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.
Stable Patients
The main trial testing DAPT with aspirin and clopidogrel in stable patients was the CHARISMA trial, which randomly assigned 15,603 stable patients to receive either clopidogrel or placebo, on top of aspirin. The population was somewhat heterogeneous: patients were eligible for enrollment if they had multiple atherothrombotic risk factors, or documented CAD, documented cardiovascular disease, or documented symptomatic PAD. Patients were not eligible if they had an established indication for clopidogrel therapy, such as recent ACS. After a median follow-up of 28 months, there was no difference between the two treatment arms in terms of relative risk (0.93, 95% CI 0.83 to 1.05; p = 0.22) ( Fig. 21.5 ).
There was an interaction between the treatment and the patient profile: patients with established atherothrombosis derived benefit from treatment with clopidogrel (hazard ratio [HR] 0.83, 95% CI 0.72 to 0.96; p = 0.01) ( Fig. 21.6 ). In contrast, patients with risk factors only derived no benefit (relative risk 1.20, 95% CI 0.91 to 1.59; p = 0.20). In a post hoc analysis, including only patients with prior cardiovascular events (prior MI, ischemic stroke, or symptomatic PAD), the rate of cardiovascular death, MI, or stroke was lower in the clopidogrel plus aspirin arm than in the placebo plus aspirin arm: 7.3% versus 8.8% (HR 0.83, 95% CI 0.72 to 0.96; p = 0.01) ( Fig. 21.7 ). Additionally, hospitalizations for ischemia were reduced (11.4% vs 13.2%; HR 0.86, 95% CI 0.76 to 0.96; p = 0.008). There was no significant difference in the rate of severe bleeding (1.7% vs 1.5%; HR 1.12, 95% CI 0.81 to 1.53; p = 0.50). However, these subgroups and post hoc analyses of an overall negative trial were not deemed sufficient to change practice, and single antiplatelet therapy remained the recommendation for secondary prevention in patients with stable CAD.
Limitations of Clopidogrel
Clopidogrel has substantial limitations, with a moderate antiplatelet effect and a delayed onset and offset of action. Moreover, the response to clopidogrel is highly variable. In a series of more than 500 patients, the response of subjects to clopidogrel was shown to follow a normal bell-shaped distribution ( Fig. 21.8 ).
Reduced effectiveness of clopidogrel has been shown in carriers of reduced-function alleles of particular enzymes, particularly the common variant CYP2C19∗2. On clopidogrel, carriers of this variant have worse clinical outcomes than noncarriers. The reduced response to clopidogrel among carriers of the reduced-function allele can, in part, be overcome with increased doses of clopidogrel. However, trials have failed to show that altering the clopidogrel dose according to functional or genetic testing improves outcomes.
Several trials have tried to adapt the clopidogrel dose according to platelet function testing or genotype. In the GRAVITAS trial, Price et al. randomly assigned 2214 patients who had undergone PCI with at least one drug-eluting stent (DES) for the treatment of stable CAD. All patients were initially treated with aspirin plus clopidogrel. Platelet function was measured using the VerifyNow P2Y 12 test, 12 to 24 hours after PCI. Patients without high on-treatment reactivity (platelet reactivity units [PRUs] < 230) were kept on the standard clopidogrel dose (75 mg). Patients with high on-treatment reactivity (PRUs > 230) were randomized to receive a high clopidogrel dose (600 mg initial dose and 150 mg thereafter) or a standard clopidogrel dose (no additional loading dose, 75 mg daily). At 6 months, the primary endpoint (death from vascular cause, nonfatal MI, or stent thrombosis) occurred in 25 patients (2.3%) on high-dose clopidogrel compared with 25 patients (2.3%) on the standard clopidogrel dose (HR 1.01, 95% CI 0.58 to 1.76; p = 0.97). Severe or moderate bleeding was not increased with the high-dose regimen. Therefore, the use of the platelet function test to guide clopidogrel dosing failed to demonstrate superiority compared with a standard treatment strategy.
Other clinical trials have evaluated platelet treatment intensification, with a switch to more potent drugs rather than increasing the clopidogrel dose in patients with high on-treatment platelet reactivity; the results were also negative (see hereafter).
Prasugrel
Prasugrel is a second-generation thienopyridine that, like clopidogrel, requires conversion from an inactive form to an active metabolite by cytochrome p450 enzymes. Compared with clopidogrel, prasugrel is metabolized more rapidly and completely to its active component. This difference in metabolism allows prasugrel to achieve a more rapid onset of action and a higher level of platelet inhibition ( Fig. 21.9 ), as well as reduced interpatient variability.
