The State of Periprocedural Antiplatelet Therapy After Recent Trials

JACC: CARDIOVASCULAR INTERVENTIONS

VOL. 3, NO. 6, 2010

© 2010 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION

ISSN 1936-8798/$36.00

PUBLISHED BY ELSEVIER INC.

DOI: 10.1016/j.jcin.2010.04.008

STATE-OF-THE-ART PAPER

The State of Periprocedural Antiplatelet Therapy After Recent Trials Nihar R. Desai, MD, MPH,* Deepak L. Bhatt, MD, MPH*† Boston, Massachusetts

The ability to mechanically dilate and treat stenoses in the coronary arteries opened a new chapter in cardiovascular medicine. Percutaneous coronary intervention (PCI) has been shown to improve outcomes among patients with acute coronary syndromes as well as improve symptoms among patients with stable coronary artery disease. Adjunctive antiplatelet therapy plays a critical role both in the periprocedural setting as well as in the long-term management of atherothrombosis. Over the past several years, clinical trials of novel compounds and treatment strategies have further refined our pharmacotherapeutic approach. Aspirin remains the cornerstone for antiplatelet therapy across the spectrum of ischemic heart disease. In contrast, studies of glycoprotein IIb/IIIa inhibitors suggest a more limited role, particularly when used in addition to contemporary dual antiplatelet therapy. Clopidogrel, the most widely used P2Y12 adenosine diphosphate receptor blocker—although having demonstrated efficacy in patients with ST-segment elevation myocardial infarction, non–ST-segment elevation acute coronary syndrome, and stable coronary artery disease undergoing PCI— has several limitations, including delay in onset, variability in response, and modest potency. The third-generation thienopyridine, prasugrel, as well as nonthienopyridine inhibitors of the P2Y12 receptor such as ticagrelor and cangrelor address these shortcomings, offering more potent, consistent, and rapid platelet inhibition. Prasugrel and ticagrelor led to significant reductions in adverse cardiovascular events, including cardiovascular mortality for the latter, whereas cangrelor met noninferiority compared with 600 mg of clopidogrel in patients with ACS undergoing PCI. There are myriad novel compounds at varying stages of development, including thrombin receptor antagonists whose role in the periprocedural and long-term setting will be defined through further study. Significant questions regarding antiplatelet therapy remain unanswered, including the role of genetic and platelet function testing to “tailor therapy”; the optimal duration of therapy; and the optimal mechanism to deliver high-quality, cost-effective antiplatelet therapy to all patients. (J Am Coll Cardiol Intv 2010; 3:571– 83) © 2010 by the American College of Cardiology Foundation

Background Percutaneous coronary intervention (PCI) has been shown to improve outcomes among patients

From the *Cardiovascular Division, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts; and the †VA Boston Healthcare System, Boston, Massachusetts. Dr. Bhatt receives research grants from AstraZeneca, Bristol-Myers Squibb, Eisai, Ethicon, Heartscape, Sanofi-Aventis, and The Medicines Company. Manuscript received March 15, 2010; revised manuscript received March 30, 2010, accepted April 15, 2010.

with acute coronary syndromes (ACS) as well as significantly improve symptoms among patients with stable coronary artery disease (CAD) (1– 4). Important advances in procedural techniques, equipment, and devices have occurred in parallel with improvements in adjunctive antithrombotic therapy. Given the importance of platelets in atherothrombosis, considerable interest has emerged in optimizing pharmacotherapy both in the periprocedural setting as well as longer term (Fig. 1). In the wake of several recent clinical trials investigating novel antiplatelet agents, we review the current state of periprocedural antiplatelet therapy.

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Aspirin Aspirin has been the mainstay of periprocedural antiplatelet therapy, regardless of PCI indication (i.e., stable angina vs. ACS). The ATC (Antiplatelet Trialists’ Collaboration) study demonstrated an approximately 25% relative risk reduction (RRR) in the cumulative incidence of vascular death, myocardial infarction (MI), or stroke with aspirin versus placebo (5). However, questions remain as to the optimal dose of aspirin. The ATC meta-analysis comparing a wide range of doses of aspirin found no incremental reduction in ischemic events from 75 mg to 1,500 mg, whereas gastrointestinal events were significantly increased in subjects receiving more than 300 mg/day of aspirin. Low-dose (75 to 100 mg/day) aspirin was compared with highAbbreviations dose (300 to 325 mg/day) aspiand Acronyms rin in the CURRENT-OASIS ACS ⴝ acute coronary 7 (Clopidogrel Optimal Loading syndrome Dose Usage to Reduce RecurADP ⴝ adenosine rent Events/Optimal Antiplatediphosphate let Strategy for Interventions) CAD ⴝ coronary artery trial, a randomized trial of disease 25,087 patients with ACS, CV ⴝ cardiovascular among whom 17,232 underwent MI ⴝ myocardial infarction PCI (6). There was no statistiNSTE-ACS ⴝ non–STcally significant difference in the segment elevation acute cumulative rate of the primary coronary syndrome end point, a composite of carPCI ⴝ percutaneous diovascular (CV) death, MI, or coronary intervention stroke between the 2 arms. RRR ⴝ relative risk Moreover, there was no differreduction ence in the incidence of stent STEMI ⴝ ST-segment thrombosis at 30 days. Of note, elevation myocardial infarction there was no difference in major TIMI ⴝ Thrombolysis In bleeding, with the Thrombolysis Myocardial Infarction In Myocardial Infarction (TIMI) VASP ⴝ vasodilatoror CURRENT definitions, alstimulated phosphoprotein though there seemed to be a higher rate of gastrointestinal bleeding in patients receiving high-dose aspirin therapy (0.24% vs. 0.38%, p ⫽ 0.05). Glycoprotein IIb/IIIa Inhibitors

Three parenteral inhibitors of the glycoprotein IIb/IIIa receptor have been extensively studied in patients undergoing PCI—abciximab, eptifibatide, and tirofiban. Earlier investigations with these potent inhibitors of platelet aggregation demonstrated reductions in adverse CV events across several settings, including PCI for stable CAD as well as ACS (7); however, recent data suggest a more limited role for these agents in the periprocedural setting.

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Early meta-analyses evaluating the efficacy of glycoprotein IIb/IIIa inhibition in patients with ACS or undergoing PCI demonstrated significant reductions in major adverse CV events, including a significant reduction in mortality at 30 days and 6 months (8,9). However, many of the early studies of glycoprotein IIb/IIIa inhibitors do not reflect current clinical practice, because few patients received concomitant antiplatelet therapy with a thienopyridine. The more contemporary ISAR-REACT (Intracoronary Stenting and Antithrombotic Regimen: Rapid Early Action for Coronary Treatment) trial showed no benefit of adjunctive glycoprotein IIb/IIIa inhibition in subjects undergoing elective PCI who were pre-treated with 600 mg of clopidogrel (10). Similar findings were noted in the ISAR-SWEET (Intracoronary Stenting and Antithrombotic Regimen: is abciximab a Superior Way to Eliminate Elevated Thrombotic risk in diabetics) trial, which studied the same question in diabetic patients (11). Several early investigations of glycoprotein IIb/IIIa inhibition among patients with non–ST-segment elevation acute coronary syndrome (NSTE-ACS) demonstrated significant RRRs in the rate of CV death or MI at 30 days, ranging from 31% to 83% (12–14). Once again, more contemporary studies of glycoprotein IIb/IIIa inhibitors have yielded conflicting results, particularly in the setting of aggressive pre-treatment with high-dose clopidogrel. The impact of abciximab versus placebo was evaluated in the ISAR-REACT 2 trial of 2,022 patients with moderate- to high-risk ACS undergoing PCI, all of whom received 600 mg of clopidogrel and high-dose aspirin (15). Although the overall trial results demonstrated a significant 3% absolute and 25% RRR with adjunctive abciximab, the benefit was limited to those with an elevation in biomarkers at presentation. With the benefit of periprocedural glycoprotein IIb/IIIa inhibition in NSTE-ACS seemingly limited to high-risk patients, a significant outstanding clinical question was the optimal timing of treatment (i.e., routine early use or delayed, provisional use). The EARLY-ACS (Early Glycoprotein IIb/IIIa Inhibition in Non-ST-Segment Elevation Acute Coronary Syndrome) trial was an international randomized controlled trial of 9,492 patients with high-risk NSTE-ACS planned for an invasive management strategy. Routine early use of eptifibatide was associated with a nonsignificant 8% RRR in the primary end point of death, MI, recurrent ischemia leading to urgent revascularization, or need for thrombotic bailout at 96 h at the expense of significantly increased rates of major bleeding (16). These findings were consistent with the findings from the ACUITY (Acute Catheterization and Urgent Intervention Triage) timing study (17). Adjunctive antiplatelet therapy with glycoprotein IIb/IIIa inhibitors has also been studied in patients with STsegment elevation myocardial infarction (STEMI) undergoing fibrinolysis or reperfusion with primary PCI. Abcix-

