Acute Myocardial Infarction: Adjunctive Pharmacologic Therapies

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, whereas 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 assessed the effects of a 1-hour intravenous infusion of streptokinase (1.5 million U) or oral aspirin (160 mg) or both in patients within 24 hours of symptoms.

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  At 5 weeks, aspirin reduced total cardiovascular mortality by 23% (absolute risk reduction of 2.4%).

Aspirin is generally well tolerated, but has an increased risk of bleeding, more frequent at higher doses (e.g. aspirin dose above 100 mg per 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 (drug dose is a range e.g. 75-81 mg per day) for long-term use.

Some patients are unable to tolerate aspirin owing to hypersensitivity from one of three types of reactions: respiratory, cutaneous, or systemic.

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  Patients with aspirin allergy presenting with ACS should undergo desensitization, if at all feasible.

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  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 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 uncontrollable.

Aspirin should be administered as soon as possible to all patients with ACS without a known intolerance.

On presentation, patients with STEMI 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.

Currently, recommendations endorse low-dose aspirin daily indefinitely for all patients following an MI.

Clopidogrel is an oral agent that blocks activation of platelets by irreversibly inhibiting the binding of adenosine diphosphate (ADP) to the P2Y ₁₂ receptor.

Clopidogrel is a prodrug that is metabolized in the liver in a multistep process, predominantly through 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 3.1 ).

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 and persists 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, clopidogrel was modestly more effective in reducing the combined risk of ischemic stroke, MI, or vascular death than aspirin.

Clopidogrel may be substituted in patients with aspirin allergy or intolerance.

The effect of adding clopidogrel to aspirin in the early phase of ACS was studied in the landmark Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) trial.

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  Cardiovascular death, MI, and stroke was reduced by 20% among patients randomized to clopidogrel (300 mg is a loading dose given initially on admission then the patient will get 75mg per day thereafter) plus aspirin, within 24 hours.

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 fibrinolytic therapy.

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  The results demonstrated that the addition of clopidogrel for patients with STEMI who were 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).

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  This study showed that adding clopidogrel (75 mg/day) to aspirin (162 mg/day) significantly reduced death, reinfarction, or stroke by 9% and mortality by 7% with no significant excess risk of fatal or cerebral bleeding.

Although these studies employed clopidogrel with a loading dose of 300 mg or no loading dose, subsequent studies suggested a faster onset of action and an added benefit with a higher loading dose of 600 mg, particularly among higher-risk patients undergoing percutaneous coronary intervention (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, double-dose clopidogrel reduced the rate of cardiovascular death, MI, or stroke, and stent thrombosis in patients undergoing PCI, but major bleeding was more common.

The cumulative data suggest that, for clopidogrel, the recommended loading dose is 600 mg with a maintenance dose of 75 mg.

Wide interindividual variability in the degree of inhibition of ADP-induced platelet function has been observed with clopidogrel; so-called “high on-treatment platelet reactivity” is reported in up to 35% of patients.

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  The mechanisms for this variability are likely multifactorial, including drug, environmental, and genetic interactions.

Proton pump inhibitors, 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, have not confirmed an adverse effect on clinical outcomes.

Clopidogrel combined with aspirin increases bleeding risk, has been associated with gastrointestinal upset, and a rare incidence of thrombotic thrombocytopenic purpura.

Clopidogrel plus aspirin has been associated with significant increases in major bleeding with coronary artery bypass graft (CABG) surgery and so should be withheld for 5 to 7 days before surgery.

Prasugrel is another thienopyridine antagonist of the platelet P2Y ₁₂ receptor and 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 3.1 ).

Prasugrel inhibits greater than 80% of in vitro ADP-induced platelet aggregation and has less interpatient variability than clopidogrel.

The efficacy of prasugrel as compared with clopidogrel on outcomes among patients with ACS 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.

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  Patients with STEMI or high-risk NSTE ACS due to undergo planned PCI were randomly assigned to prasugrel or clopidogrel.

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  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.

Prasugrel is administered as a 60-mg loading dose followed by a maintenance dose of 10 mg/day.

A lower maintenance dose of 5 mg/day has been recommended in patients who weigh less than 60 kg or who are older than 75 years.

It is recommended that prasugrel be discontinued 7 days prior to CABG surgery.

Ticagrelor is an oral cyclopentyltriazolopyrimidine that reversibly inhibits the platelet P2Y ₁₂ receptor (see Table 3.1 ).

Ticagrelor is not a prodrug and 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.

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 patients treated with aspirin in the Platelet Inhibition and Patient Outcomes (PLATO) study.

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  At 1 year, patients randomly assigned to receive ticagrelor had a significant reduction in overall mortality and also death from vascular causes, MI, or stroke.

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  No significant difference in rate of major bleeding was observed between ticagrelor and clopidogrel.

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  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 stimulates of pulmonary vagal C fibers that can cause dyspnea and an increased incidence of dyspnea was observed in the PLATO trial among patients receiving ticagrelor (14.5%), but severe in only 0.4% of patients.

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/day.

It is recommended that ticagrelor be withheld 5 days prior to CABG surgery.

After oral administration of a loading dose of a P2Y ₁₂ antagonist, clinically effective platelet inhibition may be delayed by hours, particularly among patients with STEMI.

Administered intravenously, it is a potent, direct-acting, rapidly reversible P2Y ₁₂ antagonist with predictable plasma levels and linear dose-dependent receptor inhibition (see Table 3.1 ).

An effective level (> 80%) of platelet inhibition with cangrelor is achieved within minutes after start of intravenous infusion and recovers within 60 to 90 minutes after discontinuation.

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 patients who were clopidogrel-naive with coronary artery disease requiring PCI for stable angina, NSTE ACS, or STEMI received a bolus and subsequent infusion of cangrelor or placebo.

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  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 was not accompanied by a significant increase in severe bleeding or in the need for transfusions compared with patients on 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/min infusion for the duration of the procedure or at least 2 hours.

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 should be individualized with attention to clinical syndrome, comorbidities, timing, and a careful assessment of ischemic risk and bleeding risk.