I think I might have some insight because I don't consider myself to be especially good at the game, but am nearing Real Platinum God status through sheer force of will. Just one more Lost run to go.

Anyway, I think the makings of a good run really start on the first two floors. There are lots of things that you can do to give yourself a fighting chance before things really get started.

1) try to always go down to the second floor with spirit/dark hearts. Obviously, these aren't always made available on the first floor, but more often than not they are. Blow up all tinted rocks when possible and learn to identify where secret rooms are because they often have hearts. Also, a good tip is to wait to pick these bonus hearts up until after you've cleared the floor. Even if you go down with barely any red hearts left, having a couple spirit heart buffer is really important because it gives you the best chance to get that coveted Deal with the Devil. 2) Take all of the pills you find. Yes, it's really annoying when you find a Health Down pill, but at least now you know what that pill does. Plus, all health down pills turn into health up pills if you only have one red heart left. 3) go into the cursed rooms after you've cleared a floor out. Don't sacrifice red heart damage before you've beaten the floor boss, but when the floor is clear, it's worth the gamble for either a guppy item or the rest of the item pool. 4) collect guppy items. three of these and you turn into guppy and you're golden. even ones that don't seem outwardly worth it to you are. 5) donate to the donation machine. it unlocks some excellent items later on 6) try to go down to the second floor with five cents on you. this increases the chance of finding an arcade, and using the blood bank to farm money is great. 7) always open the treasure room. this is intuitive but the last thing you'd want to do is use your only key on a golden chest and then have it bite you in the butt 8) unless you are rushing for boss rush, take your time and go into every room. the more you explore, the more fun stuff you can find. 9) learn about the unique advantages to each character and use it to your advantage. i dont want to say much here in case you havent figured out what different characters can do for you, but it pays to know what's up

Mostly, just enjoy it and try not to worry if you're "good" at the game. I'm sure if i posted some of my runs on here i'd be mocked by the community of experts but like i've had a blast pouring myself into the game, lost some runs I shouldnt have, won a couple i shouldnt have, and unlocked just about everything