Recorded at the 6th McMaster International Review Course in Internal Medicine.
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Professor Mark Crowther: Alright. Thank you everybody and welcome to the question and answer period for the thromboembolism and hematology session. My name is Mark Crowther and I'm the chair of the Department of Medicine at McMaster University. I am joined here by Dr. James Douketis, Dr. Madeleine Verhovsek, and Dr. Menaka Pai, who are today's presenters. I'm going to be chairing the question and answer session. We have a number of questions that have been pre-submitted and I will be running through those; in addition, if you have any questions that you wish to address, please type them into the question and answer box and we will address them as time allows. We have a full hour for the session so we should have lots of time to address the questions. I'm going to start by just asking questions that have been previously submitted, in the order that I have them here. And so the first question is for Dr. Verhovsek – and Madeleine, maybe I can ask you to introduce yourself when you first answer the question as well. And so the question is: “How should stroke be managed in patients with sickle cell disease?”
Professor Madeleine Verhovsek: Thanks very much, Dr. Crowther, for that question. So my name is Dr. Madeleine Verhovsek. I'm a hematologist based at McMaster University with expertise in sickle cell disease and other hemoglobinopathies. So, the question on how to manage a stroke in someone who presents acutely with sickle cell disease depends on a number of different factors, one of which includes… we are presuming, overall, the highest risk is for ischemic stroke. However, [we must] recognize that patients with sickle cell disease are also at higher risk of hemorrhagic stroke and also recognize that a lot of the treatments that we'll use for standard ischemic stroke that's happening as a result of cardiovascular risk factors are going to be focusing on anti-thrombotic therapy, for example, and very little is known about how effective or in fact safe those treatments are. So, I'd say that there is a great deal of evidence that we are missing, at this point, for adult stroke management in sickle cell disease. What is known in terms of best practices – when a patient presents with acute stroke with sickle cell disease – the best practice guidelines recommend in fact prioritization of red blood cell transfusion and, if possible, completing a red blood cell exchange transfusion with a target hemoglobin S, so a target sickle hemoglobin level below 30%. Use of things like thrombolytics really does require an individualized approach, ideally with excellent brain imaging and ideally some vascular imaging. For example, it's presumed that a patient with something like moyamoya – which brings with it an increased risk of intracranial hemorrhage – through a multidisciplinary decision-making process, that patient may be determined to not be fit for something like systemic thrombolysis because of a perceived high stroke risk. So all in all, it is a very challenging situation. The one-size-fits-all approach of red blood cell exchange transfusion can generally be applied, whereas [in decisions about] other things, particularly those related to anti-thrombotic, anti-platelet, or thrombolytic therapy, are best made – if possible – [with] both neurologic and hematology sickle cell expertise together at the table.
Mark Crowther: Thanks, Madeleine. The next question is for Dr. Douketis – and Jim, again, if you could introduce yourself when answering the question for the first time – so the question is, “you mentioned that low-molecular[-weight] heparin should be chosen over direct oral anticoagulants in splenic vein thrombosis if the patient has GI [gastrointestinal] or GU [genitourinary] cancer, is at high risk of bleeding, or is receiving chemotherapy that interacts with the DOACs. Do these same conditions apply to patients with cancer and leg DVT [deep vein thrombosis] or pulmonary embolism and to VTE [venous thromboembolism] prophylaxis in patients with cancer?”
Professor James Douketis: Hello everyone. Dzień dobry for our friends in Poland. My name is James Douketis, I'm an internist and thrombosis physician in Hamilton, Canada. And that's a very important, wide-ranging question. The short answer is that either a low-molecular-weight heparin or a DOAC should be considered in the average patient who has cancer-associated thrombosis. There are data that suggest that certain direct oral anticoagulants may be more harmful, in terms of bleeding risk in patients who have underlying gastrointestinal or genitourinary malignancies; we don't see that as much in patients who are using DOACs for more prophylactic purposes, so it may be a dose effect there. So to answer your question, in the average patient with cancer-associated thrombosis, I think a low-molecular-[weight] heparin or a DOAC are equally reasonable. In the patient who has just unusual site thrombosis, we don't have as much data with the direct oral anticoagulants. By “unusual site,” I mean in the splanchnic veins or in the cerebral sinus veins. And low-molecular[-weight] heparin is probably your default. Having said that, there are emerging data that suggest it is safe to use a direct oral anticoagulant in that situation. And as I allude to, on the prophylaxis side, we are not seeing as much of the bleeding signal with the DOACs in patients with gastrointestinal or genitourinary malignancy. So bottom line, either a low-molecular[-weight] heparin or a DOAC; maybe avoid certain DOACs in patients with cancer and underlying GI or GU malignancies when used at therapeutic doses.
Mark Crowther: Thank you very much. Moving onto the final speaker, and Dr. Pai has a whole raft of questions here. So I'm actually going to ask 2 questions – it's a 2-for-1 deal for Dr. Menaka Pai. So again, Menaka, if you could introduce yourself when you answer the question. The first question is, “according to your slides, in the severely ill group there was no difference in mortality and bleeding, but a difference of close to 5% in major thrombotic groups. Why do you interpret this as a negative result?” So, I presume this is related to the question that we were debating before we started, which is about therapeutic- versus prophylactic-dose anticoagulation.
