ijcs International Journal of Cardiovascular Sciences Int. J. Cardiovasc. Sci. 2359-4802 2359-5647 Sociedade Brasileira de Cardiologia fmgPKTXBxhQmnzxqrJ6F4tH S2359-56472017000500442 10.5935/2359-4802.20170058 Review Articles Antiplatelet Agents in Acute Coronary Syndromes Andrade Pedro Beraldo de 1 Borges Leonardo Silva Roever 2 Faculdade de Medicina de Marília Hospital das Clínicas Marília SP Brazil Hospital das Clínicas da Faculdade de Medicina de Marília - FAMEMA, Marília - SP Faculdade de Medicina de Marília Universidade Federal de Uberlândia MG Brazil Universidade Federal de Uberlândia (UFU), MG - Brazil Universidade Federal de Uberlândia Mailing Address: Pedro Beraldo de Andrade, Avenida Brigadeiro Eduardo Gomes, 3551, casa A-9, Condomínio Costa do Ipê. Postal Code: 17514-000, Residencial Vale Verde, Marília, SP - Brazil. E-mail: pedroberaldo@gmail.com; pedroberaldo@cardiol.br

Author contributions

Conception and design of the research: Andrade PB, Borges LSR. Acquisition of data: Andrade PB, Borges LSR. Analysis and interpretation of the data: Andrade PB, Borges LSR. Statistical analysis: Andrade PB, Borges LSR. Writing of the manuscript: Andrade PB, Borges LSR. Critical revision of the manuscript for intellectual content: Andrade PB, Borges LSR.

Potential Conflict of Interest

No potential conflict of interest relevant to this article was reported.

 Sep-Oct 2017 30 05 442 451 23 11 2016 28 11 2016 05 04 2017 This is an Open Access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Abstract

Under balanced conditions, hemostasis is maintained by a complex interaction between endothelium, platelets, and coagulation factors. Situations involving injury and discontinuation of the endothelial lining stimulate the adhesion, activation, and aggregation of platelets, culminating in the formation of arterial or venous thrombi. In this context, antiplatelet therapy occupies a prominent role in the management of pathologies arising from this process, notably acute coronary syndromes. The increased conceptual understanding of receptors, agonists, and antagonists of the pathophysiological cascades involved in this process has allowed the development of new drugs and refinement of the current therapy, demanding a complete knowledge of the arsenal of antiplatelet agents with respect to their indication, dosage, moment of administration, and duration of treatment. The objective of this review is to define the role of antiplatelet drugs in the management of acute coronary syndrome, revisiting aspects that have been already consolidated and addressing current and still controversial topics on the subject.

 Keywords Acute Coronary Syndrome Myocardial Infarction Platelet Aggregation Blood Platelets Inhibitors Antifibrinolytic Agents. Introduction

Ischemic heart disease is the single leading cause of death and loss of quality of life worldwide.1 In Brazil, it is estimated to be related to an annual rate of approximately 55 deaths per 100,000 inhabitants.2,3 Acute coronary syndrome (ACS), with its broad range of manifestations, takes on a leading role in these statistics, and myocardial revascularization procedures and antithrombotic pharmacotherapy are fundamental pillars of its treatment.

Hemostasis is a physiological process maintained through a complex interaction between endothelium, platelets, and coagulation factors. Under conditions of emergency and imbalance, hemostasis can lead to the formation of arterial or venous thrombi, resulting in the occurrence of acute coronary events, cerebrovascular events, or episodes of thromboembolism. In this context and along with anticoagulant therapy, antiplatelet drugs stand out in the management of these conditions.4

Situations involving injury and discontinuation of the endothelial lining stimulate platelet adhesion to subendothelial matrix proteins. This interaction activates intracellular signals that promote the release of adenosine diphosphate (ADP), adrenaline, serotonin, thrombin and thromboxane A2, potent agonists of platelet activation. Once platelets are activated, glycoprotein IIb-IIIa complexes bind to fibrinogen to constitute the final stage of platelet aggregation and thrombus formation.5

The factors activating this process and the receptors involved in it have become targets for the development of antithrombotic agents. Evidence-based medicine enabled the advent, implementation, and refinement of the current therapeutic approach. However, by increasing the population's life expectancy and the coexistence of multiple comorbidities, we often find clinical scenarios in which the risk of ischemic complications goes hand in hand with the risk of hemorrhagic complications.6 This demands complete knowledge of the arsenal of antiplatelet agents in regards to their indication, dosage, and moment of administration.

The objective of this review is to define the role of antiplatelet drugs in the management of ACS, revisiting aspects that have been already consolidated and addressing current and still controversial topics on the subject.

Development

a) Acetylsalicylic acid

Acetylsalicylic acid (ASA) at low doses selectively inhibits cyclooxygenase (COX)-1, establishing antiplatelet activity, while at high doses it inhibits COX-1 and COX-2 with anti-inflammatory and analgesic effects. This medication is rapidly absorbed, reaching a peak plasma concentration 30 minutes after intake, in the case of a regular formulation, and 4 hours after intake, in the case of an enteric release formulation.7

Since the gastrointestinal side effects of ASA increase in proportion to its dose, an oral loading dose of 150-325 mg (swallowed, if a regular formulation, and chewed, if an enteral one) is recommended for ACS, or 80-150 mg intravenously in locations in which this presentation is available, followed by 81-100 mg as maintenance.8 In the pioneering study Second International Study of Infarct Survival (ISIS)-2, ASA promoted a significant 23% reduction in cardiovascular mortality compared with placebo after 5 weeks of treatment in patients with acute myocardial infarction (AMI) with ST-segment elevation, with this effect being additive and synergistic when associated with streptokinase, reducing the rate of events by 42%.9 These benefits were corroborated by several subsequent studies and by the compilation of their data in large meta-analyses, thus becoming one of the pillars of antithrombotic pharmacotherapy in the different spectra of ACS.10

Situations that constitute a clear contraindication to ASA are rare, and include mainly active digestive bleeding and known hypersensitivity (urticaria, bronchospasm, or anaphylaxis), although different desensitization protocols have been described allowing the chronic use of this medication with proven efficacy and safety.11

B) P2Y<sub>12</sub> platelet receptor antagonists

The association between ASA and a P2Y12 receptor antagonist, known as dual antiplatelet therapy, is the treatment foundation of patients with ACS and those undergoing percutaneous coronary intervention (PCI). Ticlopidine is a first generation thienopyridine derivative that, despite its efficacy and due to its hematological (thrombocytopenia, aplastic anemia, thrombotic thrombocytopenic purpura, neutropenia) and gastrointestinal side effects, has been rapidly replaced by clopidogrel.12

b.1) Clopidogrel

Clopidogrel is a thienopyridine agent that irreversibly blocks the P2Y12 receptor. The steady-state inhibition of platelet function with clopidogrel is achieved with a maintenance dose of 75 mg after 5-7 days from treatment initiation, whereas with the administration of 300 mg and 600 mg loading doses, this effect is reached in 6 and 2 hours, respectively, a relevant aspect in the context of medical emergencies.13

In the landmark clinical trial Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE), 12,562 patients with non-ST elevation AMI treated with ASA were randomized to receive clopidogrel or placebo for 3 to 12 months.14 The clopidogrel group exhibited a significant 20% reduction in the risk of cardiovascular death, reinfarction, or stroke when compared with the placebo group, with benefits already apparent in the first hours after initiation of therapy and independent of invasive stratification. In the scenario of AMI with ST-segment elevation, two important studies validated clopidogrel as an effective adjuvant therapy. Among 3,491 patients randomized to 300 mg of clopidogrel and 75 mg of clopidogrel maintenance versus placebo in the clinical trial Clopidogrel as Adjunctive Reperfusion Therapy-Thrombolysis in Myocardial Infarction (CLARITY-TIMI) 28, of whom 99.7% underwent thrombolysis, a 36% reduction was observed in the risk of death, recurrent AMI, or occluded infarct-related artery by the time of angiography.15 In contrast, in the study, Clopidogrel and Metoprolol in Myocardial Infarction Trial (COMMIT), among 45,852 randomized patients, with 50% undergoing thrombolysis, the administration of a daily dose of 75 mg clopidogrel over a mean period of 28 days resulted in a 9% reduction in the rates of death, reinfarction, or stroke compared with placebo.16

Thus, supported by the results of randomized controlled trials in ACS and by the pharmacodynamic and pharmacokinetic characteristics of clopidogrel, a loading dose of 600 mg is recommended for patients in whom invasive risk stratification is predicted or who are referred for primary PCI, and 300 mg for patients undergoing fibrinolytic therapy. An exception should be made to patients with a history of thrombolysis who are aged ≥ 75 years, in whom the loading dose should be omitted. In the absence of a clear benefit from maintaining clopidogrel at a double dose (150 mg), the dose should be 75 mg.8