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Figure 1. Antiplatelet Pharmacotherapy Receptors involved in platelet activation and aggregation as well as sites of action of both established and novel antiplatelet drugs. (A) Adapted with permission from Meadows et al. (74). (B) Adapted with permission from Angiolillo et al. (66). ADP ⫽ adenosine diphosphate; GP ⫽ glycoprotein; PAR ⫽ protease-activated receptor; TxA2 ⫽ thromboxane A2; VWF ⫽ von Willebrand factor.

imab remains the most well-studied agent in the primary PCI setting, and a meta-analysis of 11 randomized trials demonstrated that use of adjunctive abciximab was associated with a significant reduction in mortality at 30 days and up to 1 year without an associated increase in bleeding events (18). These data notwithstanding, the efficacy of

abciximab in patients with STEMI undergoing primary PCI who were pre-treated with 600 mg of clopidogrel was recently questioned by the null findings of the BRAVE-3 (Bavarian Reperfusion AlternatiVes Evaluation-3) trial, which evaluated left ventricular infarct size with singlephoton emission computed tomography imaging (19).

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A facilitated PCI strategy employing a combination of reduced-dose fibrinolytic with intravenous abciximab was associated with significantly reduced infarct size and higher rate of complete ST-segment resolution (20), but the FINESSE (Facilitated Intervention with Enhanced Reperfusion Speed to Stop Events) trial found no benefit in major clinical outcomes with a significant increase in bleeding complications (21). Although it seems that the indications for use of glycoprotein IIb/IIIa antagonists continue to narrow, periprocedural antiplatelet therapy incorporating routine use of these potent inhibitors of platelet aggregation has been wholly questioned with the use of bivalirudin as anticoagulant support for PCI. In the REPLACE-2 (Randomized Evaluation in PCI Linking Angiomax to Reduced Clinical Events-2) trial, bivalirudin with provisional glycoprotein IIb/IIIa inhibition was shown to be noninferior to heparin plus planned glycoprotein IIb/IIIa inhibition in 6,002 patients undergoing PCI, most of whom had been pre-treated with clopidogrel (22). The ACUITY trial, of 13,819 patients with moderate- to high-risk ACS who planned to undergo PCI, not only demonstrated the noninferiority of bivalirudin with provisional glycoprotein IIb/ IIIa inhibition compared with heparin (unfractionated or low-molecular weight) with glycoprotein IIb/IIIa inhibition, but also met superiority for the net clinical end point, which included major bleeding events (23). Importantly, these findings were only applicable to the cohort of patients who received clopidogrel (24). Finally, the HORIZONS-AMI (Harmonizing Outcomes with RevasculariZatiON and Stents in Acute Myocardial Infarction) trial compared bivalirudin plus provisional glycoprotein IIb/IIIa with unfractionated heparin plus planned glycoprotein IIb/IIIa in 3,602 patients with STEMI undergoing primary PCI (25). Although there was no difference in major adverse CV events at 30 days, there was significantly less major bleeding with bivalirudin, driving the net clinical end point in favor of the direct thrombin inhibitor. Moreover, use of bivalirudin was associated with a 1.1% absolute risk reduction in the rate of CV death at 30 days, which remained significant at 1 year (26). One concern raised by the HORIZONS trial was the significantly higher risk of acute stent thrombosis in the bivalirudin arm in spite of potent background antiplatelet therapy (27). Thienopyridines

Ticlopidine, clopidogrel, and prasugrel are all oral, irreversible thienopyridine inhibitors of the platelet P2Y12 adenosine diphosphate (ADP) receptor. Dual antiplatelet therapy with aspirin and ticlopidine led to a 75% RRR in the rate of CV death, MI, need for bypass surgery, or repeat angioplasty and an 86% RRR in stent thrombosis when compared

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with aspirin and phenprocoumon, an anticoagulant (28). Further investigation of the impact of pre-treatment, which demonstrated reductions in adverse CV events, refined the optimal periprocedural use of ticlopidine (29,30). Accumulated data showed that clopidogrel was preferable to ticlopidine due to better tolerability and at least equivalent efficacy (31). The primary results and subsequent analyses of the CREDO (Clopidogrel for the Reduction of Events During Observation) trial demonstrated the benefit of clopidogrel pre-treatment as well as long-term dual antiplatelet therapy in stable patients undergoing elective PCI (32,33) whereas the efficacy of clopidogrel in patients with NSTE-ACS was established in the CURE (Clopidogrel in Unstable Angina to Prevent Recurrent Ischemic Events) trial (34). Approximately 20% of the overall CURE cohort underwent PCI, among whom clopidogrel pre-treatment was associated with a significant 30% RRR in the cumulative incidence of CV death, MI, or urgent target vessel revascularization at 28 days and a 31% RRR in the rate of CV death or MI at 1 year (35). In STEMI, intensification of antiplatelet therapy with aspirin and clopidogrel was shown to be beneficial in both the COMMIT-CCS (Clopidogrel and Metoprolol in Myocardial Infarction Trial/Second Chinese Cardiac Study) 2 (36) and CLARITY–TIMI (Clopidogrel as Adjunctive Reperfusion Therapy–Thrombolysis In Myocardial Infarction) 28 (37) trials. The PCI-CLARITY study, a prespecified analysis of 1,863 patients, evaluated the impact of clopidogrel pre-treatment versus treatment at the time of intervention (38). The former was associated with a highly significant 41% RRR in the primary end point, a composite of CV death, MI, or stroke at 30 days without an increase in major bleeding complications. Although the efficacy of early- and long-term therapy with clopidogrel had been established for patients undergoing PCI across the spectrum of ischemic heart disease, there remained several important limitations in its use for periprocedural platelet inhibition. For instance, clopidogrel is a pro-drug, and even with a 300-mg loading dose, there is an approximately 6-h delay before substantial ADP receptor antagonism. The CURRENT-OASIS 7 (6) trial investigated the role of a more intensive clopidogrel regimen, specifically a 600-mg load followed by 150 mg daily for 6 days, followed by 75 mg daily versus conventional dosing with a 300-mg load followed by 75 mg daily in 25,087 patients across the spectrum of ACS. Among the 17,232 patients with ACS who underwent PCI, the “double-dose” clopidogrel strategy resulted in a 15% RRR in the composite end point of CV death, MI, or stroke and a 42% RRR in stent thrombosis with a slight increase in major or severe bleeding events. Substantial interindividual variability in the response to clopidogrel in general and hyporesponsiveness or resistance