Professor Menaka Pai: That's a great question. So hi everybody, my name is Dr. Menaka Pai. I'm in benign hematology and thrombosis medicine, also at McMaster University. I'm pleased to be with my colleagues today. So this is a great question. And Dr. Crowther, maybe I'm just going to preface this with a motherhood statement about trials. So you know, I love randomized controlled trials – they're great. But I think what we really have to appreciate with randomized controlled trials is that they are designed to answer very specific questions. So they are giving you answers about a specific group of patients, about a specific intervention, and the effect of that intervention on very specific outcomes. And this has never been so clear as it has been with COVID-19 research, where there has just been an explosion of studies. And thank you to the questioner. You're asking about the multi-platform RCT which combined 3 large RCTs to give us some data. So, in this study, the study was actually powered, it was designed to give us an answer about a primary outcome, called “organ support-free days.” It's kind of a mash-up of survival – which is a very patient-important outcome – and organ support, which they actually defined very broadly. So, for example, the trial investigators included oxygen by high-flow nasal cannula, which they considered organ support. You know, a lot of clinicians [and] a lot of patients would not consider that true organ support. So, to truly answer your question, what I will tell you is that this trial was futile for the primary outcome, the question it was designed to answer. Even though therapeutic anticoagulation definitely did result in a numerical decrease in major thrombotic events, which is an important efficacy outcome – but a secondary outcome – it did not improve organ support-free days or survival to hospital discharge. So that is why we've all read the headline that this was a negative trial. It was not powered or designed to really answer specific questions about thromboses. An excellent question.
Mark Crowther: Alright. So along the same lines of that – I'm trying to lump these together – “according to your data, more than 40% of ICU patients will ultimately be found to have thrombotic disease. In my experience,” this is the speaker asking the question, not me, “we end up anticoagulating well over 50% of ICU patients for an approved indication. Therefore, isn't it a bit unusual to say that full-dose prophylaxis is not beneficial, since perhaps the majority of patients are actually going to end up on that treatment?”
Menaka Pai: Yes, great question. I'm glad I made that motherhood statement because I'm going to give you a kind of similar answer. I will make one clarification: you know, when we screen for blood clots, when we look for them in all patients, that's where we find that 40% of critically ill patients have clots, but when we just look at clinically evident disease, which is more like what we do in practice, that number goes down to about 20%. That's still a lot of folks who have blood clots, who have VTE. But again, your question is a good one; you're asking, “listen, we use of lot of full-dose blood thinners in the ICU. So why isn't it effective?” Well, again, the data that we have from this large multi-platform trial talks about a different population than the one you're asking about. It provided high-quality data on the use of blood thinners in patients who didn't have any other indication to get it. So these folks did not have clots already; they didn't have atrial fibrillation; they weren't on blood thinners for other good reasons at home. The data really was to answer [whether] we should use this therapy in a very preventative way to decrease organ support-free days. And in the ICU, you know, the trial showed that this was futile. So my comment is certainly that there are many reasons to use full-dose therapeutic anticoagulation in ICU patients, many standard reasons, and we should continue to do that, but right now, the data says it is futile to give that high dose for other reasons in the critically ill. Instead, the data seems to favor the status quo, which is to give them a prophylactic dose of anticoagulation in the ICU setting.
Mark Crowther: Thank you. A question for Dr. Verhovsek. What is the evidence-based or guideline-recommended infection prevention strategy in patients with sickle cell disease? I presume that's related to asplenia.
Madeleine Verhovsek: Yes, thanks very much. So it's a bit of a big question, but if we boil it down to what the evidence-based approach is, it becomes more contained. Ultimately, the infectious risk in sickle cell disease is increased for a number of reasons, you know, a lot of them being more related to the volume of use of acute care services and time spent in hospital etc., IV access. But the one thing that we know fundamentally for any patient with sickle cell disease – particularly those with SS or Sß thalassemia – is that most of the patients with those 2 genotypes will be functionally asplenic starting at a very young age, because of sickle entrapment and infarction in the spleen. So what we do know from randomized trials that have been completed in pediatrics, is that penicillin prophylaxis is very important. Now, we're at an internal medicine conference and most of us are internists – we're not looking after children; but it is important to note that in children below the age of 5, penicillin prophylaxis on a daily basis is recommended. And depending on our interpretation of the follow-up trial, there are some circumstances where it may be continued beyond the age of 5. Aside from that, we don't have a lot of evidence base to guide this, except that we know in patients who are either surgically or functionally asplenic that they do require immunization for encapsulated organisms. So we do recommend that all patients be fully immunized for haemophilus influenzae, for neisseria meningitidis, and for strep[tococcus] pneumoniae. Aside from that, that's really the start and the end of it. In terms of treatment for infections, we do always ensure that there is good coverage for encapsulated organisms in terms of empiric antibiotic coverage.
Mark Crowther: Thanks very much, Madeleine. I've got a couple of questions for me. My colleagues on this panel wonder why in the heck I'm doing a Von Willebrand disease talk, because I'm certainly not an expert in Von Willebrand disease. I'd like to thank Paula James, who provided me, with permission, the slides that I presented and also gave me some coaching in the management of Von Willebrand disease. But I can answer the questions, I think. So the first question I have is, “you mentioned a bleeding assessment tool – do you mean the one from ASH [the American Society of Hematology] that you talked about?” So I'll say that there is a wide variety of bleeding assessment tools which have been validated. Some are more complicated than others, some are meant to be used by the patient and to be self-administered by the patient prior to a visit; others are meant to be administered by professionals. There was a slide where I pointed to a free tool that's available on the American Society of Hematology app and that would certainly be one that would be generally recommended, but there are a variety. And I think it doesn't really matter which of the bleeding assessment tools you use, as long as you use one which has been validated. I would also suggest taking into account local language preferences, the patient's educational level, and the complexity of the tool, because if the person has a limited command of English and the tool is only available in English and it's 16 pages long, that's probably not going to be particularly useful. I'll move on to another question for Dr. Douketis. This is an interesting question which we get asked a lot. Jim, “why do we accompany dabigatran and edoxaban with low-molecular[-weight] heparin for the initial 5 days and not apixaban and rivaroxaban?”
