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Antiplatelet Therapy
Over the last 3 decades, clinical management and outcomes of patients presenting with acute coronary syndromes (ACSs) have improved dramatically. Better understanding of the role of the platelet in the pathophysiology of the ACS has been the fundamental pillar for that progress. The development and availability of effective pharmacologic agents and the advance of coronary revascularization procedures have been the tools by which scientific advances were translated into reductions in morbidity and mortality of patients across the spectrum of ACS, from those with ST elevation myocardial infarction (STEMI) or those with non-ST segment elevation ACS (NSTE-ACS).
Platelet and Acute Coronary Syndromes
Plaque rupture and luminal thrombus formation are the sentinel events that convert the atherosclerotic disease process from a slowly progressive condition causing insidious luminal obstruction to an acute coronary event marked by rapid deterioration of clinical condition and possible death. Plaque rupture is a term that describes the development of a gap in the fibrous cap, exposing its collagen and the underlying lipid-rich core to flowing blood. This event results in activation of the circulating platelets, which, in turn, initiates a sequence of events involving the activated platelet: adhesion, aggregation, and secretion ( Fig. 36.1 ).
Platelet activation occurs via multiple stimuli, including adenosine diphosphate (ADP) and thromboxane (TX) A 2 , but collagen and thrombin are the two most potent platelet activators. Once collagen is available for binding, platelet adhesion and activation depend on two major collagen receptors located on the platelet membrane, the integrin glycoprotein (GP) Ia/IIa (α2β1) and GP VI. Both receptors generate activation signals that enhance platelet thrombus formation. Thrombin is also a potent stimulus for platelet activation by binding and cleaving platelet protease–activated receptors (PAR), PAR 1 , and PAR 4 . This process forms a tethered-ligand that acts to initiate trans-membrane signaling, also leading to platelet activation.
Once activated, platelet adhesion occurs when platelet GP Ib-IX-V binds to tissue von Willebrand factor (vWF). At least one other receptor that participates in platelet adhesion includes the platelet receptor Ia/IIa, which binds to collagen fibrils. Platelet aggregation soon follows and is primarily mediated by the GP IIb/IIIa complex (αIIbβ3). GP IIb/IIIa adhesion proteins are found on platelets and megakaryocytes. They are the most abundant glycoprotein found on the platelet surface, with approximately 80,000 copies. The GP IIb/IIIa complex requires platelet activation, which causes a conformational change in the receptor, thereby becoming a high-affinity fibrinogen binding receptor. Fibrinogen bridges activated platelets, forming a platelet plug. The cytosolic portion of the GP IIb/IIIa complex stimulates actin rearrangement, resulting in platelet spreading, aggregation, and clot retraction. Hence, GP IIb/IIIa receptor antagonists are powerful antiplatelet drugs.
Activated platelets secrete substances from their granules that stimulate further activation and aggregation. These mediators include, but are not limited to, ADP, TXA 2 , fibrinogen, fibronectin, and thrombospondin. There are at least two receptors that bind ADP: P2Y 12 and P2Y 12 . Commercially available agents that block the P2Y 12 receptor include clopidogrel, prasugrel, ticagrelor, and cangrelor. Thromboxane A 2 is an arachidonic acid metabolite and a strong platelet stimulator. The production of TXA 2 depends on the cyclooxygenase pathway, which is irreversibly inhibited by aspirin (see Fig. 36.1 ). The aforementioned steps of adhesion, aggregation, and secretion are presented in a stepwise fashion for simplicity, but in reality, these processes occur simultaneously. By better understanding the molecular mechanisms, targets for future and more effective antiplatelet agents can be defined (see Fig. 36.1 ).
Non–ST Segment Elevation Acute Coronary Syndrome
Platelet activation is central to the process of coronary thrombus formation, the sentinel pathophysiologic step in ACS. Therefore, antiplatelet therapy is the cornerstone of treatment in NSTE-ACS. Numerous clinical trials have established that appropriate antiplatelet therapy in NSTE-ACS reduces mortality and other ischemic events. When antiplatelet therapy is used in the cardiac intensive care unit (CICU), it is imperative that physicians ensure that their patients are receiving these agents at the appropriate dosages and while cautiously observing for side effects, namely, bleeding complications.
