In 1979, Andreas Gruentzig reported his experience with the first 50 coronary angioplasty procedures. In those first 50 patients, antiplatelet therapy was empiric and consisted of 1.0 g of aspirin (approximately 65 mg) for 3 days and dextran during the procedure. In the 36 years since that publication, the scientific understanding of arterial thrombus formation in response to arterial injury and clinical experience with pharmacologic means to mitigate this process have grown by immeasurable proportions. Specifically, the understanding of surface receptors and ligands necessary for the transformation of platelets to their active state, as well as the surface proteins responsible for adherence to fibrin, leukocytes, and other platelets, has facilitated the development of therapies targeted to specific steps in the activation sequence. Clinical investigation and experience continually refine the circumstances under which specific therapies are best applied in order to maximize benefit and minimize risk. In contemporary coronary angioplasty, the interplay between arterial wall, platelets, plaque components, clinical presentation, stent design, stent components, and concomitant medications has resulted in a complex and fluid therapeutic algorithm for antiplatelet therapy before, during, and after percutaneous coronary interventions.

From the initial angioplasty procedure in 1977 through the introduction of coronary stents in the early 1990s, thrombosis at the site of angioplasty was recognized as a primary mediator of acute vessel closure during and immediately after the procedure. Heparin was empirically used successfully during and in the immediate periprocedural period, but only aspirin was administered at patient discharge. In the earliest experience with intracoronary stents in the early 1990s, stent thrombosis rates approached 20% and became a focus of postprocedure care. The empiric approach of universal oral anticoagulation with warfarin following stent implantation reduced the incidence of stent thrombosis to 3% to 5%, but at a significant cost of access site–related and non–access site–related bleeding complications. Some operators even suggested that the thrombotic risk of stents was too excessive to justify routine use.

In 1995, a landmark study changed stent practice and shifted pharmacologic strategy from antithrombotic to antiplatelet following percutaneous coronary intervention (PCI). After initial observations that 80% of stents were inadequately expanded when examined by intravascular ultrasound (IVUS), Colombo and colleagues elegantly demonstrated that full stent expansion with apposition to the artery wall was both necessary and sufficient for patients to be safely treated with 2 antiplatelet medications (aspirin and ticlopidine) rather than warfarin. The calculus again changed substantially with the introduction of drug-eluting stents. Although the benefits of a durable revascularization result have been well documented, the combination of delayed healing and polymer hypersensitivity made these stents more susceptible to late thrombosis and lengthened the duration of antiplatelet therapy after PCI.

Twenty years of clinical studies of coronary stent procedures have resulted in the following principles of contemporary PCI with regard to antiplatelet therapy: (1) stent thrombosis is platelet mediated and carries a high morbidity and mortality; (2) adequate platelet inhibition before, during, and after the procedure is associated with optimal clinical outcome; (3) bleeding avoidance is as important as preventing ischemic complications; and (4) both patient and procedural factors (including stent design) determine relative risk of stent thrombosis and the intensity and duration of platelet inhibition required for the lowest rates of both ischemic and bleeding complications. In this chapter, we outline the evidence for current antiplatelet therapies during and after PCI, as well as strategies for management of antiplatelet therapies in the setting of other medications and complicating clinical circumstances.

Pharmacokinetics of Aspirin

Aspirin is rapidly absorbed in the stomach and upper intestine when administered in a chewable formula or oral liquid to reach peak plasma levels in 30 to 40 minutes. In patients unable to take medication by mouth, rectal administration also results in rapid absorption. Aspirin is hydrolyzed to salicylic acid, which irreversibly inhibits the cyclooxygenase-1 (COX-1) activity of platelets within the portal circulation, and platelet inhibition is evident within 1 hour.

