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Combined Cardioprotectant and Antithrombotic Actions of Platelet P2Y12 Receptor Antagonists in Acute Coronary Syndrome: Just What the Doctor Ordered Michael V. Cohen and James M. Downey J CARDIOVASC PHARMACOL THER published online 2 December 2013 DOI: 10.1177/1074248413508465 The online version of this article can be found at: http://cpt.sagepub.com/content/early/2013/12/01/1074248413508465
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Article
Combined Cardioprotectant and Antithrombotic Actions of Platelet P2Y12 Receptor Antagonists in Acute Coronary Syndrome: Just What the Doctor Ordered
Journal of Cardiovascular Pharmacology and Therapeutics 201X, Vol XX(X) 1-12 ª The Author(s) 2013 Reprints and permission: sagepub.com/journalsPermissions.nav DOI: 10.1177/1074248413508465 cpt.sagepub.com
Michael V. Cohen, MD1,2 and James M. Downey, PhD2
Abstract Since the P2Y12 receptor antagonists were first introduced, they have been extensively tested in patients with acute coronary syndrome and are now standard of care. These antiplatelet drugs are very effective in reducing subsequent cardiovascular events, stent thromboses, and mortality in patients with acute myocardial infarction undergoing reperfusion therapy. Although the prevailing view is that their benefit derives from their antithrombotic properties, other unrelated pleiotropic effects appear to be equally beneficial. Accumulating clinical and animal evidence indicates that, if present at the time of reperfusion, these drugs have a direct anti-infarct effect similar to that of ischemic postconditioning. Four oral antagonists have been developed in rapid succession: ticlopidine, clopidogrel, prasugrel, and ticagrelor. Each agent had a more consistent and rapid onset of action than the previous one, and this has correlated with improved clinical outcomes when given early in treatment. Unfortunately, gut absorption causes an appreciable delay in the onset of effect, especially when morphine is used, and the constant push to minimize the doorto-balloon time has made it difficult to achieve adequate platelet inhibition at the time of percutaneous coronary intervention with an oral agent. An intravenous P2Y12 antagonist such as cangrelor may optimize treatment because it produces nearly maximal inhibition of platelet aggregation within minutes. If antiplatelet agents do protect through postconditioning’s mechanism, then they would render any other intervention that protects through that mechanism redundant. Indeed, animals treated with cangrelor cannot be further protected by pre- or postconditioning. However, interventions that use a different mechanism such as mild hypothermia or cariporide, a Naþ-Hþ exchange blocker, do add to cangrelor’s protection. Future research should be directed toward identifying interventions that can augment the protection from antiplatelet therapy and finding a way to optimize P2Y12 inhibition at reperfusion in all patients. Keywords cangrelor, clopidogrel, platelet aggregation, postconditioning, prasugrel, ticagrelor, ticlopidine
Platelet Inhibitors and Infarct Size Reduction Outcomes for patients with ST-segment elevation myocardial infarction (STEMI) have improved remarkably over the past decade. The 3-month mortality was 9.4% in the COMPlement inhibition in myocardial infarction treated with thromboLYtics (COMPLY) trial (2000-2002),1 and it was 3.2% in the d-PROTEin kinase C for the reducTION of infarct size-acute myocardial infarction (PROTECTION-AMI) trial (2008-2010).2 Mochly-Rosen and Grimes2 compiled data from 10 trials over that time period, and the trend toward steady improvement can clearly be seen. Although a number of factors may have contributed, the increased use of antiplatelet drugs during percutaneous coronary intervention (PCI) in patients with STEMI is notable. Figure 1 shows the influence of clopidogrel, a platelet P2Y12 adenosine diphosphate (ADP)-receptor blocker, aspirin, and the glycoprotein (GP) IIb/IIIa inhibitor abciximab. In 7193 patients, loading with clopidogrel or abciximab prior
to stenting reduced 1-year mortality by one-third from that seen with aspirin.3 Combining clopidogrel and abciximab was no better than either alone. When Heestermans et al4 examined the Zwolle acute myocardial infarction registry, they noticed that infarct size and 30-day mortality were reduced in patients who received an antiplatelet agent prior to rather
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Department of Medicine, University of South Alabama College of Medicine, Mobile, AL, USA 2 Department of Physiology, University of South Alabama College of Medicine, Mobile, AL, USA Manuscript submitted: August 21, 2013; accepted: September 13, 2013. Corresponding Author: Michael V. Cohen, Department of Physiology, University of South Alabama College of Medicine, MSB 3050, Mobile, AL 36688, USA. Email: [email protected]
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Figure 1. Kaplan-Meier curves for 4 treatments of patients undergoing primary percutaneous coronary intervention followed for 1 year. GP indicates glycoprotein. Adapted with permission from Witkowski et al.3
than after balloon dilatation of the coronary artery, indicating that the drugs seemed to protect against an injury that occurred in the first minutes of reperfusion. A major factor in outcomes after a myocardial infarction is infarct size. We will review many studies which show that platelet inhibitors limit infarct size in both animals and humans. We will explore possible mechanisms of this salvage. Some investigators propose that these antiplatelet drugs prevent microthrombi that impair reperfusion of the ischemic tissue, while others suggest that they prevent platelets from activating neutrophils which attack otherwise viable tissue. We have proposed that at least the P2Y12 inhibitors condition the heart and activate protective signaling as seen in pre- and postconditioning independent of any effect on platelet aggregation.
Thrombosis and Myocardial Infarction The pathophysiology of acute myocardial infarction is clear. Rupture of a coronary atherosclerotic plaque exposes thrombogenic elements in the plaque to platelets and fibrinogen and thrombosis ensues.5 Following PCI, endothelium is disrupted exposing thrombogenic elements in the vessel wall to flowing blood, and deployment of intravascular stents introduces thrombogenic elements into the coronary artery. Thus, thrombosis is a pathologic process that should be prophylactically inhibited to prevent complications of PCI. In the 1980s and 1990s, 2 types of antithrombotic agents could be used chronically. Coumarin derivatives such as warfarin interfered with hepatic production of clotting factors, and, therefore, impeded the coagulation cascade, while aspirin blocked the enzyme cyclooxygenase and production of thromboxane A2, a potent ligand released by activated platelets which causes platelet aggregation. Platelet activation and aggregation are early steps in thrombus formation. Patients with STEMI have increased platelet reactivity and higher levels of platelet–monocyte and platelet–neutrophil aggregates.6 The extent of platelet aggregation on admission correlates with the
area of microvascular obstruction assessed by contrastenhanced magnetic resonance imaging (no-reflow phenomenon), and infarct size correlates with the extent of no-reflow.6 Therefore, aspirin and anticoagulants such as warfarin interfered with different phases of the thrombotic process, and each was used in patients with myocardial infarction undergoing coronary revascularization procedures (see subsequently). Infusion of platelets into animal hearts subjected to ischemia/reperfusion increases myocardial necrosis but only if they had first been activated by pharmacologic agents or ischemia.7 Nonactivated platelets infused into isolated hearts subjected to ischemia/reperfusion increase the extent of ischemia8 and adversely affect postreperfusion hemodynamics.9 Platelet aggregation is minimized in mice with deficiency of Gq,10 GPVI (platelet collagen receptor),11,12 or P-selectin (protein responsible for platelet-endothelium interaction),13 and infarct size is smaller than that in wild-type animals following ischemia/reperfusion. Hence, platelet inhibition should be beneficial to the ischemic heart.
