<<insert slide 1 >>  Chapter title: Introduction

Time code:00:00

 

Alok A. Khorana , MD: [00:00:07] Alright, great. Thank you. Good afternoon, my name’s Alok Khorana. Thank you all for coming to this lunch session today. I know ASH is a really busy time, so we appreciate you taking the time out to come to this discussion. I’m a medical oncologist at the Cleveland Clinic, and I’m joined by a terrific panel of experts today. We’ll be discussing what’s new in VTE, evaluating the latest evidence and grades of recommendation.

 

<<insert slide 2  >>  Chapter title: Agenda

Time code: 00:33

The first speaker will be Rupert Bauersachs, talking about the challenge of VTE in cancer and implications for practicing physicians. Next, we’ll have Professor Wells talking about VTE and cancer and then the latest guidelines and standards for clinical care, which are changing very rapidly. I’ll talk about VTE prevention in patients with cancer, and we have some exciting new data that came out earlier this year and will continue to come out over the next couple of months.

[00:01:02] Finally, we’ll finish up with Professor Lord Kakkar talking about treating VTE in cancer patients from clinical evidence to clinical care. This again is an area that’s changed very rapidly over the past year or so. We’ll have time at the end, hopefully, for a panel discussion, a Q&A session, so keep those questions coming. We can get them electronically, and I promise to address as many of those questions as we can towards the end.

[00:01:28] Alright. Without any further ado, Professor Bauersachs to talk about challenge of VTE in cancer; implications for practicing physicians.

 

<<insert slide 3  >>  Chapter title:

Time code: Dr Rupert Bauersachs   01:18

 

Rupert M. Bauersachs, MD: [00:01:35] Yeah. Alok, thank you very much. Good afternoon, ladies and gentlemen.

<<insert slide 4 >>  Chapter title: Agenda

Time code: 01:22

My task now is to review with you the challenges that we have in the management of cancer-associated thrombosis. I will then review the evidence that we have for low-molecular-weight heparin in the treatment of cancer-associated thrombosis. Finally, I will derive some practical implications.

 

<<insert slide 5 >>  Chapter title: Epidemiology

Time code: 01:43

 

[00:01:59] If we look at cancer and malignant and venous thromboembolism, there’s really a double-sided relationship. We know that, for patients with cancer, venous thromboembolism is a leading cause of death, and the occurrence of VTE is associated with a largely decreased prognosis for the patients. We have - - up to 20% of the patients with cancer have VTE. And if we look at the autopsy, we see about 50% VTE deep vein thrombosis or pulmonary embolism in those cancer patients.

[00:02:39] On the other hand, venous thromboembolism often is the first sign of cancer. Even if the cancer is not apparent, they may - - it may already trigger venous thromboembolism. And we know that about 20% of the patients that we treat for venous thromboembolism have an underlying active cancer. Most importantly - - and we’ll discuss that in more detail - - our measures for prevention and treatment in cancer are less effective.

 

<<insert slide 6 >>  Chapter title:

Time code: 02:53

[00:03:09] That leads me to the first question to you: which types of cancer have the highest incidence rates for venous thromboembolism? Please vote. Prostate cancer, breast cancer, lung cancer, colon cancer, pancreatic cancer.

<<insert slide 7 >>  Chapter title:

Time code: 03:11

 

[Music]. Okay, that’s a very clear correct answer [laughter]. Pancreatic cancer really has the highest risk for developing venous thromboembolism, while it is lower for breast and prostate cancer.

 

<<insert slide 8 >>  Chapter title: Risk of VTE

Time code: 03:25

 [00:03:42] If we look at the epidemiologic data that we have in the next slide, you can see exactly that your vote was correct; pancreatic cancer has the highest risk, while prostate cancer and breast cancer have a very much lower risk of venous thromboembolism.

 

<<insert slide 9 >>  Chapter title:

Time code: 03:44

But, having said that, for practically reasons, this is not the whole truth because we know that breast cancer and prostate cancer are much more common compared to pancreatic cancer.

<<insert slide 10 >>  Chapter title:

Time code: 03:57

 

[00:04:14] Taking that together, the frequency of different types of cancer and the risk that we just discussed, in clinical practice, we are most commonly confronted with prostate-cancer patients, breast-cancer patients, lung-cancer patients that are suffering from venous thromboembolism. These are the most common patients developing cancer-associated thrombosis, while pancreatic cancer is not as common in clinical practice with venous thromboembolism.

 

<<insert slide 11 >>  Chapter title: Recurrent VTE and Bleeding

Time code: 04:29

 

[00:04:45] I was mentioning the challenges that we have in the treatment of cancer-associated thrombosis, and this is a landmark study going back to 2002 by Paolo Prandoni. He showed that, in cancer patients as compared to non-cancer patients, the risk of recurrent VTE instead of being on anticoagulant treatment is much higher. At the same time, the risk of bleeding for the cancer patients is higher compared to the non-cancer patients. So, we have a less-effective and a less-safe treatment in patients with cancer treating for venous thromboembolism.

 

<<insert slide 12 >>  Chapter title: CLOT Study

Time code: 05:08

 

[00:05:26] This is the landmark study by Agnes Lee, the CLOT Study, that first showed that if you treat long-term treatment with low-molecular-weight heparin - - in this case, dalteparin, 200 units for 1 month then followed by 150 units for the following 5 months - - you can reduce the risk of recurrence by about 50% without increasing the risk of major bleeding. So, the CLOT Study published in 2003 really changed the management and changed the guidelines, and that was really the standard recommended treatment.

<<insert slide 13 >>  Chapter title: CATCH Study

Time code: 05:49

 

[00:06:05] Another more recent study, the CATCH Study, with a similar design; long-term treatment of low-molecular-weight heparin tinzaparin compared to oral vitamin K antagonists after overlapping about 5 days with low-molecular-weight heparin, also showed a reduction. However, this reduction with low-molecular-weight heparin long-term treatment was not significant. Again, bleeding risk was comparable.

 

<<insert slide 14 >>  Chapter title:

Time code:06:16

 

[00:06:33] This is an interesting study and sub-analysis of the CATCH Study that came out recently, and it showed us another challenge that we have. If you compare the risk for GI bleeding or the risk for bleeding in patients with a GI-tract cancer, you see that both with low-molecular-weight heparin and warfarin, the risk is substantial; about one-third of the patients suffer from a clinically-relevant bleeding. And the same is true for genitourinary cancer, especially when they are treated with warfarin.

