility [40] Samples volume [40] Turnaround time Point-of-care test [40]

High [43] Low Average [42,43] Yes

P2Y12 reaction units (PRU); P2Y12 inhibition percentage (%PI); platelet reactivity index percentage (PRI%); vasodilatator associated stimulated phosphoprotein (VASP). a Results in this review are reported for 20 μM ADP only.


521

Table 4 Results of assays measuring response variability to platelet inhibitors. Study and patient demographics


Verify-now P2Y12 assay

VASP assay

PRINCIPLE-TIMI 44 [9] Healthy subjects and ACS patients with or without PCI Clopidogrel 600 mg (LD) then 150 mg/day (MD) Prasugrel 60 mg (LD) then 10 mg/day (MD) Crossover between prasugrel and clopidogrel performed between days 15 and 29 with a washout period

MPA with 20 μM ADP at 0.5 h: 52.4 ± 21.7% in prasugrel vs. 72.5 ± 10.0% in clopidogrel (p b 0.0001) MPA with 20 μM ADP at 6 h: 18.9 ± 9.5% in prasugrel vs. 52.1 ± 16.1% in clopidogrel (p b 0.0001) MPA with 20 μM ADP at 18-24 h: 23.2 ± 10.2% in prasugrel vs. 51.1 ± 14.4% in clopidogrel (p b 0.0001) MPA with 20 μM ADP at day 15 (MD; pre-crossover): 28.5 ± 12.9% in prasugrel vs. 41.5 ± 14.1% in clopidogrel (p = 0.0004) MPA with 20 μM ADP at day 29 (MD; post-crossover): 29.7 ± 13.6% in prasugrel vs. 40.2 ± 17.9% in clopidogrel (p b 0.0001) MPA with 20 μM ADP (mean MD): 29.2 ± 13.2% in prasugrel vs. 40.9 ± 15.9% in clopidogrel (p b 0.0001)

PI at 0.5 h: 45.6 ± 34.7% in prasugrel vs. 11.0 ± 8.5% in clopidogrel (p b 0.0001) PI at 6 h: 89.5 ± 10.5% in prasugrel vs. 38.4 ± 26.1% in clopidogrel (p b 0.0001) PI at day 15 (MD; pre crossover): 83.3 ± 16.0% in prasugrel vs. 65.1 ± 23.1% in clopidogrel (p b 0.0001)

TRITON-TIMI 38 substudy [35] ACS patients with PCI Prasugrel 60 mg (LD) then 10 mg/day (MD) Clopidogrel 300 mg (LD) then 75 mg/day (MD) Aspirin 325–500 mg (LD) then 75–162 mg/day (MD) TRILOGY substudy [44] ACS patients without PCI Prasugrel 5 mg/day in patients ≥75 years of age or in patients b75 years of age and weighing b60 kg, and 10 mg/day in patients b75 years of age and weighing ≥60 kg Clopidogrel 75 mg/day

MPA with 20 μM ADP at baseline: ~76% in prasugrel vs. ~80% in clopidogrel MPA with 20 μM ADP at 1–2: 46.5 ± 7.7% in prasugrel vs. 73.7 ± 1.5% in clopidogrel (p = 0.004) MPA with 20 μM ADP at day 30 (MD): 39.9 ± 3.2% in prasugrel vs. 55.2 ± 3.2% in clopidogrel (p = 0.034) n/a

n/a

PRI at baseline: ~85% in prasugrel vs. ~85% in clopidogrel PRI at 2 h: 21.5 ± ~25% in prasugrel vs. 75 ± ~15% in clopidogrel (p b 0.0001) PRI at 6 h: 7.4 ± ~7.5% in prasugrel vs. 68.4 ± ~20% in clopidogrel (p b 0.0001) PRI at 18-24 h: 10.3 ± ~15% in prasugrel vs. 64.3 ± ~20% in clopidogrel (p b 0.0001) PRI at day 15 (MD; pre-crossover): 21.7 ± 8.95% in prasugrel vs. 30.7 ± 8.95% in clopidogrel (p = 0.0001) PRI at day 29 (MD; post-crossover): 25.1 ± 10.85% in prasugrel vs. 48 ± 10.85% in clopidogrel (p b 0.0001) PRI at baseline: ~80% in prasugrel vs. ~80% in clopidogrel PRI at 1–2 h: 51.8 ± 5.1% in prasugrel vs. 78.8 ± 2.5% in clopidogrel (p b 0.001) PRI day 30 (MD): 33.6 ± 2.9% in prasugrel vs. 47.9 ± 2.7% in clopidogrel (p b 0.001) n/a

GENERATIONS trial [45] ACS patients Prasugrel 5 mg/day or 10 mg/day Clopidogrel 75 mg/day Mean results of measurements after 0.5, 1, 2, 3 and 4 h

