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Antiplatelet and Anticoagulant Drugs
Introduction
Chronic coronary artery disease (CAD) is a heterogeneous condition that encompasses patients with a history of acute coronary syndrome (ACS), patients with a history of coronary revascularization by percutaneous coronary intervention (PCI) or surgery, patients with stable angina symptoms, patients with silent myocardial ischemia, and asymptomatic patients without myocardial ischemia but with evidence of CAD by imaging. CAD is most often caused by obstructive atherosclerosis, although other mechanisms, such as vasospasm, may contribute. Across those various conditions, the role of anticoagulant and antiplatelet therapy is mainly to minimize the risk of a major adverse cardiac event, such as acute myocardial infarction (MI), stroke, or cardiovascular death, by preventing the occurrence or growth of an arterial thrombus as a consequence of plaque erosion or rupture. Because plaque erosion or rupture is ubiquitous in the coronary vasculature of patients with atherothrombosis, antithrombotic therapies constitute a cornerstone of secondary prevention.
To prevent coronary thrombosis and acute coronary events in patients with chronic CAD, who represent a high-risk group, a wide armamentarium of antithrombotic agents and strategies, ranging from single antiplatelet therapy to dual- or even triple-antithrombotic therapy and various anticoagulant agents, is available today.
With this growing number of options and combinations, the focus has shifted from using ever more potent agents to finding the optimal balance between thrombotic and bleeding risks on an individual level to select the optimal combination, intensity, and duration of treatment for each patient. Finally, CAD patients requiring oral anticoagulant (OAC) therapy for various conditions, such as atrial fibrillation, represent a growing proportion of patients with a specific benefit/risk balance regarding antithrombotic agents.
Antiplatelet Agents
Platelet-mediated thrombosis is a major pathophysiologic mechanism underlying coronary thrombosis. Platelets adhere to ruptured or eroded plaques, are activated, aggregate, and release secondary messengers, which produce further thrombosis and vasoconstriction and serve as a surface for activation of the clotting cascade ( Fig. 21.1 ). Therefore, inhibition of platelet activation or aggregation is a very effective method of preventing coronary thrombosis. The various existing antiplatelet agents can act at different points in the platelet to inhibit the cascade of platelet activation, amplification, and aggregation (see Fig. 21.1 ).
Aspirin
Aspirin (acetylsalicylic acid) has long been, and largely remains, the cornerstone of antithrombotic treatment for patients with chronic CAD.
Thromboxane receptors are expressed in platelets, inflammatory cells, the vascular wall, and atherosclerotic plaques. Low doses of aspirin irreversibly block cyclooxygenase-1 (COX-1), the enzyme that promotes the synthesis of thromboxane A 2 from arachidonic acid, by acetylating a serine residue near the narrow catalytic site of the COX-1 channel. When doses are increased, aspirin inhibits both COX-1 and COX-2, leading to antiinflammatory and analgesic effects, and it can also inhibit the formation of antiaggregatory prostacyclin. Therefore, low doses of aspirin are generally preferred.
Aspirin is rapidly absorbed in the stomach and upper small intestine. Plasma concentrations peak 30 to 40 minutes after the ingestion of uncoated aspirin. In contrast, after the administration of enteric-coated formulations, it can take up to 3 or 4 hours for plasma concentrations to reach their peak, and thromboxane inhibition can be less complete. Aspirin has a half-life of 15 to 20 minutes in plasma. Despite the rapid clearance of aspirin from the circulation, its antiplatelet effect lasts for the life of a platelet. For its effect to be translated into prevention of thrombosis, inhibition of thromboxane generation needs to be greater than 95%. It has been shown that daily administration of as low a dose as 30 mg of aspirin results in complete suppression of platelet thromboxane A 2 production after 1 week, through a cumulative process of fractional acetylation of unacetylated platelet COX-1 by successive daily doses of aspirin. Therefore, regimens of 75 to 100 mg of aspirin daily usually exceed the minimal effective dose required for a full pharmacodynamic effect, accommodating some degree of interindividual variability in drug response. With a daily generation of approximately 10% of new platelets, near normal primary hemostasis can be recovered within 2 to 3 days after the last aspirin dose. A faster rate of platelet turnover has been reported in proinflammatory settings, such as diabetes ; this can reduce the aspirin-induced pharmacodynamic effect. In patients with diabetes, twice-daily administration of aspirin has been shown to result in greater platelet inhibition than once-daily administration. However, the clinical implications of this observation remain to be demonstrated.
The benefit of aspirin in CAD patients has been documented extensively. A meta-analysis that included 287 studies evaluating antiplatelet agents (aspirin being the most represented), involving 135,000 patients, demonstrated that antiplatelet therapy reduced the combined outcomes of nonfatal MI, nonfatal stroke, and vascular death by one-third ( Fig. 21.2A ), and vascular mortality by one-sixth (with no apparent adverse effect on other deaths) across a broad group of patients with arterial diseases. In the same meta-analysis, doses of 75 to 150 mg appeared to be as effective as higher doses ( Fig. 21.2B ). Data from the CURRENT-OASIS 7 trial, which compared low doses (75–100 mg daily) and high doses (300–325 mg daily) of aspirin in ACS patients, found no reduction in efficacy with lower doses, but a reduction in the risk of major gastrointestinal bleeding (0.2% vs 0.4%; p = 0.04).