In the TRITON-TIMI 38 trial, prasugrel was compared with clopidogrel in 13,608 ACS patients (both STEMI and NSTE ACS) scheduled for PCI, with a treatment duration ranging from 6 to 15 months. The primary efficacy composite endpoint of cardiovascular death, nonfatal MI, or nonfatal stroke was reduced by prasugrel (HR for prasugrel vs clopidogrel 0.81, 95% CI 0.73 to 0.90; p < 0.001). Conversely, major bleeding not related to coronary artery bypass graft (CABG) was increased by approximately a third (HR 1.32, 95% CI 1.03 to 1.68; p = 0.03) ( Fig. 21.10 ). No differences in all-cause or cardiovascular mortality were observed between treatment arms.
A post hoc subgroup analysis of the TRITON-TIMI 38 trial showed that patients older than 75 years and with a body weight less than 60 kg derived no net clinical benefit from prasugrel and that in patients with previous stroke or transient ischemic attack (TIA), prasugrel was associated with net harm ( Fig. 21.11 ). Therefore, prasugrel is contraindicated in patients with prior TIA or stroke, and there is a warning for patients aged over 75 years or with a body weight less than 60 kg.
In the TRITON-TIMI 38 trial, prasugrel was initiated in the acute phase and continued for up to 15 months. Secondary landmark analyses for efficacy, safety, and net clinical benefit were performed from randomization to day three, and from day three to the end of the trial. Significant reductions in ischemic events, including MI, stent thrombosis, and urgent target vessel revascularization, were observed with the use of prasugrel during the first three days and from day three to the end of the trial. TIMI major non-CABG bleeding rates were similar to clopidogrel during the first three days, but were higher with prasugrel from day three to the end of the study. Assessment of net clinical benefit favored prasugrel both early and late in the trial. This trial therefore supports the use of prasugrel instead of clopidogrel in secondary prevention in ACS patients undergoing PCI, for approximately one year, after which treatment is scaled down to single antiplatelet therapy with aspirin.
However, the TRITON-TIMI 38 trial did not include medically managed patients. The TRILOGY trial was therefore specifically designed to compare prasugrel with clopidogrel in patients presenting with NSTE ACS and managed without intervention. After a median follow-up of 17 months, the primary endpoint of death from cardiovascular causes, MI, or stroke among patients aged older than 75 years occurred in 13.9% of the prasugrel group and 16.0% of the clopidogrel group (HR in the prasugrel group 0.91, 95% CI 0.79 to 1.05; p = 0.21). This trial therefore does not support the use of prasugrel in NSTE ACS patients treated conservatively during the acute phase or in secondary prevention.
The use of prasugrel has not been evaluated in unselected stable patients. In the TRIGGER PCI trial, patients with stable CAD who underwent PCI with at least one DES implantation had systematic evaluation of platelet reactivity on clopidogrel 75 mg with the VerifyNow P2Y 12 system. Patients with high platelet reactivity were randomly assigned to prasugrel 10 mg daily or clopidogrel 75 mg daily. The primary efficacy endpoint of cardiac death or MI at 6 months occurred in no patient on prasugrel versus one patient on clopidogrel. Given the low rate of ischemic events in this trial, the clinical utility of prasugrel based on platelet function evaluation in stable patients has not been established.
Similarly, the ARCTIC trial randomly assigned 2440 patients scheduled for coronary stenting (excluding STEMI patients) to a strategy of platelet function monitoring (assessed with VerifyNow and aspirin point-of-care assays), with drug adjustment (additional loading dose of clopidogrel or prasugrel followed by a daily maintenance dose of 150 mg of clopidogrel or 10 mg of prasugrel after the procedure) in patients with poor response to antiplatelet therapy, or to a conventional strategy without monitoring and drug adjustment. The primary endpoint occurred in 34.6% of the patients in the monitoring group versus 31.1% of those in the conventional-treatment group (HR 1.13, 95% CI 0.98 to 1.29; p = 0.10).
The results of the TRIGGER-PCI and ARCTIC trials do not support the use of prasugrel based on platelet function tests in stable patients. As a consequence, current guidelines do not support the routine use of a platelet function test to guide antiplatelet therapy.
Ticagrelor
Ticagrelor is a reversible and direct-acting oral antagonist of the ADP receptor P2Y 12 . It has been demonstrated that ticagrelor provides faster onset and greater inhibition of platelet aggregation than does clopidogrel. In the ONSET/OFFSET study, the onset and offset of platelet inhibition were compared between clopidogrel- and ticagrelor-treated patients. Ticagrelor achieved more rapid platelet inhibition than a loading dose of 600 mg of clopidogrel; this was sustained during the maintenance phase, and ticagrelor offset was faster after drug discontinuation ( Fig. 21.12 ).