Clinical Trials With Aspirin, Ticlopidine, and Coumarin Derivatives (Warfarin-Like Agents) The Antiplatelet Trialists Collaboration analyzed 145 randomized trials of prolonged antiplatelet therapy, mainly aspirin.14 Vascular events were significantly less common in patients with vascular disease which included acute myocardial infarction. Because of aspirin’s success in minimizing vascular events in individuals with coronary and peripheral arterial disease, efforts were expended to identify other antiplatelet agents. Thrombosis is initiated by tethering of platelets to endothelial cells via P-selectin followed by their binding to exposed collagen through GPVI receptors. These events trigger a signaling cascade leading to cross-linking of platelets and aggregation. This process is amplified by activation of platelet surface receptors for ADP and thromboxane A2, both released by the activated platelet. Ticlopidine is a thienopyridine which irreversibly blocks the platelet’s P2Y12 ADP receptors. It was developed for aspirinintolerant patients or for use with aspirin when dual antiplatelet treatment was needed. The effect of combination of ticlopidine and aspirin on incidence of death, myocardial infarction, coronary artery bypass grafting, and repeat angioplasty at 30 days after coronary artery stenting was compared to that of combination of a coumarin derivative and aspirin in patients with either acute coronary syndrome (ACS) or stable angina pectoris.15 There was a 75% decrease in cardiac events in the ticlopidine group (P < .01). All events in the antiplatelet group occurred in the first week, while events in the anticoagulant group occurred up to day 26. Occlusion of the stented vessel was observed in 0.8% of the patients treated with ticlopidine and aspirin and in 5.4% of patients treated with warfarin and aspirin (P < .004). Thus, dual anti-platelet therapy was much more effective than conventional anticoagulant treatment in prevention of vascular
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complications following stenting, mainly because of fewer instent thrombi. These results were confirmed in the STent Anticoagulation Restenosis Study (STARS).16 Although the 2 regimens of ticlopidine and aspirin and aspirin and an oral anticoagulant in the Full ANticoagulaTion versus ASpirin and TIClopidine (FANTASTIC) trial produced comparable clinical events, ticlopidine treatment resulted in fewer subacute stent occlusions (P ¼ .01).17
Early Clopidogrel Trials Despite ticlopidine’s clinical efficacy, it increased the risk of neutropenia and thrombotic thrombocytopenic purpura and caused gastrointestinal symptoms often requiring drug discontinuation. It was supplanted by clopidogrel, a second irreversible P2Y12 receptor antagonist with a much lower hematologic risk. The CLopidogrel ASpirin Stent International Cooperative Study (CLASSICS)18 examined 3 drug regimens initiated in the first 6 hours following stenting and continued for 4 weeks: daily maintenance dose (75 mg) of clopidogrel and aspirin; loading dose of clopidogrel (300 mg) followed by daily maintenance dose and aspirin; and ticlopidine and aspirin. There was no difference in incidence of vascular events in ticlopidine and combined clopidogrel groups, but patients treated with ticlopidine had significantly more neutropenia, thrombocytopenia, and rashes. A comparison of ticlopidine and aspirin versus clopidogrel (loading dose of 600 mg and daily maintenance dose of 75 mg) and aspirin initiated immediately before stenting failed to show any difference in vascular events after 1 month or scintigraphic infarct size.19 Thus, clopidogrel was established as an effective drug in patients receiving stents and it had fewer disqualifying side effects. In the Clopidogrel in Unstable angina to prevent Recurrent Events (CURE) trial, major adverse vascular events were decreased by clopidogrel in patients with non-STEMI (NSTEMI). Most were treated medically with either clopidogrel (loading dose of 300 mg and maintenance dose of 75 mg) and aspirin or placebo and aspirin for 3 to 12 months, and major adverse vascular events were decreased by clopidogrel by nearly 20% (P < .001).20 For patients with stenting, PCI was performed a median of 6 days after initiation of treatment.21 There was a 42% decrease in major vascular events in clopidogrel-treated patients. But this benefit of clopidogrel was not shared by all but rather was dependent on the time the treatment was started. The decrease in vascular events was exclusively observed in those individuals in whom stenting was performed less than 48 hours after initiation of clopidogrel treatment (P ¼ .038).22 In the CLopidogrel as Adjunctive ReperfusIon Therapy (CLARITY) studies,23,24 aspirin and clopidogrel (300 mg loading dose and 75 mg maintenance dose) in patients with STEMI treated with fibrinolysis yielded 20% to 46% risk reduction over placebo at 30 days. Clopidogrel improved patency of the infarct-related artery by up to 36% (P < .001). Coronary angiography was performed a median of 3 days following
initiation of drug. Thus, clopidogrel diminished the chance of recurrent thrombosis following fibrinolysis.
Clopidogrel’s Shortcomings Clopidogrel is an oral prodrug. It first must be absorbed from the gut and then metabolized by cytochrome P450-dependent pathways in the liver to produce active metabolites that can interact with P2Y12 receptors. In patients with ACS, a loading dose of 300 mg resulted in peak inhibition of only 20% to 30% of platelet aggregation in approximately 6 hours.25 Inhibition was only slightly less at 24 hours. Clinicians were concerned about clopidogrel’s modest effect on platelet aggregation and fretted that its slow onset of effect might result in inadequate inhibition of platelet function in the critical hours immediately after PCI. In the Clopidogrel for the Reduction of Events During Observation (CREDO) trial, 300 mg of clopidogrel or placebo was administered between a minimum of 3 hours and maximum of 24 hours before planned PCI.26 There was no difference in vascular events at 28 days among clopidogrel and placebo groups until pretreatment occurred more than 15 hours before PCI when clopidogrel reduced relative risk by 66.6% (P ¼ .011). A meta-analysis of trials of clopidogrel pretreatment versus administration of a loading dose just before or immediately after PCI confirmed that adequate pretreatment significantly decreased vascular events in the follow-up period of 7 to 365 days.27
Loading With Clopidogrel There was a clear benefit of effective platelet inhibition at the time of stenting. But the drive to shorten the interval to less than 90 minutes between hospital arrival of the patient with STEMI and commencement of revascularization made platelet inhibition at start of stenting difficult to achieve. Accordingly, the efficacy of larger loading doses was examined. Loading with 600 mg in patients with ACS produced peak platelet inhibition within 2 hours and loading with 300 mg showed peak platelet inhibition only after 6 hours.25 However, it still took 5 to 6 hours for the peak effect, 35% to 45% inhibition of platelet aggregation, to be reached. The higher loading dose consistently decreased subsequent cardiovascular events,28-31 stent thrombosis,30,31 infarct size,32 and microvascular obstruction,32 and a meta-analysis of 10 studies showed that loading doses of clopidogrel greater than 300 mg resulted in fewer cardiac deaths or myocardial infarctions than loading doses of 300 mg.33 In 1 study, there was no difference in periprocedural ischemic events or cardiovascular complications at 30 days in patients with stable angina pectoris treated with either 300 mg or 600 mg of clopidogrel immediately before PCI.34 But platelets would not have been inhibited until several hours after the procedure with either dose, possibly accounting for lack of clinical effect. However, in neither Intracoronary Stenting and Antithrombotic Regimen: Rapid Early Action for Coronary Treatment-4 (ISAR-REACT)35 nor PRAGUE-836 trials did early or late administration of 600 mg clopidogrel before
