Kelly Fan, MD, identifies the group three disease of Pulmonary Hyperpertenion (PH), due to chronic lung disease and hypoxia. Dr. Fan discusses the prognosis and why it is a problem in patients with chronic lung disease, describes diagnostic workup, and explains management and the role of PAH medications.
Back to Symposium Page »
our next speaker. We're going to stay on the lungs for a while. This is Kelly fan, one of the pulmonologist from scripts. Uh, he's a fellow alumnus of UCSD, as I am. And so we're going to talk about the complicated issue of patients who have lung disease and develop pulmonary hypertension and how that should be addressed. So, Kelly, thanks for joining us this year. Uh, take it away. Yeah. All right. Thank you. Good morning, everyone. Thanks for joining us in the talk today. I'm going to be talking about pulmonary arterial hypertension and chronic lung disease. Mhm. No disclosures. So by now in the conference, we've discussed groups 12 and four pulmonary hypertension, and I'm going to be talking about group three disease due to chronic on disease and hypoxia. My talk will focus on the COPD and I'll d populations. As data is most robust. And these two groups, the concept that I present today can be extrapolated to the management of patients with other lung diseases, including sarcoidosis, combined pulmonary fibrosis and emphysema, connective tissue related lung disease, and pulmonary longer Hans cell histiocytosis, just to name a few. Traditionally we think of Group three pulmonary hypertension as a second area effect of hypoxic vessel constriction with poor prognosis and very limited treatment options for most patients. This concept is true, however, a subset of chronic lung disease patients may exhibit a pH phenotype. My talk will help us identify this subset of chronic lung disease patients and provide the latest evidence for use of pH medications and Group three pulmonary hypertension. This is outlined My talk. We're going to start by discussing prognosis and why pulmonary hypertension is a problem in patients with chronic lung disease. Next, we will discuss the diagnostic work up with the goal of identifying the patients who may benefit from Ph therapies. And finally we will discuss management and the role of pH medications. So prevalence estimates for pulmonary hypertension and chronic lung disease varies depending on whether echocardiogram or right heart catheterization was a method used to assess for pulmonary hypertension. Data is biased. Force patients with severe disease undergoing workout for lung transplantation and is much more limited in patients with mild disease as echocardiogram is just not routinely performed regardless, all studies agree that patients with chronic lung disease and worsening pulmonary hypertension have increased mortality and exacerbations. The Aspire Registry is a database of about 1400 patients who underwent a comprehensive workout for pulmonary hypertension. About 101 patients were identified with COPD as the cause of pulmonary hypertension. As seen in this graph, COPD patients with the mean P A pressure over 40 have a decreased cumulative survival at five years, compared to patients with only moderately elevated mean pH pressures. Yeah, yeah, the same trend can be seen in I p F patients. This graph is taken from the you knows database. Over 6000 lung transplant candidates with YPF were identified from 2005 to 2013. Almost half of the I P F patients had right heart, Cath confirmed P a pressure of at least 25. We see a three year survival probability difference between patients with mean P, a pressure above 25 those below. In comparison to patients with groups, 1 to 4 or five patients with Group three disease have the worst cumulative survival. This graph is again taken from this fire registry, and we see that the 178 identified Group three patients have a decreased survival compared to the other groups with five year survival well under 40%. Yeah, so the argument can be made well. Of course, Group three pulmonary hypertension patients will have a poor prognosis as advanced COPD. Advanced idiopathic pulmonary fibrosis are very difficult conditions to manage. While this is true that Aspire and Yunos databases show that there's actually not a perfect correlation between the severity of the COPD or I p f and the severity of the patients pulmonary hypertension. So looking at this table from the Aspire Registry, we see that COPD patients with a mean p a pressure over 40. They actually had a higher predicted F E V 1% than patients with moderately elevated mean pH pressures on CT imaging. There was no statistical difference in total emphysema score between the two groups. Yeah, this concept can also be seen in the I p F population and going back to our Yunos database. We see