Antiplatelet Medications in the Intensive Care Unit

Antiplatelet therapy is the cornerstone of prevention and management of cardiovascular and cerebrovascular disease, significantly reducing the risk of thrombotic complications.1 Common indications for antiplatelet therapy include acute coronary syndrome (ACS), chronic coronary artery disease, cerebrovascular disease, and peripheral artery disease.1 Since these conditions are so common, many critically ill patients are either currently taking antiplatelet agents on admission or will be started on this therapy during hospitalization. For this reason, it is important to understand the differences between antiplatelet agents to ensure safety and efficacy. This article will focus on common antiplatelet agents encountered in the intensive care unit (ICU).Antiplatelet medications include oral and parenteral agents in 3 main drug classes based on the mechanism of action: cyclooxygenase (COX) inhibitors, P2Y12 receptor inhibitors, and glycoprotein IIb/IIIa inhibitors (GP IIb/IIIa).2 There are other less commonly used classes of antiplatelet medication, but the aforementioned groups represent the primary agents in clinical practice.2 These classes differ based on mechanism of action and pharmacokinetic and pharmacodynamic principles, as seen in Table 1.Aspirin is one of the most commonly used and easily accessible antiplatelet agents. Its primary mechanism is through irreversible inhibition of the COX-1 enzyme, which prevents thromboxane A2 production. Blocking this production ultimately prevents platelet aggregation. Lower doses of aspirin (75-100 mg) have been shown to provide sufficient antithrombotic effects, whereas higher doses (>100 mg) have only shown increased risk of bleeding without additional antithrombotic benefit.1,2The P2Y12 inhibitors work by blocking the P2Y12 receptor on platelets, which inhibits adenosine diphosphate–mediated platelet aggregation.2 Of the P2Y12 receptor inhibitors, clopidogrel and prasugrel are both irreversible platelet inhibitors that are prodrug medications and require metabolic activation.2 Prasugrel has a more rapid onset and potent platelet inhibition compared with clopidogrel, but it also has an increased risk of bleeding.3 Ticagrelor is a newer P2Y12 inhibitor agent with increased potency and faster onset of action compared with clopidogrel, and it does not require metabolic activation.2 Although there are instances of rare intracranial bleeding, ticagrelor was associated with lower rates of nonintracranial fatal bleeding and death due to vascular causes and was shown to have a mortality benefit over clopidogrel.4 The dosing of these P2Y12 inhibitors depends primarily on the loading or maintenance dosing strategy being administered, most commonly in patients presenting with an ACS (Table 2).2,3,5–8Cangrelor, a nonthienopyridine adenosine triphosphate analog, is the only intravenous P2Y12 receptor antagonist with an immediate onset of action (within 2 minutes), short half-life (3-6 minutes), and reversible binding properties.2,9 This allows for a quick cessation of its antiplatelet effects, allowing platelet function to recover within 1 hour of discontinuation.9 Cangrelor was approved by the US Food and Drug Administration in 2015 by demonstrating superior efficacy in reducing thrombotic complications compared with clopidogrel in patients undergoing percutaneous coronary intervention (PCI). It is ideal for situations requiring immediate and reversible antiplatelet therapy, such as ischemic events during PCI or in patients at high risk for procedural complications, including bleeding or emergent surgery.2,9The GP IIb/IIIa inhibitors, including abciximab, eptifibatide, and tirofiban, are administered intravenously with a rapid onset of action and work by blocking fibrinogen binding to the GP IIb/IIIa receptor, which inhibits the final pathway of platelet aggregation. Tirofiban and eptifibatide have short platelet-bound half-lives, whereas abciximab comparatively has a much higher affinity for the receptor, leading to a longer platelet-bound half-life.10Significant drug-drug interactions can exist with certain antiplatelet agents when combined with inhibitors and/or inducers of different cytochrome P450 (CYP450) enzymes. Concomitant use of clopidogrel with CYP2C19 inhibitors such as omeprazole or esomeprazole should be avoided, as they can significantly reduce metabolism of clopidogrel to its active form and its antiplatelet effect. Concomitant use of CYP3A4 inhibitors (eg, azole antifungals) and inducers (eg, rifampin) with ticagrelor should be avoided, as they can decrease and/or increase serum concentrations of ticagrelor, leading to reduced efficacy or bleeding.11 In addition to potential drug interactions with antiplatelet agents, it is important to recognize specific contraindications or rare adverse effects of these medications that may limit their use. Prasugrel, for