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Adjunctive Pharmacologic Therapies in Acute Myocardial Infarction
Acute myocardial infarction (MI) remains a major cause of death and disability worldwide. While advances in primary reperfusion therapy have resulted in significant reductions in morbidity and mortality among patients with acute MI, adjunctive pharmacologic therapies continue to play a vital role. The rapid initiation of adjunctive therapies in the cardiac intensive care unit (CICU) setting are indicated in the acute and convalescent phases of management to reduce adverse outcomes. These adjunctive treatments are directed at further reducing the short- and long-term risks of death, recurrent MI, angina, and congestive heart failure (CHF). They work by reducing ischemia and coronary reocclusion, limiting the loss of myocardium and myocardial function, preventing adverse ventricular remodeling, reducing the risk of arrhythmias, and slowing the progression of atherosclerosis. Empiric evidence accumulated from more than three decades of clinical trial experience has demonstrated the important benefits of certain therapies while uncovering the hazards of others, such that clinicians now have evidence-based guidance on appropriate pharmacologic management following acute MI. Reinforcing the importance of a comprehensive approach to evidence-based therapies, studies have documented that more consistent application of evidence-based therapies for patients with MI significantly improves outcomes.
Acute MI is defined as myocardial necrosis in a clinical setting consistent with acute myocardial ischemia and can be divided into ST elevation MI (STEMI, including STEMI-equivalent presentations, such as left bundle branch block) and non-ST elevation MI (NSTEMI). Acute MI is commonly the consequence of an occlusive or near-occlusive coronary thrombus at the site of an eroded or ruptured atherosclerotic plaque, the pathophysiology of which is discussed elsewhere in this book. Acute MI results in loss of myocardium, acute and potentially chronic diastolic and systolic ventricular dysfunction, and increased susceptibility to potentially fatal arrhythmias. The ultimate goal of therapy for acute MI, whether primary or adjunctive, is to preserve myocardium and myocardial geometry and function and, thereby, reduce cardiovascular morbidity and mortality. Since multiple trials of reperfusion therapy for patients with STEMI have shown a consistent reduction in mortality, the primary early management of patients with acute STEMI is aimed at the occlusive coronary thrombus, employing early reperfusion therapy using thrombolytic agents or mechanical devices. Early and successful reperfusion can interrupt the “march to necrosis” that progresses as a wave front from endocardium to epicardium with the goal of preserving the myocardium and limiting adverse ventricular remodeling. Additional evidence supports the use of adjunctive pharmacologic therapies in addition to reperfusion therapy in the management of acute MI patients. These adjunctive therapies should also be considered as alternative therapies for STEMI patients in whom thrombolytic therapy or primary percutaneous coronary intervention (PCI) are contraindicated, for widening the time window for reperfusion when therapy cannot be instituted early, for reducing reperfusion injury in patients given late reperfusion therapy, and for achieving and maintaining complete reperfusion. Specifically, the aims of adjunctive therapy are to limit consequences of ischemia or infarction, optimize healing, and reduce adverse and recurrent events. Survivors of STEMI represent a special group of patients at greater jeopardy for increased morbidity and mortality. As a result, they stand to benefit greatly from adjunctive therapies and comprehensive secondary prevention.
This chapter focuses on evidence-based adjunctive medical therapies indicated for patients with acute MI, with a predominant focus on STEMI, which is relevant for physicians managing patients during and following the CICU phase. It also discusses and summarizes recommendations from the American College of Cardiology and American Heart Association (ACC/AHA) practice guidelines for management of STEMI and non-ST elevation acute coronary syndromes (NSTE ACS).
Antiplatelet Therapy
Platelets play a critical role in thrombus formation at sites of plaque rupture or erosion; therefore inhibiting platelets plays a central role in the treatment of STEMI and NSTE ACS. The involvement of platelets in the initiation of thrombus is a multistep process of adhesion, activation, and aggregation, each step of which involves binding and activation of certain receptors and a cascade of intracellular signaling pathways ( Fig. 12.1 ). The importance of platelet inhibitors as therapeutic agents for acute MI was first highlighted by the Second International Studies of Infarct Survival (ISIS-2) trial, in which randomization to aspirin compared with placebo among patients with STEMI reduced mortality to a similar degree compared with reperfusion by streptokinase. More recent clinical trials of inhibitors of other mediators of platelet activation and aggregation—such as the P2Y 12 receptor, thrombin receptor, and the glycoprotein IIb/IIIa receptor—have reinforced the critical importance of platelet inhibition as a therapeutic target for patients with ACS. The current standard of care for treatment of patients with ACS endorses multireceptor inhibition by routine use of aspirin in combination with a P2Y 12 antagonist, a combination commonly termed dual antiplatelet therapy (DAPT).