The field of antiplatelet therapy for NSTE-ACS has evolved and changed rapidly over the last few decades. While aspirin was the only available agent for many years, the 1990s were dominated by the development and use of intravenous GP IIb/IIIa inhibitors. These agents demonstrated the value of effective and rapid platelet inhibition, but were associated with increased bleeding complications. In the late 1990s and early 2000s, P2Y 12 inhibitors were developed. Their value of GP IIb/IIIa inhibitors took some time to clarify, but soon they were supplanting intravenous agents because of ease of use, reduced cost, and less concern about bleeding. Newer P2Y 12 inhibitors demonstrated higher efficacy and further improvement in outcomes, but again at the cost of excess bleeding. The newer thrombin receptor antagonists appeared to have lower bleeding complications in the early trials but subsequently were found to have the same features: enhanced efficacy with increased risk of bleeding. The most recent addition to the antiplatelet armamentarium is the intravenous P2Y 12 inhibitor, cangrelor, which provides immediate inhibition and can be followed by an oral agent that inhibits the same receptor.
Acetylsalicylic Acid (ASA or Aspirin)
The importance of effective and early use of aspirin in ACS was established decades ago. Fortunately, the awareness of this fact among the public and health care professionals encountering these patients is very high. In many instances, patients reach for aspirin as they are calling emergency medical services for the acute onset of chest pain. The dispatchers receiving the calls instruct patients to use aspirin if they have it available and first responders immediately provide it upon arrival to the scene. For those who did not receive it, almost all patients with chest pain are given aspirin in the emergency department.
When aspirin is given acutely as a tablet it should be chewed in order to achieve rapid platelet inhibition within approximately 20 minutes. Aspirin blocks the production of TXA 2 by irreversibly acetylating a serine residue on cyclooxygenase 1. This prevents the conversion of arachidonic acid to prostaglandin H 2 , a precursor of TXA 2 . TXA 2 causes vasoconstriction and platelet aggregation. Unless there is a well-documented severe allergic reaction, all patients with ACS should be treated with 162 mg to 325 mg of nonenteric coated aspirin promptly after presentation. The American College of Cardiology (ACC)/American Heart Association (AHA) guidelines for treatment of NSTE-ACS give aspirin a class IA recommendation for its immediate and indefinite use in this patient population. Regardless of whether the patient will require percutaneous or surgical revascularization, the first dose should be followed by indefinite daily ASA: 81 mg/day in patients treated concomitantly with ticagrelor and 75 to 325 mg/day in all others.
The benefit of aspirin in unstable angina has been demonstrated in several trials. In the Veterans Administration Cooperative Trial, 1266 men with unstable angina were randomized to either aspirin or placebo. The incidence of death or acute myocardial infarction (MI) was reduced by 51% in the aspirin group (5.0% vs. 10.1%, P = .0005). Examined individually, both nonfatal MI and death were dramatically reduced by more than 50% in the aspirin group, although the reduction in death did not quite reach the level of statistical significance (3.4% vs. 6.9%, P = .005 for acute MI and 1.6% vs. 3.3%, P = .054). Further confirmation of the benefit of aspirin in reducing death and nonfatal MI was demonstrated in other trials.
Despite the extensive body of literature describing the benefits of aspirin, more conclusive data about the appropriate dosing have not been available until the last few years. As little as 30 mg/day of aspirin chronically can completely inhibit serum TXB 2 production ; many studies suggest equal benefit with doses of less than 150 mg daily compared to higher doses when taken long term. While only 30 mg/day of aspirin are needed to inactivate TXA 2 production, the rapidity of platelet inactivation should also be considered in the context of ACS. In a small study involving 18 healthy volunteers, chewing 162 mg and 324 mg, but not 81 mg of aspirin resulted in maximal inhibition of TXA 2 within 15 minutes.
Many large, blinded, controlled trials in addition to several meta-analyses of placebo-controlled trials have evaluated the optimal aspirin dose in treating patients with nearly every clinical manifestation of atherosclerosis, including stroke, transient ischemic attack (TIA), percutaneous coronary and peripheral interventions, carotid endarterectomy, and MI. In all of these trials, there is no relationship between increasing aspirin dosage and improved clinical efficacy. However, increasing aspirin doses significantly increases the risk of bleeding. An analysis of 31 trials including 192,036 patients examined the association between aspirin dose and bleeding complications. Data were divided into several categories, including major bleeding, minor bleeding, gastrointestinal, stroke, fatal/life threatening, and total bleeding episodes. In all categories, aspirin doses higher than 100 mg/day were associated with significantly more events.
