TY - JOUR
AU1 - Price, Matthew, J.
AB - Abstract Purpose. The efficacy and safety of new antiplatelet therapies, as well as antiplatelet therapies in development, are reviewed. Summary. Variability in the response to treatment with aspirin has been recognized for more than 40 years. Thienopyridine antiplatelet agents are now a standard pharmacologic component in the management of patients undergoing percutaneous coronary intervention (PCI) and stent placement. However, investigators have recently described wide inter-individual variability in the level of platelet inhibition following treatment with the thienopyridine clopidogrel, with a small number of patients classified as “non-responders” or “resistant.” Such variability in response is likely to have important clinical implications, because antiplatelet therapy plays a key role in the prevention and treatment of cardiovascular disease, For example, recent studies have demonstrated that diminished response to clopidogrel may be associated with increased cardiac events after PCI. Even with larger-than-approved loading doses, clopidogrel requires several hours to reach a steady-state effect, and therapy must be discontinued for several days prior to surgery in order to avoid major bleeding events. Clinical trials of prasugrel, a new oral thienopyridine with a more rapid onset of platelet inhibition, have demonstrated significant reductions in adverse cardiovascular outcomes and stent thrombosis; however, there is an increased risk for major bleeding events with prasugrel in some subgroups of the study populations. These limitations have led to development of agents that may potentially overcome such clinical challenges. AZD6140, a novel, potent oral P2Y12 antagonist, demonstrated more effective platelet inhibition versus clopidogrel in a large randomized trial of patients with acute coronary syndrome. However, patients taking AZD6140 reported dyspnea significantly more frequently than those taking clopidogrel. Cangrelor, a novel intravenous P2Y12 receptor antagonist with a rapid onset of action and complete reversibility of platelet inhibition within 20–50 minutes of administration, may offer advantages over currently approved antiplatelet therapies. A new oral antiplatelet thrombin-receptor antagonist, TRA-SCH 530348, is in early clinical trials. Unlike currently available drugs, TRA-SCH 530348 effectively prevents thrombin-induced activation of platelets. Conclusion. Each new class of antiplatelet therapies has the potential for specific benefits and adverse effects in clinical use. Aspirin, AZD6140, Cangrelor, Cardiovascular diseases, Clopidogrel, Dosage, Mechanism of action, Pharmacokinetics, Platelet aggregation inhibitors, Prasugrel, Product development, Thienopyridines, Toxicity, TRA-SCH 530348 Variability in patients’ response to treatment with aspirin has been recognized for more than 40 years.1,–7 Studies in small numbers of patients have suggested that there is a correlation between aspirin resistance and clinical outcomes with aspirin therapy.8 More recently, investigators have described variability in the level of platelet inhibition afforded by treatment with the thienopyridine clopidogrel, with a small number classified as “non-responders” or “resistant.”9 The clinical implications of this variability in response is likely important, given the high prevalence of atherosclerotic disease and the pivotal role of antiplatelet therapy in its prevention and treatment. Variability in platelet response to antiplatelet therapy A growing body of data demonstrates the wide inter-individual variability in the inhibitory response to clopidogrel. One study to document the individual variability of response to clopidogrel therapy analyzed ex vivo platelet function in a database of 544 subjects with risk factors for or documented vascular disease, patients with heart failure or a history of ischemic stroke, and patients undergoing coronary stenting.8 When platelet aggregation was induced with adenosine diphosphate (ADP), there was wide variability in response to clopidogrel 75 mg/day that followed a typical bell-shaped distribution (Figure 1).8 Another study found that individual variability in response to clopidogrel extends to the interval between administration of a loading dose and cardiac catheterization.10 The recently reported Low Responsiveness to Clopidogrel and Sirolimus- or Paclitaxel-eluting Stent Thrombosis (RECLOSE) trial was the first to establish that nonresponsiveness to clopidogrel is a strong predictor of stent thrombosis in patients receiving drug-eluting stents.11 By ADP-induced platelet reactivity measured via light transmittance aggregometry, 13% of 804 patients were considered non-responders to a 600-mg loading dose of clopidogrel. After six months of dual antiplatelet therapy with clopidogrel 75 mg/day and aspirin 325 mg/day, subacute or late thromboses were documented in 3.1% of all patients, but the incidence was 8.6% among nonresponders compared with 2.3% among responders (p = 0.001). In a prospective study of predominantly elective patients undergoing percutaneous coronary intervention (PCI) with drug-eluting stents, a significant association was noted between platelet reactivity