Aspirin
One pathway that participates in the regulation of platelet activity involves the conversion of arachidonic acid to thromboxane A 2 (TXA 2 ) and other prostaglandins by the platelet cyclooxygenase (COX) enzymes, COX-1 and COX-2. Constitutive COX-1 promotes platelet aggregation, thrombosis, and vasoconstriction, and protects gastrointestinal mucosa. In contrast, inducible COX-2 is proinflammatory via prostaglandin E 2 (PGE 2 ) and antithrombotic and vasodilatory via prostaglandin I 2 (PGI 2 [prostacyclin]). Aspirin (acetylsalicylic acid) exerts antiplatelet actions through acetylation of a serine residue on COX-1 to irreversibly block the production of TXA 2 which, in turn, inhibits platelet activation and aggregation. The effect of aspirin can be detected within 30 to 40 minutes of ingestion and lasts for the life of the platelet (7 to 10 days). Low-dose aspirin appears to selectively inhibit COX-1, while higher doses inhibit both COX-1 and COX-2. Low-dose aspirin may therefore block TXA 2 production while sparing PGI 2 synthesis.
The efficacy of aspirin in acute STEMI was established in the randomized ISIS-2 trial, which used a 2 × 2 factorial design to assess the effects of a 1-hour intravenous infusion of streptokinase (1.5 million U) or oral aspirin (160 mg) or both in patients presenting within 24 hours of the onset of symptoms. At 5 weeks, aspirin reduced nonfatal reinfarction by 50%, nonfatal stroke by 46%, total cardiovascular mortality by 23% (absolute risk reduction of 2.4%) and the risk of any vascular event by 23%. Reduction of cardiovascular mortality was enhanced by the combination of antiplatelet and fibrinolytic therapy; cardiovascular mortality was decreased by 25% with streptokinase alone and by 42% with streptokinase and aspirin combined (absolute risk reduction of 5.2%), indicating that low-dose aspirin alone was as effective as streptokinase and that the combination was synergistic. Aspirin therapy also appeared to reduce the rate of reocclusion. Patients taking aspirin had fewer cardiac arrests, but slightly more minor bleeding. Aspirin did not increase the risk of cardiac rupture or bleeding requiring transfusion. A subsequent meta-analysis of MI trials using aspirin and the thrombolytic agents streptokinase and alteplase showed that aspirin reduces coronary reocclusion and recurrent ischemic events.
Aspirin is generally well tolerated, but its use has been associated with an increased risk of bleeding, including serious gastrointestinal bleeding and rare intracranial (including intracerebral) hemorrhage. Adverse bleeding events appear more frequent at higher doses (>100 mg/day). When aspirin is combined with other antiplatelet therapy, such as P2Y 12 antagonists, the risk of bleeding is increased. Results from the Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) trial suggest there is an interaction between the dose of aspirin and the risk of bleeding with combined aspirin plus clopidogrel such that the risk was mitigated by use of low-dose aspirin (<100 mg). For secondary prevention, the absolute benefits of aspirin are considered to far outweigh the risk of major bleeding ; collective evidence supports low-dose aspirin (75 to 81 mg) for long-term use.
Some patients are unable to tolerate aspirin owing to hypersensitivity from one of three types of reactions: respiratory sensitivity, cutaneous sensitivity, and systemic sensitivity. Respiratory sensitivity has been designated aspirin-exacerbated respiratory disease (AERD); patients with AERD often manifest Samter's triad of asthma, aspirin sensitivity, and rhinitis/nasal polyps. Aspirin ingestion may precipitate an asthma exacerbation in patients with AERD; thus, a history of moderate or severe asthma can be considered a significant risk factor for AERD. Cutaneous reactions to aspirin consist of urticaria, which can occur alone or simultaneously with angioedema. Systemic sensitivity to aspirin results in an anaphylactoid reaction, characterized by hypotension, swelling, laryngeal edema, generalized pruritus, tachypnea, and obtundation. When angioedema is accompanied by hypotension, it is generally considered an anaphylactoid reaction rather than a cutaneous reaction. Patients with respiratory or cutaneous hypersensitivity to aspirin may be candidates for aspirin desensitization ; patients with aspirin allergy presenting with ACS should undergo desensitization, if at all feasible. Aspirin desensitization is not feasible for individuals known to have an anaphylactoid response. For patients with irremediable intolerance to aspirin, use of another antiplatelet agent, such as a P2Y 12 antagonist, is recommended.