The Clopidogrel and Aspirin Optimal Dose Usage to Reduce Recurrent Events−Seventh Organization to Assess Strategies in Ischemic Syndromes (CURRENT-OASIS) 7 trial enrolled 17,263 patients with ACS who underwent early percutaneous coronary intervention (PCI) in a 2 × 2 randomized factorial design: 600 mg versus 300 mg loading dose of clopidogrel and high-dose (300 to 325 mg) versus low-dose (75 to 100 mg) of daily aspirin. The primary outcome was cardiovascular death, MI, or stroke at 30 days. There was no significant difference in the primary outcome between the high-dose and low-dose aspirin groups (4.1% vs. 4.2%; P = .76). Major bleeding was also not different in the high-dose and low-dose aspirin groups (1.5% vs. 1.3%, P = .2), but high-dose aspirin recipients reported more minor bleeding events ( Fig. 36.2 ). Very similar conclusions could be drawn from The Treatment with ADP Receptor Inhibitors: Longitudinal Assessment of Treatment Patterns and Events after Acute Coronary Syndrome (TRANSLATE-ACS) study, in which 10,123 patients with MI who underwent PCI were discharged on dual antiplatelet therapy, including either 325 or 81 mg of aspirin. At 6 months, there were no statistically significant differences between the 2 groups in the rate of major adverse cardiovascular events (death, MI, stroke, or unplanned revascularization) with an adjusted hazard ratio (HR) of 0.99 (95% confidence interval [CI], 0.85–1.17). However, bleeding complications were significantly more frequent with high-dose aspirin (24.2% vs. 19.5%; adjusted odds ratio [OR], 1.19; 95% CI, 1.05–1.34). The increased bleeding events were mostly in minor bleeding events not requiring hospitalization.
Adenosine Diphosphate Receptor Antagonists
The oral ADP receptor antagonists include ticlopidine, clopidogrel, prasugrel, and ticagrelor. Ticlopidine is rarely used due to its unfavorable side effect profile of nausea, vomiting, diarrhea, neutropenia, and—rarely—thrombotic thrombocytopenic purpura along with a longer time to onset of platelet inhibition than clopidogrel; thus, it will not be discussed.
Clopidogrel.
The introduction of clopidogrel to the field of ACS management has had a dramatic effect on the algorithms of therapy used all over the world. Moreover, it introduced the concept of dual antiplatelet therapy (DAPT) and the class of P2Y 12 inhibitors, which remain the mainstay of therapy today.
The daily dose of clopidogrel is 75 mg. In circumstances when rapid platelet inhibition is desired, such as ACS, a loading dose of clopidogrel 300 or 600 mg for NSTE-ACS or 600 mg for STEMI can be given. The loading doses demonstrate additional antiplatelet aggregation properties when compared to aspirin alone and are considered as class I recommendations by the respective ACC/AHA guidelines.
When added to aspirin in patients with NSTE-ACS, clopidogrel offers additional reduction in vascular events and death, as established in the Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) study. The study randomized 12,562 patients presenting with NSTE-ACS to receive aspirin plus clopidogrel versus aspirin plus placebo. The study was designed to examine two primary outcomes: the first was a composite of cardiovascular death, MI, or stroke and the second comprised the first primary outcome plus refractory ischemia. At 9 months, patients receiving aspirin plus clopidogrel had a statistically significant reduction in both primary outcomes (9.3% vs. 11.4%, P < .001 and 16.5% vs. 18.8%, P < .001; Fig. 36.3 ).
Several observations solidified the role of clopidogrel in management of this patient population. The benefit appeared within 24 hours of presentation and was seen irrespective of baseline risk stratification. Additionally, the continuation of clopidogrel after hospitalization in this group of patients further reduced subsequent ischemic vascular events (cardiovascular death, MI, or stroke). The reduction in vascular events was independent of concomitant use of antiplatelet and antithrombotic medication, antihypertensives, lipid-lowering therapy, or coronary intervention. However, a statistically significant increase in bleeding complications was seen in patients on DAPT (major bleeding 3.7% vs. 2.7% and minor bleeding 5.1% vs. 3.4%, P ≤ .001 for both).
