++
Antiplatelet and antithrombotic agents (see also Chap. 41) are cornerstone therapies to help passivate the active vascular disease process and prevent thrombotic complications, including death and recurrent myocardial ischemia. Currently, a combination of ASA, a P2Y12 antagonist (clopidogrel, prasugrel, or ticagrelor), antithrombin therapy (unfractionated heparin [UFH], low-molecular-weight heparin [LMWH], fondaparinux, or bivalirudin), and in certain instances, a platelet GP IIb/IIIa receptor antagonist represents the leading effective options. The intensity and duration of treatment are tailored to individual risk, though nearly all patients should receive DAPT and an antithrombin initially.1
++
ASA irreversibly acetylates and inhibits cyclooxygenase-1 within platelets, preventing the formation of thromboxane A2, which is a potent platelet activator and vasoconstrictor. In patients with UA/NSTEMI, ASA reduces the probability of death or MI by 25% to 30%.61
++
ASA should be initiated in patients with UA/NSTEMI at a dose of 160 or 325 mg, with the first dose chewed to rapidly establish a high blood level.1 Thereafter, daily doses of 75 to 325 mg are prescribed and continued indefinitely. Data generally support a lower dose of maintenance aspirin to minimize bleeding, especially when combined with a P2Y12 inhibitor. Debate remains regarding the optimal ASA dose after coronary artery stenting; although many interventional cardiologists prefer a 325-mg dose for 1 month after stent implantation. One arm of the Clopidogrel Optimal Loading Dose Usage to Reduce Recurrent Events-Organization to Assess Strategies in Ischemic Syndromes (CURRENT)/Organization for the Assessment of Strategies for Ischemic Syndromes (OASIS) 7 trial compared high-dose (300-325 mg) versus low-dose (75-100 mg) ASA in approximately 25,000 patients with ACS (70% with UA/NSTEMI; 70% with PCI). No difference in early efficacy or safety was seen between ASA doses, including in the subgroup undergoing PCI.62 In the Study of Platelet Inhibition and Patient Outcomes (PLATO) trial, post hoc analysis of aspirin dose on outcome was performed to understand the striking difference in efficacy of ticagrelor between countries outside North America versus inside North America. A strong association between ticagrelor superiority (over clopidogrel) was found when patients received low-dose aspirin. For this reason, the NSTEMI guidelines specifically recommend low-dose aspirin be used in combination with ticagrelor when DAPT is prescribed.63 The 2015 ESC NSTEMI guidelines recommend low-dose aspirin for maintenance therapy regardless.
+++
Oral P2Y12 Inhibitors
++
Clopidogrel is a thienopyridine derivative that blocks binding of adenosine diphosphate (ADP) to the P2Y12 receptor on the platelet surface, inhibiting ADP–mediated platelet activation and aggregation by approximately 50% to 60%. Because ASA and P2Y12 antagonists inhibit platelet function via different pathways, combined use of the two drugs represents an attractive antiplatelet strategy. The Clopidogrel in Unstable Angina to Prevent Recurrent Ischemic Events (CURE) trial randomized 12,562 patients with UA/NSTEMI to ASA alone or to the combination of ASA and clopidogrel for 3 to 12 months (average, 9 months).64 The composite end point of CV death, MI, or stroke occurred in 11.5% of patients assigned to placebo versus 9.3% assigned to clopidogrel (relative risk, 0.80; P < .001). Importantly, this benefit was similar whether patients were managed with medical therapy or with coronary revascularization.65 Major bleeding was increased in the clopidogrel arm (3.7% vs 2.7%; P = .003). Bleeding was notably increased in patients who underwent CABG surgery within the first 5 days of stopping clopidogrel.64
++
In a subgroup analysis of CURE consisting of the 2658 patients who underwent PCI after UA/NSTEMI, CV death or MI was reduced by 31% in the clopidogrel plus ASA group versus the ASA alone group (P = .002).66 In the Clopidogrel for the Reduction of Events During Observation (CREDO) trial,67 2116 patients scheduled to undergo PCI were randomized to clopidogrel or placebo in addition to ASA. A 27% reduction in the composite outcome of CV death, MI, or stroke was reported in patients treated with combination clopidogrel and ASA for 1 year versus those treated for 1 month (8.5% vs 11.5%; P = .02). As with CURE, there was an increased risk of major bleeding in the combination-therapy group (8.8% vs 6.7%; P = .07), but this excess was largely restricted to patients who underwent CABG. Thus, elective CABG (and other major surgery) should be delayed for at least 5 days after the last dose of clopidogrel. In some practices, therefore, physicians have preferred to withhold clopidogrel (as well as other thienopyridines) until the coronary anatomy is known, to be certain that CABG will not be delayed if needed.
