Introduction
Atherosclerotic plaque rupture followed by arterial thrombosis is the major determinant that leads to an acute coronary syndrome (ACS). Platelet adhesion, activation, and aggregation have a pivotal role in the cascade of events that lead to arterial thrombosis, and therefore, antiplatelet therapy is essential in the treatment of patients with ACS. Multiple platelet signaling pathways are involved in thrombus formation, which represent potential targets for antiplatelet agents. Currently, several classes of antiplatelet therapies are clinically available for both oral and intravenous administration for the treatment of patients with ACS, including unstable angina, non–ST-elevation myocardial infarction (NSTEMI), and ST-elevation MI (STEMI). This chapter provides an overview of these antiplatelet therapies used in the setting of acute MI, including describing the rationale for use, pharmacological principles, pivotal clinical trial data, and guidance for selecting the initial antiplatelet regimen in the early phase of management. Decisions regarding antiplatelet therapy for long-term secondary prevention are discussed in Chapter 35 .
Rationale for Use of Antiplatelet Therapy
The pathobiology of atherothrombosis is discussed in Chapter 3 , and the fundamental principles underlying the rationale for antiplatelet therapy are described in Chapter 13 . Injury to the arterial vessel wall (e.g., plaque rupture, fissure, or erosion) exposes the subendothelial layer and leads to recruitment and activation of platelets, as well as generation of excessive levels of thrombin. These events ultimately result in the formation of a fibrin-rich thrombus ( 
).
Platelet-mediated thrombosis follows three principal steps: (1) platelet adhesion, (2) activation and additional recruitment, and (3) aggregation ( Figure 19-1 ). Adhesion of platelets to the subendothelium during the rolling phase is mediated by the interaction between the glycoprotein (GP) Ib/V/IX receptor complex located on the platelet surface and the von Willebrand factor (vWf) and between the collagen exposed at the site of the vascular injury and the platelet collagen receptors. After adhesion, binding of collagen to these receptors triggers intracellular mechanisms that shift platelet integrins to a high-affinity state and induce the release of activating factors that enhance the interactions among adherent platelets and promote further recruitment and activation of circulating platelets (see 
). Activating factors include thromboxane A 2 (TXA 2 ), adenosine diphosphate (ADP), serotonin, epinephrine, and thrombin. Platelet activation by these mediators leads to changes in platelet shape, expression of proinflammatory molecules (e.g., soluble CD40 ligand and P-selectin) and expression of platelet procoagulant activity. The final pathway for all agonists is the conversion of the platelet GP IIb/IIIa receptor, the main receptor that mediates platelet aggregation, into its active form. Activated GP IIb/IIIa receptors bind to soluble adhesive substrates, including fibrinogen and vWf, which lead to platelet aggregation and thrombus formation mediated by platelet–platelet interactions.
Vascular injury also exposes subendothelial tissue factor, which activates the clotting cascade leading to thrombin generation. However, only a modest amount of thrombin is produced as a result of the coagulation cascade. Thrombin is one of the most potent platelet activators, and the surface of activated platelets is the main source of circulating thrombin. During arterial thrombosis, thrombin converts fibrinogen to fibrin, generating a fibrin-rich clot, and it further activates platelets by binding to protease-activated receptors (PARs) on the platelet membrane. Therefore, pathogenic thrombosis is a complex interplay between cellular (i.e., platelets) and plasma (i.e., coagulation factors) components, which interact in an auto-amplified process (see Figure 19-1 ).
Multiple receptors and signaling pathways are involved in arterial thrombosis. Therefore, several antiplatelet agents have been developed to target different components of this complex process, as described in the following section ( Figure 19-2 ).