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elective PCI have an effect on cardiovascular adverse events at 7 to 30 days. The benefit of clopidogrel loading seems to be more pronounced in patients with ACS in whom infarction is often present suggesting an anti-infarct effect with early administration. Clopidogrel does not protect all patients. In fact, 24% to 46% treated with 300 mg clopidogrel25,29,37 and 15% to 21% treated with 600 mg clopidogrel25,29 had little or no inhibition of platelet aggregation 6 to 19 hours following treatment. Gurbel et al38 measured platelet reactivity serially in patients who received a loading dose of 300 mg clopidogrel before elective coronary artery stenting and then a daily maintenance dose of 75 mg. After 2 hours of the loading dose, 63% still had less than 10% inhibition of platelet aggregation. Thirty-one percent of the patients continued to be nonresponders at 24 hours and 5 days and 15% at 30 days. Loading with 600 mg clopidogrel in patients with NSTEMI39 and STEMI40 left 36% and 55%, respectively, with high platelet reactivity at the time of PCI. Nonresponsiveness (definition is dependent on the particular study, eg, less than 10% change in platelet aggregation from baseline to post-treatment blood sample in response to 5 mmol/L ADP38) had adverse clinical implications. Nonresponders had more frequent elevations of creatine phosphokinase-MB following PCI,37 a significantly higher likelihood of subacute stent thrombosis,41 and possibly a higher likelihood of adverse cardiovascular events.39 Likely causes of clopidogrel nonresponsiveness could be poor intestinal absorption or inadequate metabolism to the active metabolite. Biotransformation of the prodrug to the active metabolite by cytochrome P450 enzyme system is affected by the CYP2C19 gene.42 The CYP2C19*2 variant allele leads to poor metabolism. In the year following deployment of drug-eluting stents, myocardial infarction occurred in 8.4%, 10.9%, and 44.4% of the patients with 0, 1, and 2 variant alleles, respectively (P ¼ .016). There are still other factors that affect clopidogrel’s pharmacokinetics that have not yet been identified.43
Improving the Pharmacology of Oral Antiplatelet Agents A third-generation thienopyridine was introduced because of the variable response to clopidogrel. Prasugrel, like clopidogrel, is a prodrug requiring hepatic metabolism to become an active metabolite that irreversibly binds to platelet P2Y12 receptors and blocks platelet aggregation. But it is metabolized by different enzymes and has a more consistent effect in patients. Inhibition of aggregation of platelets from rats fed prasugrel was 10-fold greater than that seen with clopidogrel.44 Similar observations were made in patients with stable coronary artery disease treated with either prasugrel or clopidogrel.45 In patients undergoing elective PCI, there was 74.8% inhibition of platelet activity 6 hours after 60 mg prasugrel compared to 31.8% in patients treated with 600 mg clopidogrel (P < .0001).46 In addition to prasugrel’s greater peak platelet antiaggregatory effect, the onset of effect is more
rapid.47 The median time to reach 20% inhibition of platelet aggregation was 30 minutes for prasugrel and 1.5 hours for clopidogrel (P < .001). Although 24% of the patients treated with clopidogrel had insignificant inhibition of platelet reactivity, all patients responded to prasugrel.47 In the TRIal to assess Improvement in Therapeutic Outcomes by optimizing platelet inhibitioN with PrasugrelThrombolysis in Myocardial Infarction (TRITON-TIMI)48 38 patients with ACS scheduled for PCI were treated with either prasugrel (loading dose 60 mg and daily maintenance dose 10 mg) or clopidogrel (loading dose 300 mg and daily maintenance dose 75 mg) for 6 to 15 months. Approximately 75% of the patients in each group received the study drug either during the PCI procedure or immediately after its completion, while 25% of the patients were treated prior to PCI. Prasugrel resulted in a 19% relative risk reduction in cardiovascular adverse events (P < .001)48 and an overall lower risk of myocardial infarction (P < .0001).49 Similar advantages of prasugrel over clopidogrel were observed in patients with STEMI, including a decrease in stent thrombosis (2.8% for clopidogrel and 1.6% for prasugrel, P ¼ .023).50 However, in patients with unstable angina pectoris or NSTEMI not undergoing revascularization but treated with maintenance doses of prasugrel or clopidogrel, there was no difference in cardiovascular events after a median follow-up of 17 months.51 So the important clinical difference between the 2 drugs was seen in those being revascularized.
Ticagrelor Is a Direct P2Y12 Inhibitor Although prasugrel had a favorable pharmacokinetic and genetic profile, treatment with it as established in the TRITON-TIMI 38 protocol48 could be initiated only after diagnostic angiography had revealed the patient to be a candidate for PCI. That provides little time for effective platelet inhibition before PCI.48 Montalescot and colleagues52 treated patients with NSTEMI with either a 60 mg loading dose of prasugrel just before PCI or 30 mg a median of 4.3 hours before PCI and another dose of 30 mg when it was known PCI was needed. Although only the latter group would have had any platelet inhibition at reperfusion, there was no difference in subsequent cardiovascular complications in the 2 groups. Perhaps there was still no sufficient platelet inhibition at the time of the procedure in patients pretreated with one-half of the standard loading dose, or the ischemic period was too long to allow salvage of the myocardium. The oral drug ticagrelor is a triazolopyrimidine. It is not a prodrug and is a reversible, noncompetitive inhibitor of the platelet P2Y12 receptor.53 In healthy volunteers53,54 and patients with stable coronary artery disease,54,55 loading doses of ticagrelor produced faster and more consistent platelet inhibition than either 300 mg53 or 60055 mg of clopidogrel. In patients with stable coronary artery disease, 180 mg ticagrelor led to 41% inhibition of platelet aggregation after 0.5 hours, 88% inhibition at 2 hours, and a maximal inhibition of 93% shortly thereafter.55 Corresponding inhibition by 600 mg clopidogrel was 8%, 38%, and 58%. After 5 days of maintenance
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treatment with ticagrelor, platelet inhibition ranged from 61% to 100% compared to 11% to 100% after 14 days of maintenance clopidogrel treatment.53 The rate-controlling step is still the time needed for intestinal absorption. In healthy volunteers, the median tmax for absorption was 1.5 to 3 hours.53 The PLATelet inhibition and patient Outcomes (PLATO) study in patients with ACS established ticagrelor’s superiority to clopidogrel.56 Ticagrelor decreased occurrence of combined vascular side effects, myocardial infarction, death from vascular causes, and death from any cause (P < .001). The advantage of ticagrelor over clopidogrel was seen regardless of whether the latter’s loading dose was 300 or 600 mg, and regardless of whether an invasive or noninvasive strategy was planned. Ticagrelor resulted in lower event rates throughout the follow-up period of 6 to 12 months.57 In spite of the encouraging clinical data for both prasugrel and ticagrelor, these are still oral preparations. Therefore, there is an obligatory delay between drug administration and biologic effect, probably the result of slow intestinal absorption. Although in healthy volunteers the effects of prasugrel and ticagrelor can be realized 1 to 2 hours after dosing,55 that was not the case in patients with ACS. Parodi et al58 measured platelet reactivity in patients with STEMI at baseline and 2, 4, 8, and 12 hours after loading doses of 60 mg prasugrel or 180 mg ticagrelor. High residual platelet reactivity was found in 44% and 60% of patients loaded with prasugrel and ticagrelor, respectively, at 2 hours. The mean time to achieve clinically significant platelet inhibition was 3 + 2 hours and 5 + 4 hours with prasugrel and ticagrelor, respectively. The independent predictor of this delay in biologic effect of the antagonists was morphine use. Possibly morphine slowed intestinal motility. Thus, in high-risk patients, the antiplatelet effect of the most potent oral agents is still delayed, and PCI is potentially performed without adequate platelet inhibition. This problem is magnified by the desire to shorten door-to-balloon times as much as possible, thus decreasing any pretreatment interval.
