Editor's Note:
The last decade has witnessed remarkable improvements in the understanding and treatment of pulmonary arterial hypertension (PAH). Data were presented at American College of Chest Physicians (ACCP) meeting on several studies focusing on new approaches to treating PAH. Editorial Director Nancy Otto, PharmD, had the opportunity to discuss new data on PAH with Steven Nathan, MD, Medical Director of the Advanced Lung Disease and Transplant Program at Inova Fairfax Hospital in Falls Church, Virginia. Dr. Nathan is a member of the Medscape Pulmonary Medicine Advisory Board.

Dr. Nathan: Thank you very much, Nancy. Thanks for inviting me to talk to you on this subject.

Dr. Nathan: Currently, there are 6 FDA [US Food and Drug Administration]-approved therapies for treating pulmonary arterial hypertension and they're all approved as monotherapies, but it makes intuitive sense to treat patients with combination therapy. If you look at any of the diseases that we've made a significant impact on, be it HIV or heart failure, or chemotherapy for various cancers, it's always taken some form of multimodal therapy. It makes intuitive sense therefore, that if various therapies work by themselves, then using them in combination might have potential for treating the disease more effectively. In addition, the advantage of these different medications is that they do target different pathways. If you can target the different pathways with more than 1 therapy, then it is possible that you might see a synergistic benefit .This concept is the underlying premise behind these various combination studies. There have been many different reports in the literature, most of them retrospective, small series, or open-label studies about the potential utility of combination therapy. There is also an emerging body of data looking prospectively through appropriately designed randomized, controlled studies at the efficacy of combination therapy.

A study of primary interest that was presented at CHEST this year was PHIRST-1, which focused on tadalafil in pulmonary arterial hypertension. Tadalafil is not currently approved for treating pulmonary arterial hypertension and this happened as a result of the pivotal study for this particular drug. If approved, tadalafil would be the seventh available therapy approved for treating pulmonary arterial hypertension. In essence, the tadalafil study was in part a combination drug study. Of the patients who were randomized in this study, about half of them were not on any therapy, while the other half were actually on bosentan monotherapy. This particular subpopulation does, therefore, provide us with some combination data, in terms of using both bosentan and tadalafil. To cut to the chase, the study was a positive study. Tadalafil was studied at 4 different dosages, 2.5 mg, 10 mg, 20 mg, and 40 mg, once a day. At the higher dosage form, specifically the 40 mg a day, it did appear to have a salutory effect; specifically, in terms of the primary endpoint, which was the 6-minute walk distance, there was an improvement of around 33 meters.

What is interesting, but what also makes sense, is that if you look at the subgroup of patients who received combination therapy, in other words, the group that was treated with bosentan plus tadalafil, the control-adjusted change in the 6-minute walk distance was 23 meters vs the group that went into the study on no therapy, where the placebo-controlled improvement in the 6-minute walk distance was 44 meters.

I think this does raise another point around the various combination studies, in that, as you're treating the patient, the expectation might be that you get less benefit with add-on therapy. This is actually what we've seen with many of the other prior combination drug studies. It makes intuitive sense that if you have treated the patient already and have obtained a certain amount of benefit, that might impose a so-called "ceiling" effect in terms of how much additional benefit you can get from subsequent add-on drugs. Another example of this concept is from the TRIUMPH study, which was presented at the ATS [American Thoracic Society] earlier this year, where the control-adjusted change in the 6-minute walk distance was around 20 meters.

But, getting back to the tadalafil study, as I mentioned, it was a positive study that did appear to show a benefit, not only on the 6-minute walk distance, but also the pulmonary hemodynamics, the time to clinical worsening and health-related quality-of-life measures that were performed as part of the study. So I think this is exciting data. I believe that this should be sufficient to gain FDA approval and it would certainly be helpful to have another phosphodiesterase inhibitor added to our armamentarium of options that we can offer these patients.