Antiplatelet Therapies in Myocardial Infarction
Several classes of antiplatelet agents, which are available for both oral and intravenous administration, are currently approved for clinical use in the management of patients with acute MI. These include (1) cyclooxygenase (COX)-1 inhibitors (aspirin), (2) ADP P2Y 12 receptor antagonists (ticlopidine, clopidogrel, prasugrel, ticagrelor, and cangrelor), (3) GP IIb/IIIa receptor inhibitors (abciximab, eptifibatide, and tirofiban), and (4) a PAR-1 receptor inhibitor (vorapaxar) that is approved for secondary prevention in patients after an MI (see Chapter 35 ). Details on the pharmacology and clinical trial development of these classes of antiplatelet agents are provided in the following sections.
Aspirin
Aspirin exerts its antiplatelet effects by irreversibly blocking the COX-1 enzyme by using acetylation; this enzyme is responsible for the generation of TXA 2 from arachidonic acid. Through inhibition of COX-1, aspirin decreases platelet activation mediated by the G-coupled thromboxane and prostaglandin endoperoxide receptors (see Figure 19-2 ). Aspirin is rapidly absorbed in the upper gastrointestinal tract. The plasma half-life of aspirin is approximately 20 minutes, and peak plasma levels are achieved 30 to 40 minutes after ingestion of uncoated aspirin. In contrast, it can take up to 3 to 4 hours for peak plasma levels to occur after the administration of enteric-coated formulations. Because the blockade of COX-1 induced by aspirin is irreversible, TXA 2 -mediated aggregation is prevented for the entire life span of the platelet (approximately 7 to 10 days). Daily administration of 30 mg of aspirin results in virtually complete suppression of platelet TXA 2 production after 1 week. In clinical practice, standard regimens of aspirin range from 75 to 325 mg/day. Higher doses of aspirin are required to block COX-2, which has anti-inflammatory and analgesic effects, through inhibition of the vascular PGI2 (prostacyclin), which is a platelet inhibitor and a vasodilator.
In the ISIS-2 (International Study of Infarct Survival-2) trial, aspirin therapy was associated with a significant reduction in vascular mortality in patients with suspected acute MI who were randomized to receive either aspirin, streptokinase, both agents, or placebo. Other trials consistently demonstrated an important 40% to 50% reduction in cardiovascular events with aspirin treatment in MI patients. The clinical benefit of aspirin is achieved at low doses (75 to 100 mg/day), with no additional benefit provided by higher doses. In contrast, a dose-dependent increase in the risk of bleeding has been shown, in particular, for upper gastrointestinal bleeding. Despite the therapeutic benefit of aspirin, some patients who receive long-term therapy are at risk of thrombotic events because of the insufficient inhibition of platelets, giving rise to the term “aspirin resistance.” However, the association between variability in response to aspirin and cardiovascular events has led to inconsistent findings. This is likely attributable to the type of tests being used for pharmacodynamic evaluation of aspirin effects. When tests specific for COX-1 activity are used, aspirin resistance is extremely rare and is likely caused by noncompliance; drug–drug interactions (i.e., ibuprofen) and enteric coating may also represent contributing causes. The residual ischemic risk is thus mainly because of the fact that aspirin specifically targets the TXA 2 pathway, and it is not effective in reducing platelet activation stimulated by other pathways involved in arterial thrombosis.
P2Y 12 Receptor Antagonists
The agonist ADP exerts its effects on platelets through the purinergic G-protein–coupled P2Y 1 and P2Y 12 receptors (see Figure 19-2 ). Although both receptors are involved in aggregation, ADP-stimulated effects on platelets are mediated mainly by G i -coupled P2Y 12 receptor activation, which leads to sustained platelet aggregation and stabilization of platelet aggregates, whereas P2Y 1 is responsible for an initial weak and transient phase of aggregation and change in platelet shape. The addition of a P2Y 12 receptor inhibitor to aspirin is able to reduce platelet aggregation more than what each single drug is able to achieve, and this synergism has been shown to be beneficial in clinical trials that have assessed the optimal antithrombotic regimen in patients undergoing coronary stent implantation.