Aspirin is also contraindicated in patients with active bleeding or with high-risk bleeding conditions (e.g., retinal hemorrhage, active peptic ulcer, other serious gastrointestinal or urogenital bleeding, hemophilia, and untreated severe hypertension). In patients with prior gastrointestinal bleeding attributed to peptic ulcer disease, addition of a proton pump inhibitor (PPI) to low-dose aspirin has been shown to reduce the risk of recurrent bleeding. Based on these results and evidence of the large benefit of aspirin after MI, aspirin combined with a PPI should be continued if possible, unless bleeding is life threatening or cannot be otherwise controlled.
Recommendations
Given the robust evidence of efficacy and safety, aspirin should be administered as soon as possible as adjunctive therapy to all ACS patients without known intolerance, including patients with STEMI, NSTEMI, and unstable angina. On presentation, STEMI patients should be treated with 162 to 325 mg of aspirin followed by 81 mg daily indefinitely. Non–enteric-coated aspirin should be used initially and chewed to ensure rapid absorption. While the dose of aspirin used for long-term maintenance therapy for secondary prevention has varied across studies, evidence has accrued that low doses appear to be as effective as higher doses, yet safer. A meta-analysis that included over 190,000 patients in randomized trials reported that, compared with higher doses, doses of aspirin less than 100 mg daily provided comparable efficacy with lower bleeding rates. More recently, an analysis of patient outcomes in the Treatment with ADP Receptor Inhibitors: Longitudinal Assessment of Treatment Patterns and Events After Acute Coronary Syndrome (TRANSLATE-ACS) study showed that even among MI patients treated with PCI including stent implantation, low-dose (81 mg) aspirin was associated with similar rates of adverse ischemic events but lower risk of bleeding compared with higher-dose (325 mg) aspirin. Currently, recommendations endorse low-dose aspirin daily indefinitely for patients following MI, whether or not they have undergone PCI with stent implantation.
Pericarditis is common in STEMI patients not treated with reperfusion, although its incidence has diminished in the era of rapid reperfusion. Its timing coincides with the subacute phase during healing. Successful early reperfusion attenuates transmural extension and explains why pericarditis is rare in the reperfusion era. Although nonsteroidal antiinflammatory drugs (NSAIDs), such as ibuprofen and indomethacin, and corticosteroids have been effective for pericarditis, they can cause infarct expansion, thinning, and cardiac rupture ; thus they should be avoided or used only as a last resort. High-dose aspirin (650 mg every 4–6 hours) may be used for pain control and antiinflammatory effects. Alternatively, colchicine may be used. Short-term corticosteroids and NSAIDs may be used with extreme caution. Ibuprofen should not be used because it attenuates the antiplatelet effect of aspirin and may cause infarct thinning.
P2Y 12 Platelet Antagonists
Despite COX inhibition by aspirin, platelet activation can continue through TXA 2 -independent pathways, leading to platelet aggregation and thrombus formation, suggesting that combining aspirin with other platelet inhibitors could provide added benefit. Additional agents that inhibit the platelet P2Y 12 adenosine diphosphate (ADP) receptor have been shown to have added efficacy in reducing ischemic events among patients with acute MI and DAPT: using a combination of aspirin and a P2Y 12 antagonist is currently recommended for secondary prevention for virtually all patients. The oral P2Y 12 antagonists include the thienopyridines, ticlopidine, clopidogrel, and prasugrel, which are prodrugs whose active metabolites irreversibly bind to and inhibit the P2Y 12 receptor and the direct acting, nonthienopyridine, reversible antagonist, ticagrelor ( Table 12.1 ). Ticlopidine, the oldest member of this class, was shown to reduce the risk of stent thrombosis compared with prior treatments, but owing to a risk of serious neutropenia, thrombotic thrombocytopenic purpura (TTP) and aplastic anemia, it was replaced by clopidogrel for the reduction of atherothrombotic events following stent implantation. Ticlopidine continues to have a minor role for the uncommon patient allergic to or intolerant of clopidogrel, but the availability of newer P2Y 12 antagonists has limited its current use. A parenteral short-acting reversible P2Y 12 antagonist, cangrelor, is also available for early infusion to support PCI among patients who have not been pretreated with an oral P2Y 12 antagonist (see Table 12.1 ) prior to intervention.