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in particular is another limitation (39). Several studies had demonstrated that a diminished response to clopidogrel, estimated to occur in one-third of patients, is associated with an increased risk of adverse CV events, including stent thrombosis (40). The recently completed POPULAR (Do Platelet Function Assays Predict Clinical Outcomes in Clopidogrel-Pretreated Patients Undergoing Elective PCI) study formally evaluated 8 distinct platelet function tests and demonstrated the ability of light transmittance aggregometry as well as the VerifyNow P2Y12 and Plateletworks bedside assays to detect high residual platelet reactivity, which then translated into increased rates of major adverse events, including death, MI, stent thrombosis, and stroke at 1 year (41). However, the incremental ability of these tests to predict risk over and above clinical factors was modest. Bonello et al. (42) tested the impact of a tailored approach to antiplatelet therapy in 162 clopidogrel-resistant patients, as determined by the vasodilator-stimulated phosphoprotein (VASP) assay, scheduled to undergo PCI. Subjects were randomized to usual care—thereby proceeding to intervention— or to a “VASPguided” strategy in which they received iterative loading doses of 600 mg of clopidogrel until the VASP was ⱕ50%. At 30 days, there were 2 CV deaths, 4 cases of stent thrombosis, and 2 cases of repeat revascularization, all of which occurred in the control arm. Although this was a small study, the concept of using platelet function testing and subsequently tailoring antiplatelet therapy in patients with clopidogrel resistance who are undergoing PCI is being evaluated in several large randomized trials, including the GRAVITAS (Gauging Responsiveness With A VerifyNow Assay—Impact On Thrombosis And Safety) (NCT00645918), DANTE (Dual Antiplatelet Therapy Tailored on the Extent of Platelet Inhibition) (NCT00774475), ARCTIC (Double Randomization of a Monitoring Adjusted Antiplatelet Treatment Versus a Common Antiplatelet Treatment for DES Implantation, and Interruption Versus Continuation of Double Antiplatelet Therapy) (NCT00827411), and TRIGGER-PCI (Testing Platelet Reactivity In Patients Undergoing Elective Stent Placement on Clopidogrel to Guide Alternative Therapy With Prasugrel) (NCT00910299) trials (Table 1). Importantly, however, the most prevalent cause of antiplatelet “resistance” outside the hospital seems to be noncompliance (43). Clopidogrel is a pro-drug that is activated through a 2-step, cytochrome P450 —mediated oxidation. As such, its metabolism and hence the generation of the active metabolite are influenced by genetic polymorphisms and susceptible to drug– drug interactions, which could have important clinical consequences. In fact, carriers of the CYP2C19*2 reduced function allele have been shown to have significant reductions in the amount of the active metabolite of clopidogrel as well as less platelet inhibition. These individuals are at significantly increased risk for adverse CV events, including a 3-fold increase in stent thrombosis (44). Thus,

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in addition to platelet function testing, genetic testing for the presence of the *2 allele might prove to be useful in the periprocedural setting to possibly individualize and optimize antiplatelet therapy (45). Future prospective studies are necessary before broadly endorsing such an approach. Proton pump inhibitors are competitive inhibitors of the CYP2C19 enzyme and thus are mechanistically capable of altering the pharmacokinetic, pharmacodynamic, and clinical effect of clopidogrel. In fact, there was ample ex vivo evidence highlighting such an interaction, which led to advisories from both the U.S. Food and Drug Administration and European Medicines Agency (46,47). However, the only randomized trial evaluating the impact of clopidogrel and omeprazole versus clopidogrel alone, the COGENT (Clopidogrel and the Optimization of Gastrointestinal Events) trial (48), in approximately 3,600 patients with ACS or after PCI revealed no significant adverse interaction and, in fact, demonstrated a significant reduction in gastrointestinal bleeding events. These preliminary data provide reassurance regarding the use of proton pump inhibitors with clopidogrel in patients who need both forms of therapy, although evaluation of the final published results is necessary (49). The third-generation thienopyridine, prasugrel, addressed many of the limitations of clopidogrel, because it offered more potent, consistent, and rapid inhibition of the platelet P2Y12 receptor. The 2 compounds were compared in the TRITON–TIMI 38 (TRial to assess Improvement in Therapeutic Outcomes by optimizing platelet inhibitioN with prasugrel–Thrombolysis In Myocardial Infarction) trial (50) of 13,608 patients with moderate- to high-risk ACS, including STEMI, all planned to undergo PCI. Prasugrel was administered with a 60-mg loading dose followed by 10 mg daily, and clopidogrel was given as a 300-mg loading dose and 75 mg daily as maintenance dose. At 15 months, treatment with prasugrel was associated with a 2.3% absolute and 19% relative risk reduction in the rate of CV death, MI, or stroke at the expense of a small absolute but statistically significant increase in the rate of TIMI major bleeding not related to coronary artery bypass graft surgery as well as fatal bleeding. The rate of Academic Research Consortium definite or probable stent thrombosis was reduced by 52% with more potent ADP receptor blockade, irrespective of stent type. Among the 12,844 patients who underwent PCI and stenting, prasugrel was associated with a significant reduction in adverse CV events that was consistent across stent type (51). In pre-specified subgroup analyses, treatment with prasugrel seemed to be particularly effective in subjects with diabetes mellitus (52) and those presenting with STEMI (53). In both of these groups, prasugrel as compared with clopidogrel led to significant reductions in ischemic events without an accompanying increase in the rate of major bleeding complications. Conversely, in the trial as a whole, among subjects 75

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Table 1. Ongoing Trials of Antiplatelet Therapy Clinical Trial (Registry No.)

Study Population

Study Arms

Primary End Point

ACCOAST (NCT01015287)

4,100 patients with NSTEMI planned to undergo PCI

Randomized to pre-treatment with prasugrel (30 mg at time of diagnosis with additional 30 mg at PCI) vs. prasugrel (60 mg) at PCI. Maintenance therapy in both arms will be 10 mg daily with dose reduction to 5 mg in patients ⬎75 yrs and body weight ⬍60 kg

CV death, MI, stroke, urgent revascularization, or GP IIb/IIIa inhibitor bailout at 7 days

ARCTIC (NCT00827411)

2,500 patients undergoing elective PCI with DES

Initial randomization to tailored antiplatelet therapy with VerifyNow P2Y12 vs. standard dual antiplatelet therapy. Subsequent randomization after 12 months of patients who remain eventfree to discontinuation of antiplatelet therapy or continuation of therapy

Death, MI, stroke, urgent coronary revascularization, or stent thrombosis assessed at 1 yr; death, MI, stroke, urgent coronary revascularization, or stent thrombosis at 6–18 months after second randomization

DANTE Trial (NCT00774475)

442 patients with NSTE-ACS undergoing PCI with stent implantation found to have high residual platelet reactivity with the VerifyNow P2Y12

Randomized to 75 mg of clopidogrel or 150 mg of clopidogrel

CV death, MI, or target vessel revascularization at 6 months and 1 yr

DAPT (NCT00977938)

20,645 subjects undergoing PCI

Subjects in the overall cohort who are free from death, MI, stroke, repeat revascularization, stent thrombosis, or major bleeding at 12 months will be randomized to 18 additional months of dual antiplatelet therapy or aspirin and placebo

CV death, MI, and stroke at 33 months; stent thrombosis at 33 months

GRAVITAS (NCT00645918)

2,783 subjects after DES placement for stable CAD or NSTE-ACS will have platelet function testing done with VerifyNow P2Y12

Patients with high residual platelet reactivity will be randomized to receive standard-dose clopidogrel (75 mg daily) or high-dose clopidogrel (600 mg load, 150 mg daily). A random sample of patients without high residual platelet reactivity will also be enrolled and will receive 75 mg of clopidogrel daily

CV death, MI, and definite/ probable stent thrombosis at 6 months

INNOVATE-PCI (NCT00751231)

Phase II trial in 800 patients undergoing elective PCI

Randomized to clopidogrel (300/600 mg load, followed by 75 mg daily) or elinogrel (80 mg IV bolus administered before PCI, followed by twice daily dosing of oral 50 mg, 100 mg, or 150 mg)