on clopidogrel and six-month thrombotic outcomes.12 Patients with lower P2Y12- mediated platelet reactivity were significantly less likely to experience the composite end point of cardiovascular (CV) death, MI, or stent thrombosis than those with higher scores (1.0% versus 6.5%, p = 0.008). There were no stent thromboses or CV deaths in patients responsive to clopidogrel and compliant with antiplatelet therapy, compared with 4.6% (p = 0.004) and 2.6% (p = 0.04), respectively, in nonresponsive patients. The safety and efficacy of a higher maintenance dose in clopidogrel non-responders receiving drug-eluting stents will be studied in the upcoming Gauging Responsiveness With A VerifyNow® Assay–Impact on Thrombosis and Safety (GRAVITAS) trial (ClinicalTrials.gov Identifier NCT00645918). Exploring the next generation of thienopyridines Several limitations to the use of thienopyridine antiplatelet agents have led to the development of dosages and agents that may overcome such clinical challenges. For example, because it may take 5–7 days to achieve steady-state platelet inhibition with a 75 mg/day maintenance dose of clopidogrel, a 300-mg loading dose of clopidogrel is the FDA-approved dose to be administered at the time of PCI in order to achieve steady-state platelet inhibition more rapidly.13 However, considerable individual variability of response to clopidogrel may account for suboptimal platelet inhibition in up to 30% of patients, which has been associated with subacute stent thrombosis and major CV events.13 Furthermore, the CREDO study illustrated that a reduction in adverse periprocedural events was observed only in patients treated at least six hours, and perhaps as long as 15 hours, before the procedure.14 A loading dose of 600 mg can achieve steady-state inhibition more quickly than 300 mg (at approximately four hours), but significant inter-individual variability still exists, and neither the speed to steady-state inhibition nor this variability can be improved by an even higher 900-mg dose.15 Another limitation of clopidogrel therapy is the need to postpone any necessary CV surgery until 5–7 days after discontinuation of the last clopidogrel dose in order to avoid major bleeding events.14 Prasugrel, a next-generation thienopyridine, has several characteristics that may be beneficial in patients requiring dual antiplatelet therapy.13,14,16,17 Like clopidogrel and ticlopidine, prasugrel is a pro-drug metabolized in vivo to an active metabolite that irreversibly binds the platelet P2Y12 receptor and in so doing inhibits ADP- mediated platelet activation and aggregation.13 In a two-way crossover study of 68 healthy volunteers, inhibition of platelet aggregation in response to ADP exposure was significantly higher after a 60-mg dose of prasugrel compared with a 300-mg dose of clopidogrel (p < 0.01), and achieved steady-state inhibition much more quickly.13 Three important findings of this study were that (1) the level of inhibition achieved by prasugrel is much greater than clopidogrel; (2) there is significantly less variation in this response with prasugrel compared to clopidogrel; and (3) more efficient conversion of prasugrel to its active metabolite likely explains both of these observations. To determine whether the increased inhibition of platelet aggregation with prasugrel was safe, the dose-ranging Joint Utilization of Medications to Block Platelets Optimally—Thrombolysis in Myocardial Infarction 26 (JUMBO—TIMI 26) trial compared standard clopidogrel dosing with three prasugrel regimens (loading/maintenance doses of 40/7.5 mg/day, 60/10 mg/day, and 60/15 mg/day) in 904 patients undergoing PCI.14 The incidence of the primary endpoint (clinically significant non-coronary artery bypass-related bleeding events within 30 days) was low, with no significant difference between prasugrel and clopidogrel (1.2% versus 1.7%, p = 0.59).14 There also were no significant or dose-related differences in the primary safety end point among the three prasugrel groups. While this safety study was not powered to detect a significant difference in clinical outcomes, a numerically lower rate of MI in the entire prasugrel cohort was found when compared with the clopidogrel group (5.7% versus 7.9%). In a phase III trial, Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel (TRITON-TIMI 38),14,18 13,608 adults with moderate- to high-risk acute coronary syndromes (ACS) scheduled to undergo PCI were randomized to treatment with a 60-mg loading dose of prasugrel and a 10-mg/day maintenance dose or a 300-mg loading dose of clopidogrel and a 75-mg/day maintenance dose for 6–15 months. Treatment with prasugrel was associated with a significant reduction in ischemic events but an increased risk for major bleeding (Figure 2).18 Similar reductions in the risk for the primary end point were also seen at 30 days and at 90 days after PCI. The prasugrel group also had significant reductions in the rates of MI (7.4% versus 9.7%, p < 0.001), target vessel revascularization (2.5% versus 3.7%, p < 0.001), and stent thrombosis (1.1% versus 2.4%, p < 0.001). However, major bleeding, the key primary safety endpoint, occurred in significantly more patients in the prasugrel group than