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Brian: Hello, and welcome to this episode of our podcast, and today we're going to be talking about pulmonary hypertension and some pearls of wisdom for primary care physicians and providers. My name is Brian Fortenberry, and joining me today to help discuss this and give us some insight and information is Dr. Elise Schriver. Welcome, Dr. Schriver.


Dr. Schriver: Thank you for having me.


Brian: Well, absolutely. Before we get into this and start discussing about these pulmonary hypertension issues, tell us a little bit about yourself and about your experience.


Dr. Schriver: Well, I'm Associate Clinical Professor at the Graduate School of Medicine at the University of Tennessee in Knoxville, and I'm the Director of the UT Pulmonary Hypertension Clinic in Knoxville.


Brian: So, Dr. Schriver, in today's world, whether it's on television, social media, the radio, people are very familiar with the term pulmonary hypertension. It's become part of the vernacular that maybe it didn't used to be, just because of exposure. So, you have a lot of people more concerned now if they have pulmonary hypertension, and you have radiologists and echocardiograms and all of these types of things. How do you know as a patient or even maybe as a primary care physician that's not dealing in this all the time, how do you know if you're being diagnosed with that? What parameters have to be met?


Dr. Schriver: Yes. So the term in the diagnosis, pulmonary hypertension, is used much more than it used to be, and even the Pulmonary Hypertension Association has launched an awareness campaign, so it's out there, and some patients with symptoms are asking if they have the disease, plus radiologists have become much more aware, and they're now routinely reporting on CAT scans. If the pulmonary artery is enlarged, they're calling it consistent with pulmonary arterial hypertension, and the cardiologists have always been good, but I think more so are reading pulmonary hypertension from echocardiograms, so it is a differential diagnosis that is reaching the primary care provider much more frequently. So, I would say that the correct diagnosis of Group 1 pulmonary arterial hypertension is crucial to improve patient outcomes.


Unfortunately, patients frequently present with very nonspecific symptoms, such as exertional shortness of breath or poor exercise tolerance or even chest pain or syncope, and these symptoms are very specific, and they're much more likely to be due to common heart or lung diseases, such as coronary artery disease, systolic or diastolic congestive heart failure, valvular heart disease, lung diseases, including COPD or asthma, or, commonly, obesity or just deconditioning. But it is very important to keep in mind that finding the needle in the haystack; that is, the rare patient who truly has Group 1 pulmonary arterial hypertension will improve outcomes, and even in the real patient, there is still frequently we think about a two-year delay in diagnosing these patients accurately, so we want to be able to differentiate the real deal from pulmonary hypertension that is a part of congestive heart failure or a part of lung disease.


Brian: So, is there more than one type of pulmonary hypertension?


Dr. Schriver: Yes, there is. I'll get a few definitions out of the way. Pulmonary hypertension is defined as a mean pulmonary artery pressure of greater than or equal to 25 mmHg. Group 1 pulmonary arterial hypertension, which is the disease that we're really trying to get at, is further defined as precapillary pulmonary hypertension, that is, pulmonary hypertension not due to elevated left heart filling pressure, which we can measure by a pulmonary capillary wedge pressure at right heart cath of less than or equal to 15 and evidence of elevated pulmonary vascular resistance, that is, pulmonary vascular resistance greater than three wedge units, and this is in the absence of significant lung disease or hypoxemia and the absence of chronic thromboembolic pulmonary hypertension or other rare diseases. So, to further clarify, there are now five clinical classes of pulmonary hypertension, and it's a lot, but I'd like to run through these.


So, Group 1 pulmonary arterial hypertension includes idiopathic, heritable, drug-and toxin-induced, or is associated with underlying conditions, such as connective tissue disease, HIV, portal hypertension, congenital heart disease, or schistosomiasis. Some of the drugs and toxins that are known to induce pulmonary arterial hypertension include older diet drugs no longer available, but your patient may have taken in the past, such as fen-phen, Benfluorex, previously used in Europe. Selective serotonin reuptake inhibitors when taken during pregnancy predisposed to pulmonary hypertension of the newborn. Other less-proven, but likely drugs include amphetamines, dasatinib, methamphetamines, or possible causes include cocaine, St. John's wort, amphetamine drugs like Ritalin. So those are all drugs associated with Group 1 pulmonary arterial hypertension.


