Overview of Antiplatelet Therapy for Myocardial Infarction

Clopidogrel

Clopidogrel (see Figure 19-2 ) is a second-generation thienopyridine with a more favorable safety profile compared with ticlopidine. Furthermore, clopidogrel has a pharmacological advantage over ticlopidine, because it achieves a faster onset of action through administration of a loading dose (LD). Clopidogrel is orally administrated and is a prodrug that requires metabolic transformation to exert its antiplatelet effects ( Table 19-1 ; see also Figure 20-1 ). After intestinal absorption, approximately 85% of clopidogrel is hydrolyzed by carboxylase to an inactive metabolite. The remaining approximately 15% is rapidly metabolized by hepatic cytochrome P450 (CYP) isoenzymes, in particular CYP2C19, in a two-step oxidation process with the generation of a highly unstable active metabolite that irreversibly binds to the P2Y ₁₂ receptor ( Figure 19-3 ).

Several clinical trials have shown the benefit of dual antiplatelet therapy (DAPT) with a combination of aspirin and clopidogrel in patients with ACS or who are undergoing PCI ( Table 19-2 ). In the CURE (Clopidogrel in Unstable Angina to Prevent Recurrent Events) trial, the administration of clopidogrel (300 mg LD followed by 75 mg once daily), in addition to aspirin, significantly reduced a composite of death from cardiovascular causes, nonfatal MI, or stroke by 20%, compared with aspirin alone in patients with NSTE-ACS (n = 12,562) who were medically managed or underwent revascularization (PCI or coronary artery bypass graft [CABG]). However, this occurred at the expense of an increased risk of major bleeding complications. A post hoc analysis of aspirin dose showed that bleeding events were less likely to occur with lower doses of aspirin (≤100 mg) without any trade-off in efficacy. The clinical benefit of DAPT with aspirin and clopidogrel was also shown in a lower risk population of patients who underwent elective PCI (including patients with ACS) in the CREDO (Clopidogrel for the Reduction of Events During Observation) trial and in patients with STEMI in the COMMIT (Clopidogrel and Metoprolol in Myocardial Infarction) and CLARITY (Clopidogrel as Adjunctive Reperfusion Therapy) trials.

Although clopidogrel is still the most widely used P2Y ₁₂ receptor antagonist, a considerable number of patients still continue to experience recurrent thrombotic events while receiving clopidogrel. This risk has been partially attributed to the high interindividual variability that characterizes the response to clopidogrel. Several factors have been associated with clopidogrel response variability, including clinical (i.e., poor absorption, drug–drug interactions, ACS, diabetes mellitus, obesity, chronic kidney disease), genetic (i.e., CYP polymorphisms), and cellular (i.e., accelerated platelet turnover, reduced CYP3A4 metabolic activity, or up-regulation of P2Y ₁₂ pathway) factors (see Chapter 20 ). Pharmacodynamic studies have shown that approximately 30% to 40% of patients have high platelet reactivity while on clopidogrel treatment, which translates into worse outcomes. Overall, these observations underscore the need for more potent and less variable antiplatelet agents for the treatment of MI patients.

Prasugrel

Prasugrel is an irreversible, orally administered third-generation thienopyridine. It is a prodrug, which after intestinal absorption, requires a single-step oxidation process through hepatic CYP to generate its active metabolite (see Table 19-1 and Figure 19-3 ). Although prasugrel’s active metabolite has the same in vitro affinity for the P2Y ₁₂ receptor as clopidogrel’s active metabolite, the metabolic conversion of prasugrel is more efficient, leading to higher in vivo availability. These pharmacological properties translate into a more prompt (faster onset of action), potent (enhanced platelet inhibition), and predictable (lower interindividual variability in effects) antiplatelet effect compared with clopidogrel. In particular, a 60-mg LD of prasugrel achieves 50% platelet inhibition by 30 minutes and 80% to 90% inhibition by 2 hours.

In the TRITON-TIMI 38 (Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial Infarction 38) trial, patients (n = 13,608) with moderate- to high-risk ACS scheduled for PCI were randomized to receive either prasugrel 60 mg LD followed by a 10 mg/day maintenance dose (MD) or clopidogrel 300 mg LD and 75 mg/day MD, in addition to aspirin ( Table 19-3 ) ( Table 19-e1 ). Prasugrel significantly reduced the primary efficacy endpoint (a composite of cardiovascular death, nonfatal MI, or nonfatal stroke) compared with clopidogrel over a median follow-up of 14.5 months (9.9% vs. 12.1%; hazard ratio [HR], 0.81; 95% confidence interval [CI], 0.73 to 0.90; P <.001), which was mainly driven by a reduction in nonfatal MI. A significant 52% reduction in the rate of stent thrombosis, irrespective of stent type, and a 34% decrease in need for urgent target vessel revascularization were also seen when prasugrel was used.