that the I P F patients with at least the mean p a pressure of 25 had a higher predict percent predicted forced vital capacity compared to patients without pulmonary hypertension. So, despite having a higher forced vital capacity, which suggests less severe Perenco disease. The patients with an elevated P A pressure had increased supplemental auction requirement, decreased six minute walk UH, time distances and lower cumulative survival. This suggests that there's something besides chronic lung disease in hypoxic Veysel construction contributing to the development of pulmonary hypertension. Yeah, so sure enough, there is his his the pathologic evidence suggesting a pH for genotype in patients with chronic lung disease. Vascular remodeling That scene in Ph can be found in areas of lung unaffected by fibrosis. In patients with YPF, Pulmonary hypertension and panels A and B, we see fiber and hyperplasia and mix oil changes in large and medium vessels, while panel see shows medial hypertrophy in, uh, smaller vessels. These are all pH findings that we see in a patient with a clinical diagnosis of YPF idiopathic pulmonary fibrosis. So taking together the clinical and basic science data suggests a distinct pH genotype within Group three pulmonary hypertension patients. The majority of Group three pulmonary hypertension patients have mildly elevated mean pH pressures that can be explained in secondary to their chronic lung disease and hypoxic basal constriction. Their degree of pulmonary hypertension will reflect the severity of their lung disease. A subset of Group three pulmonary hypertension patients, however, will have a mean p, a pressure that's out of proportion to the severity of their lung disease and behave actually more similarly to a pulmonary arterial hypertension patient. Yeah, so the next few slides we're going to be discussing the diagnostic approach to Group three pulmonary hypertension patients through clinical findings. Pulmonary function testing, CT imaging, an echocardiogram. The key to this algorithm is to identify the patients who clinically exhibit the PHP genotype and would benefit from the right heart catheterization. Right Heart catheterization results can change our management in these patients. Yeah, so in terms of patient symptoms, rapid disease progression Precinct Pete Complaints of chest pain Are all signs favoring pulmonary hypertension over chronic lung disease? On physical examination allowed P to split second heart sounds elevated jugular venous pressure or peripheral oedema may be seen. Pulmonary function testing will show a diffusion capacity decrease that is out of proportion to either the obstructive or restrictive impairment seen on spy Rama. Tree labs may show elevated anti pro BMP levels, and e. K G may show a write access right axis deviation on CT imaging. The measuring the diameter of the pulmonary artery can be very helpful. Amine P, a diameter greater than 29 millimeters and a ratio of mean p a diameter to aorta diameter. Greater than one are both highly sensitive parameters for detecting pulmonary hypertension with reasonable specificity. So moving on to echocardiogram, as we've heard quite a bit through this talk already, echocardiogram is an excellent screening tool with this very strong negative predictive value in the absence of pulmonary hypertension. When we look at echocardiogram, it's important to look at both the P A pressure an RV function. This is because in chronic lung disease patients, the Troika speed regurgitation jet may be difficult to visualize, which can therefore over or underestimate the RV systolic pressure compared to the right heart catheterization results. Assessing RV function by looking at RV outflow, tract diameter, trick, husband, annular plane, systolic excursion and fractional area of change may be more accurate in diagnosing P. H i l d. And predicting poor outcomes. Yeah, so after review of the patient's clinical status, pulmonary function, testing, CT imaging and echocardiogram, a decision should then be made whether or not we should pursue right heart catheterization. And again, I want to emphasize most chronic lung disease Patients will probably not require a right heart catheterization as their symptoms and degree of pulmonary hypertension will correlate to the severity of their chronic lung disease. However, in patients whose clinical worsening cannot be explained by ventilatory impairment, who have evidence of severe pulmonary hypertension or RV dysfunction on echocardiogram or when an accurate prognostic assessment is deemed important to right, heart catheterization should be considered. UM, pre lung transplant. Work up and rolling out a primary cardiac disease are other indications to get the right heart. Cath This table shows the interpretation