We used to have a higher floor for the Positive Control Airspace in the western part of the US, FL240. It was lowered as part of the fallout from 1956 Grand Canyon midair.
The regs here state you'll set the QNH of a station along the route and within 100 miles or an appropriate station. If you're flying IFR in controlled airspace you'll use whatever setting ATC gives you. I don't know where the OP got the idea we use QNE as QNH. Having seen 28.40 and 31.60 you'd be in a world of hurt stuck on 29.92. There are over 600 chunks of Class B/C/D airspace in the US each with their own altimeter setting so 21, meh.