Recorded at the 6th McMaster International Review Course in Internal Medicine.
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Professor Roman Jaeschke: Hello to all and I would like to welcome all of us for today [to the] first question and answer session. We are all a little bit anxious because it is our first session and we are somehow testing the technical solutions. Let’s hope it will work. I would like to start by thanking the organizers, and I will name them. They are McMaster University in Ontario, Canada; the Polish Institute for Evidence-Based Medicine; Medycyna Praktyczna, which is the organizer; the European Federation for Internal Medicine; the International Society for Internal Medicine; and Jagiellonian University in Krakow, where we will hopefully see you live next year. We are also endorsed by the American College of Physicians. And we are supported by over 40 national societies of internal medicine, essentially from all continents. The first session, the question and answer session, is devoted to the first 4 cardiology presentations. The moderator will be Professor Matthew Sibbald from McMaster University. Professor Sibbald – let me tell you a few things about him. He is still, I believe, running the fellowship program in cardiology at McMaster University. He is currently in the position of dean of undergraduate education at McMaster University. And he is the section editor for McMaster Textbook of Internal Medicine, which I hope you will all love after this course. Dr. Sibbald, your floor.
Dr. Matthew Sibbald: Thank you so much, Roman. It’s really a privilege and a pleasure to be with you and our 4 guest experts from around the world. We have some questions already that you’ve submitted, and we will go through them. I invite you to add more questions to the chat, which hopefully we can get to, time permitting. I’d like to introduce all of our panelists, starting with Professor Andrew Elder, Honorary Professor at Edinburgh Medical School from the University of Edinburgh in the UK, and an NHS consultant in acute medicine for older people in Edinburgh. Welcome, Professor Elder.
Professor Andrew Elder: Thank you.
Matthew Sibbald: Professor David Hasdai, the Director of the Cardiac Intensive Care Unit at the Beilinson Campus of Rabin Medical Centre at Tel Aviv University, Israel. Welcome, Professor Hasdai.
Professor David Hasdai: It’s a pleasure to be here.
Matthew Sibbald: Professor Mueller, co-founder and director of the Cardiovascular Research Institute and professor of cardiology at the University Hospital of Basel, Switzerland. Welcome, Professor Mueller. And finally, Professor Harriette Van Spall, from our own McMaster University, a scientist at the Population Health Research Institute. Welcome, Professor Van Spall. It’s a great honor to be with you all. And I think a topical place to start is really with the pandemic circumstances that we find ourselves in. There were a couple of questions related to COVID-19. And I’ll direct the first question to Professor Elder, around physical exams. COVID-19 has posed additional challenges to physical exams. Do you have any suggestions on how to overcome the negative consequences?
Andrew Elder: Well, thanks very much, Matt. The first thing I want to say is a big thanks to the organizers for inviting me to participate and also congratulations for pulling together such a fantastic program at these very difficult times for us all. I mean, there is no doubt that the pandemic is putting pressure in a whole number of ways on bedside or just clinical education in general, in the teaching of clinical medicine and its assessment. But what I would stress and what I hope you all see, in different parts of the world, is that in the words of the old Persian adage: This too shall pass. You know, we will get beyond this. There will be things that we doubtless do a bit differently because we’ve learned, for example, to do with telemedicine. There are many things that we will return to. So whilst it’s more difficult just now to do many things to do with clinical or “bedside medicine” as we call it, I think we will get beyond that. I think one of my colleagues, Brian Garibaldi from Johns Hopkins, who spoke at this meeting last year, has been doing quite a lot of work relating broadly to physical examination in patients with COVID-19. One thing that he has stressed is the power of observation of the patient. At times when it’s tougher to touch them, you know, for the obvious reasons, things as basic as respiratory rate can make a big difference in the assessment of a patient with COVID-19 and pneumonitis. And he, along with our group at Stanford and Hopkins, has been emphasizing just that, really. If you get to a point in any clinical situation where you feel there is no value in looking at your patient, then you’re asking for problems – that would be our message. So continue to observe, looking for signs of respiratory distress, looking for simple things like respiratory rate – would be my short answer.
Matthew Sibbald: Thank you so much. It’s amazing how much we’ve been able to observe on some online platforms as many of us have tried to continue our care for patients. Many of our patients with COVID-19 have also ended up in the hospital. And I’m wondering – with this next question directed at Professor Mueller – whether he might be able to comment, as we see a lot of non-STEMI [ST-elevation myocardial infarction] cases during the COVID-19 pandemic. Any advice or recommendations regarding []that happen in these patients? And how we should go about thinking about and treating them?