<<insert slide 15  >>  Chapter title:

Time code:06:52

 

[00:07:08] This is another sub-analysis coming out of the CATCH Study, published by Alok Khorana, and that looks at those patients that are suffering from recurrence while they are on anticoagulant treatment with vitamin K antagonists or low-molecular-weight heparin. So, what are predictors for treatment failures for recurrent VTE? An elevated tissue factor is associated with about three-fold increase risk for recurrence.

[00:07:37] Again, hepatobiliary cancer has a high risk of recurrence; 5.5 hazard ratio for those patients to have suffered a recurrence while on an anticoagulant treatment. Another important point, clinically, is venous compression by the bulk of the cancer by lymph nodes, that, again, is associated with a three-fold increase of recurrence in spite of anticoagulant treatment.

 

<<insert slide 16  >>  Chapter title: Approach to VTE

Time code:07:51

 [00:08:08] What do we do if a patient who is on anticoagulant treatment because of cancer-associated thrombosis suffers a recurrence? If the patient is warfarin or vitamin K antagonists, we would switch to low-molecular-weight heparin because I showed you the data that this is more effective. So, that would be the first step; switch the VKA patient to low-molecular-weight heparin.

[00:08:33] Now, what would we do if a patient suffers a recurrence while he or she is on low-molecular-weight heparin? We would then increase the dose of low-molecular-weight heparin by about a quarter. Then, of course, we would observe the patient closely. We would reassess the patient in about 5 or 7 days. If there is improvement, we would continue on that dose and resume usual follow-up.

[00:09:01] If the patient does not show improvement, we would then check the anti-Xa levels. We’d check whether there is an underlying thrombophilic diathesis. For example, if they’re on lupus anticoagulants, antiphospholipid syndrome, which is commonly associated with cancer, is there a secondary antithrombin deficiency? And we would, again, increase the dose accordingly to the anti-Xa levels.

[00:09:31] All guidelines are really - - all the guidelines recommend unanimously to have a long-term anticoagulant treatment in cancer patients because of the high-risk of recurrence.

 

<<insert slide 17 >>  Chapter title: RIETE Registry

Time code:09:28

But, if we look at the real-life data, for example, here, from the RIETE Registry, we see that, particularly, those patients with cancer, have a very low persistence.

[00:09:57] You can see that, after 1 year, only 25% of the patients are on anticoagulant treatment, and that is with excluding those patients that have died over that year. In that study, it’s 40%. So, clearly, there’s a problem with the anticoagulant treatment. And 75% of the patients that would benefit from anticoagulation, they have stopped anticoagulant treatment because of the practical challenges.

<<insert slide 18 >>  Chapter title:

Time code: 10:08

 

[00:10:24] In conclusion, we’ve seen that we have challenges in the management of cancer-associated thrombosis. We have a higher risk of bleeding in those patients. We also have a higher risk of VTE recurrence in spite of anticoagulant treatment. We have the recommendation to use long-term anticoagulation, but we see from many studies that there is low persistence.

[00:10:51] There are long-term problems with the anticoagulant treatment, and low-molecular-weight heparins have several limitations. Of course, it’s parenteral administration. It’s a high-treatment burden in a patient group that already has a limited quality of life. We have to use weight-adjusted dosing. We have a risk for heparin-induced thrombocytopenia and, again, quality of life concerns in these patients. And we still have limited efficacy. There is about a recurrence rate of 7% to 9% after 6 months.

[00:11:28] On the other hand, if we look at vitamin K antagonists, there are limitations with a narrow therapeutic window, which is extremely difficult to achieve, especially in those cancer patients. Frequent monitoring dose adjustment is required. We have interaction with food, and we have, of course, interaction with drugs, chemotherapeutic drugs. That is a real challenge; to keep the INR in the range.

[00:11:53] Often, vitamin K antagonists are less effective compared to low-molecular-weight heparin in cancer-associated thrombosis, so potential problems also with all drug intake in patients with cancer, especially during aggressive chemotherapy. Again, we have the challenges, and we need new approaches to solve those challenges and to decrease the burden for the patients with cancer in the treatment of venous thromboembolism.

<<insert slide 19  >>  Chapter title:

Time code: 12:09

 

[00:12:26] We have a final question here: what factors do you consider when you are tailoring the anticoagulation in cancer-associated thrombosis? Is it patient preference, drug-drug interactions, cancer types, risk of bleeding, or 5) all of the above?

 

<<insert slide 20 >>  Chapter title:

Time code:12:29

 

Yeah, clear. You see, it’s a complex topic. You really have to take in account several factors in the treatment of cancer-associated thrombosis, and it’s all of the above. Thank you very much. [Applause]

 

<<insert slide 21  >>  Chapter title: Dr Philip Wells

Time code:12:47

 

Philip Wells, MD, FRCPC: [00:13:05] Good afternoon. My job is to talk to you about the guidelines and the standards for care of venous thrombosis in cancer patients.

<<insert slide 22  >>  Chapter title: Agenda

Time code: 12:56

 

I’m going to review the VTE prevention guidelines and recommendations for both hospitalized and ambulatory cancer patients, what the guidelines say about acute VTE treatment, and duration of VTE treatment.

<<insert slide 23 >>  Chapter title: Guideline Organizations

Time code:13:10

 

[00:13:27] I think it’s important to put this into some context about guidelines. As you can see from this slide, these are the various organizations that many of us belong to and that have published guidelines on what we should do in these topics, but there are challenges.

[00:13:42] You can see on this slide when the guidelines were last updated. That represents the first challenge. The second challenge is, even though guidelines come out and they’re evidence-based as much as possible, there always are gaps, and guidelines aren’t necessarily followed. As Rupert showed with the Reite Registry cancer patients only 25% receiving treatment after a year, and transient risk factor of VTE patients, many of them still receiving anticoagulant therapy at a year when guidelines suggest that they shouldn’t be.

[00:14:14] So, guidelines aren’t everything, but they certainly are a good starting point. And today, what I hope to illustrate - - because it’s not all that interesting for me to go through what all these guidelines say - - but, I think I want us to pay attention to the ambiguity that exists within guidelines, the gaps that exist within these guidelines. And we hope today, from what we’ll follow, that a lot of those gaps will be filled in for all of you.