However, clopidogrel exhibits unmet limitations and needs, partly explained by its properties, such as slow onset and withdrawal and limited platelet inhibition potential. The interindividual variability of the drug's action is large, with the percentage of patients exhibiting inadequate therapeutic response estimated at up to 35%.17 The mechanisms involved are multifactorial and include drug interactions (e.g., proton pump inhibitors such as omeprazole and esomeprazole), the environment and clinical comorbidities (e.g., adherence to therapy, smoking, diabetes mellitus, obesity, ACS), in addition to genetic polymorphisms, with emphasis on the alleles that determine a loss of CYP2C19 function.18 It is known that patients with these variants are at increased risk of stent thrombosis, AMI recurrence, and death.(19 )However, although the subject is still under scrutiny in ongoing studies, the evidence currently available does not endorse the individualization of therapy based on the results of genetic tests or the measurement of platelet function.20,21 With that, a vast field of research has opened up with different treatment proposals, new P2Y12 receptor antagonists, and blockade of new targets on the surface of the platelets.

 b.2) Prasugrel

Similar to clopidogrel, prasugrel is a second-generation thienopyridine that is a prodrug and requires biotransformation to become an active metabolite. However, it has an earlier onset of action, about 30 minutes after the administration of a 60 mg loading dose, in addition to a more predictable response, due to its broad absorption, a need for a single oxidation step mediated by CYP3A4 and CYP2B6, conferring greater bioavailability, higher levels of platelet inhibition, and less variability of response among patients.22

In the Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel (TRITON)-TIMI 38 clinical trial, 13,608 patients admitted for ACS with or without ST-segment elevation undergoing PCI were randomized to receive a 60 mg loading dose of prasugrel and 10 mg maintenance dose, or a 300 mg loading dose of clopidogrel and 75 mg maintenance dose for up to 15 months.23 Prasugrel treatment was shown to be superior with a significant 19% reduction in the risk of cardiovascular death, AMI, or nonfatal stroke, with a reduction of infarction of 24% and stent thrombosis of 52%, with an even greater benefit among patients with diabetes.

Consistent with the increased antiplatelet potency of prasugrel, the study found a significant 32% increase in the risk of severe bleeding, including fatal and life-threatening bleeding. In some patients' profiles, the net clinical benefit, which considers anti-ischemic efficacy and safety, was unfavorable to prasugrel, including patients with a prior stroke or transient ischemic attack (TIA), aged ≥ 75 years, and with a body weight < 60 kg. In the latter two situations, in case there is a need to prescribe the drug and a lack of therapeutic alternatives, a maintenance dose of 5 mg is recommended.24 There are no indications to date in terms of prescribing prasugrel to ACS patients who did not undergo PCI, or in a time frame other than after the knowledge of the coronary anatomy and the realization of the interventional procedure. In patients with an indication for myocardial revascularization surgery, prasugrel should ideally be discontinued for 7 days.

 b.3) Ticagrelor

The first clinically available representative of the cyclopentyltriazolopyrimidine class, ticagrelor is a reversible P2Y12 receptor antagonist, exerting its inhibitory effect through a noncovalent attachment to a different platelet binding site than ADP. Unlike thienopyridine agents, ticagrelor is not a prodrug and acts immediately after oral absorption. It exhibits, thus, a rapid onset of action following the ingestion of a loading dose of 180 mg and a peak action in 2 hours. With a plasma half-life of 8-12 hours, ticagrelor requires a maintenance dose of 90 mg every 12 hours, and because it binds to the receptor in a reversible fashion, it has an earlier termination of action, around 2-3 days, even though the package insert recommends its suspension for 5 days before a surgical intervention. Since the metabolism of ticagrelor is mediated by CYP3A4 or CYP3A45, concomitant administration of strong inducers or CYP3A4 inhibitors during its use should be avoided.25

In the clinical trial Platelet Inhibition and Patient Outcomes (PLATO), 18,624 patients featuring all ACS manifestations (with the exception of those with AMI with ST-segment elevation who underwent thrombolysis) were randomized to receive ticagrelor or clopidogrel for 12 months.26 In the ticagrelor arm, there was a significant 16% reduction in the risk of cardiovascular death, AMI or stroke. In a prespecified hierarchical analysis, ticagrelor alone reduced the occurrence of cardiovascular death (21%), AMI (16%), and definitive stent thrombosis (33%), with no difference in the rate of severe or fatal bleeding. Despite the consistency of the results obtained among the different subgroups analyzed, there was an interaction between patients treated in North America and the rest of the world, without a clear benefit of ticagrelor in the first group. The use of high maintenance doses of ASA (≥ 200 mg) is believed to be a probable justification for this finding, prompting an alert for the prescription of doses < 200 mg in chronic use.27

Ticagrelor exhibits pleiotropic effects not mediated by its blocking of the P2Y12 receptor, including the inhibition of adenosine uptake by erythrocytes, which increases the circulating levels of adenosine.28 Adenosine is known to have several properties, including coronary vasodilation, reduction of ischemia and reperfusion injury, inhibition of inflammatory responses to stress conditions, negative chronotropic and dromotropic effect, reduction of glomerular filtration rate, and stimulation of vagal C fibers in the lungs. These effects are still under investigation and would justify, among the users of ticagrelor, a higher prevalence of dyspnea without alteration of pulmonary function tests, ventricular pauses without clinical impact or requirement of a definitive pacemaker, elevated serum creatinine and uric acid levels, as well as greater electrical stability and a reduction of sudden arrhythmic deaths, the latter still under speculation.29,30

Table 1 provides a compilation of the main indications, dosages, and recommendations regarding the prescription of P2Y12 receptor antagonists in ACSs.

Indications of the P2Y12 receptor antagonists in acute coronary syndromes
Drug Indication Loading dose Maintenance dose Duration of treatment Suspension for surgery
Clopidogrel AMI with post-thrombolysis ST elevation 300 mg* 75 mg/day 1 year 5 days
Clopidogrel ACS without ST elevationPrimary PCI 300-600 mg 75 mg/day 1 year 5 days
Prasugrel ACS treated with PCI 60 mg 10 mg/day† 1 year 7 days
Ticagrelor ACS (except post-thrombolysis) 180 mg 90 mg every 12 hours 1 year 3-5 days

AMI: acute myocardial infarction; ACS: acute coronary syndrome; PCI: percutaneous coronary intervention.

The loading dose is omitted if aged ≥ 75 years.

Maintenance dose of 5 mg if weight < 60 kg or age ≥ 75 years.

 c) Glycoprotein IIb-IIIa inhibitors

The glycoprotein IIb-IIIa inhibitors approved for clinical use - abciximab, tirofiban and eptifibatide - are potent platelet antagonists of parenteral administration, of which only the first two are commercially available in Brazil. The pharmacological characteristics of these agents are summarized in Table 2.

Pharmacological properties of glycoprotein IIb-IIIa inhibitors
Abciximab Tirofiban
Structure Monoclonal antibody Nonpeptide antagonist
Molecular weight 48 kDa < 1 kDa
Onset Rapid Rapid
Reversibility Slow (12 hours) Fast (2 hours)
Half-life 10-30 minutes 2 hours
Excretion Unknown Renal (40-70%) and biliary
Loading dose 0.25 mg/kg 25 µg/kg
Maintenance dose 0.125 µg/kg/min for 12 hours 0.15 µg/kg/min for 18 hours
Dose adjustment No ↓ 50% if clearance ≤ 30 mL/min

Abciximab is a monoclonal antibody with a high affinity for glycoprotein IIb-IIIa receptors. Following a loading dose of 0.25 mg/kg, more than 80% of the receptors are blocked, with a reduction of platelet aggregation in response to ADP stimulation to less than 20% of the baseline value. This inhibition is maintained by a continuous infusion of abciximab at a dose of 0.125 µg/kg/min, up to a maximum of 10 µg/min. Thrombocytopenia is reported in 1-4% of the patients treated with the drug, commonly detected within the first 24 hours and up to 2 hours after the initiation of its administration. This is believed to be an antibody-mediated complication, with a reversal in most cases after its suspension and an occasional requirement of platelet transfusion.31

Tirofiban is a nonpeptide tyrosine derivative that acts through a reversible and selective blockade of the glycoprotein IIb-IIIa receptor, preventing its binding to fibrinogen and to the von Willebrand factor. With renal and bile excretion, tirofiban has a plasma half-life of 1.5-2 hours, with a requirement for dose adjustment in patients with renal insufficiency and creatinine clearance ≤ 30 mL/min, but not in cases of liver disease. When administered at a loading dose of 25 µg/kg, tirofiban exhibits similar efficacy to that of abciximab. Cases of severe thrombocytopenia, although rare and reversible, have also been reported. The occurrence of severe thrombocytopenia is attributed to an immune-mediated phenomenon, since the binding of tirofiban promotes a conformational change in the receptor, with generation of antibodies against the new exposed epitope.32

The evidence that has validated the use of glycoprotein (GPIs) IIb-IIIa inhibitors in PCI, given the ability of these agents to reduce periprocedural AMI and the need for emergency revascularization, originated mainly from clinical studies conducted prior to the advent of thienopyridine agents and routine stent implantation. In the contemporary era of interventional cardiology, meta-analyses have been performed to evaluate the actual role played by these agents as adjunctive therapy for PCI.