Professor Christian Mueller: That’s a very good question. I think for the diagnosis of non-ST-elevation myocardial infarction, I think everything that has worked prior to COVID-19 also works during the pandemic. So, I think that in most patients, the clinical setting, [any] presenting symptoms suggestive of an acute coronary syndrome should be addressed in really the same way: with the detailed patient’s history, 12-lead ECG and high-sensitivity cardiac troponin being the 3 pillars of our assessment. What has been more challenging to evaluate, whether in a patient in whom the primary suspicion is COVID-19, so [one] who comes with symptoms more of a respiratory tract infection that leads the team to consider COVID-19 among the top differential diagnosis, is whether any of the cardiovascular biomarkers might be of additional value in the assessment of these patients. And since now strong evidence from several really high-quality data sets have largely confirmed the already initial observation of the teams in China – that the respiratory infection, pneumonitis, and the severity of the respiratory disease combined with the extent of whatever prior cardiovascular disease the patients might have had, the 2 of them add up to the amount of cardiomyocyte injury that is quantified by the high-sensitivity cardiac troponin concentration. Therefore, it’s not surprising that there is a close association between the concentration obtained at presentation and the risk of death in the [00:09:20] patient.
Matthew Sibbald: Thanks very much, Dr. Mueller. Maybe as a follow-up: We’ve all seen an evolution to using high-sensitivity troponin. Is there a cost to pay for the troponin to be too sensitive? In that labelling of acute coronary syndromes?
Christian Mueller: Yes, I think that there is. So perhaps to start with the, let’s say, economic cost, the cost of the assay itself is identical to that of assays with poorer sensitivities – the pure cost of getting the assay, running the assay. Everything is identical. However, as you referred to, while we had a sensitivity deficit with the old assay – we had a challenge to make sure the patient does not have myocardial infarction, because we couldn’t really trust a negative test result early on with the bad troponin assay. The challenge that we now face with the high-sensitivity assays is that – of course the benefit is we can be sure early on that the patient does not have myocardial infarction – however the rule in part, so being sure that it’s really acute myocardial infarction and not another cause of cardiomyocyte injury, that has become more sophisticated and that has led to the development of assay-specific algorithms, really, to take full advantage of high-sensitivity cardiac troponin concentration as a quantitative variable indicating the likelihood that acute myocardial infarction is the cause of acute chest discomfort. And so the most likely, the best and most validated approach is to combine the level at presentation with the absolute change, within either 1 or 2 hours to give a really precise estimate of the likelihood of acute MI, to achieve a positive predicted value that is high enough to justify the immediate consequences, including ICU admission and early coronary angiography.
Matthew Sibbald: Thank you very much.
Professor Harriette Van Spall: It highlights that for just about any condition, one can’t rely on biomarkers alone for a diagnosis, right? And that the clinical factors should be considered along with the pattern of peak and trough. This applies to many conditions of course, including heart failure, where clinicians love the NT-proBNPs, but they are not specific for heart failure, of course.
Matthew Sibbald: Thank you so much, Professor Van Spall. Any comments actually in the COVID-19 era about the use of NT-proBNPs and the diagnosis of heart failure, that we have seen many patients who come in with dyspnea and have had this challenge of trying to sort out whether this is COVID-19, heart failure, or in some cases both?
Harriette Van Spall: Right. And you know, we’ve learned a lot of different things about NT-proBNP in recent years: the absolute values are less relevant than a patient’s longitudinal values and that these baseline values vary between patients, based on their current hemodynamic and volume status, as well as their BMI, whether or not they have atrial fibrillation, whether or not they have chronic kidney disease, and whether there are any other antecedent causes that might contribute to a myocardial stretch and lung disease is one of them, so for example, patients with COPD or a pulmonary embolism can often have an elevation in the NT-proBNP and one doesn’t really know, especially in the low elevation state, whether they have heart failure or not, and so the clinical picture is important to consider. And simple things such as a history can be insightful. Of course, a lot of patients who are hospitalized with COVID-19 are those who have underlying cardiovascular disease – particularly high-risk conditions such as heart failure – so sometimes it becomes difficult on the basis of 1 or 2 variables to discern the diagnosis. And again, it’s a matter of considering exposure, pre-test probability, and then all of the other findings and diagnostic evaluation to determine what the diagnosis is. Andrew has a point.
Andrew Elder: Yes, just to recap and agree completely. Our group, we’re interested in the clinical evaluation of patients, not just with cardiovascular disease but with all sorts of problems, and one of the main messages we push is that it shouldn’t be clinical information versus the information we get from technology. They are complementary. Yes, there has been a bit of a tendency, I feel, lately, to push clinical evaluation into the background and maybe particularly for our trainees – and we’re teaching trainees, so maybe it’s our fault sometimes – but for them to believe that everything that they get from a technological test is absolutely, you know, spot-on and correct [means that] there is a bit of a problem developing, I would suggest, of people not questioning the results of technological tests enough, partly because they don’t trust or have enough experience in their own clinical beside evaluation. So in heart failure, I don’t know if anybody has been looking at predicted value of various signs in heart failure in patients with COVID-19 alone, but certainly in the general heart failure population, if you hear a third heart sound in a patient with dyspnea, you know, you are confident that there is a third heart sound, that’s got a very, very high likelihood ratio or positive predicted value for the presence of left ventricular systolic dysfunction on a subsequent ankle. And depending on the context that you work in, you will use a different balance of technology and clinical findings, but it should always be a balance.
