Transcript Details This is a transcript of a continuing medical education (CME) activity accessible on the ReachMD network. Additional media formats for the activity and full activity details (including sponsor and supporter, disclosures, and instructions for claiming credit) are available by visiting: https://reachmd.com/programs/cme/individualizing-vte-treatment-and-prevention-recurrence-placedirect-oral-anticoagulants-vte/7751/ Released: 02/08/2016 Valid until: 02/08/2017 Time needed to complete: 15 minutes ReachMD www.reachmd.com info@reachmd.com (866) 423-7849 Individualizing VTE Treatment and Prevention of Recurrence: The Place for Direct Oral Anticoagulants in VTE Welcome to CME on ReachMD. This segment, Individualizing VTE Treatment and Prevention of Recurrence: The Place for Novel Oral Anticoagulants in VTE, is jointly provided by Global Education Group and Diversified Health Communications and supported by an educational grant from Boehringer Ingelheim. Your faculty is Dr. Alok Khorana, who is a Professor of Medicine at the Cleveland Clinic Lerner College of Medicine, Case Western Reserve University. He is also the Sondra and Stephen Hardis Chair in Oncology Research, Vice-Chair for Clinical Services and Strategy of the Taussig Cancer Institute and Director of the Gastrointestinal Malignancies Program at the Cleveland Clinic, Cleveland, Ohio. 2017 ReachMD Page 1 of 9
Prior to beginning the activity, please be sure to review Dr. Khorana s financial disclosures. Please also review the learning objectives for this activity. Here is your host, Dr. Jennifer Caudle. Venous thromboembolism, or VTE, is an umbrella term for deep vein thrombosis and pulmonary embolism. It is estimated that VTE affects up to 600,000 people each year in the United States. It s associated with significant morbidity and mortality. Approximately 33% of people with VTE will have a recurrence within 10 years, with the risk being greatest in the first 2 years. Also, it is estimated that up to a hundred thousand people die as a result of VTE each year. Today we are addressing the role of novel oral anticoagulants in VTE treatment and prevention of recurrence. Dr. Khorana, welcome to our program. Thank you so much for having me. Dr. Khorana, what are some currently available treatments for VTE and prevention of recurrence? Well, the great news is we have a lot of different options. Warfarin which has been around for a number of decades remains the most widely prescribed oral anticoagulant. We also have heparin which includes unfractionated heparin and lower-molecular-weight heparin which have been replacing unfractionated heparin, fondaparinux which is a factor Xa inhibitor, and in the past few years we ve 2017 ReachMD Page 2 of 9
seen the advent of novel oral anticoagulants including dabigatran which is a direct thrombin inhibitor and rivaroxaban, apixaban, and edoxaban which are factor Xa inhibitors. What do the current clinical guidelines recommend for the acute treatment of VTE? In patients starting off with a new diagnosis of either deep vein thrombosis or pulmonary embolism, initial treatment is recommended with parenteral anticoagulation, that s either low-molecular-weight heparin, unfractionated heparin, or fondaparinux. It s important that if you re going to transition the patient to an oral anticoagulant such as warfarin, that warfarin therapy be started as soon as possible in the course of treatment, and patients remain on parenteral therapy for at least 5 days, until the INR is 2 or higher for at least 24 hours. Great. Can you discuss the choice of anticoagulant regimen for long-term therapy? For patients with a DVT or PE and no cancer, the guidelines recommend low-molecular-weight heparin over dabigatran or rivaroxaban for long-term therapy. For patients with DVT and cancer, lowmolecular-weight heparin monotherapy is recommended, and if you re not going to use low-molecularweight heparin therapy, for whatever reason, then Coumadin, or a vitamin K antagonist is preferred over dabigatran or rivaroxaban for long-term treatment according to these slightly older guidelines. So, the newer anticoagulants have just become available and the challenge is that some of the evidence-based guidelines, such as the Chest guidelines, although they were released in 2012 they were prepared in 2011. The newer agents were just starting to come on market. The guidelines do mention that rivaroxaban and dabigatran are certainly more convenient for patients, but at that time, given lack ofexperience with the agents outside of clinical trials, they gave a weaker recommendation, in favor of warfarin and low-molecular-weight heparin. In more recent prescription data analysis, it s 2017 ReachMD Page 3 of 9
