Antiplatelet therapy
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Phone:617-525-6884
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Oral Antiplatelet Agents
Oral antiplatelet agents remain a mainstay of PCI given their clear benefit in reducing the risk of stent thrombosis. Dual antiplatelet therapy with aspirin and clopidogrel has been widely accepted. The optimal duration of dual antiplatelet therapy following stent placement is not clear, and the current consensus is that 12 months of therapy should be administered to patients who are at low risk of bleeding.
Thienopyridines
The optimal timing and loading dose of clopidogrel continues to be evaluated. Several small studies have demonstrated that a 600mg-loading dose reduces platelet aggregation during PCI and reduces 30-day recurrent cardiovascular events [1]. The recent ARYMDA-2 and CLEAR PLATELETS trials had correlated a significant reduction in cardiac biomarker release and periprocedural MI’s with the 600mg clopidogrel-loading dose [2 3]. While ALBION demonstrated more rapid inhibition of platelet aggregation following a 900 mg loading dose as compared to a 600 mg dose, there was no difference in clinical events of death, MI, urgent target revascularization, repeat hospitalizations, or bleeding events in this small study [4].
Prasugrel
The safety and efficacy of prasugrel was evaluated in the TITAN-TIMI 38 trial (Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel–Thrombolysis in Myocardial Infarction-38). In the TITAN-TIMI 38 trial [5], 13,608 patients with moderate-to-high-risk acute coronary syndromes with scheduled PCI were randomized to receive prasugrel (a 60-mg loading dose and a 10-mg daily maintenance dose) or clopidogrel (a 300-mg loading dose and a 75-mg daily maintenance dose) for 6 to 15 months. The primary efficacy end point was death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke. The key safety end point was major bleeding. The primary efficacy end point occurred in 12.1% of patients receiving clopidogrel and 9.9% of patients receiving prasugrel (hazard ratio for prasugrel vs. clopidogrel, 0.81; 95% confidence interval [CI], 0.73 to 0.90; p<0.001). There was also significant reductions in the prasugrel group in the rates of myocardial infarction (9.7% for clopidogrel vs. 7.4% for prasugrel; P<0.001), urgent target-vessel revascularization (3.7% vs. 2.5%; p<0.001), and stent thrombosis (2.4% vs. 1.1%; p<0.001). Major bleeding was observed in 2.4% of patients receiving prasugrel and in 1.8% of patients receiving clopidogrel (hazard ratio, 1.32; 95% CI, 1.03 to 1.68; P=0.03). Also greater in the prasugrel group was the rate of life-threatening bleeding (1.4% vs. 0.9%; p=0.01), including nonfatal bleeding (1.1% vs. 0.9%; hazard ratio, 1.25; p=0.23) and fatal bleeding (0.4% vs. 0.1%; p=0.002). In patients with ACS with scheduled PCI, prasugrel therapy was associated with significantly reduced rates of ischemic events, including stent thrombosis, but with an increased risk of major bleeding, including fatal bleeding. Overall mortality did not differ significantly between treatment groups.
The relative antiplatelet effect of prasugrel versus high-dose clopidogrel in PCI patients was studied in the PRINCIPLE-TIMI 44 trial. The Prasugrel in Comparison to Clopidogrel for Inhibition of Platelet Activation and Aggregation–Thrombolysis in Myocardial Infarction 44 (PRINCIPLE-TIMI 44) was a randomized, double-blind, 2-phase crossover study of prasugrel compared with high-dose clopidogrel in patients undergoing cardiac catheterization for planned elective PCI. The primary end point of the loading-dose phase (prasugrel 60 mg versus clopidogrel 600 mg) was inhibition of platelet aggregation (IPA) with 20µmol/L ADP at 6 hours. Patients with PCI entered the maintenance-dose phase, a 28-day crossover comparison of prasugrel 10 mg/d versus clopidogrel 150 mg/d with a primary end point of IPA after 14 days of either drug. This study randomized 201 subjects undergoing cardiac catheterization with planned elective PCI. IPA at 6 hours was significantly higher in subjects receiving prasugrel (mean±SD, 74.8±13.0%) compared with clopidogrel (31.8±21.1%; P<0.0001). During the maintenance-dose phase, IPA with 20 µmol/L ADP was higher in subjects receiving prasugrel (61.3±17.8%) compared with clopidogrel (46.1±21.3%; P<0.0001). Results were consistent across all key secondary end points. The significant differences between the two groups were identified at 30 minutes and persisted across all time points. This study demonstrated that among patients undergoing cardiac catheterization with planned PCI, loading with 60 mg prasugrel resulted in greater platelet inhibition than a 600-mg clopidogrel loading dose. Maintenance therapy with prasugrel 10 mg/d resulted in a greater antiplatelet effect than 150 mg/d clopidogrel. Another novel oral thienopyridine (AZD6140) is being evaluated in the PLATO study [6].