<<insert slide 24 >>  Chapter title: VTE Prophylaxis in Hospitalized Patients

Time code: 14:20

 

[00:14:36] Let’s just start with hospitalized patients. I’m going to do it by organization. So, the NCCN for hospitalized patients, they recommend that if you have active cancer, you should require thromboprophylaxis throughout hospitalization. And they suggest low-molecular-weight heparin, this fondaparinux, or unfractionated heparin 5000 q8. They don’t actually give any other recommendations other than that. And these are one of the - - these are some of the most recent guidelines, right, 2018.

[00:15:02] For those undergoing major abdominal or pelvic surgery, they say, let’s look and see if patients have high-risk features, which they define by fairly standard features we’re all familiar with; previous VTE, long duration anesthesia, more advanced disease, more-advanced age, and more comorbidity or bedrest. In that case, they recommend 4 weeks of thromboprophylaxis. They don’t recommend for the prevention of catheter-related VTE, and importantly, there are no specific comments on NOACs in this guideline, even though it’s recent.

 

<<insert slide  >>  Chapter title:

Time code:15:19

 

[00:15:36] How about ASCO? The first one is quite similar; most hospitalized patients should receive thromboprophylaxis throughout hospitalization. But, the data are inadequate to support routine thromboprophylaxis in patients admitted for minor procedures or short chemotherapy infusion. Again, if you read and start looking at these things, you see that the difficulty always falls within one of the definitions of the various words within the recommendations.

[00:16:02] For those who undergo major cancer surgery, they believe they should start prophylaxis before surgery - - not a very standard practice in many places in North America - - and continue for at least 7 to 10 days. And they recommend that you extend that prophylaxis for 4 weeks if it’s major abdominal or pelvic surgery with high-risk features not defined in this particular guideline, but the previous slide did. Again, use of NOACs is not recommended.

<<insert slide 26  >>  Chapter title:

Time code: 16:12

 

[00:16:28] How about the American College of Chest Physicians? They say, for acutely-ill hospitalized medical patients at increased risk for thrombosis, recommendation is for anticoagulant prophylaxis, similar as into that first slide with low-molecular-weight heparin, low-dose unfractionated heparin, or fondaparinux. And they recommend prophylaxis for 6 to 21 days until full mobility is restored or until discharge, whichever comes first. Again, a difficult thing sometimes to operationalize; when does that full mobility actually happen? And the recommendation for prophylaxis in this guideline applies only to patients at a higher risk.

 

<<insert slide 27 >>  Chapter title: Ambulatory Patients

Time code:16:45

 

[00:17:02] What about VTE prophylaxis in ambulatory patients? The NCCN says the risk is sufficiently high in some surgical and medical oncology patients that outpatient prophylaxis shall be considered. They say the Khorana Model or Vienna Model were recommended if you do do risk assessment, and evidence in support of low-molecular-weight heparin is given. But, it’s suggested that the final recommendation should await more data, more evidence, from randomized controlled trials, some of which will be presented this week.

[00:17:33] ASCO says routine thromboprophylaxis is not recommended for ambulatory patients, but, again, it may be considered for highly select high-risk patients, not too definitive.

<<insert slide 28 >>  Chapter title:

Time code: 17:27

 

And the ACCP says, in outpatients who have no additional risk factors, they recommend against routine prophylaxis. But, with solid tumors [cough], excuse me, or with additional risk factors and low risk of bleeding, we suggest prophylactic dose low-molecular-weight heparin or low-dose unfractionated heparin.

[00:18:02] They define additional risk factors as, similar to the other guidelines, previous VTE, immobilization, hormone therapy, angiogenesis inhibitors, thalidomide, and lenalidomide. Again, prophylaxis not recommended for the prevention of catheter-related VTEs, which is so common through most guidelines.

 

<<insert slide 29 >>  Chapter title:

Time code:18:07

 

[00:18:22] Now, if we are going to do VTE risk assessment, what can we do? How can we do that? ASCO says that individual risk factors, including biomarkers, the cancer site, are not reliable enough to identify patients with cancer at high risk for VTE. So, for the outpatient setting, they recommend a risk assessment using a validated risk assessment tool. And there are a number, but the most common one, and the one that we’ve used in a couple of studies that have just been completed randomized trials is the Khorana VTE Risk Score.

 

<<insert slide 30  >>  Chapter title: Khorana VTE Risk Score

Time code: 18:36

 

[00:18:53] This is scored by basically - - as you can see on this table, there are certain cancer sites which are considered very high risk; stomach, pancreas, and we included brain in our study. And high-risk patients are considered lung lymphoma, gynecologic, bladder, and testicular CA scored 2 for the very high risk, 1 for the high risk, pre-chemotherapy platelet count over 350, hemoglobin levels less than 100, or use of erythropoietic growth factors, pre-chemotherapy weight count more than 11, and a BMI of 35 or above.

[00:19:34] You see the scoring system here, and [unintelligible] it’s determined that either 2 and above or 3 and above, depending on how you interpret the literature and where you want the cutoff to be, is considered to be high risk.

 

<<insert slide 31 >>  Chapter title: VTE in Multiple Myeloma

Time code:19:30

[00:19:47] All the guidelines tend to have some mention about multiple myeloma. There’s been a lot of fuss about multiple myeloma and venous thromboembolism within these patients. So, the NCCN says, use a risk assessment model of the International Myeloma Working Group, which I haven’t provided the details. And if they’re at high enough risk, use low-molecular-weight heparin or vitamin K antagonists. If receiving lenalidomide or thalidomide in the presence of 2 or more of these individual or disease-related factors. The bottom line is that means most patients with myeloma

[00:20:19] ASCO similarly says, patients with multiple myeloma receiving anti-angiogenesis agents with chemotherapy and/or a dexamethasone should receive low-molecular-weight heparin or aspirin. They get ambiguity there, which one should it be; what’s the balance of evidence between those two. And it shows that, really, there are still significant gaps within the literature.

 

<<insert slide 32 >>  Chapter title: Treatment

Time code: 20:24

 [00:20:41] Okay, let’s turn to treatment. Rupert already showed us some of the studies that are involved in treatment, and those studies, of course, have informed these current guidelines. So, the NCCN says, low-molecular-weight heparin, there’s monotherapy for 6 months. Patient preference and cost should be considered. Warfarin is still an alternative, even though the data suggests it’s not as good as low-molecular-weight heparin. Of course, that is just real life that not everybody can afford low-molecular-weight heparin.

[00:21:05] Three months minimum duration is recommended. They do say you can use alternatives, such as low-molecular-weight heparin followed by the warfarin, low-molecular-weight heparin followed by edoxaban or rivaroxaban. We’ll see some more of that data later in this presentation. They say, indefinite duration should be considered with active cancer or persistent risk factors. Despite the facts we see in real life, that tends not to happen.