P2Y 12 Inhibitors
P2Y 12 inhibitors act as antagonists of the platelet adenosine diphosphate (ADP) receptor P2Y 12 , thereby inhibiting platelet aggregation. This pharmacologic class includes thienopyridines (ticlopidine, clopidogrel, and prasugrel) as well as ticagrelor (a cyclopentyl-triazolo-pyrimidine [CPTP] inhibitor) and cangrelor (a short-acting intravenous ADP inhibitor).
Ticlopidine
Ticlopidine was the first P2Y 12 inhibitor available. In a randomized trial of 650 patients with unstable angina, ticlopidine reduced MI by over 50% (5.1% vs 10.9%; p = 0.006) compared with “conventional therapy.” However, the clinical application of ticlopidine was hindered by its delayed onset of action and by the development of neutropenia (2.4%); for these reasons, ticlopidine use is currently largely abandoned.
Clopidogrel
Clopidogrel is a prodrug that needs to be transformed into an active metabolite. After absorption, 85% of clopidogrel is hydrolyzed by esterases into an inactive carboxylic acid; the remaining 15% undergoes a 2-step oxidation process via hepatic cytochrome P450 isoenzymes, mainly CYP2C19 (which is associated with both steps) and, to a lesser extent, CYP1A2, CYP2B6, CYP3A4, and CYP3A5. The transient active thiol metabolite specifically and irreversibly binds to the platelet P2Y 12 receptor. Steady-state platelet function inhibition occurs after 5 to 7 days of clopidogrel maintenance dosing; for that reason, a loading dose is recommended to achieve more rapid inhibition.
Clopidogrel as Single Antiplatelet Therapy
The major randomized trial supporting the use of clopidogrel in chronic CAD patients was the Clopidogrel versus Aspirin in Patients at Risk of Ischaemic Events (CAPRIE) trial, which enrolled more than 19,000 stable patients with atherothrombosis (patients with previous ischemic stroke, previous MI, or peripheral arterial disease [PAD]). CAPRIE compared clopidogrel (75 mg daily) and aspirin (325 mg daily) in terms of reduction in risk of a composite outcome (ischemic stroke, MI, or vascular death). Patients assigned to clopidogrel had a significant but modest 8.7% relative reduction in the composite outcome compared with those assigned to aspirin (5.83% vs 5.32%, respectively; p = 0.043). There appeared to be some heterogeneity in benefit depending on subgroups ( P for interaction = 0.042), with the largest relative benefit observed in patients with PAD ( Fig. 21.3 ). Given the modest superiority, the cost of clopidogrel at the time, and the large evidence base for aspirin, aspirin has remained the first-line choice for antiplatelet therapy, but clopidogrel is an alternative for patients who are intolerant to aspirin.
Dual Antiplatelet Therapy with Aspirin and Clopidogrel
With the emergence of coronary stenting, it appeared that the combination of aspirin and an oral P2Y 12 receptor blocker was required to minimize the risk of stent thrombosis, and dual antiplatelet therapy (DAPT) with aspirin and clopidogrel rapidly became the standard of care for patients undergoing PCI. Subsequently, this combination was tested in ACS and its role was extended to secondary prevention.
Secondary Prevention after Acute Coronary Syndrome
In ACS patients, the benefit of DAPT with aspirin plus clopidogrel was established in the CURE randomized trial, which enrolled more than 12,000 patients with non-ST-segment elevation (NSTE) ACS, who were assigned to clopidogrel or placebo on a background treatment of aspirin for up to 12 months. The primary outcome (composite of death from cardiovascular cause, nonfatal MI, or stroke) occurred in 9.3% of patients in the clopidogrel group and 11.4% in the placebo group ( p < 0.001). Interestingly, the benefit of clopidogrel started early, but event curves continued to diverge for several months, suggesting continuous accrual of benefit from DAPT in secondary prevention ( Fig. 21.4 ).
The benefits of DAPT with aspirin plus clopidogrel were also demonstrated in ST-segment elevation MI (STEMI) in the CLARITY and COMMIT trials. CLARITY enrolled STEMI patients treated with thrombolysis who presented within 12 hours after symptom onset and were randomly assigned to receive clopidogrel (300-mg loading dose, followed by 75 mg once daily) or placebo. Clopidogrel reduced the primary outcome (a composite of either an occluded infarct-related artery, defined by a Thrombolysis In Myocardial Infarction [TIMI] flow grade of 0 or 1 on angiography, death, or recurrent MI before angiography) by 6.7% in absolute terms. COMMIT randomized more than 45,000 Chinese patients within 24 hours of suspected acute MI to clopidogrel or placebo in addition to aspirin. Patients assigned to clopidogrel experienced a 9% relative reduction in the primary composite outcome of death, reinfarction, or stroke (2121 [9.2%] clopidogrel vs 2310 [10.1%] placebo; p = 0.002). There was also a 7% (95% confidence interval [CI] 1% to 13%) relative reduction in all-cause mortality (1726 [7.5%] vs 1845 [8.1%]; p = 0.03).
Although the follow-up periods in the CLARITY and COMMIT trials were 1 month, and despite the lack of solid data regarding the long-term benefit of clopidogrel compared with placebo after STEMI, international guidelines recommend 12 months of DAPT after STEMI, which is consistent with non-STEMI guidelines. After 12 months, treatment is generally scaled down to single antiplatelet therapy with low-dose aspirin.
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