In this episode, PHA Canada Board Director, Sanjay Mehta, MD discusses the recently updated 2022 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension, the gaps in understanding and the reasons why.
Hi everyone. I'm Dr. Sanjay Mehta. I'm a respirologist, or pulmonologist for some of you in the US, and I have an interest in pulmonary hypertension. I've had the great honor and fortune of looking after PH patients now for 30 years of my career, largely here in London, Ontario, in Canada, but initially started my training in work and research in Montreal at McGill University.
Besides looking after patients, I'm very much involved in the community, had the great honor and privilege of working with six special individuals, patients, and families in 2008 when we founded PHA Canada, and just this year celebrated our 15th anniversary. I had the great honor of chairing the organization for five years, and I was recognized as an eternal friend of PHA Canada.
Our task today is to talk about something very exciting in the PH community, and that's the new International Clinical Practice Guidelines for Pulmonary Hypertension, published in 2022 by a combined organization, the European Society of Cardiology and the European Respiratory Society. So what is a clinical practice guideline and why is that important to patients, caregivers, and the PH community?
You can imagine the wealth of research in medicine is unbelievable and fantastic, but no physician can keep up with all the literature that's being produced in terms of excellent quality studies on how best to diagnose and treat people with lung disease, pulmonary hypertension, heart disease, cancer. This is why for probably more than 25, 30 years now, the clinical practice guidelines have become so well valued and so widely used. What it is is a group of experts who work in an area, like pulmonary hypertension, get together, sit around a table or a Zoom call, and they review the literature in the last X years, two years, five years, and say, "Okay, what are we doing right now and what do we need to change in terms of how we look after patients?"
So we're excited because just last year, 2022, we had a brand new set of clinical practice guidelines come out from the combined European Society of Cardiology and the European Respiratory Society. So two large societies, cardiologists and lung specialists, respirologists or pulmonologists, all of whom deal with pulmonary hypertension. What they want to do is capture today, in a massive document of 150 pages, what's the best way that patients with pulmonary hypertension should be assessed, should be diagnosed and should be treated?
It's very important to recognize these guidelines tell us what's the standard that we all should try to follow, not for every patient, but most patients. That's because patients are unique. You might not fill into the boxes that the guidelines tell me that patients fall into, so I'm going to adjust the guidelines a little bit based on getting to know you as a patient. Obviously, your preferences, your values and wishes, but also the nature of your pulmonary hypertension. So that's why we need guidelines and why we're very excited to have the 2022 guidelines. I should mention, this is an update from the previous ones in 2015. So seven years is a long time in the pulmonary hypertension world. A lot has changed, and that's what these guidelines are focused on.
Let's talk about a couple of the key changes to the guidelines. First and foremost, diagnosis. When we're trying to diagnose pulmonary hypertension, we depend on you to tell us your symptoms, you're short of breath, you're tired, you might have swelling of your feet and ankles, you might even have more worrisome symptoms - chest pain or lightheadedness or passing out on activity. All those things make us think about pulmonary hypertension. Then, we want to do some testing. It's very clear for many years that the first test of choice when you're thinking pulmonary hypertension as a physician or as a healthcare provider is an echocardiogram, or in brief, an ultrasound of your heart. This is one of the best ways to look at the heart and say is it working normally or not? Is there perhaps clues to pulmonary hypertension? And if there are, why might you have pulmonary hypertension?
So for example, it not only picks up pulmonary hypertension, it picks up why you might have it, such as a bad heart condition, like somebody that's had heart attacks in the past and now has heart failure. Or if you have an issue with one of your valves, that can cause pulmonary hypertension. Or perhaps if you're born with a congenital defect in your heart, that can of course also cause pulmonary hypertension. If you have none of those underlying heart conditions, then I'd look to see if you have pulmonary hypertension, how bad is it? There's several features to that, and the newest guidelines have helped us to be even more clear about how we use the echo to assess a patient who might have pulmonary hypertension. There is no definitive answer yes or no. What the echo can tell me, and your provider, is your probability of pulmonary hypertension. Is it low, is it intermediate, or is it high?
If you come in with symptoms, you're short of breath, you have some swelling, maybe other symptoms, you might have pulmonary hypertension, but many other conditions also give you the same symptoms. Lung disease like asthma can give you those symptoms. Of course, heart disease like heart failure can give you those symptoms. So the echo might say, "You know what? There's no pulmonary hypertension. The right side of the heart, which gets affected in pulmonary hypertension, is perfectly normal." So if all of those findings are not there, then I say, "You know what? You have a low probability for pulmonary hypertension." We can essentially stop there and not worry too much about pulmonary hypertension.
