Anticoagulation and antiplatelet therapy in acute coronary syndromes

Antiplatelet and anticoagulant drugs are a cornerstone of the medical treatment of acute coronary syndrome (ACS), reducing the rates of both morbidity and death.^1–4 However, reductions in ischemic events with these drugs have uniformly been accompanied by increases in bleeding complications, which reduce the net benefit.⁵ Thus, clinical research has been exploring ways to maximize the benefit while minimizing the risk.

Here, we review the guidelines and evidence supporting the use of antiplatelet and anticoagulant drugs in ACS.

ACUTE CORONARY SYNDROMES WITH OR WITHOUT ST ELEVATION

A key distinction when treating ACS is whether the electrocardiogram shows ST-segment elevation. In cases of non-ST-elevation ACS (ie, unstable angina or non-ST-elevation myocardial infarction), a second key question is whether the initial strategy will be invasive (with angiography performed urgently) or conservative (with angiography performed later). In ST-elevation myocardial infarction, another distinction is how perfusion is to be restored, ie, with primary percutaneous coronary intervention or with thrombolysis. All these questions affect the choice of antiplatelet and anticoagulant therapy.

Figure 1 and Figure 2 summarize the guidelines of the American College of Cardiology Foundation and American Heart Association.^1,2,6,7

ANTIPLATELET THERAPY

Aspirin for all

Aspirin irreversibly acetylates the enzyme cyclooxygenase-1, blocking intraplatelet formation of thromboxane A2 (Figure 3), a potent platelet aggregator and endothelial vasoconstrictor. Large clinical trials have confirmed that aspirin reduces morbidity and mortality rates by as much as 50% in patients with ACS.⁸

The ISIS-2 trial⁹ found that giving aspirin early in the emergency department significantly reduced the mortality rate.

The Antithrombotic Trialists’ Collaboration,¹⁰ in a meta-analysis of randomized controlled trials comparing different doses of aspirin in high-risk ACS patients, found no greater benefit for doses of aspirin higher than 162 mg per day when used long-term.

How to use. During an ACS, the patient should receive one dose of aspirin 325 mg (the standard high-dose pill in the United States). This dose should be chewed, as buccal absorption results in more rapid systemic effects.¹¹

Adapted from Storey RF. New developments in antiplatelet therapy. Eur Heart J Suppl 2008; 10(suppl D):D30-D37.

Thereafter, the patient should take 81 mg per day, continued indefinitely. The 81-mg dose also applies to patients who undergo a percutaneous coronary intervention with a drug-eluting stent.⁷ Previous recommendations called for higher doses, but studies have shown that higher doses pose a higher risk of bleeding without additional clinical benefit. The use of enteric-coated aspirin does not reduce this risk,¹² and its delayed release may in fact cause aspirin “pseudoresistance.”¹³

The concurrent use of nonsteroidal anti-inflammatory drugs (NSAIDs) should be avoided, as NSAIDs reversibly bind to platelets, thus preventing aspirin from binding.¹⁴ As aspirin washes out of the body, NSAIDs may then become unbound from platelets, leaving platelets activated.

P2Y12 receptor inhibitors: Clopidogrel, prasugrel, ticagrelor

These agents bind to P2Y12 receptors on platelets to inhibit adenosine diphosphate-mediated platelet activation (Figure 3). Clopidogrel and prasugrel are irreversible prodrugs, whereas ticagrelor binds reversibly.

Clopidogrel, a prodrug

Clopidogrel has a half-life of 8 hours and a time to peak concentration of 4 hours. Eighty-five percent of a dose is inactivated by gut esterases. The remainder is metabolized primarily by the cytochrome P4502C19 enzyme system into its active metabolite.

How to use. The recommended dosage is a 600-mg bolus early in the course of ACS. This is associated with a lower rate of cardiovascular events than a 300-mg dose,2,15 although no trial has rigorously compared 300-mg vs 600-mg doses using major clinical end points. In patients presenting with ACS who cannot tolerate aspirin because of hypersensitivity or major gastrointestinal contraindication, clopidogrel is an alternative.1

The CURE trial¹⁶ randomized 12,526 patients with non-ST-elevation ACS to receive clopidogrel or placebo in addition to standard therapy. Clopidogrel was associated with a 20% lower rate of cardiovascular death, myocardial infarction, or stroke in both low- and high-risk patients regardless of whether an invasive or conservative strategy was pursued.

However, patients who underwent coronary artery bypass grafting (CABG) had a 53% higher risk of bleeding (an absolute risk of 3.3%) if they received clopidogrel within 5 days of the surgery. This has led to the practice in some centers of delaying giving clopidogrel until after the coronary anatomy has been defined. This deprives the patient of the anti-ischemic benefits conferred by giving clopidogrel early and remains a contentious issue, with most suggesting that the risk-benefit ratio still favors giving clopidogrel early, before angiography, unless there is a high likelihood that surgery will ultimately be required.17 Alternatively, one could consider using a shorter-acting intravenous glycoprotein IIb/IIIa inhibitor such as eptifibatide as a “bridge” until a definitive reperfusion strategy is chosen.

Effect of CYP2C19 variants. The CLOVIS-2 study¹⁸ assessed the effects of genetic variants on the clopidogrel concentration in 106 patients who had had a myocardial infarction. The study confirmed that patients who carry certain variants of the CYP2C19 gene attain lower plasma concentrations of clopidogrel after receiving this drug.¹⁹ This accounts for its delayed onset of action as well as its variability in response in patients who have reduced expression or inhibition of this enzyme system. Doubling the standard dose in patients who carry these variants does not appear to provide clinical benefit.²⁰

Thus, the thought is emerging that one should consider using prasugrel or ticagrelor instead of clopidogrel in patients who have these polymorphisms, though this is yet to be backed by robust clinical evidence.

Possible interaction with proton pump inhibitors. Controversy exists about whether proton pump inhibitors inhibit clopidogrel’s action. Although the US Food and Drug Administration continues to warn against the concurrent use of omeprazole and clopidogrel,²¹ an analysis of the PLATO trial²² concluded that patients with ACS who were taking proton pump inhibitors were at higher risk of ischemic events regardless of whether they had been randomized to clopidogrel or ticagrelor (a drug that acts independently of the cytochrome P450 system). This observation suggests that patients on proton pump inhibitors are generally sicker and at higher risk of ischemic events regardless of the choice of antiplatelet therapy. The use of other gastroprotective agents did not appear to mitigate these risks.