Posted by Jeff Berk, BOLT International; I have one more day in the dog kennel (a.k.a. AACR 2011; Orlando) before heading back to my beloved desert. It’s been a great meeting and I SHOULD be blogging about cancer. But… the big news at ACC (can’t be in two places at once) was that MAGELLAN, rivaroxaban in prevention of VTE in the hospital, was presented.
From the press release: Rivaroxaban met its primary clinical efficacy objectives of demonstrating non-inferiority to enoxaparin in short-term use (10 ± 4 days), and superiority in long-term use (35± 4 days) when compared to short-term use of enoxaparin followed by placebo. The combined rates of major and clinically relevant non-major bleeding, the primary safety measure in the study, while low overall, were significantly higher in those treated with rivaroxaban compared with those treated with enoxaparin, followed by placebo.
So, everybody and his brother (two people, right? plural?) are talking about what this means. Since I am at a cancer meeting, today I’m going to share some insights on prevention of deep vein thrombosis / pulmonary embolism specifically from oncologists. Please note that these guys mostly specialize in the treatment of multiple myeloma. These discussions took place in February 2011. Anyway…
- Lifelong therapy for DVT / PE prophylaxis is generally done for oncology patients or those who have a permanent orthopedic or neurological deficit. The standard of care for these patients is low molecular weight heparin, as it has been shown to be more effective than warfarin.
“Lifelong therapy for DVT prophylaxis really would have to be for someone who is either a cancer patient with a high thrombotic risk or a patient who is immobile long-term for whatever reasons, for orthopedic reasons or neurologic reasons or something, but I personally don’t see a huge number of patients who need lifelong DVT prophylaxis treatment unless maybe they have had one before and they have had recurrent DVTs or recurrent PEs. I personally in my practice don’t encounter many of those patients. I think they are kind of more of an isolated phenomenon more so than the really large market of short term treatment after orthopedic procedure or other type of surgical procedure where they need treatment for a month or two at the most really”.
“Then there is the cancer setting as well. In cancer patients we know that Coumadin is less effective than low molecular weight heparin. So there is a potential, although not fully explored at this point, for a lot of these novel compounds. And, these patients may rely on the drug for longer terms”.
- Anticoagulation for the secondary prevention of thromboembolic events (strokes, deep vein thrombosis, pulmonary embolism etc.) is given to about 10% of cancer patients. These patients often die of cancer induced massive intravascular thrombosis. Panelists have been slow to adopt new oral direct thrombin inhibitors (Pradaxa; dabigatran, Xarelto; rivaroxaban) because their manufacturers carefully avoided putting cancer patients on registration trials. With the approval of these drugs for SPAF (secondary prevention of atrial fibrillation), we expect to see more focus on the hem/onc setting.
“How big of an issue is thrombotic events in your myeloma patients and are you using anything beyond warfarin or low molecular weight heparin? At this moment in time we are just doing warfarin and low molecular weight heparin. For the first time we are starting to have a discussion when the new oral anticoagulants become available, what should we do. We have cautioned that reality is that none of these oral agents have been tested in the cancer setting so that both the toxicity and the efficacy in regards to thrombosis associated with transplant may be totally different than where these things are going to be indicated which is in atrial fibrillation due to valvular disease. It kind of amazes me that none of these companies have taken on a cancer trial yet. I think they will but I think they wanted to get the drug on the market and trying to get the drug on the market with a cancer trial they were probably cautioned against it. Because you may have more adverse events? Right because of the degree of adverse events that you are going to have”.