<<insert slide 33  >>  Chapter title:

Time code:21:12

 

[00:21:28] ASCO says, similarly, 6 months. Again, patient preference and cost. NOACs, not recommended, but keep in mind, those guidelines are now presumably out of date. Indefinite duration, again, should be considered with active cancer or persistent risk factors. ‘

<<insert slide 34  >>  21:30

[00:21:46] Finally, the ACCP says, if there’s low or moderate bleeding risk, the recommendation is to extend any coagulation therapy over 3 months of therapy, grade 1b. But, if high bleeding risk, extended anticoagulation is only - - not as highly recommended with a grade 2b recommendation. And all patients that continue in use of treatment should be reassessed at periodic intervals for the obvious things; risk of bleeding, changes in health, cost, etcetera, compliance, and so forth.

[00:22:16] They do recommend low-molecular-weight heparin over vitamin K antagonist therapy. Again, no surprising given the data that Rupert has shown. But, they say patients with DBT and cancer who are not treated with low-molecular-weight heparin, recommendations for low-molecular-weight heparin over dabigatran or rivaroxaban for long-term therapy when those guidelines were written.

 

<<insert slide 35 >>  Chapter title: ISTH Guidance Statement

Time code: 22:21

 

[00:22:37] The ISTH Guidance Statement, which is quite recent, says the following: “The use of NOACs is suggested for patients with cancer and a diagnosis of acute VTE, low risk of bleeding, and no drug-drug interactions with current systemic therapy that a patient’s receiving. Edoxaban and rivaroxaban are the only NOACs that have randomized trial data to support their use. And low-molecular-weight heparin remains an acceptable alternative, of course.

 

<<insert slide 36  >>  Chapter title:

Time code: 22:50

 

[00:23:06] Low-molecular-weight heparin is suggested for patients with cancer and acute diagnosis of VTE, and a high risk of bleeding, including patients with luminal GI cancers with an intact primary, or patients with active GI mucosal abnormalities, such as ulcers, gastritis, esophagitis, or colitis. And NOACs might be an acceptable alternative if no drug-drug interactions exist with current systemic therapy.”

[00:23:31] We’re starting to see some of the new studies - - which, again, we’ll talk about shortly - - that are tilting the guidelines in a different direction.

 

<<insert slide 37  >>  Chapter title: Conclusions

Time code: 23:21

 

 In conclusion, routine thromboprophylaxis, at this point, is not recommended for ambulatory patients with cancer. That may change soon. Clinicians should periodically assess the VTE risk in their patients with cancer and review signs and symptoms of DVT and PE. And the bottom line is always, whenever we give any presentations, is that future research would be helpful. Thank you. [Applause]

 

<<insert slide 38 >>  Chapter title: Dr Alok Khorana

Time code: 23:50

 

Dr Khorana: [00:24:05] Great, thank you. Okay, we’ll move on to the third section here, which is talking about VTE prevention in patients with cancer, and both our first two speakers have really set the stage for all the data that’s come out in the last decade or so. I think we’re moving into an era of accelerating change in this field, both in terms of prevention and in terms of treatment. And Professor Kakkar’s going to talk about treatment, and I’ll talk about prevention today.

 

<<insert slide 39 >>  Chapter title: CAT Prevention

Time code: 24:18

 

[00:24:35] I think it goes without saying that cancer-associated thrombosis is worth preventing. It’s the second leading cause of death. This is from a couple of studies. The one that we did was about 3000 cancer patients in the U.S. getting chemotherapy performance status of 0 to 2 followed for causes of death for a period of 3 months. And, obviously, cancer is the number one cause of death. But, the second cause of death, typhoid infection, was a combination of venous and arteriole thromboembolism.

[00:25:00] In addition to mortality, there’s obviously potential for morbidity, potential for treatment delays, increased hospitalizations. If you get hospitalized, you’re going to stay in the hospital for a longer period of time. And overall total healthcare costs, which is one metric of how much resources are utilized, is substantially higher in cancer patients who get a blood clot vs cancer patients who don’t.

 

<<insert slide 40 >>  Chapter title: Risks Vary

Time code: 25:05

 

[00:25:22] Having said that, we have - - a common number that we use is 1 out of 5 cancer patients will get a blood clot. But, what that also means is that 4 out of 5 cancer patients will not get a blood clot. In other words, cancer patients are varying risk for VTE, and there’s a lot of risk factors that go into how risk can be determined.

[00:25:42] The most common, as you saw from the first question that Rupert had, was the type of cancer. No question, pancreas cancer. No question, brain tumors. No question, stomach cancer patients are really at high risk for VTE. But, as Rupert also told you, these are small segments of the cancer population, and we can’t really focus on primary prevention just in one type of cancer and ignore all the tons of clots that are happening in breast cancer patients, for instance.

[00:26:05] There’s a bunch of different types of risk factors that are outlined here. But, the bottom line is, you can’t really predict risks just based on individual risk factors, although everybody has their favorite risk factor. The best way to do it is from a variety of different approaches but through some type of formal assessment of type of risk.

 

<<insert slide 41 >>  Chapter title: Primary Prevention Trials

Time code: 26:07

 

[00:26:24] There’s been 3 categories of clinical trials that have utilized primary prevention. This has been going on now for about a decade or so, maybe a little bit longer than that. There are some trials that are focused just on the type of cancer. Again, historically, that’s the best-known type of cancer for primary prevention.

[00:26:42] CONCO and FRAGEM are two well-done studies, randomized trials just in the pancreas cancer population alone. They saw tons of clots, in the range of 10% to 20%, depending on how those clots were measured, but lots of clots were seen. The rates of clots were lower if patients got low-molecular-weight heparin, and both those studies were considered both statistically and clinically significant.

[00:27:04] The myeloma trials, as you just saw from Phil Wells, also showed benefit to either low-molecular-weight heparin or aspirin thromboprophylaxis, and in some studies to warfarin prophylaxis. But, again, these form really small segments - - in terms of the public health burden of cancer, form really small segments of the cancer population.

[00:27:24] There are two very large studies that address the broader picture of, if you take all types of cancer patients together, can we reduce, to a significant degree, the rate of VTE. Those two studies are PROTECHT and SAVE-ONCO. They didn’t take every single type of cancer patient, but they took a good number of 8 to 10 sites of cancer that included head and neck cancer, and breast cancer, and lung cancer, and so on, but without risks stratifying [ph] other than the site of cancer.

