Hello, it's my pleasure to be able to speak to you today about the real-world anticoagulation practice in venous thromboembolism. My name is Teresa Carmen. I'm from University Hospitals Case Medical Center. I have no disclosures relevant to this topic and I'm going to avoid off-label discussions of the anticoagulants. Today, I want to make sure we understand and recognize the need for an individual patient-centered management plan for patients with venous thromboembolism. Not all VTE is created equal. I'm going to help us develop an algorithm for comprehensive patient evaluation and to get us started on choosing our anticoagulants, we're going to discuss how comorbidities may influence the choice of anticoagulants that we're going to use. So venous thromboembolism is a spectrum of disease. We can range from pulmonary embolism, which may be massive or clinically relevant and with high clinical risk, isolated internal jugular vein thrombosis, or even IBC filter thrombosis. In addition, we have other types of venous thromboembolism, such as distal VVT or Padgett-Schroeder syndrome and incidental PE. And all of these patients with venous thromboembolism are not created equal and they all need an individual assessment and management plan. Now, there are different levels of management. Usual management would consist of clinical assessment, imaging for diagnosis, anticoagulation. We may search for a reason why and then we discharge the patient for follow-up. I think, however, we need to get past that and go to a higher level of management using our risk prediction tools, our biomarker support for diagnosis and management. Start anticoagulation while we consider the diagnosis of venous thromboembolism and then do our imaging that may be appropriate. When we talk about anticoagulation for treatment, it needs to be done in a thoughtful manner using risk factor identification, modification. We need to make sure all of our patients have cancer screening and any advanced therapies that may be indicated for deep vein thrombosis or pulmonary embolism should be assessed at that time. And then we may need to make sure that we have a complete discussion with the patient regarding their duration of therapy and management of additional symptoms and then assess the patient ongoing for post-VVT events such as post-thrombotic syndrome and post-PE syndrome. So anticoagulation should always be started at the initial suspicion for venous thromboembolism while we await definitive diagnostic testing. And that's whether you're in the office or whether you're in the emergency department. Single dose low molecular weight heparin or an unfractionated heparin drip are clinically indicated is certainly an appropriate strategy. About half the patients with DVT have pulmonary embolism at presentation and it's important to remember that the signs and symptoms of both DVT and pulmonary embolism are very non-specific and they do not have adequate positive nor negative predictive value. So we need to make sure we do definitive testing. So what diagnostic tests are most appropriate typically rely on duplex ultrasound, CTA, and even VQ scan. Pulmonary angiogram and echocardiography certainly can be supportive tools in these patients also. It's important however to remember that if you suspect pulmonary embolism confirm the diagnosis of PE and evaluate the patient for DVT. And counter to that if you suspect DVT confirm the diagnosis of DVT with duplex ultrasound but then consider evaluating the patient for pulmonary embolism as it may impact care going forward. It's also important to remember that when we treat these patients with anticoagulants that's our treatment strategy. It prevents propagation, it stabilizes the thrombus, reduces the risk for thromboembolism, and allows the body to use its own endogenous fibrinolytic system to be able to begin to recanalize the existing thrombus. It doesn't however augment or induce that thrombolytic process and if patients need additional thrombolysis or fibrinolysis through a massive or submassive event we need to be prepared to provide that therapy. Other management tools include IVC filters at thrombectomy or embolectomy or even just surveillance also ultrasound in case of isolated caffeine thrombosis may be adequate management strategies and be tools to help us take care of these patients. This is the algorithm that I use when I'm first assessing a patient. After we've made the diagnosis of venous thromboembolism I think we need to first determine the need for admission. If they have a low risk DVT or a low risk pulmonary embolism outpatient management may be completely appropriate. If they're more high risk than an inpatient admission is warranted. Depending on whether we treat them in the outpatient and are just starting a therapy or if we have them in the inpatient setting then we can further manage more complicated events such as iliofemoral DVT, massive or submassive PE, and then consider whether interventions are warranted. All of these patients need to go on to risk factor modification to further discussions regarding the length of therapy and management for any presenting post-thrombotic issues. In some studies more than 70% of deep vein thrombosis and low risk pulmonary embolism can be treated as an outpatient or with