“Final question and this is far different than anything we have been talking about. I run a number of different therapeutic panels and one of them deals with antithrombotics and all of those guys are cardiologists. I have the sense that thrombosis, and this is my paradigm but this is where I am going to look for your insight, but that DVTs and these embolisms are a big problem for these cancer patients and all I am doing is talking to cardiologists. Take the last couple of minutes and talk to me about your unmet needs for antithrombotics. They are huge. Right now we have got the empiricism of aspirin versus Coumadin versus low molecular weight heparin. We need randomized trials that are a little more exhaustive than we have. Right now we basically have a lot of descriptive experiences. I think aspirin is real. I think that Antonio Palumbo has well done an earnest effort looking at thrombosis and so far have told us a few things. One, that bortezomib is protective. Two, that aspirin in most patients does a reasonable job particularly if there is not too much in the way of steroid or other cytotoxics in the mix. But the reality is that if you want to look for level of evidence type, if you want to look at sort of VISTA, APEX, MMO9, MM010 type evidence for antithrombotics in myeloma we really don’t have it. We need to. I think there will be some work being done. Ideally oral and ideally targeting endothelial cells surface interactions because that is where the action seems to be. What is your familiarity with either these direct thrombin inhibitors or the factor Xa inhibitors? I think that institutionally experience is limited because we are very traditional. I think that aspirin and low molecular heparin remain our number ones. The use of the new anti-Xa inhibitors and so on has been very limited. I think there is an opportunity for studies interesting that area. We will be potentially working with J&J and some of their compounds. Not me directly but colleagues of mine will be looking at that”.
“I got an e-mail just the other day asking us to join a trial in myeloma with one of the oral anticoagulants. So what is your current perspective on these drugs? I think it would be awesome to have them. I mean I honestly think we are just a bit lazy as oncologists. We put people on Revlimid and thalidomide and we know they have got 10 percent DVT rate, we are just too lazy to monitor Coumadin on all of them. There is obviously the risk/benefit profile too, but I think if we had an oral drug that didn’t require monitoring and you could put people on I think we would all sleep better at night thinking about our patients on Revlimid and thalidomide. I say bring them on is my opinion about that. What would you venture is…? Our market for those is so small compared to what they are really going to do. What percentage of cancer patients in your opinion should be on any sort of anticoagulation? I think it is probably pretty high. In myeloma the DVT rate is 10 percent. I am not sure what it is in other tumors, but I think it is probably as high or higher in many other solid tumor types. So I suspect there are a lot of cancer patients out there if you have a non-monitoring, non-injectable oral anticoagulant, I think it would be quite a good market for that. But is the reason that you use them associated with drug toxicity? In other words, is it the IMiD that is raising that risk? Yeah, without the IMiDs, the risk is lowered to 3 or 4 percent. It is not very high. So it is the IMiDs that is raising it. But in the solid tumor sphere it is, again, I don’t know the facts and figures, but there is a fairly high DVT rate in some malignancies I believe. But that is not my area of expertise. I am guessing. But something like pancreatic cancer, for example, I would think there might be some uptake of that”.
“We are using low molecular weight heparin throughout all patients. I personally have no experience with some with the upcoming novel oral drugs. Second, patients with myeloma have an inherently high risk of DVT compared to non-myeloma patients and even higher than in solid cancers, lets say except prostate and pancreatic. Third, we are administering anticoagulants to all subjects who have at least one specific risk factor as outlined in the leukemia paper by Palumbo two years ago.
“It is a big problem because it really interferes with quality of life. It interferes with the treatment. It actually also is a cost problem because those episodes cost society a lot. So it is a big problem. And it is becoming more and more of a problem in oncology. We just had a direct thrombin inhibitor, Pradaxa, dabigatran, approved in the US for SPAF and I saw just today Xarelto, which is rivaroxaban, was filed also for SPAF. Are you using any of these newer agents versus warfarin yet? I am not because they are not approved. For DVT? I would. Warfarin is taking a lot of our time. It is very time consuming and it is very cumbersome. Patients are waiting for a replacement to warfarin for years. I think the FDA needs to really react relatively fast if there is strong data. And there is strong data when you look at the NEJM. I look at all those things and there is very strong data and I think they should approve as soon as possible. I think it is a big deal in the oncology practice”.
