Acetylsalicylic acid

Aspirin acts by irreversibly inhibiting platelet cyclooxygenase-1, preventing the formation of thromboxane A1 and thus diminishing platelet aggregation. Although a precursor of aspirin was derived from the willow tree and utilized as an analgesic and antipyretic as early as 400 BC, it was not recognized as an effective antiplatelet therapy for acute coronary syndromes (ACS) until the 1970s. This data was summarized by a large meta-analysis conducted by the Antiplatelet Trialists’ Collaboration in 1994, showing that among nine randomized trials of aspirin in acute or suspected myocardial infarction (MI), there was a highly significant reduction in vascular death, MI, and stroke (10.6% vs. 14.4% at 1 month, p < 0.0001) [1]. This result was largely driven by the ISIS-2 trial, a randomized 2-by-2 study of streptokinase and aspirin in acute MI [2].

Although the recommended maintenance dose of aspirin remains somewhat controversial, another meta-analysis of randomized trials of high-risk patients in 2002 showed a similar reduction in vascular events for doses between 75 and 1500 mg [3]. This is in part because the cyclooxygenase pathway is well inhibited at low doses of aspirin. There is some evidence that bleeding increases with aspirin dose. A retrospective analysis of the CURE trial has shown that patients with non-ST segment elevation myocardial infarction (NSTEMI) undergoing percutaneous coronary intervention (PCI) taking clopidogrel and aspirin less than 100 mg have similar rates of ischemic events, but less major bleeding, than patients taking higher maintenance doses of aspirin [4]. Similarly, analysis of the CURRENT-OASIS 7 trial did not show a benefit of aspirin 325 mg versus 81 mg among patients with NSTEMI in regard to ischemic outcomes, although major bleeding was also similar [5]. In addition, a recent meta-analysis of ACS patients showed higher-dose aspirin was associated with higher rates of major bleeding at 1 month [6]. Low-dose aspirin (75–162 mg) would therefore appear to provide similar efficacy to higher doses, but with less bleeding, in regard to long-term therapy following an ACS.

Clopidogrel

Clopidogrel irreversibly inhibits platelet ADP (P2Y12) receptors, which increases levels of vasodilator-stimulated phosphoprotein and thereby decreases activation of glycoprotein IIb/IIIa receptors. In the CAPRIE trial, clopidogrel was studied as an alternative to aspirin. Clopidogrel 75 mg was shown to be slightly more effective than aspirin 325 mg among a high-risk population of nearly 20,000 patients, which included patients with recent MI (5.3% vs. 5.8%, p = 0.04); rates of bleeding were similar [7]. Clopidogrel was then studied as an adjunct to aspirin therapy in the CURE trial, which included 12,562 patients with NSTEMI or unstable angina (UA). Clopidogrel (300 mg loading dose, 75 mg maintenance dose) and aspirin, as compared to aspirin alone, significantly reduced the rate of cardiovascular death, MI, or stroke (9.3% vs. 11.4%, p < 0.001). Major bleeding, however, was more frequent in the clopidogrel group (3.7% vs. 2.7%, p = 0.001) [8]. Among the 21% of patients in CURE that were treated with PCI, there appeared to be similar benefit from the addition of clopidogrel to aspirin in regard to cardiovascular death, MI, or urgent target vessel revascularization after 30 days (4.5% vs. 6.4%, p = 0.03) [9]. Furthermore, this benefit extended up to 1 year following PCI. Clopidogrel has thus been shown to be effective in NSTEMI and UA patients undergoing either medical or invasive management; although there are no dedicated trials examining the addition of clopidogrel specifically in STEMI, current guidelines nonetheless recommend its routine use for most ACS (including STEMI) [10, 11].

Some uncertainty remains regarding the optimal loading dose of clopidogrel. The CURRENT-OASIS 7 trial compared a 600 mg loading dose, 150 mg maintenance dose for 1 week, and 75 mg thereafter versus a 300 mg loading dose and 75 mg maintenance dose in patients with NSTEMI and UA. Although there was no benefit to the higher dose in the overall trial, there was a reduction in stent thrombosis in the PCI subgroup (1.6% vs. 2.3%, p = 0.001); this came at the cost of slightly higher rates of major bleeding (2.5% vs. 2.0%, p = 0.01) [5]. Pharmacodynamic studies would also appear to suggest that higher loading doses of clopidogrel have a faster onset and greater magnitude of platelet inhibition [12, 13]. In addition, a meta-analysis of clinical outcomes suggested loading doses greater than 300 mg reduced death and MI without a significant increase in bleeding [14]. Guidelines therefore indicate that a 600 mg loading dose of clopidogrel be given as soon as possible for patients with ACS (300 mg if fibrinolytics have been administered) [15].

Prasugrel

Prasugrel is also a thienopyridine that irreversibly inhibits the P2Y12 receptor, but it achieves more rapid and complete platelet inhibition than clopidogrel. A loading dose of 60 mg and maintenance dose of 10 mg of prasugrel was compared to a loading dose of 300 mg and maintenance dose of 75 mg of clopidogrel in the TRITON-TIMI 38 randomized trial, which included 13,608 patients with both STEMI and moderate- to high-risk NSTEMI or UA undergoing invasive management. The primary end point, which included cardiovascular death, MI, or stroke, was significantly lower with prasugrel at up to 15 months (9.9% vs. 12.1%, p < 0.001) [16]. This difference was driven primarily by a reduction in both procedure-related and spontaneous MI (7.4% vs. 9.7%, p < 0.0001) [17]. There was no difference in death or stroke, although stent thrombosis and urgent target vessel revascularization were also significantly lower with prasugrel.

The primary safety end point of non-CABG-related TIMI major bleeding, however, was significantly higher with prasugrel (2.4% vs. 1.8%, p = 0.03); rates of major bleeding among patients undergoing CABG were even higher (13.4% vs. 3.2%, p < 0.0001). Post hoc subanalysis revealed three groups in whom bleeding risk outweighed ischemic benefit: age greater than 75 years, weight less than 60 kg, and history of transient ischemic attack (TIA) or stroke. Current guidelines thus state that prasugrel is contraindicated in patients with a history of TIA or stroke and caution against its use in patients greater than 75 years or less than 60 kg [11]. Labeling information suggests a 5 mg dose for patients less than 60 kg, but there is little prospective data regarding the lower dose [18]. The practicality of a loading dose of prasugrel before PCI is also limited because of concerns regarding potential bleeding in patients ultimately requiring CABG.

Unlike clopidogrel, prasugrel is not currently indicated for noninvasive management of ACS. Prasugrel was again compared to clopidogrel in TRILOGY ACS, among 7243 patients less than 75 years with medically managed ACS. In regard to death, MI, or stroke, there was no difference between prasugrel and clopidogrel at up to 30 months (13.9% vs. 16.0%, p = 0.21). There did not appear to be a difference in non-CABG-related GUSTO severe or life-threatening bleeding [19].