The RAPID Trial - a discussion with Dr Michelle Sholzberg

In this episode have a conversation with Dr Michelle Sholzberg on her recent publication from the British Medical Journal entitled Effectiveness of therapeutic heparin versus prophylactic heparin on death, mechanical ventilation, or intensive care unit admission in moderately ill patients with covid-19 admitted to hospital: RAPID randomised clinical trial (BMJ 2021; 375 doi: https://doi.org/10.1136/bmj.n2400) which was co-authored by an international team on behalf of the RAPID trial investigators.

Dr. Sholzberg received her MDCM and residency training in Internal Medicine at McGill University, completed additional postgraduate training in Hematology at the University of Toronto and a research hemostasis fellowship in Toronto and internationally. Dr. Sholzberg has a Master of Science from the University of Toronto in Clinical Epidemiology and Health Care Research and was awarded the Claire Bombardier award for career promise as a scientist. She is a clinician-investigator with a focus on coagulation, the Division Head of Hematology-Oncology and the Medical Director of the Coagulation Laboratory at St. Michael’s Hospital. She is also the Director of the Hematology-Oncology Clinical Research Group and Co-director of the Hematology-Immunology Translational Research Theme of the Li Ka Shing Knowledge Institute. Dr. Sholzberg is the associate editor for illustrated materials at Research and Practice in Thrombosis and Haemostasis. Currently, she is involved in the study of: prediction tools for perioperative and traumatic bleeding, the intersection of women’s health and bleeding disorders, treatments for iron deficiency anemia, new treatments for immune thrombocytopenia and the management of COVID-19 coagulopathy.

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Dr Michelle Sholzberg: @sholzberg

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 Reference:

Sholzberg M, Tang GH, Rahhal H, AlHamzah M, Kreuziger LB, Áinle FN, Alomran F, Alayed K, Alsheef M, AlSumait F, Pompilio CE. Effectiveness of therapeutic heparin versus prophylactic heparin on death, mechanical ventilation, or intensive care unit admission in moderately ill patients with covid-19 admitted to hospital: RAPID randomised clinical trial. BMJ. 2021 Oct 14;375.

Transcript

Interview with Dr. Michelle Sholzberg

Edited slightly for readability

SUMMARY KEYWORDS

trial, patients, heparin, anticoagulation, thrombosis, therapeutic, findings, outcome, prophylactic, d dimer, anticoagulant, study, composite, death, pandemic, bias, hospital, clear, bleeding, based

SPEAKERS

Michelle Sholzberg, Jameel Abdulrehman, David Airdrie

Article discussed: Effectiveness of therapeutic heparin versus prophylactic heparin on death, mechanical ventilation, or intensive care unit admission in moderately ill patients with covid-19 admitted to hospital: RAPID randomised clinical trial. BMJ 2021;375:n2400. http://dx.doi.org/10.1136/bmj.n2400 

 David Airdrie  

Welcome to another episode of CLOT Conversations from Thrombosis Canada. I'm David Airdrie, executive director.

Jameel Abdulrehman  

I'm Jameel Adbulrehman, hematologist from Toronto General Hospital.

David Airdrie  

We're here to provide you with updates on diagnosis and management of thrombosis featuring interviews with authors of recent research publications and highlights of education programs from Thrombosis Canada. Thank you for joining us for this episode.

Jameel Abdulrehman  

In this episode, we'll be discussing a recent publication from the British Medical Journal entitled Effectiveness of therapeutic heparin versus prophylactic heparin on death, mechanical ventilation, or intensive care unit admission in moderately ill patients with covid-19 admitted to hospital: RAPID randomised clinical trial, and co-authored by an international team on behalf of the RAPID trial investigators. We're joined today by the lead author, Dr. Michelle Sholzberg. Dr. Sholzberg received her MDCM and residency training in internal medicine at McGill University, completed additional postgraduate training in hematology at the University of Toronto, and the research hemostasis fellowship in Toronto and internationally. Dr. Sholzberg has a Master’s of Science from the University of Toronto in clinical epidemiology and healthcare research, and was awarded the Claire Bombardier award for career promise as a scientist. She's a clinician investigator with a focus on coagulation, the division head of Hematology/Oncology, and the Medical Director of the coagulation laboratory at St. Michael's Hospital. She's also the director of the Hematology/Oncology Clinical Research Group, and co-director of the Hematology Immunology Translational Research Team of the Li Ka Shing Knowledge Institute. Dr. Sholzberg is the Associate Editor for illustrated materials at Research and Practice in Thrombosis and Hemostasis. Currently, she's involved in the study of prediction tools for perioperative and dramatic bleeding, the intersection of women's health and bleeding disorders, treatment for iron deficiency anemia, new treatment for immune thrombocytopenia, and the management of COVID-19 coagulopathy. Thank you for participating in our podcast today.

