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AIMS: Statins are pivotal to the secondary prevention of major adverse cardiovascular events, but some patients are statin-intolerant. We examined the effects of the proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor alirocumab on the risk of major adverse cardiovascular events according to the intensity of background statin treatment. METHODS AND RESULTS: The ODYSSEY OUTCOMES trial compared alirocumab with placebo in 18,924 patients with acute coronary syndrome and dyslipidaemia despite intensive or maximum-tolerated statin treatment (including no statin if intolerance was documented). The primary outcome (major adverse cardiovascular events) comprised coronary heart disease death, non-fatal myocardial infarction, ischaemic stroke, or unstable angina. Median follow-up was 2.8 years. Baseline statin treatment was high-intensity (88.8%), low/moderate-intensity (8.7%) or none (2.4%). Median baseline low-density lipoprotein cholesterol was 86, 89 and 139 mg/dL (P < 0.001) in these statin treatment categories, respectively. Alirocumab produced similar relative reductions in low-density lipoprotein cholesterol from baseline across statin treatment subgroups, but the mean absolute reductions differed (52.9, 56.7 and 86.1 mg/dL, respectively; P < 0.001). With placebo, the incidence of major adverse cardiovascular events was highest in the no statin subgroup (10.8%, 10.7% and 26.0% respectively). Alirocumab reduced major adverse cardiovascular events in each statin subgroup (hazard ratio 0.88, 95% confidence interval (CI) 0.80-0.96; 0.68, 0.49-0.94; and 0.65, 0.44-0.97, respectively; Pinteraction = 0.14) with a gradient of absolute risk reduction: 1.25%, 95% CI 0.34-2.16; 3.16%, 0.38-5.94; 7.97%, 0.42-15.51; Pinteraction = 0.106). CONCLUSIONS: PCSK9 inhibition with alirocumab reduces the relative risk of major adverse cardiovascular events after acute coronary syndrome irrespective of background statin treatment. However, patients on no statin are at high absolute risk for recurrent major adverse cardiovascular events; alirocumab substantially reduces that risk. PCSK9 inhibition may be an important therapeutic strategy for statin-intolerant patients with acute coronary syndrome.

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Background: Measuring circulating cardiac troponin using novel sensitive assays has revealed that even minute elevations are associated with increased mortality in patients with coronary artery disease or even in the general population. Less well defined, however, is the incremental value of measuring circulating cardiac troponin I (cTnI) by a sensitive assay for risk assessment in primary prevention. Methods: We measured circulating concentrations of cTnI, N-terminal pro-B-type natriuretic peptide (NT-proBNP), and high-sensitivity C-reactive protein (hsCRP) in 5388 individuals free of known cardiovascular disease recruited into the DETECT study, a prospective longitudinal population-based cohort study. We determined the prognostic implications for incident major adverse cardio­vascular events (MACE) during 5 years of follow-up. Results: Circulating cTnI was detectable in 19% of the subjects. Increased cTnI concentrations were associated with established risk factors for atherosclerosis and demonstrated a graded relationship with all-cause mortality and incident MACE during 5-year follow-up. A single measurement of cTnI significantly improved risk prediction over established risk factors, and also added prognostic information, when adjusted for serum concentrations of NT-proBNP and hsCRP. Conclusions: Minute increases in cTnI are associated with increased mortality and incident MACE in a large primary prevention cohort and, thus, identify contributors to cardiovascular risk not fully captured by traditional risk factor assessment.