++
It is important to recognize that the PCI-CURE and CREDO trials were performed before newer DESs were available. DESs inhibit vascular smooth muscle cell proliferation and prevent in-stent restenosis; however, they also delay regrowth of the protective vascular endothelium, which results in a longer time period during which patients are at risk for stent thrombosis.68 Because stent thrombosis has been observed up to and even beyond 1 year following placement of a first-generation DES, current guideline recommend at least 1 year of DAPT after placement of a DES.69 Patients who, for any reason, are poor candidates for long-term clopidogrel, including those who are planned for major surgery in the near future (in the next few months after the PCI procedure), should not receive a first-generation DES. Some data suggest lower rates of major adverse CV events in those treated with prolonged DAPT compared to treatment for 1 year.70 Several meta-analyses have been performed comparing different durations of DAPT following DES. Most include approximately 30,000 patients and report lower bleeding rates and lower overall mortality with shorter-duration DAPT (6-12 months), but with lower rates of stent thrombosis and MI with prolonged DAPT (> 12 months).71,72,73,74 The 2014 AHA/ACC NSTEMI guidelines recommend DAPT for up to 12 months irrespective of treatment strategy.
++
In addition to the ASA dose comparison described earlier, the CURRENT/OASIS 7 trial compared standard-dose (300-mg load; 75 mg/d) clopidogrel versus “double-dose” clopidogrel (600-mg load; 150 mg/d × 7 days; then 75 mg/d). In the overall study population, no difference was observed in the primary end point of CV death, MI, or stroke at 30 days; however, a significant interaction was observed with PCI, such that in the subgroup undergoing PCI, the higher dose strategy resulted in a 15% reduction in the primary end point and a 29% reduction in stent thrombosis. In contrast, among patients not undergoing PCI, there was a nonsignificant trend toward worse outcomes in the higher dose clopidogrel arm. Bleeding rates were increased significantly in the high-dose clopidogrel arm, both in the overall population as well as the PCI subgroup.62 The OASIS 7 results are consistent with multiple studies evaluating platelet function outcomes in supporting use of a 600-mg clopidogrel dose before PCI among ACS patients.
++
All thienopyridines are prodrugs that require more than one step of metabolism before achieving their antiplatelet effects. Clopidogrel has complex pharmacokinetic and pharmacodynamic properties that result in widely variable levels of the circulating active metabolite. The in vitro response to clopidogrel, as assessed by inhibition of ADP-mediated platelet aggregation, is heterogeneous with a normal (bell-shaped) distribution of response among individuals. After absorption, clopidogrel requires a two-step oxidation by the hepatic cytochrome P450 (CYP) system to generate an active metabolite. Multiple CYP enzymes are involved (CYP3A4, CYP3A5, CYP2C9, CYP1A2, CYP2B6, and CYP2C19), several of which have important genetic variants and are affected by concomitant medications. The clinical relevance of these findings is likely muted by the multiple other factors affecting outcome and the benefit of concomitant medications such as proton pump inhibitors. For example, initial studies suggested an in vitro interference of antiplatelet effects of clopidogrel by omeprazole,75 yet clinical trials have not generally detected a conclusive signal to suggest concomitant omeprazole use in clopidogrel-treated patients should be avoided, especially because a lower rate of gastrointestinal bleeding has been noted.76 Use of other proton pump inhibitors without such in vitro interaction may be considered77 if concerns remain.
++
Although response variability to clopidogrel has emerged as a potentially important issue in recent years, the clinical implications remain controversial for several reasons. First, many studies have defined “clopidogrel resistance” on the basis of a single measurement of platelet reactivity performed on clopidogrel; however, residual platelet aggregation to ADP is determined only in part by response to clopidogrel because patient-related factors such as diabetes, smoking, and proximity to the ACS event also contribute to platelet aggregation. Second, the limitations of currently available platelet function tests are noteworthy because the available tests correlate poorly with each other and capture neither the full functionality of the platelet nor the response to clopidogrel.
++
Prasugrel is a thienopyridine that, similar to clopidogrel, requires conversion to an active metabolite to bind to the P2Y12 receptor. Prasugrel requires only a one-step hepatic metabolism with CYP3A, CYP2B6, CYP2C9, and CYP2C19. This more favorable pharmacokinetic profile translates into better pharmacodynamics with faster onset of action, more potent and irreversible platelet inhibition, and lower interindividual variability as compared to even high doses of clopidogrel. In the Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel–Thrombolysis in Myocardial Infarction (TRITON-TIMI) 38 trial,78 which enrolled 13,608 patients with STEMI or high-risk UA/NSTEMI who were scheduled to undergo PCI, prasugrel (60-mg load; then 10 mg/d) was compared with clopidogrel (300-mg load; 75 mg/d). Both drugs were initiated at the time of PCI with no pretreatment administered in advance of PCI. The primary efficacy end point—the same as was used in the CURE trial—was a composite of CV death, MI, and stroke and was reduced from 12.1% in the clopidogrel arm to 9.9% in the prasugrel arm over a median duration of 14.5 months of follow-up (HR, 0.81; 95% CI, 0.73-0.90; P < .001) (Table 39–6). This benefit was mediated by a 24% reduction in nonfatal MI without a significant effect seen on mortality or stroke rate. Two-thirds of the MI events were procedural MIs detected based on serial cardiac enzyme measurement rather than clinical recognition of symptoms and signs.
