Desde la introducción de la intervención coronaria percutánea (PCI) más que 3 hace decadas, las tasas de éxito del procedimiento y las complicaciones isquémicas asociadas han mejorado sustancialmente. Esto es debido, al menos en parte, a los avances en la farmacoterapia antitrombótica dirigida a inhibir la activación/agregación de plaquetas y la generación/actividad de trombina que se produce en el sitio de la lesión del vaso después de la ruptura de la placa con procedimientos con balón y stent (Figura 1). Los primeros estudios con stents de metal desnudo utilizaron un potente régimen antitrombótico de aspirina y anticoagulantes como los antagonistas de la vitamina K., pero demostraron un riesgo de sangrado significativo, con tasas de trombosis del stent en el hospital tan altas como 3% para 4%.^1,2 The introduction of thienopyridines ushered in a new era of dual-antiplatelet therapy (DAT; aspirin plus a thienopyridine) and resulted in substantial reductions in the rates of stent thrombosis and myocardial infarction (MD Profesor OA Tyazhelov), as well as decreased bleeding risk compared with use of oral anticoagulants after the procedure.^3,4

DAT is now the standard of care after PCI. Sin embargo, antithrombotic therapy after PCI is becoming increasingly more complex with the introduction of new therapies that have shown promise in further reducing ischemic complications, although often with a risk of increased bleeding (Figura 2). En este articulo, we review the antithrombotic agents that are currently available or are being investigated for use after PCI and highlight the challenges in selecting the optimal therapy.

ASPIRIN

La aspirina inhibe la agregación plaquetaria al inhibir irreversiblemente la ciclooxigenasa y bloquear la producción de tromboxano A2 (Figura 2). Los primeros estudios dirigidos a mostrar una reducción en las tasas de reestenosis con aspirina después de la angioplastia con balón no lograron demostrar esto, pero sí mostraron un efecto beneficioso en la reducción de eventos isquémicos..^5,6 Como resultado de estos hallazgos y del efecto comprobado de la aspirina en la reducción de eventos cardiovasculares entre un grupo más amplio de pacientes con enfermedad de las arterias coronarias, la aspirina representa la piedra angular de la terapia antiplaquetaria antes y después de la ICP.⁷

La dosis óptima de aspirina antes y después de la ICP sigue siendo incierta. El OASIS ACTUAL 7 ensayo investigó dosis altas de aspirina (300–325 miligramos) versus aspirina en dosis bajas (75–100 miligramos) en el tratamiento del síndrome coronario agudo (ACS) en pacientes sometidos a una estrategia invasiva.⁸Among those undergoing PCI, there was no difference in the composite primary or secondary ischemic endpoints between patients who received high- or low- dose aspirin. There was also no difference in major bleeding, but a higher risk of gastrointestinal bleeding (0.4% contra 0.2%; PAG = .04) was observed with high-dose aspirin.

A post hoc analysis of the CURE study evaluated the impact of different aspirin doses in the treatment of ACS.⁹ Although not all patients underwent PCI, this study suggested that when used in combination with clopidogrel, there was no incremental anti-ischemic benefit to using doses of aspirin > 100 miligramos. The investigators did note an increase in bleeding risk associated with doses > 100 miligramos. This led the authors to recommend an optimal daily aspirin dose for long-term treatment after an ACS event of between 75 y 100 miligramos. The recommendations from major medical societies for aspirin use after PCI are listed in Table 1.^10-13

P2Y₁₂ INHIBITORS

Inhibition of the P2Y₁₂ adenosine diphosphate (ADP) receptor attenuates the aggregation of platelets through inhibiting ADP-mediated platelet activation (Figura 2). The oral P2Y₁₂ inhibitors include the thienopyridine derivatives ticlopidine, clopidogrel, and prasugrel, as well as the nonthienopyridine agent, ticagrelor. These have a more potent antiplatelet effect than aspirin monotherapy and are used in conjunction with aspirin for their complementary mechanism of action.