In certain patients, let's say you have scleroderma with a high risk of pulmonary hypertension, I might want to think about in six months, in a year, maybe repeating an echo just to make sure it hasn't developed because you're at high risk. That's important for certain categories of patients like scleroderma, like somebody that might have a family history of pulmonary hypertension.
But for the vast majority of patients without any particular risk for PH, if your echo says you have low probability, we can stop there. It doesn't mean we stop looking after you. We have to figure out why you might be short of breath. Is there lung disease, heart disease? Do you maybe need to get more regular with exercise? Or do you need to work on weight to improve your breathing? Often, many patients come to us with those symptoms, the echo is not normal. So you do have some risk of pulmonary hypertension. That risk depends on a couple of things. What the actual pressure that's measured is on the right side of the heart. If it's very high, that's very suspicious for high risk of pulmonary hypertension, and we of course have to go forward and figure out why you have high pressures in the lungs and the right side of the heart.
If the pressure is not so easily measured or it's not that high, but the right side of your heart is not normal, if the right side of the heart is enlarged, or if it's working poorly, or if there's a valve that's leaking, the tricuspid valve, all of those are called secondary signs of pulmonary hypertension. You may have pulmonary hypertension. So those are also suspicious that you are at risk for pulmonary hypertension, either intermediate or high. So in simple terms, if it's low risk on the echo or low probability, let's stop there, not think about PH too much. If there's other abnormalities that make you either intermediate or high probability, we're going to go forward and figure out if you have PH, and then if you do have PH, why you have it and how best to treat you.
In terms of treatment, it's very clear we have excellent therapies for pulmonary hypertension for most patients. It's interesting that we don't actually change a lot more in terms of your background illnesses. For example, if you have scleroderma, it's important that you have a rheumatologist look after that, but that doesn't change so much what I do for your pulmonary hypertension. But there is a category of pulmonary hypertension where it's really important that we look after the underlying disease, and that's a disease that's being recognized more and more, patients developing pulmonary hypertension because of what's called the drugs of abuse, for example, methamphetamines. But this also happens with cocaine and other drugs of abuse. It is highly recognized that if you get pulmonary hypertension from those drugs, that I can treat you with the pulmonary hypertension medications I have available for anybody with pulmonary hypertension. At the same time, if you continue the drug of abuse, you're not going to do as well. You're going to remain unwell in terms of symptoms, in terms of heart failure, and your prognosis is not as good. There's a higher chance you're not going to survive.
So there's good data and the guidelines recognize this and now strongly emphasize if you have pulmonary hypertension related, for example, to amphetamines, you really need to do everything you can to work on that addiction, to try to kick the addiction with all the resources around. Because if you can do that, it's an incredible advance in terms of your own quality of life, symptoms, heart failure, and your prognosis. So it's really important that those underlying conditions are being addressed, be they drug abuse, be they lung disease. Some people come to us with lung disease and they have significant PH. If you have sleep apnea, that needs to be treated.
If you have low oxygen levels, either when you're sleeping or when you're exerting yourself, that needs to be figured out and probably treated with oxygen to allow you to stay well. So all these other conditions are important, and the general term we use is comorbidities. Morbidity means illness. It means patients are complex. They don't just have pulmonary hypertension, they often have other conditions, lung, heart, liver, scleroderma, and it's really important that we provide complex care and thorough care to help patients deal with all of their conditions.
Let's talk a little more about how to assess individual patients. When you come to me, besides understanding you as a patient and your illness, I need to really think about one important thing, which is if you have pulmonary hypertension and I'm going to treat you, how aggressive am I going to be? We are lucky that we have multiple medications. I work in Canada where we have 10 different medications targeted at pulmonary hypertension. My colleagues in the US have 13 different medications, and various territories around the world generally have access to some medications, maybe not as many, but most territories and most patients have access to some PH targeted medications.
So how do we decide? Do I give you one, two, or three? The challenge is, again, looking at you as an individual and saying, "Okay, what's the chance that you're going to do poorly over the next year and longer?" That's an assessment of your own risk. What's your risk of getting worse? And of course, at the extreme of not surviving? If I believe based on you, the assessment of your symptoms, your echo, the catheterization, that you're at low risk for getting worse the next year and dying in the next year, I can be less aggressive. I don't need to give you three medications, because of course there's more cost and more side effects.