Cangrelor
Given the delayed bioavailability of oral thienopyridines, IV formulations of novel antiplatelet aggregates are under investigation. Cangrelor is a platelet inhibitor that competitively binds to the ADP P2Y12 platelet receptor similar to clopidogrel, which inhibits via the same platelet pathway [7]. Potential benefits of Cangrelor include the fact that it achieves 90% platelet inhibition within minutes, and that it has a half-life of 5 minutes. After this time, the platelet resumes function as well (the inhibition is reversible unlike clopidogrel which is associated with irreversible inhibition). In small preliminary studies, cangrelor was not associated with any increased bleeding events compared to placebo or compared to abciximab.
Parenteral antiplatelet agents
GP IIb/IIIa inhibition in the setting of PCI for acute coronary syndromes has been associated with improved clinical outcomes including a 30% reduction in mortality. These clinical benefits are predominantly observed among patients who are troponin positive and among patients with STEMI [8 9]. These agents carry a Class I recommendation among patients undergoing PCI for an ACS. Abciximab carries a Class IIa recommendation in the setting of STEMI and the small molecules carry a Class IIB recommendation.
The optimal timing of GP IIb/IIIa inhibition continues to be evaluated. A recent pooled analysis demonstrated that the pre-PCI administration of any of the three agents in this class is associated with improved patency on arrival to the cath lab in the setting of STEMI [10]. In the setting of Non STE-ACS, upstream administration of these agents has been associated with improved myocardial perfusion before and after PCI [11]. The ACUITY timing study failed to demonstrate that administration of a GP IIb/IIIa inhibitor in the cardiac catheterization lab is non-inferior to upstream initiation of these agents (administration in the cath lab could have been up to 27% worse in efficacy exceeding the pre-specified 25% threshold) [12]. While the median duration of upstream GP IIb/IIIa administration was only 6 hours in ACUITY, a longer duration of therapy is being assessed in the ongoing EARLY ACS trial [13].
The role of GPIIb/IIIa inhibition among patients who have been preloaded with clopidogrel continues to be evaluated. Among low-risk, elective PCI patients who were pretreated with high-dose clopidogrel, abciximab demonstrated no improvement in clinical outcomes with adjunctive abciximab [14 15]. In contrast, among high-risk ACS patients undergoing PCI, ISAR-REACT 2 demonstrated that treatment with abciximab versus placebo in patients pretreated with a 600mg-loading dose of clopidogrel was associated with a lower rate of death, MI or urgent target vessel revascularization by 30 days [15] (8.9% vs. 11.9%, p=0.03, RR 0.75). As stated earlier, there was no difference in major bleeding associated with GP IIb/IIIa inhibition in this blinded trial. The efficacy benefit was observed among those patients who were troponin positive (13.1% vs. 18.3%, p=0.02, RR 0.71). Similar benefits of combined GP IIb/IIIa inhibition in conjunction with thienopyridine administration have been observed with eptifibatide [1].
References
- Cuisset T, Frere C, Quilici J, et al. Benefit of a 600-mg loading dose of clopidogrel on platelet reactivity and clinical outcomes in patients with non-ST-segment elevation acute coronary syndrome undergoing coronary stenting. J Am Coll Cardiol 2006 Oct 3;48(7):1339-45.
- Gurbel PA, Bliden KP, Zaman KA, et al. Clopidogrel loading with eptifibatide to arrest the reactivity of platelets: results of the Clopidogrel Loading With Eptifibatide to Arrest the Reactivity of Platelets (CLEAR PLATELETS) study. Circulation 2005 Mar 8;111(9):1153-9.