“I think we will come along. This is really a personal opinion. I don’t have a lot of data. I think they will certainly represent a major replacement of warfarin. They could certainly have a major role in cancer patients. I don’t know why at present but those companies are very much concentrating in hip replacement and not very concentrated, as far as a I can tell, in some niche disease like myeloma. So we would try to have some experience in this but they were pretty much reluctant. That is because they are so afraid that there is going to be a higher bleeding (or mortality) rate in the cancer patients. I think that is why they are so afraid of putting their drugs into the oncology patients. I can see the issue but I think there is a major marketing issue more than really a scientific issue. What do you mean by a major marketing issue? At present they want to go into the major anticoagulation market. This was my impression. Now they want surgery, general surgery, and general medicine. This is where they are concentrating the effort to hit the market. Then when it will be established in that situation they will try to open up in other niche situations by myeloma or cancer. For 100 myeloma patients who you treat what percentage of those patients do you have on anticoagulant therapy? You see myeloma is very peculiar because if you use IMiDs 100 percent of them. But again, we are in an old fashioned use of anticoagulation. We are mainly using heparin and low molecular weight when we do have a high risk patient. I don’t know if this is another reason. But basically with IMiDs I have, let’s say, 100 percent of patients with bortezomib probably none of them. What if I had asked you the question for the hematology community as a whole would you venture a guess as to what percentage of patients are on an anticoagulant? Not many. Probably more in the US. Here, not many. But the risk of DVT is not low because at least 10% patients with cancer do have a DVT. But generally speaking I do see in the practice the use of anticoagulation if you have a high risk of thrombosis. Otherwise I really do not see them use a lot of anticoagulation. You would say 10 percent DVT everybody on anticoagulation. It really is not working this way at least in Italy. We do use anticoagulation when there is high risk of that otherwise we try to skip it”.
“I think the cancer patients, again, I am not an oncologist, but I do see patients with cancer that seem to be doing very well and they are dead in two weeks. I think what happens to them is that they die of cancer induced massive intravascular thrombosis. I think that warfarin is not as effective anecdotally as we hope it should be, so I think in the cancer patients probably the most effective anticoagulant will be the one that will be the one that is more preferable. And that may be rivaroxaban”.
- Medical oncologists treat almost all cancer patients for prevention of DVT / PE. The cardiologist is rarely involved.
“One of the questions that I am pushing back on my cardiologists is why they list use in cancer patients so low? Is that because you don’t see them? Yeah, that is exactly right. You hit it right on the head. We don’t see cancer patients. We don’t think about DVT prophylaxis in cancer patients primarily because our world is so narrow. I don’t even know of a single academic cardiologist that rounds in the general medicine service anymore. Cardiology itself has become so complicated that we just sort of stick to our own. I would include the cancer patients within this whole realm of VTE because that is why you are treating them because you want to prevent them from having venous disease. So I would include them within VTE but personally it doesn’t matter my radar is a separate category”.
“Where does malignancy and use of these therapies come in? I call that an orphan type indication just because that is really driven specifically by the oncologists. That is an area where I see oncology patients when I am on service but I never would prescribe long-term enoxaparin myself. It is just not something I do but that is sort of the standard of care for the oncologists. I would think that would be a situation that would be completely driven by oncology I would say. I don’t think it is a big enough issue that would sort of carry the day for one agent over the other. I think the cardiac indications you could have a second agent on formulary restricted to oncology, for example, if there was some evidence that one of these agents was sort of meaningfully different than another or had an indication for DVT/PE, prevention of treatment in cancer is another one. I don’t know I think that is sort of a niche indication”.
“I am not up at all on how cancer patients are treated in that regard. The only time I see a patient with cancer is if they have concomitant cardiovascular disease. I don’t know whether solid, liquid cancers, etc, what their risk of DVT prophylaxis is how oncologists are even treating them now because we just don’t deal with that. That is the reason”.
- There is a sense that to date Xarelto has been studied more extensively in cancer patients than Eliquis or Pradaxa. There was a program to evaluate apixaban but it has been dropped, and there is yet to be such a program for dabigatran.
“How are any of these agents going to shine in this population given the bleeding risk patients have anyway, how are any of the antithrombotic we are talking about going to positively differentiate themselves for use in these cancer patients? Well the only one that is being tested is rivaroxaban as far as I know in general medical patients, in-hospital patients. Apixaban had a program and they dropped it. Dabigatran never had one. As far as I know they are never going to have one. Is there going to be a role for these drugs in that general medical population”.
- The cancer patients tend to be on very complicated regimens already. The convenience of once daily Xarelto is going to be more recognized as a benefit in this setting.
“So in terms of convenience in this setting in particular I could see that once daily administration would be preferable. This is where I think rivaroxaban has an advantage”.