Cangrelor Is an Intravenous Antiplatelet Agent Cangrelor has a chemical structure similar to that of ticagrelor and is an intravenous, reversible blocker of the platelet P2Y12 receptor. It has a half-life of 6 h before elective coronary angiography or only for angiographically selected patients a few minutes before PCI? A randomized multicentre trial PRAGUE-8. Eur Heart J. 2008;29(12):1495-1503. Lev EI, Patel RT, Maresh KJ, et al. Aspirin and clopidogrel drug response in patients undergoing percutaneous coronary intervention: the role of dual drug resistance. J Am Coll Cardiol. 2006; 47(1):27-33. Gurbel PA, Bliden KP, Hiatt BL, O’Connor CM. Clopidogrel for coronary stenting: response variability, drug resistance, and the effect of pretreatment platelet reactivity. Circulation. 2003; 107(23):2908-2913. Sibbing D, Bernlochner I, Schulz S, et al. Prognostic value of a high on-clopidogrel treatment platelet reactivity in bivalirudin versus abciximab treated non-ST-segment elevation myocardial infarction patients: ISAR-REACT-4 (Intracoronary Stenting and Antithrombotic Regimen: Rapid Early Action for Coronary Treatment-4) platelet substudy. J Am Coll Cardiol. 2012;60(5):369-377. Bonello L, Berbis J, Laine M, et al. Biological efficacy of a 600 mg loading dose of clopidogrel in ST-elevation myocardial infarction. Thromb Haemost. 2012;108(1):101-106. Gurbel PA, Bliden KP, Samara W, et al. Clopidogrel effect on platelet REactivity in patients with Stent Thrombosis: results of the CREST study. J Am Coll Cardiol. 2005;46(10):1827-1832. Carlquist JF, Knight S, Horne BD, et al. Cardiovascular risk among patients on clopidogrel anti-platelet therapy after placement of drug-eluting stents is modified by genetic variants in both the CYP2C19 and ABCB1 genes. Thromb Haemost. 2013;109(4): 744-754. Frelinger AL III, Bhatt DL, Lee RD, et al. Clopidogrel pharmacokinetics and pharmacodynamics vary widely despite exclusion or control of polymorphisms (CYP2C19, ABCB1, PON1), noncompliance, diet, smoking, co-medications (including proton pump inhibitors), and pre-existent variability in platelet function. J Am Coll Cardiol. 2013;61(8):872-879. Sugidachi A, Ogawa T, Kurihara A, et al. The greater in vivo antiplatelet effects of prasugrel as compared to clopidogrel reflect more efficient generation of its active metabolite with similar antiplatelet activity to that of clopidogrel’s active metabolite. J Thromb Haemost. 2007;5(7):1545-1551. Wallentin L, Varenhorst C, James S, et al. Prasugrel achieves greater and faster P2Y12 receptor-mediated platelet inhibition than clopidogrel due to more efficient generation of its active metabolite in aspirin-treated patients with coronary artery disease. Eur Heart J. 2008;29(1):21-30.
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46. Wiviott SD, Trenk D, Frelinger AL, et al. Prasugrel compared with high loading- and maintenance-dose clopidogrel in patients with planned percutaneous coronary intervention: the Prasugrel in Comparison to Clopidogrel for Inhibition of Platelet Activation and Aggregation-Thrombolysis in Myocardial Infarction 44 trial. Circulation. 2007;116(25):2923-2932. 47. Brandt JT, Payne CD, Wiviott SD, et al. A comparison of prasugrel and clopidogrel loading doses on platelet function: magnitude of platelet inhibition is related to active metabolite formation. Am Heart J. 2007;153(1):66.e9-66.e16. 48. Wiviott SD, Braunwald E, McCabe CH, et al. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2007;357(20):2001-2015. 49. Morrow DA, Wiviott SD, White HD, et al. Effect of the novel thienopyridine prasugrel compared with clopidogrel on spontaneous and procedural myocardial infarction in the Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial Infarction 38: an application of the classification system from the universal definition of myocardial infarction. Circulation. 2009;119(21):2758-2764. 50. Montalescot G, Wiviott SD, Braunwald E, et al. Prasugrel compared with clopidogrel in patients undergoing percutaneous coronary intervention for ST-elevation myocardial infarction (TRITON-TIMI 38): double-blind, randomised controlled trial. Lancet. 2009;373(9665):723-731. 51. Roe MT, Armstrong PW, Fox KAA, et al. Prasugrel versus clopidogrel for acute coronary syndromes without revascularization. N Engl J Med. 2012;367(14):1297-1309. 52. Montalescot G, Bolognese L, Dudek D, et al. Pretreatment with prasugrel in non-ST-segment elevation acute coronary syndromes. N Engl J Med. 2013;369(11):999-1010. 53. Butler K, Teng R. Pharmacokinetics, pharmacodynamics, safety and tolerability of multiple ascending doses of ticagrelor in healthy volunteers. Br J Clin Pharmacol. 2010;70(1):65-77. 54. Davis EM, Knezevich JT, Teply RM. Advances in antiplatelet technologies to improve cardiovascular disease morbidity and mortality: a review of ticagrelor. Clin Pharmacol. 2013;5(1): 67-83. 55. Gurbel PA, Bliden KP, Butler K, et al. Randomized double-blind assessment of the ONSET and OFFSET of the antiplatelet effects of ticagrelor versus clopidogrel in patients with stable coronary artery disease: the ONSET/OFFSET study. Circulation. 2009; 120(25):2577-2585. 56. Wallentin L, Becker RC, Budaj A, et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2009;361(11):1045-1057. 57. Kohli P, Wallentin L, Reyes E, et al. Reduction in first and recurrent cardiovascular events with ticagrelor compared with clopidogrel in the PLATO study. Circulation. 2013;127(6):673-680. 58. Parodi G, Valenti R, Bellandi B, et al. Comparison of prasugrel and ticagrelor loading doses in ST-segment elevation myocardial infarction patients: RAPID (Rapid Activity of Platelet Inhibitor Drugs) primary PCI study. J Am Coll Cardiol. 2013;61(15): 1601-1606. 59. Storey RF, Oldroyd KG, Wilcox RG. Open multicentre study of the P2T receptor antagonist AR-C69931MX assessing safety,
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tolerability and activity in patients with acute coronary syndromes. Thromb Haemost. 2001;85(3):401-407. Bhatt DL, Lincoff AM, Gibson CM, et al. Intravenous platelet blockade with cangrelor during PCI. N Engl J Med. 2009; 361(24):2330-2341. Harrington RA, Stone GW, McNulty S, et al. Platelet inhibition with cangrelor in patients undergoing PCI. N Engl J Med. 2009; 361(24):2318-2329. Thygesen K, Alpert JS, White HD. Universal definition of myocardial infarction. Circulation. 2007;116(22):2634-2653. White HD, Chew DP, Dauerman HL, et al. Reduced immediate ischemic events with cangrelor in PCI: a pooled analysis of the CHAMPION trials using the universal definition of myocardial infarction. Am Heart J. 2012;163(2):182-190.e4. Bhatt DL, Stone GW, Mahaffey KW, et al. Effect of platelet inhibition with cangrelor during PCI on ischemic events. N Engl J Med. 2013;368(14):1303-1313. Kloner RA. Current state of clinical translation of cardioprotective agents for acute myocardial infarction. Circ Res. 2013; 113(4):451-463. Zhao Z-Q, Corvera JS, Halkos ME, et al. Inhibition of myocardial injury by ischemic postconditioning during reperfusion: comparison with ischemic preconditioning. Am J Physiol. 