Ticagrelor in Patients with Acute Coronary Syndrome
The clinical efficacy of ticagrelor in ACS patients was evaluated in the PLATO trial. In this multicenter, double-blind, randomized trial, ticagrelor (180-mg loading dose and then 90 mg daily) was compared with clopidogrel (300- to 600-mg loading dose and then 75 mg daily) in 18,624 patients admitted to hospital with an ACS with or without ST-segment elevation. At 12 months, the primary endpoint (composite of death from cardiovascular causes, MI, or stroke) occurred in 9.8% of patients receiving ticagrelor compared with 11.7% of those receiving clopidogrel (HR 0.84, 95% CI 0.77 to 0.92; p < 0.001) ( Fig. 21.13 ). Importantly, death from cardiovascular cause (a predefined secondary endpoint) was also reduced (4.0% vs 5.1%; HR 0.79, 95% CI 0.69 to 0.91; p = 0.001). No difference in the rates of major bleeding or transfusion was seen between the ticagrelor and clopidogrel groups (11.6% vs 11.2%; p = 0.43) when analyzed by intention to treat; however, this encompassed patients undergoing CABG surgery in whom bleeding rates were high. When non-CABG-related major bleeding was analyzed, ticagrelor increased bleeding (4.5% vs 3.8%; HR 1.19, 95% CI 1.02 to 1.38; p = 0.03).
Ticagrelor has specific side effects that are related to adenosine metabolism. Dyspnea was twice as frequent in patients given ticagrelor than in patients given clopidogrel, and led to treatment discontinuation in approximately 1% of patients. The dyspnea was generally mild and transient (most episodes lasted < 1 week), occurred early after initiation, and was not associated with any abnormality on examination or on lung-function tests. Holter monitoring detected more ventricular pauses during the first week in the ticagrelor group; however, these episodes were infrequent at 30 days and were rarely associated with symptoms.
Of note, an interaction ( p = 0.045) was observed between treatment effect and enrollment region, with no benefit from ticagrelor in patients enrolled in North America. This interaction might result from a negative interaction between ticagrelor and the higher dose of aspirin usually used in the United States (> 150 mg) compared with other regions. This observation has led to a recommendation to use ticagrelor with low-dose aspirin (up to 150 mg).
This trial therefore supports the use of ticagrelor instead of clopidogrel in secondary prevention in ACS patients undergoing PCI for up to 1 year, after which treatment is scaled down to single antiplatelet therapy with aspirin.
Ticagrelor in Stable Patients
In diabetic patients, the effectiveness of aspirin for the prevention of cardiovascular events is less firmly established than in the overall population, possibly because of the accelerated turnover of platelets in these patients. The THEMIS trial (NCT01991795, currently ongoing) aims to compare the effect of ticagrelor versus placebo on top of aspirin in patients with type 2 diabetes with either documented CAD or previous coronary revascularization. Patients with a history of MI or stroke are excluded, and therefore only stable patients are included.
Dual Antiplatelet Therapy Beyond 1 Year
The clopidogrel, prasugrel, and ticagrelor trials converge to show that DAPT combining aspirin and an oral P2Y 12 receptor blocker for up to one year is useful in secondary prevention. The potential benefit of DAPT beyond the first year after an ACS is less firmly established. Data come from several sources, including the PEGASUS trial and many trials testing the optimal duration of DAPT after stenting (generally including both ACS and non-ACS patients).
PEGASUS was a double-blind, international, randomized trial that included 21,162 patients who had had an MI 1 to 3 years previously and had one of several additional risk factors for atherothrombosis (age ≥ 65 years, diabetes mellitus requiring medication, a second prior spontaneous MI, multivessel CAD, or chronic renal dysfunction [defined as an estimated creatinine clearance of < 60 mL/min]). Patients were randomized to one of three arms: ticagrelor 90 mg twice daily; ticagrelor 60 mg twice daily; or placebo. All patients received low-dose aspirin. The median follow-up was 33 months. The primary endpoint (a composite of cardiovascular death, MI, or stroke) was reduced with the two ticagrelor doses, with Kaplan-Meier rates at 3 years of 7.85% in the group receiving 90 mg, 7.77% in the group receiving 60 mg, and 9.04% in the placebo group: HR for 90 mg of ticagrelor versus placebo 0.85, 95% CI 0.75 to 0.96 ( p = 0.008); and HR for 60 mg of ticagrelor versus placebo 0.84, 95% CI 0.74 to 0.95 ( p = 0.004) ( Fig. 21.14 ). The primary safety endpoint (TIMI major bleeding rate) was higher with ticagrelor (2.60% with 90 mg and 2.30% with 60 mg) than with placebo (1.06%) ( p < 0.001 for each dose versus placebo). All-cause death was not significantly different in the three groups. It appears, therefore, that the continuation of DAPT for more than one year after ACS may benefit some patients by reducing the rate of ischemic events. However, this reduction in ischemic events in a large population is counterbalanced by an increase in major bleeding, without clear benefit in terms of overall mortality reduction. Patients in whom DAPT is continued after one year have to be carefully selected; the tools allowing this selection remain to be created.