Michelle Sholzberg  

Thank you very much for having me. It's a pleasure to be here.

David Airdrie  

Considering your busy workload, we really do appreciate the time. And we start off with a couple of standard questions. First off, why did you and your colleagues feel there was a need for this study?

Michelle Sholzberg  

Thanks for the question. It's funny, when I think back to the beginning of the pandemic, it feels like a lifetime ago, but it wasn't long ago. I remember in the very early days, very early 2020, as it was becoming clear that the virus was moving across the world, and that people were dying, and that there seem to be an increased risk of thrombosis. And that patients who had elevated D-dimer levels seem to be at higher risk of critical illness and death. It became clear that this viral pandemic was going to be far more relevant for the hematologist than I think any one of us had originally thought. In those early days, on Twitter, we were very quickly receiving information from around the world, starting of course from reports in Wuhan, China. Many individuals around the world hypothesized that there may be an opportunity to alter the course of this disease with the provision of anticoagulation. And so, I think based on that early preliminary evidence, myself and many colleagues thought that there may be value, particularly from reports from Wuhan, China indicating that in patients who had been provided with heparin-based thrombotic prophylaxis, that their risk of death was lower. It was a scary but inspiring time, I think for us all.

 David Airdrie  

Absolutely. Could you give our listeners a brief overview of the study and its findings?

Michelle Sholzberg  

Sure. This is a randomized controlled trial, one-to-one therapeutic dose heparin anticoagulation, either unfractionated heparin or low molecular weight heparin, compared to strictly prophylactic dosing of those same heparins. Patients who were admitted to hospital for COVID-19, so not incidental diagnoses of COVID-19 in patients who had been admitted for other purposes, were considered for inclusion in this study. We excluded patients with clear contraindication to anticoagulation, for example, based on bleeding risk. We also excluded patients with an absolute indication for therapeutic anticoagulation. Patients were also included in the trial if they had evidence of what we now call COVID coagulopathy, which is marked by an increase in the D-dimer level. Patients who are admitted to hospital, not to the ICU, so patients requiring more level of care with a positive D-dimer are defined as either a D-dimer above the upper limit of normal, or a D-dimer greater than or equal to two times the upper limit of normal. For those who had simply a positive D-dimer, they also had to have the presence of hypoxia, that we defined as an oxygen saturation of less than or equal to 93%. So, this really was a trial of therapeutic versus prophylactic heparin in patients requiring ward-level care for COVID-19. Unfortunately, this was not a trial that included pregnant patients.

David Airdrie  

Thank you.

Jameel Abdulrehman  

Can you tell us tell us a bit about the findings, what your study found?

Michelle Sholzberg  

Yes, absolutely. The primary outcome of the trial was a composite. We looked at the composite outcome of deaths, mechanical ventilation, whether it be invasive or non-invasive, or ICU admission, and we compared the occurrence of that composite in those who are receiving therapeutic versus prophylactic heparin. While there was a numerical reduction in the primary composite outcome, it was not statistically significant. However, the odds of all-cause deaths were significantly reduced by 78% in those who received therapeutic heparin, and there was a very low odds of major bleeding.

Jameel Abdulrehman  

Perfect. The study was designed as a pragmatic trial. Can you tell us a bit about what that means in general, and in regard to this trial? And why you decided on this study design?

Michelle Sholzberg  

Sure. Pragmatic I guess just means easier to do, easier to execute, which was incredibly important in the middle of a pandemic. We could not add more to the shoulders of health care workers and patients during this very difficult time. And so, it was pragmatic, in so far that it was simple. It was straightforward. We were repurposing a drug that was already available. We were open-minded about the different types of heparins that could be used. We didn't want to be overly strict. We wanted people to be able to use whatever heparin they had at their hospital, whatever the standard care type of heparin that was used at that hospital could be used for this trial. That said, the one thing that we were very strict about was the dosing of the prophylactic arm. We were strict in really adhering to the best available evidence, and not providing intermediate doses of heparin so as not to make the two arms of the trial excessively similar, meaning to maximize the chances of us picking up an effect if there was one present.

