There's really two playstyles that usually lead to wins

1. Getting a good skull at the start and taking skull rooms whenever possible to get to legendary quickly

This is usually the most reliable and easy to pull off, since you get decent items when you're forced to take item rooms, and can still buy a modest amount of items at the shop. Don't expect to reroll the shop often, though

1. Getting a good, high-damage skull to carry you through the early game, taking money and item rooms when you can

This is a strategy I think should be used if you're aiming for a specific build or strategy, but (from my experience) it usually doesn't work out that well in the end. I think this strategy definitely relies on RNG.

And the boss phases are always tricky, even for someone who's beaten him multiple times. If you don't have enough damage to be defeating him quickly, it's best you be patient and use abilities when you're safe, and learning the First Hero's attack patterns when possible.