I've worked in large canvases (10800 x 7200 or larger) with ArtRage even prior to 4.5, and one of the things I've wanted for quite some time now is 64-bit support because I would run into the 4GB memory limit wall and the application would collapse on itself like a house of cards. I always work in large canvases because I like to be able to print them out at large sizes. With 4.5 I get none of the pauses or anything, but I am mostly working with just oils, and Matt says it's one of the least processing intensive or the least processing intensive of all the mediums. I do have a rather powerful machine, though (iMac Late 2012, 3.4Ghz i7, 32GB RAM). When working with watercolor there's a very slight but completely workable lag at 500% size. I hardly work with a brush that large, though. The simple fact of the matter is you're going to need a powerful machine to handle it. There's probably quite a lot of optimizations they can do, but the application is infinitely faster than Painter.

The only real drawback I see when working with large canvas sizes is that with a medium where the canvas' texture is clearly visible like with pastels the pattern of the canvas is clearly seen. It should perhaps be more procedurally drawn and less of a pattern.