[00:27:52] There’s one study at least that looked at biomarkers. That’s the MICROTEC Study that measured tissue-factor levels using sort of a specialized assay that’s not sort of commercially available. They also showed that there was a reduction in rates of VTE, but because this assay is not widely available, this approach hasn’t really taken off as well.

[00:28:10] Finally, there’s been some data that’s come out and some data that’s about to come out looking at risk assessment models. Phil just talked about the risk score that my research group developed a few years ago. We were funded by the NIH to look at risk score 3 and higher patients and reducing VTE in that population using dalteparin prophylaxis.

 

[00:28:34] There are also subgroup analyses of PROTECHT and SAVE-ONCO in those populations, but just based on the risk score. I’ll have a slide on that. There are two ongoing studies right now for a score of 2 or higher, and I have a couple of slides on that as well. These are the different approaches to primary prevention. This is a big deal because every cancer patient in the world shouldn’t be on a blood thinner, because not every cancer patient in the world is going to get a blood clot. It would be great if it could target primary prevention approaches to cancer patients who really need this.

 

<<insert slide 42 >>  Chapter title:

Time code: 28:47

 

[00:29:03] These are the 2 large outpatient studies that I referred to earlier, PROTECHT and SAVE-ONCO. As you can see, very, very large studies, 1100 patients for PROTECHT, 3200 patients for SAVE-ONCO. Both were statistically significant, but not clinically significant based on the low number of events that occurred in this population. As you can see on the right-hand side, the NEJM requires you to sort of blow up the rates but also to show them in the context of all - - the whole population and as you can see those 2 little squiggly lines at the bottom are the number of events that happen and these are a low number of events.

 

<<insert slide 42 >>  Chapter title:

Time code: 29:19

 

[00:29:36] So, based on these trials, I think they are proof of concept that we can reduce VTE in large populations but we really need to identify a high-risk population and so one way to do that would be using the risk or - - and this is not the only risk tool.

 

<<insert slide 44 >>  Chapter title: Risk Tools

Time code: 29:35

 

There are a bunch of risk tools that have come out over the past decade or so and that are listed here and a review in the Lancet Hematology, looking at all of these different types of risk tools and they all sort of play around with the different factors that can lead to venous thromboembolism in cancer patients and either add or subtracts from the original score.

 

[00:30:11] So, PROTECHT removes the body mass index because a lot of European investigators believe that obesity is more of an American problem than a European problem and so they added types of chemotherapy in there.  ONCOTEV, included metastatic disease for instance, as a variable. COMMPASS focused just on 4 different types of cancer. TIC-ONKO added genetic risk factors and the latest paper from the Vienna Group at B.E. Winger [ph] and colleagues actually just kept the site of cancer category. It took everything else away and then added D-dimer.

[00:30:42] So, lots of different ways to formally assess risk. The challenges, if you don’t know if any of these risk models truly protect - - predict benefit from thromboprophylaxis. In other words, it’s great that we can show that they have a high rate of VTE in the high-risk category but does having a high rate of VTE lead to clinical benefit in patients who get primary prevention?

 

<<insert slide 45 >>  Chapter title: Applying Risk Assessment

Time code: 30:48

 

[00:31:05] I would add that in 2018, there’s other ways to apply risk assessment. One is education. The majority of cancer patients are still unaware that they are at risk for DVT or PE. There’s a couple stories that were done recently where 70% of cancer patients didn’t know that they were at risk for getting a blood clot as opposed to nearly 100% knew that they were at risk for nausea and vomiting, nearly 100% knew that they were at risk for, you know hair loss and so on, and that’s a deficiency in the way, you know oncologists interact with patients and in sort of the education efforts that we have.

[00:31:37] Dr Wells at his institution instituted the risk score into their electronic medical record and the medical record triggers a warning for high-risk patients and says hey if you’re at high risk for VTE, here’s additional information about the warning signs and symptoms of DVT and I think that’s a terrific use of using risk stratification and focusing on high-risk populations.

[00:32:03] A second approach is screening. This has so far only been done primarily in clinical trials where we take high-risk patients and do ultrasound - - lower extremity ultrasounds to see if they already have a clot and in the FACS Trial and in another small or single institution study, there’s about a 10% rate of finding a DVT if you already had - - if you had a high-risk score but no symptoms and that’s a pretty high rate of pre-existing clots.

[00:32:28] There are 2 ongoing prophylaxis trials of 2 and higher so I think we’ll have some information on that, on at least the pre-existing rate of DVT in one of those studies and then at the Cleveland Clinic about a year and a half ago we actually used Phil Wells’ idea of having an electronic alert in the electronic medical record system and used that to trigger identification of high-risk patients and then we suggested to doctors hey your patient’s at high-risk for DVT, do you want to get an ultrasound of the legs?

[00:32:56] And we carried out this as a silent phase initially and then as an active phase where doctors are actually alerted and we have this paper coming out in our PTS just probably by next week and the short answer is that we found that if doctors actually did an ultrasound of the legs, about 12% of patients had a pre-existing clot and of the patients who had an ultrasound and there was no clot, none of them ended up in the hospital with a clot in the next 3 months or 4 months.

[00:33:26] Whereas patients who didn’t get an ultrasound had about 8, 10% rate or ending up in the emergency room or in the hospital, including 7 patients out of about 100 or so that had a PE and ended up in the hospital. So, I think there are ways to use risk assessment other than just prophylaxis, although that’s always the - - an important application of this tool.

 

<<insert slide 46 >>  Chapter title:

Time code: 33:32

 

[00:33:47] Speaking of prophylaxis, how do use risk assessment to target your prophylaxis, so I’ll use PROTECHT as an example. So, again, as a reminder, this was a large study. All types of cancer patients getting chemotherapy were randomized, treated on nadroparin or a placebo and if you look at the total overall rates of VTE, they’re pretty low, less than 4%, down to 2% and that’s on the left-hand column but if you look at what types of patients were enrolled in this trial about 60, 70% of these patients actually had a lower risk of getting VTE and in that population the rates of ET were even lower.

[00:34:22] And so the number needed to treat, which is in that bottom line there, is about 50 for the whole population, increases to 77 for the low-risk patients but drops dramatically to 15 for the high-risk population where you saw rates of 11% down to 4% for a score of a score of 3 or higher and I think what this tells us is, again we don’t want to give a blood thinner to every cancer patient that’s on chemotherapy or on some form of systemic therapy but - - and it would be better if we enhance the population or targeted the right population with an approach of risk assessment.

