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In custom game, it's much tougher because you don't benefit from the building bonuses. I have won once on the custom game out of the three times I tried it (with the cultist, who in my opinion is the strongest character).
Some spoilers that give hints to "git gud" below. Don't read them if you don't want hints, but I do both of these things on most runs now.
Watch out for the ring or relics that heal you, especially if you're not the cultist. If you see the +2 heal per unused energy point at the merchant, it's always worth buying it, even if you have to sacrifice your blood to pay for it.
You can sell your consumables and useless equipment at the merchant for money by right clicking it. You'll get enough money to buy things you need. It is critical to winning a run on the custom game mode for me.
I would totally suggest you make custom decks instead of using the recommended ones. Sure, there is RNG involved, but if you don't like your deck on the right hand side there is a button to make a new deck after you are done with it instead of launching into the game. I have never had to remake a deck more than once without getting what I wanted.
Are you starting with the starter decks? I'd recommend to always do the custom deck, the starter decks suck. Also don't be afraid to use your card rejection button. I've found that most of the 3-cost cards aren't worth it, with how hard it is to get energy in this game.
Just draft your deck, don't use the premade ones. They are awful.
Once in your hand the damage of these card goes through your shield and straight to your HP. Worst thing is that they are not exhausted after being played but go to the discard pile.
Yeah, Self Flagellation is brutal.