James Douketis: Thank you. That's a very practical question. The short answer is that [it's] because of the way the trial was designed to investigate these 2 direct oral anticoagulants. By “trial,” I mean the randomized study. So biologically speaking, I don't see any good reason to have a [] with low-molecular[-weight] heparin for 2 direct oral anticoagulants, but not the 2 others. But because this is the way these drugs are approved for clinical use, I think we have to adhere to that; otherwise we would be taking a bit of a therapeutic leap. So there isn't any biological reason that I can think of. I think we just do it by convention to conform with the regulations. It's a very good question.
Mark Crowther: Thanks, Jim. The next question is for Dr. Pai. This is very relevant to COVID-19. I was just reviewing a paper on COVID-19 and had to point out that it was already out-of-date, even though it was only submitted 2 weeks ago. The question is, “your lecture was reported over a month ago, which is exactly one eon in the COVID-19 world. What are the current recommendations based on subsequent evidence around the management of anticoagulation in critically ill patients? And what about in patients who aren't quite at the ICU but are at the point or near the point of going to the ICU. What is the clinical threshold where you define what is moderately ill patients versus critically ill patients?”
Menaka Pai: What a good question. This is moving so fast. And I'll tell you right now, there is more data that will be coming out soon, including some meta-analysis data, so I'm sure that my answer is going to be out of date next week. And also, I will tell you with the results show… and I will also editorialize a little bit, so I certainly welcome comments from my co-panelists if there is a spirit of healthy disagreement, which is great. Since my lecture was recorded… again, this elephant in the room study, the multi-platform RCT, both its critically ill and moderately ill arms were published as pre-prints. So I will tell you [that] for critically ill patients, not much has changed since my lecture. So I remember it compared therapeutic- to prophylactic-dose anticoagulants, looked at this, you know, funny outcome of organ support-free days, and it was very, very clear – even when we looked at that final data – that therapeutic-dose anticoagulation was futile and, using Bayesian probability, was likely inferior. So when you looked at that median organ support-free days between the groups, there just wasn't a difference. Things got a little more interesting with the moderately ill groups; that's also published as a pre-print. There is a very, very long supplemental appendix, which I'd encourage you all to read. So the headline of the published study was that this was a positive study, so the authors said that therapeutic-dose anticoagulation is preferable because it increases organ support-free days as compared to usual care thromboprophylaxis. So now, I am going to editorialize a little bit. I will say, you know, when I read this very well-done, very thoughtful, and really impressive multi-platform trial, despite the headline, the absolute effect on this outcome was pretty small. And also that study outcome, organ support-free days, is a little nuanced. Maybe these outcomes wouldn't be relevant to all patients, if there is no clear improvement in survival. The definition of organ support was pretty broad and, of course, we know that therapeutic-dose anticoagulation can possibly increase major bleeding. So my opinion is that, you know, given that small absolute risk reduction for patients – the important outcomes – and known harms… And also, another thing which I think is pretty important [is that] the majority of patients in that trial did not receive important co-interventions like dexamethasone and tocilizumab, which are now considered the standard of care for moderately ill patients, certainly in North America and certainly in Europe. So it's a positive trial, but I struggle to make a really strong, broad recommendation that every single moderately ill patient should get full-dose anticoagulation. I think we still are clinicians, we still have to use our judgement. That's patient's values and preferences; think about bleeding risk. More data is coming, I can't even talk about COVID-19 without being out of date. So that's my 2 cents on that, Dr. Crowther.
Mark Crowther: And Jim has a comment. Jim?
James Douketis: Well, I just wanted to supplement what Menaka said. You know, this has been very dynamic: when I started working on the COVID-19 unit in December, very few people were using dexamethasone and anticoagulation was not even on the radar. And now, dexamethasone is routine, a lot of people are getting tocilizumab, [and] a lot of people are getting remdesivir. I think the question I get asked as an internist more often is what's the demarcation defined between whether you decide somebody needs full-dose anticoagulation or not? In other words, what is the clinical phenotype of a patient who may benefit from anticoagulation, on the outcomes that Dr. Pai mentioned? And it's a judgment call, in my view, in that it's somebody who is ill – they're ill enough to be in hospital, they're on oxygen – but they are not ill enough to require mechanical ventilation or high-flow nasal cannula. So it is a judgement call and you do have to take other things into consideration: goals of care, bleeding risk, etc. But I think that's an important point that we get asked a lot as thrombosis physicians, but also as internists working on COVID-19 units.
Menaka Pai: And maybe I will mention, Dr. Crowther, speaking to what Jim's just said, that Jim, I think you've set a good example, certainly locally at McMaster. You know, there are trials that are ideal-world situations and there is the need to translate that evidence, as you said, to the clinical frontlines, where people need guidance. So I guess maybe… Perhaps you would agree, I would encourage the folks in the audience today to, you know, look at those trials, read them carefully, but then also talk to your peers, set up some, you know, standard care, standard processes. So whatever your group decides to do – and there is probably some grey area and probably some risk stratification – [doing] it systematically, I think, really can raise the level of care for these patients, who are really complex. Regardless of the fast-changing evidence, standardization really matters.