That was the only combination therapy study that I recall presented at CHEST. There was mention of some of the other studies that had previously been published in pulmonary hypertension and it might be worthwhile mentioning those as well. The ones of interest included some long-term data from 2 drug studies that were previously presented. These included long-term data on ambrisentan from patients who had previously been enrolled in the ARIES-1 and ARIES-2 studies. The bottom line, as I recall, from this particular follow-up study was that the change in the 6-minute walk distance was, for the most part, sustained through the 2 years of follow-up. There were a handful of patients, however, who dropped out during the course of the 2 years, some from progression of disease, and there were others who died during the course of this study. However, for the patients who continued in the study, and at 2 years there were still 261 of the original 383 patients enrolled, 82% of them remained on monotherapy and 18% had some form of add-on therapy as part of their regimen. For both doses that have been approved by the FDA, the 5-mg dose and the 10-mg dose of ambrisentan, for the most part, there was stabilization of disease as well as sustainability of the change in the 6-minute walk distance. As we get long-term follow-up data on all these different relatively new agents, I think it is reassuring to clinicians in the field that they can safely continue these medications. However, as yet, there is no panacea for pulmonary arterial hypertension, and physicians still need to follow these patients closely once they have them on therapy because they might become candidates for add-on therapy or for transitioning to more aggressive therapies if they fail to have a sustained response. Therefore, one shouldn't be complacent at any time when treating a patient with pulmonary arterial hypertension.

There were also long-term data on sildenafil presented by Dr. Lew Rubin, and those were the results of the Super-2 study. Very similar to what I mentioned for the long-term data on ambrisentan, there was sustained improvement in these patients as well at 2 years. What we're used to seeing from most of these studies is either a median or mean change in the 6-minute walk distance. What was presented in this study were patients categorized in groups based on how much change in the 6-minute walk distance was achieved. So, if I took my notes correctly, and hopefully I did, at 2 years, there were about 29% of patients who continued on sildenafil who obtained and sustained an improvement in the 6-minute walk distance of greater than 60 meters. There were another 7% or 8% who had a sustained improvement in this 6-minute walk distance of between 30 and 60 meters, and there were another 8% or 9% who had a change in their 6-minute walk distance of 0% to 30%. So, it looked like for many patients, there was sustained improvement in their 6-minute walk distance up to 2 to 3 years after starting in the study. In addition, the majority of the patients had the same or improved functional capacity. However, once again, even though we have these drugs, there are always some patients who will progress and who might benefit from other forms of therapy as well.

There were also long-term data from the TRIUMPH study. I mentioned the TRIUMPH study was initially presented at ATS earlier this year and that was, as I recall, a 12-week study. What was presented at the CHEST meeting this year was long-term follow-up on the 206 patients who enrolled in the open-label extension of that study. The initial study, as I mentioned earlier, demonstrated a 20-meter increase in the 6-minute walk distance at 12 weeks in the treatment arm. This was a "peak 6-minute walk distance," in that it was taken at the peak time of drug exposure. If one looked at the trough 6-minute walk distance -- in other words, before the patient took their first dose of inhaled treprostinil -- the change in the 6-minute walk distance was 14 meters. That's a difference to be expected with inhaled treprostinil, compared to subcutaneous or IV [intravenous], where we have sustained levels and exposure to the drug.

Moving onto the long-term follow-up, what was gratifying to see was that there appeared to be ongoing improvement in the 6-minute walk distance, somewhere in the range of 30 to 33 meters at 9 to 12 months. However, there was a caveat in the results that were presented, in that, for those patients who dropped out, discontinued, or died during the course of the study, they didn't use the last observation carried forward, so the change in the 6-minute walk distance might be somewhat inflated since those patients who didn't make it through 9 or 12 months were not accounted for.

Nonetheless, I think this was important information and will be important for clinicians to know if and when inhaled treprostinil does get approved. So from my standpoint, these presentations constituted the major new data on pulmonary hypertension presented at the CHEST meeting.