The half-life of aspirin is short at 15 to 20 minutes. However, the circulating platelets are irreversibly inhibited for the duration of their lifespan, which is approximately 10 days. Approximately 10% of platelets are replaced each day; hence, almost 50% of platelets continue to be inhibited at 5 to 6 days after a single loading dose.¹

Optimal Dosing of Aspirin in PCI

Aspirin has been used empirically in all angioplasty since Gruentzig’s initial report. There is a single reported angioplasty study that randomized patients to an arm that did not include aspirin treatment. Although not designed to assess the necessity of aspirin (but rather restenosis rates), the study is often quoted as being the basis for the universal use of aspirin in contemporary practice. In this study, the periprocedural events included a Q-wave myocardial infarction (MI) rate of 6.8% in the placebo arm, compared to 1.3% in the aspirin arm. Performed in the balloon angioplasty era with a small number of patients, the applicability to current practice is questionable, yet this study remains an important influence regarding the primacy of aspirin as a pharmacologic adjunct to angioplasty.

The minimum effective dose prior to PCI in patients presenting with acute coronary syndrome has not be studied prospectively. Considering available data, the current guidelines for treatment of ST-segment elevation myocardial infarction (STEMI) recommend 162 to 325 mg of non–enteric-coated aspirin given as early as possible prior to primary PCI as a Class I recommendation.² In elective PCI, guidelines suggest a loading dose of 325 mg prior to PCI in aspirin-naïve patients and 81 to 325 mg in patients on chronic aspirin therapy.³

Aspirin sensitivity/allergy is an important consideration prior to PCI because as many as 3% to 5% of patients being considered for PCI report a history of respiratory or cutaneous symptoms or reactions after aspirin ingestion. A number of aspirin desensitization protocols are available, using sequential administration of escalating doses of oral aspirin. Patients with true anaphylaxis to aspirin can be desensitized, although at increased risk. In our practice, we generally desensitize those patients with sensitivity, but in cases of true anaphylaxis or where the patient does not consent to desensitization, we have proceeded successfully with thienopyridine monotherapy.

Many well-designed randomized trials have shown that a maintenance dose of aspirin less than 100 mg is effective as secondary prevention in patients with coronary atherosclerosis.^4,5 These studies, which did not include patients who underwent PCI, are insufficient to confirm that low-dose aspirin would suffice to prevent stent thrombosis. However, in the PCI-CURE trial,⁶ a post hoc analysis of the PCI cohort of the CURE (Clopidogrel in Unstable Angina to Prevent Recurrent Events) trial,⁷ 2658 patients with acute coronary syndromes undergoing PCI were stratified into 3 aspirin dose groups and followed up to 1 year. The high-dose group received more than 200 mg, and the low-dose group received less than 100 mg, with the moderate-dose group receiving doses in between. The moderate- and high-dose groups had similar rates of cardiovascular death, MI, or stroke compared to the low-dose group. From a safety standpoint, major bleeding was increased with high-dose aspirin with net adverse clinical events (death, MI, stroke, and major bleeding) favoring low-dose aspirin over high-dose aspirin. Therefore, in this observational analysis of patients undergoing PCI, low-dose aspirin appeared to be as effective as higher doses in preventing ischemic events but was also associated with a lower rate of major bleeding and an improved net efficacy-to-safety balance.

In the CURRENT-OASIS⁸ study, 25,086 patients with an acute coronary syndrome who were referred for an invasive strategy were randomized to higher dose aspirin (300-325 mg daily) or lower dose aspirin (75-100 mg daily). The primary outcome was cardiovascular death, MI, or stroke at 30 days. There was no significant difference between higher dose and lower dose aspirin with regard to the primary outcome. From a safety standpoint there was no increase in major bleeding (2.3% vs 2.3%; hazard ratio [HR], 0.99 [95% confidence interval (CI), 0.84-1.17]; P = .9). between the groups. However, the rate of minor bleeding was increased (5.0% vs 4.4%; HR, 1.13 [95% CI, 100-1.27]; P = .04) and major gastrointestinal bleeding was more frequent (0.4% vs 0.2%; P = .04) with higher dose aspirin.

Most recently, the ADAPT-DES registry⁹ followed 8582 patients after PCI with stent implantation who were treated with low-dose aspirin and clopidogrel and had platelet functional testing performed to detect both clopidogrel and aspirin nonresponsiveness prior to discharge. In this study, aspirin nonresponsiveness did not predict stent thrombosis events, MI, or death. However, aspirin responsiveness was associated with a higher likelihood of clinically evident bleeding. Small case series have also described successful PCI with stent placement using P2Y₁₂ inhibitors alone in patients unable to take aspirin. Finally, although thienopyridine discontinuation is frequently identified as a clinical factor strongly associated with stent thrombosis, aspirin discontinuation is less predictive. Discontinuation of aspirin in clinical trials has been reported to be as high as 18%. Taken together, these data suggest that aspirin may not be as important as previously thought in the prevention of post-PCI ischemic complications, a hypothesis that certainly deserves further study, particularly in cases of aspirin allergy or the need for oral anticoagulation.