of right heart calf results Based on the Six World Symposium on pulmonary Hypertension definitions, it's really the Group three patients with severe pulmonary hypertension defined as a mean P a pressure over 35 or a mean p a pressure over 25 with decreased cardiac index who are most likely to benefit from ph therapies. Yeah, so once you have again your clinical findings, your pulmonary function, testing, imaging results, echocardiogram and once you finalize your right heart cath results, you can then characterize patients as having more of a pH genotype, or chronic lung disease. Genotype presence of Group one ph Risk factors out of proportion. DLC oh decrease evidence of only mild fibrosis on CT imaging. Significant right ventricular dysfunction, severe elevation and mean pH pressures and decreased cardiac index are all factors that favor a pulmonary arterial hypertension Vienna type. On the other hand, the absence of Group one risk factors severe, restrictive or obstructive physiology on your spire. Um, a tree test a proportional DLC oh, decrease severe fibrosis on CT imaging Only mild RV dysfunction on echocardiogram and only mild elevation and P a pressure with a preserved are re function are all suggested that chronic lung disease is a primary culprit for the patient's symptoms. Yeah, so in terms of management approach, all Group three pH patients should be optimally treated for their chronic lung disease as listed on this slide. So these treatments include inhaler or antibiotic therapies. Um, I should also include um immuno suppressive medications as indicated airway clearance therapies. Um, anti inflammatory agents to reduce risk of exacerbations use of supplemental oxygen pulmonary rehab with exercise. These are all therapies that should be provided for all patients, patients should also be screened for sleep disordered breathing and considered for lung transplant evaluation. Um, so although this is a pulmonary hypertension conference, I have to emphasize the importance of this slide and providing standard of care treatments for chronic lung disease patients. Again, most of our patients will end up only needing the therapies listed listed on this slide. Yeah, so now moving on to the kind of the meat of our talk here, um, this This is the controversial, somewhat controversial topic of using pH medications in Group three pulmonary hypertension patients. So first again, just to recap. Okay, Make sure patients are treated adequately for their chronic lung disease. As explained on the last flight, that's the most important concept. Um, it's also important to note that ph therapies have not been approved for use in Group three pulmonary hypertension and can be dangerous. There are concerns about the vessel dilatory effect exacerbating V Q mismatch and vaso dilation of inclusively lesions leading to pulmonary oedema. As outlined in the diagnostic algorithm. The key is to identify the Group three patients with the pH for genotype who are the most likely to benefit from pulmonary vessel dilator therapies. Mhm. So this is a list of the many randomized controlled studies looking at pH Therapies and Group three patients over the last two decades. I'm going to highlight a few of these studies and then discuss the recently published Inhale to Proximal study from New England this year. Again, given the poor prognosis these patients have, as I showed earlier, it's not surprising that there there have been so many attempts over the last years looking at whether these medications could potentially help Group three patients. Yeah, so first study that I'm going to discuss is the Artemus I PF study. Uh, this was a randomized, double blind, placebo controlled, event driven trial. Looking at whether Amber sent in at 10 mg daily reduces the rate of YPF progression. Um, this was a well designed study. But although close to 500 patients were enrolled, this study was actually terminated early as interim analysis indicated a low likelihood of showing efficacy. Amber scent and treated patients were more likely to have disease progression, lung function, decline, hospitalization and death. Mhm. So a significant weakness of this study is actually the patient population enrolled. We see that only about 10%. So looking at this line here, we see that only about 10% of patients had pulmonary hypertension. So it's not surprising that a ph therapy and percent and was ineffective the boss sent in and pulmonary hypertension and, uh, interstitial lung disease treatment study, uh, in right heart. Cath confirmed P h i L D patients similarly showed no improvement in the thermodynamics functional capacity or symptoms. So when you take the bus sent in and the, uh, Amber Sentence study has shown here together, E. R s as a class are not recommended for treatment of