With most patients with NSTE-ACS being referred to coronary angiography and revascularization early in the course of their admission to the CICU, it is important to clearly define the value of clopidogrel therapy in patients undergoing PCI. The PCI CURE substudy examined whether treatment with clopidogrel plus aspirin prior to PCI reduced postprocedure ischemic complications. Patients were pretreated with aspirin and either clopidogrel or placebo. After stenting, over 80% of patients were started on open-label clopidogrel agent for 4 weeks and then resumed taking placebo or clopidogrel for an additional 8 months. In the clopidogrel arm, the primary outcome of death, MI, or urgent target vessel revascularization within 30 days was significantly reduced compared to those receiving aspirin alone (4.5% vs. 6.4%, P = .03). In patients receiving clopidogrel for at least 8 months, there were fewer events of cardiovascular death, MI, or revascularization from any cause ( P = .03) (see Fig. 36.3 ).
The loading dose of clopidogrel given early in the course of NSTE-ACS therapy has changed over time as well. The 600-mg dose has been found to inhibit platelets more rapidly and effectively than the 300-mg dose. Clinically, this may translate into fewer short-term ischemic events after PCI. Cuisset et al. demonstrated that patients who received the 600-mg loading dose of clopidogrel prior to PCI for an NSTE-ACS had fewer subsequent ischemic events (defined as cardiovascular death, acute or subacute stent thrombosis, recurrent ACS, and stroke) within 1 month when compared to those receiving a 300-mg loading dose (5% vs. 12%; P = .02). These findings were subsequently confirmed in the Antiplatelet Therapy for Reduction of Myocardial Damage During Angioplasty 2 (ARMYDA-2) trial, in which the higher loading dose resulted in a reduced incidence and size of periprocedural MI.
The AHA/ACC guidelines for management of NSTE-ACS give clopidogrel a class IB indication in patients who cannot take aspirin. With an early invasive strategy, a preprocedural loading and maintenance dose of clopidogrel or ticagrelor should be given (class IB). If an ischemia-guided strategy is taken and no intervention is performed, clopidogrel or ticagrelor is recommended for up to 12 months (class IB), although ticagrelor is preferred. If intervention is performed, the patient should receive clopidogrel, prasugrel, or ticagrelor for at least 12 months (class IB). Ticagrelor is preferred over clopidogrel in early invasive and initial ischemia-guided strategies (class IIa).
Prasugrel.
The second ADP receptor antagonist to gain U.S. Food and Drug Administration (FDA) approval was prasugrel. Like clopidogrel, prasugrel is a thienopyridine prodrug that must be converted into its active metabolite in order to irreversibly bind to the P2Y 12 receptor. The loading dose of prasugrel (60 mg) appears more potent than 600 mg of clopidogrel. Similarly, the maintenance dose of prasugrel (10 mg) maintains a higher degree of platelet inhibition than a daily dose of 150 mg of clopidogrel.
The largest clinical investigation to date to examine prasugrel was the Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel–Thrombolysis in Myocardial Infarction (TRITON–TIMI) 38. In that study, 13,608 patients with moderate-to-high-risk ACS scheduled for PCI were randomized to receive prasugrel (a 60-mg loading dose and a 10-mg daily maintenance dose) or clopidogrel (a 300-mg loading dose and a 75-mg daily maintenance dose) for 6 to 15 months. All patients received aspirin in addition to the thienopyridine agent. The primary efficacy endpoint was a combined endpoint of cardiovascular death, nonfatal MI, or nonfatal stroke, while the key safety endpoint was major bleeding. There was a statistically significant 19% reduction in the primary endpoint (cardiovascular death, nonfatal MI, or stroke) in the prasugrel group ( Table 36.1 ). The use of prasugrel was also associated with significant reduction in other ischemic complications, such as MI, urgent target-vessel revascularization, and stent thrombosis.