In summary, currently available data indicate that a loading dose of 325 mg before PCI followed by low-dose aspirin after PCI (100 mg or less) is a reasonable standard. However, there is some evidence to suggest that the necessity of aspirin should be formally reexamined.

Upon arterial injury, circulating platelets are exposed to subendothelial proteins such as von Willebrand factor, vitronectin, and collagen. Platelet collagen receptors mediate more firm attachment of platelets and result in the release of platelet-dense granules, which contain, among other vasoactive components, the extracellular signaling purine nucleotide adenosine diphosphate (ADP). ADP acts locally to attract and activate other platelets and amplify the local response to injury. The primary receptor for ADP on the platelet is the P2Y₁₂ receptor, which is a member of a large family of purine and pyrimidine nucleotide receptors.

Thienopyridines are a group of compounds that have antithrombotic activity mediated through irreversible binding and inactivation of the P2Y₁₂ receptor. The first thienopyridine, tinoridine, was isolated in 1970 and has anti-inflammatory and analgesic properties; it is currently marketed in a number of countries worldwide as a nonsteroidal anti-inflammatory. Ticlopidine is a tinoridine derivative that exhibited antithrombotic properties, and was first marketed in Europe in 1978 for prevention of clotting in hemodialysis and cardiopulmonary bypass. It subsequently proved effective in patients with other clinical manifestations of atherosclerosis, such as in transient ischemic attacks (TIAs), stroke, and peripheral vascular disease, and became available in the United States in 1991. In 1995, Colombo and colleagues demonstrated that P2Y₁₂ inhibition with ticlopidine was an important strategy to avoid stent thrombosis, and ticlopidine became a standard of care. With wider use, hematologic dyscrasias from ticlopidine helped to accelerate the development of other, less toxic thienopyridines. Although the P2Y₁₂ receptor was not cloned until 2001, its existence was inferred from the effects of thienopyridines on platelet function. Due to the success of thienopyridines, nonthienopyridine P2Y₁₂ receptor antagonists have been developed, including those that do not irreversibly inactivate the receptor.

There are now 4 P2Y₁₂ inhibitors that have clinical utility in the treatment of atherosclerotic cardiovascular disease and, in particular, have clinical data supporting their use during and after PCI.

Clopidogrel (Plavix)

Pharmacokinetics of Clopidogrel

Clopidogrel is a prodrug that is rapidly absorbed in the intestine following oral administration. However, 85% of the dose is eliminated as an inactive metabolite. Following intestinal absorption, clopidogrel is activated in the liver by 2 sequential oxidative steps. The first step results in the formation of 2-oxo-clopidogrel, which is then further metabolized by cytochrome P450 isoforms including CYP3A4/5 and CYP2C19 to generate the active metabolite. Variability in the efficiency of this second step is mediated through differences in CYP2C19 alleles, resulting in different degrees of platelet inhibition depending on genotype. The active metabolite irreversibly binds to the P2Y₁₂ receptor, inhibiting ADP binding of the platelet. Once clopidogrel binds to the P2Y₁₂ receptor, platelet function is inhibited for the lifespan of the platelet, generally 7 to 10 days.

Dosing of Clopidogrel in PCI

While the practice of using thienopyridines to prevent stent thrombosis after PCI was introduced by Colombo’s observations in 1995, it was not until 5 years later that PCI-CURE established the principal of thienopyridine pretreatment. Randomizing 2658 subjects with non–ST-segment elevation myocardial infarction (NSTEMI) to clopidogrel or placebo for 6 days before PCI, clopidogrel was associated with a relative risk of 0.7 compared to placebo for a composite end point of death, MI, or urgent revascularization at 30 days. ISAR-REACT showed that clopidogrel had a similar magnitude of effect as glycoprotein IIb/IIIa inhibitors in elective PCI.

