Selection from: Practical Approaches to Vascular Complications in Systemic Sclerosis (SSc)

Long-term Goals and Emerging Combination Treatment Paradigms in PAH (Slides With Transcript)  CME

Myung H. Park, MD, FACC   Disclosures

Introduction

Slide 1.

Thank you, Dr Silver. I'd like to thank the organizers and especially Dr Silver for allowing me to participate in this very important event.

Treating SSc Patients

Slide 2.

I think we all recognize that scleroderma patients that develop PAH suffer from very high rates of mortality and morbidity. Certainly, current approved therapies do improve outcomes, but they are less effective in the subset of SSc patients than in idiopathic patients. It is more imperative that we know how to follow these patients once the initial therapy is started. We've got to ask ourselves, what are our long-term goals in PAH, and more importantly, how and when should a treatment response be assessed? And, what is the current evidence regarding combination therapies in PAH?Slide 3.

Choosing the initial therapy, I must say, is a very difficult decision-making process. As Dr Channick mentioned, you first have to know your clinical data, the weakness, the strength of each drug that was tested at the scenario, the population that it involved. Also know the severity of the disease of your patient. Are they low-risk category or high-risk category? Patient preference plays a big factor. It is not uncommon for a patient to walk in my office, first visit, having read the internet, goes into a chat room, and be well versed on the pros and cons of each drug, or they think they are, and have a very defined idea of what they think they should be getting. This is a very common scenario in this day and time. The other thing is the comorbidity of the patients, especially among the scleroderma population where they are older, they are on more medications, their side effect profile and the other disease that they carry, definitely does weigh into what you would or would not give them. And, of course, you cannot discount your own experience with that therapy.Slide 4.

If choosing the initial drug is difficult, forming a long-term treatment strategy is an extremely difficult process. This is because we really don't have a clear guideline as of yet, and what we are hoping to accomplish when we ask ourselves in all this treatment is, we want our patients to live better, and we want our patients to live longer. How do we know we are achieving that, because let's face it: we really don't have a readily available measurement in this disease. We don't have a blood pressure to measure, we don't have a cholesterol panel to check, and we don't have an ejection fraction (EF) to measure for left systolic heart failure. We are really hampered because the pulmonary circulation in the right ventricle is notoriously difficult to image and get a direct measurement.

Survival in PAH

Slide 5.

We've been depending on all of the indirect assessment, as was gone over by Dr Highland. The short-term goals — yes, we try to improve the functional class, we try to improve the quality of life and 6-minutewalk, but what are we really after? We really want to reverse the right ventricle from remodeling, and we want to improve survival. Toward this end, what have we learned thus far?Slide 6.

We have several therapies and yes, we have definitely improved survival in this disease state. This is from the original studies, long-term publications using epoprostenol. This is from the French group, and this is from the Chicago group at Rush. You can see that in this patient population–this is comparing to their historical controls, and this is comparing to the NIH estimated controls–you can see that, yes, survival is better, but if you look at the 2-year survival and the 3 year, it's about 78% and about 63% on the so-called gold standard therapy of epoprostenol. So the question is, can we do better than this? Since then, other studies have published their results with long-term studies. This is the treprostinil, the other procyclin, the inhaled iloprost, and of course, bosentan. . Keep in mind that all these therapies are using epoprostenol as a rescue therapy for people that fail, but you could see that, yes, we have made some outcome improvement, but we really do have a long way to go.Slide 7.

Which parameters that we really can measure when they're on treatment tell us the patient is doing better or worse? Again, this is from the epoprostenol study. After 3 months of being on epoprostenol,, you could see that people who reached functional class I and II do better than those who stay functional class III and IV. The same thing was demonstrated by the Chicago group as well.Slide 8.

We've been talking a lot about the 6-minute-walk distance, and the French group have, again, demonstrated that for those patients that can walk greater than 380 m, they have a long, more favorable outcome than those patients who could not achieve that distance.Slide 9.

Interestingly, when they look at the same set of population and looked at the absolute distance, change in distance, which was the median of 112 m, and survival, it was identical. I find it to be very provocative in thinking perhaps looking at setting an arbitrary number, it's not the right thing to do for everybody that we are treating, and perhaps what we should be focusing on is percent change based on their age and other demographics. This is also being studied at this time point.