 

<<insert slide 47  >>  Chapter title:

Time code: 34:40

 

[00:34:55] There have been now a full analysis of all the trials that have looked at sort of the risk score and finding the benefit to high-risk cancer patients, that’s shown here, NICE reduction relative risk reduction of about 60% and this P-value was statistically decrease significant. There is actually a new or individual level patient meta-analysis that was published or presented at ASH last year shows the same thing.

[00:35:17] And, so the bottom line is at least in high-risk patients, the clinical benefit seems to be greater and so there appears to be more clinical efficability. All of these studies have been for a score cutoff of 3 or higher.

 

<<insert slide 48 >>  Chapter title:

Time code:35:12

 

[00:35:31] Now, if we have so much data to support primary prevention and if cancer-associated VTE is so terrible for cancer patients, then why isn’t primary prophylaxis more effaceable in current oncology practice and certainly in my practice we don’t do primary prevention even though this is an area I am really focused on.

[00:35:49] A number one issue for - - from our perspective at least is that almost all the primary prevention studies thus far have been with a daily self-injection. At least in the United States, daily self-injection is extremely expensive and obviously they’re inconvenient and cancer patients are going through a lot of stuff already. To ask them to do a daily self-injection with the number needed to treat in 30, 40, 50 ranges is challenging.

[00:36:13] The second reason obviously has been that evident rates in these largest registration type studies have been low and there’s no FDA approval for any anticoagulant for this reason and there have been high rates observed in the risk adapted studies but either in pancreatic cancer, which there is a lot of nihilism about pancreatic cancer or in patients with a high-risk score but those are pooled data and not from a single randomized trial so setting for all of these reasons is not a big push for primary prevention right now.

 

<<insert slide 49  >>  Chapter title: NOACs in Primary Prevention

Time code: 36:24

 

[00:36:40] That could potentially change based on 2 trials that started out a few years ago and have both completed. CASSINI is a study that I’m co-chairing and Professor Kakkar is part of it as well, that takes patients with a score of 2 or higher and randomizes them to rivaroxaban 10 mg once a day or placebo once a day. That study just completed a few months ago. The late-breaking abstract is accepted at ASH and I’ll be presenting the data on Tuesday morning.

[00:37:10] And a second study which is being led by Dr Philip Wells looks at apixaban 2.5 mg twice a day, same population risk of 2 or higher and that study also completed a couple months ago and hopefully we’ll have data on that very soon as well.

 

<<insert slide 50 >>  Chapter title: CASSINI

Time code: 37:03

 

This is a study design for CASSINI. The abstract is publically available but the slides from my presentation are embargoed until Tuesday so I’m only going to speak to what’s in the abstract and the figure I’m going to show on the next slide is also what’s publically available and I can’t go more - - say more than that.

[00:37:43] But basically, it’s taking all adult patients with different types of cancers, starting a new chemotherapy regimen, randomizing to rivaroxaban or placebo. A big difference between CASSINI in a word is that CASSINI has a baseline ultrasound to make sure that patients don’t already have a blood clot before they go on study. This is based on some of the data that I just showed you and they have ultrasounds every 8 weeks while the patients are on study.

 

<<insert slide 51 >>  Chapter title:

Time code: 37:29

 

[00:38:08] Results of CASSINI are shown here. There’s sort of 3 different analyses. As you can see, placebo is red, rivaroxaban is blue, rivaroxaban reduced sort of events in all 3 graphs but there’s some differences.

 

<<insert slide 52 >>  Chapter title:

Time code: 37:43

 

The first graph on the left is the primary analysis which is events up to day 180 and although there was a reduction, it wasn’t statistically significant because about a third of events occurred after patients - - patients didn’t stay on drug for the full 6 months when they switched their chemotherapy regimens or their cancers progressed even off the drug but they were still followed for clots and about a third of events occurred after patients had stopped taking the drug.

 

<<insert slide 53 >>  Chapter title:

Time code: 38:05

 

[00:38:43] If you focus just on the time patients were on the drug, which has been the primary analysis in other trials, that there’s a significant reduction from 6% down to about a 4% absolute risk reduction, P-value for that is statistically significant and interestingly,

 

<<insert slide 54  >>  Chapter title:

Time code: 38:21

 

the combination of VTE plus all cause mortality, which was a pre-specified analysis for this study. Also, was lower because deaths in the rivaroxaban were lower and the hazard ratio for that is 0.75, and that P-value is also significant at 0.03. So, a lot more detail Tuesday morning at 7:30 but that’s all I can share with you so far.

 

<<insert slide  55>>  Chapter title: AVERT

Time code: 38:38

 

[00:39:25] AVERT has a very similar study design, using a different agent, apixaban, a couple of clear differences. One is there was no screening at baseline and there was no screening during the course of the study. They took about 500 patients newly diagnosed cancer or site or progression after complete or partial remission, starting a new course of chemotherapy and then a risk score of 2 or higher, randomized apixaban 2.5 twice a day, same treatment period 6 months and everything symptomatic, so no screening at baseline and no screening along the way.

[00:39:56] I think they included incidental PE that was - - if it was discovered but not - - didn’t screen for PE. Those results aren’t out yet but hopefully they’ll be out in the next very short timeframe. So, if these studies are both considered to be positive, this really becomes a supportive care issue and

 

 

 

<<insert slide 56 >>   Chapter title: Supportive Care

Time code: 39:09

 

as an oncologist I’m very used to doing risk adapted approaches to supportive care. For instance, if you have patients who are at risk for febrile neutropenia and if you have a certain risk for febrile neutropenia, we start those patients on primary growth factor support.

[00:40:32] Similarly, if you have patients who are known to have - - be getting a regimen that’s a highly emetogenic regimen then we treat those patients with a combination of drugs - - different drugs, antiemetic drugs than we would otherwise. So, I think that’s an approach that would easily be translated into this field and lead to prevention of VTE.

 

<<insert slide 57 >>  Chapter title: Summary

Time code: 39:42

 

So, patients have cancer at varying risks for VTE but we can predict that risk. Data from the low-molecular-weight heparins has established the feasibility and safety of outpatient prophylaxis. There is certainly benefit for patients with a risk of 3 or higher based on pooled-analyses and there are emerging data that might expand this definition of high-risk to a cutoff of 2 or higher. So, stay tuned, lots more data to come out over - - very, very soon and thank you for your attention.