Antecedentes: La medición de troponina cardíaca en circulación mediante nuevos ensayos sensibles ha revelado que incluso mínimas elevaciones se asocian con mayor mortalidad en pacientes con enfermedad arterial coronaria, o incluso en la población general. Sin embargo, menos conocido es el valor incremental o agregado de la medición de la troponina I cardiaca (cTnI) circulante mediante un ensayo sensible para la evaluación del riesgo en prevención primaria. Métodos: Se midieron las concentraciones circulantes de cTnI, de pro- péptido natriurético tipo B N-terminal (NT-proBNP), y de proteína C reactiva de alta sensibilidad (PCRus), en 5388 personas sin enfermedad cardiovascular conocida reclutadas en el estudio DETECT, un estudio prospectivo longitudinal de cohorte de base poblacional. Se determinaron las implicancias pronósticas en la incidencia de eventos adversos cardiovasculares mayores (MACE) durante 5 años de seguimiento. Resultados: La cTnI se detectó en el 19% de los sujetos. El aumento de las concentraciones de cTnI se asoció con factores de riesgo establecidos para la aterosclerosis y demostró una relación gradual con la mortalidad por todas las causas y la incidencia de MACE durante los 5 años de seguimiento. Una sola medición de cTnI mejoró significativamente la predicción del riesgo por encima de los factores de riesgo establecidos, y también agregó información pronóstica cuando se ajustó por la concentración sérica de NT-proBNP y PCRus. Conclusiones: Mínimos incrementos de cTnI se asociaron con mayor mortalidad e incidencia de MACE en una gran cohorte de prevención primaria y, por tanto, la identificación de sujetos con riesgo cardiovascular no siempre son detectados completamente por la evaluación de factores de riesgo tradicionales.

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Background: Measuring circulating cardiac troponin using novel sensitive assays has revealed that even minute elevations are associated with increased mortality in patients with coronary artery disease or even in the general population. Less well defined, however, is the incremental value of measuring circulating cardiac troponin I (cTnI) by a sensitive assay for risk assessment in primary prevention. Methods: We measured circulating concentrations of cTnI, N-terminal pro-B-type natriuretic peptide (NT-proBNP), and high-sensitivity C-reactive protein (hsCRP) in 5388 individuals free of known cardiovascular disease recruited into the DETECT study, a prospective longitudinal population-based cohort study. We determined the prognostic implications for incident major adverse cardio¡vascular events (MACE) during 5 years of follow-up. Results: Circulating cTnI was detectable in 19% of the subjects. Increased cTnI concentrations were associated with established risk factors for atherosclerosis and demonstrated a graded relationship with all-cause mortality and incident MACE during 5-year follow-up. A single measurement of cTnI significantly improved risk prediction over established risk factors, and also added prognostic information, when adjusted for serum concentrations of NT-proBNP and hsCRP. Conclusions: Minute increases in cTnI are associated with increased mortality and incident MACE in a large primary prevention cohort and, thus, identify contributors to cardiovascular risk not fully captured by traditional risk factor assessment.(AU)

Antecedentes: La medición de troponina cardíaca en circulación mediante nuevos ensayos sensibles ha revelado que incluso mínimas elevaciones se asocian con mayor mortalidad en pacientes con enfermedad arterial coronaria, o incluso en la población general. Sin embargo, menos conocido es el valor incremental o agregado de la medición de la troponina I cardiaca (cTnI) circulante mediante un ensayo sensible para la evaluación del riesgo en prevención primaria. Métodos: Se midieron las concentraciones circulantes de cTnI, de pro- péptido natriurético tipo B N-terminal (NT-proBNP), y de proteína C reactiva de alta sensibilidad (PCRus), en 5388 personas sin enfermedad cardiovascular conocida reclutadas en el estudio DETECT, un estudio prospectivo longitudinal de cohorte de base poblacional. Se determinaron las implicancias pronósticas en la incidencia de eventos adversos cardiovasculares mayores (MACE) durante 5 años de seguimiento. Resultados: La cTnI se detectó en el 19% de los sujetos. El aumento de las concentraciones de cTnI se asoció con factores de riesgo establecidos para la aterosclerosis y demostró una relación gradual con la mortalidad por todas las causas y la incidencia de MACE durante los 5 años de seguimiento. Una sola medición de cTnI mejoró significativamente la predicción del riesgo por encima de los factores de riesgo establecidos, y también agregó información pronóstica cuando se ajustó por la concentración sérica de NT-proBNP y PCRus. Conclusiones: Mínimos incrementos de cTnI se asociaron con mayor mortalidad e incidencia de MACE en una gran cohorte de prevención primaria y, por tanto, la identificación de sujetos con riesgo cardiovascular no siempre son detectados completamente por la evaluación de factores de riesgo tradicionales.(AU)

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