 Hi, my name is Joanna Molina-Rosavi and I am one of the cardiac electrophysiologist here at Texas Heart Institute. I'm going to be talking today about bleeding risk of anticoagulation. As introduction, there is no anticoagulant that reduces robotic risk without simultaneously increasing the risk of bleeding. The decision to administer an anticoagulant is based on the assessment that the risk of thrombosis, and its complications is greater clinical concern than the risk of bleeding, and its complications for the specific patient at a specific point in time. So on the pathogenesis of anticoagulant-associated bleeding, the loss of vascularity integrity is important because technically anticoagulants do not cause bleeding on itself. Bleeding is caused by a breach in the wall of the blood vessel. However, anticoagulants interfere with the normal hemostatic process that resolves microscopic bleeding events that would otherwise never become clinically apparent. As a result, anticoagulation may contribute to hematoma expansion and may convert clinically insignificant bleeding to clinically significant bleeding. Other factors are breaches of vascular integrity may be mechanical like trauma, tumor invasion, thrombosis, or hypertension, or it can be due to altered endothelial cell barrier function, like the cases with sepsis, ischemia, or certain chemotherapeutic drugs or biological agents. Microbleeds is another factor and other subclinical bleeding events as well. Subclinical bleeding like cerebral microbleeds and occult bleeding in other sites such as the GI tract may present as clinically significant bleeding when the individual is receiving anticoagulant. Microbleeds are clinically silent, minor bleeding events that are apparent only in imaging studies and these studies or studies that have been looking at microbleeds, the term generally is restricted to bleeding in the brain. So these are MRIs done in the brain randomly on patients that are not on anticoagulation and it seems that some people with certain risk factors like diabetes, hypertension, and other things of that sort tend to express some microbleeding in the brain. But the screening of cerebral microbleeds or occult GI bleeds is not routinely used as one of, you know, a factor to decide if we're going to start or not individuals on anticoagulation. So risk factors of bleeding, well there's many factors and there's risk factors related to the anticoagulant itself. So drug class is one of the things, in general the risk of life threatening and fatal bleeding is slower with the DOAX or direct oral anticoagulants like the Bicotran and the direct factor 10A inhibitors like Epixoban and Doxoban, Riveroxoban and all of these compared of course with the warfarin or vitamin K antagonist. And also the evidence of this lower risk comes from several randomized trials that have compared the DOAX to warfarin itself in trials for retrofibrillation or VTE. And the absolute risk in patients with AFib and VTE may differ because these conditions may be distributed across the population differently. They're very different patient populations, the patients with AFib and the patients with venous thromboembolism. So regarding anticoagulation initiation, there's numerous studies that have demonstrated that the risk of bleeding is highest during the initial period, typically defined as the first three months of anticoagulation. So regardless of the anticoagulant that is being started. The mechanism is not completely understood. One hypothesis is that subclinical bleeding, if present, becomes apparent early in the course of anticoagulation. And a related concept to all of this is that the individuals who have not bled during the first three months of anticoagulation are a select subgroup of individuals who have an inherently lower risk of future bleeding. Which is to be taken with a grain of salt because we see patients bleeding at any point during anticoagulation treatment. Dose level is another risk factor and of course the intensity of anticoagulation. There be either prophylactic, therapeutic, super therapeutic generally correlates with bleeding risk. The intensity of warfarin is based of course on the INR for the DOAX is based on the standard drug dose in which one we pick for a specific patient. Although dose intensity tends to correlate with bleeding risk, studies using low intensity warfarin did not demonstrate a substantial reduction of bleeding risk by targeting a lower INR. So there's also the bias of the physician on the inappropriate dose reduction on certain patients that we feel are too much risk of bleeding. So we presumably are driven by the clinician some justified presumption that lower doses will preserve efficacy while reducing bleeding. And it happens frequently with DOAX and this will lead to avoidable thrombosis including a stroke. So risk factors related to the patient and we can't change basically. It's older age of course. The cut-ups are defined and you know there's variable cut-ups for medications, for studies for all sorts of things or risks as well. And of course the risk of bleeding is increased with age in its linear basically. Higher than 60 years old is where we kind of start and then from there the risk is linear to the age of the patient. Non-white rates are also at higher risk. There was a big cohort study of about 20,000 patients with AF. And basically on three-year follow-up the highest risk of intracranial bleeding was amongst Asians compared to whites. It was about a 4.1 hazard ratio which is pretty substantial. Following that is Hispanics in blacks with a hazard ratio of about 2 compared to whites and the least amount of intracranial bleeding happened amongst whites. The sex of the patient, unlike thrombosis risk, which appears to differ between men and women, bleeding risk does not appear to differ significantly by sex. Prior bleeding is another risk factor. Specifically intracranial haemorrhage is a big one. Prior ICH confers an increased risk of recurrent intracranial haemorrhage approximately 2 to 3% per year, which is about a 10-fold higher than the general population risk. And patients with intracranial haemorrhage can restart anticoagulation if the risk of re-bleeding is less than the risk of ischemic stroke and its consequences. Now, this is a complete different topic on alternatives to start anticoagulation or not and this is where the mechanical ways of stroke prevention like watchmen, Lariat and all those devices come into place. GI bleeding, GI lesions can re-bleed with the risk of re-bleeding somewhat predicted by endoscopic findings. That's why we typically seek GI clearance. Once they look at the lesion itself and they can give us some feedback on the safety of restarting an anticoagulant. Post-surgical, of course, sites of surgical bleeding are generally considered to be transient risk factors and anticoagulation following surgery is often initiated within one to three days or so depending on the surgery or as long as there were no unexpected surgical issues that would increase bleeding