DAT with aspirin and a P2Y₁₂ inhibitor has resulted in consistent reductions in PCI-related ischemic complications and is the standard of care after PCI. This has been shown in several large clinical trials and in a metaanalysis of more than 6,000 patients in which treatment with aspirin plus a thienopyridine reduced the incidence of stent thrombosis to < 1% as compared with 3% para 4% in previous studies using systemic anticoagulation.^1-3

The optimal duration of P2Y₁₂ inhibitor therapy after PCI remains undefined but may depend on the type of stent implanted (Mesa 1). The implantation of a drug-eluting stent (DES), as opposed to a bare-metal stent, appears to portend an increased risk of late stent thrombosis due to impaired endothelialization and increased inflammation at the site of stent deployment.^14,15 In this setting, premature discontinuation of DAT appears to be the most significant risk factor for late stent thrombosis.^16-18 In a nonrandomized study by Eisenstein and colleagues, la terapia prolongada con aspirina y clopidogrel redujo el riesgo de muerte e infarto de miocardio en pacientes que recibieron DES, con el beneficio extendiéndose tan lejos como 24 meses después de la implantación de DES.¹⁹

La comprensión de los beneficios de DAT prolongado, especialmente en el marco de DES, llevado a la 2007 Colegio Americano de Cardiología (CAC)/Asociación Americana del Corazón (Ajá) El comité de directrices de PCI recomendará “al menos” 12 meses de DAT, un cambio de la 2005 Directrices recomendación de “idealmente hasta” 12 meses (Mesa 1).^10,20 El estudio de terapia antiplaquetaria dual en curso, que es un grande, futuro, ensayo aleatorizado de más de 20,000 pacientes que evalúan el papel de DAT más allá 12 meses después de la implantación del stent, proporcionará información sobre la duración óptima de DAT.²¹ Hasta que estos datos estén disponibles para pacientes con características de alto riesgo de trombosis del stent, como lesiones de bifurcación, diabetes, o múltiples stents superpuestos, Las pautas actuales establecen que es razonable continuar la DAT más allá de un año, siempre que se considere cuidadosamente la relación riesgo-beneficio de la DAT prolongada..²⁰

TICLOPIDINA

ticlopidina, la primera tienopiridina disponible, demostraron reducciones significativas en los eventos isquémicos después de la PCI. En el estudio STARS, aspirina con ticlopidina redujo la incidencia de muerte, revascularización de la lesión diana, trombosis de los vasos, o MI en 30 dias para 0.5% en comparación con 3.6% monoterapia con aspirina y 2.7% con aspirina más warfarina.²²

La ticlopidina ahora ha sido reemplazada en gran medida por otros P2Y disponibles.₁₂ inhibidores como el clopidogrel debido a la incidencia de efectos secundarios adversos graves, como púrpura trombocitopénica trombótica y agranulocitosis. En dos ensayos aleatorios, clopidogrel and ticlopidine showed similar efficacy in terms of major adverse cardiac events, but clopidogrel was associated with significantly fewer side effects than ticlopidine.^23,24

CLOPIDOGREL

Clopidogrel has been extensively studied for use in the setting of PCI and after stent implantation. The PCI-CURE trial demonstrated the beneficial effect of clopidogrel plus aspirin in reducing cardiovascular death or MI for up to 1 year after stenting among patients presenting with a non–ST-elevation acute coronary syndrome.²⁵ en este estudio, the rate of cardiovascular death or MI was reduced from 12.6% in those receiving aspirin plus clopidogrel for 4 weeks after PCI to 8.8% in those receiving DAT for up to 1 y el menor espesor se observa en. similar, the CREDO study evaluated a pre-PCI clopidogrel load of 300 mg followed by 12 months of daily clopidogrel (75 mg/d) against no clopidogrel loading followed by daily clopidogrel for 28 days only. en este estudio, patients who were assigned to the clopidogrel load followed by 12 months of daily therapy had a 26.9% relative reduction in the 12- month incidence of the composite of death, MD Profesor OA Tyazhelov, or stroke (PAG = .02).²⁶ Data from this study suggest that a 300-mg load should be given at least 6 hours before PCI to allow adequate platelet inhibition; sin embargo, with a 600-mg load, administración 2 hours prior to PCI may be a safe interval. In patients on long-term clopidogrel who are undergoing PCI, maintenance doses alone may not be sufficient. Reloading is recommended and is usually accomplished with a 300-mg load.²⁰