In the treatment of non-ST-elevation ACS, a meta-analysis involving 31,402 patients demonstrated a mild but significant benefit in the reduction of death and AMI at 30 days, favoring the use of glycoprotein IIb-IIIa inhibitors, especially among patients considered to be at high risk (e.g., patients with positive myocardial necrosis markers, increased thrombotic load, or complex lesions).33 A meta-analysis involving seven randomized trials and 19,929 patients evaluated the most appropriate timing for administration of glycoprotein IIb-IIIa inhibitors.34 A strategy of early infusion prior to the admission of the patient to the catheterization laboratory was unable to reduce the incidence of mortality at 30 days or recurrent AMI. However, it was associated with a higher rate of severe bleeding.

Although primary PCI reduces mortality compared with fibrinolysis, suboptimal reperfusion is observed in a non-negligible proportion of patients, with distal embolization playing a central role in the genesis of this phenomenon. In this sense, there has been great interest in the role of glycoprotein IIb-IIIa inhibitors in this clinical scenario. A meta-analysis including large contemporary clinical trials conducted during pretreatment with clopidogrel and including 10,085 patients, assessed the efficacy and safety of glycoprotein IIb-IIIa inhibitors as adjunctive therapy for primary PCI in AMI with ST-segment elevation.35 No reduction was observed in mortality at 30 days with the use of these inhibitors or recurrence of AMI, but there was an increased rate of severe bleeding. However, a meta-regression analysis observed a benefit favoring glycoprotein IIb-IIIa inhibitors among patients at higher risk (age ≥ 65 years, hemodynamic instability, anterior AMI, diabetics).

Based on the hypothesis that an increased local concentration of abciximab would enhance its antiplatelet, antithrombotic, and anti-inflammatory effects, intracoronary bolus administration of this drug has been tested during primary PCI. A meta-analysis including six randomized trials and 1,246 patients concluded that compared with intravenous infusion, intracoronary administration of abciximab resulted in a significant reduction of 57% in mortality and 43% in the need for target vessel revascularization at 30 days, without an increase in severe bleeding rate, although these findings were not subsequently confirmed in a large randomized study involving 2,065 patients.36,37

Thus, glycoprotein IIb-IIIa inhibitors play an important role as adjunctive therapy in PCI, but the prescription of these agents is restricted to non-programmed situations, especially in the catheterization laboratory, with emphasis on patients with high-risk non-ST-segment elevation ACS and without previous treatment with P2Y12 receptor inhibitors, from the presence of thrombotic complications during PCI (abrupt vessel occlusion, slow epicardial flow, coronary dissection, lateral branch occlusion) to AMI with ST-segment elevation in high-risk patients or in the presence of an increased thrombotic load. Upon consideration of these agents, the risk profile of the patients should be considered in regard to the occurrence of hemorrhagic events, which are known promoters of increased morbidity and mortality.

Although the use of glycoprotein IIb-IIIa inhibitors has no influenced on the efficacy of the new oral antiplatelet drugs (ticagrelor, prasugrel) in the treatment of ACS, further research is required regarding their use in patients treated with the new P2Y12 receptor inhibitors, or those with CYP2C19 genetic variants or low clopidogrel response, or regarding the option of reducing or suppressing its maintenance dose.

 d) Pretreatment with P2Y<sub>12</sub> receptor antagonists

In the acute phase of ACS, a scenario characterized by a prothrombotic status and intense platelet activation, dual antiplatelet agglutination represents an important therapeutic step, and it is intuitive to assume that a potent and early pharmacological action is capable of conferring anti-ischemic efficacy, reducing thrombotic events (periprocedural infarction, stent thrombosis, coronary reocclusion), especially among patients undergoing invasive risk stratification and PCI. However, counterpoints to pretreatment with P2Y12 receptor antagonists include the increased prevalence of hemorrhagic complications with antithrombotic therapy, as well as a possible delay in implementing surgical treatment in patients with multivessel disease and indication of revascularization, prolonging the hospitalization duration and increasing the risk of bleeding related to surgery. Still, there is scarce evidence from randomized clinical trials with adequate casuistry and statistical power for a clear and definitive response to this topic.

The trial Clopidogrel for the Reduction of Events During Observation (CREDO) is one of the pioneer studies suggesting a benefit from early dual antiplatelet therapy initiated immediately after diagnosis. This trial randomized 2,116 patients, including 66% diagnosed with ACS.38 The objective of the trial was to evaluate the benefit of a loading dose of 300 mg of clopidogrel 3-24 hours prior to PCI and maintenance of the dual therapy for 12 months. Pretreatment with clopidogrel was associated with a nonsignificant reduction of 18% in the risk of death, AMI, or emergency revascularization at 28 days. However, in a prespecified subgroup analysis, a significant reduction of 38.6% in the primary outcome was observed in patients whose therapy was initiated 6 hours before PCI, the conceptual basis for the adoption of this strategy.

In the era of new and potent P2Y12 receptor inhibitors, the study Comparison of Prasugrel at the Time of Percutaneous Coronary Intervention or as Pretreatment at the Time of Diagnosis in Patients with Non-ST-Elevation Myocardial Infarction (ACCOAST) randomized 4,033 patients with non-ST-segment elevation ACS to receive a 30 mg dose of prasugrel at the time of diagnosis (pretreatment) plus 30 mg in case of PCI, compared with 60 mg immediately prior to the procedure.39 The primary efficacy endpoint, composed of cardiovascular death, AMI, stroke, urgent revascularization, or unplanned use of glycoprotein IIb-IIIa inhibitors at 7 days did not differ between groups, whereas the safety outcome, severe bleeding occurrence by TIMI classification, was almost double among those pretreated with prasugrel, with its use in such circumstances being discouraged.

Even though ticagrelor was administered early in the PLATO study, prior to invasive stratification, the study did not evaluate pretreatment or not with the drug. In contrast, the study Administration of Ticagrelor in the Cath Lab or in the Ambulance for New ST Elevation Myocardial Infarction to Open the Coronary Artery (ATLANTIC) randomized 1,862 patients with ST-segment elevation AMI to ticagrelor at a dose of 180 mg, prior to transfer to primary PCI, including prehospital transport, against a loading dose administered in the catheterization laboratory.40 The ≥ 70% resolution of ST-segment elevation or TIMI 3 flow in the infarct-related artery at angiography, surrogate endpoints that comprised the investigation hypothesis of the study, did not differ between the strategies. The authors observed a highly significant interaction related to the use of prehospital morphine, evidencing a benefit in the primary objective among patients who did not use the opioid derivative. Ongoing studies are evaluating the effects of morphine on the pharmacokinetic and pharmacodynamic properties of P2Y12 receptor inhibitors.41 An interesting finding in one of the study's secondary endpoints, concerning the occurrence of definite stent thrombosis at 30 days, consisted of a significant reduction of this complication favoring pretreatment, despite a difference of only 31 minutes between administration of the drug in the two groups. Despite generating a hypothesis, this evidence supports the early onset of the double antiaggregation.

Head-to-head comparisons between ticagrelor and prasugrel are necessary. A randomized study evaluating the occurrence of ischemic or hemorrhagic complications in 1,230 patients diagnosed with AMI who underwent PCI showed no difference between the drugs and was prematurely interrupted because of futility.(42 )Designed to access the superiority of ticagrelor versus prasugrel in 4,000 patients with ACS and invasive stratification planning, the Rapid Early Action for Coronary Treatment (ISAR-REACT) 5, with greater statistical robustness, will contribute to the definition of future regulations.43 On the other hand, the comparison between pretreatment and no pretreatment with dual antiplatelet aggregation will be investigated in the currently ongoing clinical trial Downstream Versus Upstream Strategy for the Administration of P2Y12 Receptor Blockers (DUBIUS), which plans to include 2,520 patients with non-ST-segment elevation ACS undergoing an early invasive strategy (NCT02618837).

 e) Optimal duration of dual antiplatelet therapy

Dual platelet inhibition for a period of 1 year is recommended for patients diagnosed with ACS, especially those who underwent percutaneous myocardial revascularization, regardless of the type of stent; this recommendation is based on the results of randomized clinical trials such as CURE and, more recently, TRITON-TIMI 38 and PLATO, indicating an early and continuous benefit of dual antiplatelet therapy over 12 months of treatment.44,45