The timing and dose of clopidogrel loading prior to PCI, in both elective cases and acute coronary syndromes, have been extensively studied. Muller et al¹⁰ compared the effect of a high clopidogrel loading dose (600 mg) versus a loading dose of 300 mg on platelet aggregation in response to ADP in patients undergoing PCI. Faster and more profound suppression of platelets was achieved following a 600-mg loading dose.¹⁰

In the CREDO trial,¹¹ there was no reduction in events (death, MI, or stroke), compared with placebo, when 300 mg of clopidogrel was given 3 hours prior to the procedure. However, in a prespecified subgroup analysis, patients who received 300 mg of clopidogrel at least 6 hours before PCI experienced a relative risk reduction of 38.6% (95% CI, –1.6%-62.9%; P = .051) at 28 days.

Following a load of 600 mg of clopidogrel, peak suppression of platelet activity is seen by 2 hours after administration. In 428 patients undergoing PCI, the 30-day composite rate of major adverse cardiac events was not significantly different in patients undergoing PCI within 2 hours after a loading dose of 600 mg or at a later time point.¹²

The ARMYDA-2 trial was the first randomized trial to evaluate the impact of a 600-mg loading dose in comparison to the 300-mg conventional loading dose in patients undergoing PCI. Three hundred twenty-nine patients with typical exertional angina and a positive stress test or non-ST-segment elevation acute coronary syndrome (ACS) were randomized to either 300 or 600 mg of clopidogrel between 4 and 8 hours prior to PCI. The composite end point (death, MI, or target vessel revascularization) was significantly higher in patients treated with the conventional dose of clopidogrel than in patients treated with the high loading dose (12% vs 4%; P = .041). The incidence of MI was significantly higher in patients treated with the conventional dose (5% vs 15%). Bleeding complications were similar, and the difference in frequency of entry site hematoma was not statistically significant (7.1% vs 4.7%; P = .56). Furthermore, significantly more patients in the conventional-dose arm had elevations of cardiac biomarkers following the procedure (creatine kinase [CK]-MB, P = .038; troponin I, P = .021; myoglobin, P = .002). In this study, the event-free survival at 30 days significantly favored the high loading dose (P = .017). Multivariate analysis identified pretreatment with the 600-mg dose of clopidogrel and statin therapy as independent predictors of decreased risk of periprocedural MI (P = .044 and P = .020, respectively). Additional benefit was noted in high-dose patients who were on statin therapy before the intervention (P = .017).¹³ A loading dose of 900 mg was studied, but no additional benefit beyond that of 600 mg was seen.

To obtain maximum clinical benefit in clopidogrel-naïve patients, the data suggest that it is reasonable to treat patients with a 600-mg loading dose if administered at least 2 hours prior to PCI to ensure full antiplatelet activity. Benefit from a 300-mg loading dose is not expected unless administered at least 6 hours prior to PCI.

Administering a loading dose of clopidogrel routinely to patients prior to diagnostic coronary angiography may be problematic should coronary artery bypass grafting (CABG) be necessary, as there is an increased risk of bleeding and reoperation in patients undergoing bypass surgery while on clopidogrel. Current American College of Cardiology Foundation (ACCF)/American Heart Association (AHA) guidelines for CABG surgery recommend clopidogrel and ticagrelor be discontinued for at least 5 days prior to elective CABG surgery and 24 hours prior to urgent CABG surgery.¹⁴

It is not infrequent that patients on chronic clopidogrel therapy are referred for PCI. Two studies have examined the impact of reloading of clopidogrel. The Antiplatelet Therapy for Reduction of Myocardial Damage During Angioplasty (ARMYDA-4 RELOAD) trial was conducted to evaluate safety and effectiveness of clopidogrel reloading in patients on chronic clopidogrel therapy undergoing PCI. Five hundred three patients on chronic clopidogrel therapy for greater than 10 days presenting with stable angina and ACS were randomized to receive either 600 mg of clopidogrel loading 4 to 8 hours before PCI or placebo. The primary end point of 30-day incidence of death, MI, or target vessel revascularization (TVR; major adverse cardiac events [MACEs]) was not significantly different between the reload and placebo arms (6.7% vs 8.8%, respectively; odds ratio [OR], 0.75 [95% CI, 0.37-1.52]; P = .50). In patients with stable angina, 1-month MACEs were not significantly different (P = .36), whereas ACS patients had significant clinical benefit with reloading (P = .033). There was no excess bleeding in the reload arm.¹⁵