2003;285(2): H579-H588. Yang X-M, Proctor JB, Cui L, Krieg T, Downey JM, Cohen MV. Multiple, brief coronary occlusions during early reperfusion protect rabbit hearts by targeting cell signaling pathways. J Am Coll Cardiol. 2004;44(5):1103-1110. Cohen MV, Yang X-M, Downey JM. The pH hypothesis of postconditioning: staccato reperfusion reintroduces oxygen and perpetuates myocardial acidosis. Circulation. 2007;115(14): 1895-1903. Staat P, Rioufol G, Piot C, et al. Postconditioning the human heart. Circulation. 2005;112(14):2143-2148. Roubille F, Lairez O, Mewton N, et al. Cardioprotection by clopidogrel in acute ST-elevated myocardial infarction patients: a retrospective analysis. Basic Res Cardiol. 2012;107(4):275. Freixa X, Bellera N, Ortiz-Pe´rez JT, et al. Ischaemic postconditioning revisited: lack of effects on infarct size following primary percutaneous coronary intervention. Eur Heart J. 2012;33(1): 103-112. Tarantini G, Favaretto E, Marra MP, et al. Postconditioning during coronary angioplasty in acute myocardial infarction: the POST-AMI trial. Int J Cardiol. 2012;162(1):33-38. So¨rensson P, Saleh N, Bouvier F, et al. Effect of postconditioning on infarct size in patients with ST elevation myocardial infarction. Heart. 2010;96(21):1710-1715. Yang X-C, Liu Y, Wang L-F, et al. Reduction in myocardial infarct size by postconditioning in patients after percutaneous coronary intervention. J Invasive Cardiol. 2007;19(10):424-430. Lønborg J, Kelbaek H, Vejlstrup N, et al. Cardioprotective effects of ischemic postconditioning in patients treated with primary percutaneous coronary intervention, evaluated by magnetic resonance. Circ Cardiovasc Interv. 2010;3(1):34-41. Barrabe´s JA, Inserte J, Mirabet M, et al. Antagonism of P2Y12 or GPIIb/IIIa receptors reduces platelet-mediated myocardial injury
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Journal of Cardiovascular Pharmacology and Therapeutics XX(X) after ischaemia and reperfusion in isolated rat hearts. Thromb Haemost. 2010;104(1):128-135. Kupatt C, Wichels R, Horstkotte J, Krombach F, Habazettl H, Boekstegers P. Molecular mechanisms of platelet-mediated leukocyte recruitment during myocardial reperfusion. J Leukoc Biol. 2002;72(3):455-461. Barrabe´s JA, Garcia-Dorado D, Mirabet M, et al. Antagonism of selectin function attenuates microvascular platelet deposition and platelet-mediated myocardial injury after transient ischemia. J Am Coll Cardiol. 2005;45(2):293-299. Kingma JG Jr, Plante S, Bogaty P. Platelet GPIIb/IIIa receptor blockade reduces infarct size in a canine model of ischemia-reperfusion. J Am Coll Cardiol. 2000;36(7):2317-2324. Kunichika H, Ben-Yehuda O, Lafitte S, Kunichika N, Peters B, DeMaria AN. Effects of glycoprotein IIb/IIIa inhibition on microvascular flow after coronary reperfusion. A quantitative myocardial contrast echocardiography study. J Am Coll Cardiol. 2004; 43(2):276-283. Yang Y-J, Zhao J-L, You S-J, et al. Different effects of tirofiban and aspirin plus clopidogrel on myocardial no-reflow in a miniswine model of acute myocardial infarction and reperfusion. Heart. 2006;92(8):1131-1137. Sakuma T, Sari I, Goodman CN, Lindner JR, Klibanov AL, Kaul S. Simultaneous integrin avb3 and glycoprotein IIb/IIIa inhibition causes reduction in infarct size in a model of acute coronary thrombosis and primary angioplasty. Cardiovasc Res. 2005;66(3):552-561. Wang K, Zhou X, Huang Y, et al. Adjunctive treatment with ticagrelor, but not clopidogrel, added to tPA enables sustained coronary artery recanalisation with recovery of myocardium perfusion in a canine coronary thrombosis model. Thromb Haemost. 2010;104(3):609-617. Wang K, Zhou X, Zhou Z, et al. Blockade of the platelet P2Y12 receptor by AR-C69931MX sustains coronary artery recanalization and improves the myocardial tissue perfusion in a canine thrombosis model. Arterioscler Thromb Vasc Biol. 2003;23(2): 357-362. Reimer KA, Jennings RB. The ‘‘wavefront phenomenon’’ of myocardial ischemic cell death. II. Transmural progression of necrosis within the framework of ischemic bed size (myocardium at risk) and collateral flow. Lab Invest. 1979;40(6):633-644. Schwartz LM, Sebbag L, Jennings RB, Reimer KA. Duration and reinstatement of myocardial protection against infarction by
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ischemic preconditioning in open chest dogs. J Mol Cell Cardiol. 2001;33(9):1561-1570. Barrabe´s JA, Garcia-Dorado D, Mirabet M, et al. Lack of effect of glycoprotein IIb/IIIa blockade on myocardial platelet or polymorphonuclear leukocyte accumulation and on infarct size after transient coronary occlusion in pigs. J Am Coll Cardiol. 2002;39(1):157-165. Yang X-M, Liu Y, Cui L, et al. Platelet P2Y12 blockers confer direct postconditioning-like protection in reperfused rabbit hearts. J Cardiovasc Pharmacol Ther. 2013;18(3):251-262. Cohen MV, Downey JM. Ischemic postconditioning: from receptor to end-effector. Antioxid Redox Signal. 2011;14(5):821-831. Yang X-M, Liu Y, Cui L, et al. Two classes of anti-platelet drugs reduce anatomical infarct size in monkey hearts. Cardiovasc Drugs Ther. 2013;27(2):109-115. Yang X-M, Cui L, Alhammouri A, Downey JM, Cohen MV. Triple therapy greatly increases myocardial salvage during ischemia/reperfusion in the in situ rat heart. Cardiovasc Drugs Ther. 2013;27(5): 403-412. Miki T, Liu GS, Cohen MV, Downey JM. Mild hypothermia reduces infarct size in the beating rabbit heart: a practical intervention for acute myocardial infarction? Basic Res Cardiol. 1998;93(5):372-383. Tissier R, Hamanaka K, Kuno A, Parker JC, Cohen MV, Downey JM. Total liquid ventilation provides ultra-fast cardioprotective cooling. J Am Coll Cardiol. 2007;49(5):601-605. Yang X, Liu Y, Yang X-M, et al. Cardioprotection by mild hypothermia during ischemia involves preservation of ERK activity. Basic Res Cardiol. 2011;106(3):421-430. Xu Z, Jiao Z, Cohen MV, Downey JM. Protection from AMP 579 can be added to that from either cariporide or ischemic preconditioning in ischemic rabbit heart. J Cardiovasc Pharmacol. 2002; 40(4):510-518. Weinbrenner C, Liu GS, Downey JM, Cohen MV. Cyclosporine A limits myocardial infarct size even when administered after onset of ischemia. Cardiovasc Res. 1998;38(3):676-684. Menees DS, Peterson ED, Wang Y, et al. Door-to-balloon time and mortality among patients undergoing primary PCI. N Engl J Med. 2013;369(10):901-909. Mentzer RM Jr, Bartels C, Bolli R, et al. Sodium-hydrogen exchange inhibition by cariporide to reduce the risk of ischemic cardiac events in patients undergoing coronary artery bypass grafting: results of the EXPEDITION study. Ann Thorac Surg. 2008;85(4):1261-1270.