A recent topic of discussion is the maintenance of dual antiplatelet therapy for more than 12 months among individuals undergoing PCI. A meta-analysis encompassing six randomized clinical trials and 33,435 patients with a previous history of AMI showed that extending the dual antiaggregation after 1 year promotes a significant reduction of combined cardiovascular events compared with monotherapy with ASA, demonstrating an isolated reduction of cardiovascular death, AMI, stroke, and stent thrombosis at the expense of an increased occurrence of severe bleeding.46

Thus, the prescription of dual antiplatelet therapy for more than 12 months in patients undergoing PCI in the presence of an ACS can be considered.47 Such a decision should be based on a risk and benefit analysis, offering this option to patients predisposed to recurrence of ischemic events (e.g., previous AMI; diabetes mellitus; left ventricular dysfunction; type, diameter, and extent of implanted stent; chronic renal failure; peripheral arterial disease) but without a high risk of bleeding. The adoption of risk scores is an auxiliary tool in the decision-making process, and a judicious clinical judgment should prevail, especially the individualization of behaviors. Other speculative topics of interest and under current investigation consist of long-term monotherapy with an antiplatelet agent of higher inhibitory potency, such as ticagrelor (NCT01813435; NCT02270242), as well as the association between a P2Y12 inhibitor and factor Xa inhibitors, in detriment to ASA, in the management of patients with ACS.48

f) Patients requiring oral anticoagulation

Patients with atrial fibrillation, a recent episode of venous thromboembolism, and those with mechanical valve prostheses may require PCI in the occurrence of an ACS. In this scenario, the treatment involves triple therapy, consisting of an anticoagulant agent and two antiplatelet drugs, including ASA, a situation that exponentially increases the risk of hemorrhagic complications.49 Considering the increased potency and current absence of scientific evidence, the use of prasugrel or ticagrelor should be avoided, with clopidogrel being the P2Y12 antagonist of choice in this situation. Reducing the duration of triple therapy would add greater safety to the treatment, with the discontinuation of an antiplatelet therapy as early as possible.50 Although there are proposed flowcharts by expert consensus (Figure 1), the issue is still controversial and ongoing research evaluating the efficacy and safety of new oral anticoagulants associated with clopidogrel or ticagrelor will influence future standards on the subject.

Triple therapy, after percutaneous coronary intervention in acute coronary syndrome, in patients requiring oral anticoagulation. Source: Adapted from Roffi et al.44

In the study What is the Optimal antiplatElet and Anticoagulant Therapy in Patients with Oral Anticoagulation and Coronary StenTing (WOEST), 573 patients using oral anticoagulation with warfarin undergoing PCI, including approximately 30% during an ACS, were randomized to receive clopidogrel alone or in combination with ASA.51 At the end of 1 year of follow-up, triple therapy promoted a significant increase in the risk of bleeding, including severe manifestations, with no benefit in reducing death, AMI, stroke, revascularization of the target vessel, or stent thrombosis. Based on this research hypothesis, the Open-Label, Randomized, Controlled, Multicenter Study Exploring Two Treatment Strategies of Rivaroxaban and a Dose-Adjusted Oral Vitamin K Antagonist Treatment Strategy in Subjects with Atrial Fibrillation who Undergo Percutaneous Coronary Intervention (PIONEER AF-PCI) trial demonstrated that the association between rivaroxaban 15 mg and a P2Y12 inhibitor, as well as rivaroxaban 2.5 mg twice daily and dual antiplatelet therapy, reduced the occurrence of clinically significant bleeding when compared with triple therapy with warfarin, in addition to general or recurrent hospitalization due to adverse events.52,53

Conclusion

Antiplatelet pharmacotherapy plays a decisive role in the clinical and invasive management of ACS. The greater knowledge of the pathophysiology of the cascades involved in this process has allowed the advent of more effective types of treatment, often associated with an increased risk of bleeding. However, the safety of any prescription is paramount in contemporary practice, since hemorrhagic complications carry a high risk of morbidity and mortality. Many ongoing research studies keep this topic current, controversial, and subject to constant regulatory changes. Thus, by always guiding ourselves by common sense, individualized approaches, and estimation of risks and benefits, we can directly interfere in the patients' prognosis and evolution.

Sources of Funding

There were no external funding sources for this study.

Study Association

This study is not associated with any thesis or dissertation work.

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Boersma E Harrington RA Moliterno DJ White H Théroux P Van de Werf F Platelet glycoprotein IIb/IIIa inhibitors in acute coronary syndromes: a meta-analysis of all major randomised clinical trials Lancet 2002 359 9302 189 198 34 De Luca G, Navarese EP, Cassetti E, Verdoia M, Suryapranata H. Meta-analysis of randomized trials of glycoprotein IIb/IIIa inhibitors in high-risk acute coronary syndromes patients undergoing invasive strategy. Am J Cardiol. 2011;107(2):198-203. De Luca G Navarese EP Cassetti E Verdoia M Suryapranata H Meta-analysis of randomized trials of glycoprotein IIb/IIIa inhibitors in high-risk acute coronary syndromes patients undergoing invasive strategy Am J Cardiol 2011 107 2 198 203 35 De Luca G, Navarese E, Marino P. Risk profile and benefits from GP IIb-IIIa inhibitors among patients with ST-segment elevation myocardial infarction treated with primary angioplasty: a meta-regression analysis of randomized trials. Eur Heart J. 2009;30(22):2705-13. 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Early and sustained dual oral antiplatelet therapy following percutaneous coronary intervention: a randomized controlled trial JAMA 2002 288 19 2411 2420 Erratum in: JAMA. 2003;289(8):987 39 Montalescot G, Bolognese L, Dudek D, Goldstein P, Hamm C, Tanguay JF, et al; ACCOAST Investigators. Pretreatment with prasugrel in non-ST-segment elevation acute coronary syndromes. N Engl J Med. 2013;369(11):999-1010. Montalescot G Bolognese L Dudek D Goldstein P Hamm C Tanguay JF ACCOAST Investigators Pretreatment with prasugrel in non-ST-segment elevation acute coronary syndromes N Engl J Med 2013 369 11 999 1010 40 Montalescot G, van't Hof AW, Lapostolle F, Silvain J, Lassen JF, Bolognese L, et al. Prehospital ticagrelor in ST-segment elevation myocardial infarction. N Engl J Med. 2014;371(11):1016-27. Montalescot G van't Hof AW Lapostolle F Silvain J Lassen JF Bolognese L Prehospital ticagrelor in ST-segment elevation myocardial infarction N Engl J Med 2014 371 11 1016 1027 41 Kubika J, Adamski P, Ostrowska M, Sikora J, Kubica JM, Sroka WD, et al. Morphine delays and attenuates ticagrelor exposure and action in patients with myocardial infarction: the randomized, double-blind, placebo-controlled IMPRESSION trial. Eur Heart J. 2016;37(3):245-52. Kubika J Adamski P Ostrowska M Sikora J Kubica JM Sroka WD Morphine delays and attenuates ticagrelor exposure and action in patients with myocardial infarction: the randomized, double-blind, placebo-controlled IMPRESSION trial Eur Heart J 2016 37 3 245 252 42 Motovska Z, Hlinomaz O, Miklik R, Hromadka M, Varvarovsky I, Dusek J, et al. Prasugrel versus ticagrelor in patients with acute myocardial infarction treated with primary percutaneous coronary intervention: multicenter randomized PRAGUE-18 study. Circulation. 2016;134(21):1603-12. Motovska Z Hlinomaz O Miklik R Hromadka M Varvarovsky I Dusek J Prasugrel versus ticagrelor in patients with acute myocardial infarction treated with primary percutaneous coronary intervention: multicenter randomized PRAGUE-18 study Circulation 2016 134 21 1603 1612 43 Schulz S, Angiolillo DJ, Antoniucci D, Bernlochner I, Hamm C, Jaitner J, et al. Randomized comparison of ticagrelor versus prasugrel in patients with acute coronary syndrome and planned invasive strategy--design and rationale of the iNtracoronary Stenting and Antithrombotic Regimen: Rapid Early Action for Coronary Treatment (ISAR-REACT) 5 trial. J Cardiovasc Transl Res. 2014;7(1):91-100. 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Gibson CM Pinto DS Chi G Arbetter D Yee M Mehran R Recurrent hospitalization among patients with atrial fibrillation undergoing intracoronary stenting treated with 2 treatment strategies of rivaroxaban or a dose-adjusted oral vitamin k antagonist treatment strategy Circulation 2016 135 4 323 33 Artigos de Revisão Antiplaquetários nas Síndromes Coronarianas Agudas Andrade Pedro Beraldo de 1 Borges Leonardo Silva Roever 2 Hospital das Clínicas da Faculdade de Medicina de Marília - FAMEMA, Marília - SP Universidade Federal de Uberlândia (UFU), MG - Brasil Correspondência: Pedro Beraldo de Andrade, Avenida Brigadeiro Eduardo Gomes, 3551, casa A-9, Condomínio Costa do Ipê. CEP: 17514-000, Residencial Vale Verde, Marília, SP - Brasil. E-mail: pedroberaldo@gmail.com; pedroberaldo@cardiol.br

Contribuição dos autores

Concepção e desenho da pesquisa: Andrade PB, Borges LSR. Obtenção de dados: Andrade PB, Borges LSR. Análise e interpretação dos dados: Andrade PB, Borges LSR. Análise estatística: Andrade PB, Borges LSR. Redação do manuscrito: Andrade PB, Borges LSR. Revisão crítica do manuscrito quanto ao conteúdo intelectual importante: Andrade PB, Borges LSR.