Several oral P2Y 12 receptor inhibitors (ticlopidine, clopidogrel, prasugrel, and ticagrelor) have been developed to be used in addition to aspirin for the prevention of ischemic events during the acute management and secondary prevention after an MI ( Table 19-1 ). The first available P2Y 12 receptor inhibitor was the first-generation thienopyridine ticlopidine. Although ticlopidine in combination with aspirin was shown to be superior compared with either aspirin alone or anticoagulation in combination with aspirin for prevention of thrombotic events in patients undergoing percutaneous coronary intervention (PCI), its use has been largely abandoned because of its frequent side effects, including life-threatening hematologic disorders. The following sections will provide an overview on the pharmacology and clinical trial development of P2Y 12 receptor inhibitors currently approved for clinical use, focusing on studies performed in the acute phase of ACS.
| Clopidogrel | Prasugrel | Ticagrelor | Cangrelor | |
|---|---|---|---|---|
| Pharmacological class | Thienopyridine | Thienopyridine | CPTP | ATP analogue |
| Receptor blockade | Irreversible | Irreversible | Reversible | Reversible |
| Administration route | Oral | Oral | Oral | IV |
| Frequency | Once daily | Once daily | Twice daily | Bolus plus infusion |
| Prodrug | Yes | Yes | No ∗ | No |
| Onset of action | 2–8 hrs | 30 min–4 hrs † | 30 min–4 hrs † | 2 min |
| Offset of action | 7–10 days | 7–10 days | 3–5 days | 30–60 min |
| CYP drug interaction | CYP2C19 | No | CYP3A | No |
| Approved settings | ACS and stable CAD PCI | ACS undergoing PCI | ACS (full spectrum) | P2Y 12 receptor inhibitors naïve patients undergoing PCI |
∗ Although most ticagrelor-mediated antiplatelet effects are direct, approximately 30% to 40% are attributed to an active metabolite (AR-C124910XX).
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.
| Trial | Patients (no.) | Setting | Treatment arms | Primary Endpoint | Results |
|---|---|---|---|---|---|
| CURE | 12,562 | NSTE-ACS | Aspirin+clopidogrel vs. aspirin | CV death, nonfatal MI, or stroke at 1 yr | 9.3% vs. 11.4%; HR, 0.80; 95% CI, 0.72–0.90; P <.001 |
| PCI-CURE | 2658 | NSTE-ACS treated with PCI | Aspirin+clopidogrel vs. aspirin | CV death, MI, or revascularization within 30 days | 4.5% vs. 6.4%; RR, 0.70; 95% CI, 0.50–0.97; P = .03 |
| CREDO | 2116 | Patients undergoing PCI (including ACS) | Aspirin+clopidogrel vs. aspirin | CV death, MI, or stroke at 1 yr | 8.5% vs. 11.5%; RRR, 26.9%; 95% CI, 3.9%–44.4%; P = .02 |
| COMMIT | 45,852 | STEMI | Aspirin+clopidogrel vs. aspirin | Death, reinfarction, or stroke at 28 days | 9.2% vs. 10.1%; OR, 0.91; 95% CI, 0.86–0.97; P = .002 |
| CLARITY | 3491 | STEMI | Aspirin+clopidogrel+FA vs. aspirin+FA | Occluded infarct-related artery, death, or recurrent MI before angiography | 15.0% vs. 21.7%; OR, 0.64; 95% CI, 0.53–0.76; P <.001 |
| CURRENT-OASIS 7 | 25,087 | ACS referred for an early invasive strategy | Aspirin+double-dose clopidogrel vs. aspirin+standard dose clopidogrel | CV death, MI, or stroke at 30 days | 4.2% vs. 4.4%; HR, 0.94; 95% CI, 0.83–1.06; P = .30 |
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.