The ARMYDA-8 RELOAD-ACS study evaluated the benefit of administering a 600-mg dose of clopidogrel compared with placebo in patients with NSTEMI on chronic clopidogrel therapy for more than 10 days. The primary end point of 30-day incidence of death, MI, and TVR occurred in 4.1% of patients in the reload arm versus 14.1% of patients in the placebo arm (OR, 0.26 [95% CI, 0.10-0.73]; P = .013). The benefit in the reload arm was driven mainly by reduction of periprocedural MI in the reload arm. There was no difference in bleeding outcomes between the 2 groups.¹⁶ Taken together, the ARMYDA-4 and ARMYDA-8 studies indicate that patients presenting with ACS while on chronic clopidogrel therapy would benefit from reloading using a 600-mg dose of clopidogrel.

Genetic variability in the metabolism of clopidogrel leads to variability in the antiplatelet effect as measured by in vitro testing and in the clinical effectiveness of clopidogrel after PCI with stenting. The GRAVITAS trial measured the degree of routine platelet inhibition in 2214 subjects and randomized half of the patients to receive high-dose clopidogrel (150 mg/d). Although the higher dose of clopidogrel did not improve outcomes, individuals with better responsiveness as measured by VerifyNow P2Y₁₂ platelet functional testing (Accriva Diagnostics, San Diego, CA) had the lowest risk of adverse events. An on-treatment VerifyNow measurement (12-24 hours after PCI) of less than 208 P2Y₁₂ reaction units was associated with a 60-day HR of 0.28 for cardiovascular death, MI, and stent thrombosis.

Similarly, Thrombolysis in Myocardial Infarction (TIMI)-38 showed that clopidogrel was associated with less severe bleeding but more evidence of post-PCI ischemic events (cardiovascular death, nonfatal MI, nonfatal stroke), including a 50% increase in stent thrombosis, compared to prasugrel. Both of those observations are consistent with variations of genes that result in reduced conversion of clopidogrel to the active metabolite. All evidence for safety and efficacy of clopidogrel must be interpreted in the context of the individual variation in clopidogrel responsiveness.

Prasugrel (Effient)

Pharmacokinetics of Prasugrel

Prasugrel, the third thienopyridine to become available after ticlopidine and clopidogrel, is a more rapid, potent, and consistent antiplatelet agent. Prasugrel is a prodrug that is absorbed in the intestine and rapidly hydrolyzed by esterases to a thiolactone metabolite, which is then oxidized in a single cytochrome P450 (CYP)-dependent step to the active metabolite. CYP3A4/5 and CYP2B6 play a major role in this conversion, whereas CYP2C19 and CYP2C9 are less important; clinically, there is universal responsiveness to the drug. As with clopidogrel, the active metabolite irreversibly binds to the platelet P2Y₁₂ receptor, thus inhibiting ADP-activated platelet activation and aggregation for the life of the platelet.

The active metabolite of prasugrel reaches peak plasma levels within 30 minutes. A dose-proportionate concentration is noted between doses of 5 and 60 mg. Prasugrel does not interact to any clinically significant extent with other drugs, including those also metabolized by the hepatic CYP isoenzymes CYP3A4, CYP2C9, CYP2C19, and CYP2B6, which are responsible for prasugrel metabolism. Therefore, prasugrel has a pharmacokinetic and pharmacodynamic profile that compares favorably with those of existing antiplatelet agents.