interstitial lung disease patients Group three pulmonary hypertension patients with interstitial lung disease Moving on to real cigarette. So real cigarette for idiopathic interstitial pneumonia Associated pulmonary hypertension Study. This was a multi center double blind, um, study with six minute walk test as the primary endpoint. So, in contrast to the design of the Amber Sentence study that I just showed this study enrolled patients with right heart Cath confirmed pre capillary physiology with me MP, a pressure of 33 normal wedge pressure PVR of 4.81 unit and a w h o functional class of 3 to 4. So the researchers anticipated promising results in this study as prior studies with radio signal, UH showed efficacy and well tolerable ability and pH patients with connective tissue disease. However, this was not the case. This graph shows that there was no difference in time to clinical worsening event in the real cigarette and placebo groups. Patients and the real cigarette group also experienced a greater number of serious adverse events and death than in the placebo group. As a result of this unfavourable risk benefit profile, the study was terminated early. One possible explanation is that the study allowed patients with forced vital capacity as low as 45% predicted and a mean p a pressure as low as 25 millimeters of mercury to be enrolled. This might have enabled patients with only mild home Mary hypertension and severe, uh, pulmonary fibrosis to be enrolled. Regardless, the authors of the study concluded that Real Sigma and patients with pulmonary hypertension and idiopathic interstitial pneumonia is contra indicated. Okay, so now transitioning to PDE five inhibitors, the sub NFL trial of exercise performance and I pf study, um looked at increase in six men walked out test distance as the primary outcome. 180 patients with Advanced YPF defined as a D L C O under 35% predicted were enrolled. Um, as as we see from the baseline patient characteristic table, neither echocardiogram or right heart cath data was required for enrollment, and this pattern is actually kind of seen commonly, an older studies on the Group three, uh, population. So although the primary endpoint of improvement in six minute walk test distance was not met, sildenafil did improve a number of secondary endpoints, including quality of life measures, um, arterial auction saturation and D l C O. In group three, we see there was a trend towards mortality difference, uh, mortality benefit at 28 weeks in the sildenafil arm, a follow up study looked at the combination of unintended nib, which is, uh, a favor antibiotic medication and sildenafil in patients with severe YPF. And that study did not. That study did not demonstrate quality of life benefit, but showed good safety, good safety data. Yeah, So the NFL has also been studied in COPD patients. Um, this multi center randomized, um, pilot study looked at sildenafil and pre transplant COPD patients with severe pulmonary hypertension. The primary endpoint was reduction and pulmonary vascular resistance. Uh, this was a small study. Only 18 patients were enrolled in the sildenafil arm to attend in the placebo group. All patients had right hard have confirmed pre capillary pulmonary hypertension mean p. A pressure was 39 p. V r. 6 to 7 Woods unit Cardiac index 2.4 Results showed that sildenafil was a safe medication and COPD patients with severe pulmonary hypertension, uh, and resulted in reduced PVR increased cardiac index and uh, the L C O decrease both index scores. There was not a trend towards worsening hypoxia hypoglycemia in the sildenafil group, so moving forward there will unlikely the additional large studies of sildenafil and Group three pH patients. But this medication is viewed as a safe consideration as bridge to Transplant Ridge. A lung transplant. Yeah, so this brings us to the topic of process Cyclones and the recently published increase Try increased Trial. So this is a 16 week trial looking at inhaled for processing mill with the brand name of TV's oh, in interstitial lung disease, patients with right heart cath documented pre capillary pulmonary hypertension. Um, inhale proportional was administered by ultrasonic pulse delivery nebulizer. Um, information about this can be found on their website. Each breath contains six micrograms of proportional and up to 12 breasts were taken four times daily. In this study, the primary endpoint was changed in six minute walk. Test distance and secondary endpoints included anti pro BMP levels in time to clinical worsening. Uh, 326 patients were enrolled with similar baseline characteristics as we see in this table, um, importantly, for based on human dynamics, enrolled patients had a mean p a pressure of 37. They have normal wedge pressure and PVR over six