TABLE 36.1
Pivotal Randomized Trials Comparing Efficacy and Safety of Newer P2Y 12 Inhibitors to Clopidogrel
| TRITON Trial , a | PLATO Trial , b | |||||||
|---|---|---|---|---|---|---|---|---|
| Prasugrel | Clopidogrel | HR (95% Cl) | P Value | Ticagrelor | Clopidogrel | HR (95% Cl) | P value | |
| Efficacy Endpoints | ||||||||
| Composite primary endpoint c (CV death, MI, or stroke) | 9.9% | 12.1% | 0.81 (0.73–0.90) | <.001 | 9.8% | 11.7% | 0.84 (0.77–0.92) | <.001 |
| All-cause mortality | 3.0% | 3.2% | 0.95 (0.78–1.16) | .64 | 4.5% | 5.9% | 0.78 (0.69–0.89) | <.001 |
| Stent thrombosis (definite or probable) | 1.1% | 2.4% | 0.48 (0.36–0.64) | <.001 | 2.2% | 2.9% | 0.75 (0.59–0.95) | .02 |
| Safety Endpoints d | ||||||||
| Non-CABG major bleeding (TIMI criteria) | 2.4% | 1.8% | 1.32 (1.03–1.68) | .03 | 2.8% | 2.2% | 1.25 (1.03–1.53) | .03 |
| CABG-related major bleeding (TIMI criteria) | 13.4% | 3.2% | 4.73 (1.9–11.82) | <.001 | 5.3% | 5.8% | 0.94 (0.82–1.07) | .32 |
| Intracranial bleeding | 0.3% | 0.3% | 1.12 (0.58–2.15) | .74 | 0.3% | 0.2% | 1.87 (0.98–3.58) | .06 |
| Major or minor bleeding (TIMI criteria) | 5.0% | 3.8% | 1.31 (1.11–1.56) | .002 | 11.4% | 10.9% | 1.05 (0.96–1.15) | .33 |
CABG, Coronary artery bypass graft; CI, confidence interval; CV, cardiovascular; HR, hazard ratio; MI, myocardial infarction; PCI, percutaneous coronary intervention; TIMI, Thrombolysis in Myocardial Infarction.
a More than 13,000 patients with ACS undergoing PCI, randomized in a 1:1 blinded fashion.
b More than 18,000 patients with ACS, randomized in a 1:1 blinded fashion.
c At 15 months of follow-up for TRITON but only at 12 months for PLATO.
d Selected bleeding endpoints reported in both trials using TIMI criteria to facilitate comparison and perspective.
However, prasugrel therapy was associated with increased bleeding complications. Major bleeding not related to coronary artery bypass graft (CABG) was more frequent with prasugrel compared to clopidogrel therapy (2.4% vs. 1.8%, HR, 1.32; 95% CI, 1.03–1.68; P = .03). Even more concerning, a similar statistically significant increase was noted in fatal bleeding (0.4% vs. 0.1%; P = .002). Efforts were then made to identify subgroups of patients in whom the harm caused by increased bleeding complications supersedes the benefit of reduced ischemic events. Patients who had a previous stroke or TIA had net harm from prasugrel (HR, 1.54; 95% CI, 1.02–2.32; P = .04), patients greater than or equal to 75 years of age or weighing less than 60 kg had no net benefit from prasugrel (HR, 0.99; 95% CI, 0.81–1.21; P = .92 and 1.03; 95% CI, 0.69–1.53; P = .89, respectively). Accordingly, prasugrel is contraindicated in patients with previous history of stroke or TIA (class III) and not recommended for those age 75 years or older or who weigh 60 kg or less (FDA black box warning).
It is important to note that the TRITON trial examined the role of prasugrel as an adjunct to an early invasive strategy and thus was given at the time of PCI. It was unclear if the reduction in ischemic events noted in TRITON can be replicated in patients treated medically or using a selective ischemia-guided strategy. For that purpose, The Targeted Platelet Inhibition to Clarify the Optimal Strategy to Medically Manage Acute Coronary Syndromes (TRILOGY ACS) study was conducted, a randomized, double-blind trial of approximately 10,300 patients with high-risk NSTE-ACS who were intended to undergo medical therapy. Patients were randomized to clopidogrel versus prasugrel, with aspirin as background antiplatelet therapy in both arms. More than 72% of patients were younger than 75 years and received prasugrel 10 mg/day, but those older than 75 years or who weighed less than 60 kg were treated with 5 mg daily. At 17 months, the reduction of the primary endpoint (cardiovascular death, MI, or stroke) in the prasugrel arm was not statistically significant (13.9% vs. 16.0%; HR 0.91; 95% CI, 0.79–1.05; P = .21). The trial concluded that among patients with NSTE-ACS treated medically, prasugrel did not significantly reduce the frequency of adverse ischemic events compared with clopidogrel with similar risks of bleeding.
Ticagrelor.