- Patti G, Colonna G, Pasceri V, et al. Randomized trial of high loading dose of clopidogrel for reduction of periprocedural myocardial infarction in patients undergoing coronary intervention: results from the ARMYDA-2 (Antiplatelet therapy for Reduction of MYocardial Damage during Angioplasty) study. Circulation 2005 Apr 26;111(16):2099-106.
- Montalescot G, Sideris G, Meuleman C, et al. A randomized comparison of high clopidogrel loading doses in patients with non-ST-segment elevation acute coronary syndromes: the ALBION (Assessment of the Best Loading Dose of Clopidogrel to Blunt Platelet Activation, Inflammation and Ongoing Necrosis) trial. J Am Coll Cardiol 2006 Sep 5;48(5):931-8.
- Wiviott SD, Braunwald E, McCabe CH, et al. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2007 Nov 15;357(20):2001-15.
- 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 Dec 18;116(25):2923-32.
- Greenbaum AB, Grines CL, Bittl JA, et al. Initial experience with an intravenous P2Y12 platelet receptor antagonist in patients undergoing percutaneous coronary intervention: results from a 2-part, phase II, multicenter, randomized, placebo- and active-controlled trial. Am Heart J 2006 Mar;151(3):689.
- Newby LK, Ohman EM, Christenson RH, et al. Benefit of glycoprotein IIb/IIIa inhibition in patients with acute coronary syndromes and troponin t-positive status: the paragon-B troponin T substudy. Circulation 2001 Jun 19;103(24):2891-6.
- Montalescot G, Borentain M, Payot L, et al. Early vs late administration of glycoprotein IIb/IIIa inhibitors in primary percutaneous coronary intervention of acute ST-segment elevation myocardial infarction: a meta-analysis. JAMA 2004 Jul 21;292(3):362-6.
- Gibson CM, Kirtane AJ, Murphy SA, et al. Early initiation of eptifibatide in the emergency department before primary percutaneous coronary intervention for ST-segment elevation myocardial infarction: results of the Time to Integrilin Therapy in Acute Myocardial Infarction (TITAN)-TIMI 34 trial. Am Heart J 2006 Oct;152(4):668-75.
- Bolognese L, Falsini G, Liistro F, et al. Randomized comparison of upstream tirofiban versus downstream high bolus dose tirofiban or abciximab on tissue-level perfusion and troponin release in high-risk acute coronary syndromes treated with percutaneous coronary interventions: the EVEREST trial. J Am Coll Cardiol 2006 Feb 7;47(3):522-8.
- 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 Feb 14;297(6):591-602.
- Giugliano RP, Newby LK, Harrington RA, et al. The early glycoprotein IIb/IIIa inhibition in non-ST-segment elevation acute coronary syndrome (EARLY ACS) trial: a randomized placebo-controlled trial evaluating the clinical benefits of early front-loaded eptifibatide in the treatment of patients with non-ST-segment elevation acute coronary syndrome--study design and rationale. Am Heart J 2005 Jun;149(6):994-1002.
- Kastrati A, Mehilli J, Schuhlen H, et al. A clinical trial of abciximab in elective percutaneous coronary intervention after pretreatment with clopidogrel. N Engl J Med 2004 Jan 15;350(3):232-8.
- 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 Apr 5;295(13):1531-8.
Acknowledgement and Attribution Regarding Sources of Content
Some of the initial content on this page may be incorporated in part from copyleft sources in the public domain including wikis such as Wikipedia and AskDrWiki. Drug information for patients came from the The National Library of Medicine. Infectious disease information may have come from the Centers for Disease Control (CDC). Differential Diagnoses are drawn from clinicians as well as an amalgamation of 3 sources: 1.The Disease Database; 2. Kahan, Scott, Smith, Ellen G. In A Page: Signs and Symptoms. Malden, Massachusetts: Blackwell Publishing, 2004:3; 3. Sailer, Christian, Wasner, Susanne. Differential Diagnosis Pocket. Hermosa Beach, CA: Borm Bruckmeir Publishing LLC, 2002:7 .
