Our institutional chest pain algorithm is revised annually by an interdisciplinary committee representing both cardiology and emergency services, reflecting the complex and collaborative nature of modern chest pain management. Since we last published our chest pain algorithm in December 2008,1 a number of important clinical trials related to adjunctive antiplatelet agents in the treatment of acute coronary syndromes (ACS) have been published. In this paper, we will review the recent data on the efficacy and safety of conventional and emerging antiplatelet agents, and we will discuss incorporation of such findings into the annual updates to the institutional ACS algorithm.
NEW APPROVED ANTIPLATELET AGENTS
Prasugrel, a thienopyridine ADP receptor antagonist, which, like clopidogrel, is a pro-drug, but bypasses a major step of enzymatic hepatic metabolism that clopidogrel must undergo, has demonstrated a more rapid onset of action and higher degree of platelet inhibition as compared with clopidogrel.2 The administration of 60 mg of prasugrel 30 minutes prior to percutaneous coronary intervention (PCI) achieves superior platelet inhibition, compared with a loading dose of 600 mg of clopidogrel 2 hours prior to PCI.3 The benefit of prasugrel as compared with clopidogrel has been demonstrated in the TRITON TIMI 38 trial which randomized 13,608 patients to either a 60-mg loading dose and a 10 mg per day maintenance dose of prasugrel or a 300-mg loading dose followed by a 75 mg per day maintenance dose of clopidogrel, prior to PCI for ACS.4 The primary efficacy end point was death from cardiovascular causes, nonfatal myocardial infarction (MI), or nonfatal stroke, whereas the key safety end point was major bleeding.4 At 15 months, there was a significant decrease in the primary end point of cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke from 12.1% in the clopidogrel group to 9.9% in the prasugrel group, representing a hazard ratio of 0.81 for the prasugrel group compared with the clopidogrel group.4 Additionally, the use of prasugrel was associated with a reduction in myocardial infarction, target vessel revascularization, and both early and late stent thrombosis after either the use of bare metal or drug-eluting stents.4 In contrast, there was a significant increase in both major and life-threatening bleeding in the prasugrel group, with many of the patients suffering major bleeding in the prasugrel arm having a history of stroke, being older than 75 years, and having a body weight of less than 60 kg.4 Thus, it appears that prasugrel, if used in a preselected population of patients at lower risk of bleeding, can lead to a significant decrease in adverse cardiac events in patients undergoing PCI for ACS, as compared with clopidogrel.
Further subgroup analysis of the 3534 patients in the TRITON study who presented with ST segment elevation MI (STEMI), demonstrated that significant benefit was derived from prasugrel in patients presenting with STEMI.5 In this study, in patients with STEMI, the hazard ratio for the primary end point of cardiovascular death, nonfatal MI, and nonfatal stroke in the prasugrel group as compared with the clopidogrel group was 0.68 at 30 days and 0.79 at 15 months.5 Additionally, unlike in the overall TRITON cohort, there was a significant reduction in rates of cardiovascular death and no significant increase in rates of life-threatening or minor bleeding in the prasugrel group as compared with the clopidogrel group, although this finding should be interpreted conservatively, given the absence of an interaction between randomized drug type, clinical syndrome, and bleeding.5 Recent American College of Cardiology/American Heart Association (ACC/AHA) guidelines have designated the use of 60-mg prasugrel immediately prior to PCI for patients presenting with STEMI, a class IB indication.6 Therefore, our updated 2010 clinical pathway for ACS and chest pain (Fig. 1) now recommends that patients presenting with STEMI (level 1 ACS) can receive either an immediate loading dose of 60 mg of prasugrel or 600 mg of clopidogrel. The interventional cardiologist attending will make the decision whether to administer clopidogrel or prasugrel to the patient. Based on the recent data from the TRITON study, we have established contraindications for the administration of prasugrel, that may predispose a patient to having a significant bleeding event related to prasugrel therapy, including history of a prior stroke or transient ischemic attack, history of intracranial pathology, age greater than 75 years, weight less than 60 kilograms, active bleeding, recent gastrointestinal or genitourinary bleeding, significant anemia, hepatic impairment, thrombocytopenia, plan for surgery within 1 week, or if the patient is taking anticoagulant therapy.