Mark Crowther: Thank you. And continuing on the 2-for-1, for Dr. Pai, which… So I'll paraphrase this question: “Is there a role for antiplatelet agents in the management or prevention of thrombosis in patients with COVID-19?” And then Part 2 is, if they are on antiplatelets or, let's say they're on rivaroxaban for atrial fibrillation when they come in to the hospital, “can they be left on an agent or should they be switched to a low-molecular-weight heparin?”
Menaka Pai: Yes, good question, a two-part question. So first, you know, talking about antiplatelet drugs, RECOVERY, which is another one of these mega-trials, this again is an extremely well-designed trial from the UK [and it] was the first out of the gate with information on antiplatelets; they looked at aspirin in hospitalized patients, which include a broad array of severity. And they've just come out with the pre-print saying that ASA [aspirin] does not improve survival. So I think that's important – again, survival of the patient is an important outcome. So right now, data is saying that [there is] no real effect and we know that, again, more is going to be coming out about this. So I would say [with] antiplatelet drugs, unless there is another indication, you're not getting a huge win. So, what do you do if they are on an anti-thrombotic drug for a different indication? OK, first of all, we don't have really clear data on this group; all of the big trials excluded people who were already on anticoagulation. Second, I'll [ask] why do we really like heparin for COVID-19? Well, because we feel that heparin has pleiotropic anti-inflammatory effects; it does all kinds of things beyond blood thinning. And there is always a little hesitation. We don't want to give other anticoagulants because they may not have these magical anti-inflammatory effects. I will tell you my approach – again in the absence of data… As Dr. Douketis pointed out, we have now started giving COVID-19 patients far more powerful anti-inflammatory drugs, like dexamethasone and IL-6 inhibitors. So I think you don't have to be as worried about forsaking the anti-inflammatory effects of heparin if you are using other standards of care. So my suggestion is [to] use your clinical judgement, use the anticoagulation that works for your patient based on their preferences, based on your patient's renal function, based on their ability to take things orally while they are in the hospital, based on the need for a short-acting or reversible drug if there are bleeding risks. And you know, I think that [one can] emphasize the use of other anti-inflammatory drugs that offer very potent effects that probably dwarf that of heparin. So I'm not super sticky about switching people automatically to low-molecular-weight heparin. I know there is a small study that compared low-molecular-weight heparin and rivaroxaban – [there are] some methodologic concerns about that comparison – but I think this is an area where you know, clinical common sense should rule until we have better data.
Mark Crowther: And Jim?
James Douketis: Well, I just wanted to also pick up on Menaka's point. You know, another question that we get asked a lot is, “what if I have COVID-19 and I'm not sick enough to be in the hospital? Should I go on aspirin or should I take my blood thinner?” And the short answer is “no.” But it's a really interesting question because, as Dr. Pai alluded to, giving these anticoagulants, you know, mainly for a presumed anti-cytokine-mediating effect… so, the premise is that you are going to take anticoagulants while you have COVID-19 to prevent that progression to COVID-19 pneumonitis. And the answer practically is “no, there is no indication.” There are at least 3 large trials evaluating different anticoagulants in COVID-19-positive patients who have not been hospitalized. So you don't have to recommend anything. We don't know if anything works and, frankly, as Menaka said, there is no biological reason why an antiplatelet would work in those patients who are not in the hospital situation.
Mark Crowther: Excellent. Thank you. Question for Dr. Verhovsek. And… please keep the answer under 3 hours: “How should iron overload be diagnosed and treated in patients with sickle cell disease?”
Madeleine Verhovsek: Well, I think I can keep this pretty quick. Actually, the short answer is, “very similarly to other anemic patients.” So you know, in internal medicine or in benign hematology, we are all very familiar with treating iron overload related to hemochromatosis, where there is increased intestinal iron absorption, and then we just give the patient a series of phlebotomies to get the iron down. Unfortunately, in a patient with an inherited anemia, like sickle cell disease or transfusion-dependent thalassemia, we can't do that because it's counter-productive in lots of ways. So the treatment involves iron chelation therapy most of the time. What is available will depend on the setting. Locally in Canada, for sickle cell disease – and this is all well-supported by evidence – our first line is oral therapy with diferocirox; film-coated tablets is the formulation that's preferred at our setting. And typically, I will do an R2* MRI sequence to assess the liver iron concentration before I start chelation. You know, we're all very familiar with using ferritin as a marker of iron overload and transferrin saturation. In sickle cell disease, because it's an inflammatory state, the ferritin as a stand-alone test is less reliable, so having some objective measure of what the liver iron concentration – and indeed, in some situations, also assessing to see whether there is baseline cardiac iron overload – is an important baseline investigation before initiating chelation. So, the 3 main chelators that are available globally are diferocirox, Desferal – otherwise known as deferoxamine – or deferiprone. The first and the last that I've listed are oral; the one in the middle is parenteral, which can be administered either subcutaneously or intravenous[ly]. So you know, often times – because of the nature of the monitoring that is required [due to] some of the side effect profile of those 3 medications I listed – a lot of times that iron chelation therapy is managed in a specialist clinic, but there is no reason that that care cannot be managed by a skilled and committed internist or other non-specialized hematologist, for example. It just requires post-monitoring of the iron blood parameters as well as some lab markers, such as liver enzymes, on a regular basis. The last note I'll make is [that] the intensity and duration of chelation [in] someone with sickle cell disease is going to vary considerably depending on how and why and over what period of time they became iron overloaded. Many of the patients are just getting intermittent transfusions during hospitalizations or acute problems over their lifetime, so a lot of times it won't even come to light that they have iron overload until they are well into adulthood. And as long as we can avoid more transfusions, and particularly the unnecessary transfusions, in my experience treating that iron overload can be dealt with over a limited period. [They are not necessarily] going to be on therapy long-term, as opposed to some of the patients who need to be on chronic transfusions for primary or secondary stroke prophylaxis, for example. They may require life-long chelation therapy because of the ongoing iron load associated with transfusion.