Group 2 pulmonary hypertension is pulmonary hypertension due to left heart disease, which include systolic, diastolic, and valvular heart disease, and that's diagnosed at right heart cath by elevated left heart filling pressures that is greater than or equal to a wedge of 15. 


Group 3 pulmonary hypertension is pulmonary hypertension due to lung disease or hypoxemia, and this includes sleep disordered breathing with nocturnal hypoxemia. 


Group 4 is chronic thromboembolic pulmonary hypertension, and, by definition, this is pulmonary hypertension that persists after three months of anticoagulation for pulmonary embolism. 


Group 5 is pulmonary hypertension of unclear or multifactorial mechanisms, including hematologic disorders, splenectomy, systemic disorders, such as sarcoidosis or odd, rare conditions, such as fibrosing mediastinitis or even chronic renal failure with or without dialysis.  So there are many types of pulmonary hypertension, but only Group 1 is referred to as pulmonary arterial hypertension.


Brian: Okay. So, we talked about those five different types. Do treatment guidelines apply to all types of pulmonary hypertension?


Dr. Schriver: Medications specifically directed at treating pulmonary arterial hypertension are referred to as advanced pulmonary arterial hypertension treatment, and these are only indicated for Group 1 pulmonary arterial hypertension. This is the condition where scientific studies prove their usefulness, and these medicines are only approved by the FDA for Group 1 pulmonary arterial hypertension. In addition, in Group 4 pulmonary hypertension, that is, chronic thromboembolic hypertension, the recommendation is surgery, pulmonary thromboendarterectomy, but for patients who have an inadequate response to the surgery or are not surgical candidates, then riociguat is a medication approved by the FDA to treat Group 4 pulmonary hypertension.


Brian: Okay. How should a primary care physician or provider go about evaluating patients that have maybe this exercise intolerance for possible Group 1 pulmonary arterial hypertension?


Dr. Schriver: We should be aware of risk factors that increase the pretest probability of pulmonary arterial hypertension, including a positive family history of pulmonary hypertension, autoimmune disease, especially systemic sclerosis spectrum diseases, including mixed connective tissue disease, HIV, congenital heart disease, and portal hypertension. On physical exam, we can find a fixed split s2 or tricuspid regurgitation murmur or findings of autoimmune disease, including scleroderma and facial telangiectasias, but the physical exam is often unrevealing until right heart failure develops, and we would like to diagnose the condition before that time. Testing for common heart and lung diseases should also include EKG, echocardiogram, possible cardiac stress test, chest x-ray, chest CT, and pulmonary function studies.


Brian: So, Dr. Schriver, what types of test results might suggest the diagnosis of a pulmonary hypertension?


Dr. Schriver: Well, on a plain chest x-ray, we can often see an enlarged main pulmonary artery or on a lateral view see an enlarged right ventricle. On a chest CT, the radiologist will often report dilation of the main pulmonary artery greater than 29 mm or enlargement of right heart structures. On the echocardiogram, an estimated right ventricular systolic pressure can be calculated from the velocity of the tricuspid regurgitant jet. In addition, dilation of right heart or inferior vena cava suggest pulmonary hypertension but not necessarily Group 1 pulmonary arterial hypertension.


Brian: Okay. So, I've heard of pulmonary hypertension centers. Do all the patients that have suspected pulmonary hypertension need to be referred to a pulmonary hypertension center or not?


Dr. Schriver: Well, the most recent comprehensive guidelines, which are the 2015 European Society of Cardiology/European Respiratory Society Guidelines on the diagnosis and treatment of pulmonary hypertension in patients with a clinical suspicion of hypertension, recommends consideration of lung disease, including nocturnal hypoxemia and consideration of left heart disease, and these patients, again, should be evaluated for signs, symptoms, risk factors, and testing, as discussed above. If the diagnosis of underlying lung or left heart disease is confirmed, and there are no signs of severe pulmonary hypertension or severe right heart dysfunction, then the recommendation is to treat the underlying disorder. That is, the treatment of Group 2 pulmonary hypertension is the treatment of the underlying heart disease. The treatment of Group 3 pulmonary hypertension is the treatment of the underlying lung disease, or hypoxemia. In those patients, they don't need further evaluation of pulmonary hypertension, which is probably due to their underlying heart and lung disease and does not require advanced pulmonary arterial hypertension treatment.