pretty clear that the new direct oral anticoagulants certainly are being widely used in the market as well as initial treatment of VTE. What do the guidelines recommend for prevention of VTE in orthopedic patients? In orthopedic patients, it is primarily patients undergoing either total hip or total knee arthroplasty; at least one of the following drugs are recommended for 10 to 14 days for prophylaxis. It can be lowmolecular-weight heparin, fondaparinux, apixaban, dabigatran, unfractionated heparin, Coumadin, or aspirin. Rivaroxaban and apixaban do also have approval for prophylaxis in this setting as well. For patients undergoing major orthopedic surgery who refuse injection, for comfort reasons or for copayment issues, the guidelines recommend apixaban or dabigatran rather than other forms of prophylaxis. Dr. Khorana, what is the role of new oral anticoagulant agents in the prevention and management of VTE? Those have also been in practice for a while now; the use of warfarin is very challenging because it involves rigorous monitoring, there are issues related to bridging at the time of interruptions or if there are procedural issues, and there s a big problem with drug-drug interactions. I m an oncologist and interactions with chemotherapy is sort of a big issue and there s a lot of inter-patient variability. And there are dietary restrictions as well that are not always followed by patients. And so, although highly effective, warfarin has a lot of challenges. The new oral agents definitely have advantages over warfarin in that their effect is more predictable, it doesn t require monitoring, and there s not a lot of drug-diet interactions and certainly fewer drug-drug interactions. So, in general, the novel oral agents are much more patient-friendly and much more convenient to use. It should be noted that none of the 2017 ReachMD Page 4 of 9
newer agents are appropriate for patients who have a heart valve replacement, so the indications are either treatment of VTE or non-valvular heart disease, and so in that setting you would recommend continuing the use of warfarin. What about for patients with cancer-associated VTE? So, VTE is a big problem in cancer patients. According to most estimates, at least 1 in 5 cancer patients will develop a blood clot at some point in their natural history. Unfortunately, here, warfarin continues to be the dominantly used anticoagulant, even though for about 10 years, guidelines have been recommending low-molecular-weight heparin monotherapy for treatment. In terms of the newer agents, they have not been tested head-to-head versus warfarin, although they have been shown to have non-inferior efficacy compared to Coumadin, both in subgroup analyses of individual treatment trials as well as in pooled analyses of all of the NOAC cancer subgroups. There are also active cancer statistic studiesunderway with some of the newer oral agents. At this time, clinical guidelines are still recommending low-molecular-weight heparin therapy, although based on some data presented at ASH, it appears that the use of novel oral agents may be increasing in this population and certainly in settings where you re considering warfarin or in the setting of after 6 months of treatment where there are no data, it is not unreasonable to use NOACs in this setting. If you re just tuning in, you are listening to CME on ReachMD. I m your host, Dr. Jennifer Caudle, and today I m speaking with Dr. Alok Khorana. Dr. Khorana, what are some of the bleeding risks that are associated with novel oral anticoagulants and how do they compare to warfarin? 2017 ReachMD Page 5 of 9
Well, the major side effect of anticoagulation, any anticoagulation, is bleeding. There s been a lot of concern about bleeding as related to the newer oral agents, but it s important to understand that bleeding occurs in any patient on anticoagulation. It s sort of the predictable side effect of anticoagulation. There s one study from 2013 that shows that over a 12-month period there were about 6-1/2 million patients taking anticoagulants in the US of whom about 5% presented to the ER with a bleeding event and two-thirds of those patients needed to be hospitalized. So, bleeding is very common in this population unfortunately, just based on the mechanism of action which is to make the blood less coagulable. However, when you look at NOACs, there is a very nice Cochrane review that compared NOACs to conventional treatment for DVT, looking at 11 studies with over 25,000 participants, and the conclusion was efficacy is similar and the bleeding risk is lower with NOACs than with conventional treatment of VTE. So, one of the benefits of warfarin is that it can be reversed and currently there are no approved reversal agents for the novel oral anticoagulation agents, or NOACs. So, what is in the pipeline for novel oral anticoagulation reversal agents and how close are we really to seeing them used in practice? Yes, so this has been a big criticism of the novel oral agents, is that there s not an approved reversal agent, or there wasn t until very recently, and to some extent it s more of a concern in the case of rarebut-critical situations as there may be life-threatening bleeding. As I mentioned, bleeding generally is less relevantto warfarin and maybe a slightly lower rate compared to warfarin with the NOACs. But of course for clinicians it s important that even on the rare occasions when there is a life-threatening bleed happening that there will be a reversal agent that can safely bring the patient to a better situation. So, there have been ongoing studies with multiple reversal agents. One was actually just approved. This is a drug called idarucizumab, or Praxbind, which is approved specifically for patients on dabigatran. There are two other agents that are currently in clinical development, andexanet, which is an antidote for rivaroxaban, apixaban, and edoxaban that had a later-phase New England Journal paper earlier this year and is expected to get approval soon, and PER977 which is an antidote for all 4 novel oral agents. Each of these agents work differently in terms of their specificity, in terms of the mechanism, and the one that I mentioned, Praxbind, or idarucizumab, was just approved a few weeks ago and is already 2017 ReachMD Page 6 of 9
