While characters leaving a work for any reason, whether its because they were Put on a Bus or Killed Off for Real, isn't new to viewers, when it happens to main character it becomes more notable. This is because the work or its premise is central to that character so their removal could cause some issues.
There are two solutions when this happens; one is that they introduce a new main character. More often then not they be Suspiciously Similar Substitute. Though, they could be different enough for them not to be compared to their predecessor. Another way is to have one of the supporting cast ascend to main character status. Usually this is given to those who are fan favorites so it be easier to get behind. Though, they could potentially lose favor of the audience because they are