PRU at baseline among patients b75 years of age and weighing ≥60 kg: ~235 (150–270) in prasugrel vs. ~240 (150–260) in clopidogrel PRU at day 30 among patients b75 years of age and weighing N60 kg: 64 (33–128) in prasugrel vs. 200 (141–260) in clopidogrel (p b 0.001); difference persisted between months 1–30 PRU at baseline among patients b75 years of age and weighing b60 kg: ~220 (160–290) in prasugrel vs. ~240 (140–260) in clopidogrel PRU at day 30 among patients b75 years of age and weighing b60 kg: 139 (86-203) in prasugrel vs. 209 (148-283) in clopidogrel (p = 0.51); difference persisted between months 18–30 PRU at baseline among patients ≥75 years of age: ~240 (190–300) in prasugrel vs. ~240 (195–290) in clopidogrel PRU at day 30 among patients ≥75 years of age: 164 (105–216) in prasugrel vs.222 (148268) in clopidogrel (p b 0.05); difference persisted between months 1–24 MPA with 20 μM ADP at baseline in patients Mean PRU among patients ≥75 years of age: ≥75 years of age: ~80 (73–85)% in prasugrel 175.5 ± 57.19 in prasugrel 5 mg vs. 5 mg vs. ~80 (73–85)% in prasugrel 10 mg vs. 84.1 ± 47.72 in prasugrel 10 mg vs. 212.3 ± 69.65 in clopidogrel ~80 (73–85)% in clopidogrel (p b 0.001) Mean PRU among patients b65 years of age: Mean MPA with 20 μM ADP in patients 177.0 ± 67.29 in prasugrel 5 mg vs. ≥75 years of age: 57 ± 14% in prasugrel 85.5 ± 60.24 in prasugrel 10 mg vs. 5 mg vs. 45.5 ± 11.07% in prasugrel 10 mg 181.2 ± 71.80 in clopidogrel vs. 63 ± 14% in clopidogrel (p b 0.001) MPA with 20 μM ADP at baseline in patients b65 years of age: ~75 (70-85)% in prasugrel 5 mg vs. ~75 (70-85)% in prasugrel 10 mg vs. ~75 (70-85)% in clopidogrel (p b 0.001) Mean MPA with 20 μM ADP in patients b65 years of age: 56.8 ± 11.62% in prasugrel 5 mg vs. 46 ± 12% in prasugrel 10 mg vs. 59.1 ± 13.44% in clopidogrel (p b 0.001)

Mean PRI among patients ≥75 years of age: 44.3 ± 18.87% in prasugrel 5 mg vs. 22.7 ± 11.90% in prasugrel 10 mg vs. 55.0 ± 18.86% in clopidogrel Mean PRI among patients b65 years of age: 54.7 ± 18.67% in prasugrel 5 mg vs. 27.7 ± 15.84% in prasugrel 10 mg vs. 54.5 ± 21.82% in clopidogrel

ADP — adenosine diphosphate; LD — loading dose; MD — maintenance dose; MPA — maximum platelet aggregation; PI — platelet inhibition; PRI — platelet reactivity index; PRU — P2Y12 reaction units. ~ approximate values estimated from data represented graphically in original reports.

Recently, the Working Group on On-Treatment Platelet Reactivity published updated American and European practice guidelines containing recommendation geared towards facilitating the correct choice of antiplatelet medication, based on a patient's specific characteristics

[47,48]. With respect to personalized antiplatelet therapy, HOPR to ADP predicts likely treatment failure, while low on-treatment platelet reactivity to ADP is associated with bleeding. From these recommendations arose the concept of a therapeutic window for P2Y12 inhibitors.

522


Table 5 High on-treatment platelet reactivity cut-off values. Clinical trial


VerifyNow P2Y12assay

VASP assay

PRINCIPLE-TIMI 44 [9]

MPA 20 μM ADP N50% IPA 20 μM ADP b20% n/a n/a MPA 20 μM ADP N50% IPA 20 μM ADP b20%

n/a

n/a

n/a PRU N 208 or PRU N 230 or PRU N 178 PRU N 235

PRI N 50% n/a PRI N 50%

TRITON-TIMI 38 substudy [35] TRILOGY substudy [44] GENERATIONS trial[45]

IPA — inhibition of platelet aggregation; MPA — maximum platelet aggregation; P2Y12 reaction units (PRU); P2Y12 inhibition percentage (%PI); vasodilatator associated stimulated phosphoprotein (VASP).

Evidence shows that VASP is the most specific assay to determine the biological efficacy of P2Y12 inhibitors. Using VASP as an example, a PRI ≥50% is optimal in managing ischemic events while a PRI b16% is associated with an increased incidence of major bleeding [48,49]. Bonello et al. showed that a 10% increase in PRI can be used to predict both thrombotic (OR 1.44, 95% CI 1.2–1.72, p b 0.001) and bleeding (OR 0.75, 95% CI 0.59–0.96, p = 0.024) events during a 1 year follow-up period in ACS individuals treated with prasugrel 60 mg LD after PCI [49]. Based on these findings, platelet reactivity following prasugrel LD has the potential to identify patients at risk of treatment failure or high risk of bleeding, showing a strong relationship between platelet reactivity after prasugrel LD and long-term patient outcomes. This further emphasizes the usefulness of platelet reactivity in personalized medicine, with the best outcomes of antiplatelet therapy likely to occur in individuals inside the therapeutic window [49].