++
++
Importantly, definite or probable stent thrombosis (per the Academic Research Consortium definition) was reduced from 2.4% with clopidogrel to 1.1% with prasugrel (P < .001).78 Interestingly, most of the stent thromboses were observed within the first 30 days after randomization, regardless of whether DES or bare-metal stents were used, a finding that highlights the relatively high frequency of early stent thrombosis after ACS, in distinction to much lower rates after elective PCI. Interpreting the magnitude of benefit on stent thrombosis and procedural MI is challenging, given that clopidogrel was not administered before catheterization and the dose used was only 300 mg.
++
Bleeding rates were significantly increased in the prasugrel arm of the trial, including an increase from 1.8% to 2.4% in TIMI major bleeding (HR, 1.32; 95% CI, 1.03-1.68; P = .03) as well as notable increases in life-threatening and fatal bleeding. Patients older than age 75 years or with body weight below 60 kg were at particular risk for bleeding, such that the increase in bleeding negated any efficacy advantage. Those with prior stroke or transient ischemic attack had a prohibitive increase in bleeding, and a net harm was identified; in such patients, prasugrel is contraindicated. Among individuals who underwent CABG after at least one dose of study drug, major bleeding rates were 13.4% in the prasugrel arm and 3.2% in the clopidogrel arm (P < .0001).78 Thus, although some institutions have become comfortable performing CABG after clopidogrel administration, such a strategy would not be prudent after using prasugrel given the much higher rates of surgical bleeding anticipated.
++
Ticagrelor is a nonthienopyridine, direct-acting, and reversible oral antagonist of the P2Y12 receptor. This agent does not require conversion to an active metabolite and provides more rapid onset of action and a more potent and predictable antiplatelet response than clopidogrel. Ticagrelor achieves rapid antiplatelet activity after oral loading, with therapeutic activity observed within 30 minutes and near full activity at 2 hours.79
++
In PLATO,80 ticagrelor (180-mg loading dose; 90 mg twice daily) was compared with clopidogrel (300- to 600-mg loading dose; 75 mg/d) in 18,624 patients with STEMI or UA/NSTEMI, including patients managed with and without PCI. At the end of the 12-month follow-up period, the primary end point (CV death, MI, and stroke) was reduced from 11.7% in the clopidogrel arm to 9.8% in the ticagrelor arm (HR, 0.84; 95% CI, 0.77-0.92; P < .001) (see Table 39–6). In addition to significant reductions in MI alone, there was also a significant 21% relative risk reduction in vascular mortality and a 22% reduction in total mortality (5.9% vs 4.5%; P < .001). Similar to the CURRENT/OASIS 7 and TRITON-TIMI 38 trials, stent thrombosis was reduced significantly with the more potent oral antiplatelet regimen. Also consistent with prior studies, an increase in non-CABG major bleeding was observed in the ticagrelor arm (4.5% vs 3.8%; P = .03); however, bleeding rates after CABG were lower with ticagrelor, likely because of the shorter half-life and more rapid reversibility of the drug.80
++
In contrast to TRITON-TIMI 38, clopidogrel pretreatment was permitted in PLATO; however, only 27% of patients received 600 mg of clopidogrel within the first 24 hours after their ACS event, again raising questions of what the comparative benefit of this novel compound would be versus a more aggressive clopidogrel strategy.