Predicting Mortality and Pulmonary Arterial Hypertension

Slide 10.

How about hemodynamics? Dr Channick had gone over the importance of knowing your right heart catheterization numbers. Yes, it is crucial, and these are on patients on epoprostenol, getting a heart catheterization after being on epoprostenol for 3 months, and the predictors of worse outcome are the ones whose mean right arterial pressure stayed high, greater than 10 mm Hg, whose mixed venous was low, indicative of a low-output state, and, again, who failed to increase their cardiac index by more than half a liter. This is really demonstrating that for patients that really cannot mobilize their right ventricle, they don't do well.

How about this? I think this is very interesting. Mean pulmonary arterial (PA) pressure less than 59 mm Hg portends a worse prognoses. Some may think this is counterintuitive. Isn't that what we're trying to do by giving these medications — we're trying to lower the PA pressure? But, you have to understand that there are many ways that the mean PA pressure can increase or decrease. For the patients that have this much severe right ventricular (RV) failure, who die of RV dysfunction, a decline in the mean PA pressure can be indicative of worsening heart failure. This is another reason why just following an echocardiogram even when you're in treatment, may not be telling the whole story.Slide 11.

To come up with noninvasive, easily measured, and reproducible markers, of course, people have looked to biomarkers. BNP is one that has been studied to some degree, and this is from the group in Japan. Of 49 patients that received either IV or oral prostacyclin, you can see that patients who had a BNP less than 180 pg/mL had a more favorable outcome than those who had a greater BNP.Slide 12.

This next study is from my own group. Again, these are all patients on epoprostenol. If you look at the BNP markers, those who had an acute drop in the BNP had a very favorable course without hospitalizations; if they had transplant, of course, they all lived. On the other hand, those who had a lingering high BNP throughout the clinical course, despite being on epoprostenol, did not do as well. There is something about the ventricle taking into effect the first immediate few months that I really think tells a story in the long run.Slide 13.

On-therapy prognostic indicators maybe: that we need to achieve a functional class I or II, achieve a walk distance of 280 m–but perhaps we should go for percent change, hemodynamics to be normalized, and a certain BNP marker. But again, there is a discussion of whether this should be intrapatient variability as well.Slide 14.

What are some of the newer markers? Dr Highland has mentioned the N-terminal-pro-BNP. Because this is a bigger marker, more stable at room temperature, easily measured, some have claimed that this is more accurate and certainly a lot of this has been studied in patients with left heart disease.

This is a publication that came out specifically on scleroderma patients with PAH. They studied 49 patients, screened with an echocardiogram. They went to a heart catheterization; and 23 were confirmed to have PAH and 26 were not. You can see the striking difference in the N-terminal pro-BNP. As interestingly when these patients were separated by the walk distance, you could see that those who were not able to walk 250 m or less have a much higher BNP than those who were able to walk more. I do think that these kinds of biomarkers do have a place, especially when you're dealing with a group or population with a lot of comorbidities and ailments, who may not really give you the reliable results from the exercise focus study.Slide 15.

This is another pro-BNP study, studying the control population, idiopathic PAH; those with associated PAH, where the scleroderma population would be and the connective tissue disease. You could see the very elevated BNP level in all the groups. Again, after 3 months of epoprostenol, all the patients had a very nice decline in the NT-pro-BNP levels.Slide 16.

The focus of how to exactly measure what we're doing, of course, has been a debate that's been going on for some time, and like I stated before, we are very much hampered because an echocardiogram really cannot give us a reliable measure when it comes to the right ventricle. A lot of our interest has now been focusing on the magnetic resonance imaging (MRI). MRI has a lot of advantages. It has very high special resolution. We're not limited to the window limitations that Dr Highland mentioned with advanced lung disease, where it's really difficult to see, it's like looking through a glass of snow with all the fuzziness. Because of these advantages, we can get an accurate assessment of chamber size and function of the right ventricle. You can also image extra cardiac structures, and you can also do wide-spectrum and other clinical utilities, and of course, you don't have to give them any nephrotoxic agents or radiation.