No pre-specified primary end point

LANCELOT 201 (NCT00312052)

Phase II trial of 600 patients with CAD

Randomized to E5555 (50 mg, 100 mg, or 200 mg daily) or placebo

Safety and tolerability (6 months)

LANCELOT 202 (NCT00548587)

Phase II trial of 600 patients with ACS

Randomized to E5555 (50 mg, 100 mg, or 200 mg daily) or placebo

Safety and tolerability (12 weeks)

TRA-CER (NCT00527943)

12,500 subjects with ACS

Randomized to SCH 530348 (40 mg loading dose, 2.5 mg daily) vs. placebo

CV death, MI, stroke, recurrent ischemia with repeat hospital stay, and urgent coronary revascularization at end of study

TRA-2P-TIMI 50 (NCT00526474)

26,450 patients with history of CAD, CVA, or PAD

Randomized to SCH 530348 (2.5 mg daily) vs. placebo

CV death, MI, stroke, and urgent coronary revascularization at end of study

TOPAS-1 (NCT00914368)

Phase II trial of 450 patients who have either had or not had stent thrombosis or MI within 6 months of PCI while on dual antiplatelet therapy

All subjects will undergo platelet function testing with both VerifyNow P2Y12 and VASP assays

Establish VerifyNow P2Y12 (PRU) and VASP (PRI, %) cutoff level of platelet inhibition in patients with and without clinical events.

TRIGGER-PCI (NCT00910299)

2,150 subjects with high residual platelet reactivity with the VerifyNow P2Y12 after elective PCI with DES

Randomized to prasugrel (60 mg load, 10 mg daily) vs. clopidogrel (75 mg daily)

CV death or MI at 6 months

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Table 1. Continued Clinical Trial (Registry No.) TRILOGY-ACS (NCT00699998)

Study Population 10,300 patients with NSTE-ACS being initially medically managed

Study Arms Randomized to prasugrel (30 mg load if administered, followed by 5 mg or 10 mg maintenance) or clopidogrel (300 mg load if administered, followed by 75 mg daily)

Primary End Point CV death, MI, or stroke at end of study

ACCOAST ⫽ Comparison of Prasugrel at PCI or Time of Diagnosis of Non-ST Elevation Myocardial Infarction Trial; ACS ⫽ acute coronary syndrome; ARCTIC ⫽ Double Randomization of a Monitoring Adjusted Antiplatelet Treatment Versus a Common Antiplatelet Treatment for DES Implantation, and Interruption Versus Continuation of Double Antiplatelet Therapy Trial; CAD ⫽ coronary artery disease; CV ⫽ cardiovascular; CVA ⫽ cerebrovascular accident; DANTE ⫽ Dual Antiplatelet Therapy Tailored on the Extent of Platelet Inhibition; DAPT ⫽ Dual Antiplatelet Therapy; DES ⫽ drug-eluting stents; GP IIb/IIIa ⫽ glycoprotein IIb/IIa receptor; GRAVITAS ⫽ Gauging Responsiveness With A VerifyNow Assay—Impact On Thrombosis And Safety; INNOVATE-PCI ⫽ A Phase 2 Safety and Efficacy Study of PRT060128, a Novel Intravenous and Oral P2Y12 Inhibitor, in Non-Urgent PCI; LANCELOT 201 ⫽ Safety and Tolerability of E5555 and Its Effects on Markers of Intravascular Inflammation in Subjects With Coronary Artery Disease; LANCELOT 202 ⫽ Safety and Tolerability of E5555 and Its Effects on Markers of Intravascular Inflammation in Subjects With Acute Coronary Syndrome; MI ⫽ myocardial infarction; NSTE-ACS ⫽ non–ST-segment elevation acute coronary syndrome; NSTEMI ⫽ non–ST-segment elevation myocardial infarction; PAD ⫽ peripheral artery disease; PCI ⫽ percutaneous coronary intervention; PRI ⫽ platelet reactivity index; PRU ⫽ platelet reactivity unit; TIMI ⫽ Thrombolysis In Myocardial Infarction; TOPAS-1 ⫽ Tailoring Of Platelet Inhibition to Avoid Stent Thrombosis; TRA-CER ⫽ Trial to Assess the Effects of SCH 530348 in Preventing Heart Attack and Stroke in Patients With Acute Coronary Syndrome; TRA-2P-TIMI 50 ⫽ Trial to Assess the Effects of SCH 530348 in Preventing Heart Attack and Stroke in Patients With Atherosclerosis; TRIGGER-PCI ⫽ Testing Platelet Reactivity In Patients Undergoing Elective Stent Placement on Clopidogrel to Guide Alternative Therapy With Prasugrel; TRILOGY-ACS ⫽ Comparison of Prasugrel and Clopidogrel in Acute Coronary Syndrome Subjects; VASP ⫽ vasodilator-stimulated phosphoprotein.

years of age or older, those weighing ⬍60 kg, and those with a prior history of transient ischemic attack (TIA) or stroke, the balance of safety and efficacy favored clopidogrel over prasugrel (50). Furthermore, prasugrel does not seem to be prone to alterations in its pharmacokinetics, pharmacodynamics, or clinical efficacy on the basis of genetic polymorphisms (54). There are several ongoing clinical trials involving prasugrel (Table 1), including the TRILOGY-ACS (Comparison of Prasugrel and Clopidogrel in Acute Coronary Syndrome Subjects Trial) (NCT00699998), ACCOAST Comparison of Prasugrel at PCI or Time of Diagnosis of Non-ST Elevation Myocardial Infarction Trial) (NCT01015287), and TRIGGER PCI trials (NCT00910299).

reversible, ADP receptor antagonists—the former is an oral agent, whereas the latter is parenterally administered. Both compounds provide more potent, rapid, and consistent platelet inhibition compared with clopidogrel (59). In the PLATO (Study of Platelet Inhibition and Patient Outcomes) trial, 18,624 patients across the spectrum of ACS were randomized to treatment with ticagrelor (180-mg load, followed by 90 mg twice daily maintenance) or clopidogrel (300- to 600-mg load, followed by 75 mg daily maintenance) (60). At 1 year, there was a highly significant, 16% RRR in the rate of CV death, MI, or stroke with ticagrelor compared with clopidogrel (Fig. 2). The benefit of ticagrelor was seen by 30 days and persisted throughout the study period. In the overall trial population, there was also a significant 1.1%

Cilostazol

Cilostazol, a reversible inhibitor of phosphodiesterase III that has been approved for use in patients with peripheral arterial disease, has also been tested in patients undergoing PCI. Several small studies with short follow-up intervals have demonstrated that therapy with aspirin and cilostazol is as effective as treatment with aspirin and ticlopidine in patients undergoing elective stenting (55). Compared with conventional dual antiplatelet therapy with aspirin and a thienopyridine, the addition of cilostazol (so-called “triple antiplatelet therapy”) has produced conflicting results (56 –58). Nonthienopyridine P2Y12 Inhibitors

Intensification of antiplatelet therapy with thienopyridine inhibitors of the P2Y12 receptor represented a major step forward in PCI. One of the limitations of this entire class of agents is that they are irreversible ADP receptor antagonists, particularly problematic for patients with 3-vessel or left-main CAD who require surgical revascularization that must then be delayed several days to allow recovery of platelet function. Ticagrelor and cangrelor are 2 novel,

Figure 2. Primary Results of the PLATO Trial Primary results of the PLATO (Study of Platelet Inhibition and Patient Outcomes) trial (ticagrelor vs. clopidogrel in acute coronary syndromes). Cumulative Kaplan-Meier estimates of the rate of the primary efficacy end point (death from vascular causes, myocardial infarction, or stroke) for ticagrelor and clopidogrel at 12 months. Reprinted with permission from Wallentin et al. (60).