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Combined Cardioprotectant and Antithrombotic Actions of Platelet P2Y12 Receptor Antagonists in Acute Coronary Syndrome: Just What the Doctor Ordered Michael V. Cohen and James M. Downey J CARDIOVASC PHARMACOL THER published online 2 December 2013 DOI: 10.1177/1074248413508465 The online version of this article can be found at: http://cpt.sagepub.com/content/early/2013/12/01/1074248413508465
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Article
Combined Cardioprotectant and Antithrombotic Actions of Platelet P2Y12 Receptor Antagonists in Acute Coronary Syndrome: Just What the Doctor Ordered
Journal of Cardiovascular Pharmacology and Therapeutics 201X, Vol XX(X) 1-12 ª The Author(s) 2013 Reprints and permission: sagepub.com/journalsPermissions.nav DOI: 10.1177/1074248413508465 cpt.sagepub.com
Michael V. Cohen, MD1,2 and James M. Downey, PhD2
Abstract Since the P2Y12 receptor antagonists were first introduced, they have been extensively tested in patients with acute coronary syndrome and are now standard of care. These antiplatelet drugs are very effective in reducing subsequent cardiovascular events, stent thromboses, and mortality in patients with acute myocardial infarction undergoing reperfusion therapy. Although the prevailing view is that their benefit derives from their antithrombotic properties, other unrelated pleiotropic effects appear to be equally beneficial. Accumulating clinical and animal evidence indicates that, if present at the time of reperfusion, these drugs have a direct anti-infarct effect similar to that of ischemic postconditioning. Four oral antagonists have been developed in rapid succession: ticlopidine, clopidogrel, prasugrel, and ticagrelor. Each agent had a more consistent and rapid onset of action than the previous one, and this has correlated with improved clinical outcomes when given early in treatment. Unfortunately, gut absorption causes an appreciable delay in the onset of effect, especially when morphine is used, and the constant push to minimize the doorto-balloon time has made it difficult to achieve adequate platelet inhibition at the time of percutaneous coronary intervention with an oral agent. An intravenous P2Y12 antagonist such as cangrelor may optimize treatment because it produces nearly maximal inhibition of platelet aggregation within minutes. If antiplatelet agents do protect through postconditioning’s mechanism, then they would render any other intervention that protects through that mechanism redundant. Indeed, animals treated with cangrelor cannot be further protected by pre- or postconditioning. However, interventions that use a different mechanism such as mild hypothermia or cariporide, a Naþ-Hþ exchange blocker, do add to cangrelor’s protection. Future research should be directed toward identifying interventions that can augment the protection from antiplatelet therapy and finding a way to optimize P2Y12 inhibition at reperfusion in all patients. Keywords cangrelor, clopidogrel, platelet aggregation, postconditioning, prasugrel, ticagrelor, ticlopidine
Platelet Inhibitors and Infarct Size Reduction Outcomes for patients with ST-segment elevation myocardial infarction (STEMI) have improved remarkably over the past decade. The 3-month mortality was 9.4% in the COMPlement inhibition in myocardial infarction treated with thromboLYtics (COMPLY) trial (2000-2002),1 and it was 3.2% in the d-PROTEin kinase C for the reducTION of infarct size-acute myocardial infarction (PROTECTION-AMI) trial (2008-2010).2 Mochly-Rosen and Grimes2 compiled data from 10 trials over that time period, and the trend toward steady improvement can clearly be seen. Although a number of factors may have contributed, the increased use of antiplatelet drugs during percutaneous coronary intervention (PCI) in patients with STEMI is notable. Figure 1 shows the influence of clopidogrel, a platelet P2Y12 adenosine diphosphate (ADP)-receptor blocker, aspirin, and the glycoprotein (GP) IIb/IIIa inhibitor abciximab. In 7193 patients, loading with clopidogrel or abciximab prior
to stenting reduced 1-year mortality by one-third from that seen with aspirin.3 Combining clopidogrel and abciximab was no better than either alone. When Heestermans et al4 examined the Zwolle acute myocardial infarction registry, they noticed that infarct size and 30-day mortality were reduced in patients who received an antiplatelet agent prior to rather
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Department of Medicine, University of South Alabama College of Medicine, Mobile, AL, USA 2 Department of Physiology, University of South Alabama College of Medicine, Mobile, AL, USA Manuscript submitted: August 21, 2013; accepted: September 13, 2013. Corresponding Author: Michael V. Cohen, Department of Physiology, University of South Alabama College of Medicine, MSB 3050, Mobile, AL 36688, USA. Email: [email protected]
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Figure 1. Kaplan-Meier curves for 4 treatments of patients undergoing primary percutaneous coronary intervention followed for 1 year. GP indicates glycoprotein. Adapted with permission from Witkowski et al.3
than after balloon dilatation of the coronary artery, indicating that the drugs seemed to protect against an injury that occurred in the first minutes of reperfusion. A major factor in outcomes after a myocardial infarction is infarct size. We will review many studies which show that platelet inhibitors limit infarct size in both animals and humans. We will explore possible mechanisms of this salvage. Some investigators propose that these antiplatelet drugs prevent microthrombi that impair reperfusion of the ischemic tissue, while others suggest that they prevent platelets from activating neutrophils which attack otherwise viable tissue. We have proposed that at least the P2Y12 inhibitors condition the heart and activate protective signaling as seen in pre- and postconditioning independent of any effect on platelet aggregation.
Thrombosis and Myocardial Infarction The pathophysiology of acute myocardial infarction is clear. Rupture of a coronary atherosclerotic plaque exposes thrombogenic elements in the plaque to platelets and fibrinogen and thrombosis ensues.5 Following PCI, endothelium is disrupted exposing thrombogenic elements in the vessel wall to flowing blood, and deployment of intravascular stents introduces thrombogenic elements into the coronary artery. Thus, thrombosis is a pathologic process that should be prophylactically inhibited to prevent complications of PCI. In the 1980s and 1990s, 2 types of antithrombotic agents could be used chronically. Coumarin derivatives such as warfarin interfered with hepatic production of clotting factors, and, therefore, impeded the coagulation cascade, while aspirin blocked the enzyme cyclooxygenase and production of thromboxane A2, a potent ligand released by activated platelets which causes platelet aggregation. Platelet activation and aggregation are early steps in thrombus formation. Patients with STEMI have increased platelet reactivity and higher levels of platelet–monocyte and platelet–neutrophil aggregates.6 The extent of platelet aggregation on admission correlates with the
area of microvascular obstruction assessed by contrastenhanced magnetic resonance imaging (no-reflow phenomenon), and infarct size correlates with the extent of no-reflow.6 Therefore, aspirin and anticoagulants such as warfarin interfered with different phases of the thrombotic process, and each was used in patients with myocardial infarction undergoing coronary revascularization procedures (see subsequently). Infusion of platelets into animal hearts subjected to ischemia/reperfusion increases myocardial necrosis but only if they had first been activated by pharmacologic agents or ischemia.7 Nonactivated platelets infused into isolated hearts subjected to ischemia/reperfusion increase the extent of ischemia8 and adversely affect postreperfusion hemodynamics.9 Platelet aggregation is minimized in mice with deficiency of Gq,10 GPVI (platelet collagen receptor),11,12 or P-selectin (protein responsible for platelet-endothelium interaction),13 and infarct size is smaller than that in wild-type animals following ischemia/reperfusion. Hence, platelet inhibition should be beneficial to the ischemic heart.