Harriette Van Spall: Matt, I would add that more than half of the patients hospitalized for heart failure now have preserved ejection fraction and in these patients the NT-proBNP levels seen in the setting of acute decompensation tend to be lower. There are certain conditions in which there is a deficiency in NT-proBNP, so… obese patients with heart failure preserved ejection fraction tend to have really low NT-proBNPs. So the positive predicted value… the thresholds vary based on the kind of heart failure and it’s a matter of piecing together all of the aspects of, you know, your history, your physical exam, and your laboratory investigations with the diagnostics to come up with a diagnosis – and HFpEF in particular is a challenging one [that is] often conflated with other conditions. And so that particular diagnosis is often incorrect and we need to exclude certain other causes of dyspnea before we hang our hat on HFpEF as a diagnosis.
Christian Mueller: If I may add to this, particularly when talking about patients presenting with acute shortness of breath to the emergency department, I think there is no doubt that BNP or NT-proBNP is the strongest variable in our diagnostic assessment. However, as you referred to, I mean, it should be and needs to be complemented, in addition to our clinical assessment, with echocardiography to then identify the phenotype of heart failure. But I think we just ignore the fact that the right heart may be the cause of heart failure in some of these patients. So I think the beauty of this kind of global marker [is] that it alarms us whenever there is increased hemodynamic stress. And then of course, imaging, in addition to the clinical assessment, will help identify the main driver of heart failure in these patients. And I think [with] COVID-19 and NT-proBNP, it’s identical to the combination of pneumonia in general and heart failure. I mean, these are conditions that co-exist in a relevant number of patients, as they both affect elderly patients. It’s therefore quite common to have both diseases, both syndromes, in the same patient.
Andrew Elder: Yes, if I may, just agree with everybody. One of the commoner errors I will see on our wards – and I am a generalist and I’m dealing predominantly with older patients, as all generalists are, lots of multimorbidity, – but one of the commonest problems we will see is a breathless patient has come in and has been sent for an echo and the patient would be, you know, described and presented to me and the trainee will say “they don’t have heart failure” and I’ll say “how’s that?” They’ll say, “well, because the echo didn’t show left ventricular systolic dysfunction.” And you know, different places around here have different access to BNP and very often it won’t be done, but they base their diagnosis on the test and then you go to the bedside, you might find either a full house of signs of heart failure, yes? Or you might find none at all, yes? And both of these findings can greatly help sort out what the likely cause is.
Matthew Sibbald: It’s interesting, that reflects 1 of the participants’ questions: Under time limitations, what’s the most rewarding or important parts of physical exam that we concentrate on. I wonder if you might just speak to that, Andrew.
Andrew Elder: Well, … rewarding… I mean, I think that it depends which component of the value of the physical exam we’re talking about, because in my talk I stressed that the utility or the value of the physical exam is not simply around its diagnostic value. You know, [with] the simple act, I believe, of placing your fingers on the radial artery of a patient as you’re speaking to them, I’m doing more by doing that than assessing the rate and rhythm of their pulse: I’m forming, I feel, a connection with them, that the literature in fact suggests patients still do value. So I would say, from the point of view of connecting with your patient, that that’s a rewarding part of the physical exam. From a diagnostic point of view, the answer to the question depends entirely on the context – what’s the clinical question that you are asking? You know, the value of what you do, from a diagnostic point of view, would depend on whether you are asking, “does this patient have valvular heart disease?,” “does this patient have heart failure?” You know, these would be the top 2 that spring to my mind. So the answer to the question would depend on the clinical context, largely.
Matthew Sibbald: Thank you so much. We’ve been talking a lot about acute care presentations. I wonder if we might just shift and think how we can provide some advice to family physicians and primary care physicians, after they’ve left the hospital with a diagnosis of coronary disease? And I am going to direct the next question to Professor Hasdai. What advice or suggestions would you have for improving patient care for those who have been labelled with chronic coronary syndromes according to the recent guidelines?
David Hasdai: OK, that’s a great question, thank you. The guidelines stress that once you make the diagnosis of chronic coronary syndromes, many of these patients might have an intervention or event, and after the event they become stable, so-called, then they are chronic coronary syndrome patients. You do not send them off and [not] see them until the next time they have an event. It’s incumbent upon us to examine these patients periodically to see their risk-factor profile, their ECG, to see whether they have dysrhythmias, to see their cholesterol, their blood pressure. And these things affect their prognosis, many times much more than a simple intervention. So it is incumbent upon every institution and every physician that attends to these patients to have some kind of a periodic check-up by a cardiovascular caregiver who assesses the risk of these patients and makes sure that their risk-factor profile is well addressed, have they stopped smoking, do they take their statins, that their cholesterol is under 55 mg/dL or even under that, their blood pressure is under 130/80, if they are asymptomatic, that they do not have any kind of arrhythmia or atrial fibrillation which might affect the antithrombotic therapy that they receive. So the main point I would stress is that you do not make the diagnosis, a 1-time diagnosis, and see these patients once they have an event down the road. The wisdom is to see these patients on a periodic basis and to avoid the subsequent possible event down the road.