Mark Crowther: Excellent. Thanks very much. A question that I will address: “Are intramuscular injections safe in patients with Von Willebrand disease?” There is no simple answer to this. The large majority of patients who are labelled as having Von Willebrand disease will have a mild bleeding disorder and those patients, in general, can safely receive intramuscular injections. [In] the patients with the more complex forms, the type 2 or type 3, intramuscular injections should probably be managed in concert with the hemophilia service because of the potential complexities. Those patients are extraordinarily rare and in almost all circumstances will be followed closely by people who are really expert in the management of Von Willebrand disease. And so, I would say that if you have a patient who's got mild type 1 Von Willebrand disease who is asking whether or not she can get the COVID-19 vaccination, the answer is yes. If they have a more serious bleeding disorder or they've been diagnosed with one of the type 2 or type 3 disorders, you would want to seek some extraordinary advice. If the patient has type 1 but has had previous severe bleeds and has used, for example, tranexamic acid, you might consider advising them to take a dose of tranexamic acid around the time of the vaccination. But in general, by far the large majority of patients who have the milder bleeding disorders can safely receive intramuscular injections. Another question, from the live question and answer session for Dr. Douketis is, “what is the role of anticoagulants in infective endocarditis?”
James Douketis: That's a really interesting question, I think, because, you know, on face value you say, “well, anticoagulants shouldn't do anything” because we don't use it for non-thrombotic kind of embolic situations, whether it's in this case infective emboli or fat emboli or tumor emboli or amniotic fluid emboli. But you know, there is always some element of thrombosis, maybe at the microscopic level, with infective endocarditis. So I think it is a good question. I think we just don't do it because, you know, trials have never been done. Often, patients with IE [infective endocarditis] have other problems, like thrombocytopenia, [maybe] bleeding, so we have to consider the risk of anticoagulation. But I think it's a good theoretical question. I [think we just don't] do it because there is no trial evidence and, you know, biologically we're treating an infectious process, but I mean, Menaka or Mark, what do you folks think?
Mark Crowther: The other issue is of marantic endocarditis: they can get emboli in their head and there is a risk of those converting to hemorrhagic stroke. So it's a very interesting question. It's definitely one that in an environment where endocarditis is more common, it would be well worth doing a study to look at this, because I've always wondered about this. It doesn't really make sense to have patient that's got endocarditis that isn't infective and have, you know, a sensation that they need to be anticoagulated and then right beside them you have a patient who has got an endocarditis that looks exactly the same on imaging but they've got a positive blood culture, and in those patients we don't anticoagulate. Menaka, thoughts?
Menaka Pai: It's also tough, you know, I think about… like Jim, I work in a large cardiovascular hospital where we provide thrombosis opinions. And it's hard because many of the infectious endocarditis patients we have in hospital are very ill. And they would likely meet criteria for just you know, general prophylaxis of sick, septic medical patients anyway. So this is a trial that's crying out to be done, I think. And Mark, you commented about hemorrhagic transformation. Yes, these patients can be really complex. So slicing and dicing who would benefit and who could potentially be harmed – I think that's a fantastic question.
Mark Crowther: Thanks very much. And the next question is another COVID-19 question for Dr. Pai, a question about D-dimer levels. I guess I'm going to make it a bit bigger than the question that's asked. “Should we be using D-dimer levels or testing D-dimers of patients who aren't going to be hospitalized?” And then secondarily: “Other than them being high in people with COVID-19, what value do they have?”
Menaka Pai: Oh, yes. So listen, early on, I remember the early days of the pandemic. It feels like a million years ago [but] it's just in March, actually, last year. It was en vogue to measure D-dimers serially. In fact, many of our studies used D-dimers as a way to stratify patients for interventions, though generally that was baseline D-dimers. So I think this question is, “should we measure D-dimers? Is it a proxy for other bad things that are happening or things that are going to happen? Is it an independent predictor of poor outcome?” And my answer is “we don't know.” And there are a lot of studies that are out there, but they are really challenging because people [did] not measure D-dimers systematically, people were not blinded to outcomes, and outcome assessment was probably done differently in patients who did or did not have D-dimer elevation. You know, I don't know. I think, Mark, these patients are really pro-inflammatory and I think the D-dimers reflect that. But I am not convinced that there is a magical predictive value in hospital. I'm also not convinced that there is a lot of merit in using D-dimer as a predictive tool in out-patients when we have other clinical factors that actually tell us about how these patients progress. I will also make a statement – I am also a lab medicine physician, as some of the other panelists are – we have an international shortage of sodium citrate, or blue-top tubes. These are the tubes that we use to measure D-dimers. So I will say that whenever we talk about doing lab tests, there is always a cost. And so I [say sure], measure a D-dimer, but be prudent and certainly don't over-order because there are real-world implications to our early love of D-dimers in this pandemic. And I would be happy to hear what the rest of you folks think about this.
Mark Crowther: It's interesting… 20 years ago, when D-dimers were coming out, there were lots of point-of-care tests. If we wanted to use it, maybe a point-of-care test would be a great solution at the moment. I agree with you completely: just because it's high, it doesn't mean it has predictive value and just because we can measure it, it doesn't mean we should. That seems to be a common thread in lots of different areas of medicine. The ability to measure something doesn't mean we actually should be measuring that. Thank you. A question for Dr. Verhovsek: patients with sickle cell anemia going for tonsillectomy. That's an interesting question. Let's broaden it out a little bit, so if you could answer that one specifically and then say in general for surgery.