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Figure 3. Primary Results of the PLATO-Invasive Trial Primary results of the PLATO-Invasive trial (ticagrelor vs. clopidogrel in patients with acute coronary syndromes managed with an invasive strategy). Cumulative Kaplan-Meier estimates of the rate of the primary efficacy end point (death from vascular causes, myocardial infarction, or stroke) for ticagrelor and clopidogrel at 12 months among patients managed with an invasive strategy. Reprinted with permission from Cannon et al. (61).

absolute risk reduction in death from vascular causes, a 1.4% absolute risk reduction in all-cause death, and a 33% RRR in the rate of definite stent thrombosis with ticagrelor. Although major bleeding, as defined in the study protocol was not significantly increased between groups, use of ticagrelor was associated with an increased rate of major bleeding not related to coronary artery bypass graft surgery as well as a numerical excess of intracranial hemorrhage. Ventricular pauses of at least 3 s and dyspnea were seen more commonly in subjects receiving ticagrelor, as were increases in serum uric acid and creatinine concentrations. The pre-specified analysis of patients who were managed with an early invasive strategy mirrored the findings in the overall study cohort with a significant 16% RRR in adverse CV events as well as a

reduction in all-cause mortality (Fig. 3) (61). Among patients with STEMI, the cumulative rate of the primary end point was also significantly reduced with ticagrelor and, notably, without an accompanying increase in the bleeding complications (62). Cangrelor offers potent (⬎90%) platelet inhibition within minutes of infusion that is rapidly reversible, such that platelet function normalizes within 60 min of discontinuation of infusion. Its efficacy in patients undergoing PCI was evaluated in the CHAMPION (Cangrelor versus Standard Therapy to Achieve Optimal Management of Platelet Inhibition) PCI and CHAMPION PLATFORM trials. The former randomly assigned 8,877 patients undergoing PCI, 85% with ACS, to receive cangrelor infusion (30␮g/kg bolus followed by 4-␮g/kg infusion) or 600 mg of clopidogrel within 30 min of intervention (63). Patients initially receiving cangrelor received 600 mg of clopidogrel after an average infusion time of 2.1 h. The primary end point, a composite of death, MI, or ischemia-driven revascularization at 48 h, occurred in 7.5% of subjects in the cangrelor arm and 7.1% in the clopidogrel arm (Table 2). There was also no statistically significant difference in the rate of stent thrombosis at 48 h or in the combined ischemic end point at 30 days. However, cangrelor was demonstrated to be noninferior to 600 mg of clopidogrel. The CHAMPION PLATFORM trial included 5,326 patients with NSTE-ACS who had undergone diagnostic angiography and were found to have CAD amenable to percutaneous revascularization (64). Patients were randomly assigned to receive either cangrelor (30-␮g/kg bolus followed by an infusion of 4 ␮g/kg for 2 to 4 h) or placebo for the duration of the PCI procedure. Subjects initially in the placebo group received a 600-mg loading dose of clopidogrel at the conclusion of the intervention, whereas those initially in the active treatment arm received 600 mg of

Table 2. Pre-Specified and Exploratory Efficacy End Points for Cangrelor and Clopidogrel at 48 h Among Patients Without STEMI in the CHAMPION PCI Trial Cangrelor Group (n ⴝ 3,889)

Clopidogrel Group (n ⴝ 3,865)

Odds Ratio (95% CI)

p Value

1° end point: death, MI, or ischemia-driven revascularization

290 (7.5)

276 (7.1)

1.05 (0.88–1.24)

0.59

MI

278 (7.1)

256 (6.6)

1.09 (0.91–1.29)

0.36

13 (0.3)

23 (0.6)

0.56 (0.28–1.11)

0.10 0.42

End Point Adjudicated end points

Ischemia-driven revascularization Death from any cause

8 (0.2)

5 (0.1)

1.59 (0.52–4.87)

Stent thrombosis

7 (0.2)

11 (0.3)

0.63 (0.25–1.63)

0.34

Stroke

6 (0.2)

7 (0.2)

0.85 (0.29–2.54)

0.77

Q-wave MI

4 (0.1)

10 (0.3)

0.40 (0.12–1.27)

0.12

Exploratory end points Death, Q-wave MI, or ischemia-driven revascularization

23 (0.6)

34 (0.9)

0.67 (0.39–1.14)

0.14

Death, Q-wave MI, or stent thrombosis

18 (0.5)

23 (0.6)

0.78 (0.42–1.44)

0.42

Data presented as n (%) unless otherwise indicated. Reprinted with permission from Harrington et al. (63). CHAMPION ⫽ Cangrelor versus Standard Therapy to Achieve Optimal Management of Platelet Inhibition; CI ⫽ confidence interval; MI ⫽ myocardial infarction; PCI ⫽ percutaneous coronary intervention; STEMI ⫽ ST-segment elevation myocardial infarction.

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Figure 4. Primary Results of the CHAMPION-PLATFORM Trial Primary results of the CHAMPION-PLATFORM (Cangrelor versus Standard Therapy to Achieve Optimal Management of Platelet Inhibition) trial (cangrelor vs. clopidogrel in ACS). Cumulative Kaplan-Meier estimates of the rate of the primary efficacy end point (death, myocardial infarction, or ischemia-driven revascularization) for cangrelor and clopidogrel at 48 h in the CHAMPION-PLATFORM trial. Reprinted with permission from Bhatt et al. (64).

clopidogrel after conclusion of the cangrelor infusion. At 48 h, there was a nonsignificant 13% RRR in the cumulative incidence of death, MI, or ischemia driven revascularization (Fig. 4). There was, however, a significant reduction in the secondary end points of all-cause death and stent thrombosis associated with cangrelor compared with placebo at 48 h. Neither of the CHAMPION trials had a primary safety end point. Instead, they reported the rates of various

bleeding end points, including TIMI, ACUITY, and Global Use of Strategies to Open Occluded Arteries (GUSTO). There was no difference in GUSTO severe or moderate or TIMI major bleeding in either study, although there was a significantly increased rate of ACUITY major bleeding in the PLATFORM trial and a trend toward higher ACUITY major bleeding in the PCI trial (p ⫽ 0.06), consisting entirely of an excess of groin hematomas (63,64).

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Elinogrel (PRT060128)—a reversible, potent P2Y12 inhibitor of the platelet ADP receptor available in both intravenous and oral preparations—was studied in a phase II trial, the ERASE-MI (Early Rapid Reversal of Platelet Thrombosis with Intravenous Elinogrel before PCI to Optimize Reperfusion in Acute Myocardial Infarction) trial (65), of 70 patients with STEMI undergoing primary PCI. Although there was no significant benefit comparing elinogrel versus placebo, there were no safety concerns raised by the 4 different doses that were tested. Elinogrel will be the subject of additional clinical trials, including the INNOVATE-PCI (A Phase 2 Safety and Efficacy Study of PRT060128, a Novel Intravenous and Oral P2Y12 Inhibitor, in Non-Urgent PCI) trial (NCT00751231). Thrombin Receptor Antagonists

Although ADP is an important mediator of platelet activation, and ADP antagonism has been shown to be quite efficacious in both the periprocedural and long-term settings, thrombin is an even more potent agonist of platelet activation and therefore an attractive therapeutic target. Moreover, thrombin inhibition might allow selective blockade of platelets involved in atherothrombosis while preserving platelet function in primary hemostasis, thus representing a safer alternative for intensifying antiplatelet therapy (66). Orally active thrombin receptor antagonists SCH530348 and E5555 are currently being tested in clinical trials (Table 1). The Road Ahead for Periprocedural Antiplatelet Therapy

