21+3
The "Extreme 21+3" is basically unbeatable without using a hidden computer and deep penetration. The House edge ridiculous.
The regular 21+3 where all of the payoffs are 9:1 is more beatable by targeting flushes. You're looking for an imbalance in suits left unplayed. For more info you can check Eliot Jacobsen's Book "Advanced Advantage Play" pages 141-149
One thing, his book uses a penetration of 100 cards on a six deck game as his benchmark. I'd suspect if you have really deep pen the win rates he describes could be much higher. I'd pay close attention to the shuffle as well. A non-random shuffle or new cards with an incomplete wash could present an opportunity for an observant player.
Regarding the optimal first card, I'd think anything from a 3 thru Queen would be most optimal giving you the most outs to make a straight.