Clinical Trials With Aspirin, Ticlopidine, and Coumarin Derivatives (Warfarin-Like Agents) The Antiplatelet Trialists Collaboration analyzed 145 randomized trials of prolonged antiplatelet therapy, mainly aspirin.14 Vascular events were significantly less common in patients with vascular disease which included acute myocardial infarction. Because of aspirin’s success in minimizing vascular events in individuals with coronary and peripheral arterial disease, efforts were expended to identify other antiplatelet agents. Thrombosis is initiated by tethering of platelets to endothelial cells via P-selectin followed by their binding to exposed collagen through GPVI receptors. These events trigger a signaling cascade leading to cross-linking of platelets and aggregation. This process is amplified by activation of platelet surface receptors for ADP and thromboxane A2, both released by the activated platelet. Ticlopidine is a thienopyridine which irreversibly blocks the platelet’s P2Y12 ADP receptors. It was developed for aspirinintolerant patients or for use with aspirin when dual antiplatelet treatment was needed. The effect of combination of ticlopidine and aspirin on incidence of death, myocardial infarction, coronary artery bypass grafting, and repeat angioplasty at 30 days after coronary artery stenting was compared to that of combination of a coumarin derivative and aspirin in patients with either acute coronary syndrome (ACS) or stable angina pectoris.15 There was a 75% decrease in cardiac events in the ticlopidine group (P < .01). All events in the antiplatelet group occurred in the first week, while events in the anticoagulant group occurred up to day 26. Occlusion of the stented vessel was observed in 0.8% of the patients treated with ticlopidine and aspirin and in 5.4% of patients treated with warfarin and aspirin (P < .004). Thus, dual anti-platelet therapy was much more effective than conventional anticoagulant treatment in prevention of vascular
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complications following stenting, mainly because of fewer instent thrombi. These results were confirmed in the STent Anticoagulation Restenosis Study (STARS).16 Although the 2 regimens of ticlopidine and aspirin and aspirin and an oral anticoagulant in the Full ANticoagulaTion versus ASpirin and TIClopidine (FANTASTIC) trial produced comparable clinical events, ticlopidine treatment resulted in fewer subacute stent occlusions (P ¼ .01).17
Early Clopidogrel Trials Despite ticlopidine’s clinical efficacy, it increased the risk of neutropenia and thrombotic thrombocytopenic purpura and caused gastrointestinal symptoms often requiring drug discontinuation. It was supplanted by clopidogrel, a second irreversible P2Y12 receptor antagonist with a much lower hematologic risk. The CLopidogrel ASpirin Stent International Cooperative Study (CLASSICS)18 examined 3 drug regimens initiated in the first 6 hours following stenting and continued for 4 weeks: daily maintenance dose (75 mg) of clopidogrel and aspirin; loading dose of clopidogrel (300 mg) followed by daily maintenance dose and aspirin; and ticlopidine and aspirin. There was no difference in incidence of vascular events in ticlopidine and combined clopidogrel groups, but patients treated with ticlopidine had significantly more neutropenia, thrombocytopenia, and rashes. A comparison of ticlopidine and aspirin versus clopidogrel (loading dose of 600 mg and daily maintenance dose of 75 mg) and aspirin initiated immediately before stenting failed to show any difference in vascular events after 1 month or scintigraphic infarct size.19 Thus, clopidogrel was established as an effective drug in patients receiving stents and it had fewer disqualifying side effects. In the Clopidogrel in Unstable angina to prevent Recurrent Events (CURE) trial, major adverse vascular events were decreased by clopidogrel in patients with non-STEMI (NSTEMI). Most were treated medically with either clopidogrel (loading dose of 300 mg and maintenance dose of 75 mg) and aspirin or placebo and aspirin for 3 to 12 months, and major adverse vascular events were decreased by clopidogrel by nearly 20% (P < .001).20 For patients with stenting, PCI was performed a median of 6 days after initiation of treatment.21 There was a 42% decrease in major vascular events in clopidogrel-treated patients. But this benefit of clopidogrel was not shared by all but rather was dependent on the time the treatment was started. The decrease in vascular events was exclusively observed in those individuals in whom stenting was performed less than 48 hours after initiation of clopidogrel treatment (P ¼ .038).22 In the CLopidogrel as Adjunctive ReperfusIon Therapy (CLARITY) studies,23,24 aspirin and clopidogrel (300 mg loading dose and 75 mg maintenance dose) in patients with STEMI treated with fibrinolysis yielded 20% to 46% risk reduction over placebo at 30 days. Clopidogrel improved patency of the infarct-related artery by up to 36% (P < .001). Coronary angiography was performed a median of 3 days following
initiation of drug. Thus, clopidogrel diminished the chance of recurrent thrombosis following fibrinolysis.
Clopidogrel’s Shortcomings Clopidogrel is an oral prodrug. It first must be absorbed from the gut and then metabolized by cytochrome P450-dependent pathways in the liver to produce active metabolites that can interact with P2Y12 receptors. In patients with ACS, a loading dose of 300 mg resulted in peak inhibition of only 20% to 30% of platelet aggregation in approximately 6 hours.25 Inhibition was only slightly less at 24 hours. Clinicians were concerned about clopidogrel’s modest effect on platelet aggregation and fretted that its slow onset of effect might result in inadequate inhibition of platelet function in the critical hours immediately after PCI. In the Clopidogrel for the Reduction of Events During Observation (CREDO) trial, 300 mg of clopidogrel or placebo was administered between a minimum of 3 hours and maximum of 24 hours before planned PCI.26 There was no difference in vascular events at 28 days among clopidogrel and placebo groups until pretreatment occurred more than 15 hours before PCI when clopidogrel reduced relative risk by 66.6% (P ¼ .011). A meta-analysis of trials of clopidogrel pretreatment versus administration of a loading dose just before or immediately after PCI confirmed that adequate pretreatment significantly decreased vascular events in the follow-up period of 7 to 365 days.27
Loading With Clopidogrel There was a clear benefit of effective platelet inhibition at the time of stenting. But the drive to shorten the interval to less than 90 minutes between hospital arrival of the patient with STEMI and commencement of revascularization made platelet inhibition at start of stenting difficult to achieve. Accordingly, the efficacy of larger loading doses was examined. Loading with 600 mg in patients with ACS produced peak platelet inhibition within 2 hours and loading with 300 mg showed peak platelet inhibition only after 6 hours.25 However, it still took 5 to 6 hours for the peak effect, 35% to 45% inhibition of platelet aggregation, to be reached. The higher loading dose consistently decreased subsequent cardiovascular events,28-31 stent thrombosis,30,31 infarct size,32 and microvascular obstruction,32 and a meta-analysis of 10 studies showed that loading doses of clopidogrel greater than 300 mg resulted in fewer cardiac deaths or myocardial infarctions than loading doses of 300 mg.33 In 1 study, there was no difference in periprocedural ischemic events or cardiovascular complications at 30 days in patients with stable angina pectoris treated with either 300 mg or 600 mg of clopidogrel immediately before PCI.34 But platelets would not have been inhibited until several hours after the procedure with either dose, possibly accounting for lack of clinical effect. However, in neither Intracoronary Stenting and Antithrombotic Regimen: Rapid Early Action for Coronary Treatment-4 (ISAR-REACT)35 nor PRAGUE-836 trials did early or late administration of 600 mg clopidogrel before
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elective PCI have an effect on cardiovascular adverse events at 7 to 30 days. The benefit of clopidogrel loading seems to be more pronounced in patients with ACS in whom infarction is often present suggesting an anti-infarct effect with early administration. Clopidogrel does not protect all patients. In fact, 24% to 46% treated with 300 mg clopidogrel25,29,37 and 15% to 21% treated with 600 mg clopidogrel25,29 had little or no inhibition of platelet aggregation 6 to 19 hours following treatment. Gurbel et al38 measured platelet reactivity serially in patients who received a loading dose of 300 mg clopidogrel before elective coronary artery stenting and then a daily maintenance dose of 75 mg. After 2 hours of the loading dose, 63% still had less than 10% inhibition of platelet aggregation. Thirty-one percent of the patients continued to be nonresponders at 24 hours and 5 days and 15% at 30 days. Loading with 600 mg clopidogrel in patients with NSTEMI39 and STEMI40 left 36% and 55%, respectively, with high platelet reactivity at the time of PCI. Nonresponsiveness (definition is dependent on the particular study, eg, less than 10% change in platelet aggregation from baseline to post-treatment blood sample in response to 5 mmol/L ADP38) had adverse clinical implications. Nonresponders had more frequent elevations of creatine phosphokinase-MB following PCI,37 a significantly higher likelihood of subacute stent thrombosis,41 and possibly a higher likelihood of adverse cardiovascular events.39 Likely causes of clopidogrel nonresponsiveness could be poor intestinal absorption or inadequate metabolism to the active metabolite. Biotransformation of the prodrug to the active metabolite by cytochrome P450 enzyme system is affected by the CYP2C19 gene.42 The CYP2C19*2 variant allele leads to poor metabolism. In the year following deployment of drug-eluting stents, myocardial infarction occurred in 8.4%, 10.9%, and 44.4% of the patients with 0, 1, and 2 variant alleles, respectively (P ¼ .016). There are still other factors that affect clopidogrel’s pharmacokinetics that have not yet been identified.43
Improving the Pharmacology of Oral Antiplatelet Agents A third-generation thienopyridine was introduced because of the variable response to clopidogrel. Prasugrel, like clopidogrel, is a prodrug requiring hepatic metabolism to become an active metabolite that irreversibly binds to platelet P2Y12 receptors and blocks platelet aggregation. But it is metabolized by different enzymes and has a more consistent effect in patients. Inhibition of aggregation of platelets from rats fed prasugrel was 10-fold greater than that seen with clopidogrel.44 Similar observations were made in patients with stable coronary artery disease treated with either prasugrel or clopidogrel.45 In patients undergoing elective PCI, there was 74.8% inhibition of platelet activity 6 hours after 60 mg prasugrel compared to 31.8% in patients treated with 600 mg clopidogrel (P < .0001).46 In addition to prasugrel’s greater peak platelet antiaggregatory effect, the onset of effect is more
rapid.47 The median time to reach 20% inhibition of platelet aggregation was 30 minutes for prasugrel and 1.5 hours for clopidogrel (P < .001). Although 24% of the patients treated with clopidogrel had insignificant inhibition of platelet reactivity, all patients responded to prasugrel.47 In the TRIal to assess Improvement in Therapeutic Outcomes by optimizing platelet inhibitioN with PrasugrelThrombolysis in Myocardial Infarction (TRITON-TIMI)48 38 patients with ACS scheduled for PCI were treated with either prasugrel (loading dose 60 mg and daily maintenance dose 10 mg) or clopidogrel (loading dose 300 mg and daily maintenance dose 75 mg) for 6 to 15 months. Approximately 75% of the patients in each group received the study drug either during the PCI procedure or immediately after its completion, while 25% of the patients were treated prior to PCI. Prasugrel resulted in a 19% relative risk reduction in cardiovascular adverse events (P < .001)48 and an overall lower risk of myocardial infarction (P < .0001).49 Similar advantages of prasugrel over clopidogrel were observed in patients with STEMI, including a decrease in stent thrombosis (2.8% for clopidogrel and 1.6% for prasugrel, P ¼ .023).50 However, in patients with unstable angina pectoris or NSTEMI not undergoing revascularization but treated with maintenance doses of prasugrel or clopidogrel, there was no difference in cardiovascular events after a median follow-up of 17 months.51 So the important clinical difference between the 2 drugs was seen in those being revascularized.
