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 fourth of these e-briefs; in this installment, our expert faculty answer some questions about guideline updates posed by participants in our peer-to-peer teleconferences.

In December 2009, a joint focused update to the ACC/AHA ST-segment elevation myocardial infarction (STEMI) and ACC/AHA/SCAI percutaneous coronary intervention (PCI) guidelines was published with several modifications to pharmacologic approaches in invasive strategies. While the 2007 ACC/AHA unstable angina (UA)/non-ST-segment elevation myocardial infarction (NSTEMI) guidelines have not yet been updated, some changes in the focused update have relevance to invasive strategies in NSTEMI. In this e-brief, expert faculty discuss with participants how those changes and some recent data regarding the use of antiplatelet agents may affect clinical practice.

Applying Guideline Updates for the Use of Thienopyridines
Question: How have the recommendations for the use of thienopyridines in ACS changed in the most recent guideline update?

Answer: The 2009 joint focused update for STEMI and PCI states that patients with definite or likely UA/NSTEMI who have been selected for an invasive management strategy should receive dual-antiplatelet therapy with aspirin and a thienopyridine.¹ Although the 2007 UA/NSTEMI guidelines still recommend a 300-mg loading dose of clopidogrel upstream in invasive strategies, many clinicians report now using 600 mg of clopidogrel as a loading dose in NSTEMI patients who are to undergo PCI.² This strategy is based on a series of smaller trials showing that the 600-mg loading dose provides more rapid onset of antiplatelet therapy, with a peak level occurring 2 to 4 hours after administration. ARMYDA 2 (Antiplatelet Therapy for Reduction of Myocardial Damage During Angioplasty), which compared a 600-mg loading dose with the conventional 300-mg dose, is one of these trials that showed a benefit in reducing peri-PCI events in those receiving the 600-mg dose.³

CURRENT-OASIS 7 (Clopidogrel Optimal Loading Dose Usage to Reduce Recurrent Events/Optimal Antiplatelet Strategy for Interventions 7) also used a 600-mg loading dose.⁴ Although preliminary data did not show a significant reduction in the trial as a whole on the primary endpoint of the combined rate of cardiovascular death, myocardial infarction (MI), and stroke, patients who received a 600-mg loading dose of clopidogrel followed by 150 mg/day for 7 days and who then underwent PCI had a 22% lower risk of MI and a 30% reduction in the risk of stent thrombosis compared with those who received standard clopidogrel dosing.⁴ Another option is to give 300 mg of clopidogrel in the ED and then administer another 300 mg immediately before PCI, although that strategy has not been tested in an outcomes trial.

In addition, the 2009 joint focused update for STEMI and PCI guidelines gives a class I level of evidence B recommendation for the use of prasugrel (60 mg PO) at the time of PCI if clopidogrel is not used.¹ This recommendation is based on TRITON-TIMI 38, which reported a significant absolute reduction (2.2%) and relative reduction (19%) in the rate of death due to cardiovascular causes, nonfatal MI, or nonfatal stroke in patients who were treated with prasugrel (60-mg loading dose, 10-mg/day maintenance dose) compared with patients treated with clopidogrel (300-mg loading dose, 75-mg/day maintenance dose).⁵ The difference in this primary endpoint was largely due to the significant reductions in nonfatal MI (7.3% vs. 9.5%, HR 0.76, P < 0.001). A significant increase in the rate of bleeding, particularly TIMI major hemorrhage, was observed with the use of prasugrel (2.4% in prasugrel patients vs. 1.8% in clopidogrel patients).⁵ In another study comparing prasugrel with clopidogrel, Montalescot and colleagues reported a significant reduction in ischemic events without an apparent excess in bleeding in STEMI patients undergoing PCI who received prasugrel.⁶ Prasugrel has also been shown to significantly reduce the rate of definite or probable stent thrombosis. Patients with a history of stroke or transient ischemic attack, patients 75 years of age or older, and those with a body weight of less than 60 kg, however, have been reported to have no net clinical benefit from prasugrel due to higher rates of bleeding compared with the overall cohort.⁵

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Managing Patients Who May Be Resistant to Antiplatelet Therapy
Question: What about the patient who is already on a maintenance dose of thienopyridine but develops ACS and is slated for an invasive strategy? Should this patient be re-bolused?

Answer: Possibly. There is some concern that if the patient develops ACS while on clopidogrel and aspirin therapy, the patient may be among the 4% to 30% of patients who are resistant to antiplatelet therapy.⁷ Recent clinical data indicate that the use of an increased loading dose of clopidogrel in resistant patients undergoing PCI may help reduce resistance.⁷ In the RELOAD (Reload With Clopidogrel Before Coronary Angioplasty in Subjects Treated Long Term With Dual Antiplatelet Therapy) study, a significant reduction in poor and/or slow response to clopidogrel was seen in patients receiving maintenance clopidogrel therapy (≥ 7 days of 75 mg) who received a bolus-dose prior to PCI. Additionally, no differences in clinical safety or efficacy were found between the three different reloading strategies tested, with all patients eventually receiving the highest tested loading dose (900 mg).⁸ Based on these studies, it is reasonable to re-bolus a patient who develops ACS while on maintenance therapy. Additionally, TRITON-TIMI 38 reported a higher level of platelet inhibition in patients treated with prasugrel compared to those treated with clopidogrel.⁵ Therefore, switching patients who develop ischemia despite treatment with clopidogrel to this more potent agent may be a reasonable strategy to overcome clopidogrel resistance.

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REFERENCES

1. 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 (updating the 2004 guideline and 2007 focused update) and 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. J Am Coll Cardiol. 2009;54(23):2205-2241.

2. Anderson JL, Adams CD, Antman EM, et al. ACC/AHA 2007 guidelines for the management of patients with unstable angina/non ST-elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. 2007;116(7):e148-e304.

3. 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;111:2099-2106.

4. Mehta SR. CURRENT-OASIS 7: A 2x2 factorial randomized trial of optimal clopidogrel and aspirin dosing in patients with ACS undergoing an early invasive strategy with intent for PCI. European Society of Cardiology 2009 Congress; August 30-September 2, 2009; Barcelona, Spain.

5. Wiviott SD, Braunwald E, McCabe CH, et al. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2007;357:2001-2015.

6. 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. 2009;373:723-732.

7. Nguyen TA, Diodati JG, Pharand C. Resistance to clopidogrel: a review of the evidence. J Am Coll Cardiol. 2005;45(8):1157-1164.

8. Collet J-P, Silvain J, Landivier A, et al. Dose effect of clopidogrel reloading in patients already on 75-mg maintenance dose; the reload with clopidogrel before coronary angioplasty in subjects treated with dual antiplatelet therapy (RELOAD) study. Circulation. 2008;118:1225-1233.

"Dr. James Hoekstra was very professional and informative. He did an excellent job in explaining to me the different, specific measures that could be used to improve the care of patients with ACS. This was the best peer-to-peer CME activity I have participated in. Thanks Med-IQ staff and Dr. Hoekstra" — Cardiologist, Illinois

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

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