Potencial Conflito de Interesse

Declaro não haver conflito de interesses pertinentes.

 Resumo

Em condições de equilíbrio, a hemostasia é mantida através de uma complexa interação entre endotélio, plaquetas e fatores de coagulação. Situações que cursam com injúria e descontinuidade do revestimento endotelial estimulam a adesão, ativação e agregação de plaquetas, culminando com a formação de trombos arteriais ou venosos. Neste contexto, a terapia antiplaquetária ocupa um papel de destaque no manejo das patologias advindas deste processo, notadamente as síndromes coronarianas agudas.O maior domínio conceitual dos receptores, agonistas e antagonistas das cascatas fisiopatológicas envolvidasneste processo possibilitou o desenvolvimento de novos fármacos e o refinamento da terapêutica atual, tornando necessário o pleno conhecimento do arsenal antiplaquetário no que tange à sua indicação, posologia, momento de administração e duração do tratamento. O objetivo desta revisão é definir o papel dos fármacos antiplaquetários no manuseio da síndrome coronariana aguda, revisitando aspectos já consolidados e abordando tópicos atuais e ainda controversos acerca do tema.

Palavras-chave Síndrome Coronariana Aguda Infarto do Miocárdio Inibidores da Agregação de Plaquetas Plaquetas Antifibrinolíticos. Introdução

A doença isquêmica do coração configura a principal causa mundial isolada de morte e perda de qualidade de vida.1 No Brasil, estima-se que ela esteja relacionada a uma taxa anual de aproximadamente 55 óbitos por 100.000 habitantes.2,3 A síndrome coronariana aguda (SCA), em seus diferentes espectros de manifestação, assume protagonismo nessas estatísticas, sendo os procedimentos de revascularização miocárdica e a farmacoterapia antitrombótica os pilares fundamentais de seu tratamento.

A hemostasia é um processo fisiológico mantido através de uma complexa interação entre endotélio, plaquetas e fatores de coagulação. Em condições emergenciais e de desequilíbrio, a hemostasia pode culminar na formação de trombos arteriais ou venosos, traduzindo-se na ocorrência de eventos coronarianos agudos, cerebrovasculares ou episódios de tromboembolismo. Neste contexto, de forma adjuvante à terapia anticoagulante, os fármacos antiplaquetários se destacam no manejo dessas condições.4

Situações que cursam com injúria e descontinuidade do revestimento endotelial estimulam a adesão de plaquetas a proteínas da matriz subendotelial. Essa interação ativa sinais intracelulares que promovem a liberação de difosfato de adenosina (ADP), adrenalina, serotonina, trombina e tromboxano A2, potentes agonistas da ativação plaquetária. Uma vez que as plaquetas são ativadas, ocorre a ligação dos complexos de glicoproteína IIb-IIIa ao fibrinogênio, constituindo a etapa final da agregação das plaquetas e geração do trombo.5

Os fatores ativadores deste processo e dos receptores envolvidos nele se tornaram alvos para o desenvolvimento de agentes antitrombóticos. A medicina baseada em evidências possibilitou o advento, implementação e refinamento da abordagem terapêutica atual. Entretanto, mediante uma maior expectativa de vida da população e a coexistência de múltiplas comorbidades, deparamo-nos frequentemente com cenários clínicos nos quais o risco de complicações isquêmicas caminha lado a lado ao risco de complicações hemorrágicas.6 Assim, faz-se necessário um domínio pleno do arsenal antiplaquetário no que tange à sua indicação, dosagem e momento de administração.

O objetivo desta revisão é definir o papel dos fármacos antiplaquetários no manuseio da SCA, revisitando aspectos já consolidados e abordando tópicos atuais e ainda controversos acerca deste tema.

 Desenvolvimento a) Ácido acetilsalicílico

O ácido acetilsalicílico (AAS) em baixa dosagem inibe seletivamente a cicloxigenase (COX)-1, determinando atividade antiplaquetária, ao passo que em doses elevadas inibe a COX-1 e a COX-2, com efeitos anti-inflamatórios e analgésicos. Sua absorção é rápida, com pico de concentração plasmática obtido após 30 minutos da ingestão da formulação regular e 4 horas após a formulação de liberação entérica.7

Tendo em vista que os efeitos colaterais gastrointestinais do AAS aumentam proporcionalmente à sua dose, recomenda-se na SCA uma dose de ataque de 150-325 mg via oral (engolido se formulação regular e mastigado se formulação entérica), ou 80-150 mg por via intravenosa em locais que dispõem desta apresentação, seguido por 81-100 mg como manutenção.8 No estudo pioneiro Second International Study of Infarct Survival (ISIS)-2, o AAS promoveu redução significativa de 23% na mortalidade cardiovascular comparado a placebo após 5 semanas de tratamento em pacientes com infarto agudo do miocárdio (IAM) com supradesnivelamento do segmento ST, sendo esse efeito aditivo e sinérgico quando associado à estreptoquinase, reduzindo em 42% a taxa de eventos.(9 )Tais benefícios foram corroborados por diversos estudos subsequentes e pela compilação de seus dados em grandes metanálises, tornando-se assim um dos pilares da farmacoterapia antitrombótica nos diferentes espectros da SCA.10

São raras as situações que configuram uma clara contraindicação ao AAS, com destaque para sangramentos digestivos ativos e hipersensibilidade conhecida (urticária, broncoespasmo ou anafilaxia), embora estejam descritos diferentes protocolos para dessensibilização que permitem seu uso crônico com eficácia e segurança comprovadas.11

b) Antagonistas do receptor plaquetário P2Y<sub>12</sub>

A associação entre AAS e um antagonista do receptor P2Y12, denominada terapia antiplaquetária dupla, representa a base do tratamento de pacientes com SCA e daqueles submetidos à intervenção coronária percutânea (ICP). A ticlopidina é um derivado tienopiridínico de primeira geração que, a despeito de sua eficácia e em virtude de seus efeitos colaterais hematológicos (trombocitopenia, anemia aplásica, púrpura trombocitopênica trombótica, neutropenia) e gastrointestinais, foi rapidamente substituída pelo clopidogrel.12

b.1) Clopidogrel

O clopidogrel é um agente tienopiridínico que bloqueia de forma irreversível o receptor P2Y12. O estado de equilíbrio na inibição da função plaquetária com o clopidogrel é alcançado pela dose de manutenção de 75 mg após 5-7 dias de seu início, ao passo que com a administração de doses de ataque de 300 mg e 600 mg, esse efeito é atingido em 6 e 2 horas, respectivamente, aspecto relevante no contexto das emergências médicas.13

No histórico ensaio clínico Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE), 12.562 pacientes com SCA sem supradesnivelamento do segmento ST tratados com AAS foram randomizados para tratamento com clopidogrel ou placebo por um período de 3 a 12 meses.14 O grupo clopidogrel exibiu uma redução significativa de 20% no risco de morte cardiovascular, reinfarto ou acidente vascular encefálico (AVE) comparado ao grupo placebo, sendo que o benefício já é aparente nas primeiras horas após o início da terapia e independente da realização de estratificação invasiva. No cenário do IAM com supradesnivelamento do segmento ST, dois importantes estudos validaram o clopidogrel como terapêutica adjuvante efetiva. Entre 3.491 pacientes randomizados para 300 mg de ataque e 75 mg de manutenção de clopidogrel contra placebo no ensaio clínico Clopidogrel as Adjunctive Reperfusion Therapy-Thrombolysis in Myocardial Infarction (CLARITY-TIMI) 28, dos quais 99,7% foram submetidos à trombólise, constatou-se uma redução de 36% no risco de óbito, IAM recorrente ou artéria coronária relacionada ao infarto ocluída no momento da angiografia.15 Já no estudo Clopidogrel and Metoprolol in Myocardial Infarction Trial (COMMIT), dentre 45.852 pacientes randomizados, sendo 50% submetidos à trombólise, a administração de uma dose diária de 75 mg de clopidogrel por um período médio de 28 dias promoveu redução de 9% nas taxas de morte, reinfarto ou AVE comparada a placebo.16

