WHAT IS PEER TO PEER?
Med-IQ's new complimentary, certified continuing medical education (CME) activity,
Peer to Peer: A New Model for Improving Guideline- and Evidence-Based ACS Care, is connecting healthcare professionals from across the country. This exciting, first-of-its-kind CME series provides participants with access to acute coronary syndrome (ACS) faculty experts during personalized sessions focusing on improving ACS patient care in their practices. This real-time exchange of ideas has helped address some of the major challenges that clinical practices face in managing ACS cases.

WHAT ARE E-BRIEFS?
Each month, Med-IQ will publish a short e-brief to highlight real-world questions, opportunities for improvement, and front-line perspectives gained from these ACS Peer to Peer teleconferences. Below, you'll find the seventh of these e-briefs; in this installment, our expert faculty answer two questions regarding the use of a currently available agent and an emerging agent.

Late last year, two developments in ACS antiplatelet management emerged:

• In November 2009, the US Food and Drug Administration (FDA) approved new label information for clopidogrel that advises avoidance of concomitant proton pump inhibitor (PPI) use due to a potential reduction in clopidogrel effectiveness
• Also in November 2009, a new drug application was filed for ticagrelor, a novel antiplatelet agent; the FDA has announced that the Cardiovascular and Renal Drugs Advisory Committee review will occur on July 28, 2010

In this e-brief, faculty explore these recent developments and how they might affect your clinical practice.

Examining the Recent Label Changes Regarding Clopidogrel and PPIs
Question: Should I be concerned about drug-drug interactions in my patients with ACS who take both clopidogrel and a PPI?

Answer: Although the antiplatelet effect of clopidogrel is somewhat reduced in patients taking PPIs, data from prospective trials suggest that this is probably of little clinical significance in terms of cardiovascular outcomes. Clopidogrel is a prodrug that is activated by cytochrome P450 (CYP) isoenzymes, especially CYP2C19. The PPIs—omeprazole, esomeprazole, and lansoprazole, in particular—are inhibitors of CYP2C19. Thus, as described in the OCLA (Omeprazole Clopidogrel Aspirin) study, PPIs can impair clopidogrel's ability to inhibit platelet aggregation.¹ This interaction at the enzymatic level, however, does not necessarily translate into poor cardiovascular outcomes in patients taking both medications.

Although the writing committee for the ACC/AHA guidelines requires additional data before making an official recommendation, in 2008 an ACCF/ACG/AHA expert consensus panel recommended the use of PPIs to prevent or treat antiplatelet-drug–associated gastrointestinal (GI) bleeding in high-risk ACS patients receiving dual antiplatelet therapy.^2,3 Recent findings from several observational studies, however, raised concerns that the diminishment of antiplatelet activity in patients receiving both clopidogrel and PPIs might translate into worse outcomes. For example, the retrospective cohort Clopidogrel Medco Outcomes Study compared 1-year outcomes of patients with coronary stents who were taking clopidogrel plus PPIs with those taking clopidogrel alone.⁴ In patients who had no previous history of major cardiovascular events, major cardiac events—hospitalization for stroke, myocardial infarction, angina, or coronary artery bypass graft (CABG)—occurred in 32.5% of patients on combination therapy versus 21.2% of patients receiving only clopidogrel (OR, 1.79; CI, 1.62-1.97). In patients with a preceding cardiovascular event, the effect was even more pronounced, with 39.8% versus 26.2%, respectively (OR, 1.86; CI, 1.63-2.12).⁴ It is important to note, however, that findings from observational studies can be misleading; the patients who received PPIs were not matched to those who did not receive PPIs, and many high-risk characteristics (eg, older, more comorbid conditions, etc.) were present. Thus, these other factors may have contributed to higher event rates in those patients receiving PPIs.

In contrast to observational studies, analyses of data from several landmark randomized clinical trials have not revealed a significant interaction between PPI use and diminished clopidogrel efficacy. A subgroup analysis of the CREDO (Clopidogrel for the Reduction of Events During Observation) trial evaluated the risk of death, acute myocardial infarction, or stroke in more than 2,000 patients who received clopidogrel or placebo with or without a PPI.⁵ Although patients who received PPIs had higher baseline risk and worse overall outcomes, the relative benefit of clopidogrel in reducing adverse cardiovascular outcomes at 1 year was similar in patients regardless of PPI use.⁵

In the TRITON-TIMI 38 (Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition With Prasugrel-Thrombolysis in Myocardial Infarction 38) trial, 13,608 patients with ACS were randomly assigned to receive prasugrel or clopidogrel; one-third of patients were on a PPI at baseline. Researchers found no association between PPI use and a risk of the primary endpoint for patients treated with clopidogrel (HR, 0.94; 95% CI, 0.80-1.11; P = 0.46) or prasugrel (HR, 1.00; 95% CI, 0.84-1.20; P = 0.97).⁶

The COGENT (Clopidogrel and the Optimization of Gastrointestinal Events) trial was the first randomized clinical study to evaluate the effect of combination therapy with omeprazole and clopidogrel in patients undergoing percutaneous coronary intervention. Although the trial was halted due to bankruptcy of the sponsor, preliminary results revealed no significant difference in cardiovascular outcomes between combination therapy and clopidogrel alone and found that combination therapy conferred a reduction in GI effects.⁷

Given these findings, clinicians should feel reasonably confident in continuing to prescribe PPIs in ACS patients on clopidogrel and aspirin who are at risk of GI bleeding or who have another indication for PPI therapy. H2-receptor antagonists are an alternative therapeutic option for preventing GI bleeding, but they are generally not considered to be as effective as PPIs.⁸

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Exploring Possible Roles of Emerging Agent Ticagrelor
Question: Given its pending FDA approval, what role might the new antiplatelet agent ticagrelor play in ACS management?