The likelihood of bleeding in patients who require coronary artery bypass graft surgery is significantly higher in patients pretreated with prasugrel compared with clopidogrel,4 and the duration of time required for normal platelet function to recover may be longer. As a result, since approximately 10% of patients with NSTEMI undergo CABG after angiography, our guidelines do not recommend administration of prasugrel to patients without known coronary anatomy (except for those with STEMI, in whom CABG is rarely performed). Rather, patients with ACS are preloaded with clopidogrel as previously described. If PCI is subsequently performed as per the discretion of the interventional cardiologist, selected patients at high risk for atherothrombotic events and/or stent thrombosis, and low risk for bleeding may subsequently be switched to prasugrel.
DRUG RESPONSIVENESS AND INTERACTIONS
Clopidogrel is a prodrug that must be metabolized by a number of hepatic enzymes, including CYP450–1A2 and CYP450–2C19, to be converted into its active metabolite. Therefore, any factors that may alter the function of enzymes like CYP450–2C19 (eg, concurrent medicines, environmental factors, and even genetic polymorphisms) may theoretically lead to alterations in the biologic activity of clopidogrel in the bloodstream, with ensuing implications on its effectiveness in the treatment of ischemic events. A retrospective cohort study of 8205 patients who were discharged after ACS evaluated the effect of the concomitant use of proton pump inhibitors (PPI) and clopidogrel on adverse event rates up to 2 years after discharge.7 The study by Ho et al demonstrated that patients who were taking both clopidogrel and a PPI had a significantly increased risk of death or rehospitalization for ACS as compared with patients not taking a PPI, with an odds ratio for risk of death or readmission for ACS of 1.25.7 However, a later randomized trial by Cuisset et al randomized 104 patients with NSTEMI who were taking clopidogrel to either the PPI omeprazole or pantoprazole, and demonstrated that after 1 month, patients receiving pantoprazole had a significantly better platelet response to clopidogrel as measured by platelet reactivity assay.8 Most recently, the large-scale, randomized COGENT trial demonstrated no adverse effect of omeprazole on cardiovascular outcomes in patients taking clopidogrel.9 Nonetheless, to minimize the likelihood of even a pharmacodynamic interaction between PPIs and clopidogrel, our 2010 ACS clinical pathway only allows for the use of pantoprazole concurrently with clopidogrel in patients who absolutely require the use of a PPI for gastrointestinal prophylaxis.
As a result of a Food and Drug Administration “boxed warning” on clopidogrel related to the diminished effectiveness of the drug in patients with impaired ability to convert the drug into its active form,10 the ACC and AHA issued a joint clinical alert. Although this alert acknowledges that genetic polymorphisms in the P450 enzymatic system can lead to certain patients demonstrating poor metabolism of clopidogrel, it concludes that there is insufficient data to recommend either routine genetic testing or platelet reactivity testing of patients starting clopidogrel.11 However, the alert does recommend that patients who have either ischemic complications on clopidogrel or demonstrate through platelet reactivity testing to be poor clopidogrel metabolizers, should either switch to double-dose clopidogrel or prasugrel,10 which is the practice we have adopted in our ACS patient population.
While our previous ACS clinical pathway had already included the findings of the ARMYDA-2 study, which demonstrated the benefit of a 600-mg loading dose of clopidogrel as compared with a 300-mg loading dose in patients with ACS undergoing PCI,12 we have increased the dose of clopidogrel following PCI based on the recent OASIS 7 trial. This trial of 25,086 patients presenting with ACS both randomized patients to either a loading dose of 600 mg of clopidogrel followed by 150 mg daily for 7 days and then 75 mg of clopidogrel daily thereafter or a loading dose of 300 mg of clopidogrel followed by 75 mg thereafter and to either high-dose aspirin (300–325 mg) or low-dose aspirin (75–100 mg) following PCI.13 While the overall trial did not demonstrate a significant difference in the primary end point of cardiovascular death, myocardial infarction, or stroke among patients assigned to higher dose aspirin, the primary outcome occurred in 3.8% of patients in the double-dose clopidogrel group as compared with 4.6% in the standard-dose clopidogrel group, with a P value of 0.03.12 Additionally, in the subgroup of patients who underwent PCI, double-dose clopidogrel was associated with a significant reduction in the rate of stent thrombosis, which was a prespecified secondary outcome.12 Thus, our 2010 ACS clinical pathway not only recommends that all ACS patients undergoing PCI who receive clopidogrel should be administered a pre-PCI 600 mg loading dose, but also that post-PCI patients should receive 150 mg daily of clopidogrel for 7 days followed by 75 mg daily thereafter (in the absence of bleeding).