example, is contraindicated in patients with a past medical history of stroke or transient ischemic attack due to a significantly increased risk of adverse cerebrovascular events, such as thrombotic stroke and intracranial bleeding.2 Additionally, a rare but serious adverse effect, thrombotic thrombocytopenic purpura, has been reported with clopidogrel use and may necessitate immediate medication attention. Symptoms include thrombocytopenia, microangiopathic hemolytic anemia, neurological findings, renal dysfunction, and fever.1,12Compared with other P2Y12 inhibitors, clopidogrel may lead to more unpredictable patient responses due to a variety of reasons such as metabolic, clinical, and genetic factors. It is a prodrug that requires 2-step metabolism involving several CYP450 enzymes, of which CYP2C19 is the largest contributor.13 Individuals can have phenotypic alterations (eg, CYP2C19 poor metabolizers) that can lead to decreased efficacy and an increased risk of thrombotic events when taking clopidogrel. Genetic and P2Y12 platelet function testing can be used to help identify patients who may be clopidogrel nonresponders. Genetic testing can help identify CYP2C19 alleles associated with poor clopidogrel metabolism, while platelet function testing is a direct measure of platelet reactivity. Both types of testing are available at the bedside for rapid assessment of the patient, however each has its own advantages and disadvantages. For example, platelet function testing provides a direct measure of response to antiplatelet therapy, taking into account genetic and nongenetic factors that could decrease effectiveness of antiplatelet agents. There can be notable interindividual variability in response, however, and accurate assessment of platelet reactivity requires that the patient be on antiplatelet therapy at the time of testing. Genetic testing, on the other hand, does not have inter-individual variability and can be done prior to the patient taking an antiplatelet agent. However, it will only take into account genetic factors for decreased antiplatelet effectiveness.13 Although these tests are available, guidelines do not recommend routine use but note they can be beneficial and should be considered in those who are at high risk for or who have had recurrent ischemic events.13 If decreased responsiveness or nonresponsiveness to clopidogrel is suspected, the patient should be considered for an alternative P2Y12 inhibitor such as ticagrelor or prasugrel.13Due to patient variability in response to antiplatelet medications, there may be a multitude of reasons for potential switching between P2Y12 inhibitors, including decreased effectiveness, drug-drug interactions, and affordability. Given the different pharmacodynamic profiles of each agent, changes in platelet inhibition while transitioning between agents remains a significant concern due to the potential for thrombotic complications.14 When transitioning a patient between oral agents, the indication for the medication, when the event occurred (acute/ early versus late), and when the last dose of the current agent was taken should be considered to determine when to start the new agent and at what dose (loading vs maintenance dose).14 In the context of transitioning a patient from intravenous cangrelor to an oral P2Y12 inhibitor, the timing can differ between various agents, as outlined in Table 3. Cangrelor achieves high P2Y12 receptor occupancy, preventing other agents from binding to the receptor. The active metabolites of clopidogrel and prasugrel are unstable with short half-lives and bind to the same site as cangrelor. If these agents are administered during a cangrelor infusion or when cangrelor concentrations are high, their active metabolites cannot bind to the P2Y12 receptor. This results in a lack of antiplatelet effect and ischemic protection. In contrast, ticagrelor, a reversible P2Y12 receptor antagonist, has a distinct site on the P2Y12 receptor and a longer half-life ranging from 6 to 12 hours.14 Therefore, ticagrelor can be safely administered before or during a cangrelor infusion without causing drug interactions or loss of efficacy.9,14Critically ill patients can be initiated or continued on antiplatelet medications for a variety of reasons that may require ICU admission, such as ACS, PCI, acute ischemic stroke, and endovascular and neuroendovascular procedures (eg, intracranial stents, flow diverters).15 Depending on the indication, dual antiplatelet therapy (DAPT) with aspirin and a P2Y12 inhibitor versus single antiplatelet therapy may be warranted. Benefits of DAPT include reducing the risk of stent thrombosis and recurrent ischemic events compared with single antiplatelet therapy; however DAPT increases the bleeding risk and requires risk-benefit assessments.16 DAPT has historically been recommended for cardiovascular indications, such as after PCI or coronary artery