Dr. Nathan: I believe the concept of attacking the disease at multiple points through the different pathways is likely to be more efficacious. As mentioned, the 3 major pathways that we know of that are important in the disease are the prostacyclin, the nitric oxide, and the endothelin pathways. It makes some sort of sense that if we attack all 3 or perhaps 2 of these pathways, we're going to get added benefit. However, there are many things in medicine that make intuitive sense but which don't pan out when subjected to the necessary studies. Therefore, it is important that we complete these studies before combination therapy is uniformly adopted. Most of the studies that are being done are combination therapy of 2 drugs, but I suspect in the future we will see emerging data on combination therapy using 3 drugs. In actual effect, the oral treprostinil study, which is now completed and is currently being analyzed, did likely include some patients on triple drug therapy. The inclusion criteria for that particular study included patients on either bosentan or sildenafil or the combination bosentan plus sildenafil. So there will likely be a subset of patients within the context of the oral treprostinil study who will be treated with sildenafil, bosentan, and oral treprostinil. Three oral agents targeting all 3 pathways will make for some very interesting results to be looked for.

Dr. Nathan: Yes, I think that this is very much an emerging concept. All the therapies that have been trialed, including all the ones that I mentioned already, have been trialed in WHO [World Health Organization] group 1 pulmonary arterial hypertension. That includes the classic idiopathic pulmonary arterial hypertension or PPH, familial pulmonary hypertension, connective tissue disorders, congenital heart disease, and portopulmonary hypertension. The studies have mostly been limited to these patients. Now, if you look at the WHO classification of pulmonary hypertension, group 3 is of particular interest, that is pulmonary hypertension related to hypoxia and parenchymal lung disease. The diseases within this group include conditions like COPD and other entities such as interstitial lung disease, specifically idiopathic pulmonary fibrosis. Another condition characterized by diffuse parenchymal lung involvement is sarcoidosis, which is included under group 5 (miscellaneous) based on the WHO classification.

The question that has to be asked in many of these patients with advanced lung disease, especially considering the lack of other effective therapies, is what if we treat their pulmonary hypertension? There have been a number of studies that have come out in the last few years that have looked at the prevalence and impact of pulmonary hypertension in COPD and also in IPF [idiopathic pulmonary fibrosis]. What is clear is that pulmonary hypertension does complicate the disease course of these patients, including in up to 50% of patients with advanced COPD. Patients with COPD and associated pulmonary hypertension have clearly been shown to have a significantly worse prognosis. This then begs the question of what if you treat the pulmonary hypertension associated with COPD? Specifically, if we treat the pulmonary hypertension, perhaps improve this a little, will we improve the functional capacity of these patients and will we ultimately improve their outcomes? This is definitely a hot area and one that remains to be investigated further. There a lot of folks talking about it but not much literature coming out on this as yet. But it does raise the concept of so-called "disproportionate" pulmonary hypertension. Specifically, when is the pulmonary hypertension disproportionate to the underlying parenchymal lung disease? In this case, the underlying obstructive lung disease since we're talking about COPD. It is a broad concept that hasn't been well defined, but perhaps "disproportionate" pulmonary hypertension would be pulmonary hypertension that is not fully explained by the degree of underlying obstructive lung disease. In the context of COPD, this might be patients who have lesser forms of obstruction and more severe pulmonary hypertension. There's an interesting paper that is constantly referred to that was published in Chest about 3 and a half years ago. The first author was Gabriel Thabut,^[1] and in this particular paper, they demonstrated a prevalence of pulmonary hypertension of around 50%; of these, there were about 10% of patients who had more severe pulmonary hypertension. As I recall, they defined that as a mean PA pressure of greater than 40 mm Hg. When they did a comparison of mean PA pressures to the FEV1 [forced expiratory volume in 1 second], they identified a subgroup of patients who we could perhaps be regarded as having disproportionate pulmonary hypertension with higher pressures and moderate obstructive lung disease. This group of patients constituted about 7% of the cohort. If you look at drug studies for PH that have been done in COPD patients, there haven't been many at all. There have only been 2 such studies to my knowledge. The first of these looked at stroke volume response to sildenafil, but unfortunately this was a negative study. More recently, in the European Respiratory Journal,^[2] there was a prospective, randomized (2:1), double-blind study of bosentan in 30 COPD patients. Again, in this particular study, no significant benefit was demonstrated. However, I think what's important is that we have to get smart with the design of these studies. If you look at the latter paper that was published in the ERJ, they took patients with very severe COPD. I think if we're going to study PH in the context of COPD, we've got to look for that subset of patients who we surmise have "disproportionate" pulmonary hypertension as described by Thabut and his colleagues. Another shortfall of this paper was that pulmonary hypertension was diagnosed by echocardiography. It's been shown in a number of studies now that echo is notoriously inaccurate to diagnose pulmonary hypertension in patients with advanced lung disease, especially COPD, where you have a large acoustic window from the hyperinflation associated with the underlying obstructive disease. To summarize, I certainly think this is a hot area and one that needs to be investigated further. The concept of disproportionate pulmonary hypertension needs to be defined better in the context of these studies.