a shortened hospital admission. This actually is currently meeting with the most recent guidelines from the American Society of Hematology as well as the American College of Chest Physicians. Absolute criteria for admission at least at our hospital system, signs or symptoms of pulmonary embolism, iliofemoral DVT or severely symptomatic DVT, any complicating comorbidity that may put your anticoagulation may make your anticoagulation more complicated. If the patient doesn't have the ability to follow an outpatient treatment regimen, if they're not medically facile, or if they lack reasonable follow-up after discharge, they should probably be admitted so that those social issues can be addressed. If you're going to send the patient home, you need to be able to educate the patient. You're sending them home to be their own health care provider. A low-risk patient needs to be reliable, have few comorbidities, and be very educable. They also have to have resources to cover their drugs, whether that's low-molecular weight heparin or if that's a DOAC. And they need clinical follow-up at least within one to two weeks, but ideally within 48 hours. DOAC starter packs are very helpful in this setting and can provide the patient with education as well as a comprehensive care plan for the first month of therapy. If you're going to use low-molecular weight heparin followed by warfarin, the patient has to have adequate INR follow-up within two to three days of starting warfarin therapy. This is some data from the Garfield DTE registry. This is a prospective observational registry that enrolled just over 10,000 patients with venous thromboembolism. About 60% had deep vein thrombosis, 38% pulmonary embolism, and 91% of these patients were treated with anticoagulation alone. It's interesting that in this study of 10,000 patients, only about 27% were managed in the outpatient setting. Not all of these patients were high risk, but we still do end up admitting a majority of our patients with venous thromboembolism. And those patients who do get admitted, usually we start with low-molecular weight heparin or infractionated heparin initially. I think a DOAC is perfectly acceptable in these patients if there are no interventions that are anticipated and you don't think the patient's going to require any other therapies. Symptomatic intermediate risk pulmonary embolism needs risk stratification. We should make sure we get an echo on all these patients and biomarkers, such as troponin and BNP, as well as lactic acid in some of these patients. For patients with massive pulmonary embolism or high-risk submassive pulmonary embolism, we should consider those patients for intervention. Certainly this may be life-saving for some of these patients. Patients with ileofebrile or severely symptomatic DDT may also be considered for intervention. And then I think long-term we need to determine the appropriate anticoagulation strategy, and this is done based on clinical comorbidities. This is more data from the Garfield registry, and you can see in this publication about a third of the patients were treated with DOAC. 17% treated with parenteral anticoagulation alone. About a quarter were treated with parenteral anticoagulation followed by vitamin K antagonists, and then again about 16% were initially started on a parenteral agent and then converted to a DOAC. So it does look as though there are a number of different management strategies that people use in the real world, and no single management strategy is going to be appropriate for all of your venous pulmonary embolism patients. So how do we choose? If you're going to consider an intervention or a surgery, you're going to want to have the patient either on a short-acting or more intermediate-acting agent, such as low-molecular weight heparin or unfractionated heparin. You may ultimately make your decisions based on whether the patient's more fit for an oral agent or a parenteral agent, or even on potential for reversal if they're at high risk of bleeding. Certainly there's a number of underlying comorbidities that will ultimately influence how you're going to treat these patients, and I think all of these considerations need to be at the forefront of your thought processes. So I think most patients should be considered for a DOAC first, but that doesn't mean a DOAC is always appropriate or always optimal for the patient. We also base our choices on experience, and that's what the patient and the practitioner are most comfortable with. Again, is there a need for intervention? Also, is your patient at low risk, intermediate, or high risk for bleeding, recurrent venous thromboembolism, or the future need for an intervention or procedure? In clinical situations, in both venous thromboembolism, your low to intermediate risk patients I think are going to do well with most therapies. We have limited data on the DOACs in malignancy, but this is certainly expanding. But again, I don't think this is necessarily first-line therapy for all patients. In highly inflammatory states, sometimes I feel the DOACs may not perform as well, and I don't necessarily advocate them in this setting. And certainly in high-risk thrombophilia, especially in the hospital for the antibody syndrome, which we'll discuss later. There are other