TABLE 12.1
Properties of Platelet P2Y 12 ADP Receptor Antagonists
| Clopidogrel | Prasugrel | Ticagrelor | Cangrelor | |
|---|---|---|---|---|
| P2Y 12 receptor blockade | Irreversible | Irreversible | Reversible | Reversible |
| Route of administration | Oral | Oral | Oral | Intravenous |
| Frequency of administration | Once daily | Once daily | Twice daily | Bolus plus infusion |
| Prodrug | Yes | Yes | No | No |
| Onset of action | 2–8 h | 30 min–4 h | 30 min–4 h | 2 min |
| Offset of action | 7–10 d | 7–10 d | 3–5 d | 30–60 min |
| Interactions with CYP-metabolized drugs | CYP2C19 | No | CYP3A4/5 | No |
| Indications for use | ACS and stable CAD undergoing PCI | ACS undergoing PCI | ACS (full spectrum) | PCI not pretreated with oral P2Y 12 antagonist |
| Loading dose | 300–600 mg | 60 mg | 180 mg | 30 µg/kg bolus |
| Maintenance dose | 75 mg daily | 10 mg daily | 90 mg twice daily | 4 µg/kg/min infusion |
ACS, Acute coronary syndrome; CAD, coronary artery disease; PCI, percutaneous coronary intervention.
Clopidogrel
Clopidogrel is an oral agent that blocks activation of platelets by irreversibly inhibiting the binding of ADP to the P2Y 12 receptor. Clopidogrel is a prodrug that is metabolized in the liver in a multistep process, predominantly though the cytochrome P450 isoform CYP2C19, to a short-lived active metabolite that binds to the ligand binding site of the P2Y 12 receptor (see Table 12.1 ). Clopidogrel has a more potent antiplatelet effect than aspirin.
In contrast to aspirin, clopidogrel produces significant platelet inhibition after 2 to 3 days, but may take 4 to 7 days to achieve its full effect, reinforcing the need for a loading dose. The onset of clopidogrel antiplatelet action is reported at 2 to 6 hours after a loading dose. The platelet-inhibiting effects persist for 7 to 10 days after therapy is stopped.
Clopidogrel monotherapy has been shown to have benefits in reducing the risk of adverse ischemic events among patients with a history of or at high risk for atherosclerotic heart disease. In the Clopidogrel versus Aspirin in patients at Risk of Ischaemic Events (CAPRIE) trial, which compared outcomes among patients with atherosclerotic vascular disease randomly assigned to clopidogrel versus aspirin, clopidogrel was modestly more effective in reducing the combined risk of ischemic stroke, MI, or vascular death. As a result, for long-term prevention, clopidogrel may be substituted for aspirin in patients with aspirin allergy or intolerance.
The effect of adding clopidogrel to aspirin in the early phase of acute coronary syndromes was studied in the landmark CURE trial. Patients presenting with NSTE ACS who received aspirin were randomly assigned to receive a loading dose of 300 mg of clopidogrel at the time of hospital admission, followed by 75 mg/day, versus placebo. The primary endpoint of cardiovascular death, MI, and stroke was reduced by 20% among patients randomized to clopidogrel plus aspirin. The benefit was observed early, with significant reductions in adverse ischemic events seen within 24 hours of clopidogrel administration, and was consistent across the spectrum of risk and regardless of treatment strategy, with significant risk reductions evident among patients receiving medical management, PCI, or coronary artery bypass graft (CABG) surgery (although clopidogrel was associated with an increase in perioperative bleeding for patients undergoing CABG).
Despite the early hazard of increased perioperative bleeding, patients in the CURE trial who were randomly assigned to clopidogrel plus aspirin and underwent CABG surgery had improved ischemic outcomes. Among patients who underwent CABG surgery, there was a 21% reduction in cardiovascular death, MI, or stroke. There was an increase in major bleeding but no significant excess of life-threatening bleeding. The investigators concluded that, overall, the benefits of starting clopidogrel on admission appeared to outweigh the risks, even among those who proceeded to CABG during the initial hospitalization.