Ticagrelor is an ADP P2Y 12 receptor inhibitor. Unlike clopidogrel and prasugrel, ticagrelor is a reversible, direct-acting agent. Ticagrelor is a more potent platelet inhibitor with a more rapid onset of action than clopidogrel.
The role of ticagrelor in contemporary therapy of ACS was established in the Study of Platelet Inhibition and Patient Outcomes (PLATO) trial, a multicenter, double-blind, randomized trial that compared ticagrelor to clopidogrel therapy with background aspirin. The study compared ticagrelor (180 mg loading dose, 90 mg twice daily thereafter) and clopidogrel (300 to 600 mg loading dose, 75 mg daily thereafter) for the prevention of cardiovascular events in 18,624 patients admitted with ACS, with or without ST segment elevation. The composite primary endpoint (cardiovascular death, MI, or stroke at 12 months) occurred in 9.8% of patients receiving ticagrelor compared to 11.7% in the clopidogrel group (HR, 0.84; 95% CI, 0.77–0.92; P < .001) (see Table 36.1 ). It is important to note that cardiovascular death and all-cause death were reduced in the ticagrelor group (4.0% vs. 5.1%, P = .001 and 4.5% vs. 5.9%, P < .001, respectively). No significant difference in the rates of major bleeding was found between the ticagrelor and clopidogrel groups (11.6% and 11.2%, respectively; P = .43). However, ticagrelor was associated with a higher rate of major bleeding not related to CABG (4.5% vs. 3.8%; P = .03). There was also a treatment difference noted by region and North Americans appeared to have less of a benefit from ticagrelor than Europeans. This was later attributed to a higher dose of aspirin therapy in the North American patients.
These findings led to the recommendation to give a daily maintenance dose of 81 mg of aspirin when ticagrelor is being coadministered. In light of the PLATO trial, ticagrelor was given a class IIA recommendation in the 2014 NSTE-ACS American guidelines and a class IA recommendation in the European guidelines and in the subsequent ACC/AHA update on DAPT.
Dyspnea was more common in the ticagrelor group than the clopidogrel group (13.8% vs. 7.8%), but this only led to discontinuation of the drug in 0.9% of patients compared to 0.1% in the clopidogrel group. The dyspnea is thought to be an adenosine-mediated effect that was mild and short lived. Most patients had resolution of symptoms if they continued on therapy. Bradycardia was slightly more common in the ticagrelor group (4.4% vs. 4%), but there was no statistical difference in pacemaker insertion, syncope, or heart block between the two groups.
Cangrelor.
Cangrelor is a rapid-acting, reversible, nonthienopyridine adenosine triphosphate (ATP) analogue that is administered intravenously (IV) to block the ADP receptor P2Y 12 . There were three large-scale trials to study the efficacy and safety of cangrelor in the setting of ACS: Cangrelor versus Standard Therapy to Achieve Optimal Management of Platelet Inhibition (CHAMPION) PCI, CHAMPION PLATFORM, and CHAMPION PHOENIX.
CHAMPION PCI was conducted on more than 8000 ACS patients undergoing PCI to compare two antiplatelet strategies: cangrelor (30 µg/kg IV bolus given before PCI and followed by an infusion of 4 µg/kg per minute for 2 to 4 hours) and clopidogrel 600 mg orally prior to PCI. The primary endpoint (a composite of death, MI, or ischemia-driven revascularization at 48 hours) was not significantly different between cangrelor and clopidogrel arms (7.5% vs. 7.1%; OR, 1.05; 95% CI, 0.88–1.24; P = .59). There was no difference in major bleeding according to the Thrombolysis in Myocardial Infarction (TIMI) or Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO) criteria.
CHAMPION PLATFORM was a double-blind, placebo-controlled study that randomized 5362 patients undergoing PCI to either cangrelor or placebo at the time of PCI, followed by clopidogrel 600 mg. The primary endpoint was similar and enrollment was stopped when an interim analysis concluded that the trial would be unlikely to show superiority (primary endpoint occurred in 7.0% of the cangrelor patients and 8.0% of the placebo patients, P = .17). There was, however, a statistically significant decrease in two prespecified secondary endpoints with cangrelor versus placebo: stent thrombosis (0.2% vs. 0.6%; OR, 0.31; 95% CI, 0.11–0.85; P = .02) and all-cause death (0.2% vs. 0.7%; OR, 0.33; 95% CI, 0.13–0.83; P = .02).