However, if the patient does have lung disease or left heart disease and they have signs of severe pulmonary hypertension or right ventricular dysfunction, then referral to an expert pulmonary hypertension center is recommended, and if no underlying heart disease or lung disease explained the pulmonary hypertension, then recommendation to a pulmonary hypertension center would be recommended.


Brian: So if they go to this pulmonary hypertension center, what further testing is typically done there?


Dr. Schriver: Noninvasive testing, such as an echocardiogram, can arrive at the diagnosis of suspected pulmonary hypertension, but a right heart cath is needed to confirm the diagnosis of pulmonary hypertension, so at a pulmonary hypertension center, we would perform a detailed right heart cath to try to confirm the diagnosis of pulmonary arterial hypertension, and, again, the three factors we're looking for would be the presence of pulmonary hypertension that is a mean pulmonary arterial pressure of 25 or greater plus a pulmonary capillary wedge pressure of less than or equal to 15 plus an elevated pulmonary vascular resistance greater than 3 wedge units.


Brian: I gotcha. You referred there to this right heart catheterization. Should they do a right heart catheterization prior to going to the pulmonary hypertension center to confirm the diagnosis?


Dr. Schriver: Well, current guidelines recommend right heart cath testing to evaluate for pulmonary arterial hypertension to be limited to expert pulmonary hypertension centers in order to improve the safety and the information gained from this testing. At pulmonary hypertension centers, detailed testing at right heart cath may be done, including detailed oxygen saturation testing to exclude a left-to-right shunt, pulmonary vasodilator testing in patients who may be candidates for calcium channel blocker treatment, and maneuvers to unmask diastolic dysfunction in patients with high pretest probability for this disease causing the pulmonary hypertension.


If we're suspicious that the patient really has Group 2 pulmonary hypertension due to diastolic dysfunction, which is the most common mimic of Group 1 pulmonary arterial hypertension, then at the time of the right heart cath, we can give the patient a volume challenge, such as an infusion of 500 cc saline over 10 minutes and then repeat our numbers to see if their pulmonary artery pressures go up or even exercise the patient to see if the pulmonary artery pressures and their left heart filling pressures go up, so that is definitely better done in a center with experience in sorting out the fine details of whether the patient really has this disease.


Brian: Right. So, that's something you're definitely going to get in pulmonary hypertension center that you really wouldn't get outside of there without that expertise. So, if the patient is confirmed to have this Group 1 pulmonary arterial hypertension after they've gone through the right heart catheterization, what treatment is recommended? What can you do at this point?


Dr. Schriver: Well, this is becoming very much increasingly complex. There are three treatment pathways with now an increasing plethora of medications. The three treatment pathways are endothelin receptor antagonist, the nitric oxide pathway, and prostacyclin analogs, and I'd like to mention those drugs, just because there're so many of them out there now that primary care providers may see their patients conceivably on. The endothelin receptor antagonists are all oral medications, and these include: ambrisentan branded as Letairis, bosentan branded as Tracleer, macitentan branded as Opsumit. The nitric oxide pathway includes also all oral medicines, the phosphodiesterase 5 inhibitors: sildenafil marketed as Revatio, tadalafil marketed as Adcirca, the guanylate cyclase stimulator riociguat marketed as Adempus; and the prostacyclin analogs, the oldest medicine is epoprostenol given as a continuous intravenous infusion indefinitely, Flolan or the newer version Veletri. Iloprost can be given by inhalation marketed as Ventavis, and treprostinil when given orally is branded as Orenitram, inhaled branded as Tyvaso, and subcutaneously or intravenously branded as Remodulin. The oral prostacyclin receptor agonist selexipag is marketed as Uptravi. Calcium channel blockers are reserved for only a select class of patients that have a positive acute vasodilator testing response at right heart cath.