The Clopidogrel as Adjunctive Reperfusion Therapy –Thrombolysis in Myocardial Infarction (CLARITY-TIMI) 28 study tested the effect of clopidogrel on angiographic and clinical outcome among patients younger than 75 years with STEMI who were treated with standard fibrinolytic therapy. Patients were randomly assigned to receive 300 mg of clopidogrel coincident with the fibrinolytic agent followed by 75 mg/day or placebo; angiographic infarct-related artery patency and adverse events were assessed at 2 to 8 days. The results demonstrated that the addition of clopidogrel for STEMI patients receiving fibrinolytic therapy improved the patency rate of the infarct-related artery and significantly reduced adverse ischemic events with no significant increase in bleeding complications.
The effect of the addition of clopidogrel to aspirin for patients with STEMI was further studied in the Clopidogrel and Metoprolol in Myocardial Infarction Trial/Second Chinese Cardiac Study (COMMIT/CCS-2), in which over 45,000 patients with suspected STEMI receiving aspirin 162 mg/day were randomly allocated to clopidogrel 75 mg daily (with no loading dose) or placebo. The results showed that adding clopidogrel to aspirin significantly reduced death, reinfarction, or stroke by 9% and mortality by 7%. The benefit was consistent among younger and older patients and among patients who did or did not receive fibrinolytic therapy, with no significant excess risk of fatal or cerebral bleeding.
While these studies employed clopidogrel with a loading dose of 300 mg or no loading dose, subsequent studies suggested a faster onset of action and added benefit with a higher loading dose of 600 mg, particularly among higher-risk patients undergoing PCI. In the Clopidogrel and Aspirin Optimal Dose Usage to Reduce Recurrent Events−Seventh Organization to Assess Strategies in Ischemic Syndromes (CURRENT-OASIS-7) trial, patients with acute coronary syndromes were randomly assigned to double-dose clopidogrel (600 mg on day 1, 150 mg on days 2 to 7, then 75 mg daily) versus standard dose (300 mg on day 1, then 75 mg daily). Among patients undergoing PCI, compared with standard dose, double-dose clopidogrel reduced the rate of cardiovascular death, MI, or stroke, and stent thrombosis. Major bleeding was more common with double-dose than with standard-dose clopidogrel.
The cumulative data suggest that, for clopidogrel, the recommended loading dose is 600 mg with a maintenance dose of 75 mg. Among patients with STEMI receiving fibrinolytic therapy, patients younger than 75 years should receive 300 mg followed by 75 mg daily. As discussed earlier, clopidogrel plus aspirin has been associated with significant increases in major bleeding with CABG surgery. Clopidogrel should be withheld for 5 to 7 days before surgery, if feasible.
Wide interindividual variability in the degree of inhibition of ADP-induced platelet function has been observed among patients treated with clopidogrel; so-called “high on-treatment platelet reactivity” (HPR) is reported in up to 35% of patients. The mechanisms for this variability are likely multifactorial, including drug, environmental, and genetic interactions. Clopidogrel's action depends on biotransformation to its active metabolite in the liver, largely by CYP2C19, and studies have linked the presence of CYP2C19 loss-of-function alleles, such as CYP2C19*2, with an increased risk of cardiovascular events in patients with ACS or after PCI treated with clopidogrel. As a consequence, the United States Food and Drug Administration (FDA) issued a boxed warning for clopidogrel recommending the use of other treatments for individuals known to be poor metabolizers and who have two copies of the CYP2C19 loss-of-function alleles. Studies have also suggested an increased risk of bleeding with clopidogrel among patients with CYP2C19*17 gain-of-function alleles. To date, however, there has been no firm evidence from prospective studies or retrospective studies of major trials supporting the use of genetic testing (or platelet reactivity testing) to personalize the clopidogrel dose or the decision to switch to an alternate P2Y 12 antagonist.
PPIs, such as omeprazole and esomeprazole, which are strong inhibitors of CYP2C19, are associated with decreased inhibition of platelet aggregation by clopidogrel. However, most clinical studies, including a prospective randomized trial, have not confirmed an adverse effect on clinical outcomes by PPI use among patients receiving clopidogrel. For patients receiving DAPT who are at higher risk of upper gastrointestinal bleeding, the benefit of PPI use appears to outweigh the risk, although some have advocated for the use of a PPI with weaker inhibitory effects on CYP2C19, such as pantoprazole.
Clopidogrel therapy is generally well tolerated but may be associated with adverse effects. As discussed earlier, clopidogrel combined with aspirin increases major and minor bleeding risk, both acutely and during follow-up. Clopidogrel has been associated with gastrointestinal upset and a rare incidence of thrombotic thrombocytopenic purpura. Plasma exchange should be considered if thrombotic thrombocytopenic purpura develops.