The capability to mechanically dilate and treat stenoses in the coronary arteries represented a major change in the management of ischemic heart disease. Since 1977, when the first angioplasty procedure was successfully performed, tremendous advances have been made in the techniques, devices, and therapies offered in the cardiac catheterization laboratory. These improvements have been paralleled by advances in adjunctive pharmacotherapy. By exploring both the historical context of antiplatelet therapy as well as reviewing recent therapeutic developments, we have sought to provide a contemporary overview of periprocedural antiplatelet therapy. With myriad choices for antiplatelet agents (not to mention anticoagulants), selection of the optimal periprocedural regimen can be quite a daunting task. Background therapy with aspirin continues to be the unwavering, cornerstone of antiplatelet therapy. Broadly speaking, the trend toward more potent inhibition of the platelet P2Y12 receptor has catalyzed a steady decline in the need for routine adjunctive glycoprotein IIb/IIIa inhibition, which will only be hastened by the increasing use of bivalirudin in routine clinical practice. At this point, their most compelling indication remains use in the catheterization laboratory to support complex coronary interventions in high-risk pa-

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tients or as a bailout therapy once angiographic complications occur. However, novel approaches being studied such as intracoronary delivery of glycoprotein IIb/IIIa inhibitors might yet lead to resurgence in their use (67). Clopidogrel will likely remain the most commonly used adjunctive agent in the periprocedural setting in the short term, the advent of several new platelet antagonists of the P2Y12 receptor notwithstanding. The results of the TRITON and PLATO trials offer empirical verification of the intuitive hypothesis that more potent antiplatelet inhibition would yield greater reduction in adverse ischemic events at the expense of more bleeding complications. Although the design of the TRITON–TIMI 38 trial had some limitations, including comparison with 300 mg of clopidogrel and lack of pre-treatment, prasugrel deserves to play an important role in patients with ACS undergoing PCI when the coronary anatomy has been delineated. We feel that it deserves particular consideration in patients with STEMI and in those with diabetes, where the balance of benefit and risk should be maximized. Moreover, we feel that it should be the antiplatelet agent of choice in those who had thrombotic occlusion of an intracoronary stent while actually taking clopidogrel and, if future studies validate, also in those patients with residual platelet reactivity despite treatment with clopidogrel. The role of pre-treatment with prasugrel, the impact of a lower maintenance dose (i.e., 5 mg) in elderly patients and the underweight and its role in patients with stable CAD undergoing PCI remain outstanding questions. Although the PLATO trial results were impressive, ticagrelor was not tested uniformly against a 600-mg loading dose of clopidogrel or against a 150-mg maintenance dose of clopidogrel in the PLATO trial, requires twice daily dosing, and has yet to be approved by the Food and Drug Administration. The requisite twice daily dosing, although theoretically capable of antagonizing platelets entering the circulation after the first dose, clearly poses a challenge for patient compliance compared with a once-daily dosing regimen. Furthermore, its reversibility, which in the immediate periprocedural setting is certainly an asset, might become a liability in its long-term use where nonadherence might expose patients to a more immediate risk of adverse ischemic events, including stent thrombosis. Finally, the risk of excess bleeding for patients undergoing emergent coronary artery bypass graft surgery would not be obviated with this compound, which would still require a few days for return of normal platelet function (68). Despite these factors, the results of the PLATO trial are unambiguous and make it difficult to foresee how practitioners could refrain from routinely using an agent in compliant patients with ACS undergoing PCI if it is approved. The CHAMPION trials were instructive on many fronts, including highlighting the difficulty of ascertaining periprocedural MI in patients with baseline biomarker elevation undergoing PCI soon after presentation. In some respects,

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both the CHAMPION-PLATFORM and PCI trials are subject to the same limitation as TRITON–TIMI 38 in that they both required performance of a diagnostic angiogram with demonstration of occlusive coronary disease amenable to PCI before randomization. As a result, neither CHAMPION study protocol tested cangrelor against several hours of pre-treatment with clopidogrel. Taken together, both also highlight the clinical efficacy of 600 mg of clopidogrel, which proved to be a high hurdle for cangrelor to overcome. In spite of the inability of cangrelor to demonstrate superiority in these trials, its noninferiority compared with 600 mg of periprocedural clopidogrel could enable it to fill a conspicuous gap in clinical practice, specifically, facilitating potent periprocedural platelet inhibition in patients unable to tolerate or properly absorb oral medications, of particular concern in patients with cardiogenic shock or those who are vomiting or who are heavily sedated (69). These observations as well as promising post hoc exploratory analyses of the CHAMPION trials might merit further study of cangrelor (70). The preceding decade has witnessed an impressive expansion of the pharmacotherapeutic arsenal in CV medicine. Despite seemingly countless compounds, innumerable trials, and a limitless body of published data, several significant questions regarding antiplatelet therapy remain unanswered. For one, the optimal length of dual antiplatelet therapy in patients undergoing PCI with drug-eluting stents remains a point of controversy. The ongoing DAPT (Dual Antiplatelet Therapy) trial (NCT00977938) will compare standard therapy for 12 months with extended therapy for 30 months in 15,000 patients receiving drug-eluting stents, regardless of indication. Furthermore, platelet function testing and genetic testing might produce a paradigm-shift in antiplatelet therapy. The promise of “personalized medicine” could conceivably be realized with the application of these tools, although admittedly still in their infancy and in need of rigorous evaluation. Given the recent discussions in the U.S. about health care reform, cost control, and system realignment, periprocedural antiplatelet therapy is ripe for meaningful comparative effectiveness and cost-effectiveness research. In fact, with generic clopidogrel coming soon, there is a real possibility that “tailored therapy” would allow us to leverage scientific advances into improved outcomes as well as cost savings. The need for carefully designed studies that acknowledge these broader policy issues cannot be overstated. Finally, antiplatelet therapy has proven not to be immune from the quality issues that plague many areas of our health care system. Despite widespread dissemination of clinical practice guidelines and a series of national initiatives to improve guideline adherence, the quality of care delivered to patients with ACS remains suboptimal. Specifically, the underuse, overuse, and misuse of antiplatelet medications remains a serious problem deserving attention (71–73).

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Reprint requests and correspondence: Dr. Deepak L. Bhatt, Brigham and Women’s Hospital, 75 Francis Street, PBB-146, Boston, Massachusetts 02115. E-mail: [email protected]. edu.