risk. Comorbidities is another important thing, specifically liver disease, kidney disease, diabetes, cancers, all of these are going to interfere with our patients that's being anticoagulated. Liver disease can affect circulating levels of several endogenous percoagulants and anticoagulant factors and this effect is probably greatest in individuals with very severe liver disease, cirrhosis and all those sorts of things. Kidney disease can cause uremic platelet dysfunction in anemia both of which can increase the bleeding risk. CKD can affect the metabolism of DOAX which are renally cleared and excreted to some degree. Of all the DOAX, the big retran is the most dependent on renal clearance approximately 80 to 85% so someone with kidney disease you don't want to use predaxa. Epixaban is the least dependent on renal clearance about 25% and this is typically the drug of choice with renal patients here and all of the others kind of fall in between predaxa and epixaban. Diabetes is another big one that may increase bleeding risk by effects of the vasculature on the vascular tear as well as other complications related to chronic inflammation state. Cancer and cancer therapy can increase bleeding risk by causing from acytopenia, increasing inflammatory cytokines and disrupting vascular integrity at the primary tumor site or metastasis. Two more blood vessels are more likely to have structural and functionally immaturities that are more prone to bleed, they're more friable, which may also make them more inherently prone to bleeding. So a big concern patients are being anticoagulated comes with the need to use concomitant antiplatelet medication or patients with CAD that have had stents and they need to be on a dual antiplatelet therapy or aspirin or just, you know, P2Y12 therapy for the coronary disease. So several studies have looked into this. One of the first ones is warfarin plus aspirin versus doac plus aspirin. This is not dual antiplatelet, this is just aspirin comparing doac and warfarin. And these studies specifically is a cohort study of about 14,000 patients with atrial fibrillation. Amongst these patients the risk of intracranial hemorrhage was lower. Of course, I mean I've seen in many studies comparing doac to warfarin. Also adding aspirin, intracranial hemorrhage was lower with doac plus aspirin compared with warfarin plus aspirin. On a hot starts ratio of 0.46. And the risk of GI bleeding was pretty similar. There was no big differences between doac and warfarin plus aspirin. And any other bleeding was also more prominent in the group with warfarin plus aspirin compared to doac plus aspirin. Dual versus single antiplatelet therapy with warfarin versus doac. Also several randomized trials. One of the bigger ones is pioneer trial comparing bleeding rates with one of three approaches. So it's a riveroxaban 15 milligrams plus a p2y12 inhibitor versus riveroxaban 2.5. So much lower dose twice a day daily plus dual antiplatelet therapy. And p2y12 inhibitor plus aspirin or vitamin K plus dual antiplatelet therapy. There's about 2,000 patients with atrial fibrillation who had undergone PCI. And the clinically significant bleeding was lowest with riveroxaban plus aspirin at about 17%. Followed by riveroxaban plus dual antiplatelet therapy at about 18%. And then followed by warfarin plus dual antiplatelet therapy that jumps up to 27% risk of bleeding. The Augustus randomized trial also evaluated these comparisons about 4,600 patients with atrial fibrillation plus either acute coronary syndrome or PCI who were taking p2y12 already before any intervention were assigned to receive either a pixaban or warfarin basically plus aspirin or placebo. So the findings were similar with lower bleeding risk and those who took a pixaban at about 10% versus warfarin about 15% and with placebo and these are dual antiplatelet therapy but if they had received placebo instead of aspirin it was about 9% and aspirin 16%. So many bleeding risk scores have been developed. One of the wider used bleeding risk scores that we tend to use this has blood. Now any of these scores they really don't dictate 100% if we are going to go forward with anticoagulation or not but it's to give us an idea on where we are, what we expect with a patient that we're starting anticoagulation for or if it's even worth going a different route as we said before with another mechanical means of stroke prevention. Now I'm not going to go into detail on all of the validation of the scores but just to kind of give you an idea of what these scores look at basically to decide what the bleeding risk score is for each patient. So has blood looks at hypertension as being the age and you get one point per each of these elements of the scale. So A looks at abnormal renal and liver function and you get one point for each. So this is the one that can give you two points. Stroke is another point. Bleeding tendency or predisposition is another one. L for label INRs if patient is some warfarin. E, elderly and we're talking about older than 65 years old gives you another point. And D for drugs and these could be aspirin or NSAIDs or another point for excess alcohol use. And as we see as you get more points your bleeds per 100 patient year increases and above five points there's insufficient data but you can say that the bleeding risk is pretty high for a patient with more than five points. Other scores that are used, this came from a pretty big trial. It's called atria. This one looks at anemia, gives you three points, several severe renal disease. Age more than 75 as compared to the has blood one that used a cut off of 65 years old. Any prior hemorrhage and diagnosed hypertension. These are the elements that this scale looks at. Other ones like hemorrhages look a few more items here but again same concept and look in kind of assessing what the bleeding risk for the patient is and what to expect down the line when starting anticoagulation. So talking about risk reduction for someone that needs to be on anticoagulation. So risk of anticoagulant associated bleeding can be minimized by periodically reviewing the indication for anticoagulation. Risk benefit ratio dose anticoagulant adherence, concomitant medications including anticoagulant agents, NSAIDs and other over the counter medications and patient comorbidities that may affect the dosing. So combined use of anticoagulants and anticoagulant medications should be restricted to settings in which the benefit is expected to outweigh the risk of bleeding. Patients should avoid routine use of NSAIDs for pain or fever when other agents such as acetaminophen or Tylenol are available and when an NSAID is indicated patients should limit the duration of the use and or use a selective cox two inhibitor if appropriate for whatever is needed. Good blood pressure control is important and attention to fall risk may be helpful. Gastric protection is widely used on these patients with PPI's or you know H2 blockers in these patients despite limited evidence of efficacy. Thank you so much for your attention.