Higher doses of clopidogrel after PCI (600-mg load, 150 mg/d for 6 dias) have been examined in the CURRENT- OASIS 7 trial.⁸ Although the overall trial results showed no incremental benefit to high-dose clopidogrel, en lo preespecificado (aunque después de la aleatorización) análisis de subgrupos de más de 17,000 pacientes que se sometieron a ICP, hubo una reducción en el resultado secundario de trombosis del stent en 30 días con la dosis más alta (1.6% contra 2.3%; cociente de riesgo [HORA], 0.68; 95% intervalo de confianza [CI], 0.55–0,85; PAG < .001). Sin embargo, esto fue a un costo de mayor aumento (2.5% contra 2%; HORA, 1.24; 95% CI, 1.05–1.46; PAG = .01) y sangrado menor.

La variabilidad interindividual significativa en la respuesta al clopidogrel ha sido bien descrita..²⁷Interacciones con drogas, como los inhibidores de la bomba de protones, se han asociado con una respuesta farmacodinámica disminuida a clopidogrel, y en estudios observacionales, se han asociado con peores resultados clínicos.^28,29 Sin embargo, análisis observacionales de prospectiva, ensayos clínicos aleatorizados no han corroborado esto.^30,31 El ensayo COGENT aleatorizó prospectivamente a los pacientes a un fármaco combinado de omeprazol y clopidogrel o a clopidogrel solo y mostró una reducción de la hemorragia gastrointestinal sin un aumento de los eventos cardiovasculares.³² Aunque COGENT estaba limitado por el modesto tamaño de su muestra, duración relativamente breve del seguimiento, y su terminación prematura debido a consideraciones financieras, es la única fuente de datos aleatorios que examina esta interacción fármaco-fármaco. Una declaración de consenso del ACC, Ajá, y el American College of Gastroenterology recomienda el uso de inhibidores de la bomba de protones con un agente antiplaquetario de tienopiridina en personas con alto riesgo de hemorragia gastrointestinal.³³

Loss of function mutations in the CYP2C19 allele that metabolizes the clopidogrel prodrug have also been associated with worse clinical outcomes for patients taking clopidogrel after an ACS event. In a meta-analysis of patients on clopidogrel after stenting, there was an HR for stent thrombosis of 2.67 (95% CI, 1.69–4.22; PAG < .0001) for heterozygotes versus wild-type, y 3.97 (95% CI, 1.75–9.02; PAG = .001) for homozygotes versus wild type.34 However, the CYP2C19 mutation appears to have no impact on clinical outcomes with the other P2Y₁₂ inhibidores, prasugrel and ticagrelor.^35,36

The use of platelet function testing to direct clopidogrel dosing after PCI was prospectively tested in the GRAVITAS trial.³⁷ en este estudio, clopidogrel nonresponders, as defined by and assessed with the use of a pointof- care platelet function test, were randomized to highdose clopidogrel at 150 mg per day versus standard dose clopidogrel (75 mg/d). No reduction in the primary outcome of MI, cardiovascular death, or stent thrombosis was observed with high-dose clopidogrel as compared with standard dose despite demonstrating modest reductions in platelet reactivity. Whether the hypothesis underlying GRAVITAS was incorrect or there were methodological limitations to the trial (including a modest sample size with fewer endpoint events than originally assumed) is under debate.

Further studies are ongoing to test whether platelet function testing or genotyping should play a role in selecting the dose of clopidogrel or in selecting alternative agents such as prasugrel to reduce ischemic events after PCI.^38,39 Until these data are available, the ACC/AHA writing committee for the Clinical Expert Consensus Document on the use of clopidogrel concluded that “the evidence base is insufficient to recommend either routine genetic or platelet function testing at the present time” and that “there is no information that routine testing improves outcome in large subgroups of patients.” However, they do state that for those at high risk for adverse events who are also identified as poor metabolizers of clopidogrel, other agents such as prasugrel should be considered.⁴⁰ The current guidelines for clopidogrel use are listed in Table 1.