The latest CHAMPION PHOENIX trial included 11,145 patients undergoing urgent or elective PCI. They received IV cangrelor or a loading dose of 600 mg or 300 mg of clopidogrel. The primary endpoint was the composite of death, MI, ischemia-driven revascularization, or stent thrombosis at 48 hours, which occurred in 4.7% of the cangrelor group and 5.9% in the clopidogrel group (adjusted OR, 0.78; 95% CI, 0.66–0.93; P = .005). The key secondary endpoint was stent thrombosis at 48 hours, which occurred in 0.8% of the cangrelor group and 1.4% in the clopidogrel group (OR, 0.62; 95% CI, 0.43–0.9; P = .01). The primary safety endpoint of severe bleeding at 48 hours occurred in 0.16% of the cangrelor group and 0.11% of the clopidogrel group (OR, 1.5; 95% CI, 0.53–4.22; P = .44). These findings led to the conclusion that cangrelor significantly reduced the rate of ischemic events, including stent thrombosis, during urgent or elective PCI, with no significant increase in severe bleeding.
A pooled analysis of patient-level data from the three CHAMPION trials compared cangrelor with clopidogrel or placebo to assess its effects on thrombotic complications during and after PCI. The use of cangrelor reduced the odds of death, MI, and ischemia-driven revascularization at 48 hours (3.6% for cangrelor vs. 4.4% for the control group, P = .0014). Stent thrombosis was decreased from 0.8% in the control group to 0.5% in the cangrelor group ( P = .0008). There was no difference in the primary safety outcome of GUSTO severe or life-threatening bleeding (0.2% in both groups), but cangrelor did cause and increase in GUSTO mild bleeding (16.8% vs. 13%, P < .0001). Currently, there are no ACC/AHA guideline recommendations for the use of cangrelor in any setting.
Vorapaxar
Vorapaxar is an oral protease-activated receptor-1 (PAR-1) antagonist that inhibits thrombin-induced platelet activation. Thrombin activates platelets through two PARs, PAR-1 and PAR-4, and stimulates a more rapid platelet activation response. Preclinical models showed that selective PAR-1 inhibition resulted in potent reduction in thrombin-induced platelet aggregation and preserved primary hemostatic function.
The Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome (TRACER) trial was a multinational, double-blind, randomized trial that compared vorapaxar (loading dose of 40 mg and daily maintenance dose of 2.5 mg) with placebo in 12,944 patients who had NSTE-ACS. The primary endpoint (composite of cardiovascular death, MI, stroke, recurrent ischemia with rehospitalization, or urgent coronary revascularization) was reduced with vorapaxar, but the reduction did not reach statistical significance. However, a composite of cardiovascular death, MI, or stroke was significantly reduced with vorapaxar (14.7% vs. 16.4%; HR, 0.89; 95% CI, 0.81–0.98; P = .02). The trial was terminated early after a safety review showed that rates of moderate to severe bleeding and intracranial hemorrhage were significantly increased with use of vorapaxar. Given the failure to meet the primary endpoint and the increased bleeding complications, there are no indications for vorapaxar in treatment of ACS.
Glycoprotein IIb/IIIa Receptor Antagonists
Platelet aggregation depends on the GP IIb/IIIa receptor located on the surface of platelets. Often called the final common pathway, the GP IIb/IIIa receptor on the activated platelet undergoes a conformational change that allows binding of fibrinogen and vWF, which, in turn, cross-links with GP IIb/IIIa receptors on other activated platelets, promoting platelet aggregation.
The GP IIb/IIIa receptor antagonists were initially approved as adjunctive pharmacologic agents that reduce the ischemic complications of PCI, particularly in patients at high risk of abrupt closure in the prestent era. The significant success of these agents in reducing abrupt closure and periprocedural myonecrosis established the importance of aggressive platelet inhibition in reducing ischemic complications. It was only natural that these agents be tested in other clinical situations in which the activated platelets play a fundamental role, namely, ACS. It is also important to note that most of the evidence demonstrating the efficacy of IIb/IIIa inhibitors in reducing ischemic complications was accumulated prior to the routine use of clopidogrel and prior to approval of newer and more potent ticagrelor and prasugrel. The intravenous IIb/IIIa receptor antagonists available for use in the United States include abciximab, eptifibatide, and tirofiban.
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