ANTIPLATELET AGENTS CURRENTLY UNDER INVESTIGATION
While the addition of prasugrel to our armamentarium of antiplatelet agents recommended in our ACS clinical pathway is the focus of our 2010 update, recent data indicates that ticagrelor may be a promising emerging antiplatelet agent for patients presenting with ACS. Ticagrelor is an oral, nonthienopyridine, ADP antagonist, which, unlike clopidogrel and prasugrel, is not a prodrug. It remains investigational in the United States at the time of this writing. The PLATO trial compared ticagrelor (180-mg loading dose, 90 mg twice daily thereafter) and clopidogrel (300- to 600-mg loading dose, 75 mg daily thereafter) for the prevention of cardiovascular events in 18,624 patients admitted to the hospital with any type of ACS including NSTEMI or STEMI.14 The study assessed the primary end point of death from vascular causes, myocardial infarction, or stroke at 12 months, and demonstrated a 9.8% event rate in patients taking ticagrelor versus an 11.7% rate for those receiving clopidogrel.13 Additionally, there were significant reductions in cardiovascular death and death from any cause in the ticagrelor group, without an increase in the risk of either overall major bleeding, or life-threatening or fatal bleeding (although non-CABG-related bleeding was increased with ticagrelor).13 Ticagrelor use was associated with the sensation of dyspnea and ventricular pauses, both of which rarely required drug discontinuation.15 Ticagrelor, therefore, appears to be just as effective as prasugrel and does not appear to lead to increased overall bleeding events. Given the reduction in mortality present with this agent in contrast to other drugs, we anticipate that ticagrelor (once FDA approved) will replace clopidogrel and prasugrel as the antiplatelet agent of choice in ACS.
Our 2010 ACS clinical pathway reflects the most up to date, rigorously studied clinical trial data relating to improving adjunctive pharmacologic therapy for patients presenting with ACS. While the treatment of ACS continues to evolve, we will continue to refine our clinical pathways for ACS patients and to focus on including the most recent clinical data that will lead to improved patient outcomes.
1. Goyal N, Stant J, Esposito F, et al. Updating the chest pain algorithm: incorporating new evidence. Crit Pathw Cardiol
2. Wiviott SD, Antman EM, Winters KJ, et al. Randomized comparison of prasugrel (CS-747, LY640315), a novel thienopyridine P2Y12 antagonist, with clopidogrel in percutaneous coronary intervention: results of the Joint Utilization of Medications to Block Platelets Optimally (JUMBO)-TIMI 26 trial. Circulation
3. 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
4. Wiviott SD, Braunwald E, McCabe CH, et al. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med
5. 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, randomized controlled trial. Lancet
6. Kushner FG, Hand M, Smith SC Jr, et al. 2009 Focused updates of the ACC/AHA guidelines for the management of patients with ST-elevation myocardial infarction (updating the 2004 guideline and 2007 focused update) and the ACC/AHA/SCAI guidelines on percutaneous coronary intervention (updating the 2005 guideline and 2007 focused update): a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation.
7. 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
8. Cuisset T, Frere C, Quilici J, et al. Comparison of omeprazole and pantoprazole influence on a high 150-mg clopidogrel maintenance dose the PACA (Proton Pump Inhibitors And Clopidogrel Association) prospective randomized study. J Am Coll Cardiol
9. Bhatt DL, Cryer BL, Contant CF, et al. Clopidogrel with or without Omeprazole in Coronary Artery Disease. N Engl J Med
11. Holmes D Jr, Dehmer G, Kaul S, et al. ACCF/AHA Clopidogrel clinical alert: approaches to the FDA “boxed warning”: a report of the American College of Cardiology Foundation Task Force on Clinical Expert Consensus Documents and the American Heart Association. Circulation
12. Patt 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 Study. Circulation
13. The CURRENT-OASIS 7 Investigators. Dose comparisons of clopidogrel and aspirin in acute coronary syndromes. N Eng J Med
14. Wallentin L, Becker RC, Budaj A, et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med
15. 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
Keywords:© 2011 Lippincott Williams & Wilkins, Inc.
acute coronary syndromes; acute myocardial infarction; clinical pathways; prasugrel