 Jameel Abdulrehman  

You mentioned that some centers would use low molecular weight heparin. Other centers would use unfractionated heparin. It sounds like that was done for pragmatic reasons, based on what was available to centers. Is there a preferred heparin agent that you'd recommend for today? Low molecular weight heparin versus unfractionated heparin?

Michelle Sholzberg  

Yeah, great question. I should actually lead with the words low molecular weight heparin over unfractionated heparin, as unfractionated heparin binds nonspecifically to a whole bunch of other stuff, rendering it potentially less efficacious as an anticoagulant. Really, low molecular weight heparins are preferred. I should also mention, just from a pragmatic perspective, this is an open-label trial. So of course, from a methodological perspective, or from a rigor perspective, it would be great for this to have been a blinded trial, but that would not have been pragmatic nor feasible in the middle of a pandemic, when it was already really hard just to manage regular clinical care and where PPE was very limited at the time.

 Jameel Abdulrehman  

You mentioned with the primary composite outcome, death, invasive mechanical ventilation, non-invasive mechanical ventilation, admission to the ICU. There is no statistical difference, and no statistical difference with VTE. But there was significantly less death in the therapeutic heparin group. Why do you think that was?

 Michelle Sholzberg  

That's the million-dollar question. That's the million-dollar question. I think that what we saw and what other trials in this space have also identified is that there does seem to be a benefit with therapeutic dose heparins, that family of drugs, and that benefit does not seem to extend to non-heparin anticoagulants, like the direct oral anticoagulants based on what we know thus far. You're designing a clinical trial, and especially at a time where you don't even fully understand the disease. It's before any treatments were available. And like my co-principal investigator, Peter Juni, always said, he said, this is at the time before penicillin. We didn't even know what we were treating. We developed a primary composite outcome that included a bunch of relevant clinical outcomes, both for the individual patient but also for the healthcare system, thinking about resource constraints with regards to bed availability, etc. We developed this sort of catch-all composite outcome. We didn't expect, based on historical data conducted in patients who'd received heparin, that, for example, prophylactic heparin doesn't seem to translate into a mortality difference in many other settings. We didn't expect to see such a mortality difference. Now, when you look at all of the secondary outcomes, which are all of the individual components of the primary composite outcome, plus, venous events and arterial events, everything is numerically going in the direction of suggesting benefit with therapeutic heparin. Death is the one where it completely becomes sort of abundantly clear that there is a benefit to therapeutic heparin. Why this may be, it's possible that heparin, with its anticoagulant effects, its anti-inflammatory effects, its benefit in the management of acute lung injury that has been demonstrated in previous animal models, that it decreases the risk of progressive respiratory failure. And microvascular thromboses may be part of that process. That's the hypothesis. We don't know that for certain. But it really does seem that amongst this trial and other trials, that therapeutic dose heparin is of benefit. And the risk of using it is incredibly low in this patient population, the non-critically ill patient population.

 Jameel Abdulrehman  

Okay, perfect. The COVID patients we see hospitalized today might be different from those included in the study. At least in Canada, most people are vaccinated, we have different variants of COVID now. The non-anticoagulant treatment may be different now compared to when the study was first conducted. Should these changes put any limitations on our interpretations of the findings?

Michelle Sholzberg  

Right. Absolutely, right. It's remarkable to live in a time where data from a year and a half ago or a year ago may not necessarily be relevant to the same disease that we're treating today. It's a limitation of the speed at which this virus mutates. And also, a wonderful limitation of therapeutics being very rapidly developed for COVID-19, both from a preventative and therapeutic perspective. I don't think that anyone knows the degree of benefit that a patient would experience today with therapeutic heparin-based anticoagulation if they were admitted to hospital and were not critically ill compared to a year and a half ago. I think what is very reassuring is the uniformly low risk of major bleeding. If my loved one was admitted to hospital today, would I want them to receive therapeutic heparin if they were not critically ill? The answer is yes, I would. I'd be particularly inclined if they had a positive D-dimer value. I don't think that anyone knows specifically how to quantify that benefit when you apply it to today's COVID.