woods units. So clearly a pH type physiology patients had DLC oh, 30% predicted, which can be considered out of proportion to their baseline forced vital capacity at over 60% predicted uh, so in terms of the primary endpoint of six minute walk test distance, there was a significant difference of 31 m by 16 weeks. Secondary endpoints were also met. There was a 15% decrease in anti pro BNP levels with inhaled proportional as compared with uh, anti pro BMP increase of 46% in the placebo group. Clinical worsening occurred in 22% of patients in the trip. Asano compared with 33% in the placebo group. There was also a decrease in interstitial lung disease exacerbations in the inhaled for proximal group. Yeah, um, as for safety data, there was no significant difference in serious adverse events or treatment related increase in supplemental auction use inhalation. It's thought that inhalation preferentially directs blood flow to the best ventilated young lung units, and this will reduce the risk of V two mismatch compared to I V or subcutaneous process. Cycling's inhale to proximal seems to be better tolerated due to the more localized effects. The most frequently reported adverse events or cough, headache, dyspepsia, dizziness, fatigue and diarrhea. To date, this is the largest and most promising study that looked at a specific pH therapy and Group three pulmonary hypertension patients with interstitial lung disease, so inhale to personnel or TV's oh is now awaiting FDA approval to become the first medication actually approved for the use of Group three ill patients. Yeah, yeah, So to recap the four classes of ph. Medications, E R. A s, uh, and real single are avoided and I'll d. Interstitial lung disease patients. I didn't talk about the specific study, but both sentence has been shown to be safe and COPD pH patients For what? What? What is worth PDE five inhibitors have not shown benefit, but they do have a good safety profile and are very commonly used off label as a bridge to lung transplantation. Um, inhaled across Tamil, as we just discussed in the increased study is a very, um, promise has shown very promising data. And Group three, I'll be patient and waiting. FDA Review Currently again It should be noted that use of any of these medications should be got done cautiously and limited to patients with a right heart half showing severe pulmonary arterial hypertension out of proportion to the patient's chronic lung disease. And again, I have to circle back to the slide I showed earlier about standard of care treatments for their underlying chronic lung disease. Just because the patient has a pH. Genotype, it doesn't mean we should forget about treating their underlying chronic lung disease as well. Yeah, so take home points from my talk. Pulmonary hypertension and chronic lung disease is associated with increased mortality and worse outcomes. A subset of Group three pH patients may exhibit a pulmonary arterial hypertension genotype Consider work up and right heart catheterization and patients with symptoms out of proportion to their ventilatory defects. Once your work up is complete, determine what contributes to the patients what contributes to pulmonary hypertension in the patient. And how does pulmonary hypertension contribute to the patient's symptoms in chronic lung disease? Patients with the pH, uh, genotype consider a trial of PD five or process cycling therapies or referral to a Ph. Ph. Center. So these are my references, and I think we have have a couple of questions. So question one. Do any faculty members use a cardiopulmonary exercise? Stress tests? Um, does it have any use for screening discrimination? Yeah. So, um, for for me personally, I I use I use CPAC a reasonable amount. Um, a lot of times it is a more much more involved study and with the covid pandemic may be harder to schedule. But, um, it is, uh, will give you preliminary information on whether you know the patient's symptoms are more pulmonary related or cardiogenic and nature again. That said, I think the general algorithm still following the echocardiogram and right heart cap. You still have to end up getting those studies before consideration of use of any of the Ph therapies. But it's a fairly easy to perform noninvasive study. So does it. Okay, okay. I think no more questions. Thanks very much, Kelli. That's, uh it's great to have some new data about using these meds. Uh, you know, this is a complicated disease, lots of people, the lungs of the primary problem, and most of time, focusing on that is the most rewarding. But some people do have this phenotype where Ph is a big problem for them with RV failure. And it's good to have some randomized control data that supports and and to know that they only specific therapies help them. So thank you for that.