Hematologic complications Recognized hematologic complications include leukopenia, anemia and neutropenia [12,13]. Thienopyridines, including prasugrel, show toxicity in vitro towards both neutrophil granulocytes and lymphocytes [50]. Neutrophil toxicity is mediated by a decrease in the electrical potential across the inner mitochondrial membrane, which is associated with reactive oxygen species accumulation, mitochondrial loss of cytochrome c, and apoptosis. Prasugrel is cytotoxic in both neutrophils and lymphocytes in a dose-dependent manner, beginning at concentrations of 100 μM. In neutrophils, the cytotoxicity of prasugrel is inhibited by the myeloperoxidase inhibitor rutin (20 μM) but not by the cytochrome p450 (CYP) 3A4 inhibitor ketoconazole (1 μM), indicating that myeloperoxidase is the main enzyme responsible for the generation of thienopyridine toxic metabolites in neutrophils, while neither rutin (20 μM) nor the CYP3A4 inhibitor ketoconazole (1 μM) decreased cytotoxicity in lymphocytes, indicating that cytotoxicity in lymphocytes is mediated by the parent compound [50]. In another study, prasugrel metabolites generated by a rat microsomal system were not toxic to neutrophils, although they did interfere with neutrophil function [51]. Thrombotic thrombocytopenic purpura describes a rare blood clotting disorder characterized by abnormal systemic microvascular aggregation of platelets causing brain and organ ischemia. Clinical presentation of this condition shows thrombocytopenia, fragmentation of erythrocytes and elevated lactate dehydrogenase levels [52]. Platelet inhibitors have been associated with thrombotic thrombocytopenic purpura [12]. Several cases induced by prasugrel were included in the Food and Drug Administration Adverse Event Reporting System database, which prompted this agency to include a warning about this ADR in 2010. Blood in urine and blood in stool have been reported in the context of thrombotic thrombocytopenic purpura [13,53].

Dermatotoxicity and cutaneous hypersensitivity syndrome reactions Hypersensitivity syndrome reactions (HSRs) are idiosyncratic ADRs that cannot be predicted by the dose, length and frequency of treatment. Instead, HSRs depend on an individual's susceptibility to a particular drug [54]. The risk of HSRs associated with prasugrel use, including anaphylactic reactions, is recognized in the Effient product information [13]. Prasugrel HSRs are further described in case reports. Generalized pruritic maculopapular rash is the most common manifestation of prasugrel HSR. Patient age ranged between 52 and 76 years, while first symptoms of rash development occurred after 2–7 days of prasugrel exposure [55–58]. Faster onset of reaction occurred in a patient with a history of clopidogrel hypersensitivity [57]. A skin biopsy revealed parakeratosis and spongiotic crusting on the skin surface with epidermal spongiosis, intercellular edema and acanthosis in one patient [55]. Urticaria related to prasugrel use was also recently described [59]. Liver involvement is not described in these reports. Angioedema can accompany cases of prasugrel HSR [55,60]. Prasugrel was switched to clopidogrel in a few studies, resulting in improvement of HSR symptoms [55,58]. Hepatotoxicity and drug-induced liver injury Prasugrel showed comparable efficacy and tolerability in a small sample of patients with and without hepatic impairment [61]. It is often difficult to identify hepatotoxicity of platelet inhibitors, as baseline liver injury is usually one of the main risk factors for this ADR, and patients with baseline liver damage are generally excluded from studies [62,63]. As of 2011, data on hepatotoxicity were absent [64]. Idiosyncratic drug-induced liver injury with prasugrel presented in a 40 yearold woman with a history of smoking and elevated baseline liver enzymes (aspartate transaminase 208 IU/L, alanine transaminase 93 IU/L and γ-glutamyl transpeptidase 240 IU/L). After 23 days of prasugrel therapy, the patient's condition worsened, with aspartate transaminase 115 IU/L, alanine transaminase 155 IU/L and γ-glutamyl transpeptidase 723 IU/L, accompanied by eosinophilia (9.7%). Symptoms subsided upon replacement of prasugrel with clopidogrel [65]. Prasugrel worsened hepatic toxicity in a rat model of arthritis induced by peptidoglycan polysaccharide, manifesting as liver granulomas and giant cell formation [66]. Peptidoglycan polysaccharide can induce inflammation in humans, and one needs to be aware that prasugrel can further exacerbate this condition. Endocrine and metabolic disturbances The Effient product information contains a warning about the risk of hypercholesterolemia/hyperlipidemia as a treatment-emergent ADR

Note to Table 6: LD — loading dose; IPA — inhibition of platelet aggregation; MD — maintenance dose; MPA — maximum platelet aggregation; PI — platelet inhibition; PRI — platelet reactivity index; PRU — P2Y12 reaction units.