Matthew Sibbald: Thanks so much. I mean, the role of aspirin has certainly developed a lot of interest in this group of chronic coronary patients, particularly amongst those who haven’t required a stent or had a myocardial infarction. I know the recommendation is still a class 2B, suggesting that it could be used. What you do in your own practice?
David Hasdai: Well, I think this is 1 of the major changes that took place in the past, I would say, 3 to 4 years. I think that around 20 years ago, every American, every European over the age of 50 would receive aspirin on a primary prevention basis and there are several studies which have kind of refuted this hypothesis that aspirin is a wonder drug for primary prevention. Once a patient has a revascularization procedure or an acute coronary syndrome, then he answers the criteria of having secondary prevention aspirin. And so far, let’s say that the evidence is quite strong regarding the use of aspirin on a secondary prevention basis. When we are talking about prevention 1.5, as we call it, which means that the patient has coronary artery disease but has never had acute coronary syndrome or did not undergo a revascularization procedure, actually the evidence is quite scant regarding the use of aspirin, hence the recommendation of that 2B basis. So if you have a patient that you do a coronary angio or a CT [for] and you see that he has coronary atherosclerosis, you may consider giving him aspirin, provided that the risk of hemorrhagic complications is not very high. And provided that you advise him that the evidence is not very robust regarding the use of aspirin in this regard.
Matthew Sibbald: It sounds like a very reasoned approach. I’m curious: amongst the other panelists, how does this play out in your practices as well? I know that Professor Mueller, you were nodding. Any comments here?
Christian Mueller: I think it’s important, as David said, to really clearly differentiate between secondary and primary prevention. And I think for those who had revascularization or myocardial infarction, at least to me, we should really appreciate the value that aspirin provides. At least from my perspective, I am more concerned by the over-emphasis and the kind of interest of the pharmaceutical industry trying to position anti-platelets as an alternative to aspirin in this setting. So I think that for those patients with events, aspirin, I assume, really still has enormous value. However, I fully agree, of course, with David that in primary prevention, hardly any indication is left and those with imaging evidence of diffuse atherosclerosis or coronary artery disease, again, I think we don’t know and in the absence of really strong data, I think it’s [correct] to assume that the extent of coronary artery disease [seen] by imaging may help us in selecting those patients that might still benefit from the drug.
Matthew Sibbald: Professor Elder, any comments about the elderly population?
Harriette Van Spall: Yes, I think this is supported by the ARRIVE and ASPREE trials and even in the ASCEND [trial], the nominal benefit was outweighed by the risk of bleeding, and so many of our cardiovascular patients have other conditions – like atrial fibrillation, where they need anticoagulation – that aspirin portends a really high risk of bleeding. And we know now from these 3 trials that there is really no significant benefit to [be derived] from the use of aspirin as a primary preventive agent and there is equivocal data on its role in patients with high coronary artery calcium scores. But that’s one population where I might consider using it in the primary prevention sphere.
Andrew Elder: Yes, thanks. I mean, I agree with everything that has been said, but what I would add is that there is no doubt at all that there is a creeping epidemic of preventative polypharmacy, particularly amongst older patients. And remember they may not just be being offered preventative drugs for their possible vascular disease or in relation to hypertension – vascular prevention with anti-platelets. They may also be being offered preventative drugs for bone disease, bisphosphonates, calcium, and vitamin D. And there are other preventative drugs that are more and more frequently dished out. So the individual patient, particularly when they are seeing different specialists for each of their different morbidities, can easily accumulate an enormous list of drugs. And the more drugs that you’re on, the more likely it is you’ll have an interaction between 2 and the more likely it is you’ll have an adverse effect. So I would encourage all colleagues, be they generalists or specialists, to look at the overall tablet burden for the patient before adding any drug, particularly if there is doubt about its preventative utility.
Harriette Van Spall: And by decreasing [the] aspirin we use, one might see decreases in unnecessary PPI use, which is another common drug used prophylactically – probably because of the high uptake of aspirin therapy in older people.
Andrew Elder: Yes, you are exactly right. One drug often follows another. So you will be the same. You see patients every day, you look at the drug list and you ask, “why the person is on this?” And it’s either very difficult to find out, or when you do find out, the justification is actually a bit flimsy. So be critical about the drug lists that your patients end up [with].
David Hasdai: I think one of the critical points is that the patient has a complication from a drug that was given based on an evidence-based indication. It’s unfortunate, but you can say “OK, that was a risk worth taking.” [But] when a patient has a complication and the drug was originally not indicated, that’s really something which is heart-breaking, I would say. So always think first about this indication, because if there is no indication and you give a drug and then the patient has the complication, you could feel very bad about it.
Matthew Sibbald: Thank you very much. I think a related question that often comes up in practice is whether we should be combining all those anti-vitamins as per the COMPASS regime, rivaroxaban on top of aspirin, for prevention in higher-risk patients? Any comments there, Professor Hasdai?