Prasugrel
Prasugrel is another thienopyridine antagonist of the platelet P2Y 12 receptor. Like clopidogrel, prasugrel is a prodrug that is metabolized into an active metabolite that irreversibly binds to and blocks the ligand binding site of the P2Y 12 receptor (see Table 12.1 ). Prasugrel is a more potent inhibitor of ADP-induced platelet aggregation than clopidogrel and, at doses recommended, inhibits greater than 80% of in vitro ADP-induced platelet aggregation. Prasugrel also has less interpatient variability in its antiplatelet effects than clopidogrel.
The efficacy of prasugrel as compared with clopidogrel on outcomes among patients with acute coronary syndromes undergoing PCI was examined in the Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel–Thrombolysis in Myocardial Infarction (TRITON-TIMI) 38 trial. In the study, patients with STEMI or high-risk NSTE ACS who had undergone coronary angiography and were to undergo planned PCI were randomly assigned to prasugrel or clopidogrel. Treatment with prasugrel resulted in a significant reduction in cardiovascular death, MI, and stroke, and stent thrombosis, but a 32% increased risk of bleeding, including fatal bleeding. In post hoc subgroup analyses, three subgroups were identified that had less net clinical benefit or even had clinical harm in the trial. These included patients with a history of stroke or transient ischemic attack (who had an increased risk of intracranial hemorrhage), the elderly (>75 years), and those with a body weight of less than 60 kg. Among patients without any of these three risk factors, treatment with prasugrel resulted in significant net clinical benefit compared with clopidogrel. The ischemic benefit of prasugrel compared with clopidogrel was particularly evident in those with diabetes and among patients with STEMI.
Prasugrel is administered as a 60-mg loading dose followed by a maintenance dose of 10 mg daily. A lower maintenance dose of 5 mg has been recommended in patients who weigh less than 60 kg or who are older than 75 years. Due to its greater antiplatelet potency and the large increase in perioperative bleeding observed in the TRITON-TIMI 38 trial with prasugrel, it is recommended that prasugrel be discontinued 7 days prior to CABG surgery.
Ticagrelor
Ticagrelor is an oral cyclopentyltriazolopyrimidine that reversibly inhibits the platelet P2Y 12 receptor (see Table 12.1 ). Unlike thienopyridines, ticagrelor is not a prodrug. It does not bind to the ADP-binding site; instead, it binds to a separate site of the P2Y 12 receptor, thereby inhibiting G-protein activation and signaling. The onset of action of ticagrelor is faster than clopidogrel, with 40% platelet inhibition in 30 minutes after dosing with a peak effect in approximately 2 hours. Ticagrelor has a plasma half-life of 8 to 12 hours. As a reversible P2Y 12 receptor inhibitor, the offset of ticagrelor action is faster than with thienopyridines.
The effect of ticagrelor compared with clopidogrel for treatment of patients with ACS was examined among 18,624 aspirin-treated patients in the Platelet Inhibition and Patient Outcomes (PLATO) study. At 1 year, patients randomly assigned to receive ticagrelor had a significant (16%) reduction in death from vascular causes, MI, or stroke. Of note, overall mortality was also reduced with ticagrelor. No significant difference in rate of major bleeding was observed between ticagrelor and clopidogrel, but ticagrelor was associated with a higher rate of major bleeding not related to CABG. Additional analyses from the PLATO study have shown that the efficacy of ticagrelor is preserved without excess bleeding hazard among the elderly, women, patients with diabetes, and patients with STEMI. Ticagrelor was generally well tolerated, but adverse effects included increased non-CABG-related bleeding, dyspnea, ventricular pauses (mostly asymptomatic), and increased serum creatinine.
Ticagrelor also has non-P2Y 12 receptor–mediated effects that include blocking the equilibrative nucleoside transporter-1, which can result in increased plasma concentrations of adenosine. The clinical significance of this observation is unknown, but adenosine has been shown to mediate in coronary vasodilation, reduction of ischemia, and reperfusion injury, along with stimulation of pulmonary vagal C fibers that can cause dyspnea. An increased incidence of dyspnea was observed in the PLATO trial among patients receiving ticagrelor (14.5%) compared with clopidogrel (8.7%). Dyspnea was considered severe in only 0.4% of patients and patients with dyspnea had no related abnormalities in pulmonary function testing. A significant interaction between the aspirin maintenance dose and the benefit of ticagrelor was observed in the PLATO trial such that the greatest reduction in ischemic events was observed with ticagrelor in combination with low-dose (< 100 mg daily) aspirin.