comorbid diseases such as chronic kidney disease, liver disease, cancer, and other medications that may influence your choice of therapy. And then conversations with the patients regarding their desire or lack thereof for monitoring, cost of the agents, reversibility, should they get into a situation where there's bleeding or the need for reversing anticoagulation, and whether they prefer once or twice daily doses. When we look at the direct oral anticoagulants, there's certainly a number of expanding indications for these drugs. We do know from our trials that these are bioaffective, and they're very similar to conventional therapies in venous thromboembolism. They provide us ease of dosing, they're safe, and the monitoring and dose adjustments are not typically required. However, we have yet to solve all of the problems that we have with DOACs. There is actually an inability to monitor the agents. And while they have a wide therapeutic index, some patients may benefit from monitoring. They have a short half-life, and they may leave the patients unprotected with missed doses. Drug interactions are few, but they certainly may impact your choice of therapy. And I think the list of drugs that we need to be concerned about is ever-expanding. These drugs are renally clear, and while dose adjustments are not necessarily recommended with the patients with venous thromboembolism, they certainly may be required for your patients with atrial fibrillation. And again, these drugs are not to be used in all patients, not for antiphosphate-bidding antibodies, patients with underlying valves, pregnant or breastfeeding. Let's talk one word about compliance. This is a study that was done out of Mayo Clinic, Scottsdale. They looked at 324 patients. They used the Marisky Medication Adherence Scale. They had two-thirds of their patients on DOACs, demonstrated medium or high adherence, and then they had patients on Warfarin with about a 95% medium or high adherence. So in this study, compliance is not really drug-dependent. This is another trial now out of the VA, and this looked at patients being prescribed DOACs. You can see the number of patients being prescribed Bigotran, Reviroxidine, or Pixivan. And you can see that the proportion of days covered was roughly similar between all three drugs and about 90%. The proportion of days covered, less than 80%. Again, very similar in all of these patients, and upwards of about 22%. And it didn't seem to matter if these patients were started on a DOAC de novo, or if they were previously on Warfarin and converted to a DOAC. Their percentage of days covered were roughly the same. So compliance is not necessarily a drug issue. I don't know that DOACs increase our adherence to these medications. It really is an underlying patient issue in many cases. That's important to realize, too, that sometimes patients or practitioners will dose-adjust patients and their DOAC levels. And dose adjustments in patients with BTE is really relatively common. This is from the ARRETI registry, and you can see that in patients who had dose adjustments, there was a significant increased risk of adverse events. BTE recurrence was increased tenfold. Major bleeding had a hazard ratio of 1.04, and the hazard ratio for mortality was 1.4, so about a 40% increase. So dose adjustments in patients with venous thromboembolism are really not warranted for the DOACs, and we need to be very careful in these patient populations. If you feel as though you may need a dose adjustment for whatever reason, whether it's low body weight or frailty, et cetera, it's probably just better not to be using these drugs in this setting. This is the latest data that we have or the latest recommendations that we have regarding the use of direct oral anticoagulants in patients with obesity. So previously, we had guidelines from the International Society on Thrombosis and Hemostasis from 2016 that suggested maybe we should not use these drugs in patients with a weight greater than 120 kilos or a BMI greater than 40. They've gone back and now reassessed this data based on phase 4 studies, and you can see that at least in apixaban as well as rivuloxaban, we seem to have similar outcomes in our patients with a BMI greater than 135, weight greater than 140, and even our BMI greater than 40, although they do recognize that there's less data for apixaban in this setting than there is for rivuloxaban. So the current guidelines are suggesting that for patients with a BMI greater than 40 or a weight greater than 120, there's really no need for a dose adjustment in these patients. There are fewer supporting data for apixaban and rivuloxaban. They did comment specifically that the data is insufficient, however, to provide any recommendations regarding the dose reduction that we may use for secondary DTD prophylaxis following our primary treatment duration. So I think we need to be thoughtful with respect to using these drugs in patients with obesity. They did also comment specifically on the use of these drugs following bariatric surgery, and you can see that there are at least some concerns that the availability of these drugs may be reduced following different types of bariatric surgery, and they recommended that switching to vitamin K antagonists or a DOAC may be considered