 

<<insert slide  >>  Chapter title: Lord Ajay Kakkar

Time code: 40:10

 

Lord Ajay K. Kakkar, MD, PhD: [00:41:21] Well, Professor Khorana, ladies and gentleman thank you very much. I’m now going to move to the question of treating established venous thromboembolic disease in the cancer patient and

<<insert slide 59 >>  Chapter title: Agenda

Time code: 40:21

 

 

over the next 15 minutes I want to cover 4 areas, just to rehearse once again why all the guidelines provide the use of low molecular weight heparin as the standard of care for preventing - - for treating established venous thromboembolism in the cancer patient and preventing recurrent thromboembolic disease.

 

<<insert slide 60 >>  Chapter title: LMWH in CAT

Time code: 40:40

 

[00:41:49] To look at the rationale for the use of the non-vitamin K over anticoagulants, the factor Xa inhibitors for treating this population of patients, those were data available from subgroup analyses of the principle VTE treatment studies for the Xa inhibitors in the general thrombosis population. Rehearse the 2 contemporary trials randomized trials that have established now the basis for the use of Xa inhibitors routinely in the management of patients with established thromboembolic disease and then try and determine what the use of those agents is already showing us beyond the trial setting.

[00:42:31] So, we have seen some of these data in the talk by Professor Bauersachs. The trials that have compared extended low molecular weight heparin treatment for 3 to 6 months against a vitamin K antagonist for the treatment of deep vein thrombosis or pulmonary embolism in patients with active malignancy and overall those trials have shown us that the use of a low molecular weight heparin is associated with a 50% reduction in the frequency of recurrent thromboembolic disease in the cancer patient compared to use of a vitamin K antagonist such as warfarin for the prevention of recurrent thromboembolism.

[00:43:14] The use of low molecular weight heparin over an extended period, some 3 to 6 months compared to warfarin is associated with more or less the same rate of bleeding, slightly higher in some of the studies but not significantly so and so it’s on that basis as we saw from Professor Wells that guidelines both in Europe and in North America primarily recommend the use of low molecular weight heparin as the treatment choice for the management of patients presenting acutely with venous thromboembolism and extending that therapy to prevent recurrent thromboembolic disease.

 

 

<<insert slide 61  >>  Chapter title: NOACs in CAT

Time code: 42:40

[00:43:47] Now, what we know of course in the last 4 or 5 years is that the vitamin - - the non-vitamin K oral anticoagulants either direct thrombin inhibitors or direct factor Xa inhibitors have become established for the treatment of venous thromboembolism. In those studies, small numbers of patients with their cancer-associated thrombosis were included in the randomized population.

[00:44:14] The randomization in those studies was one of the NOACs compared to a vitamin K antagonist for the prevention of recurrent thromboembolic disease but those studies suggested even though there were small numbers of highly selected patients with a cancer-associated thrombosis included in the randomized population that compared to a vitamin K antagonist a Xa inhibitor or a thrombin inhibitor was likely to be more effective in preventing recurrent thromboembolism and associated with a lower frequency of bleeding complications.

[00:44:49] Now, that wasn’t the right test for a NOAC because clearly the standard of care was extended low molecular weight heparin that was better than the vitamin K antagonist and therefore comparing a Xa inhibitor or a thrombin inhibitor, a vitamin K antagonist in a highly selected cancer population while thought to be an appropriate comparison upon which to draw recommendations for widespread clinical use. Nevertheless, these type of analyses suggested very strongly that it was justifiable to perform studies where a Xa inhibitor might be compared to low molecular weight heparin over an extended period for the management of patients presenting with deep vein thrombosis or pulmonary embolism.

<<insert slide  62>>  Chapter title:

Time code: 44:28

 

[00:45:36] And, indeed at last year’s American Society of Hematology Meeting and following that presentation at the American Society of Clinical Oncology 2 trials were presented, the HOKUSAI VTE CANCER Study where the Xa inhibitor edoxaban was compared to extended low molecular weight heparin and the SELECT-D Study where the Xa inhibitor rivaroxaban was compared to extended low molecular weight heparin for the management of cancer-associated thrombosis.

 

<<insert slide 63 >>  Chapter title: SELECT-D

Time code: 44:48

 

[00:46:07] The SELECT-D Study was a multi-center phase 3 pilot study. In that trial, patients presenting with a cancer-associated thrombosis that was symptomatic of deep vein thrombosis or any type of pulmonary embolism, symptomatic or incidental, were randomized to receive rivaroxaban in the full treatment dose - - full treatment regimen, that’s 20 mg - - 15 mg twice daily for 3 weeks followed by 20 mg once a day thereafter for 6 months. The comparative was low molecular weight heparin dalteparin sodium in the full treatment dose for a month followed by 5 months of the reduced dose, 75% of the full treatment dose.

 

<<insert slide 64 >>  Chapter title:

Time code: 45:48

 

[00:46:57] And there was stratification as you can see here for certain variables and these were the results: It was quite striking that in this study the frequency of recurrent venous thromboembolism was reduced from some 11% in the low molecular weight heparin population to about 4% in those patients receiving extended rivaroxaban but the rate of major bleeding was increased from 4% in the low molecular weight heparin group to 6% in the group of patients receiving extended rivaroxaban.

[00:47:30] Now, in this trial the bleeding, this increased risk of major bleeding manifested itself principally in patients who had a cancer-associated thrombosis associated with GI malignancy, an important observation.

 

<<insert slide 65 >>  Chapter title: Hokusai VTE Cancer

Time code: 46:38

 

If we then turn to the HOKUSAI VTE CANCER Study, you can see here 1000 patients similarly randomized with acute venous thromboembolic disease to either edoxaban - - edoxaban regimen includes a period of treatment with parenteral therapy, low molecular weight heparin for some 5 to 7 days followed by edoxaban or to low molecular weight heparin, again a full treatment dose for a month and then 75% of the full treatment dose thereafter.

[00:48:19] And, the primary endpoint in the study with edoxaban was a composite of recurrent venous thromboembolism and major bleeding and the reason that that particular design rather than the traditional approach taken in thrombosis treatment studies and having a primary efficacy endpoint, recurrent venous thromboembolism and a main safety endpoint, major bleeding. The decision was taken in this study that since both events could be considered treatment failure for established thrombosis in the cancer patient, it would be entirely appropriate to have a composite endpoint of venous thromboembolism or major bleeding for the trial.

