AVERROES trial terminated early: apixaban associated with "important" relative risk reduction for stroke and systemic embolism in AF

The phase 3 AVERROES (Apixaban Versus Acetylsalicylic acid (ASA) to Prevent Strokes) trial, designed to show the superiority of apixaban over aspirin for the prevention of stroke or systemic embolism in high-risk atrial fibrillation patients unsuitable for treatment with a vitamin K antagonist (warfarin), was terminated early following a recommendation from the Data Monitoring Committee. Final study visits took place between 1 July and 15 August this year. A predefined interim analysis had shown clear evidence of a clinically important reduction in stroke and systematic embolism and an acceptable safety profile for apixaban compared to aspirin. The principal investigator, Dr Stuart Connolly from Population Health Research Institute, McMaster University, Hamilton, Ontario, Canada, and the study's sponsors accepted the recommendation to terminate the trial.
AVERROES was a double-blind randomised trial which recruited 5600 patients with atrial fibrillation (mean age 70 years) demonstrated or expected to be unsuitable for treatment with a vitamin K antagonist (because of difficulty in controlling treatment effect, increased risk of haemorrhage, patient refusal to take warfarin or intermediate stroke risk). So far, aspirin is the only effective treatment for stroke prevention in patients unsuitable for warfarin.
Apixaban, a Factor Xa inhibitor, has already been investigated for the prevention of deep vein thrombosis, following orthopaedic surgery, and after acute coronary syndrome - but not so far in patients with atrial fibrillation. The AVERROES trial compared the effects of apixaban and aspirin in these patients. Another trial, ARISTOTLE (not yet completed) is studying apixaban against warfarin in patients suitable for warfarin.
The AVERROES study was performed at 520 sites worldwide and recruitment was completed in December 2009. The primary endpoint was a composite of stroke or systemic embolism, while the primary safety endpoint was major haemorrhage. Secondary and tertiary endpoints were a composite of stroke, systemic embolism, myocardial infarction or vascular death, and total death.
At the interim analysis results showed that the annual rate of stroke or systemic embolism (the primary outcome) was 3.9% per year on aspirin and 1.7% per year on apixaban (HR 0.45, p<0.001). The rate of major haemorrhage was 1.4% per year on aspirin and 1.6% per year on apixaban (HR 1.18, p=0.33). The rate of haemorrhagic stroke was 0.2% per year in both treatment groups and there was no evidence of hepatic toxicity or other major adverse events.
Commenting on the results, Dr Connolly said: "The results of AVERROES are truly impressive. The reduction in stroke and systemic embolism is very important and the increased risk of haemorrhage is small. It appears that apixaban will be an excellent treatment for the many patients with atrial fibrillation who are unsuitable for warfarin. These findings will reduce the burden of stroke in society.”

* Atrial fibrillation is a common heart rhythm disorder in which the upper chamber of the heart beats improperly. Patients with AF are at increased risk of stroke because of the formation of blood clots in the upper chamber. The standard therapy for the prevention of stroke and other embolic events in AF is warfarin.

El Estudio Averroes con el anticoagulante oral apixaban concluye antes de tiempo debido a una clara evidencia de eficacia

Pfizer y Bristol-Myers Squibb han anunciado el cierre anticipado del ensayo clínico fase III AVERROES, que se está desarrollando en pacientes con fibrilación auricular, debido a que los resultados del análisis preliminar llevado a cabo por el Comité de Monitorización de Datos (DMC en sus siglas inglesas) ha revelado una clara evidencia, clínicamente significativa, de la reducción de episodios de ictus y embolismos sistémicos en pacientes con fibrilación auricular intolerantes o no aptos para recibir tratamiento con antagonistas de la vitamina K tratados con apixaban frente a aspirina. Este análisis también ha demostrado un perfil de seguridad aceptable para apixaban en comparación con aspirina.
El estudio AVERROES (Apixaban versus ácido acetilsalicílico en la prevención de ictus) incluye a 5.600 pacientes con fibrilación auricular con riesgo de sufrir un ictus que no toleraban o no eran adecuados para recibir tratamiento con un antagonista de la vitamina K como la warfarina. Los pacientes incluidos en el estudio recibieron apixaban 5mg dos veces al día, o aspirina, de 81mg a 324mg, una vez al día de forma aleatoria. La investigación se ha desarrollado en 36 países y ha sido coordinada por el instituto Population Health Research Institute (PHRI) de la McMaster University y Hamilton Health Sciences.

-Continuación del tratamiento con apixaban
Los investigadores participantes en el estudio AVERROES ya han sido informados de la decisión de dar por terminado el estudio, una posibilidad que ya se había contemplado inicialmente si los datos de eficacia resultaban ser estadísticamente significativos. Bristol-Myers Squibb y Pfizer están trabajando conjuntamente para cerrar el ensayo y asegurarse de que los pacientes son informados convenientemente de la posibilidad de comenzar el tratamiento con apixaban en un estudio abierto de acceso extendido al medicamento. El PHRI completará la evaluación final de los datos extraídos del estudio AVERROES, que publicará cuando el análisis esté completo, en el Congreso Europeo de Cardiología que se celebrará en Estocolmo a finales de agosto de este año.