in the clopidogrel group (2.4% versus 1.8%, p = 0.03), and there were higher rates of life-threatening (1.4% versus 0.9%, p = 0.01) and fatal (0.4% versus 0.1%, p = 0.002) bleeding during prasugrel treatment. The TRITON-TIMI 38 investigators conducted a post hoc analysis to assess which patients may not achieve a net clinical benefit from prasugrel (that is, the combination of ischemic and bleeding outcomes).18 Patients with one of three risk factors appeared not to gain a net clinical benefit from prasugrel over clopidogrel: patients with a history of stroke or transient ischemic attack (TIA), patients aged 75 years or older, and patients weighing less than 60 kg. Importantly, patients with a history of stroke or TIA had a strong trend toward a higher rate of major bleeding (p = 0.06), including intracranial hemorrhage in six patients in the prasugrel groups (2.3%) compared with none in the clopidogrel group (p = 0.02). Although this post hoc subgroup analysis of a small group of patients should be interpreted with caution, clinicians need to weigh the benefits and risks of intensive inhibition of platelet aggregation in selected subgroups of patients with ACS undergoing PCI. Other antiplatelet agents in development The first reversible oral ADP receptor antagonist, AZD6140, has been evaluated in several clinical trials. AZD6140 has a plasma half-life of approximately 12 hours and requires twice daily (BID) dosing.19 In studies in human volunteers, AZD6140 nearly completely inhibited platelet aggregation two hours after dosing, with a lessening of platelet inhibition over the 24 hours after dosing. In the clinical trial Dose confirmation Study assessing anti-Platelet Effects of AZD6140 versus clopidogrel in non-ST-segment Elevation myocardial infarction-2 (DISPERSE-2), patients were randomized to treatment with AZD6140 90 or 180 mg BID or clopidogrel 75 mg once daily (QD) for up to 12 weeks.17 AZD6140 inhibited platelet aggregation in a dose-dependent manner, and both doses achieved greater levels of inhibition than clopidogrel. At four weeks, treatment with AZD6140 at 90 mg and 180 BID achieved 79% and 95% inhibition of platelet aggregation (IPA), respectively, at four hours after the dose, compared with an IPA of 64% with clopidogrel (p < 0.001). DISPERSE-2 also evaluated the safety of AZD6140.19 During the first four weeks of the study, total bleeding rates were 9.8% and 8.0% in the AZD6140 90 mg BID and 180 mg BID groups, respectively, compared with 8.1% in the clopidogrel group; the respective major bleeding rates were 7.1%, 5.1%, and 6.9%. None of the inter-group differences was statistically significant. An interesting finding was that dyspnea was reported significantly more frequently in both AZD6140 groups than in the clopidogrel group (p < 0.0002), although discontinuation of treatment was no more frequent in the AZD6140 groups. Another antiplatelet agent under clinical investigation, cangrelor, is a selective and specific antagonist of the P2Y12 receptor.20,21 Cangrelor has novel features, including an intravenous formulation, short half-life (3–5 minutes), and reversibility.20 It has a rapid onset of action, can achieve nearly complete inhibition of platelet aggregation, and its effects can be completely reversed in 20–50 minutes. The rapid onset and reversibility of the effects of cangrelor were demonstrated in a study of 200 patients undergoing PCI, in which the response to an infusion of 1, 2, or 4 μg/kg/min for up to 24 hours (in addition to aspirin and heparin) was dose related and maximal 15 minutes after initiation (Figure 3).21 In 199 other patients in the same study, the clinical effects of cangrelor (4 μg/kg/min with aspirin and heparin) were compared with the glycoprotein IIb/IIIa inhibitor abciximab.21 There was little difference in the occurrence of the composite endpoint (death, MI, or reintervention) at seven days between cangrelor (5.7%) and abciximab (5.4%), and no significant differences in the incidence of major (1% and 2%, respectively) or minor (6% and 7%, respectively) bleeding. A phase III trial of 9,000 patients with unstable angina, MI, or ACS scheduled for PCI is in progress to compare the effectiveness of cangrelor and clopidogrel, with a primary composite endpoint of all-cause mortality, MI, or ischemia driven revascularization (IDR) in the 48 hours after randomization.22 Compared with the thienopyridines, cangrelor may eliminate the need for administration of a loading dose hours before PCI and provide substantially greater antiplatelet effects, yet much more data is needed to substantiate this theory.21 A new oral antiplatelet agent, TRA-SCH 530348, is under development for the prevention of atherothrombotic events in patients with ACS, peripheral arterial disease, or a history of MI or stroke.23 Unlike currently available drugs, this thrombin-receptor antagonist effectively prevents thrombin-induced activation of platelets and subsequent thrombus formation. Preliminary results from a study of TRA-SCH 530348 in 1031 patients on clopidogrel and aspirin found similar incidences of major or minor bleeding with doses ranging from 10–40 mg/day that were comparable to those in patients given placebo. During 60 days of