Conversely, if you're high risk, and that typically to me means you have more than a one in five chance of not surviving the next year, I need to be as aggressive as I can. Typically that means three medications, one of which really should be an infusion therapy with prostacyclin analogs, either intravenous or subcutaneous, under the skin, continuously 24 hours a day. That's the most aggressive treatment we have right now. Three medications including infusions, and if you're high risk, you absolutely should be on that treatment. If we agree, the patient and us, that that's their goals, that they're able to look after all these medications, especially the complex infusions, and of course that they can tolerate the side effects that they might suffer from these medications.
In between low and high there's an intermediate category, and that's important because it means you're at some risk, but not high, but not as good as low. So most people believe that we should be fairly aggressive in the patients with intermediate risk of doing poorly in the next year, and that means typically at least two medications, usually pills, which is advantageous and more convenient. Sometimes a third medication, especially after the first couple of months if you're not doing as well as we would like, both you the patient and us, the providers, and then very much considering whether you need to go on to infusion therapies as well. It is important. More aggressive treatment is clearly more effective in pulmonary hypertension. Two drugs are generally almost always better than one, and three drugs are often better than two.
Yet some people still do very well on a single oral medication. There is a role for trying a single oral medication in patients with pulmonary hypertension, but typically those that are more complex. So yes, you have pulmonary hypertension, but you also have significant lung disease, either scarring of the lung called fibrosis, or underlying COPD from smoking or perhaps sleep apnea, or you have underlying heart disease, a little bit of heart failure, valve disease, atrial fibrillation. So those patients we define now as pulmonary hypertension with comorbidities. Those other important conditions that affect you from day to day, and that of course affect you in the long term. We recognize that being too aggressive with PH medications in those patients is not always better. You may not respond as well and you may indeed have more side effects. So that's a concern. So in those patients, one medication is reasonable with very close follow-up, reassessing you and your risk of getting worse very much within the first couple of months and then repeatedly thereafter.
If you're doing well on one medication, fantastic. We're happy. We can continue to follow. If you're not doing so well, then it takes a discussion about available therapies, do we try a second one, do we switch perhaps? All of those of course are individual decisions based on you as an individual. But really important, this risk idea at the baseline, when you first get diagnosed, helps us determine what initial therapy we would recommend and what most patients would agree to. That risk idea is really important, not just at baseline when you get diagnosed, but also over time. So every time you get reassessed by your pulmonary hypertension team, your risk of getting worse the next year is reassessed. If you're responding to treatments and now you're low risk, fantastic. It means whatever treatment we agreed to and you're on is doing a good job and we can rest a little bit, monitor you carefully, but let you be active and then reassess you in three to six months.
If you're not that good, if you're still intermediate risk, or worse, if you're in high risk, then I'm worried that you haven't responded well enough to the first treatments. We really need to be more aggressive. It should be recognized that most patients don't get to low risk. In fact, most patients stay intermediate. About 70% of all treated patients stay at intermediate risk, so that's not great. We also realized that it was such a big group of patients, it was hard to define in that group whether some were okay and some were not. So the most recent guidelines have for the first time said it's not robust enough or clear enough to just have low, intermediate, and high risk. Let's split the intermediate into two, intermediate low and intermediate high.
So now we have four categories of risk. Low risk, still fantastic. Whatever treatment you're on, we're happy. High risk, of course not very good. We want to think about being aggressive, infusion therapy or transplant. Similarly, if you're intermediate high, that's not good. Your chance of getting worse is quite significant, at least 10, perhaps 20% over the next year of not surviving, and we really want to think of you like a high risk patient and be as aggressive as possible with treatment. Conversely, if you're intermediate low, not as good as low but not bad. So there we have to make a judgment call. If we think you want to be more aggressive and we think we can be more aggressive with treatment, then fantastic. We have options available. If you on the other hand are comfortable, you feel better, and you're worried about the side effects of adding a third medication, then we can allow you to continue on, monitor you very closely, and see if you stay intermediate low, things aren't too bad, definitely don't want you to get to intermediate high, which might happen.
So this framework is a little more robust, a little more discerning of how patients are doing between low to high risk and really help us fine tune the medications that we have available to help you. It is important that the risk is not complicated to figure out. It depends on our assessment of you essentially at the bedside in the clinic. How are you feeling? Are you short of breath when you do your everyday activities? Can you walk up a flight as stairs comfortably? If you can do your everyday activities quite comfortably, then I'm not so worried. That's generally tending to be low or intermediate low risk. If you can't do those activities, then I'm a little more worried. Similarly, I test your capacity on a six minute walk test, and if you can do quite well on the walk test, ideally more than 440 meters, that's an excellent prognosis because you're low risk.