PRASUGREL

Prasugrel is a newer thienopyridine with a more rapid onset and extent of inhibition of platelet activity.⁴¹ In the TRITON-TIMI 38 estudio, patients with ACS and planned PCI were randomized to clopidogrel (300-mg load, 75 mg daily) or prasugrel (60-mg load, 10 mg daily) in addition to aspirin and followed for up to 15 months.42 In this trial, prasugrel was associated with a lower rate of cardiovascular death, MD Profesor OA Tyazhelov, or stroke than clopidogrel (9.9% contra 12.1%; HORA, 0.81; PAG < .001); this was mostly driven by a reduction in nonfatal MI that was also associated with an increase in TIMI major bleeding unrelated to coronary artery bypass grafting (2.4% contra 1.8%; HORA, 1.32; PAG = .03). There was also increased fatal and life-threatening bleeding, seen especially in those with a history of transient ischemic attack or stroke. In the TRITON-STENT substudy of more than 12,000 patients who received at least one stent, prasugrel showed a reduction in both early and late stent thrombosis in both DES and bare-metal stents as compared with clopidogrel (1.13% contra 2.35%; HORA, 0.48; PAG < .0001).⁴³

los 2009 updated ACC/AHA ST-elevation myocardial infarction (STEMI) guidelines included prasugrel as an acceptable adjunctive therapy in the setting of primary PCI.⁴⁴ Sin embargo, as noted by the US Food and Drug Administration, which approved the drug for use in the United States in 2009, prasugrel is contraindicated in patients with a history of transient ischemic attack or stroke and should generally be avoided in patients older than 75 años.

TICAGRELOR

Ticagrelor is a reversible, direct-acting, nonthienopyridine inhibitor of the P2Y₁₂ ADP receptor. It too is a more rapid and potent inhibitor of platelets than clopidogrel and was compared to clopidogrel head-to-head in an international, double-blind, randomized controlled trial in more than 18,000 patients with ACS in the PLATO study.⁴⁵ Ticagrelor showed a reduction in the composite primary endpoint of vascular death, MD Profesor OA Tyazhelov, or stroke when compared to clopidogrel (9.8% contra 11.7%; HORA, 0.84; PAG < .001), and there was no difference in the rate of major bleeding (11.6% contra 11.2%; PAG = .43). Sin embargo, there was both a higher rate of bleeding unrelated to coronary artery bypass grafting (4.5% contra 3.8%; PAG = .03) and more fatal intracranial bleeds with ticagrelor than with clopidogrel.

In the PLATO trial, más que 10,000 patients received a stent, and ticagrelor was associated with a reduced rate of stent thrombosis: definite (1.3% contra 1.9%; PAG = .009); probable or definite (2.2% contra 2.9%; PAG = .02); and possible, probable, or definite (2.9% contra 3.8%; PAG = .01). The PLATO-Invasive analysis examined 13,408 patients with a planned early invasive strategy and demonstrated results that mirrored the overall study, with a reduction in the primary composite endpoint but without an increase in major bleeding, suggesting that ticagrelor may be an attractive option for ACS patients being managed with a planned early invasive strategy.⁴⁶ The agent is approved for use in the European Union but not yet in the United States, as the US Food and Drug Administration continues to review data from the trial concerning a difference in observed treatment effect in the United States compared with the overall trial.

OTHER ANTITHROMBOTIC AGENTS

Cilostazol
Cilostazol selectively inhibits 5’3’-cyclic nucleotide phosphodiesterase III and has antiplatelet and vasodilating effects. It has been shown to reduce restenosis rates with coronary stents.^47,48Two single-center, nonrandomized studies showed that cilostazol, when added to aspirin and a P2Y₁₂ inhibitor, reduced stent thrombosis and other ischemic complications.^49,50 Sin embargo, in a randomized multicenter clinical trial of patients receiving DES, there was no benefit of adding cilostazol to aspirin plus clopidogrel in the reduction of death, MD Profesor OA Tyazhelov, accidente cerebrovascular isquémico, revascularización de la lesión diana, or stent thrombosis despite a statistically significant reduction in platelet reactivity levels.⁵¹ The routine use of adjuvant cilostazol after PCI is not currently recommended by the major medical societies.

Elinogrel
Elinogrel is a novel P2Y₁₂ inhibitor that is available in both oral and intravenous formulations and is the first reversible and competitive inhibitor of the ADP P2Y₁₂ receptor. It is a more potent antiplatelet agent than clopidogrel, with a more rapid onset and offset of action. Its enhanced platelet inhibition, competitive binding nature, and rapid reversibility make it a potentially attractive option. Se requerirán grandes ensayos clínicos para probar esta hipótesis..