David Hasdai: I think that in my talk I stressed that in chronic coronary syndromes, the spectrum starts from giving no antithrombotic therapy and extends to giving at least 2 or 3 drugs as antithrombotic therapy. So we have a wide spectrum of patients; so as we said before, patients who have no indication for antithrombotic therapy would be the patients who never had an MI, acute coronary syndrome, or revascularization. On the other hand, we have patients who have a very extensive atherosclerotic burden, patients with recurrent events, with peripheral vascular disease, with chronic kidney disease. And these patients, [those] with chronic coronary syndromes, will have the high event rates. And based on the COMPASS study and PEGASUS, post-MI patients may derive benefit from dual therapy, antithrombotic therapy on top of the aspirin: Ticagrelor 60 mg b.i.d.or maybe Xarelto 2.5 mg b.i.d. Again, you have to weigh and balance the benefit versus the harm that you may cause. But if you have a patient who does not have a high hemorrhagic risk and who has a profile with a high ischemic risk, they may derive benefit from receiving combined antithrombotic therapy.
Matthew Sibbald: Thank you so much. Any other comments from the panel, related [to that]?
Christian Mueller: Perhaps a question to my colleagues: I mean, seeing the COMPASS data, I had expected a stronger uptake of the approach in the cardiology community than the one that I observe, at least in my clinical setting. Do you have a similar observation that it’s really rather uncommonly used? Or is it different in your settings?
David Hasdai: Well, I can comment on that because I see many of these patients. I think that your comment is very well-taken. And I think it stems, among other reasons, from the fact that many physicians see a stable patient. And COMPASS, I think the medium time from the event was 7.5 years or so. So you have a patient who had an MI – remote MI, 7 or 8 years ago – who had no hemorrhagic complication, who was doing fine as far as this is concerned. And then he had another drug on top of the aspirin. And then he has a hemorrhagic complication. And COMPASS did show that they had more hemorrhagic complications with the dual therapy. And then you feel bad because you say “I did something that had the intention to intervene and it is evidence-based, yet the patient had some kind of complications”. And [that] makes you feel bad, but I think that once you get more and more experience with these drugs and you pick the right patients, then you do not have a high event rate in terms of complication rates. But I think you also become more confident in giving these drugs. So I think that… you should give it based on evidence, you should choose the right patient. And if you do not chose the right patient [they might] have an adverse experience, and then you are not going to use these drugs.
Harriette Van Spall: The other consideration could be peripheral arterial disease. And you know, that might be a population – based on clinical trial evidence – that benefits from the combination. Of course, you know, basic things like smoking cessation are important interventions that are often under-emphasized by clinicians. And so, pharmacotherapy is important as is basic lifestyle preventive strategies. And I think we also have to think higher-level because a lot of individual-level interventions are unsuccessful. We need to think about public health policy and higher-level interventions that make it easier for people to remain healthy and living well as they age. But you know, I use rivaroxaban and aspirin in peripheral arterial disease patients because they reduce cardiovascular events and limb events. And many of them, actually, have not been diagnosed as having coronary artery disease. They are high risk for coronary events by virtue of presenting with peripheral arterial events. And they are undertreated. So often times, they come to the hospital without being on a statin, [they] haven’t quit smoking, and it’s a great opportunity to improve care.
David Hasdai: Yes, I agree. Actually, we’re talking about chronic coronary syndrome patients, but many of them have underdiagnosed peripheral vascular disease. Again, in the COMPASS study, there is a sub-study which shows that the combination of aspirin and rivaroxaban was very, very effective in reducing peripheral ischemic events as well as coronary ischemic events. So in my practice, actually I agree with you: I single out the patients with PVD and CAD, and when I have a patient with these two conditions, those are the patients that I primarily give rivaroxaban with aspirin. And my experience, actually, has been very good giving these 2 drugs together. We do not see many adverse events, if we pick the right patients.
Harriette Van Spall: Yes, and ischemic/bleeding risk has to be weighed, the risk of bleeding versus the risk of ischemia. So [with] patients who have comorbidities that present a high risk of bleeding, you would adopt a different approach. So, the clinical trial evidence [is] generated in a highly restrictive population, [but] we generalize it to patients with comorbidities, and then we have to bring in our clinical judgement – you know, bleeding risk scores – and layer that on top of the clinical trial patients so that we can generalize evidence to who we are actually seeing.
Andrew Elder: Yes. So I just agree again with what’s being said. There is a danger in extrapolating the results from the generally very tightly controlled studies that are done to patients who wouldn’t have gone into that study in the first place. [That’s] number 1. Number 2 is that we’re all individuals. And it’s difficult to explain risk, I think. I’m not sure doctors are that good at explaining risk and maybe COVID-19 has taught us that, about the science, the explanation of risk. But I think we should be trying to explain it to each individual patient we meet, because they are all unique individuals. You know, number 1, if you take these drugs, they ain’t going to make you feel better, yes? Because some people think they [will], that they’re there to make you feel better. Number 2 – they could make you feel worse or they might prevent something happening to you, yes? And if you are then able to put some numbers around it for the individual, all the better [if they’re] based on bleeding scores and other scores that can be used, but try and engage the patient – as I’m sure most people do – in the discussion about the treatment they should have.