This effect was hampered by significantly increased rates of non-CABG–related Thrombolysis In Myocardial Infarction (TIMI) major bleeding; CABG-related TIMI major bleeding, life-threatening bleeding, and fatal bleeding were also increased. However, the net clinical benefit was still in favor of prasugrel-treated patients. The benefit achieved by prasugrel over clopidogrel was consistent in patients with STEMI and was particularly notable in patients with DM and in those who experienced recurrent events. Clinical outcomes with prasugrel treatment were not affected by CYP polymorphisms or drug interference with CYP2C19 enzymes. The results were also consistent, irrespective of aspirin dose. In contrast, a neutral effect was found in low body weight patients (<60 kg) and older adults (≥75 years), and a net harm was shown in patients with a history of stroke or transient ischemic attack. Among patients (n = 346) who underwent isolated CABG and who received the study drug before the procedure, there was a reduction in all-cause and cardiovascular mortality with prasugrel compared with clopidogrel, although there was a higher 12-hour chest tube blood loss.

The efficacy of prasugrel compared with clopidogrel in medically managed ACS was tested in the TRILOGY-ACS (Targeted Platelet Inhibition to Clarify the Optimal Strategy to Medically Manage Acute Coronary Syndromes) trial (see Table 19-3 ). Aspirin-treated patients (n = 9326) with an NSTE-ACS who underwent medical management were randomized to receive either prasugrel (30 mg LD followed by 10 mg MD) or clopidogrel (300 mg LD and 75 mg MD). Prasugrel MD was adjusted to 5 mg for patients who were aged 75 years or older or who weighed less than 60 kg. Clopidogrel pretreatment before randomization occurred in approximately 96% of patients. The primary endpoint was a composite of cardiac death, MI, or stroke among patients aged younger than 75 years (n = 7243). After a median follow-up of 17 months, there were no differences between prasugrel and clopidogrel in the primary ischemic endpoint (13.9% vs. 16%; HR, 0.91; 95% CI, 0.79 to 1.05; P = .21). Importantly, the rates of non-CABG–related severe or life-threatening bleeding according to the GUSTO (Global Use of Strategies to Open Occluded Coronary Arteries) criteria, TIMI major bleeding, and intracranial bleeding were low and similar between groups. Moreover, in the secondary analysis on patients (n = 2083) aged 75 years or older, prasugrel 5 mg was not associated with an ischemic benefit compared with standard clopidogrel, although there was no increase in bleeding. Importantly, in the prespecified substudy on patients aged younger than 75 years who underwent angiography before randomization (n = 3085), prasugrel led to a significant reduction in the risks of the composite primary endpoint compared with clopidogrel, with a trend toward an increased risk of major bleeding. These data suggest that when angiography is performed for ACS and anatomic coronary disease is confirmed, the benefits and risks of a more intense antiplatelet therapy exist whether the patient is treated with drugs or PCI.

Ticagrelor

Ticagrelor is an orally administered cyclopentyltriazolopyrimidine that directly and reversibly inhibits the platelet P2Y ₁₂ receptor ( Table 19-1 and Figure 19-3 ). Ticagrelor is not a prodrug and does not require metabolic activation, although approximately 30% to 40% of its antiplatelet effects are attributed to an active metabolite (AR-C124910XX) generated through the hepatic CYP3A system (CYP3A4 and CYP3A5). Ticagrelor does not bind directly to the platelet ADP-binding site on the P2Y ₁₂ receptor; it reversibly binds to a distinct site on the receptor and prevents ADP from causing activation of the P2Y ₁₂ pathway in a noncompetitive fashion through allosteric modulation. Ticagrelor is rapidly absorbed after oral administration and has a half-life of 7 to 12 hours, thus requiring twice daily dosing. Compared with clopidogrel, ticagrelor achieves a faster, more potent and more predictable antiplatelet effect, with a faster offset of action.