Madeleine Verhovsek: Yes. Absolutely. So this is a question that comes up fairly often and up until a few years ago, we didn't have very good evidence-based results with which to guide our practice. But the TAPS trial, which was published a few years ago in The Lancet, took a look at whether patients going for low- and medium-risk surgery with sickle cell disease would be OK to go without any pre-op transfusion versus an arm where there was pre-op transfusion. And in fact, there were a number of patients with tonsillectomy who were included in the trial and specifically, although the numbers were small, there were no adverse outcomes in the tonsillectomy group who had pre-op transfusion as opposed to several adverse complications – including several episodes of acute chest syndrome – in those who did not. So as a general rule of thumb, what do we mean by transfusions? So in the TAPS trial, they included patients who had SS and S–beta-thalassemia. In the intervention arm, in the transfusion arm, that group was further stratified based on whether their pre-op hemoglobin was below 100 or at 100 [g/L] or above. Those patients whose pre-op hemoglobin was below 100 [g/L], their transfusion consisted essentially of simple transfusion targeting a hemoglobin of 100 g/L, which is 10 g/dL. And then in the patients who had a higher baseline hemoglobin, the strategy was slightly different; they had partial manual exchange transfusion with the target hemoglobin S, so they were aiming to get the sickle hemoglobin below 60%. And so, with that kind of stratified approach, there was a statistically significant reduction in post-operative complications in all comers, whether it be with low-risk or medium-risk surgeries. That doesn't include the very minor risk procedures, such as very minor dental work or skin biopsy, things of that nature, but anything involving the airway, anything of an ENT [ear, nose, and throat] nature, abdominal surgery etc., would fall into the guidance from the TAPS trial. To kind of go from there, there isn't good evidence for much more high-risk procedures, but generally, when we think of things like cardiovascular surgery, neurosurgery, often times we will take a somewhat more aggressive approach, which may include a full, automated red blood cell exchange transfusion, for example, targeting a sickle hemoglobin level below 50% or below 30%, and ensuring that the hemoglobin concentration is adequate for somebody who is going to be undergoing a procedure were there will be blood loss associated with that. So generally we're aiming for that target of 100 g/L, 10 g/dL, as a pre-operative hemoglobin.
Mark Crowther: Thanks, Madeleine. If you can just briefly… there is a question in the Q&A from the same person: “How long before surgery should you be doing the transfusion if you are going to transfuse?”
Madeleine Verhovsek: Yes, excellent question. I would have to go back to the primary study protocol to see exactly how they operationalized that. At our center, I try to do it within 2 to 3 days before surgery, where possible, and definitely within 1 week before surgery. We've generally been able to do that with good success and, you know, the further out you get from surgery, the less certain you are going to be that those values that you are targeting are going to hold for the day of surgery.
Mark Crowther: Excellent, thanks very much. Jim, you wanted to make a comment on the D-dimer question, and then if I can pair that [with] the next question on the list here. “You mentioned DOAC drug interactions. Could you please list the main ones that we should be concerned about?” And also the D-dimer comment.
James Douketis: Sure. Let me talk about the DOAC issue first. I think we're only recently, in last few years, starting to recognize how there are in fact interactions between direct oral anticoagulants and other drugs. So, the 3 areas that I try to remember when I am prescribing a DOAC is [whether] the patient is on 1 of 3 categories. The first [question] is are they on an anticonvulsant? Things like carbamazepine and phenytoin are inducers of the enzymes that metabolize the DOACs, so they can lower the actual therapeutic levels. And the second category is antimicrobials, so things like rifampin, [that's] another inducer, whereas another drug like a macrolide, [such as] erythromycin is an inhibitor, which can increase levels. So anticonvulsants, antimicrobials, and then the third category is antiarrhythmics – not [such] commonly used drugs [as] verapamil or quinidine, but these are also agents that have an inhibitory effect and may increase levels. So bear [that] in mind; be careful. I think our pharmacists at our hospitals or our clinics are very attuned to this and very helpful. So be aware of these and, in some cases, there are a lot of alternatives: different anticonvulsants, you know, different antimicrobials. And then there is a whole array of other drugs that are not as commonly used antiretroviral agents, but one that I think is important in our hospitalized patients is dexamethasone, because we're using that more and more in a variety of situations, [and it] also has an inducing effect. So just bear these in mind. And just really quickly to the point about the D-dimer: as Dr. Pai mentioned, you know, I think the default is not to do it routinely. And actually in the multi-platform heparin trials, there was a benefit irrespective of D-dimer level. So, [that's] even more reason not to do it routinely. It's probably, as Menaka said, just a marker of an inflammatory state and overall patient morbidity status.
Mark Crowther: Thanks, Jim. We move onto the next question, for Dr. Pai. We've touched on this already, but I think it's a really important question and I'm actually going to expand it as well. So the question is, “should we use prophylactic-dose heparin in home-treated COVID-19 patients?” And then also I'm going to extend that to ask, “what about patients who got discharged from the hospital but who are still on oxygen and are at home? Should they be on anticoagulant prophylaxis as well?”