Assim, amparado pelos resultados de ensaios clínicos randomizados em SCA e pelas características farmacodinâmicas e farmacocinéticas do clopidogrel, recomenda-se uma dose de ataque de 600 mg para pacientes com previsão de estratificação de risco invasiva ou encaminhados para ICP primária e de 300 mg para pacientes submetidos à terapia fibrinolítica. Exceção deve ser adotada em pacientes trombolisados com idade ≥ 75 anos, onde se omite a dose de ataque. Na ausência de um benefício claro com a utilização de uma dose dobrada (150 mg) na manutenção do clopidogrel, esta deve ser de 75 mg.8

Entretanto, o clopidogrel exibe limitações e necessidades não atendidas, em parte explicadas por suas propriedades, como um início de ação e término lentos e potencial de inibição plaquetária limitado. A variabilidade interindividual à ação do fármaco é grande, estimando-se em até 35% o porcentual de pacientes que exibem uma resposta terapêutica inadequada.17 Os mecanismos envolvidos são multifatoriais e incluem interações medicamentosas (ex.: inibidores da bomba de prótons como omeprazol e esomeprazol), o ambiente e comorbidades clínicas (ex.: aderência à terapêutica, tabagismo, diabetes mellitus, obesidade, SCA), além de polimorfismos genéticos, com ênfase aos alelos determinantes de perda de função do CYP2C19.18 Sabe-se que pacientes portadores destas variantes exibem maior risco de trombose de stent, recorrência de IAM e morte.19 Porém, apesar de ser assunto ainda sob o escrutínio de estudos em andamento, as evidências hoje disponíveis não endossam a individualização da terapia baseada no resultado de testes genéticos ou da mensuração da função plaquetária.20,21 Com isso, abriu-se um vasto campo de pesquisas com diferentes propostas de tratamento, novos fármacos antagonistas do receptor P2Y12 e bloqueio de novos alvos na superfície das plaquetas.

 b.2) Prasugrel

Assim como o clopidogrel, o tienopiridínico de segunda geração prasugrel é uma pró-droga e requer biotransformação para se tornar um metabólito ativo. Entretanto, possui um início de ação mais precoce, cerca de 30 minutos após a administração de uma dose de ataque de 60 mg, além de uma reposta mais previsível, pela ampla absorção, necessidade de uma única etapa de oxidação mediada pelo CYP3A4 e CYP2B6, conferindo maior biodisponibilidade, maiores níveis de inibição plaquetária e menor variabilidade de resposta entre os pacientes.22

No ensaio clínico Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel (TRITON)-TIMI 38, 13.608 pacientes admitidos por SCA com ou sem supradesnivelamento do segmento ST submetidos à ICP foram randomizados para receber prasugrel 60 mg de ataque e 10 mg de manutenção ou clopidogrel 300 mg de ataque e 75 mg de manutenção por até 15 meses.23 O tratamento com prasugrel mostrou-se superior com uma redução significativa de 19% no risco de morte cardiovascular, IAM ou AVE não fatal, com destaque para a redução de infarto (24%) e trombose de stent (52%), sendo o benefício ainda maior entre os pacientes com diabetes.

Consistente com a maior potência antiplaquetária do prasugrel, o estudo constatou um aumento significativo de 32% no risco de sangramento grave, incluindo sangramentos fatais e ameaçadores à vida. Em alguns perfis de pacientes, o benefício clínico líquido, no qual se pesa a eficácia anti-isquêmica e a segurança, mostrou-se desfavorável ao prasugrel, incluindo em pacientes com passado de AVE ou acidente isquêmico transitório (AIT), com idade ≥ 75 anos e peso corporal < 60 kg. Nestes dois últimos, mediante a necessidade de prescrição do fármaco e na impossibilidade de alternativas terapêuticas, recomenda-se o uso de dose de manutenção de 5 mg.24 Não há, até o momento, indicações para a prescrição de prasugrel a pacientes com SCA que não realizaram ICP, bem como em janela de tempo outra que após o conhecimento da anatomia coronariana e efetivação do procedimento intervencionista. Em pacientes com indicação de cirurgia de revascularização miocárdica, o prasugrel deve idealmente ser suspenso por 7 dias.

 b.3) Ticagrelor

Primeiro representante clinicamente disponível da classe denominada ciclopentiltriazolopirimidina, o ticagrelor é um antagonista reversível do receptor P2Y12, exercendo seu efeito inibitório através de uma ligação não covalente a um sítio de ligação plaquetário distinto do ADP. Diferentemente dos fármacos tienopiridínicos, o ticagrelor não é uma pró-droga e apresenta ação imediata após sua absorção oral. Exibe, assim, um rápido início de ação após a ingestão de uma dose de ataque de 180 mg e com pico de ação em 2 horas. Com meia-vida plasmática de 8-12 horas, o ticagrelor exige uma dose de manutenção de 90 mg a cada 12 horas e por ligar-se ao receptor de modo reversível, apresenta um término de ação mais precoce, ao redor de 2-3 dias, embora sua bula recomende a suspensão por 5 dias que antecedam uma intervenção cirúrgica. Uma vez que o metabolismo do ticagrelor é mediado pelo CYP3A4 ou CYP3A45, deve-se evitar a administração concomitante de fortes indutores ou inibidores do CYP3A4 durante a sua utilização.25

No ensaio clínico Platelet Inhibition and Patient Outcomes (PLATO), 18.624 pacientes representativos de todas as manifestações da SCA (com única exceção daqueles com IAM com supradesnivelamento do segmento ST submetidos à trombólise) foram randomizados para receber ticagrelor ou clopidogrel pelo período de 12 meses.26 No braço ticagrelor, houve uma redução significativa de 16% no risco de morte cardiovascular, IAM ou AVE. Em uma análise hierárquica pré-especificada, o ticagrelor reduziu isoladamente a ocorrência de morte cardiovascular (21%), IAM (16%) e trombose definitiva de stent (33%), sem diferença quanto à taxa de sangramento grave ou fatal. Apesar da consistência dos resultados obtidos entre os diversos subgrupos analisados, constatou-se uma interação entre pacientes tratados na América do Norte e no resto do mundo, sem um benefício claro do ticagrelor no primeiro grupo. Credita-se o uso de doses elevadas de manutenção do AAS (≥ 200 mg) como provável justificativa a esse achado, motivando um alerta para a prescrição de doses < 200 mg no uso crônico.27

O ticagrelor exibe efeitos pleiotrópicos não mediados por seu bloqueio do receptor P2Y12, como a inibição da captação de adenosina pelos eritrócitos, o que aumenta o nível circulante de adenosina.28 Sabidamente, a adenosina possui inúmeras propriedades, incluindo vasodilatação coronariana, redução de isquemia e injúria de reperfusão, inibição de respostas inflamatórias a condições de estresse, efeito cronotrópico e dromotrópico negativo, redução da taxa de filtração glomerular e estimulação de fibras C vagais nos pulmões. Estes efeitos ainda estão em investigação e justificariam, entre os usuários de ticagrelor, a maior prevalência de dispneia, porém sem alteração de provas de função pulmonar, de pausas ventriculares sem repercussão clínica ou necessidade de marcapasso definitivo, elevação dos níveis séricos de creatinina e ácido úrico, bem como maior estabilidade elétrica e redução de mortes súbitas arrítmicas, esta última em caráter especulativo.29,30

A Tabela 1 fornece uma compilação das principais indicações, dosagens e recomendações acerca da prescrição dos antagonistas do receptor P2Y12 nas SCAs.

Indicações dos antagonistas do receptor P2Y12 nas síndromes coronarianas agudas
Fármaco Indicação Dose de ataque Dose de manutenção Duração do tratamento Suspensão para cirurgia
Clopidogrel IAM com supradesnível de ST pós-trombólise 300 mg* 75 mg/dia 1 ano 5 dias
Clopidogrel SCA sem supradesnível de STICP primária 300-600 mg 75 mg/dia 1 ano 5 dias
Prasugrel SCA tratada com ICP 60 mg 10 mg/dia† 1 ano 7 dias
Ticagrelor SCA (exceto pós-trombólise) 180 mg 90 mg de 12/12 horas 1 ano 3-5 dias

IAM: infarto agudo do miocárdio; SCA: síndrome coronariana aguda; ICP: intervenção coronariana percutânea.

Omite-se a dose de ataque se idade ≥ 75 anos.

Dose de manutenção de 5 mg se peso < 60 kg ou idade ≥ 75 anos.

c) Inibidores da glicoproteína IIb-IIIa

Os inibidores da glicoproteína (IGPs) IIb-IIIa aprovados para uso clínico - abciximabe, tirofibana e epitifibatide - constituem potentes antagonistas plaquetários de administração parenteral, sendo apenas os dois primeiros comercializados no Brasil. As características farmacológicas destes encontram-se resumidas na Tabela 2.