Matthew Sibbald: Thank you so much. That’s a nicely nuanced discussion about the complexities that we face with this increasing armamentarium of medical therapy that we have available and trying to contextualize that for patients. You know, I think a similar challenge confronts us with those patients who have chronic heart failure syndromes as well, and our armamentarium is growing. And there were a number of questions related to how we integrate newer medications into those regimes, how we use ARNIs and SGLT2 inhibitors. So I might direct an opening question in this area to Professor Van Spall, the question was about the cost of introducing ARNIs and SGLT2 inhibitors in Canada, in contrast to using beta blockers and mineralocorticoid-receptor antagonists – but I think it’s really internationally relevant, as to how we manage this diverse group of potential medical therapies in patients with chronic heart failure and how we can balance out the pill burden and patient satisfaction with their long-term outcomes.
Harriette Van Spall: I think access and affordability are important, as is drug pricing. And federal efforts to negotiate fair drug pricing will lead us [to] the best, in terms of global pricing of pharmacotherapies, particularly new, non-generic pharmacotherapies. The US does the worst and Canada is somewhere in between. I think that for many healthcare systems that support drug costs through benefits – and Canada is 1 of them, at least for people over the age of 65 – we really need to focus on adopting evidence and we have the luxury of not worrying so much about costs. But in the context of clinical trials, again, with selective populations that show efficacy and are less likely to have adverse effects, these drugs have been shown to be cost-effective. So I think the trepidation of introducing a regimen that is supported by evidence, that is clearly effective at reducing cardiovascular death, heart failure hospitalizations… you know, we ought not to be hesitant and we ought to provide best care to our patients without the traditional approach that used to be commonplace, where we started a class of medication or 2, waited to see how the patients responded, and if they weren’t symptomatic anymore we sort of just stopped with the titration of medications. We have shifted now to a mindset that there is no biological reasoning to adopt such practices, that historically we tested 1 drug on the background of another, but that’s not the way we need to deliver care. We need to think about the biology and there is no evidence to suggest that we ought not to introduce SGLT2 inhibitors and ARNIs and beta blockers, and MRAs concomitantly, in a safe way, over a span of days to weeks,; but there is no reason why we should stay with the age-old practice of beta blockers [and] ACE inhibitors first, see how the patient does, consider an MRA next, see how the patient does, and then consider an SGLT2 inhibitor. There’s been lots of studies over the last several years showing that the prognosis of heart failure with reduced ejection fraction is as severe or worse than malignancies. We would not adopt this wait-and-see approach for managing patients with metastatic disease; we ought not to do it in heart failure. So cost is important – negotiating, advocating for your patients. You know, there are younger patients who quality clinically for a drug, who are not on a work drug plan. And I call our pharma reps and I say, you know, could we have a sample for the next 6 months for this patient? And in the meantime, get social work or other support in place, but the patient then has the benefit of being on a therapy that improves survival after early initiation. So we take on the role of a social worker sometimes, of a negotiator. We consider healthcare system viability [and] sustainability, but we are first and foremost here to serve our patients and to adopt effective regimens for their care.
Matthew Sibbald: Thank you so much.
David Hasdai: I can give you my experience from Israel. We have a national health system and we have a national health basket. And each year new drugs are considered. For example, the ARNIs were approved on a universal basis to patients with left ventricular dysfunction and symptomatic heart failure 3 years ago. Then, after they are approved in the health basket, they are available to every patient at no cost. And a year ago, the SGLT2 inhibitors were also approved in the national health basket. And this makes it easier to prescribe these drugs, because once they are approved by the national health basket, the cost issue becomes a non-issue. But obviously, I think that on top of the economic issue, there is the issue of giving patients 4 or 5 drugs just for heart failure, and then many of these patients also have a chronic coronary syndrome. So they give statins; some of them receive aspirin, and maybe another antithrombotic therapy, and so on; and maybe they are diabetic so they receive other diabetic drugs on top of SGLT2 inhibitors and so on. So I think that would be a major issue on top of the economic issue, that you see a patient [who] comes in with a basket of drugs and he pours it on your desk and says “this is what I take.”