bypass graft surgery.16 Outside of these indications, there has also been use of DAPT in patients with intracranial atherosclerotic disease or after neuroendovascular procedures.15,17This risk of bleeding can be increased with use of DAPT or in combination with an anticoagulant.2 Due to this concern, the recommended duration of DAPT can vary based on indication but ideally should not be continued indefinitely. The American College of Cardiology and American Heart Association recommend DAPT for at least 12 months in patients with ACS, with adjustments based on bleeding risk.16 By contrast, the duration of DAPT for patients with intracranial atherosclerotic disease or who received neuroendovascular procedures can vary but normally would not be longer than 90 days.15,17 In the majority of cases, once DAPT is discontinued, single platelet therapy would be continued long term, most likely using aspirin alone.15–17Intravenous cangrelor was originally approved for use as adjunct therapy to PCI or as bridging therapy prior to cardiac surgery in high-risk patients.9 Although cangrelor is still used for these indications, its use has expanded in clinical practice beyond cardiac surgery. It is now used in high-risk patients undergoing PCI in the setting of cardiogenic shock—a population excluded from initial cangrelor trials—as well as those at elevated risk of stent thrombosis during interruption of oral antiplatelet therapy. Furthermore, cangrelor has been incorporated into neuroendovascular procedures as a strategy to prevent in-stent thrombosis.9,18Prior to the widespread use of P2Y12 inhibitors in treating ACS, GP IIb/IIIa inhibitors were intravenous antiplatelet agents widely used as adjunct therapy to parenteral anticoagulants at the time of PCI. In today’s shorter times to revascularization and effective periprocedural antiplatelet therapy, the use of these agents has significantly decreased. Additionally, the use of GP IIb/IIIa inhibitors during PCI concurrently with anticoagulants has often been associated with higher risk of bleeding and should be reserved for select high-risk patients, such as those with large thrombus burden.3,16Premature discontinuation of P2Y12 inhibitors increases the risk of thrombotic events. When antiplatelet therapy must be temporarily held in anticipation of a procedure, perioperative management of patients on these agents requires an assessment of the risk of bleeding and thrombosis. If temporary discontinuation is necessary (eg, for a surgical procedure), guideline recommendations on when these agents should be held prior to the procedure are dependent on the specific agent’s serum half-life and duration of irreversible platelet inhibition.19 Ticagrelor should be discontinued 3 to 5 days prior to the procedure, clopidogrel for 5 days, and prasugrel for 7 to 10 days. Aspirin may be continued in most cases prior to procedure without interruption. However, if the patient is at high risk for bleeding and interruption of aspirin is necessary, discontinuation 7 days or less prior to procedure is recommended.19 In patients at high risk for stent thrombosis who need a surgical procedure, such as those who had recent cardiac stent placement, bridging therapy with different agents has been evaluated. Two randomized controlled trials evaluated the use of cangrelor specifically as bridging therapy to cardiac surgery and found continued platelet inhibition with no increase in bleeding rates.20,21 Although these results seem promising, routine use of bridging therapy with cangrelor is not recommended.19Therapy should be resumed as soon as possible after the procedure to prevent any thrombotic events. It would be reasonable to withhold antiplatelet therapy postprocedure in patients at high risk for bleeding, such as those with thrombocytopenia.19 Upon restarting these agents, patients should be closely monitored for bleeding. If bleeding does occur, no specific reversal agents currently exist for antiplatelet medications; therefore treatment is mostly supportive care. There has been minimal literature surrounding use of desmopressin and platelet transfusions for reversal in patients with intracranial hemorrhage due to antiplatelets.22 Current guidelines recommend consideration of a single dose of desmopressin in those deemed appropriate candidates but only recommend platelet transfusion in those undergoing neurosurgical procedures.22Antiplatelet therapy continues to play a critical role in the prevention and management of cardiovascular and cerebrovascular diseases. There are now multiple antiplatelet medications available, both oral and parenteral, each with its own unique pharmacokinetic and pharmacodynamic parameters. Use of these agents in the ICU should take into consideration each agent’s characteristics, as well as the patient’s specific risk of thrombotic versus bleeding events with disruption minimized as much as possible.