I have not found that to be the case. I run my code through gulp-babel and done. There is no runtime AFAIK, although there was one for traceur.

I have also had no real problems interopping with other big libraries. I think the biggest point of discontinuity would be the class keyword vs other class-like libraries (like coffeescript's implementation). Even that's not too bad, I'm able to extend those using es6 class syntax, I just need to be careful about calling super and setting up the constructor properly.