after four weeks of parenteral treatment following a bariatric procedure. So most of these patients should go home either on low-molecular weight heparin or fondant paranox for at least that four-week period prior to considering a vitamin K antagonist or a DOAC. And again, I think you have to be thoughtful based on the type of surgery, whether you're going to use a DOAC going forward in that setting or not. Among patients with chronic kidney disease, it's always a little bit unknown how safe these drugs are. This is a recent meta-analysis that included 10 randomized controlled trials, and you can see that in at least these five trials included in the first analysis and the scores plot, there was no difference in recurrent venous thromboembolism in the overall group, nor no difference in mild chronic kidney disease or moderate to severe kidney disease. When you looked at bleeding, bleeding favored DOACs in the group as a whole. It also favored DOACs in patients with mild kidney disease, and while there were fewer patients with moderate to severe disease, also DOACs seemed to perform a little bit better compared to vitamin K antagonists. This is another recent systematic review. It was more of a descriptive review of thrombosis and bleeding outcomes. They looked at nine studies and similarly found no difference in venous thromboembolism recurrence, no difference in bleeding in patients with even moderate chronic kidney disease. However, they did identify that the risk of bleeding seemed to increase with worsening renal impairment with all of these DOACs except epixidine. So I do think that we have some data and some guidelines in using particularly epixidine in patients with significant renal disease. These are the guidelines and comparators between the dose recommendations in the European guidelines versus the U.S. guidelines. We'll call your attention that if you have a sort of moderate renal disease down to a creatinine clearance of about 30, there's no dose adjustment for apixaban, no dose dose adjustment for vigatran, and no dose adjustment for rivaroxaban. However, there is a dose adjustment for edoxaban. If you have more severe renal disease, the only drug that really should be used in this setting is probably apixaban, although there were some patients in the edoxaban trial that did have fairly significant renal impairment. But we should not be using the vigatran nor rivaroxaban in our patients with fairly severe renal disease. Anticoagulants or DOACs in anticlosporolipid antibody syndrome have become a fairly recent hot topic since this trial was published initially in 2018. This was the TRAPS trial that looked at warfarin compared to rivaroxaban in high-risk anticlosporolipid antibodies. Patients with triple positive anticlosporolipid antibodies, they were intended to enroll more than 500 patients. However, the trial was stopped at 120 patients by the Data Safety and Monitoring Committee because of an excess number of events seen on rivaroxaban compared to warfarin. That prompted this review and meta-analysis that looked at just over 400 patients from 47 studies. The majority of these patients were on rivaroxaban. Overall, there was a 16% recurrent thromboembolic rate with DOACs and about a seven-fold increased risk for recurrence in patients with triple positive APLA and rivaroxaban. Yet a third trial, the Toledo trial, was published three years follow-up looking at rivaroxaban versus vitamin K antagonists. Again, triple positive APLA patients, recurrent thromboembolic rates nearly doubled in the patients with rivaroxaban compared to vitamin K antagonists. Most of these were stroke, and so from that perspective, we now have a warning on the pathogens or the DOACs against their use in patients with anticlosporolipid antibody syndrome. Well, what about chronic liver disease? This is actually a situation where we end up facing quite a bit in our high-risk patients. Many of these patients are going to present with fairly profound liver disease, and unfortunately, it's sort of a mixed thrombotic and bleeding state, so they have certain factors associated with their liver disease that may make them prothrombotic, and yet they have other factors that may make them a little more anticoagulated or more at risk for bleeding. You can see that in our patients with DOACs in liver disease, we do have hepatic metabolism in most of our DOACs, and we do run the risk of changes in drug exposure and effects on the INR. In general, because there is some degree of liver clearance in all of these patients, we have recommendations that in patients with Child Acute A, there's no dose adjustment required, and most of these patients are safe for any of our DOACs. If we have more severe liver disease, Child Acute B, we should be very cautious with apixaban or bigotrin, and frankly, I tend to avoid these drugs altogether, but when you get to very severe liver disease, DOACs are really not recommended. In most of these patients, what is recommended is low-molecular weight heparin. It has a fairly good safety profile. The anticoagulant effect is very rapid. We have the ability to reverse it if we need to. If there's underlying renal disease, we may have to rely on unfractionated heparin. Unfortunately, again, the DOACs are probably not warranted