If you're pretty good, over 350 meters, but not perfect, that's still not bad. Clearly as the six minute walk distance falls, especially under 150, under 165, that's concerning. So all these things have very simple gradations, but they're very simple tests to do in the clinic. The final one is a blood test, and many of you might have heard of this blood test called BNP [Brain Natriuretic Peptide], and there's a derivative form called NT-proBNP, which is even better. In simple terms, we all have this floating around our blood, but at low levels because we're not in heart failure. In patients with pulmonary hypertension, if you're in right-sided heart failure, or specifically right ventricular heart failure, the BNP levels in your blood go up. So the guidelines have defined four categories. If you're under 350, low risk, up to 650, intermediate low risk, over 650 I'm worried, and over 1,100, that's really worrisome for high risk, that you're in bad heart failure and may not do well over the next year in terms of prognosis.
So fairly simply in the clinic at the bedside, your symptoms, which we put together as the functional class, WHO or NYHA, your six minute walk distance, and the BNP together, three parameters help me understand your risk from visit to visit and very appropriately adjust treatment based on all the wonderful treatments that we've developed.
Talking about treatment, one of the things I've always believed personally and recommended to all my patients is exercise. There have been recommendations that most patients with pulmonary hypertension should be performing some kind of regular physical activity. Of course, we're cautious. Many of you know that when you push yourself too hard, you get lightheaded, you get dizzy, you may even pass out, and you may get chest tightness or pain. Those are all bad signs. The heart's not happy or the brain's not happy. All of us agree you should never push on exercise to get any of those symptoms. And yet getting short of breath on exercise is not dangerous. It's good for me, I try and do that regularly, and it's good for all of you.
The new guidelines in 2022 absolutely emphasize this. A strong recommendation that all patients with pulmonary hypertension should be assessed for regular exercise therapy, either as part of a rehabilitation program, where it can be monitored, or under the guidance of your pulmonary hypertension team, and then doing the exercise on your own, within those limits of not pushing hard enough to get worrisome symptoms. There's no question that regular exercise can improve your sense of wellbeing, your symptoms, clearly your exercise capacity improves, and there's even a sense that your long-term prognosis can improve. So I think it's really important that exercise rehab is now a strong recommendation.
Other recommendations that have changed, importantly, is one that is now recommended to not generally do in PH patients, and that's treatment with blood thinners or anticoagulants. This has a long history of use in pulmonary hypertension. In fact, 25 years ago it was one of our only treatments for patients with pulmonary hypertension, and there are studies that people, in fact, on blood thinners did better. Prognosis was better, survival was better. The studies were never fantastic, and that was important, the limitation. More recently, some larger studies have been done, both European and American, and have suggested that the benefit of blood thinners is not so marked as it used to be, and largely because we have so many other wonderful therapies. So if you're on PH targeted medications, it's harder to show that another medication like a blood thinner also has a benefit. So guidelines are fairly strong, saying most patients should not be treated with blood thinners. There are a small number of patients that you might want to consider specifically.
For example, if you've had blood clots, then yes, you should be on a blood thinner. Even if you've had surgery, pulmonary endarterectomy for blood clots caught causing pulmonary hypertension known as CTEPH, [chronic thromboembolic PH], then you should be on blood thinners indefinitely and likely lifelong. But the vast majority of patients who have not had blood clots and have PH from other reasons, like scleroderma or idiopathic, without a cause, really should not be on blood thinners, largely because of the risk of bleeding, which is significant over many years.
In terms of other treatments, we've chatted about the fact that most people should be on two medications. Some need to go on to three medications if they're not doing well on two. So the question often arises is if I have 10 medications and there's multiple options largely in three different families of medications, why should patients simply not just be on one medication from each of those three families targeting all the pathways which I can target to make your pulmonary hypertension better?
That's a reasonable question. Should we be really aggressive upfront, give you three medications, and get you the best we can for the long term? So this has long been a discussion point in the pulmonary hypertension world, and an excellent study called the TRITON study in the last few years did assess exactly that, taking patients with newly diagnosed pulmonary hypertension, specifically PAH, pulmonary arterial hypertension, so not clots, not lung disease or heart disease, but idiopathic, heritable, perhaps related connective tissue disease, and saying, "Let's give all of you two medications. And in half of you, let's give you a third medication." I should emphasize, all of those are pills. So either two pills or three different kind of pills every day. And then do you do better if you're on three medications from the beginning?