Ticagrelor is administered as a loading dose of 180 mg followed by a maintenance dose of 90 mg twice per day. When ticagrelor is prescribed for DAPT, the aspirin dose should be 81 mg daily. Although ticagrelor is a reversible P2Y 12 antagonist, due to the high level of platelet inhibition achieved, it is recommended that ticagrelor be withheld 5 days prior to CABG surgery.
Cangrelor
After oral administration of a loading dose of a P2Y 12 antagonist, the onset of antiplatelet activity is not immediate; the achievement of clinically effective platelet inhibition may be delayed by hours. This delay is more pronounced among patients with STEMI, in whom multiple factors may contribute to delayed gastrointestinal drug absorption. Among patients presenting with STEMI receiving loading doses of prasugrel or ticagrelor in the Rapid Activity of Platelet Inhibitor Drugs (RAPID) trial, effective levels of platelet inhibition were not observed until 4 hours after administration. Thus many patients undergoing primary PCI within minutes of presenting with STEMI may have inadequate platelet inhibition at the time of stent implantation, which may contribute to the higher risk of stent thrombosis observed in that setting. Achievement of rapid platelet inhibition by the intravenous P2Y 12 antagonist cangrelor may have particular attractiveness for use in patients with STEMI or high-risk ACS undergoing urgent PCI who have not been adequately preloaded with an oral P2Y 12 antagonist.
Cangrelor has several unique properties as an antiplatelet agent (see Table 12.1 ). It is a potent, direct-acting, rapidly reversible P2Y 12 antagonist with predictable plasma levels and linear dose-dependent receptor inhibition. An effective level (>80%) of platelet inhibition with cangrelor is achieved within minutes after start of intravenous infusion. Platelet function then recovers within 60 to 90 minutes after discontinuation of the infusion.
Cangrelor has been studied in a number of trials, the most important of which was the Cangrelor versus Standard Therapy to Achieve Optimal Management of Platelet Inhibition (CHAMPION) PHOENIX trial, in which 10,942 clopidogrel-naive patients with coronary artery disease requiring PCI for stable angina, NSTE ACS, or STEMI received a bolus and subsequent infusion of cangrelor or placebo for at least 2 hours or the duration of the procedure, whichever was longer. Patients treated with cangrelor received a loading dose of clopidogrel at the end of infusion, while patients receiving placebo received a loading dose of clopidogrel at the time of PCI procedure. Following the procedure, patients were treated with a standard maintenance dose of oral P2Y 12 inhibitor and aspirin. The composite rate of death, MI, ischemia-driven revascularization, or stent thrombosis at 48 hours was significantly lower in the cangrelor group than in the clopidogrel group and the individual rate of stent thrombosis at 48 hours was lower in the cangrelor group than in the clopidogrel group. The observed reduction of 22% in ischemic events in patients treated with cangrelor was not accompanied by a significant increase in severe bleeding or in the need for transfusions compared with patients on clopidogrel, although there was an overall increase in bleeding with cangrelor. In a notable substudy from CHAMPION PHOENIX, the improved efficacy of cangrelor compared with clopidogrel was preserved among patients 75 years of age or older, and despite a 10-fold greater risk of severe bleeding complications among patients, in comparing these older patients with younger patients, cangrelor did not increase the risk of severe bleeding compared with clopidogrel.
In light of these favorable results, cangrelor may be considered for use in patients with STEMI or high-risk ACS undergoing urgent PCI who have not been adequately preloaded with an oral P2Y 12 antagonist. Cangrelor is administered as a 30-µg/kg intravenous bolus infused over 1 minute before PCI, followed by a 4-µg/kg per minute infusion for the duration of the procedure or at least 2 hours. During infusion, cangrelor blocks binding of the active metabolites of the thienopyridines, clopidogrel, and prasugrel to the platelet P2Y 12 receptor and those active metabolites are present in blood for a relatively short interval after administration. For this reason, a loading dose of clopidogrel should be administered after cangrelor is stopped. Prasugrel loading can be administered at the end of the cangrelor infusion or up to 30 minutes before cangrelor is stopped. Because ticagrelor binds to a separate site on the P2Y 12 receptor and there is no interaction between ticagrelor and cangrelor, ticagrelor loading can be administered before or during the infusion of cangrelor.
