Stamina was the issue in my second season which is why I let myself get eliminated from the CL.
By season 3 I had a deep squad together. I rotate players and have been fortunate with injuries. In match I have 3 players that get fully depleted but get 3 subs.
The only real trouble I've had are from international breaks. It's unfair because I think your cpu opponent always has players at max stamina going into matches, even if they're international players themselves. I had a CL match with players right after the international break and 14 of my players were internationals -_- and some of them even if they made it to the team would have obviously been bench players yet come back with half stamina still even though they probably barely played or didn't at all.
My biggest pet-peeve last year was there were players that had a market value of 20M and it would take 45M to sign them and if you were a small club you really had no shot. So to be able to actually play with the players you wanted to you had to start with their team. Last years game i managed Argentina just so i could use Messi and Aguero and played my season as Cardiff (South Wales) which my biggest signing was Gio Dos Santos 