Well, the study was excellent, and it showed that everybody did very well in that study, either on two or three different pills over the first three to six months. There wasn't a big difference between the two groups until you looked at later, one or two years, where it seemed that maybe patients on three different medications did a little better, possibly. This was not a strong endpoint like the others. So the guidelines looked at this carefully and said, "You know what? It's very clear that two medications in the beginning are very effective." So the vast majority of patients do not need three medications. So we do not recommend starting three. Let's start two in essentially everybody, and then monitor carefully for the first three months, then six months. If you're not doing as well as you would like or as I would like, based again on that risk, then we can easily add a third medication. So very important that right now, most people do not need to start on three medications.
The final thing in the guidelines I think is really important to recognize is what's the recommendation for the care you receive at the PH centers that you go to? It's very clear that PH centers often give the best care because of the expertise of the physicians, the very important collaboration of other healthcare providers, especially PH focused nurses, as well as often pharmacists, physiotherapists, and our colleagues, other physicians that help us, rheumatologists, radiologists, sometimes surgeons. That is the best care for PH, which is very well recognized.
It's also clear that all patients in a PH center probably should participate in some registry, a patient registry. What does that mean, a patient registry? Well essentially it means using a tool to collect your data on you as a person, your age, your sex, the kind of PH, the severity of PH, the treatments you're getting, and how you're doing with your PH over time, and collecting that data together with all the other patients at your center and all the other patients at the other PH centers in the country, in the US, in Canada, and why not globally?
So such PH registries are being set up, are being populated with data from around the world already. So the US has one funded by the Pulmonary Hypertension Association, Canada has one called CPHR, and there's a couple of very large registries in Europe, COMPERA, as well as the French registry. The key is this, it's just a tool. If we have all that data on you and your kind of pulmonary hypertension and how you're doing, we can then use that to do research and say, "How are patients doing? Are they doing well enough? Are they doing better in this country or that country or on these medications or those medications," because maybe perhaps there's a better medication that people aren't using or others are using. So all of those provide important answers to questions that may be not as easy to do in just a simple research study.
So this is an example of what's called real world data or real world evidence. Collecting data on actual patients, actual treatments, and what's happening in practice. That's very important. We have very, very good studies in pulmonary hypertension called randomized controlled trials. I take a bunch of patients, half get treatment A, half get a placebo or treatment B, and that teaches me something. But it's not the same thing as collecting data on thousands or 10,000 or 100,000 patients, which is what patient registries can do to provide even more evidence. So that's a strong recommendation from the guidelines. Relatedly, they also recommend that PH centers should collaborate with their local PHAs or pulmonary hypertension associations. Now hopefully all of you are connected with your local PHA. We have a fantastic PHA Canada, PHA in the US, and there's PHA Europe, PHA UK, as well as many others in the world.
Those organizations are incredibly important because their mission usually, most importantly, is looking after you, the patient, and your caregivers, your family and friends, educating you about pulmonary hypertension, supporting you, advocating for you with government, with media, making sure you have access to medications that can help you if they're not all approved in your local territories or countries. As well, they all have individual purposes. Sometimes it's as simple as connecting patients and caregivers together, in conferences or webinars or zoom sessions, where you can see other patients that are dealing with the same issues you are and you don't feel as isolated, which many patients with PH when they first get diagnosed feel, when they think nobody else that suffers with the same thing because they've never heard about it. That is not true, as you know, when you connect with a PHA, which teaches you that many, many others are affected and want to connect with you and help you deal with your illness.
So the guidelines 2022, not the last version, there's going to be more. But the most recent, the most current, the thorough, and the most exciting for the best guidelines, advice to me as a physician and others around the world on how best to diagnose PH patients, how to follow them, how to assess them, and how to manage them. In the end, all we want is the same thing. We want you to have the best quality of life for as long as you can, and to live as long as you can with the medications and approaches we have to treatment. So very important that you understand that, because guidelines are not written for me, they're written for me to help you, and it's a really neat idea that patients understanding guidelines can improve their care.
If you go to your physician and say, "In my situation, what do the guidelines say that I should be on treatment wise, or what should I be having testing wise," that might challenge your doctors and your PH teams to say, "This is good. I like this collaboration between this patient and family, understanding that the guidelines are important and that there are other avenues to improve their care. So that partnership, you advocating for yourself, critically important, and guidelines can help you do that. It's been a pleasure as always to chat with you all.
I'm Dr. Sanjay Mehta. I have the great honor of being a pulmonary hypertension doctor, and that's because I'm aware that my patients are rare.
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