The efficacy and safety of ticagrelor in patients with ACS were evaluated in the Phase III PLATO (Platelet Inhibition and Patient Outcomes) trial (see Table 19-3 ). There are key differences between the PLATO and TRITON-TIMI 38 trial designs, as summarized in Table 19-e1 . In the PLATO trial, ACS patients (n = 18,624) were randomized to receive either ticagrelor (180 mg LD followed by 90 mg twice daily MD) or clopidogrel (300 to 600 mg LD followed by 75 mg/day MD) in addition to aspirin for 12 months. The trial embraced the whole spectrum of patients with ACS, including those intended to undergo invasive as well as noninvasive management. Patients pretreated with clopidogrel were eligible for study entry, and study drug LD administration occurred before or after angiography, but before PCI. Compared with clopidogrel, ticagrelor significantly reduced the primary endpoint (a composite of death from vascular causes, MI, or stroke) at 12 months (9.8% vs. 11.7%; HR, 0.84; 95% CI, 0.77 to 0.92; P <.001), including a significant 21% reduction in cardiovascular death and a 16% reduction of MI. Ticagrelor treatment also significantly reduced the rates of definite or probable stent thrombosis.

Although protocol-defined major bleeding was similar between groups (11.6% vs. 11.2%; P = .43), ticagrelor led to a significantly increased hazard of non-CABG–related PLATO and TIMI major bleeding, as well as fatal intracranial hemorrhage. Importantly, the benefit of ticagrelor over clopidogrel was consistent across multiple prespecified subgroups, including patients who were treated initially with a noninvasive or invasive (followed by PCI or CABG) strategy. Accordingly, patients with STEMI, diabetes mellitus, who were older than 75 years of age, weighed less than 60 kg, who had a previous stroke or transient ischemic attack, with recurrent cardiovascular events, chronic kidney disease, and with or without CYP2C19 loss-of function polymorphisms, also benefitted from ticagrelor therapy. Bleeding outcomes were also consistent across subgroups, with no groups experiencing harm with ticagrelor.

Importantly, a geographic interaction was found in the trial, with patients enrolled in North America not experiencing a reduction in the primary endpoint by ticagrelor treatment. Although these findings can be attributed to play of chance, a post hoc assessment found this to be possibly explained by the use of high-dose (≥300 mg/day) aspirin, which was more common in North America. Although subsequent studies failed to demonstrate any effect of aspirin dosing on the pharmacokinetic and pharmacodynamic profile of ticagrelor, the use of low-dose aspirin (≤100 mg) is currently recommended in ticagrelor-treated patients.

Non-P2Y ₁₂ –mediated effects of ticagrelor related to increased plasma levels of adenosine have been described. Under normal conditions, adenosine has a short half-life and is rapidly up-taken by red blood cells and metabolized. Ticagrelor has been shown to significantly inhibit cellular uptake of adenosine by blocking the sodium-dependent equilabrative nucleoside transporters (ENT-1), and thus, increasing adenosine plasma concentrations. Adenosine has multiple cardiac and extracardiac properties that include inhibition of platelet aggregation (mainly through the activation of A _2A G-coupled receptors), arterial vasodilation, reduction in inflammatory response, negative chronotropic and dromotropic effects, stimulation of pulmonary vagal C fibers that mediate the sensation of dyspnea, and a role in the regulation of kidney glomerular filtration. Although ticagrelor does not directly act on adenosine receptors, it enhances the biological effects of adenosine, which may contribute to the overall benefits of ticagrelor, including a reduction in cardiovascular mortality, and to the nonbleeding side effects of ticagrelor, such as a higher incidence of dyspnea (15% to 22% of ticagrelor-treated patients) and ventricular pauses and increased levels of creatinine and uric acid during treatment compared with clopidogrel ( Figure 19-4 ). These side effects are usually self-limiting and have no impact on clinical outcomes, but were responsible for the higher discontinuation rate of ticagrelor compared with clopidogrel in the PLATO trial. Importantly, no effect of ticagrelor on specific pulmonary function parameters, such as spirometry, lung volumes, diffusion capacity, and pulse oximetry, have been shown.

