That's the other thing I didn't really like about Isaac, it felt really reliant on items. A bad-item run in Spelunky is a challenge, a bad-item run in Isaac felt like a waste of time. And the pills you collect having random effects that could ruin a game entirely through no fault of your own, really.
See, I can see the logic there, but when you're playing the game and you pick up a "pic of mom," how are you supposed to know that that relates to increased shooting speed? Like, to work that out you've kind of had to reverse-engineer the item. Shot speed may have been visible (not always), but other things aren't. Like, toothpicks. Makes your tears go red and... what does that mean? There were just loads of things like that. As I say, I imagine if you have an encyclopaedic knowledge of all the items and their effects you can have a good time, but the game made it as hard as possible to attain this and so I didn't feel it deserved my time attempting it. It would have been a much better game if only it was a tiny bit player-friendly.