523

Table 6 Results of HOPR trials expressed in % of patients over/under the cut-offs values defined in Table 5. Clinical trial


VerifyNow P2Y12assay

VASP assay

PRINCIPLE-TIMI 44 [9] Clopidogrel 600 mg (LD) then 150 mg/day (MD) Prasugrel 60 mg (LD) then 10 mg/day (MD)

MPA 0.5 h (LD): Prasugrel: 50; Clopidogrel: 98.6 p b 0.0001 MPA 6 h (LD): Prasugrel: 0; Clopidogrel: 49.4 p b 0.0001 MPA 18–24 h (LD): Prasugrel: 0; Clopidogrel: 51.1 p b 0.0001 MPA 15 day pre crossover (MD): Prasugrel: 7.5; Clopidogrel: 21.3 p = 0.07 MPA 29 day post crossover (MD): Prasugrel: 8.7; Clopidogrel: 25.0 p = 0.007 IPA 0.5 h (LD): Prasugrel: 42.9; Clopidogrel: 87.7 p b 0.0001 IPA 6 h (LD): Prasugrel: 0; Clopidogrel: 27.3 p b 0.0001 IPA 18–24 h (LD): Prasugrel: 0; Clopidogrel: 30.4 p b 0.0001 IPA mean over MD phase: Prasugrel: 2.4; Clopidogrel: 12.8 p = 0.02 n/a

n/a

n/a

n/a

PRI 1–2 h (LD): Prasugrel: 57; Clopidogrel: 96 p b 0.001 PRI 30 day (MD): Prasugrel: 24; Clopidogrel: 43 p = 0.033 n/a

TRITON-TIMI 38 substudy[35] Prasugrel 60 mg (LD) then 10 mg/day (MD) Clopidogrel 300 mg (LD) then 75 mg/day (MD) TRILOGY substudy[44] Prasugrel 5 mg/day or 10 mg/day depending on age and weight Clopidogrel 75 mg/day

n/a

GENERATIONS trial[45] Prasugrel 5 mg/day or 10 mg/day Clopidogrel 75 mg/day

MPA ≥75 years of age: Prasugrel 5 mg: 74.6 Prasugrel 10 mg: 27.1 Clopidogrel: 85.7 MPA b65 years of age: Prasugrel 5 mg: 79.5 Prasugrel 10 mg: 30.4 Clopidogrel: 75.9 p b 0.05 for all except P 5 mg and Clopidogrel comparison in patients b65 years of age (p = 0.562) IPA ≥75 years of age: Prasugrel 5 mg: 32.4 Prasugrel 10 mg: 1.4 Clopidogrel: 52.9 IPA b65 years of age: Prasugrel 5 mg: 39.7 Prasugrel 10 mg: 8.9 Clopidogrel: 48.1 p b 0.05 for all except P 5 mg and Clopidogrel comparison in patients b65 years of age (p = 0.177)

PRU N230 baseline: Prasugrel: 46; Clopidogrel: 50 PRU N230 2nd h: Prasugrel: 30; Clopidogrel: 45 PRU N230 from 1st to 30th month: Prasugrel: 10–15 Clopidogrel: 38–42 PRU N208 baseline: Prasugrel: 55; Clopidogrel: 57 PRU N208 2nd h: Prasugrel: 38; Clopidogrel: 50 PRU N208 from 1st to 30th month: Prasugrel: 10–25 Clopidogrel: 48–50 PRU N178 baseline: Prasugrel: 68/Clopidogrel: 69 PRU N178 2nd h: Prasugrel: 49/Clopidogrel: 62 PRU N178 from 1st to 30th month: Prasugrel: 20–30 Clopidogrel: 55–65 ≥75 years of age: Prasugrel 5 mg: 14.1 Prasugrel 10 mg: 0 Clopidogrel: 40.6 b65 years of age: Prasugrel 5 mg: 22.1 Prasugrel 10 mg: 0 Clopidogrel: 22.8 p b 0.05 for all except Prasugrel 5 mg and Clopidogrel comparison in patients b65 years of age (p = 0.805)

≥75 years of age: Prasugrel 5 mg: 43.3 Prasugrel 10 mg: 3.1 Clopidogrel: 61.2 b65 years of age: Prasugrel 5 mg: 61.6 Prasugrel 10 mg: 9.5 Clopidogrel: 65.8 p b 0.05 for all except Prasugrel 5 mg and Clopidogrel comparison in patients b65 years of age (p = 0.462)