maintenance therapy, there was a 46% decrease in CV events in the group receiving the highest dose, although the study was not powered to show a reduction in clinical events.24 The clinical efficacy of TRA-SCH 530348 will be examined in the TRACER study, which will determine whether SCH 530348, when added to the existing standard of care for preventing heart attack and stroke in patients with ACS, will yield additional benefit in preventing heart attack and stroke (ClinicalTrials.gov Identifier NCT00527943). Conclusion The inter-individual variability in the inhibitory response to clopidogrel is well established. Prospective studies have demonstrated that a diminished response to clopidogrel may be associated with increased cardiac events after PCI. Clopidogrel has several limitations in clinical use. Even with larger-than-approved loading doses, clopidogrel requires several hours to reach a steady-state effect, and therapy must be discontinued for several days prior to surgery in order to avoid major bleeding events. Clinical trials of prasugrel, a new oral thienopyridine with a more rapid onset of much greater ADP-induced platelet inhibition, have demonstrated reductions in adverse CV outcomes and stent thrombosis but with an increased risk for major bleeding events in some subgroups in the study populations. Other new agents are currently being evaluated in large, randomized trials of ACS patients. Figure 1. Open in new tabDownload slide Individual variability in ex vivo platelet response to adenosine diphosphate (ADP) among patients treated with clopidogrel 75 mg/day (n = 544). Reprinted with permission from reference 8. Figure 1. Open in new tabDownload slide Individual variability in ex vivo platelet response to adenosine diphosphate (ADP) among patients treated with clopidogrel 75 mg/day (n = 544). Reprinted with permission from reference 8. Figure 2. Open in new tabDownload slide Cumulative Kaplan-Meier estimates of the primary efficacy endpoint (cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke) and the key safety endpoint (major bleeding) in 13,604 patients with acute coronary syndromes undergoing percutaneous coronary intervention in the TRITON—TIMI 38 trial. Reprinted with permission from reference 18. Figure 2. Open in new tabDownload slide Cumulative Kaplan-Meier estimates of the primary efficacy endpoint (cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke) and the key safety endpoint (major bleeding) in 13,604 patients with acute coronary syndromes undergoing percutaneous coronary intervention in the TRITON—TIMI 38 trial. Reprinted with permission from reference 18. Figure 3. Open in new tabDownload slide Platelet aggregation response to adenosine phosphate during infusion of cangrelor or placebo in patients undergoing percutaneous coronary intervention. Reprinted with permission from reference 21. Figure 3. Open in new tabDownload slide Platelet aggregation response to adenosine phosphate during infusion of cangrelor or placebo in patients undergoing percutaneous coronary intervention. Reprinted with permission from reference 21. References 1 Krasopoulous G, Brister SJ, Beattie WS et al. 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PubMed 21 Greenbaum AB, Grines CL, Bittl JA et al. Initial experience with an intravenous P2Y12 platelet receptor antagonist in patients undergoing percutaneous coronary intervention: Results from a 2-part, phase II, multicenter, randomized, placebo- and active-controlled trial. Am Heart J. 2006 ; 151 : 689.e1 –689.e10. Crossref Search ADS 22 A Clinical Trial to Demonstrate the Efficacy of Cangrelor. www.clinicaltrials.gov/ct2/show/NCT00305162?term=cangrelor&rank=3 (accessed 2008 Jan 14). 23 Drug Development Technology: TRA-SCH-530348—A novel oral anti- platelet agent. www.drugdevelopment-technology.com/project_printable.asp?ProjectID=4020 (accessed 2008 Jan 14). 24 Moliterno DJ, Becker RC, Jennings LK et al; TRA-PCI Study Investigators. Results of a multinational randomized, double-blind, placebo-controlled study of a novel thrombin receptor antagonist (SCH 530348) in percutaneous coronary intervention. Presented at the 56th Annual Scientific Session of the American College of Cardiology; March 24–27, 2007 ; New Orleans, LA. Author notes Based on the proceedings of a symposium held December 4, 2007, during the ASHP Midyear Clinical Meeting and Exhibition in Las Vegas, NV, and supported by an educational grant from Daiichi Sankyo, Inc. and Eli Lilly and Company. Dr. Price received an honorarium for his participation in the symposium and for the preparation of this article. Dr. Price reports serving on the speakers’ bureau for Boston Scientific and The Medicines Company, as a consultant for Volcano Corporation and has received research support and honoraria from Accumetrics and Cordis Corporation, respectively. Copyright © 2008. American Society of Health-System Pharmacists, Inc. All rights reserved.
TI - New antiplatelet therapies in development
JF - American Journal of Health-System Pharmacy
DO - 10.2146/ajhp080157
DA - 2008-07-01
UR - https://www.deepdyve.com/lp/oxford-university-press/new-antiplatelet-therapies-in-development-64BKnLlkN6
SP - S11
VL - 65
IS - 13_Supplement_5
DP - DeepDyve
ER -