This is under intense study at this point where the anatomic evaluation, assessing volume, mass, and function has been very well validated. There are several studies underway looking at the curvature ratio, enhanced contrast, and PA flow velocity to give us a noninvasive MRI to derive thermodynamics. Most interestingly is can we use this to follow patients? Will it show us a reliable degree of right ventricle remodeling?Slide 17.

This is a study that just came out. Sixty-four patients, all with pulmonary hypertension, initial baseline with right heart catheterization and MRI and at 1 year. You can see that this is the baseline data and these are the usual indices that we see, functional class, 6-minute walk, and yes, they were predictive of outcome. But, if you look at the blue, the MRI derived indices, the stroke volume and the right and left ventricular end-diastolic dimensions were very, very important as baseline predictors of outcome.Slide 18.

Looking at this in a graphic format, the two that have come up again and again are the stroke volume index, and the right ventricular end-diastolic volume index. Patients that have a low stroke line index and a high right ventricle, again, it all makes sense; they do worse than the patients who did not.Slide 19.

If you look at the follow-up on therapy at 1 year, you can see that the traditional markers sort of fall out, but what does stay as significant is patients who have a lower or falling decrease in stroke volume index, increasing right ventricle end-diastolic dimension, and a decreasing of the dimension. These were the patients that actually had the highest mortality rates.

Therapeutic Approaches

Slide 20.

How can we use this marker when we have patients on all these therapies? This one study demonstrated that in these patients on epoprostenol, measuring the right ventricle stroke volume and correlating with 6-minute-walk distance, there was a very nice correlation as you can see: as the 6-minute-walk distance went up, so did the right ventricular stroke volume. This is 1 patient that they presented and just to orient you, this is the right ventricle, this is the septum, this is the left ventricle here, and in a normal, healthy heart, this would be much smaller with a ventricle bowing, not bowing so much as it is now. You had this baseline, 4 months, 8 months, and 12 months. As you can see, at the end of the treatment at 1 year, the septum is bowing much more the way it should, toward the right ventricle. It has lost some of its dyssynchrony, and actually it's a much more regular shape as well, although it's still very, very big.Slide 21.

Another study in San Diego demonstrated that one of the surgical cures that were mentioned in this disease is a thromboendarterectomy for patients that had chronic thromboembolic disease. Among patients that underwent the surgery, they measured the MRI mass and then the right ventricle, and demonstrated that there was a significant decline in the right ventricular mass before and after the surgery. It did not quite reach the normalcy state. This was done about 4 months after the surgical procedure, but you could see the significant decline in the right ventricle geometry.Slide 22.

To better study this, there is currently a study underway called Combination of Pulmonary Arterial Hypertension Sildenafil Study (COMPASS) 3, which is an open-label, phase 4 study, where patients are all put on bosentan as a monotherapy. Then sildenafil is added at week 16, if they do not achieve a threshold of 380 m. The primary objective is to determine the percentage of patients who need a combination therapy. But more important, I feel, is that there is a concomitant MRI study that will be performed, along with right heart catheterization, echocardiogram, 6-minute walk, and everything else. This will be the first and the largest prospectively designed evaluation to see how we can use this modality in PAH.Slide 23.

Bringing it all together as far as follow-up, factors to consider are, again, risk assessing your patient: how are they doing lately? Are they doing well, are they getting sick? Functional class? 6-minute walk? Are they on oral or parenteral agents or are they on combination already? What were their echocardiogram and hemodynamic data? The follow-up frequency has to be based on these factors. Obviously, they do differ between the stable and the low risk, versus the stable and the high risk. There are some patients that I see as frequently as every 3 to 4 weeks, and some patients that I see every 3 to 6 months. I cannot underscore enough the importance of a dedicated nurse that we have at our specialty centers. My nurses spend hours on the phone taking care of these complex patients and triaging them, and hopefully forestalling any disasters. There is currently a consensus statement recommendation that will have all these parameters that will be published next year.Slide 24.

On to combination therapy. Where are we in 2007?Slide 25.