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[13]. However, no reports about this ADR or its mechanism of development are available in the literature. Baseline hypercholesterolemia is associated with the occurrence of major cardiac adverse events after PCI in prasugrel patients [67], as well as higher rates of serious bleeding [17]. Patients suffering from hypercholesterolemia are more likely to have thrombosis, for which reason they are more likely to be put on prasugrel, in turn leading to higher rates of bleeding [30]. A mouse model of hypercholesterolemia revealed that P2Y12 receptor activation was strongly linked to the platelet hyperreactivity associated with this condition. In mice with elevated cholesterol levels, P2Y12 inhibition with cangrelor (AR-C69931MX) led to a superior decrease in platelet aggregation compared with normocholesterolemic controls [68]. This shows that P2Y12 inhibitors have more efficient antiplatelet effects in hypercholesterolemic patients compared to normal patients. A history of hypercholesterolemia is strongly associated with a diagnosis of diabetes mellitus [30]. Prasugrel shows superior effects in diabetes mellitus patients than other platelet inhibitors [69]. Infection Serebruany et al. describe a case of possible immune suppression after long-term aggressive clopidogrel use followed by prasugrel use. A 65 year-old male was hospitalized for suspected pneumonia upon exposure to prasugrel (10 mg/day) following 4 years of clopidogrel (150 mg/day for the first 13 months). The patient developed apparent blindness, signs of liver, kidney and lung failure, as well as an intensive petechial rash covering the entire body by day 9 of prasugrel treatment. Fatal sepsis complicated by systemic inflammatory response syndrome occurred by day 16. The mechanism of this ADR likely involves the dysregulation of the platelet–neutrophil–endothelial crosstalk necessary to combat infections, followed by an inability to fight infections [70]. In vitro tests reveal that thienopyridines, including prasugrel, have the potential to induce apoptosis in neutrophils and lymphocytes, by a mechanism believed to be mediated by mitochondrial toxicity, in a concentration-dependent manner [50,51]. A small in vivo trial using healthy volunteers revealed that prasugrel has anti-inflammatory properties, stopping acute systemic inflammation through inhibition of a broad spectrum of platelet aggregation pathways [71]. On the other hand, prasugrel had exacerbated peptidoglycan polysaccharide-induced arthritis and joint inflammation in a rat model. In addition, prasugrel treatment led to increased RANTES (regulated on activation, normal T cell expressed and secreted) and decreased interleukin-10 levels in this peptidoglycan polysaccharide arthritis model, compared to treatment conditions lacking prasugrel [66]. The discrepancies between these studies can be explained by the considered populations, one using an animal model of systemic inflammation, while the other study used healthy volunteers. Other adverse events Other mentioned ADRs of prasugrel include gastrointestinal toxicity such as nausea and diarrhea, respiratory complications such as dyspnea and cough, central nervous system toxicity such as headache, dizziness, fatigue, contusion and extremity pain, as well as neuromuscular and skeletal adverse events such as back and extremity pain, and fatigue [13]. Dyspnea is an ADR of prasugrel only in the presence of a baseline underlying disease associated with shortness of breath [72]. A search of PubMed and Google Scholar databases did not identify any reports of pancreatitis. Epigastric discomfort developed after 1 month of dual aspirin and prasugrel treatment in a 58 year-old male ACS patient. Gastroendoscopies revealed edematous esophageal mucosa with blood clots, as well as ulceration with inflammation and granuloma gangraenescens. Necrotic tissues with partly degenerated atypical fusiform of epithelioid cells was revealed by biopsy. Thickening of the middle-lower segment of the esophageal wall with a few small lymph nodes at the mediastinum was further noted, as was an irregular esophageal wall with stiff movement, with peeling esophageal

mucosa. Symptoms began improving within 7 days of interrupting platelet inhibitors and starting treatment with proton pump inhibitors (PPI). Esophageal lesions completely healed in 2 months [73]. Drug–drug interactions The antiretroviral drug ritonavir blocks prasugrel bioactivation, leading to a potential loss of antiplatelet benefits in human immunodeficiency virus-infected ACS patients [74]. Other contra-indicated pharmaceutical agents include chronic non-steroidal anti-inflammatory drugs and warfarin, as these may increase the risk of bleeding [13]. Prasugrel patients may safely take aspirin (75–325 mg/day), heparin, GPIIb/IIIa inhibitors, statins, ranitidine, digoxin, and drugs that elevate gastric pH including H2 blockers [13,75–80]. The strong CYP3A4 inhibitor ketoconazole decreased the Cmax of R-138727 without significant decreases in its exposure or %IPA [81]. Likewise, strong CYP3A4 inducers did not have a significant effect on R-138727 Cmax or on prasugrel's therapeutic potential [82]. Despite proof of their extensive use as co-medication in ACS patients [6], a search of the PubMed and Google Scholar databases did not uncover any reports regarding interaction between prasugrel and either angiotensinconverting enzyme inhibitors, angiotensin-receptor blockers, calcium channel blockers or β-blockers. These findings are supported by a recent review [83]. In vitro data show that omeprazole, esomeprazole and rabeprazole have the potential to inhibit the formation of R-138727 in human liver microsomes, with IC50 values of 9–25 μM, and significantly decreased its antiplatelet activity. Inhibition of prasugrel metabolism correlates directly with CYP3A4 inhibition [84]. However, the concentrations needed to achieve these levels of inhibition are higher than the in vivo Cmax of the PPIs. For example, the omeprazole IC50 was 10-fold higher than its Cmax [85]. In vivo, lansoprazole decreased R-138727 AUC0–t and Cmax without any consequence on its effect [86]. Clinical data from the TRITON TIMI-38 and TRILOGY studies do not support a significant interaction between PPIs and prasugrel [11,77,86]. Findings from the PRINCIPLE TIMI-44 study, a small study analyzing 102 prasugrel patients (25 treated with PPIs and 77 not treated with PPIs) revealed that concomitant PPI use was associated with a trend towards lower platelet inhibition [77]. Prasugrel use with concomitant smoking was associated with significantly superior prevention of CV death, MI or stroke, compared to nonsmoking, in a recent large analysis of ACS patients from TRITON TIMI-38 and TRILOGY (p b 0.004). Smoking induces CYP1A2, one of the enzymes involved in prasugrel metabolism and generation of its active metabolite. In fact, prasugrel was not significantly superior to clopidogrel in non-smokers (p = 0.112), while it was significantly superior in smokers (p b 0.001) [87]. Further evidence that it is indeed CYP1A2 induction that makes prasugrel superior in smokers is provided by ticagrelor, a non-substrate of this enzyme. Ticagrelor was equally efficacious regardless of patient smoking status [88]. Smoking had no effect on the efficacy of prasugrel in other reports [89,90]. The body of proof regarding clinical benefits in terms of CV outcomes in smokers compared to non-smokers remains somewhat complicated by confusing classifications such as “cigarette smoking” or “tobacco use”, as well as a lack of information on the frequency of smoking. This provides inconsistent information regarding the amount of nicotine delivered or exposure to other components of cigarette smoke, making it difficult to identify the chemicals that enhance platelet inhibitory effects [91]. Prasugrel and R-95913 are weak inhibitors of CYP2B6, CYP2C19 and CYP2D6 [92]. For example, prasugrel decreased the metabolism of bupropion, a CYP2B6 substrate, without significant clinical implications. Prasugrel is unlikely to require dose adjustments in patients treated with other CYP2B6 substrates, unless the co-medication is solely a substrate of CYP2B6, has a narrow therapeutic index, or is given at or near the maximum therapeutic dose [75], examples of which include the chemotherapeutic agent cyclophosphamide, the antiretroviral drugs efavirenz and nevirapine, as well as propofol [93].


