The other important point for physicians prescribing anticoagulation to prevent stroke or systemic embolism is the risk of major bleeding.  As shown in Figure 3, in the clinical trials there was a reduction in major bleeding with the NOACs, with most of the benefit appearing as a dramatic and very surprising reduction in intracranial hemorrhage.[1] 

One can speculate as to why this is possible.  What is it about the NOACs that is driving the reduction in the most feared complication of anticoagulant therapy? 

Perhaps the most biologically plausible explanation for the reduction in intracranial hemorrhage is simply that the first step in hemostasis requires tissue-factor complexed with factor VII.  When there is insufficient factor VII in the immediate milieu of the very first droplet of blood that crosses the vessel wall, the body cannot start a clot, ie, form a thrombus.  This may be how warfarin works: in the brain there is a rich expression of tissue factor, but when warfarin is suppressing factors II, VII, IX, and X, the brain milieu may be lacking a sufficient amount of factor VII.  This is an hypothesis, of course, but it is important for physicians to have an idea of the mechanism, because the biggest surprise of all of these trials was the large reduction in intracranial hemorrhage with the NOACs.  

Another point that it is important for physicians to understand when reading the results of these clinical trials in the premier journals is, How did the investigators define a major bleed?  In all these trials, major bleeding was defined using the standardized definition of the International Society of Thrombosis and Hemostasis [ISTH], ie, a major bleed is defined as either a decrease of ≥2 g/dL in the patient’s hemoglobin level or requirement for a 2-unit transfusion of packed red blood cells.  In addition to those parameters, bleeding in any critical anatomic site, which included pericardial and/or retroperitoneal bleeding, and certainly intracranial hemorrhage, was also defined as major bleeding.  Finally, of course, fatal bleeding was also defined as “major.”