Dr Channick has given me a really good segue into this, and this is a table of all the published, randomized, controlled trials, and as he stated, look at how similar the baseline assessment of walk distance is. Although, if you kind of follow the function class recorded, you see a huge preponderance of the function class II, and I think this very nicely underscores what he was telling. These are the 6-minute-walk distance improvements; the raw number and placebo-corrected. These are the percentages with the connective tissue disease, and for those studies these are the walk distances that were recorded for the scleroderma population. You can see that, on the average, we were able to increase their walk distance anywhere from about 30 m to 40 m or 45 m. For the scleroderma population it's much less. And, of course, about 20% to 30% of the patients' cohort were in the category.Slide 26.

The question, of course, is can we do better? Intuitively, yes. We have therapies that target different pathological pathways, and if you look at all the other chronic diseases — hypertension, cancer, heart failure — we use more than 1 drug and we try to target more than 1 pathway. Why not in right heart failure? Indeed, there are several advantages. You can have a potential additive effect, you can have a synergistic effect, and you can possibly minimize toxicity by using less of one drug. Of course, there are potential risks, as well, such as drug-to-drug interactions and, of course, we can never forget the cost of all these treatments.Slide 27.

With this in mind, there have been some small pivotal studies that have been done as in this Safety and Pilot Efficacy Trial in Combination With Bosentan for Evaluation in Pulmonary Arterial Hypertension (STEP) study, where inhaled iloprost — prostacyclin — was added to bosentan. In this12-week study, there was an increase by 30-m — placebo-adjusted 26 m — in the patients that received iloprost and bosentan that almost met significance. When we looked at clinical worsening, there was a definite difference in clinical worsening with patients that received iloprost combination therapy.Slide 28.

This is another combination trial that just got released at the American Thoracic Society (ATS) this year. This is adding sildenafil on top of epoprostenol, and versus placebo. They received 3 doses titrated every 4 weeks as tolerated. There was a treatment-adjusted increase of 26 m, with a mean pulmonary arterial pressure decrease, and a time to clinical worsening that was delayed.Slide 29.

This is to show you the changes in the 6-minute walk at weeks 4, 8, 12, and 16. You can see a very nice effect of using combination therapy, which is surprising since we all consider epoprostenol to be the gold standard of treatment.Slide 30.

With all that background, the question becomes exactly when do you jump the gun? When do you add your second-line therapy or third-line therapy? Should you wait until the patient deteriorates, or should you be more preemptive? This is a study out of Germany, and they had a goal-oriented therapy approach where a patient was aimed to achieve a walk distance. Again, you see this number, of 380 m; to reach a peak volume of oxygen (VO2) of 10.4 during a cardiopulmonary stress test (there are some studies to demonstrate this in the pulmonary hypertension population); and to generate a systolic blood pressure of 120 mm Hg also during exercise. They were initially treated with bosentan. If they met those goals during follow-up, they were continued. If they didn't, then sildenafil was added; if they failed again, inhaled iloprost was added. If they failed again, the inhaled iloprost was switched to IV iloprost, and the last resort, of course, is the urgent transplant evaluation.Slide 31.

Using that mode, and this is yellow, they demonstrated the outcome was markedly better using the goal-oriented approach to their own historical controls. This is the expected survival based on the NIH formula. Perhaps what we need to do is come up with a reasonable way to follow our patients that will help us know when to do these things. That's what we're trying to achieve.Slide 32.

These are the ongoing clinical trials and all the combination therapy. This is covering the oral, inhaled, longer-acting prostacyclin. This is the PACE study that I just shared with you. This is the iloprost on top of sildenafil study; this is the longer-acting PDI5 inhibitor; and there is a similar Pfizer study going on, and all 3 forms of COMPASS study. The COMPASS-2 is the event-driven study, probably one of the largest we are enrolling; and COMPASS-3 is the MRI study I just now shared with you.

Summary

Slide 33.

To summarize, pulmonary hypertension is an aggressive disease, with poor prognosis. We do have our therapies; we need to quickly evaluate them to assess a response. Potential to improve the long-term outcome by targeting multiple pathways is really exciting. Current, ongoing clinical trials have to be finished for us to have reasonable guidance for the next step, and for us to determine which combination really works best in the subset of the scleroderma patients. Thank you so much for your attention.