in patients with more advanced liver disease, and warfarin can actually be very difficult to monitor, so in many of these patients, we do rely on low-molecular weight heparin. Now, we talked briefly about the effects of bariatric surgery on our DOACs, and I'm just going to make a couple additional points about the effects of just general gastrointestinal tract surgery on these drugs. So, the site of absorption is variable for the different drugs. Ribaroxaban needs to pass through the stomach. It needs to have that acid, so we cannot deliver that by a J-tube directly to the intestines. In addition, if for some reason the patient's had a gastrectomy or a partial gastrectomy or even an esophageal pull-through, this is probably not the drug we want to be using. Pixivan is absorbed probably mostly in the stomach, although there is distal small bowel and proximal colon absorption, according to some manuscripts, and so when a patient's missing a portion of their ileum and proximal colon, I also get very worried about using pixivan in these patients. The lack of ability to monitor the drug, I'm not certain that I feel very comfortable even with the pixivan. Edoxaban is less well-studied overall. It seems to dissolve in the stomach and is absorbed in the proximal small bowel, and dabigatran should likely be avoided in patients with small bowel resectional bypass because that's where most of the absorption takes place. So, I think following the bariatric surgery, we talked about the preferred use of omolecular heparin for a period of time and then either a vitamin K antagonist or a DOAC, but I think you have to be very careful. You have to know how much bowel is missing in these patients. It's particularly important in our patients with colorectal cancer or who have had any type of bypass for a Whipple procedure or esophageal surgery, etc. I think you have to be very wary about the use of these drugs in some of these patients. Now, when we talk about DOACs and cancer-associated venous thromboembolism, these are the guidelines from 2018 that looked at using an individual treatment regimen and shared decision-making for these patients. What we've come to realize in most of our cancer trials is these DOACs do a fair job of preventing recurrent venous thromboembolism compared to our omolecular heparin standard that we had historically been using. However, there does seem to be higher bleeding, particularly in some patient groups, and so trying to incorporate those patient values and patient preferences for an injectable agent versus an oral agent and incorporating the concerns over bleeding with these patients really should be taken into consideration. So, how do we make these decisions? Patient preference is one. Cost is another. We've been fairly reliably able to get low-molecular heparin covered now as a standard of care. DOAC coverage may not be consistent, so that might make a difference. Again, chronic kidney disease, liver disease, hypoalbuminemia, ruparoxaban and opixaban are both albumin-bound in circulation, so in patients who have very low albumin, you in theory have a more circulating drug, and I do worry to some extent about these patients, particularly if they're at high risk of bleeding. Any degree of thrombocytopenia with a platelet count less than 50, I think you have to be wary of all anticoagulants, but in this setting, also, I do prefer the low-molecular heparins. And then, of course, concomitant medications. Compliance. Again, we've talked about that. The issue is not solved by using a DOAC alone. The availability to reverse the drug may also make a difference, particularly if your patient lives in an urban setting versus a rural setting. And then the type of cancer. In most of these clinical trials, GI and even GU bleeding were most common. Clearly, we saw an increased risk of bleeding in patients with esophageal malignancies, and we tend to avoid these drugs in that setting. We know that we have very few drug-drug interactions. We certainly have some common players that we think about relative to our DOACs. However, I will say, particularly in the world of cancer, that list is expanding, and I think we have to be aware of how these drugs may interact to either increase or decrease our DOAC plasma levels. Both of these, obviously, put our patients at risk, and we want to be aware of these as new drugs come along. So, in conclusion, I think many of our DTE patients can be treated as outpatient. It's unclear if this is really widely appreciated or employed, but it seems to be a minority of patients that actually are using this as an option. There are many different anticoagulation options available. DOACs, I think, are preferred in many settings for the ease of use, but it doesn't solve all of the issues related to our anticoagulants. And our patients who need these drugs really are very clinically complex, and those complexities may make the DOACs impractical. No agent is suitable for all patients. I think we have to use all of our available tools to risk assess and look at the strategies for management and use them as appropriate for clinical success. And with that, I thank you for your attention.

venous thromboembolism

individualized approach

anticoagulant therapy

diagnostic tests

comorbidities

patient education