REFERENCES

1. Antman EM, Anbe DT, Armstrong PW, et al. ACC/AHA guidelines for the management of patients with ST-elevation myocardial infarction— executive summary. A report of the American College of Cardiology/ American Heart Association Task Force on Practice Guidelines (Writing Committee to revise the 1999 Guidelines for the Management of Patients With Acute Myocardial Infarction). J Am Coll Cardiol 2004;44:671–719. 2. Keeley EC, Boura JA, Grines CL. Primary angioplasty versus intravenous thrombolytic therapy for acute myocardial infarction: a quantitative review of 23 randomised trials. Lancet 2003;361:13–20. 3. Cannon CP, Weintraub WS, Demopoulos LA, et al. Comparison of early invasive versus conservative strategies in patients with unstable coronary syndromes treated with the glycoprotein IIb/IIIa inhibitor tirofiban. N Engl J Med 2001;344:1879 – 87. 4. Mehta SR, Cannon CP, Fox KA, et al. Routine vs selective invasive strategies in patients with acute coronary syndromes: a collaborative meta-analysis of randomized trials. JAMA 2005;293:2908 –17. 5. Antiplatelet Trialists’ Collaboration. Collaborative overview of randomised trials of antiplatelet therapy—I: prevention of death, myocardial infarction, and stroke by prolonged antiplatelet therapy in various categories of patients. BMJ 1994;308:81–106. 6. Mehta SR. A 2x2 Factorial Randomized Trial of Optimal Clopidogrel and Aspirin Dosing in Patients with ACS Undergoing an Early Invasive Strategy with Intent for PCI (CURRENT-OASIS 7) Trial. Late Breaking Clinical Trial. Presented at: European Society of Cardiology Congress; August 30 –September 2, 2009; Barcelona, Spain. 7. Bhatt DL, Topol E. Current role of platelet glycoprotein IIb/IIIa inhibitors in acute coronary syndromes. JAMA 2000;284:1549 –58. 8. Kong DF, Califf RM, Miller DP, et al. Clinical outcomes of therapeutic agents that block the platelet glycoprotein IIb/IIIa integrin in ischemic heart disease. Circulation 1998;98:2829 –35. 9. Karvouni E, Katritsis DG, Ioannidis JP. Intravenous glycoprotein IIb/IIIa receptor antagonists reduce mortality after percutaneous coronary intervention. J Am Coll Cardiol 2003;41:26 –32. 10. Kastrati A, Mehilli J, Schuhlen H, et al. A clinical trial of abciximab in elective percutaneous coronary intervention after pretreament with clopidogrel. N Engl J Med 2004;350:232– 8. 11. Mehilli J, Kastrati A, Schühlen H, et al. Randomized clinical trial of abciximab in diabetic patients undergoing elective percutaneous coronary interventions after treatment with a high loading dose of clopidogrel. Circulation 2004;110:3627–35. 12. Topol EJ, Ferguson JJ, Weisman HF, et al. Long-term protection from myocardial ischemic events in a randomized trial of brief integrin ␤3 blockade with percutaneous coronary intervention. JAMA 1997;278: 479 – 84. 13. The PURSUIT Trial Investigators. Inhibition of platelet glycoprotein IIb/IIIa with eptifibatide in patients with acute coronary syndromes. Platelet glycoprotein IIb/IIIa in unstable angina: receptor suppression using integrilin therapy. N Engl J Med 1998;339:436 – 43. 14. Platelet Receptor Inhibition in Ischemic Syndrome Management in Patients Limited by Unstable Signs and Symptoms (PRISM-PLUS) Study Investigators. Inhibition of the platelet glycoprotein IIb/IIIa receptor with tirofiban in unstable angina and non-Q-wave myocardial infarction. N Engl J Med 1998;338:1488 –97. 15. Kastrati A, Mehilli J, Neumann FJ, et al. Abciximab in patients with acute coronary syndromes undergoing percutaneous coronary intervention after clopidogrel pretreatment: The ISAR-REACT 2 randomized trial. JAMA 2006;295:1531–38.

582

Desai and Bhatt Periprocedural Antiplatelet Therapy

16. Guigliano RP, White JA, Bode C, et al. Early versus delayed, provisional eptifibatide in acute coronary syndromes. N Engl J Med 2009;360:2176 –90. 17. Stone GW, Bertrand ME, Moses JW, et al. Routine upstream initiation vs deferred selective use of glycoprotein IIb/IIIa inhibitors in acute coronary syndromes: the ACUITY Timing trial. JAMA 2007; 297:591– 602. 18. De Luca G, Suryapranata H, Stone GW, et al. Abciximab as adjunctive therapy to reperfusion in acute ST-segment elevation myocardial infarction: a meta-analysis of randomized trials. JAMA 2005;293: 1759 – 65. 19. Mehilli J, Kastrati A, Schulz S, et al. Abciximab in patients with acute ST-segment-elevation myocardial infarction undergoing primary percutaneous coronary intervention after clopidogrel loading. Circulation 2009;119:1933– 40. 20. Thiele H, Engelmann L, Elsner K, et al. Comparison of pre-hospital combination fibrinolysis plus conventional care with pre-hospital combination fibrinolysis plus facilitated percutaneous coronary intervention in acute myocardial infarction. Eur Heart J 2005;26:1956 – 63. 21. Ellis SG, Tendera M, de Belder MA, et al. Facilitated PCI in patients with ST-elevation myocardial infarction. N Engl J Med 2008;358: 2205–17. 22. Lincoff AM, Bittl JA, Harrington RA, et al. Bivalirudin and provisional glycoprotein IIb/IIIa blockade compared with heparin and planned glycoprotein IIb/IIIa blockade during percutaneous coronary intervention. JAMA 2003;289:853– 63. 23. Stone GW, McLaurin BT, Cox DA, et al. Bivalirudin for patients with acute coronary syndromes. N Engl J Med 2006;355:2203–16. 24. Lincoff AM, Steinhubl SR, Manoukian SV, et al. Influence of timing of clopidogrel treatment on the efficacy and safety of bivalirudin in patients with non–ST-segment elevation acute coronary syndromes undergoing percutaneous coronary intervention. J Am Coll Cardiol Intv 2008;1;639 – 48. 25. Stone GW, Witzenbichler B, Guagliumi G, et al. Bivalirudin during primary PCI in acute myocardial infarction. N Engl J Med 2008;358: 2218 –30. 26. Mehran R, Lansky AJ, Witzenbichler B, et al. Bivalirudin in patients undergoing primary angioplasty for acute myocardial infarction (HORIZONS-AMI): 1-year results of a randomised controlled trial. Lancet 2009;374:1149 –59. 27. Morrow DA. Antithrombotic therapy to support primary PCI. N Engl J Med 2008;358:2280 –2. 28. Schömig A, Neumann F-J, Kastrati A, et al. A randomized comparison of antiplatelet and anticoagulant therapy after the placement of coronary-artery stents. N Engl J Med 1996;334:1084 –9. 29. Steinhubl SR, Lauer MS, Mukherjee DP, et al. The duration of pretreatment with ticlopidine prior to stenting is associated with the risk of procedure-related non–Q-wave myocardial infarctions. J Am Coll Cardiol 1998;32:1366 –70. 30. Steinhubl SR, Ellis SG, Wolski K et al. Ticlopidine pretreatment before coronary stenting is associated with sustained decrease in adverse cardiac events: data from the Evaluation of Platelet IIb/IIIa Inhibitor for Stenting (EPISTENT) Trial. Circulation 2001;103:1403–9. 31. Bhatt DL, Bertrand ME, Berger PB, et al. Meta-analysis of randomized and registry comparisons of ticlopidine with clopidogrel after stenting. J Am Coll Cardiol 2002;39:9 –14. 32. Steinhubl SR, Berger PB, Mann JT III, et al. Early and sustained dual oral antiplatelet therapy following percutaneous coronary intervention: a randomized controlled trial. JAMA 2002;288:2411–20. 33. Steinhubl SR, Berger PB, Brennan DM, et al. Optimal timing for the initiation of pre-treatment with 300 mg clopidogrel before percutaneous coronary intervention. J Am Coll Cardiol 2006;47:939 – 43. 34. Yusuf S, Zhao F, Mehta SR, et al. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med 2001;345:494 –502. 35. Mehta SR, Yusuf S, Peters RJ, et al. Effects of pretreatment with clopidogrel and aspirin followed by long-term therapy in patients undergoing percutaneous coronary intervention: the PCI-CURE study. Lancet 2001;358:527–33.