 

<<insert slide 66 >>  Chapter title:

Time code: 48:00

 

[00:49:07] And, you can see here on the left-hand side of the slide but for the primary composite endpoint the experimental regimen edoxaban was non-inferior to extended low molecular weight heparin for the combination of preventing thromboembolism and major bleeding but when you look at the breakdown of the components of that composite endpoint, recurrent venous thromboembolism and major bleeding, it’s striking once again that you see an identical pattern to the pattern seen in the SELECT-D Study. So, the rate of recurrent thromboembolism in the low molecular weight heparin group 11% reduced to some 7.9% in favor of edoxaban. The rate of major bleeding increased from 4 to 6.9% in the edoxaban group.

[00:50:10] So, what was achieved in this study identical to the previous study that I presented with rivaroxaban, a reduction - - a significant reduction in the frequency of recurrent thromboembolic disease in patients receiving a Xa inhibitor but again with some increase in major bleeding.

 

<<insert slide 67 >>  Chapter title: Bleeding

Time code: 49:23

 

Now, if you look at the HOKUSAI VTE CANCER Study and look at the distribution of major bleeding, you can see here that bleeding principally manifests itself in the GI tract.

[00:50:45] So, the excess in bleeding seen with the Xa inhibitor was seen in patients primarily with upper GI malignancy and

 

<<insert slide 68 >>  Chapter title:

Time code:49:45

if one looks further at a sub - - of a post talk analysis of the edoxaban population to look at the time to bleeding events in the 2 groups of patients defined as those having primarily GI malignancy and those having no GI cancer, you can see on the left-hand side of the slide how the presentation of bleeding in the GI population manifests itself as a higher rate of bleeding in patients randomized to receive edoxaban and that increased bleeding presents itself over the complete duration of exposure to the drug and time compared to the low molecular weight heparin group.

[00:51:39] Whereas if you look on the right-hand side of this slide what you see is something very interesting for non-GI malignancy patients, there’s effectively no difference in the overall experience of bleeding between patients randomized to receive either low molecular weight heparin or the Xa inhibitor edoxaban.

 

<<insert slide 69 >>  Chapter title:

Time code: 50:50

 

So, in both trials we see very similar patterns, improved efficacy in terms of a lower rate of recurrent thromboembolic disease in favor of patients randomized to receive either rivaroxaban or edoxaban with a higher rate of major bleeding and in both studies that major bleeding manifests itself as bleeding in patients who have primary GI malignancy.

[00:52:30] Now, of course, there was some - - there are some other bleeding events and in particular patients with genitourinary malignancy, not to the same extent as upper GI malignancy in the analyses that have been made available but it does suggest that those patients with a mucosal lesion, potentially also those with a primary tumor or those having other mucosal lesions are at greater risk of bleeding associated with a Xa inhibitor.

 

<<insert slide 70 >>  Chapter title: Database Analysis

Time code: 51:50

 

[00:53:01] Now, how have we practiced? Well, these are interesting data from Professor Khorana and colleagues. Looking at large claims databases in the United States and looking at the use of different anticoagulants over a 5 year period and you can see here that in that period, 2009 to 14, about 40% of patients received low molecular weight heparin for treatment of their cancer-associated thrombosis at half still in that period receiving a vitamin K antagonist for treatment of cancer-associated thrombosis despite the early pivotal studies, the CLOT Study that we had seen published in 2003.

 

<<insert slide  71>>  Chapter title:

Time code: 52:36

 

[00:53:46] Further analysis of these claims databases in a subsequent period demonstrate a further uptake of low molecular weight heparin, a reduced use of vitamin K antagonist but interestingly before the randomized trials comparing a NOAC with a low molecular weight heparin some 20% of patients already receiving a direct Xa inhibitor for treatment of their cancer-associated thrombosis certainly here in the United States in these particular claims databases.

[00:54:18] So, very interesting that extrapolating from the non-cancer population, colleagues have already been of the opinion that they should and could use one of the Xa inhibitors for management of their patients. Interestingly, that clinical institution is confirmed by the randomized trials and what’s striking also is a very important question and that is how we can ensure a higher persistence of therapy in our patients with a cancer-associated thrombosis because we have seen from data that Professor Bauersachs presented to us that there is a poor persistence generally in patients treated with low molecular weight heparin for their cancer-associated thrombosis over time and yet all the guidelines tell us that these patients remain at very high risk for recurrent thromboembolism while they have active cancer or while they’re receiving active anti-cancer therapy, systemic therapies.

 

<<insert slide 72 >>  Chapter title: Persistence with Therapy

Time code: 54:10

 

[00:55:19] In these data, you can see how the use of an oral intervention be it a vitamin K antagonist or in this case the Xa inhibitor rivaroxaban is associated with a higher persistence for therapy over time and that must be an important determinant for the risk of recurrent thromboembolic disease and therefore the data from the randomized trials supporting the use of Xa inhibitors in terms of clinical outcome might well be predicted to be associated with a higher persistence over time and therefore potentially improved clinical outcome.

<<insert slide 73 >>  Chapter title: GARFIELD VTE

Time code: 54:51

 

[00:56:00] Now, it’s very interesting when we look at data from large registries and these are data from GARFIELD VTE Registry which is a large registry conducted in some 28 countries, some 450 randomly selected sites, including some 11,000 patients of about 10% of whom are patients with a cancer-associated thrombosis but this population remain a great challenge. They have compared to the non-cancer population and these are contemporary data rather than the data the Prandonian [ph] colleagues presented some 15 years ago, a higher mortality than those presenting with venous thromboembolism and no cancer, at greater risk of bleeding and at greater risk of recurrent venous thromboembolism. They also are more frequently associated with hospitalization events and interestingly at greater frequency of arterial thromboembolic events.

[00:57:02] So, where appropriate, safe anticoagulation has the potential to impact on a number of outcomes in these patients that drive poor clinical outcome and I think here at ASH in 2018,

<<insert slide 74 >>  Chapter title: Summary

Time code: 56:08

 

we can now say that the Xa inhibitors have been validated for efficacy and safety in the management of cancer-associated thrombosis, efficacy in terms of a lower rate of recurrent thromboembolism, safety in terms of yes a higher rate of major bleeding but that bleeding seems to be associated principally with patients with GI malignancy and others with mucosal lesions and as I have said the appropriate use, properly supervised has the opportunity - - the potential to improve clinical outcomes for cancer-associated thrombosis.  Thank you very much indeed.

 

<<insert slide 74  >>  Chapter title:

Time code: 56:47

 

Dr Khorana: [00:58:00] Thank you very much for being such an attentive audience and for all these great questions [applause] and enjoy the rest of your meeting. Thank you [music].