Dosing of Prasugrel in PCI

Prasugrel is more potent than clopidogrel on several fronts. In a randomized, double-blind, crossover study in patients undergoing cardiac catheterization with planned PCI, loading with 60 mg of prasugrel resulted in greater platelet inhibition than a 600-mg clopidogrel loading dose. Maintenance therapy with prasugrel 10 mg/d resulted in a greater antiplatelet effect than 150 mg/d of clopidogrel.¹⁷ Antiplatelet effects of prasugrel have not been found to change with moderate liver disease, end-stage renal disease, diabetes, or smoking. However, in a population pharmacokinetic analysis of the Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition With Prasugrel–Thrombolysis in Myocardial Infarction 38 (TRITON-TIMI 38), patients older than 75 years had 19% higher exposure to the active metabolite of prasugrel compared with patients less than 75 years old and 25% higher exposure compared with patients less than 60 years old. In addition, patients <60 kg had 30% higher exposure than patients ≥60 kg and 42% higher exposure than patients ≥85 kg.¹⁸

The pivotal trial of the safety and efficacy of prasugrel was TRITON-TIMI 38, published in 2007.¹⁹ In this trial, 13,608 patients with moderate- to high-risk ACS (including unstable angina, NSTEMI, and STEMI) with planned PCI and who were naïve to thienopyridine therapy were randomized to receive either a 300-mg loading dose of clopidogrel followed by 75 mg daily or a 60-mg loading dose of prasugrel followed by 10 mg daily. Patients with unstable angina/NSTEMI or STEMI treated initially with medical therapy were randomized and treated only after the coronary anatomy was known to be suitable for PCI; patients with STEMI and planned primary PCI were randomized and treated on first contact. The primary efficacy end point was death from cardiovascular causes, nonfatal MI, or nonfatal stroke. The key safety end point was major bleeding, and patients at high risk for bleeding were excluded. Over a median duration of therapy of 14.5 months, the primary composite end point occurred in 12.1% of the patients receiving clopidogrel and 9.9% of patients receiving prasugrel (P < .001). The primary efficacy end point was driven by a 24% reduction in MI (including both fatal and nonfatal MI). There was no significant difference between the 2 treatment groups in the rate of stroke or death from cardiovascular causes not preceded by recurrent MI. The beneficial effect of prasugrel was seen across the board in patients presenting with STEMI (HR, 0.79 [95% CI, 0.65-0.97]; P = .02) and non–ST-segment elevation ACSs (HR, 0.82 [95% CI, 0.73-0.93]; P = .002). An important finding from TRITON–TIMI 38 was a significant reduction in stent thrombosis among patients receiving prasugrel. Overall, for the duration of the trial, Academic Research Consortium (ARC)-defined definite or probable stent thrombosis was reduced by 52% (1.1% vs 2.4%; HR, 0.48 [95% CI, 0.36-0.64]; P < .001), and definite (angiographic or autopsy proven) stent thrombosis was reduced by 58% (0.9% vs 2.0%; HR, 0.42 [95% CI, 0.31-0.59]; P < .001) in patients in the prasugrel arm. These findings were similar among patients receiving bare metal stents or drug-eluting stents. The reduction in stent thrombosis was also noted before and after 30 days of PCI (P < .0001 and P = .03, respectively).

Conversely, the increased potency of prasugrel resulted in higher rates of bleeding. The main safety end point of non–CABG-related TIMI major bleeding was observed more frequently with prasugrel than clopidogrel (2.4% vs 1.8%; HR, 1.32 [95% CI, 1.03-1.68]; P = .03); there was also an increase in non–CABG-related TIMI major or minor bleeding (5.0% vs 3.8%; HR, 1.31 [95% CI, 1.11-1.56]; P = .002) and bleeding requiring transfusion (4.0% vs 3.0%; HR, 1.34 [95% CI, 1.11-1.63]; P < .001). Regarding non–CABG-related bleeding, the increased rate was driven predominantly by an increase in spontaneous bleeding (1.6% vs 1.1%; HR, 1.51 [95% CI, 1.09-2.08]; P = .01), commonly gastrointestinal bleeding, with no difference in intracranial bleeding. The rate of major bleeding was not significantly different between the 2 groups within the first 30 days. However, after 30 days, a significant increase in TIMI major bleeding was observed (1.42% vs 0.97%; HR, 1.48 [95% CI, 1.04-2.09]; P = .03). Still, the prespecified net end point of all-cause death, MI, stroke, and non-CABG TIMI major bleeding was evaluated and significantly favored the prasugrel group over the clopidogrel group (12.2% vs 13.9%; HR, 0.87 [95% CI, 0.79-0.95]; P = .004).²⁰