Menaka Pai: A great question. I feel like a broken record, Mark. “There is insufficient evidence. There is insufficient evidence,” but I will be a broken record again. This is a very valid question because, you know, we have some observational data that shows maybe about 1 in 200, maybe a little less, of patients who have COVID-19 and are not hospitalized develop VTE. So, you're really talking about 2 different populations: the ones who never get to hospital and then the ones that are discharged. There have been some expert opinions saying that maybe after hospital discharge, patients who are higher-risk for VTE should get prophylaxis; examples have been patients who have history of VTE, patients who are still extremely immobile, [or] maybe patients who've had mechanical ventilation. This is an area of study and it would be nice to give you more specific information soon. You know, I think because we have no robust data to support a broad recommendation, again, this is where your individualized approach matters. So you know, consider the patient's thrombosis risks, consider their bleeding risks, and then really tailor the recommendation for the patient. And then, Mark, the other question, you know, I think that comes up a lot, I get this a lot from community physicians. You know, we're seeing patients who never went to hospital, never needed hospitalization. We don't have any evidence supporting the use for prophylaxis in patients with mild COVID-19 at home. How about those in long-term care centers who are not in hospital, but they are receiving dexamethasone? Maybe they are receiving low-flow oxygen? There might be good reasons for giving these patients prophylaxis, because they are moderately ill but they have not made it to hospital. But again, given the frailty of some of these patients, I am a big promotor of individualized bleeding and clotting risk assessment. No broad recommendations from me on this one.
Mark Crowther: Thanks, Menaka. There was a study that a group of us did out of New Orleans. We managed to accumulate about 2500 patients who were never hospitalized but were PCR-positive; these were all patients who had a single visit to the emergency department, were diagnosed with COVID-19 based upon that, and then were very carefully followed in a large US health maintenance organization. And of those 2500 patients, within the next, about 1 month of follow-up – this was [early in COVID-19] – there were 3 DVTs. So the rate was 0.14%, which is extraordinarily low. And we also followed patients who were admitted to the medicine unit but [were] discharged and there were also just a small handful of DVTs in those patients. So, again, I think people look at those kind of results and say, “oh, there were 3 DVTs, these people should get prophylaxis,” but to counter to that [are] 2 things: one is, you know, we don't know that the anticoagulants are going to be effective for preventing those, but more importantly, [there is] the toxicity of those anticoagulants being administered to 2500 patients, which may or may not prevent an outcome in 3 patients. So I agree with you completely, I think the evidence does not support broad recommendations. And as Dr. Douketis said, there are studies going on looking this, so let's wait for the results of those studies. But certainly, in general, this is a question I get asked a lot: “I have COVID-19, I'm at home, should I get the anticoagulants?” And the answer to that is, “unless you've got another reason for anticoagulants, I think the general recommendation is…”
Menaka Pai: It's the number one WhatsApp question from friends and family to thrombosis doctors. I think what you're alluding to, Mark, is [it's] important that we want to get more precise. We want to figure out who those 3 DVTs were and why they got it. I think that's going to be the next phase of COVID-19 research, being able to get a little bit more narrow. And I think that's going to do better for patients.
Mark Crowther: Thanks very much. Another question for Dr. Verhovsek. So, Madeleine, sickle cell disease was kind of a neglected disease and suddenly, there is a lot of interest. What do you think are the next 2 big therapies that are going to modify sickle cell disease? We have gene therapy, we have new drugs. In 5 years, what are going to be the drugs are going to be really exciting are we're going to be thinking about using routinely for sickle cell disease? Drugs or interventions.
Madeleine Verhovsek: Wow, OK, that's a tough one. I wish I had a crystal ball to know for sure. And the answer to the question, I feel like it needs to filter through like a global health equity lens, to be honest, because there has been a tremendous amount of research in sickle cell therapeutics, particularly over the past 10 years and, increasingly, over the last 3 to 5 years. You've mentioned a couple of them; I think stem cell transplant is an area where there has been a fair amount of research and, increasingly, there are a number of groups and corporations, in fact, looking at different ways of doing gene therapy. There is a huge amount of interest and enthusiasm about what's going to come of the gene therapy research. It's been happening in fits and starts for several decades. And we are really seeing some very promising results from several of the research enterprises there. You know, that ultimately has a potential to become a cure for sickle cell, depending on how effective that is. And then the question becomes, “what is the toxicity like?” And as long as that balance is good, then that looks very promising, but then the next question is, “what will the price tag be?” And when we see the burden of sickle cell disease being very heavy in places like sub-Saharan Africa and in parts of India and elsewhere, you know, what is the access to those therapies going to look like? So it ends up being… [problem with the connection].
Mark Crowther: I think we just lost Menaka. Did we just lose Menaka?
Menaka Pai: Oh, I'm still here.
Mark Crowther: Yes, Menaka… Sorry, Madeleine. We lost Madeleine; she disappeared. St. Joseph's is not paying its internet bill. OK, we will move on. Sorry, Madeleine. Hopefully you can hear us or you'll come back. A question for Dr. Douketis… We're getting towards the end; we've got 8 more minutes. “As a rule, we do not monitor DOACs using laboratory tests. Are there any situations where we should consider monitoring?” Particularly routine monitoring, [not] in exceptional circumstances, but just routinely – are there settings where you want to monitor DOAC levels?
James Douketis: Let me just preface my statement by saying that we have Madeleine back, so I think we should have her complete her response. Nice to have you back, Madeleine.
Madeleine Verhovsek: Thanks, Jim. I don't know where I went. I'm on the hospital, you know, LAN line, computer Internet connection. I'm not sure where you lost me, either. Maybe Mark could update me?
Mark Crowther: You were just finishing the statement about the global health lens and how what we say for the United States or Canada or Western Europe probably is not going to be particularly relevant in the rest of the world.
Madeleine Verhovsek: Yes, OK. And had you already heard me drone on about where gene therapy is going? Or [did it get] cut off before that?