Recommendations
Collective evidence indicates that all patients with ACS and all patients undergoing PCI with stent implantation should receive DAPT, with aspirin and a P2Y 12 antagonist, in the absence of contraindications. Aspirin should be administered immediately and the P2Y 12 antagonist should be administered as early as feasible after presentation. The selection of the P2Y 12 antagonist from among the available choices requires an assessment of multiple factors considered in the context of the available clinical trial evidence and should be individualized with attention to clinical syndrome, comorbidities, timing, and a careful assessment of ischemic risk and bleeding risk. There may also be a need to consider medication adherence and cost issues. Prasugrel is indicated for ACS patients undergoing PCI, whereas clopidogrel and ticagrelor may be considered for ACS patients with or without revascularization. Clopidogrel and ticagrelor should be withheld for 5 days and prasugrel for 7 days prior to CABG surgery. For STEMI patients undergoing primary PCI who have not been adequately pretreated with a P2Y 12 antagonist, an intravenous cangrelor infusion at the time of PCI may be considered with subsequent transition to an oral P2Y 12 antagonist. Although recent evidence suggests that the duration of DAPT may be shortened for patients whose indication for PCI is stable ischemic heart disease, a full 12 months of DAPT is recommended for patients with ACS or those undergoing PCI in the setting of ACS.
Glycoprotein IIb/IIIa Antagonists
The final common pathway of platelet aggregation involves crosslinking of activated platelets via binding of the platelet glycoprotein IIb/IIIa (GP IIb/IIIa) receptor to the divalent ligand, fibrinogen (see Fig. 12.1 ). The GP IIb/IIIa receptor is the most abundant protein on the surface of the platelet and, with platelet activation, it undergoes a conformational change exposing the receptor binding site in a high-affinity state. The GP IIb/IIIa receptor emerged as a therapeutic target to treat cardiovascular events with the isolation of monoclonal antibodies that block the binding of the receptor to fibrinogen and were shown in animal models of coronary thrombosis to improve patency rates after fibrinolysis and reduce rethrombosis.
These early studies eventually led to the clinical development of the three currently available GP IIb/IIIa antagonists, abciximab, eptifibatide, and tirofiban. These agents were studied extensively in patients with ACS and patients undergoing PCI, where they were generally shown to reduce adverse ischemic outcomes with an increase in bleeding complications. Notably, the evidence supporting the use of intravenous GP IIb/IIIa receptor antagonists in patients with ACS was established before the common use of oral DAPT.
Abciximab
The humanized chimeric monoclonal antibody, abciximab, binds to the GP IIb/IIIa receptor with high avidity after intravenous administration. The Evaluation of 7E3 for the Prevention of Ischaemic Complications (EPIC), Evaluation in PTCA to Improve Long-Term Outcome with Abciximab GP IIb/IIIa Blockade (EPILOG) and Evaluation of Platelet IIb/IIIa Inhibition for Stenting (EPISTENT) trials showed that administration of abciximab as a bolus followed by a 12-hour infusion significantly reduced the incidence of adverse ischemic events among patients undergoing PCI, a benefit that seemed enhanced among troponin-positive ACS patients. A meta-analysis of trials of abciximab use during primary PCI for STEMI reported that abciximab was associated with significant reductions in mortality and recurrent MI. Nevertheless, abciximab has been associated with significantly increased rates of bleeding, raising questions regarding the benefit and safety of abciximab in the contemporary era when patients are commonly pretreated with a P2Y 12 antagonist. However, abciximab may be useful as adjunctive therapy to reduce acute ischemic events among select high-risk patients undergoing primary PCI with stenting or as a provisional “bail-out” agent for thrombotic complications during PCI. Of note, abciximab is not indicated for upstream use in patients with NSTE ACS.
Tirofiban
Tirofiban is a synthetic, nonpeptide, small molecule inhibitor of the GP IIb/IIIa receptor on platelets. In the Platelet Receptor Inhibition in Ischemic Syndrome Management in Patients Limited by Unstable Signs and Symptoms (PRISM-PLUS) trial, upstream intravenous tirofiban reduced adverse ischemic events, both prior to and following revascularization procedures in patients with NSTE ACS. Tirofiban is indicated for reducing thrombotic complications for patients with NSTE ACS. In early PCI trials with tirofiban, outcomes were not significantly improved by tirofiban but there was concern that dosing was inadequate to achieve optimal platelet inhibition. A higher-dose regimen was developed and tested, with potentially improved outcomes ; the higher-dose regimen is recommended in practice guidelines for operators choosing to use tirofiban to support primary PCI.
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