Prasugrel and cancer The relationship between prasugrel use and cancer risk is complex. Two years long life-time pre-clinical studies in rat showed that exposure to 100 mg/kg, which was considered the maximally tolerated dose, led to diffuse hepatocyte hypertrophy in both genders and increased the severity of hepatic eosinophilic foci in males only. While altered cell foci can progress to benign and even malignant hepatocellular neoplasia, these adverse events were considered to have resulted from the induction of drug-metabolizing enzymes [94,95]. In mouse, 300 mg/kg increased the incidence of hepatocellular adenoma in both genders, while both 100 mg/kg and 300 mg/kg were associated with hepatocellular adenoma in females. Hepatocellular carcinoma was also observed at the same doses. Furthermore, a weak association was found with intestinal and lung cancer. However, it was concluded that prasugrel was neither a complete carcinogen nor a cancer promoter [94,95]. The published TRITON-TIMI 38 data (mean follow-up 14.5 months) draw attention to an unexpectedly high incidence of colorectal cancer. Thirteen new colorectal neoplasms were identified in the prasugrel arm (0.2% of sample) compared to 4 in the clopidogrel arm (0.1% of sample) (p = 0.03). The explanation provided by the TRITON-TIMI 38 investigators was that the increased incidence of gastrointestinal bleeding in the prasugrel arm likely led to a more detailed clinical examination of these patients, which in turn led to an easier detection of cancer [6,94,96]. Based on findings from the CHARISMA trial comparing dual clopidogrel and aspirin therapy with aspirin alone, thienopyridines do not cause cancer despite a substantial bleeding risk. Long-term studies with clopidogrel and ticlopidine were also not associated with cancer, and based on a similar chemical structure, prasugrel is unlikely to have a substantial cancer risk [31,95–97]. Another hypothesis is that prasugrel use promotes already-present cancers, with a possible explanation being that chronic oral platelet inhibition causes disruption of tumor-platelet aggregates, leading to propagation of initially silent tumors [31,95]. Further analysis of the TRITON-TIMI 38 trial, particularly the unpublished data, puts the initial assessment under scrutiny. These late data reveal a higher incidence of new cancers, particularly solid cancers, in prasugrel patients (n = 92) compared to clopidogrel patients (n = 64) (HR 1.44, p = 0.02). These differences are even more striking when grouping new and worsening solid cancers [n = 112 (1.6%) in prasugrel and n = 69 (1.0%) in clopidogrel, HR 1.62, p = 0.001] [31,94]. Differences in cancer rates between clopidogrel and prasugrel become evident after 4 months of treatment, indicating that while prasugrel may not necessarily cause cancer, it may promote it, a period of 4 months representing a fair length of time for metastasis [31]. Most cases of breast, prostate and lung cancer were identified within 6 months of treatment initiation, making it unlikely that prasugrel has a direct effect on cancer development over such a short period of time [94]. Female gender provides an additional risk factor, as the divergence between clopidogrel and prasugrel becomes apparent after less than 2 months in females [98]. Serebruany et al. describe the case of a 70 year-old diabetic woman with a family history of colorectal and prostate cancer who received dual antiplatelet therapy comprising of prasugrel and aspirin following MI. The patient was diagnosed with solid lung nodules after 4 months of treatment, as well as multiple brain metastases. The patient died within the next 2 months [98]. The role of platelet aggregation in tumor metastasis is a controversial topic. There is evidence in the literature that platelet clots can both promote, as well as stop, tumor metastasis. The pro-metastatic properties of platelets have long been recognized. This is reviewed in detail by Goubran et al. [99]. Platelets help tumor cells at numerous steps in the metastasis process, including promoting intravasation, traveling in the blood stream by shielding the tumor cells from immunosurveillance and shear mechanical pressure, tethering, extravasation, angiogenesis, as well as additional release of pro-angiogenesis factors and tumor growth factors [99,100].