Harriette Van Spall: And that’s why my talk started off with “how do we tackle the global burden of heart failure?” It’s primarily prevention. It’s managing the risk factors before the incidence of heart failure. And it’s also initiating therapies that we know are going to reduce the incidence of heart failure – and SGLT2 inhibitors are among those therapies. It’s also knowing when to apply certain therapies and when to not apply certain therapies. So in the setting of infarction and heart failure, I would not introduce ARNIs. Now we have a hot line session at ACC where data are going to be presented, but the company released the statement that ARNIs are not effective at reducing cardiovascular endpoints in the setting of acute MI. So I would offer those patients ACE inhibitors. In patients with heart failure who have diabetes, it’s very easy to initiate SGLT2 inhibitors. I would also say that we need to consider the cardiovascular outcome trials that showed that in diabetics with coronary artery disease and diabetics with 3 coronary risk factors – even without established coronary disease – SGLT2 inhibitors decrease the incidence of heart failure. So you know, upfront initiation of therapy, recognizing hypertensive heart disease for the epidemic that it is, and managing hypertension early – so that you are not setting the patient up for a lifetime of chronic cardiovascular complications – managing atrial fibrillation, obesity, and diabetes – preventing heart failure is really where it’s at. Once a patient has heart failure… half of all of the cases have heart failure with preserved ejection fraction, for which there has been no treatment to reduce mortality. Half of them [have] reduced ejection fraction and we now have the 4 pillars: ARNIs, MRAs, beta blockers, [and] SGLT2 inhibitors. I initiate them within a span of days. I start with beta blockers first, except [for] patients [who] are acutely decompensated. In patients who are hypertensive, you can start an ARNI and consider an SGLT2 inhibitor or an MRA. In a patient who has chronic kidney disease, consider early use of SGLT2 inhibitors, MRAs, because we know those reduce renal endpoints. So think like a nephrologist as well as a cardiologist. A patient who has hyperkalemia, you know, start the SGLT2 because we know MRAs are better tolerated in patients with SGLT2 inhibitors. Patients who are hospitalized don’t need to be initiated on ACE inhibitors first. We now know from PIONEER that it’s safe to initiate ARNIs in the hospitalized setting. So initiate your 4 classes at low doses, keeping in mind what the background comorbidities are, and then slowly up-titrate them. So you have them on the right class, hospitalization is a great opportunity to get the right classes on board. And then up-titrate them as out-patients. And always keep the basics, you know, the risk factor modification, the lifestyle, [and] the nutrition aspects at the forefront, because disease can be a death sentence or it could be an opportunity to transform your life and get [into] a better health state. And I have tried to motivate patients [by] saying “you know, this was a horrible event. I know it was a terrible shock, but let’s work together so that this event transforms you to a better health state than you ever were before. And let’s work on it together.” I think with frequent contact, frequent initiation of these conversations about smoking cessation, weight maintenance, [or] nutrition, patients are quite willing to work with you. Not everyone is successful at addressing those issues, but I think they go hand in glove with the medical therapy that we offer. Half of all re-admissions following hospitalization are not for heart failure. So you still have to keep all of the other comorbidities in mind, you know. Vaccinate your patients so that they are not coming in with the pneumonia or COVID-19. Manage their kidney disease. You know, renal dysfunction is a common cause for re-admission. Ensure that you are not over-diuresing them at the expense of up-titrating the evidence-informed drug classes we talked about. Manage the COPD. Refer them to a respiratory specialist so that they get best care for their lung disease, which often accompanies heart disease. So it’s sort of stepping back from being a cardiologist for some of us and being holistic in your approach. And that approach should include access, social support, empowering the patient through digital health initiatives and other self-care apps, engaging their family members, you know, next of kin – who often is relied on for disease management – and referring them to services that can improve their outcomes. And this includes multidisciplinary clinics for heart failure care [or for] select patients, nurse home visits. So it’s a comprehensive approach that’s required to really get patients to their best health, not just applying pharmacotherapy, but thinking broadly. I am excited about this topic. Can you tell?
David Hasdai: I just have one comment. Some of these drugs can be a two-edged sword, for example MRAs. If you have a patient that is not going to monitor the calcium levels, you may cause more damage than benefit. And the same pertains to ARNIs. So sometimes I do avoid giving new drugs which are very effective to patients who I know will not monitor that properly. Maybe it will take months until they do a chemistry test or whatever. And that’s one of the reasons I would not give these drugs. So I do think, going back to our prior topic, I would try to avoid causing damage. And I would pick out the patient that will benefit from these drugs and avoid giving these drugs to a patient who might not use these drugs in the appropriate manner.
Harriette Van Spall: I would say that’s prudent, but I think we need to give patients the benefit of the doubt and actually engage in services that reach the patient where they are. So you know, if they are not coming in for lab testing – why is [that]? Is it a person who is in charge of somebody else’s care? Or a person who is getting paid hourly, who can’t make lab hours? In that case, what about community lab services that can go to the patients’ home? You know, what about the use of digital care to make sure that you contact the patient who can’t come in physically to see you in your clinic? And I think, particularly in this era, there are so many ways to be creative in reaching patients at the frequency that they need to receive best therapy and also safe monitoring. And I think, you know, we need to step up our game a little bit [and] change the way we deliver care so that more patients rather than fewer can access that care.
David Hasdai: Sure. Good point.
Matthew Sibbald: One group of patients that there is a question around and maybe we could comment on is those whose ejection fraction is not yet 40% but somewhere between that 40% and 25% range. Is there a nuanced approach to that group?