Answer: Ticagrelor is a reversible oral P2Y12 adenosine diphosphate (ADP) receptor antagonist that has been investigated for the reduction of major adverse cardiac events in patients with ACS. It is chemically distinct from the thienopyridines and is the first agent in a new chemical class, the CPTPs (cyclo-pentyl-triazolo-pyrimidines).⁹

The PLATO (Platelet Inhibition and Patient Outcomes) trial compared ticagrelor to clopidogrel in the prevention of cardiovascular events in 18,624 patients admitted to the hospital with ACS, with or without ST-segment elevation.¹⁰ The primary endpoint was the composite of death from vascular causes, myocardial infarction, or stroke at 1 year. This endpoint occurred in 9.8% of patients receiving ticagrelor compared with 11.7% of those receiving clopidogrel (HR, 0.84; 95% CI, 0.77-0.92; P < 0.001). No significant differences in the overall rate of major bleeding were found between the two groups (P = 0.43), although ticagrelor was associated with a higher rate of major non–CABG-associated bleeding than clopidogrel.¹⁰

The reversible nature of ticagrelor may reduce concerns about CABG-associated bleeding for patients who receive treatment in the emergency department, but are then determined to require CABG.¹⁰ In addition, ticagrelor is not metabolized in the liver; thus, the impact of genetic variability of CYP2C19 enzyme function—such as that seen with clopidogrel—would not apply to ticagrelor.¹⁰ For similar reasons, the concern about the diminished antiplatelet effect of clopidogrel in patients taking a PPI also does not apply to ticagrelor. Experts believe that this agent, if approved, could represent an advance in the management of ACS patients.

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REFERENCES

1. Gilard M, Arnaud B, Cornily JC, et al. Influence of omeprazole on the antiplatelet action of clopidogrel associated with aspirin. J Am Coll Cardiol. 2008;51(3):256-260.

2. Kushner FG, Hand M, Smith SC Jr, et al. 2009 Focused updates: ACC/AHA guidelines for the management of patients with ST-elevation myocardial infarction and ACC/AHA/SCAI guidelines on percutaneous coronary intervention. Circulation. 2009;120(22):2271-2306.

3. Bhatt DL, Scheiman J, Abraham NS, et al. ACCF/ACG/AHA 2008 expert consensus document on reducing the gastrointestinal risks of antiplatelet therapy and NSAID use: a report of the American College of Cardiology Foundation task force on clinical expert consensus documents. J Am Coll Cardiol. 2008;52(18):1502-1517.

4. Aubert RE, Epstein RS, Teagarden JR, et al. Proton pump inhibitors effect on clopidogrel effectiveness: the Clopidogrel Medco Outcomes Study [abstract no. 3998]. Circulation. 2008;118:S815.

5. Dunn SP, Macaulay TE, Brennan DM, et al. Baseline proton pump inhibitor use is associated with increased cardiovascular events with and without the use of clopidogrel in the CREDO Trial [abstract no. 3999]. Circulation. 2008;118:S815.

6. O'Donoghue ML, Braunwald E, Antman EM, et al. Pharmacodynamic effect and clinical efficacy of clopidogrel and prasugrel with or without a proton-pump inhibitor: an analysis of two randomised trials. Lancet. 2009;374(9694):989-997.

7. Bhatt D. COGENT: A prospective, randomized, placebo-controlled trial of omeprazole in patients receiving aspirin and clopidogrel. Presented at: Transcatheter Cardiovascular Therapeutics; Sept. 21-15, 2009; San Francisco.

8. Taha AS, McCloskey C, Prasad R, Bezlyak V. Famotidine for the prevention of peptic ulcers and oesophagitis in patients taking low-dose aspirin (FAMOUS): a phase III, randomised, double-blind, placebo-controlled trial. Lancet. 2009;374: 119-125.

9. AstraZeneca submits US New Drug Application for ticagrelor (BRILINTA™), an investigational antiplatelet agent. November 19, 2009. Astrazeneca 2010. Available at http://www.astrazeneca-us.com/about-astrazeneca-us/newsroom/research/7470811?itemId=7470811. Accessed on May 28, 2010.

10. Wallentin L, Becker RC, Budaj A, et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2009;361(11):1045-1057.

Educational Strategies in Atrial Fibrillation: Improving Guideline-Based Care at the Practice Level Register today for your personalized, certified CME teleconference in atrial fibrillation (AF). This exciting new CME series allows you to discuss guideline- and evidence-based care regarding rate and rhythm control in AF with a faculty expert. For more information, call (toll-free) 866 858 7434 or e-mail concierge@med-iq.com, or you can register today by completing this brief online form.   This activity has been approved for AMA PRA Category 1 Credit™. This activity is supported by an educational grant from sanofi-aventis U.S.

This activity is supported by an educational grant from sanofi-aventis U.S.

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