JACC: CARDIOVASCULAR INTERVENTIONS, VOL. 3, NO. 6, 2010 JUNE 2010:571– 83

36. Chen ZM, Jiang LX, Chen YP, et al. Addition of clopidogrel to aspirin in 45,852 patients with acute myocardial infarction. Lancet 2005;366: 1607–21. 37. Sabatine MS, Cannon CP, Gibson CM, et al. Addition of clopidogrel to aspirin and fibrinolytic therapy for myocardial infarction with ST-segment elevation. N Engl J Med 2005;352:1179 – 89. 38. Sabatine MS, Cannon CP, Gibson CM, et al. Effect of clopidogrel pretreatment before percutaneous coronary intervention in patients with ST-elevation myocardial infarction treated with fibrinolytics: the PCI-CLARITY study. JAMA 2005;294:1224 –32. 39. Wang TH, Bhatt DL, Topol EJ. Aspirin and clopidogrel resistance: an emerging clinical entity. Eur Heart J 2006;27:647–54. 40. Matetzky S, Shenkman B, Guetta V, et al. Clopidogrel resistance is associated with increased risk of recurrent atherothrombotic events in patients with acute myocardial infarction. Circulation 2004;109: 3171–5. 41. Breet NJ, van Werkum JW, Bouman HJ, et al. Comparison of platelet function tests in predicting clinical outcome in patients undergoing coronary stent implantation. JAMA 2010;303:754 – 62. 42. Bonello L, Camoin-Jau L, Arques S, et al. Adjusted clopidogrel loading doses according to vasodilator-stimulated phosphoprotein phosphorylation index decrease rate of major adverse cardiovascular events in patients with clopidogrel resistance: a multicenter randomized prospective study. J Am Coll Cardiol 2008;51:1404 –11. 43. Serebruany V, Cherala G, Williams C, et al. Association of platelet responsiveness with clopidogrel metabolism: role of compliance in the assessment of “resistance.” Am Heart J 2009;158:925–32. 44. Mega JL, Close SL, Wiviott SD, et al. Cytochrome P-450 polymorphisms and response to clopidogrel. N Engl J Med 2009;360:354 – 62. 45. Bhatt DL. Tailoring antiplatelet therapy based on pharmacogenomics: how well do the data fit? JAMA 2009;302:896 –7. 46. Gilard M, Arnaud B, Cornily JC, et al. Influence of omeprazole on the antiplatelet action of clopidogrel associated with aspirin: the randomized, double-blind OCLA (Omeprazole CLopidogrel Aspirin) study. J Am Coll Cardiol 2008;51:256 – 60. 47. Ho PM, Maddox TM, Wang L, et al. Risk of adverse outcomes associated with concomitant use of clopidogrel and proton pump inhibitors following acute coronary syndrome. JAMA 2009;301: 937– 44. 48. Bhatt DL. A Prospective, Randomized, Placebo-Controlled Trial of Omeprazole in Patients Receiving Aspirin and Clopidogrel (COGENT). Late Breaking Clinical Trial. Presented at: Transcatheter Cardiovascular Therapeutics Annual Meeting; September 24, 2009; Washington, DC. 49. Depta JP, Bhatt DL. Omeprazole and clopidogrel: should clinicians be worried? Cleve Clin J Med 2010;77:113– 6. 50. Wiviott SD, Braunwald E, McCabe CH, et al. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2007;357:2001–15. 51. Wiviott SD, Braunwald E, McCabe CH, et al. Intensive oral antiplatelet therapy for reduction of ischaemic events including stent thrombosis in patients with acute coronary syndromes treated with percutaneous coronary intervention and stenting in the TRITONTIMI 38 trial: a subanalysis of a randomised trial. Lancet 2008;371: 1353– 63. 52. Wiviott SD, Braunwald E, Angiolillo DJ, et al. Greater clinical benefit of more intensive oral antiplatelet therapy with prasugrel in patients with diabetes mellitus in the Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel– Thrombolysis in Myocardial Infarction 38. Circulation 2008;118: 1626 –36. 53. 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 2008;371:1353– 63. 54. Mega JL, Close SL, Wiviott SD, et al. Cytochrome P450 genetic polymorphisms and the response to prasugrel: relationship to pharmacokinetic, pharmacodynamic, and clinical outcomes. Circulation 2009; 119:2553– 60.

JACC: CARDIOVASCULAR INTERVENTIONS, VOL. 3, NO. 6, 2010 JUNE 2010:571– 83

55. Park SW, Lee CW, Kim HS, et al. Comparison of cilostazol versus ticlopidine therapy after stent implantation. Am J Cardiol 1999;84: 511– 4. 56. Lee CW, Park SW, Hong MK, et al. Triple versus dual antiplatelet therapy after coronary stenting: impact on stent thrombosis. J Am Coll Cardiol 2005;46:1833–37. 57. Lee SW, Park SW, Kim YH, et al. Comparison of triple versus dual antiplatelet therapy after drug-eluting stent implantation (from the DECLARE-Long trial). Am J Cardiol 2007;100:1103– 8. 58. Kim H. Randomized trial evaluating the efficacy of cilostazol on ischemic vascular complications after drug-eluting stent implantation for coronary heart disease: Influence of Cilostazol-Based Triple Antiplatelet Therapy on Ischemic Complication After Drug-Eluting Stent Implantation (CILON-T) study. Late Breaking Clinical Trial. Presented at: American College of Cardiology Scientific Session; March 15, 2010; Atlanta, GA. 59. Sabatine MS. Novel antiplatelet strategies in acute coronary syndromes. Cleve Clin J Med 2009;76 Suppl 1:S8 –15. 60. Wallentin L, Becker RC, Budaj A, et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2009;361: 1045–57. 61. Cannon CP, Harrington RA, James, S. Comparison of ticagrelor with clopidogrel in patients with a planned invasive strategy for acute coronary syndromes (PLATO): a randomised double-blind study. Lancet 2010;375:283–93. 62. Steg G. Ticagrelor compared with clopidogrel in patients with acute coronary syndromes, the PLATelet Inhibition and patient Outcomes (PLATO) trial: outcomes in patients with STEMI undergoing PCI. Late Breaking Clinical Trial. Presented at: American Heart Association Scientific Session; November 15, 2009; Orlando, FL. 63. Harrington RA, Stone GW, McNulty S, et al. Platelet inhibition with cangrelor in patients undergoing PCI. N Engl J Med 2009;361: 2318 –29. 64. Bhatt DL, Lincoff AM, Gibson CM, et al. Intravenous platelet blockade with cangrelor during PCI. N Engl J Med 2009;361: 2330 – 41. 65. Berger JS, Roe MT, Gibson CM, et al. Safety and feasibility of adjunctive antiplatelet therapy with intravenous elinogrel, a directacting and reversible P2Y12 ADP-receptor antagonist, before primary percutaneous intervention in patients with ST-elevation myocardial

Desai and Bhatt Periprocedural Antiplatelet Therapy

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infarction: the Early Rapid Reversal of Platelet Thrombosis with Intravenous Elinogrel before PCI to Optimize Reperfusion in Acute Myocardial Infarction (ERASE MI) pilot trial. Am Heart J 2009;158:998 –1004. 66. Angiolillo DJ, Capodanno D, Goto S. Platelet thrombin receptor antagonism and atherothrombosis. Eur Heart J 2010;31:17–28. 67. Deibele AJ, Jennings LK, Tcheng JE, et al. Intracoronary eptifibatide bolus administration during percutaneous coronary revascularization for acute coronary syndromes with evaluation of platelet glycoprotein IIb/IIIa receptor occupancy and platelet function: the Intracoronary Eptifibatide (ICE) trial. Circulation 2010;121:784 –91. 68. 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: 2577– 85. 69. Osmancik P, Jirmar R, Hulikova K, et al. A comparison of the VASP index between patients with hemodynamically complicated and uncomplicated acute myocardial infarction. Catheter Cardiovasc Interv 2010;75:158 – 66. 70. Faxon DP. Antiplatelet therapy: cangrelor for ACS—lessons from the CHAMPION trials. Nat Rev Cardiol 2010;7:124 –5. 71. Bottoroff MB, Nutescu EA, Spinler S. Antiplatelet therapy in patients with unstable angina and non-ST elevation myocardial infarction: findings from the CRUSADE National Quality Improvement Initiative. Pharmacotherapy 2007;27:1145– 62. 72. Roe MT, Parsons LS, Pollack CV Jr., et al. Quality of care by classification of myocardial infarction: treatment patterns for STsegment elevation vs non-ST elevation myocardial infarction. Arch Intern Med 2005;165:1630 – 6. 73. Bhatt DL, Roe MT, Peterson ED, et al. Utilization of early invasive management strategies for high-risk patients with non-ST elevation acute coronary syndromes: results from the CRUSADE quality improvement initiative. JAMA 2004;292:2096 –104. 74. Meadows TA, Bhatt DL. Clinical aspects of platelet inhibitors and thrombus formation. Circ Res 2007;100:1261–75.

Key Words: antiplatelet 䡲 periprocedural 䡲 therapy 䡲 trials.