Mark Crowther: No, you were there.
Madeleine Verhovsek: So, the other therapies that we're looking at include things like crizanlizumab, voxelotor, and L-glutamine – and of course it's the pharmaceutical-grade L-glutamine that was studied in trials. Those are available to varying degrees in different parts of the world. So, for example, in Canada, none of those are Health Canada-approved, so our patients in Canada with sickle cell don't have access to those treatments. Your original question, Mark, was what I think is going to be the most promising. I would say, personally, looking at the results from crizanlizumab, voxelotor, and L-glutamine, [that] the clinical improvement is incremental with those therapies, but none of them provide this blockbuster, you know, taking somebody who is sick and in and out of the hospital all the time to being completely well. So I think a lot of patients and healthcare teams looking after people with sickle cell are really looking to these more curative therapies and how we can optimize the approach that we're taking. Ultimately, are the treatments going to be effective and accessible to the patients who most need these treatments?
Mark Crowther: Excellent. Thanks very much. And Jim, maybe I'll just refresh the question for Jim: laboratory testing for DOACs, when we should consider using it?
James Douketis: Thanks. And I will be really quick. The short answer is “hardly ever.” I don't want to say “never” because we never say that in clinical medicine, but the reason why I say “hardly ever” is because, first of all, there isn't a good test – like we have in INR for vitamin K antagonists – that is reliable in the sense that the value is predictable in a certain individual patient; there is a lot of intra-patient variability. Secondly, we don't know what an appropriate therapeutic level is for a DOAC. Having said that, there may be very specific situations that you would do this in, in collaboration with a hematology specialist. For example, where you don't have another alternative: let's say [you have] a patient who is a transplant recipient, cannot receive a vitamin K antagonist, and has to be on a DOAC, but they are on immunosuppressing drugs that have drug interactions – one goes to the other category. There, you might consider doing it, but really, the default should be we do not do it.
Mark Crowther: Thanks very much, Jim. One for Menaka, again, and it's another D-dimer question. It's a slightly different question; it's not whether or not D-dimer should predict therapy, but more is the maximum D-dimer level a prognostic factor and does it predict outcome?
Menaka Pai: Yes, we don't have any evidence to say that. Again, you know… look, I think we do have a lot of great theories about the pathophysiology of COVID-19. And as things get worse, that inflammatory cytokine storm gets worse and as go cytokines, so goes the D-dimer. So I think it is just one piece of evidence to say that a patient is sick, but we don't have really great data that will actually prognosticate or map peak D-dimer; we don't even know really when to measure peak D-dimer with the outcomes in these patients. Certainly, patients who are showing more evidence of organ inflammation are the ones that you are going to watch out for.
Mark Crowther: Thanks very much, Menaka. And just in the interest of time, I've got 2 quick questions for Von Willebrand disease that I will do at the end. So the first is, “what is the role of anti-fibrinolytic drugs in Von Willebrand disease?” Again, I think it really comes down to the severity of the patient's bleeding disorder and the classification of the type that they have. For most patients with type 1 Von Willebrand disease, by far the most common clinical manifestation is going to be menorrhagia. Anti-fibrinolytic drugs are in general a standard therapy that are provided to patients who have clinically important menorrhagia, using either tranexamic acid or epsilon-aminocaproic acid. There is little bit of controversy about how effective those drugs are, but they certainly would be routinely used. And if a patient has clinically important bleeding, they should be considered there. A couple of subtleties, with respect to that: for patients undergoing dental procedures, you can actually create mouthwashes with tranexamic acid or epsilon-aminocaproic acid. Both are widely used – again, [there is] not great evidence to support their use – but I think [they are] probably pretty effective. They are usually compounded at a pharmacy; they aren't available commercially. But they are reported to be highly effective by patients. And then the second question, which is one more… we have a lot of evidence-free-zone questions today. “Can patients with Von Willebrand disease be treated with antithrombotic drugs for cardiovascular indications?” And you know, this is a very complicated question and a variation of it is that you have a patient [who] comes into the hospital for orthopedic surgery and has a bleeding disorder. They get appropriate factor replacement and then post-operatively they develop a DVT. How do you manage that? That is a really complicated question, so I would say that, in general, for patients with a mild bleeding disorder – type 1 Von Willebrand disease has got minimal clinical manifestations – I would treat them exactly the same as I would treat everybody else, just warn them that they have an enhanced risk of bleeding. If they have anything more than a mild bleeding disorder, these kinds of decisions should be made in consult with the hemophilia or bleeding service that's available to you. Almost everywhere in the world, there are hemophilia services now and these people have become really expert in this. I would not want to have a patient who has type 3 Von Willebrand disease, of whom we have 2 in the practice Dr. Verhovsek and I share, who comes into the hospital with an acute myocardial infarction [and] just gets put on routine therapy without some very specific discussions with the hemophilia service, because of the complexities of that treatment. So I would say that in general for simple bleeding disorders, mild clinical manifestations, you can safely use standard therapy, but anything more complicated should be managed in consult with the service. Again, from my talk, I just want to thank Dr. Paula James, who provided me with the slides and is the real expert in this field. And in closing this session, it's now noon, I would like to thank our respondents, Dr. Douketis, Dr. Verhovsek, and Dr. Pai for really great answers to a lot of really complicated questions. And for those of you who are following, we are going to take a 15-minute break and then at 15 minutes after the next hour we will be reconvening for the awards ceremony for the best case report contest. So we will see those of you who wish to attend in 15 minutes or so on. Thank you to our other people answering the questions for the hematology section today. Thanks very much.