Cangrelor

Although prasugrel and ticagrelor are characterized by more prompt, potent, and predictable antiplatelet effects, leading to greater clinical efficacy over clopidogrel, these drugs still present limitations inherent to orally administered antiplatelet agents, including delayed pharmacodynamic effects in patients with STEMI, slow offset of action, and an inability to exert reliable and predictable platelet inhibition in patients who are hemodynamically unstable or sedated, intubated, in shock, under therapeutic hypothermia, or who have nausea or vomiting. Cangrelor is an analogue of adenosine triphosphate (ATP) and is the first reversible intravenous P2Y ₁₂ inhibitor. It directly binds to the P2Y ₁₂ receptor in a predominantly competitive manner without the need for being metabolized (see Table 19-1 and Figure 19-3 ). Cangrelor achieves very potent (>80%) antiplatelet effects, reaching steady-state concentrations within a few minutes, and is characterized by a linear dose-dependent pharmacokinetic profile that leads to very stable pharmacodynamic effects. Because of its very short half-life (3 to 5 minutes), cangrelor has a fast offset of action, with platelet aggregation returning to baseline levels within 30 to 60 minutes.

The role of cangrelor as adjunctive antiplatelet therapy in patients who require PCI has been tested in three large-scale phase III clinical trials. Although the first two trials, namely the CHAMPION (Cangrelor versus Standard Therapy to Achieve Optimal Management of Platelet Inhibition)-PCI and the CHAMPION-PLATFORM trials, were interrupted for futility and failed to document any ischemic benefit of cangrelor over DAPT with aspirin and clopidogrel, pitfalls in study endpoint definitions (i.e., the definition of MI) may have contributed to these results. A pooled analysis of the CHAMPION-PCI and CHAMPION-PLATFORM trials, which used the Universal Definition of MI (see Chapter 1 and Chapter 7 ) to define MI events, showed a significant reduction in the primary endpoint with the use of cangrelor.

The hypothesis-generating data from this analysis led to the design of the CHAMPION PHOENIX trial, which evaluated if addition of cangrelor on top of DAPT with aspirin and clopidogrel in patients undergoing PCI could reduce the occurrence of acute ischemic complications (see Table 19-3 ). The study included P2Y ₁₂ receptor inhibitor–naïve patients across the spectrum of coronary artery disease (CAD) manifestations (stable angina, NSTE-ACS, and STEMI). After angiography, patients (n = 11,145) were randomized to receive either a cangrelor bolus (30 μg/kg) followed by infusion (4 μg/kg per minute for 2 to 4 hours) or a clopidogrel LD (300 or 600 mg before or immediately after the PCI, as per institutional standard). In the cangrelor arm, patients received 600 mg of clopidogrel at the end of the infusion. Adjunctive cangrelor therapy significantly reduced the primary efficacy endpoint (a composite of death from any cause, MI, ischemia-driven revascularization, and stent thrombosis) at 48 hours (4.7% vs. 5.9%; adjusted odds ratio [OR] with cangrelor, 0.78; 95% CI, 0.66 to 0.93; P = .005), which was primarily driven by a reduction in the hazard of MI (3.8% vs. 4.7%; P = .02). The use of cangrelor led to a significant reduction in the rate of stent thrombosis at 48 hours (0.8% vs 1.4%; OR, 0.62; 95% CI, 0.43 to 0.90; P = .01). Intraprocedural stent thrombosis, which was shown to be associated with an increase in adverse outcomes at 48 hours and 30 days, was also significantly reduced.

The rate of severe bleeding at 48 hours was not significantly increased by cangrelor using the GUSTO criteria and other definitions of bleeding. However, the rate of major bleeding according to the more sensitive ACUITY criteria was significantly higher in patients treated with cangrelor, which was primarily driven by a higher incidence of hematomas at the vascular access sites. Overall, the net rate of adverse clinical events (ischemic plus bleeding events) was significantly reduced by the use of cangrelor. The clinical benefit of adjunctive cangrelor therapy was consistent at 30 days and across multiple prespecified subgroups, such as those defined by different clinical presentations (stable angina, NSTE-ACS, or STEMI), dose and timing of clopidogrel loading, stent type, and duration of study drug infusion.

These results were further confirmed by a pooled analysis on approximately 25,000 patients enrolled in the three CHAMPION trials, which showed consistent results using the PHOENIX definition of MI. Cangrelor was also tested as a bridging strategy in patients (n = 210) on thienopyridine treatment (including patients with a recent MI) and who required CABG; it showed high and stable levels of platelet inhibition up to 7 days of infusion, with a rapid offset after discontinuation before surgery. This strategy was not associated with an increased risk of major bleeding or side effects before or during CABG, although these findings need to be interpreted with caution because the study was not powered for clinical outcomes.