Ticagrelor Is a Direct P2Y12 Inhibitor Although prasugrel had a favorable pharmacokinetic and genetic profile, treatment with it as established in the TRITON-TIMI 38 protocol48 could be initiated only after diagnostic angiography had revealed the patient to be a candidate for PCI. That provides little time for effective platelet inhibition before PCI.48 Montalescot and colleagues52 treated patients with NSTEMI with either a 60 mg loading dose of prasugrel just before PCI or 30 mg a median of 4.3 hours before PCI and another dose of 30 mg when it was known PCI was needed. Although only the latter group would have had any platelet inhibition at reperfusion, there was no difference in subsequent cardiovascular complications in the 2 groups. Perhaps there was still no sufficient platelet inhibition at the time of the procedure in patients pretreated with one-half of the standard loading dose, or the ischemic period was too long to allow salvage of the myocardium. The oral drug ticagrelor is a triazolopyrimidine. It is not a prodrug and is a reversible, noncompetitive inhibitor of the platelet P2Y12 receptor.53 In healthy volunteers53,54 and patients with stable coronary artery disease,54,55 loading doses of ticagrelor produced faster and more consistent platelet inhibition than either 300 mg53 or 60055 mg of clopidogrel. In patients with stable coronary artery disease, 180 mg ticagrelor led to 41% inhibition of platelet aggregation after 0.5 hours, 88% inhibition at 2 hours, and a maximal inhibition of 93% shortly thereafter.55 Corresponding inhibition by 600 mg clopidogrel was 8%, 38%, and 58%. After 5 days of maintenance
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treatment with ticagrelor, platelet inhibition ranged from 61% to 100% compared to 11% to 100% after 14 days of maintenance clopidogrel treatment.53 The rate-controlling step is still the time needed for intestinal absorption. In healthy volunteers, the median tmax for absorption was 1.5 to 3 hours.53 The PLATelet inhibition and patient Outcomes (PLATO) study in patients with ACS established ticagrelor’s superiority to clopidogrel.56 Ticagrelor decreased occurrence of combined vascular side effects, myocardial infarction, death from vascular causes, and death from any cause (P < .001). The advantage of ticagrelor over clopidogrel was seen regardless of whether the latter’s loading dose was 300 or 600 mg, and regardless of whether an invasive or noninvasive strategy was planned. Ticagrelor resulted in lower event rates throughout the follow-up period of 6 to 12 months.57 In spite of the encouraging clinical data for both prasugrel and ticagrelor, these are still oral preparations. Therefore, there is an obligatory delay between drug administration and biologic effect, probably the result of slow intestinal absorption. Although in healthy volunteers the effects of prasugrel and ticagrelor can be realized 1 to 2 hours after dosing,55 that was not the case in patients with ACS. Parodi et al58 measured platelet reactivity in patients with STEMI at baseline and 2, 4, 8, and 12 hours after loading doses of 60 mg prasugrel or 180 mg ticagrelor. High residual platelet reactivity was found in 44% and 60% of patients loaded with prasugrel and ticagrelor, respectively, at 2 hours. The mean time to achieve clinically significant platelet inhibition was 3 + 2 hours and 5 + 4 hours with prasugrel and ticagrelor, respectively. The independent predictor of this delay in biologic effect of the antagonists was morphine use. Possibly morphine slowed intestinal motility. Thus, in high-risk patients, the antiplatelet effect of the most potent oral agents is still delayed, and PCI is potentially performed without adequate platelet inhibition. This problem is magnified by the desire to shorten door-to-balloon times as much as possible, thus decreasing any pretreatment interval.
Cangrelor Is an Intravenous Antiplatelet Agent Cangrelor has a chemical structure similar to that of ticagrelor and is an intravenous, reversible blocker of the platelet P2Y12 receptor. It has a half-life of 6 h before elective coronary angiography or only for angiographically selected patients a few minutes before PCI? A randomized multicentre trial PRAGUE-8. Eur Heart J. 2008;29(12):1495-1503. Lev EI, Patel RT, Maresh KJ, et al. Aspirin and clopidogrel drug response in patients undergoing percutaneous coronary intervention: the role of dual drug resistance. J Am Coll Cardiol. 2006; 47(1):27-33. Gurbel PA, Bliden KP, Hiatt BL, O’Connor CM. Clopidogrel for coronary stenting: response variability, drug resistance, and the effect of pretreatment platelet reactivity. Circulation. 2003; 107(23):2908-2913. Sibbing D, Bernlochner I, Schulz S, et al. Prognostic value of a high on-clopidogrel treatment platelet reactivity in bivalirudin versus abciximab treated non-ST-segment elevation myocardial infarction patients: ISAR-REACT-4 (Intracoronary Stenting and Antithrombotic Regimen: Rapid Early Action for Coronary Treatment-4) platelet substudy. J Am Coll Cardiol. 2012;60(5):369-377. Bonello L, Berbis J, Laine M, et al. Biological efficacy of a 600 mg loading dose of clopidogrel in ST-elevation myocardial infarction. Thromb Haemost. 2012;108(1):101-106. Gurbel PA, Bliden KP, Samara W, et al. Clopidogrel effect on platelet REactivity in patients with Stent Thrombosis: results of the CREST study. J Am Coll Cardiol. 2005;46(10):1827-1832. Carlquist JF, Knight S, Horne BD, et al. Cardiovascular risk among patients on clopidogrel anti-platelet therapy after placement of drug-eluting stents is modified by genetic variants in both the CYP2C19 and ABCB1 genes. Thromb Haemost. 2013;109(4): 744-754. Frelinger AL III, Bhatt DL, Lee RD, et al. Clopidogrel pharmacokinetics and pharmacodynamics vary widely despite exclusion or control of polymorphisms (CYP2C19, ABCB1, PON1), noncompliance, diet, smoking, co-medications (including proton pump inhibitors), and pre-existent variability in platelet function. J Am Coll Cardiol. 2013;61(8):872-879. Sugidachi A, Ogawa T, Kurihara A, et al. The greater in vivo antiplatelet effects of prasugrel as compared to clopidogrel reflect more efficient generation of its active metabolite with similar antiplatelet activity to that of clopidogrel’s active metabolite. J Thromb Haemost. 2007;5(7):1545-1551. Wallentin L, Varenhorst C, James S, et al. Prasugrel achieves greater and faster P2Y12 receptor-mediated platelet inhibition than clopidogrel due to more efficient generation of its active metabolite in aspirin-treated patients with coronary artery disease. Eur Heart J. 2008;29(1):21-30.
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