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On the other hand, platelets may also have anti-carcinogenic properties. Platelets could inhibit metastasis by trapping tumor cells upon entry into the blood, thus preventing them from spreading to other locations. Platelet aggregates are thus believed to keep cancer cells trapped locally and prevent their dissemination via the blood. From this perspective, prasugrel can act as a tumor promoter by breaking or preventing the formation of platelet-tumor cell aggregates. Prasugrel is the most potent thienopyridine, providing an explanation as to why it could be associated with higher cancer rates than clopidogrel [31, 95]. Furthermore, platelet factor-4 diminishes tumor growth [101]. Clopidogrel and ticlopidine significantly reduce platelet factor-4 release [102,103]. Since prasugrel is more potent than clopidogrel and ticlopidine, it should reduce platelet factor-4 release to a greater degree, therefore promoting cancer growth [95]. In follow-up in vitro and animal studies, prasugrel was nongenotoxic in a bacterial reverse mutation assay, and it did not increase tumor cell proliferation in human lung, colon or prostate tumor cell lines. Lifetime bioassays revealed an increase in the incidence of hepatocellular adenomas with 100 mg/kg in female mice and 300 mg/kg in both genders. This however represents an exposure in the mouse that is at least 250-fold higher than the clinical exposure following a 10 mg daily dose in humans. These findings were considered to be related to enzyme induction [100]. Enzyme induction associated with the use of high doses of non-genotoxic compounds is common in lab animals, and unlikely to be relevant in humans [104]. Furthermore, an increase in the incidence of eosinophilic altered cell foci in the liver, centrilobular hypertrophy of the hepatocytes, as well as thyroid follicular cell hypertrophy, were observed at doses exceeding 100 mg/kg. These morphological changes were also considered to be related to enzyme induction, and therefore deemed to be non-relevant in humans. Similar findings were observed in rats at doses exceeding 100 mg/kg, all of which were considered to have resulted from enzyme induction [100]. Studies with phenobarbital in animal models, a well-known hepatic enzyme inducer, show that altered hepatic foci develop following drug administration. Phenobarbital leads to constitutive androstane receptor activation, CYP2B induction, increased hepatocyte proliferation, liver hypertrophy, inhibition of apoptosis, and finally development of altered hepatic foci. For phenobarbital specifically, enzyme induction is dependent on constitutive androstane receptor activation, and this pathway is proved to be less important in human enzyme induction [105]. Enzyme induction in animal models, particularly CYP2B, is associated with reactive oxygen species generation, which suggests that while nongenotoxic itself, phenobarbital could be an efficient tumor promoter [105]. Findings from animal models with prasugrel are similar to those of phenobarbital; however there is no definitive evidence to suggest that prasugrel indeed induces hepatic enzymes in humans [100]. Doses of 1 mg/kg did not induce tumor cell proliferation in mouse xenograft models of human colon, lung or prostate tumors. There were no differences in tumor weight between prasugrel-treated mice and control animals [100]. Based on these findings, prasugrel is unlikely to be a true carcinogen or a cancer promoter, as the only location of cancer was in the liver. If prasugrel were a true cancer promoter, neoplasia would have also been induced in other organs. However, one cannot exclude the possibility that prasugrel is a liver carcinogen, suggesting that we need to closely monitor cancers in humans, especially hepatocellular adenomas. The possibility that co-medication administered to ACS patients is in part responsible for the increased cancer incidence cannot be excluded either. Statins, angiotensin-converting enzyme inhibitors, angiotensin II-receptor blockers, β-blockers and calcium channel blockers are commonly administered in ACS patients, along with antiplatelet medication [6]. Statins were generally not associated with cancer, however there are within-class differences. For example, hydrophobic statins (i.e. simvastatin, lovastatin and fluvastatin) were protective against breast cancer, while hydrophilic statins (i.e. pravastatin and atorvastatin) were not associated with breast cancer incidence [106]. Overall, use of statins was