Prespecified landmark analyses for efficacy were performed from randomization to day 3 and from day 3 to the end of the trial to examine individually the effects of the loading dose and the maintenance dose in patients enrolled in TRITON-TIMI 38.²¹ Significant reductions in ischemic events, including MI, stent thrombosis, and urgent TVR, were observed with the use of prasugrel, both during the first 3 days and from 3 days to the end of the trial. TIMI major non-CABG bleeding was similar to that of clopidogrel during the first 3 days but was significantly greater with the use of prasugrel from 3 days to the end of the study. Net clinical benefit significantly favored prasugrel both early and late in this trial. One criticism of TRITON-TIMI 38 was the choice of a 300-mg loading dose of clopidogrel, rather than the more effective dose of 600 mg.

A post hoc analysis of TRITON-TIMI 38 identified 3 patient groups who did not experience a net benefit from prasugrel: patients ≥75 years old, patients weighing <60 kg, and patients with a prior history of stroke or TIA. Any 1 of these 3 factors was associated with increased bleeding, and in patients with prior stroke or TIA, there was no benefit compared to clopidogrel, but a strong trend toward increased major bleeding, including intracranial bleeding. Importantly, these findings led to prasugrel labeling instructions in the United States to indicate that the drug should not be used in these specific subgroups.

Ticagrelor (Brilinta)

Ticagrelor is a potent P2Y₁₂ receptor antagonist that is not a thienopyridine. This drug belongs to the cyclopentyltriazolopyrimidine class. In contrast to thienopyridine agents, ticagrelor reversibly binds to the P2Y₁₂ receptor and does not require metabolic activation.

Pharmacokinetics of Ticagrelor

Although the parent compound does not require activation for platelet inhibition, ticagrelor is metabolized primarily by the CYP3A isoenzyme into an active metabolite (AR-C124910XX). This metabolite exerts similar potency in inhibiting the P2Y₁₂ receptor and is present at about 40% of the parent concentration.

Ticagrelor is rapidly absorbed, with maximum levels achieved in 90 to 120 minutes. However, significant platelet inhibition is noted within 30 minutes of administration of a loading dose of 180 mg of ticagrelor.

Compared with clopidogrel, ticagrelor achieved 1.6 times greater platelet inhibition 1 to 2 hours after a 180-mg loading dose than that seen 8 hours after administration of a 600-mg clopidogrel loading dose. Platelet inhibition by ticagrelor continued to be significantly higher than clopidogrel at the end of 6 weeks of treatment (P < .0001).²² The degree of platelet inhibition is similar at 24 hours after discontinuation of clopidogrel and ticagrelor, and the antiplatelet effect seen on day 3 after the last dose of ticagrelor was similar to that seen on day 5 after clopidogrel (Fig. 16-1).²² Although there may be benefit to the rapid offset (as in patients in need of coronary artery bypass surgery), ticagrelor would be a less attractive choice in patients with poor compliance, because discontinued treatment would result in a reduction of platelet inhibition within a shorter time period, potentially increasing risk of cardiovascular events and stent thrombosis.

Excretion of ticagrelor and its active metabolite occurs through the hepatobiliary system. Severe hepatic impairment is a contraindication to use of ticagrelor, with no restriction in mild liver disease. CYP3A inhibitors, including diltiazem and ketoconazole, increase the plasma concentration of ticagrelor. Ticagrelor increases the levels of simvastatin, as it is a CYP3A substrate. Therefore caution should be used in patients on high doses of simvastatin.²³ Similar to prasugrel, there is no alteration in efficacy of ticagrelor with any specific CYP2C19 genotype.