Harriette Van Spall: Excellent question. The guideline-recommended thresholds are based on historic recruitment practices for clinical trials. So 35 used to be used as a threshold, and then 40 was used as a threshold. From a pathophysiologic point of view, we know that the renin-angiotensin-aldosterone system is a big culprit, and the sympathetic nervous system, in the re-modelling occurs up until about an EF of 50, maybe a little bit higher in women, so there are sex differences layered on top of what I’m talking about. LVEF is a continuum. It’s not clearly demarcated biologically the way we have recruited patients in trials. And we have ample evidence now that those who have benefited from this class of agents, with an EF less than 40%, that benefit extends beyond – to at least 45%, if not a little bit higher, for women in particular. So I actually offer patients in a low or mid-range EF these therapies. If you see LV dilatation, that makes it easier to offer them these therapies because we know that this eccentric re-modelling depends on this underlying pathophysiology that we see across the EF range up until your preserved EF. And there is increasing evidence that RAAS inhibition is effective, in females in particular, [up] to EFs of about 55%. So the 4 classes I talked about… you know, we don’t have clinical trial data, but based on what we see through multiple trials that include the preserved EF population, there are some benefits seen in that mid-range EF, Matt, and then a higher range potentially for RAAS inhibitors and the setting of HFpEF. So the RAAS inhibitors in HFpEF have reduced heart failure hospitalizations – not death in general, but there might be a benefit higher, into the 55 to 60 range, in females. And we now know virtually from the ACE, ARNI, ARB, and MRA trials that there is a sex–EF interaction. And it may be because of the cavity size of women. It may be that their normal EF range differs from men, but you could be a little bit generous with your female patients. Does that answer your question, Matt? We also know, I mean, I’ve led machine learning, AI studies in our clinical trial data sets to show that… you know, phenotypes are more predictive of outcomes than EF ranges, for example. So EF is important because it helps guide therapy. But there are also clinical phenotypes that are more responsive to certain therapies and that have greater prognostic value than EF alone. So, unfortunately, we’re in the situation where we need to generalize data a little bit outside of the clinical trial population. And we do it when possible.
Matthew Sibbald: Thanks so much. Conscious of time, I’m going to turn to 2 questions from the Q&A function of Zoom. And perhaps we will end with these. The first is really about a patient with a cardiac bypass many years ago [who is] on anticoagulation due to atrial fibrillation, and has been cardioverted but now on sinus. And he’s not able to tolerate all those anticoagulants. So the question was really about what the optimal regime would be. And we’re not given more information on why they cannot tolerate all those anticoagulants, but the query really is, Would aspirin alone suffice? I’m interested in the panelists’ ideas here.
David Hasdai: Well, you know, today we have different risk scores, and I think that in Europe and in the States now, the CHA2DS2–VASc score is the premiere risk score. If a patient has a high-risk CHA2DS2–VASc score and atrial fibrillation, even remote atrial fibrillation, we have no idea if the patient has maybe a short event or asymptomatic events in the interim also. So we do assume that the patient does have afib[rillation] here and there. And that’s the reason I would try to strive to give an NOAC. There are certain patients that cannot tolerate NOACs or warfarin because they have hemorrhagic complications, and there are certain devices that can be implanted in a percutaneous intervention, in which the left atrial appendage is occluded, and that might be a solution for these very niche patients who cannot receive an NOAC or warfarin.
Matthew Sibbald: Thank you very much. And then perhaps the last question, which returns us full circle back to the physical exam. It was really around seeing a need to re-structure the cardiac physical exam, especially around palpation and auscultation, to focus only on specific features with demonstrated utility. Prof. Elder?
Andrew Elder: Thanks. It looks like we’ve got about 15 second left, so I will be quick, but the short answer to the question is yes. I think an evidence-based physical examination curriculum would certainly be useful and that could be, as I point out in my talk, most helpfully structured around Steve McGee’s excellent book, Evidence-Based Physical [Diagnosis], Simel and Rennie’s book, The Rational Clinical Exam. And these 2 put together all the evidence that there is for the physical exam. And I would also suggest in a lesser league, our own large survey of doctors around the world, about 4000 doctors, asking them what they find useful in the physical exam, OK? And they find things like taking the radial pulse helpful, but they don’t find trying to work out the character of the GVP very helpful at all. So some of the things that we teach, we shouldn’t really be teaching and we should make it much more evidence-based.
Matthew Sibbald: Well, on that note, a big hand of applause for all of our panelists. It’s been truly a pleasure having this discussion with you and going through this question and answer period. I’m so appreciative of all the wisdom that you’ve shared and I have learned lots. I hope all those on the call felt that they are coming away with little nuggets of clinical wisdom that they can apply to their practice. And I hope to see you at the rest of the MIRCIM events.
Harriette Van Spall: Thank you, Matt. Thank you all. It was a pleasure meeting you.
David Hasdai: Thank you.
Andrew Elder: Thank you very much.
Harriette Van Spall: Bye.
