This paper presents the results of a research related to medical image subtraction algorithms. The selected area is of direct digital X-Ray angiography, where subtraction algorithms are the basis of most acquisition and reviewing protocols. The goal of this research is to analyze the currently existing image subtraction algorithms and to propose a new approach based on the experienced limitations, respectively to develop a new imaging technique that allows both contrast agent and radiation dose reduction. The enhancement of the subtraction algorithms is targeted by two means: a) noise reduction on image frames, b) identification of contrast agent injected regions. Both aspects will be studied based on the analysis of the spatio-temporal signal variation that image pixel intensities represent, therefore the resulting algorithm can not be used real time during image acquisition, but as a post processing technique during review. The temporal variation of pixel intensities was then analyzed and a patter check was followed to identify pixels being part of a contrast agent injected region. This information was used to highlight regions of interest and to increase the contrast in poorly injected areas.