| Trial | Patients (no.) | Setting | Treatment Arms | Primary Endpoint | Results |
|---|---|---|---|---|---|
| TRITON-TIMI 38 | 13,608 | ACS patients undergoing PCI | Aspirin+prasugrel vs. aspirin+clopidogrel | CV death, nonfatal MI or nonfatal stroke | 9.9% vs. 12.1% (15 mos); HR, 0.81; 95% CI, 0.73–0.90; P <.001 |
| TRILOGY-ACS | 9326 | Medically managed NSTE-ACS | Aspirin+prasugrel vs. aspirin+clopidogrel | CV death, MI, or stroke at 17 mos in patients with age <75 yrs | 13.9% vs. 16.0%; HR, 0.91; 95% CI, 0.79–1.05; P = .21 |
| ACCOAST | 4033 | NSTEMI scheduled for angiography | Pretreatment with prasugrel 30 mg vs. placebo | CV death, MI, stroke, GPI bailout, or urgent revascularization at 7 days | 10.0% vs. 9.8%; HR, 1.02; 95% CI, 0.84–1.25; P = .81 |
| PLATO | 18,624 | ACS | Aspirin+ticagrelor vs. aspirin+clopidogrel | Death from vascular causes, MI. or stroke | 9.8% vs. 11.7% (12 mos); HR, 0.84; 95% CI, 0.77–0.92; P <.001 |
| CHAMPION PHOENIX | 11,145 | Patients undergoing PCI | Aspirin+clopidogrel+cangrelor vs. aspirin+clopidogrel | Death from any cause, MI, IDR, and stent thrombosis at 48 hr | 4.7% vs. 5.9%; OR, 0.78; 95% CI, 0.66–0.93; P = .005 |
| TRACER | 12,944 | NSTE-ACS | Standard APT+vorapaxar vs. standard APT+placebo | CV death, MI, stroke, recurrent ischemia with rehospitalization, or urgent coronary revascularization | 18.5% vs. 19.9% (2 yrs); HR, 0.92; 95% CI, 0.85–1.01; P = .07 |
| TRA 2P-TIMI 50 | 26,449 | Patients with history of MI, ischemic stroke, or PAD | Standard APT+vorapaxar vs. standard APT+placebo | CV death, MI, or stroke | 9.3% vs. 10.5% (36 mos); HR, 0.87; 95% CI, 0.80–0.94; P <.001 |
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.
| Characteristics | TRITON-TIMI 38 | PLATO |
|---|---|---|
| Setting | ACS scheduled for PCI | ACS (invasive and noninvasive) |
| Medically managed patients | No | Yes |
| Timing of LD administration | After angiography ∗ | Before angiography |
| Clopidogrel pretreated patients | No | Yes (46% of total population) |
| Clopidogrel LD | 300 mg | 300–600 mg |
| Primary endpoint | CV death, nonfatal MI, or nonfatal stroke | Death from vascular causes, nonfatal MI, or nonfatal stroke |
| Major safety endpoint | Non-CABG–related TIMI major and life-threatening bleeding † | Total PLATO-defined major bleeding (CABG- and non–CABG-related) ‡ |
| Follow-up duration (median) | 14.5 mos | 9 mos |
∗ Pretreatment before angiography was allowed in patients with planned primary PCI for STEMI.
† TIMI major bleeding is defined as any intracranial bleeding, clinically overt signs of hemorrhage associated with a drop in hemoglobin of ≥5 g/dL, or fatal bleeding. 165
‡ PLATO major bleeding is defined as either major life-threatening bleeding (fatal bleeding, intracranial bleeding, intrapericardial bleeding with cardiac tamponade, hypovolemic shock, or severe hypotension because of bleeding and requiring pressors or surgery, a decline in the hemoglobin level of ≥5 g/dL, or the need for transfusion of at least 4 U of red blood cells) or other major bleeding (bleeding that leads to clinically significant disability or bleeding either associated with a drop in the hemoglobin level of at least 3.0 g/dL, but less than 5.0 g/dL, or requiring transfusion of 2 to 3 units of red blood cells.
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.