Propriedades farmacológicas dos inibidores da glicoproteína IIb-IIIa
Abciximabe Tirofibana
Estrutura Anticorpo monoclonal Antagonista não peptídico
Peso molecular 48 kDa < 1 kDa
Início de ação Rápido Rápido
Reversibilidade Lenta (12 horas) Rápida (2 horas)
Meia-vida 10-30 minutos 2 horas
Excreção Desconhecida Renal (40-70%) e biliar
Dose de ataque 0,25 mg/kg 25 µg/kg
Dose de manutenção 0,125 µg/kg/min por 12 horas 0,15 µg/kg/min por 18 horas
Ajuste de dose Não ↓ 50% se clearance ≤ 30 mL/min

O abciximabe é um anticorpo monoclonal com alta afinidade pelos receptores da glicoproteína IIb-IIIa. Após dose de ataque de 0,25 mg/kg, observa-se um bloqueio superior a 80% dos receptores, com redução da agregação plaquetária em resposta ao estímulo pelo ADP a menos de 20% do valor basal. Essa inibição é mantida pela infusão contínua de abciximabe a uma dose de 0,125 µg/kg/min, até um máximo de 10 µg/min. Relata-se a ocorrência de trombocitopenia em 1-4% dos pacientes tratados com o fármaco, comumente detectada nas primeiras 24 horas e em até 2 horas após o início de sua administração. Acredita-se que seja uma complicação mediada por anticorpos, com reversão na maior parte dos casos após sua suspensão, sendo por vezes necessária a transfusão de plaquetas.31

A tirofibana é um derivado tirosínico não peptídico que age através de bloqueio reversível e seletivo do receptor de glicoproteína IIb-IIIa, impedindo sua ligação ao fibrinogênio e ao fator de von Willebrand. De excreção renal e biliar, a tirofibana possui meia-vida plasmática de 1,5-2 horas, sendo o ajuste de dose necessário em pacientes com insuficiência renal com depuração de creatinina ≤ 30 mL/min e dispensado em casos de doença hepática. Quando administrada em dose de ataque de 25 µg/kg, a tirofibana exibe eficácia equivalente à do abciximabe. Casos de trombocitopenia grave, embora raros e reversíveis, também foram relatados. Atribui-se a ocorrência da trombocitopenia grave a um fenômeno imunomediado, uma vez que a ligação da tirofibana promove uma alteração conformacional no receptor, com a geração de anticorpos contra o novo epítopo exposto.32

As evidências que validaram a utilização de IGP IIb-IIIa na ICP, dada sua capacidade de redução de IAM periprocedimento e necessidade de revascularização de urgência, originaram-se sobretudo de estudos clínicos conduzidos anteriormente ao advento dos tienopiridínicos e implante rotineiro de stents. Na era contemporânea da cardiologia intervencionista, metanálises foram realizadas com o intuito de avaliar o real papel desempenhado por esses agentes como terapia adjuvante à ICP.

No tratamento da SCA sem supradesnivelamento do segmento ST, uma metanálise envolvendo 31.402 pacientes demonstrou um benefício discreto mas significativo na redução de morte e IAM aos 30 dias favorável à utilização dos IGP IIb-IIIa, notadamente entre os pacientes considerados de alto risco (ex.: pacientes com marcadores de necrose miocárdica positivos, elevada carga trombótica, ou lesões complexas).33 Uma metanálise reunindo sete estudos randomizados e 19.929 pacientes avaliou o momento mais adequado para a administração de IGP IIb-IIIa.34 A estratégia de infusão precoce, anterior à admissão do paciente ao laboratório de intervenção, não reduziu a incidência de mortalidade aos 30 dias, bem como de IAM recorrente. No entanto, associou-se a uma maior taxa de sangramento grave.

Embora a ICP primária reduza a mortalidade quando comparada à fibrinólise, observa-se reperfusão subótima em uma proporção não desprezível de pacientes, atribuindo-se à embolização distal um papel central na gênese deste fenômeno. Neste sentido, houve um grande interesse no papel dos IGP IIb-IIIa neste cenário clínico. Uma metanálise incluindo grandes ensaios clínicos contemporâneos conduzidos na vigência de pré-tratamento com clopidogrel e totalizando 10.085 pacientes, analisou a eficácia e segurança dos IGP IIb-IIIa como terapia adjunta à ICP primária no IAM com supradesnivelamento do segmento ST.35 Não se constatou redução de mortalidade aos 30 dias com a utilização desses inibidores, ou de recorrência de IAM, porém houve um aumento na taxa de sangramento grave. No entanto, empregando-se uma análise de metarregressão, observou-se um benefício favorável aos IGP IIb-IIIa entre os pacientes de maior risco (idade ≥ 65 anos, instabilidade hemodinâmica, IAM anterior, diabéticos).

Mediante a hipótese de que maior concentração local de abciximabe potencializaria seus efeitos antiplaquetários, antitrombóticos e anti-inflamatórios, testou-se a administração intracoronariana deste medicamento em bolus durante a ICP primária. Uma metanálise incluindo seis estudos randomizados e 1.246 pacientes concluiu que, comparada à infusão intravenosa, a administração intracoronariana de abciximabe promoveu redução significativa de 57% de mortalidade e de 43% na necessidade de revascularização do vaso-alvo aos 30 dias, sem incremento na taxa de sangramento grave, embora esses achados não tenham sido confirmados em um grande estudo randomizado subsequente envolvendo 2.065 pacientes.36,37

Assim, os IGP IIb-IIIa desempenham um importante papel como terapia adjunta à ICP, mas sua prescrição fica restrita a situações não programadas, sobretudo no laboratório de intervenção, com destaque aos pacientes com SCA sem supradesnível do segmento ST de alto risco e sem tratamento prévio com inibidores do receptor P2Y12, à presença de complicações trombóticas durante a ICP (oclusão abrupta do vaso, fluxo epicárdico lento, dissecção coronariana, oclusão de ramo lateral), ao IAM com supradesnivelamento do segmento ST em pacientes de alto risco ou diante de grande carga trombótica. Fundamentando a opção pela administração desses agentes, deve-se considerar o perfil de risco dos pacientes para a ocorrência de eventos hemorrágicos, sabidamente promotores de maior morbimortalidade.

Embora a utilização de IGP IIb-IIIa não tenha influenciado a eficácia dos novos fármacos antiplaquetários orais (ticagrelor, prasugrel) no tratamento das SCA, seu emprego em pacientes tratados com os novos inibidores do receptor P2Y12, assim como mediante variantes genéticas do CYP2C19, hiporresponsividade ao clopidogrel, ou opção por redução ou supressão de sua dose de manutenção, requer novas investigações.

 d) Pré-tratamento com antagonistas do receptor P2Y<sub>12</sub>

Na fase aguda da SCA, cenário caracterizado por um estado pró-trombótico e por intensa ativação de plaquetas, a dupla antiagregação plaquetária representa uma importante etapa terapêutica, sendo intuitivo supor que uma potente e precoce ação farmacológica seja capaz de conferir eficácia anti-isquêmica, com redução de eventos trombóticos (infarto periprocedimento, trombose de stent, reoclusão coronariana), notadamente entre pacientes submetidos à estratificação de risco invasiva e ICP. Entretanto, contrapontos ao pré-tratamento com antagonistas do receptor P2Y12 incluem um aumento na prevalência de complicações hemorrágicas advindas da terapia antitrombótica, assim como um eventual retardo na instituição do tratamento cirúrgico em pacientes multiarteriais com indicação de revascularização prolongando o tempo de hospitalização e aumentando o risco de sangramentos relacionados à cirurgia. No momento, são escassas as evidências advindas de ensaios clínicos randomizados com casuística e poder estatístico adequado para uma resposta clara e definitiva ao tema.

Dentre os estudos pioneiros que sugerem o benefício da terapia antiplaquetária dupla precoce e iniciada imediatamente após o diagnóstico está o Clopidogrel for the Reduction of Events During Observation (CREDO), que randomizou 2.116 pacientes, dos quais 66% com diagnóstico de SCA.38 O objetivo do estudo era avaliar o benefício de uma dose de ataque de 300 mg de clopidogrel 3-24 horas antes da realização de ICP, bem como da manutenção da terapia dupla por 12 meses. O pré-tratamento com clopidogrel foi associado a uma redução não significativa de 18% no risco de óbito, IAM ou revascularização de urgência aos 28 dias. Entretanto, em uma análise pré-especificada de subgrupos, constatou-se uma redução significativa de 38,6% no desfecho primário em pacientes cuja terapêutica fora iniciada 6 horas antes da ICP, fundamentando conceitualmente a adoção dessa estratégia.

