Updated Non-ST-Segment Elevation Acute Coronary Syndrome Guidelines

For the first time, one antiplatelet agent has been recommended over another for non—ST-segment elevation acute coronary syndrome.

For 2014, the American Heart Association (AHA) and the American College of Cardiology (ACC) have updated the treatment guidelines for non—ST-segment elevation acute coronary syndrome (NSTE-ACS).¹ This new guideline includes numerous updates, but, most notably, it has specifically recommended one antiplatelet agent over another for the first time.

For patients with NSTE-ACS who are undergoing early invasive treatment strategy or ischemia-guided strategy, the AHA/ACC Task Force on Practice Guidelines now suggests it is reasonable to use ticagrelor (Brilinta) in preference to clopidogrel (Plavix) for P2Y12 treatment. In fact, the task force give this suggestion a class IIa recommendation and a level B evidence rating, meaning the benefit of the treatment outweighs any risk, though additional studies with focused objectives are needed, since the available evidence is from either a single randomized trial or nonrandomized studies.¹

Similarly, in patients with NSTE-ACS undergoing percutaneous coronary intervention (PCI) with stenting, the guidelines recommend it is reasonable to choose ticagrelor over clopidogrel.¹ With regard to prasugrel (Effient), the available evidence suggests there is no benefit to its administration for upstream therapy in patients with NSTE-ACS, but it is reasonable to consider prasugrel over clopidogrel for patients undergoing PCI who are not at a high risk for bleeding complications.^1-4

Since these updated recommendations put newer P2Y12 agents back in the spotlight, it is prudent to remember the particular warnings and contraindications of these drugs.

For instance, prasugrel should not be administered in any patient with a prior history of stroke or transient ischemic attack (TIA), due to a higher risk of bleeding seen in the TRITON-TIMI 38 trial (black box warning).^2,5 Furthermore, use of prasugrel is generally not recommended in any patient over the age of 75, due to similar risk of bleeding, or in patients who weigh <60 kg (black box warning). However, patients who weigh <60 kg may receive a lower daily dose of 5 mg.⁵

Ticagrelor has a few unique drug interactions and adverse effects worth mentioning, as well. Listed as a black box warning, concomitant maintenance aspirin doses >100 mg/day may reduce the efficacy of ticagrelor and should be avoided.⁶ In the PLATO study, patients who received >100 mg of aspirin seemed to have no benefit (composite endpoint of vascular death, MI, or stroke) with ticagrelor and more bleeding.⁷ The mechanism of this interaction as theorized by the PLATO authors is that, by administering aspirin at doses >80 mg /day, the inhibition of prostacyclin production at these concentrations will offset the potent P2Y12 inhibition and additional prostacyclin release caused by ticagrelor.^7-8

Prostacyclin (specifically PGI2) likely inhibits platelet aggregation and causes vasodilation.⁸ Although its production by COX-1 is readily inhibited by aspirin, its production by COX-2 is still maintained at normal daily aspirin doses. But, at the end of the day, the suppression of PGI2 from higher doses of aspirin isn't enough to overcome the inhibitory effects of TXA2 to initiate or predispose a patient to thrombosis, unlike COX-2 inhibitors. Moreover, if P2Y12 inhibition-mediated prostacyclin release was blunted in a clinically significant manner by aspirin, we should see this effect with clopidogrel and prasugrel, which we don’t.

Perhaps, everyone who received aspirin 325 mg daily in the PLATO trial were located in North America, where ticagrelor performed terribly, while virtually nobody elsewhere received the dose. The FDA advisory panel regarding ticagrelor seems to agree.⁹

The AHA/ACC NSTE-ACS guideline update for 2014 will no doubt mark an increase in the use of ticagrelor for this patient population. As pharmacists, it is crucial to understand the risks and benefits of these agents in order to best educate clinicians and patients alike.

Reference:

1. Amsterdam EA, Wenger NK, Brindis RG, et al. 2014 AHA/ACC Guideline for the Management of Patients With Non-ST-Elevation Acute Coronary Syndromes: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. 2014 Sep 23. pii: CIR.0000000000000134. [Epub ahead of print]

2. 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.

3. Roe MT, Armstrong PW, Fox KA, et al. Prasugrel versus clopidogrel for acute coronary syndromes without revascularization. N Engl J Med. 2012;367:1297-309

4. Montalescot G, Bolognese L, Dudek D, et al. Pretreatment with prasugrel in non-ST-segment elevation acute coronary syndromes. N Engl J Med. 2013;369:999-1010

5. Effient (prasugrel) [prescribing information]. Indianapolis, IN: Eli Lilly & Co; October 2013

6. Brilinta (ticagrelor) [prescribing information]. Wilmington,DE: AstraZeneca; December 2013

7. James S, Angiolillo DJ, Cornel JH, et al. Ticagrelor vs. clopidogrel in patients with acute coronary syndromes and diabetes: a substudy from the PLATelet inhibition and patient Outcomes (PLATO) trial. Eur Heart J. 2010;31:3006-16

8. FitzGerald GA, Oates JA, Hawiger J, et al. Endogenous biosynthesis of prostacyclin and thromboxane and platelet function during chronic administration of aspirin in man. J Clin Invest. Mar 1983; 71(3): 676—688’

9. Gaglia MA, Waksman R. Overview of the 2010 Food and Drug Administration Cardiovascular and Renal Drugs Advisory Committee Meeting Regarding Ticagrelor. Circulation. 2011; 123: 451-456