available on the market. Wonderful. How are the NOAC-related bleeding episodes currently managed? It s important to recognize most bleeding is not major bleeding. Number one, let s have patients just stop taking the drug and that should improve the situation very quickly in a very good situation. So there are also nonspecific reversal strategies that are available including the use of prothrombin complex concentrate, activated PCC, and recombinant factor VII, and all of these have shown some degree of efficacy. Dabigatran can at least be partially removed with hemodialysis, although the rationale for using that is less, now that we do have Praxbind available. And then oral charcoal may reduce dabigatran and apixaban absorption if it s not administered too late after the last drug intake. Well, let s examine a couple of specific cases and discuss treatment approaches. As we do this, let s discuss how to communicate with the patient to ease concerns and improve adherence to treatment. Case number one: Jason is a 70-year-old patient about to undergo total knee arthroplasty. He has type 2 diabetes and moderate impaired renal function. His GFR is 58 ml/min. Jason does not like needles and is concerned about bleeding risk. Can you discuss this case for us? Sure. So, this is an older patient who is about to undergo total knee replacement. He does have some comorbidities including diabetes and renal dysfunction and is not a fan of needles, as very few people are. In this setting, there are several agents that are available. I think it s well recognized with this setting, total knee replacement in the setting of comorbidities, does carry a high risk of venous thromboembolism, and is otherwise a very safe procedure. So it s important that we do what we can to prevent a VTE event from occurring. Agents that are available in this setting include low-molecular- 2017 ReachMD Page 7 of 9
weight heparin, fondaparinux, apixaban, dabigatran, Coumadin, or aspirin. So for patients who are refusing injectable agents, as I mentioned, including the NOACs there s a bunch of oral anticoagulants available in this setting. It is important to make sure that patients understand the need for using a blood thinner in this setting and that they adhere to their oral agent if that is what you choose to use. Case number two: Maggie, is a 48-year-old breast cancer patient undergoing chemotherapy and she presents with complaints of right calf tenderness. Can you discuss this particular scenario? Cancer-related thrombosis is also a very common occurrence. It accounts for about 1 in 5 blood clots and 1 in 5 cancer patients get a blood clot. So, it s a fairly prevalent public health problem. As I mentioned, the guidelines recommend low-molecular-weight heparin monotherapy as being sort of the treatment of choice, but patients, especially in the United States, may refuse this, not just because of concerns about injectables, but also because of copayment issues related to injectables. So the appropriate guideline recommended treatment would be low-molecular-weight heparin monotherapy for up to 6 months. For patients who refuse that, using an oral anticoagulant in this setting would make sense. Options include warfarin, but this is a patient who is on chemotherapy, so you can certainly choose to use novel oral agents as they have less drug-drug interactions, known drug-drug interactions with chemotherapy. Certainly other decisions need to be made at the 6-month time point in patients in whom the cancer is in remission and who are not on active treatment. The general consensus is to discontinue anticoagulation at that time point, although there will still be a continued risk of recurrent VTE, but for the majority of patients who are going to continue to receive active treatment, the consensus is also to continue anticoagulation indefinitely, but there are no randomized data in the post- 6-month setting and so any of the oral anticoagulants, or continuing low-molecular-weight heparin would be an option at that time point. It is important to communicate to cancer patients that they remain at very high risk for recurrence, even on anticoagulation, but certainly if they go off of anticoagulation in the initial time period after diagnosis. So it s very important to make sure that patients understand why they re on a blood thinner and how important it is that they stay on it to prevent a fatalor significantly morbid complications, such as recurrent VTE, from happening. 2017 ReachMD Page 8 of 9
Well, I d like to thank our guest, Dr. Khorana, for helping us better understand the role of NOACs in VTE treatment and prevention of recurrence. Thank you. Announcer Close This segment of CME on ReachMD is jointly provided by Global Education Group and Diversified Health Communications and supported by an educational grant from Boehringer Ingelheim. To receive your FREE CME credit or to download this segment, go to reachmd.com/cme. Thank you for listening. 2017 ReachMD Page 9 of 9