Jameel Abdulrehman  

That's challenging. In the discussion paper, you talk a bit about the limitations of the open-label trial, the possibility of performance bias and detection bias. Could you tell us a bit about that?

Michelle Sholzberg  

For sure. As with any trial conducted in COVID-19, they're all open-label, or I should say, I'm not aware of any COVID-19-related clinical trial that is not open-label. With that comes the potential risk for systematic error bias. Particularly when we are looking at outcomes that require a change in clinician behavior, that may be particularly problematic. Meaning that if the treating physician is aware that a given patient is already on therapeutic heparin and the patient develops progressively worsening respiratory issues, they're likely going to feel less inclined to consider a pulmonary embolism on the differential diagnosis and therefore may be less inclined to scan the patient. Versus the opposite, which is the patient who's in the prophylactic arm. You therefore have the opportunity for bias, where you have more patients who could potentially just be scanned, and therefore they could have more thrombotic events detected in the prophylactic arm just based on the change in physician behavior, with the awareness of what treatment arm the patient had been randomized to. That's particularly relevant for outcomes like thrombosis. It's also as equally relevant for outcomes like bleeding. In the same way, you may be more inclined to consider that the patient is bleeding when they're on therapeutic heparin compared to them not being on therapeutic heparin. Where performance bias and detection bias really are not problematic are for very objective outcomes. Things like death, things like especially invasive mechanical ventilation, there are clear documents that substantiate the presence of these outcomes. And additionally in our trial, what we did to further mitigate the risk of these biases is that we had external and independent adjudication of all primary and secondary events, as you well know, Jameel, because you were one of those external adjudicators. What that meant is that you and another expert evaluated all of the source documents. And those documents were all redacted, so you didn't know which arm the patient fell into, and you reviewed the source documents to tell us if you agreed or did not agree with the site's determination of the presence or absence of a given outcome. That is a way to really minimize the risk of these biases. We were very careful with that. Another thing that was really, I think, fantastic that we were able to do with your help, was we also adjudicated the cause of death, which I think is unique and I think helpful when what we found is that most patients died of hypoxic respiratory failure.

 Jameel Abdulrehman  

Perfect. Okay, thank you. You had alluded to a few other clinical trials looking at anticoagulation and COVID patients, such as the ATTACC, ACTIV-4a and REMAP-CAP trials. How should we put the findings from all these studies together? What are the takeaway points?

 Michelle Sholzberg  

I think it's so important, now more than ever, to have multiple trials using different types of methods with different investigators in different geographic parts of the world with different funding sources that are evaluating the same types of therapies. The fact that the multi-platform trial of REMAP-CAP, ACTIV-4a, and ATTACC, as well as the findings of HEP-COVID, another trial in the space, and our trial all pointing in the same direction, all suggesting benefit of therapeutic heparin for patients who are not critically ill admitted to hospital for COVID. This is really reassuring for really the most responsible physician who's managing these patients, and also for the patients, and for us too, as trialists, because we're all moving very quickly conducting these trials. We really want to feel as confident as we possibly can that our findings are reproducible, in different settings, and we were all able to do that. I think it is critical to consider the evidence that comes from RAPID with the evidence that comes from these other trials. All of the guideline efforts to date take into consideration the results of all of these trials, and now they're increasing international and national guidelines that suggest therapeutic heparin for patients admitted to the hospital who are not critically ill with COVID-19. Our trial is certainly limited. We were ultimately underpowered. And so, our results must be taken into consideration with the findings of others. 

Jameel Abdulrehman  

Thank you.

 David Airdrie  

It's just amazing work in such a short period of time, your trial and the others as well. Is there anything that you'd like to add before we finish today?

 Michelle Sholzberg  

I suppose the one thing that I would say is that being part of this trial with wonderful international colleagues, and really courageous and generous patients around the world has been such a privilege. It was just an incredible experience for me, and one that I could not have done without my colleagues, especially my co-principal investigators, Mary Cushman and Peter Juni. And everyone who participated in the trial, most importantly, the patience. I hope never again to have to design and conduct and analyze a trial so quickly. Our feeling that pressure the way that we all did, I hope never to have to feel that again. But what an experience and one that I'll take with me forever.

 David Airdrie  

Wonderful. And thank you so much for taking the time to join us today. We really appreciate it and look forward to talking to you again.

 Michelle Sholzberg  

Thank you very much.