Dosing of Ticagrelor in PCI

The Dose Confirmation Study Assessing Antiplatelet Effects of AZD6140 Versus Clopidogrel in Non–ST-Segment Elevation Myocardial Infarction-2 (DISPERSE-2) trial was performed to compare the safety and initial efficacy of ticagrelor versus clopidogrel in patients with non–ST-segment elevation ACSs. Nine hundred ninety patients who were treated with standard therapy for ACS, including aspirin, were randomized in a double-blind fashion to receive ticagrelor 90 mg twice daily, ticagrelor 180 mg twice daily, or clopidogrel 300-mg loading dose plus 75 mg once daily for up to 12 weeks. Patients randomized to receive ticagrelor were also subrandomized to either a 180- or 270-mg loading dose of ticagrelor. There was no difference in the primary outcome of major and minor bleeding at 4 weeks between the ticagrelor groups and the clopidogrel group (P = .43 and P = .96, respectively). The use of a loading dose of ticagrelor did not significantly affect bleeding rates. There was no difference in any of the secondary clinical end points (all-cause death, cardiovascular death, MI, stroke, or recurrent ischemia) between the ticagrelor 90 mg and clopidogrel groups. However, there was a dose-dependent increase in the rate of reported dyspnea and asymptomatic ventricular pauses with ticagrelor.²⁴

The Study of Platelet Inhibition and Patient Outcomes (PLATO) was the pivotal trial evaluating the efficacy and safety of ticagrelor.²⁵ This multicenter, double-blind, randomized trial enrolled 18,624 patients from 43 countries with ACS with or without ST-segment elevation, who were randomized to receive either ticagrelor as a 180-mg loading dose followed by 90 mg twice daily or clopidogrel as a 300- to 600-mg loading dose followed by 75 mg daily thereafter. In contrast to TRITON-TIMI 38, which excluded patients receiving thienopyridines within 5 days and delayed study drug administration until coronary angiography was performed, the PLATO investigators administered the study drugs as early as possible within 24 hours of chest pain and included patients already treated with clopidogrel. The primary efficacy end point was a composite of death from cardiovascular causes, MI, or stroke. The major safety end point was major bleeding, which was a more inclusive than TIMI-defined major bleeding used in TRITON-TIMI 38.¹⁹ In PLATO, major bleeding was defined as a decrease of 3.0 g/dL in the hemoglobin, transfusion of 2 units of packed red blood cells, or bleeding that led to a significant clinical disability.

The results of the study demonstrated a significant reduction in the primary composite end point in patients treated with ticagrelor compared to clopidogrel (9.8% vs. 11.7%; HR, 0.84 [95% CI, 0.77-0.92]; P < .001). This benefit was replicated in the 13,408 patients treated with a planned invasive strategy.

Despite the higher potency and efficacy of ticagrelor as an antiplatelet agent, no significant difference in the rates of major bleeding, as defined by the trial, was found between the ticagrelor and clopidogrel groups (11.6% vs 11.2%, respectively; P = .43). The rate of fatal intracerebral hemorrhage was significantly greater with ticagrelor therapy, but this was offset by a higher rate of nonintracranial fatal bleeding with clopidogrel, resulting in an overall similar rate of fatal bleeding with the 2 therapies. Although there was no difference in CABG-related bleeding, non–CABG-related TIMI major bleeding was significantly more frequent with ticagrelor (HR, 1.25 [95% CI, 1.03-1.53]; P = .03).

As noted in DISPERSE-2, dyspnea occurred more frequently in the ticagrelor group than the clopidogrel group, and Holter monitoring revealed a higher incidence of ventricular pauses in the first week in the PLATO study. The proposed mechanism of both dyspnea and ventricular pauses is ticagrelor’s interference with the normal clearance of adenosine. The ventricular pauses were rarely symptomatic, with no increased requirement of pacemaker implantation. The levels of creatinine and uric acid increased slightly more during the treatment period with ticagrelor than with clopidogrel. The exact pharmacologic mechanisms leading to these effects are unclear at the present time.

A main criticism of the PLATO trial was the lack of reduction in the primary end point seen among 1814 patients enrolled in the United States and Canada.²⁶ Although no clear explanation is available, a maintenance dose of 300 mg of aspirin was used in these sites, and aspirin dose has been a referenced explanation for the regional differences. Therefore, the US Food and Drug Administration (FDA) issued a warming directing the use of less than 100 mg of aspirin as a maintenance dose when used concurrently with ticagrelor.²⁷ Table 16-1 shows a comparison of oral antiplatelet agents.