To complicate matters further, the guidelines now include guidelines for monotherapy, sequential combination therapy, or upfront combination therapy. So the treatment has to be very much individualized, depending on how severe the disease is and many specific factors related to each patient.


Brian: It sounds like there are a ton of different types of medications and treatment options like that, so given that information, how are patients on treatment for pulmonary arterial hypertension, how are they followed, and how complicated is that?


Dr. Schriver: Well, there's a growing consensus among pulmonary hypertension physicians that more aggressive treatment, often with a combination of medicines from several different therapeutic categories, attempting to get the patient into a low-risk category, may improve the long term survival. So, in clinical follow up, we like to follow a number of different tests, and typically we like to see the patient back in the office with no signs of right heart failure, that is, no jugular venous distention, edema, anasarca, no progression of symptoms. We like to have their symptoms under control. We would call that Functional Class 1 or 2 which means symptoms only with an ordinary amount of exercise, such as their daily activities but still able to perform those activities.


We do a simple exercise test in the office called a six-minute walk distance. We'd like to see a good distance on those. Further detailed exercise testing can be done, and there are some parameters that are considered acceptable. The pro-brain natriuretic peptide, or just the plain brain natriuretic peptide, we like to have well within normal limits, and on echocardiogram, we'd like to see a normal right atrial area and absence of pericardial effusion. If we can have all of those parameters at a low-risk category, then we feel that the risk of the patient dying within a one-year period can be less than five percent, and that's the goal in office follow up for these patients.


Brian: So, the advanced pulmonary arterial hypertension treatments, do they improve mortality?


Dr. Schriver: It appears that they do. In the pretreatment area, the mean pulmonary arterial hypertension survival was about two point eight years. Now with the revealed registry which is following patients in the current treatment era, the five-year survival is 65%, and that's for all types of medicine started within six months of a diagnosis, so we think that our current treatment is progressively improving survival, which is why it's so important to diagnose these patients properly, but then the medicines are expensive, complex, and have side-effects, and you don't want to treat your patient if they're not a true Group 1 pulmonary arterial hypertension.


Brian: That makes sense. Well, for our listeners out there that might want different resources, might want more detailed information regarding this, where can they go, and what resources would you suggest they go to to learn more about this.


Dr. Schriver: The 2015 European Society of Cardiology/European Respiratory Society Guidelines for the Diagnosis and Treatment of Pulmonary Hypertension is an excellent summary, and that's available online if you just Google it. Also, the Pulmonary Hypertension Association will allow professionals to sign up for a free journal, Advances in Pulmonary Hypertension, and they can either get this online, or if they register, they will be mailed a free hard copy which comes out, I believe, quarterly.


Brian: Okay. I tell you what, there's a lot of information there, a lot going on, and pulmonary hypertension in general and, like you were saying, Group 1 arterial hypertension, that’s probably something that physicians are seeing more and more of these days, wouldn't you agree?


Dr. Schriver: I think so, and especially it's being reported more on echocardiograms, and it's being reported more by radiologists on CAT scanning, so it's important for the primary care provider to have some idea of which patients need further testing and which ones need to be referred on and which ones can be comfortably treated if the pulmonary hypertension is felt due to their underlying heart and lung disease. By far, congestive heart failure is the most common cause of pulmonary hypertension, and pulmonary hypertension due to congestive heart failure should be treated as congestive heart failure.


Brian: Well, I tell you, you have given us some incredible information and some places to go to get more detailed information. Dr. Schriver, I can't tell you how much I appreciate your being here today to discuss this with us. Thank you.


Dr. Schriver: Enjoyed it. Thank you so much.


Speaker 1: Thank you for listening to this episode of Your Practice Made Perfect with your host Brian Fortenberry. Listen to more episodes, subscribe to the podcast and find show notes at SVMIC.com/podcast. The contents of this podcast are intended for information purposes only and do not constitute legal advice. Policyholders are urged to consult with their personal attorney for legal advice, as specific legal requirements may vary from state to state and change over time.