Na era dos novos e potentes inibidores do receptor P2Y12, o estudo Comparison of Prasugrel at the Time of Percutaneous Coronary Intervention or as Pretreatment at the Time of Diagnosis in Patients with Non-ST Elevation Myocardial Infarction (ACCOAST) randomizou 4.033 pacientes com SCA sem supradesnivelamento do segmento ST para receberem uma dose de ataque de 30 mg de prasugrel no momento do diagnóstico (pré-tratamento), acrescida de 30 mg em caso de ICP, comparada a 60 mg imediatamente antes do procedimento.39 O desfecho primário de eficácia, composto por morte cardiovascular, IAM, AVE, revascularização de urgência ou uso não programado de IGP IIb-IIIa aos 7 dias não diferiu entre os grupos, ao passo que o desfecho de segurança, ocorrência de sangramento grave pela classificação TIMI, foi quase o dobro entre aqueles pré-tratados com prasugrel, sendo assim desaconselhado seu uso nessas circunstâncias.

Embora no estudo PLATO o ticagrelor tenha sido administrado precocemente, antecedendo a estratificação invasiva, o estudo não realizou uma comparação entre o pré-tratamento ou não com o fármaco. Já no estudo Administration of Ticagrelor in the Cath Lab or in the Ambulance for New ST Elevation Myocardial Infarction to Open the Coronary Artery (ATLANTIC), 1.862 pacientes com IAM com supradesnivelamento do segmento ST foram randomizados para uma dose de ataque de 180 mg de ticagrelor antes da transferência para ICP primária, incluindo no transporte pré-hospitalar, contra uma dose de ataque administrada no laboratório de intervenção.40 A resolução do supradesnivelamento do segmento ST ≥ 70% ou fluxo TIMI 3 na artéria relacionada ao infarto no momento da angiografia, desfechos substitutos que consistiram na hipótese de investigação do estudo, não diferiu entre as estratégias. Os autores observaram uma interação altamente significativa relacionada ao uso de morfina pré-hospitalar, evidenciando um benefício no objetivo primário entre pacientes que não fizeram uso do derivado opioide. Estudos em andamento estão avaliando os efeitos da morfina nas propriedades farmacocinéticas e farmacodinâmicas dos inibidores do receptor P2Y12.41 Um interessante achado em um dos desfechos secundários do estudo, relativo à ocorrência de trombose definitiva do stent aos 30 dias, consistiu na redução significativa dessa complicação favorecendo o pré-tratamento, a despeito de uma diferença de apenas 31 minutos entre a administração do fármaco nos dois grupos. Trata-se de uma evidência, embora geradora de hipótese, que fornece sustentação ao início precoce da dupla antiagregação.

Comparações diretas entre ticagrelor e prasugrel fazem-se necessárias. Um estudo randomizado avaliando a ocorrência de complicações isquêmicas ou hemorrágicas em 1.230 pacientes com diagnóstico de IAM submetidos à ICP não demonstrou diferença entre os fármacos, sendo prematuramente interrompido por futilidade.42 Desenhado para acessar a superioridade do ticagrelor frente ao prasugrel em 4.000 pacientes com SCA e planejamento de estratificação invasiva, o estudo Rapid Early Action for Coronary Treatment (ISAR-REACT) 5, dotado de maior robustez estatística, contribuirá para a definição das normativas futuras.(43 )Por sua vez, o cotejamento entre o pré-tratamento ou não com dupla antiagregação plaquetária será investigado no ensaio clínico Downstream Versus Upstream Strategy for the Administration of P2Y12 Receptor Blockers (DUBIUS), atualmente em andamento, que prevê a inclusão de 2.520 pacientes com SCA sem supradesnivelamento do segmento ST submetidos à estratégia invasiva precoce (NCT02618837).

 e) Duração ideal da terapia antiplaquetária dupla

A dupla inibição plaquetária por um período de 1 ano é recomendada a pacientes com diagnóstico de SCA, sobretudo aqueles submetidos à revascularização miocárdica percutânea, independentemente do tipo de stent; esta recomendação é fundamentada em resultados de ensaios clínicos randomizados como o CURE e, mais recentemente, TRITON-TIMI 38 e PLATO, que apontam um benefício precoce e contínuo da terapia antiplaquetária dupla ao longo de 12 meses de tratamento.44,45

Tópico recente de discussão refere-se à manutenção da terapia antiplaquetária dupla por período de tempo superior a 12 meses entre indivíduos submetidos à ICP. Uma metanálise englobando seis ensaios clínicos randomizados e 33.435 pacientes com histórico de IAM prévio demonstrou que estender a dupla antiagregação após 1 ano promove redução significativa de eventos cardiovasculares adversos combinados quando comparada à monoterapia com AAS, demonstrando ainda redução isolada de morte cardiovascular, IAM, AVE e trombose de stent à custa do incremento na ocorrência de sangramento grave.46

Assim, a prescrição de terapia antiplaquetária dupla por período superior a 12 meses em pacientes submetidos à ICP na vigência de uma SCA pode ser considerada.47 Tal decisão deve-se pautar na análise de risco e benefício, ofertando esta opção aos pacientes predispostos à recorrência de eventos isquêmicos (ex.: IAM prévio; diabetes mellitus; disfunção ventricular esquerda; tipo, diâmetro e extensão do stent implantado; insuficiência renal crônica; insuficiência arterial periférica) mas que não exibam risco elevado de sangramento. A adoção de escores de risco mostra-se uma ferramenta auxiliar no processo de decisão, devendo prevalecer um julgamento clínico ponderado e principalmente a individualização de condutas. Outros tópicos especulativos de interesse e sob investigação atual consistem na monoterapia a longo prazo com agente antiplaquetário de maior potência inibitória, como o ticagrelor (NCT01813435; NCT02270242), bem como na associação entre um inibidor P2Y12 e inibidores do fator Xa, em detrimento ao AAS, no manejo de pacientes com SCA.48

f) Pacientes que requerem anticoagulação oral

Pacientes com fibrilação atrial, episódio recente de tromboembolismo venoso e portadores de próteses valvares mecânicas podem requerer ICP na vigência de uma SCA. Neste cenário, a conduta envolve terapêutica tripla, composta por um agente anticoagulante e dois fármacos antiplaquetários, incluindo o AAS, situação que eleva exponencialmente o risco de complicações hemorrágicas.49 Considerando-se a maior potência e ausência atual de evidências científicas, deve-se evitar o uso de prasugrel ou ticagrelor, sendo o clopidogrel o antagonista P2Y12 de escolha nessa situação. A redução na duração da terapia tripla agregaria maior segurança ao tratamento, com interrupção de um antiplaquetário assim que possível.50 Embora existam fluxogramas propostos por consenso de especialistas (Figura 1), o tema ainda é controverso e pesquisas em andamento avaliando a eficácia e segurança dos novos anticoagulantes orais associados a clopidogrel ou ticagrelor influenciarão as normativas futuras acerca do tema.

Terapia tripla após intervenção coronariana percutânea na síndrome coronariana aguda em pacientes que requerem anticoagulação oral. Fonte: Adaptado de Roffi et al.44

No estudo What is the Optimal antiplatElet and Anticoagulant Therapy in Patients with Oral Anticoagulation and Coronary StenTing (WOEST), 573 pacientes em uso de anticoagulação oral com varfarina submetidos à ICP, dos quais aproximadamente 30% na vigência de uma SCA, foram randomizados para receber clopidogrel isolado ou em associação com AAS.51 Ao final de 1 ano de acompanhamento, a terapia tripla promoveu um aumento significativo no risco de sangramento, incluindo as manifestações graves, sem benefício na redução de morte, IAM, AVE, revascularização do vaso-alvo ou trombose de stent. Amparado por essa hipótese investigativa, o ensaio Open-Label, Randomized, Controlled, Multicenter Study Exploring Two Treatment Strategies of Rivaroxaban and a Dose-Adjusted Oral Vitamin K Antagonist Treatment Strategy in Subjects with Atrial Fibrillation who Undergo Percutaneous Coronary Intervention (PIONEER AF-PCI) demonstrou que a associação entre rivaroxabana 15 mg e um inibidor P2Y12, bem como rivaroxabana 2,5 mg duas vezes ao dia e terapia antiplaquetária dupla, reduziu a ocorrência de sangramento clinicamente significante quando comparados à terapia tripla com varfarina, além de mortalidade geral ou hospitalização recorrente por eventos adversos.52,53

Conclusão

A farmacoterapia antiplaquetária ocupa um papel decisivo no manejo clínico e invasivo das SCAs. O maior conhecimento fisiopatológico das cascatas envolvidas neste processo possibilitou o advento de formas mais eficazes de tratamento trazendo, muitas vezes, um maior risco de sangramento. Entretanto, a segurança de qualquer prescrição mostra-se primordial na prática contemporânea, uma vez que as complicações hemorrágicas carreiam um elevado risco de morbimortalidade. Muitas pesquisas em andamento tornam o tópico atual, controverso e sujeito a constantes mudanças de normativas. Assim, pautando-nos sempre pelo bom senso, individualização de condutas e estimativa de riscos e benefícios, podemos interferir de forma direta no prognóstico e evolução dos pacientes.

Fontes de Financiamento

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Vinculação Acadêmica

Não há vinculação deste estudo a programas de pós-graduação.