Antagonistas del receptor de trombina
Atopaxar y vorapaxar son dos nuevos agentes que se dirigen a la activación plaquetaria inducida por trombina mediante la inhibición del receptor activado por proteasa 1 y están siendo estudiados en pacientes con SCA y enfermedad arterial coronaria (Figura 2). Los ensayos clínicos de fase temprana de estos medicamentos han sido prometedores, lo que sugiere una reducción en los eventos isquémicos cuando se agrega a la terapia estándar.^52,53 En el contexto de una ICP no urgente, vorapaxar fue bien tolerado en una fase 2 estudio.⁵² Se necesitan más datos para evaluar el papel de estos agentes después de la PCI para definir qué pacientes pueden tener el mayor beneficio (equilibrado contra los efectos secundarios tolerables) con estas drogas.

Anticoagulantes orales
Desde los primeros ensayos con warfarina que mostraron una reducción de los eventos isquémicos después de la ICP, there has been hope for a role of oral anticoagulants, in addition to standard of care, to further drive down thrombotic complications after PCI.²² Phase 2 trials of novel oral anticoagulants, such as the factor Xa inhibitors, apixaban and rivaroxaban, as well as the oral direct thrombin inhibitor, dabigatran, have all shown some reductions in ischemic complications after an ACS event at the risk of increased bleeding.^54-56 Sin embargo, this additional bleeding risk remains a significant concern and may limit their applicability. Data are forthcoming from large clinical trials that will clarify their role in this setting.

ANTITHROMBOTIC TREATMENT AFTER PCI FOR PATIENTS REQUIRING LONG-TERM ANTICOAGULATION

The optimal antithrombotic therapy after coronary stenting for patients with an indication for long-term anticoagulant therapy is not clear. El riesgo de complicaciones trombóticas y tromboembólicas debe sopesarse frente al riesgo de hemorragia al considerar la adición de DAT además de la anticoagulación oral crónica. (llamada triple terapia). Los análisis de registros pequeños sugieren un aumento significativo de las complicaciones hemorrágicas con la terapia triple en comparación con la DAT sola.^57,58 Seleccionar a los pacientes apropiados para la triple terapia antitrombótica implica comprender sus indicaciones para la anticoagulación oral y los riesgos asociados con la interrupción de la anticoagulación, así como sus factores de riesgo de sangrado. Evitar la triple terapia en ancianos, usando stents baremetal con una duración más corta de DAT, y un cuidadoso seguimiento de la razón internacional normalizada (apuntando al extremo inferior del rango terapéutico objetivo) are reasonable strategies to mitigate bleeding risk.

CONCLUSIÓN

As a result of a better understanding of the pathophysiology of ischemic complications after PCI, significant improvements in antithrombotic therapy have translated into important reductions in the ischemic complications of the procedure. With multiple newer and more powerful antithrombotic agents available, selecting the optimal therapy has become increasingly more challenging. Although use of the more potent antiplatelet and anticoagulant therapies has resulted in a reduction in ischemic events such as stent thrombosis, this is almost always at the cost of increased bleeding. Choosing the optimal therapy for a patient after PCI depends on factors such as the type of stent implanted and comorbidities of the patient and must be tailored to balance the ischemic and bleeding risk of that individual. Ongoing trials will help to define the most appropriate regimen for these patients.

John P. Manejo de pacientes con tumores del tracto gastrointestinal Ubicación, Maryland, is a fellow in the Division of Cardiovascular Medicine, Duke Clinical Research Institute, Duke University Medical Center in Durham, Carolina del Norte. He has disclosed that he holds no financial interest in any product or manufacturer mentioned herein.

Robert A. Manejo de pacientes con tumores del tracto gastrointestinal Ubicación, Maryland, is Richard S. Stack, Maryland, Distinguished Professor of Medicine at Duke University, and Director, Duke Clinical Research Institute in Durham, Carolina del Norte. He has disclosed that he is a paid consultant to AstraZeneca, Bristol-Myers Squibb, Merck, Medochemie Ltd, and The Medicines Company, and receives grant/research funding from AstraZeneca, Bristol-Myers Squibb, Merck, Novartis, Portola, and The Medicines Company. Dr. Harrington may be reached at (919) 668-8749.