++
Several unique side effects have been observed with ticagrelor, which may be adenosine mediated, and contribute to a slightly higher rate of discontinuation of ticagrelor than clopidogrel. These include dyspnea, which tends to occur early after starting the drug in 10% to 15% of treated patients but is not associated with evidence of heart failure and usually lasts less than a week. Ventricular pauses also occurred more commonly in the ticagrelor group early after treatment initiation, but these also tended to decrease in frequency over time, were rarely symptomatic, and were not associated with clinically significant bradycardia. It should be noted that although reversible, this drug still has residual antiplatelet effects for up to 5 days among individuals on chronic therapy.79
++
Clopidogrel, prasugrel, and ticagrelor each receive a Class I recommendation in the current AHA/ACC NSTEMI guidelines, with a preference for ticagrelor over clopidogrel for patients managed with an early invasive or ischemia-guided strategy (Class IIa).1
+++
Glycoprotein IIb/IIIa Inhibitors
++
When the platelet is activated, the GP IIb/IIIa receptors on the platelet surface increase in number and demonstrate improved binding affinity for fibrinogen. The binding of fibrinogen to receptors on different platelets results in aggregation. The platelet GP IIb/IIIa receptor antagonists act by occupying the receptors sites, thus opposing fibrinogen and von Willebrand factor binding. The occupancy of 80% or more of the receptor sites and inhibition of platelet aggregation to ADP by 80% or more results in potent antiplatelet effects. The various GP IIb/IIIa antagonists, however, possess significantly different pharmacokinetic and pharmacodynamic properties (see Chap. 41). The role of GP IIb/IIIa inhibitors in the contemporary treatment of patients with ACS continues to undergo a reappraisal, and overall usage has decreased significantly in recent years. The main reasons for the decreased utilization stems from lack of benefit evidenced from pretreatment versus in-lab provisional use and the introduction of rapidly acting, potent oral antiplatelet agents. For these reasons, the current AHA/ACC NSTEMI guidelines give GP IIb/IIIa inhibitors a Class IIb recommendation when used with DAPT in an early invasive approach.
+++
Adjunctive Glycoprotein IIb/IIIa Inhibitor Use During Percutaneous Coronary Intervention
++
The efficacy of GP IIb/IIIa antagonists during PCI has been documented in numerous trials, with particular benefit seen for patients with NSTEMI. In many of the earlier trials, however, high-dose clopidogrel loading had not occurred. Subsequently, the Intracoronary Stenting and Antithrombotic Regimen: Rapid Early Action for Coronary Treatment (ISAR-REACT)-2 study compared abciximab versus placebo immediately before PCI in 2022 patients with UA/NSTEMI who were treated with ASA and 600 mg of clopidogrel. Abciximab reduced the primary end point of death or MI by 25% (P = .03). This benefit was restricted to patients with elevated troponin values.81
+++
Comparison of Upstream Versus Delayed Glycoprotein IIb/IIIa Inhibitor Use
++
Two recent trials have compared routine upstream versus delayed selective GP IIb/IIIa inhibitor use in high-risk patients with UA/NSTEMI. In the Acute Catheterization and Urgent Intervention Triage Strategy (ACUITY) Timing trial, 9207 patients assigned to receive a GP IIb/IIIa inhibitor in the primary ACUITY randomization were randomized subsequently in a 2 × 2 factorial design to routine upstream GP IIb/IIIa initiation or deferred selective therapy started in the catheterization laboratory.82 In the upstream arm, 98.3% of patients received GP IIb/III inhibitors versus 55.7% in the delayed arm. At 30 days, the composite ischemia outcome was not significantly different between the two arms, but rates of major bleeding were significantly higher in the upstream GP IIb/IIIa inhibitor arm. A major limitation of this study was that in the early upstream arm, GP IIb/IIIa inhibitors were only started an average of 4 hours before PCI.82
++
The Early Glycoprotein IIb/IIIa Inhibition in Non–ST-Segment Elevation Acute Coronary Syndrome (EARLY ACS) trial also compared a strategy of early, routine GP IIb/IIIa inhibition (with eptifibatide) versus a strategy of delayed provisional use among 9492 patients with NSTE-ACS who were planned for invasive therapy.83 Early ACS required an infusion of 12 hours or more before PCI in the upstream eptifibatide arm, and patients received an average of 21 hours of therapy before PCI compared with 4 hours in ACUITY Timing. Provisional GP IIb/IIIa inhibitor at the time of PCI was used in only 26% of patients. Compared with the delayed, provisional strategy, upstream eptifibatide did not result in a significant reduction in the primary end point of death, MI, urgent revascularization for ischemia, or a thrombotic complication during PCI at 4 days (9.3% vs 10.0%; odds ratio, 0.92; P = .23). Moreover, no significant difference was observed in the secondary end point of death or MI at 30 days. No benefit was observed in key subgroups, including those who were troponin positive and those not loaded with clopidogrel. In contrast, rates of TIMI major (2.6% vs 1.8%; P = .015) and minor (3.6% vs 1.7%, P <.001) bleeding were significantly increased in the early upstream eptifibatide arm.83
++
Taken together, these findings suggest that an appropriate strategy is to defer GP IIb/IIIa inhibitor use until the decision to perform PCI has been made and to use them selectively among high-risk patients defined clinically or angiographically. Upstream use should be restricted to patients with ongoing clinical instability and perhaps those with dynamic ST-segment changes, particularly when oral ADP receptor antagonist loading is not performed. Upstream use is no longer recommended simply on the basis of troponin elevation.