Dr. Nathan: Similar concept here, since we know that pulmonary hypertension complicates the course of patients with interstitial lung disease. This has been studied mostly in patients with IPF, where the prevalence is around 40%. IPF has a very poor prognosis. The median survival of these patients is anywhere in the range of around 2.5 to 4 years, so certainly, a much worse survival than patients with COPD. We don't have any effective therapies as yet for treating pulmonary fibrosis. PH has also clearly been shown to have a negative impact on outcomes in patients with IPF. So what if we target this with PAH therapies? If we can ameliorate this, will we affect the functional abilities of these patients and will we ultimately alter the disease course?

The pulmonary hypertension we see in IPF tends to be more mild. Most patients with pulmonary hypertension in the context of this disease have mean PA pressures in the range of around 25 to 30 mm Hg, although there is certainly a subgroup of patients who have more severe pulmonary hypertension as well. So it does make some sense to try and target the pulmonary hypertension. There haven't been many studies as yet looking at this. There was a small case series from the group at UCSF [University of California San Francisco] and UCLA [University of California Los Angeles] that was published in Chest about 2 years ago using sildenafil in about 14 patients.^[3] They showed a benefit based on the change in the 6-minute walk distance. This report has provided the foundation for a larger prospective study that's currently being done through the IPF Network, looking at sildenafil in patients with more advanced IPF and likely underlying pulmonary hypertension. This study is currently actively enrolling and this should hopefully provide a definitive answer as to whether sildenafil is of any utility in patients with IPF.

There was another study, the ACTIVE study of inhaled iloprost which was one of the very few prospective studies looking at treating the pulmonary hypertension of IPF. Unfortunately, the pulmonary hypertension was, once again, diagnosed based on echo and not on the gold standard right heart catheterization. The study results were presented at the CHEST meeting in 2007. Unfortunately, it was a negative study based on the change in the 6-minute walk distance. I think that this does underscore a few points. First, we need to design these studies properly. We need to define pulmonary hypertension appropriately with right heart catheterization. We then need to preselect a group of patients who are most likely to benefit from the therapy and perhaps look for patients with more moderate to severe pulmonary hypertension rather than all comers with pulmonary hypertension. I think we need to do a more precise job in defining the patient population to be studied to best enable positive results from these various studies that hopefully will continue to be implemented.

Another important lesson from the ACTIVE study is that, while there was some pilot data to suggest that inhaled iloprost was useful in patients with IPF, this was not borne out in a larger, prospective study. So the lesson from this is, don't rely on small pilot or open-label series. We need the large prospective studies to definitively know if these various medications work or not.

Dr. Nathan: It was my pleasure. I appreciate the opportunity to express my views in this forum. Thank you very much.