Systematic adjudication of myocardial infarction end-points in an international clinical trial.

BACKGROUND: Clinical events committees (CEC) are used routinely to adjudicate suspected end-points in cardiovascular trials, but little information has been published about the various processes used. We reviewed results of the CEC process used to identify and adjudicate suspected end-point (post-enrolment) myocardial infarction (MI) in the large Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin (Eptifibatide) Therapy (PURSUIT) trial. METHODS: The PURSUIT trial randomised 10,948 patients with acute coronary syndromes to receive eptifibatide or placebo. A central adjudication process was established prospectively to identify all suspected MIs and adjudicate events based on protocol definitions of MI. Suspected MIs were identified by systematic review of data collection forms, cardiac enzyme results, and electrocardiograms. Two physicians independently reviewed all suspected events. If they disagreed whether a MI had occurred, a committee of cardiologists adjudicated the case. RESULTS: The CEC identified 5005 patients with suspected infarction (46%), of which 1415 (28%) were adjudicated as end-point infarctions. As expected, the process identified more end-point events than did the site investigators. Absolute and relative treatment effects of eptifibatide were smaller when using CEC-determined MI rates rather than site investigator-determined rates. The site-investigator reporting of MI and the CEC assessment of MI disagreed in 20% of the cases reviewed by the CEC. CONCLUSIONS: End-point adjudication by a CEC is important, to provide standardised, systematic, independent, and unbiased assessment of end-points, particularly in trials that span geographic regions and clinical practice settings. Understanding the CEC process used is important in the interpretation of trial results and event rates.

Disagreements between central clinical events committee and site investigator assessments of myocardial infarction endpoints in an international clinical trial: review of the PURSUIT study.

BACKGROUND: Limited information has been published regarding how specific processes for event adjudication can affect event rates in trials. We reviewed nonfatal myocardial infarctions (MIs) reported by site investigators in the international Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin (Eptifibatide) Therapy (PURSUIT) trial and those adjudicated by a central clinical events committee (CEC) to determine the reasons for differences in event rates. METHODS: The PURSUIT trial randomised 10,948 patients with acute coronary syndromes to receive eptifibatide or placebo. The primary end-point was death or post-enrolment MI at 30 days as assessed by the CEC; this end-point was also constructed using site-reported events. The CEC identified suspected MIs by systematic review of clinical, cardiac enzyme, and electrocardiographic data. RESULTS: The CEC identified 5005 (46%) suspected events, of which 1415 (28%) were adjudicated as MI. The site investigator and CEC assessments of whether a MI had occurred disagreed in 983 (20%) of the 5005 patients with suspected MI, mostly reflecting site misclassification of post-enrolment MIs (as enrolment MIs) or underreported periprocedural MIs. Patients for whom the CEC and site investigator agreed that no end-point MI had occurred had the lowest mortality at 30 days and between 30 days and 6 months, and those with agreement that a MI had occurred had the highest mortality. CONCLUSION: CEC adjudication provides a standard, systematic, independent, and unbiased assessment of end-points, particularly for trials that span geographic regions and clinical practice settings. Understanding the review process and reasons for disagreement between CEC and site investigator assessments of MI is important to design future trials and interpret event rates between trials.

Polimorfismos de los receptores -β adrenérgicos y su relación con el riesgo de insuficiencia cardiaca, etiología y prevalencia de infarto al miocardio / Polymorphysm of beta-adrenergic receptors and risk of heart failure, etiology and prevalence of myocardial infarction

Introducción: Los polimorfismos de los receptores ß-adrenérgicos (AR) influencian el grado de actividad del receptor. Los ßAR tienen un rol importante en la regulación de la contractilidad y podrían tener implicancias en el riesgo de desarrollar insuficiencia cardiaca (IC), como en su pronóstico y respuesta terapéutica. Objetivo: Evaluar los genotipos e interacciones genéticas entre los polimorfismos del ß1 y ßAR como predictores de riesgo de desarrollar IC, su relación con la etiología de la IC y prevalencia de infarto. Métodos: Se genotipificaron 80 pacientes con IC y 88 sujetos sanos por edad y sexo. Los pacientes con IC tenían FE<35 por ciento y CF II-IV de la NYHA. Los polimorfismos se determinaron amplificando por la Reacción de Polimerización en Cadena (PCR) los genes de los ßAR y analiz¨¢ndolos con enzimas de restricción (PCR-RFLP). Los datos se analizaron mediante los tests estadísticos c2, Fisher, regresión loguística y razón de disparidad. Los datos se ajustaron por edad y sexo. Las interacciones entre los polimorfismos ß1AR Arg389 →Gly, ß2Ar Gln27 →Glu y ß2AR Thr 164 →lle se evaluaron en función del riesgo a desarrollar ICC. Resultados: Las frecuencias de los genotipos ß2AR Gln27→Glu y 1 AR Arg389→Gly fueron diferentes en los sujetos con IC comparados con los controles. La presencia del ß2AR Glu27Glu pero no de la variante 1 AR Gly389Gly fue predictor de ICC (OR ajustado=2,81; Cl=1,49 a 5,31 para el 2AR Glu27Glu; p=0,001 y OR ajustado=0,58; Cl=0,13 a 2,53; p=0,466 para b1AR Gly389Gly). Se encontró una interacción entre los polimorfismos ß1AR Arg389Arg y los polimorfismos del ß2AR Arg16Arg, Gln27Gln, y Thr164Thr. Estas interacciones se asociaron a una reducción en el riesgo de IC (OR=0,25, Cl=0,09 a 0,69; p=0,009; OR=0,18, Cl=0,07 a 0,46, p<0,001 y OR=0,48, Cl=0,25 a 0,91, p=0,026, respectivamente). Además, en los pacientes con IC, la frecuencia del polimorfismo 2AR Glu27Glu se asoció con una mayor incidencia de infarto al miocardio (con infarto: 0,534, sin = 0,313, p=0,01). Conclusiones: La variante Glu27Glu del ß2AR fue un predictor de IC, los polimorfismos del ß2AR Arg16Arg, Gln27Gln, y Thr164Thr y 1AR Arg389Arg se asociaron a una disminución del riesgo de ICC. El genotipo y frecuencia del alelo ß2AR Gln27 ----- Glu se relacionó a la etiología de la ICC y con la prevalencia de infarto al miocardio. Estos hallazgos pueden ser relevantes en la predicción de riesgo de ICC, su pronóstico y respuesta terapéutica.