I'd encourage people not to sleep on Isaac just because he's not as well equipped as Dante: his tears are perhaps more powerful than Dante's bullets.
Dante may be able to hack through literal spawns of hell, but Isaac has defeated not only Satan, but Mega Satan.
The question for me here is about durability. I'd imagine Dante has the edge, but how much of an edge? Isaac has the ability to deal out far more damage than he can take (as most video game protagonists do), but could Dante withstand it long enough to launch a serious combo on Isaac? I'm genuine unsure.
I am rooting for Isaac in this one, but I'm not sure he's the deserving winner.