Top spot slipped from Barca's grasp last week as they were held to a goalless draw at Sevilla while Real Madrid earned a 2-1 away win over Real Sociedad.
Frustrated defender Gerard Pique said it would be "very difficult" for Barca to retain the title, expressing his belief that "it's going to be difficult for Madrid to lose points" having seen what has happened in the games since the restart.
Those comments, made after the Sevilla game on Friday, were regarded by some as a reference to refereeing decisions Madrid received in their favor during wins over Eibar and Valencia.
And the issue came to the fore again when Catalan media were unhappy VAR did not rule out a goal from Karim Benzema against Sociedad, while Adnan Januzaj had a goal disallowed for the hosts.
Madrid boss Zinedine Zidane hit out at constant talk about officials and insisted his team were deserving winners on Sunday, but Setien can understand the furore.
"There are things that we cannot control and that do not depend on us," said Setien.
"Regarding [the Madrid] game, everyone has seen how it has been and everyone will make the assessments that are appropriate
"Pique, not now but always, has always seemed a very intelligent person.
"I do not speculate [about VAR or Pique's words]. I hear a series of words and the frustration of having lost two points pushes you to say that LaLiga is going to be difficult.
"In moments of frustration one may not have refined comments. Regarding the VAR, it is a tool that can undoubtedly make us better.
"You have to use it because it gives us a clearer view of reality when you have to make quick decisions. The good thing is to be able to see them with different angles and with vision.
"It is understandable that we think about why some actions are reviewed and others not, in some matches yes and others no. And one may think that it is not being used well.
"What seems clear is, there is always controversy and there will always be these problems that are inherent in football."
Madrid are top due to their superior head-to-head record and eight matches remain ahead of Barca's home clash with Athletic Club on Tuesday.
Setien added: "Athletic are a tough, difficult team and they defend well. The games we have played against them have not been easy."