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either protective or neutral, however differences remain with respect to each single drug and types of cancer being assessed [107]. Angiotensinconverting enzyme inhibitors [108–112] and angiotensin II-receptor blockers [108–110,113] were weakly associated with both cancer risk and protection. β-blockers (i.e. metoprolol and sotalol) led to an increased risk of recurrent breast cancer [112], while calcium channel blockers were overall weakly associated with cancer [109], particularly lung cancer [108]. Contradictory associations are reported because these agents are considered as a class rather than individual drugs [109]. A possible explanation for the differences between clopidogrel and prasugrel could be that patients on prasugrel suffer from more severe disease and are therefore more likely to be on co-medication. Additionally, prasugrel may have unknown effects on other drugs that clopidogrel doesn't have, but this hypothesis cannot be tested based on available data. Based on the alarming findings of the TRITON-TIMI 38 trial, the risk of cancer in humans cannot be dismissed. Following these unexpected findings, patients should have been followed for a longer period of time after the completion of the trial in order to elucidate the risk of cancer [114]. Therefore, based on available evidence, prasugrel is not a cancer initiator but it may promote already existing cancer, either directly or through its platelet inhibitory effects. More data from clinical studies with a longer follow-up period, ideally designed to uncover cancers, are needed. Which P2Y12 inhibitor is preferred? Recent clinical trials showed that prasugrel and ticagrelor significantly reduce the rate of CV death, MI or stroke compared to clopidogrel in large samples of ACS patients. While more efficacious, these two drugs have an inferior safety profile to clopidogrel [6,115]. Therefore, the debate over which P2Y12 inhibitor is preferred in ACS patients remains. Superior platelet inhibition was observed in prasugrel-treated patients in the PRINCIPLE-TIMI 44 trial and in the ACAPULCO study. These were shown by LTA, VerifyNow P2Y12 assay and VASP. Based on these findings, prasugrel was preferred to high-dose clopidogrel in instances when the clinical goal is to achieve higher levels of IPA [9, 116]. Decreased platelet reactivity in prasugrel is generally supported by lower rates of major adverse cardiac events, coupled with a higher risk of hemorrhagic adverse events [6,8]. Thus, the choice of treatment rests with the physician, based on perceived benefit and risk assessment in individual patients. For example, prasugrel did not decrease the incidence of CV death or MI in a small sample of patients with stable disease despite HOPR while on clopidogrel, while it led to a trend towards an increased risk of non-coronary artery bypass surgery TIMI bleeding [10]. Another important consideration is the severity of the underlying CV condition. Prasugrel was not superior to clopidogrel in patients with unstable angina or non-ST segment elevation MI treated without revascularization in TRILOGY ACS. The incidence of severe bleeding was also similar [11]. Prasugrel was not superior to placebo in decreasing the incidence of CV death, MI or stroke in non-ST segment elevation MI patients treated at the time of diagnosis before undergoing coronary angiography and PCI in the ACCOAST trial. However, the rates of major bleeding and life-threatening bleeding not related to coronary artery bypass surgery were higher in prasugrel patients compared to placebo [117]. Based on these findings, prasugrel is equally efficient yet less safe than clopidogrel in lower-risk populations. A head-to-head comparison between prasugrel and ticagrelor is unlikely to yield any definitive results at this time. This is especially complicated by different population characteristics in clinical trials with prasugrel and ticagrelor [118]. Prasugrel can be administered at any point in ST segment elevation MI patients, yet its administration is recommended only after coronary anatomy is known in non-ST segment elevation MI patients. Ticagrelor however can be administered at any time in ACS patients. Based on these premises, ticagrelor is

hypothesized to be superior to prasugrel as pre-treatment regardless of clinical presentation and coronary anatomy. This is under investigation in the ongoing ISAR-REACT 5 trial [119]. Conclusion Prasugrel is overall associated with a superior platelet inhibition potential compared to clopidogrel. This is supported by clinical data, which show better CV outcomes in prasugrel patients compared to clopidogrel patients, as well as in vitro assays. However, higher rates of hemorrhagic adverse events, particularly major bleeding, are associated with this drug, a consequence of its superior platelet inhibition potential. While a direct link between prasugrel and cancer is yet to be demonstrated, we discussed this topic in light of findings from different trials. Treatment decisions rest with each patient's physician, and a risk-benefit assessment should be made on a case-by-case basis, taking into account each patient's risk factors and underlying disease characteristics. 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Prasugrel hydrochloride for the treatment of acute coronary syndromes.

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High Platelet Reactivity in Patients with Acute Coronary Syndromes Undergoing Percutaneous Coronary Intervention: Randomised Controlled Trial Comparing Prasugrel and Clopidogrel.

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Association of aspirin dose and vorapaxar safety and efficacy in patients with non-ST-segment elevation acute coronary syndrome (from the TRACER Trial).

Frailty and outcome in elderly patients with acute coronary syndrome.

Meta-Analysis of Comparison of the Newer Oral P2Y12 Inhibitors (Prasugrel or Ticagrelor) to Clopidogrel in Patients With Non-ST-Elevation Acute Coronary Syndrome.

Cytomegalovirus in Plasma of Acute Coronary Syndrome Patients.

Switching patients from clopidogrel to novel P2Y12 receptor inhibitors in acute coronary syndrome: comparative effects of prasugrel and ticagrelor on platelet reactivity.

Estimation of serum neopterin in patients with acute coronary syndrome.

Efficacy and Safety of Intracoronary versus Intravenous Administration of Tirofiban during Percutaneous Coronary Intervention for Acute Coronary Syndrome: A Meta-Analysis of Randomized Controlled Trials.

Impact of non-inhibited platelet supplementation on platelet reactivity in patients treated with prasugrel or ticagrelor for an acute coronary syndrome: An ex vivo study.