An Interview with Lead Investigator Prof Olivier Sitbon
Written by James Coker | Reporter, European Medical Journal | @EMJJamesCoker
Disclosure: This is a non-commercial feature.
During this year’s European Respiratory Society (ERS) international congress a plethora of exciting new studies were presented which will help improve treatments for patients from this area of medicine. One of these were results from the PORTICO trial, which assessed the safety and efficacy of macitentan (OPSUMIT®, Actelion Pharmaceuticals Ltd., Allschwil, Switzerland) in 85 patients diagnosed with portopulmonary hypertension (PoPH). Following 12 weeks of treatment, significant improvements in pulmonary vascular resistance (PVR), mean pulmonary arterial pressure (mPAP), and cardiac index were observed in patients treated with this drug in comparison to placebo.1,2 These data are especially important because there is currently limited evidence supporting the use of approved treatments for pulmonary arterial hypertension (PAH) in PoPH, which is the fourth most common form of PAH. This is largely due to the fact that those patients have typically been excluded from clinical trials for PAH on safety grounds. To find out more about the findings and their implications, we spoke to the lead investigator of the trial, Prof Olivier Sitbon, Professor of Respiratory Medicine, Université Paris-Sud, Paris, France. We also discussed other related areas, such as the evolution in PAH therapies in recent years and the ways in which increased collaboration between different fields of medicine can enhance outcomes for patients with PoPH.
Advances in PAH Treatment
We firstly discussed the ways in which treatment approaches for PAH have developed in recent years. “We have a lot of drugs available to treat PAH. It depends on the countries, but we have between 10–14 drugs available,” explained Prof Sitbon. “All the drugs we have are targeting three dysfunctional pathways: prostacyclin, endothelin, and nitric oxide. In the past we treated patients with only one drug, monotherapy, targeting one of these pathways.”3
This has now evolved to the point where combination therapy is used as initial treatment and then, if necessary, a third drug is added to the combination. Prof Sitbon also commented that a novel drug named selexipag, which targets the prostacyclin pathway, has greatly enhanced the ability of physicians to treat this condition. “It’s quite simple, we initiate a double oral combination therapy in the majority of patients and if treatment goals are not met, we add a third drug, either an oral such as selexipag, or a parenteral prostacyclin for the most severe patients,” he outlined.
We then moved onto the results from the PORTICO trial, which Prof Sitbon played a pivotal role in as lead investigator. With a lack of evidence supporting therapies approved for PAH in PoPH patients, the findings of this study were eagerly anticipated. The data to date have mainly come from single-centre, and observational retrospective open-label studies; indeed, there had previously not been a randomised clinical trial (RCT) demonstrating that a PAH treatment improved cardiopulmonary haemodynamics in PoPH.
In PORTICO, the patients were randomised to either receive 10 mg of macitentan, an orally active endothelin receptor antagonist (n=43), or placebo (n=42). In comparison with placebo, those receiving macitentan had a 35% reduction in PVR, meeting the primary endpoint of the study. In addition, mPAP was reduced by 5.99 mmHg and cardiac index increased by 0.52 L/min/m2 in the patients treated with macitentan versus placebo. Also of major significance was the fact that the hepatic safety profile of the patients was consistent with that observed in previous clinical trials. Greater use macitentan should therefore lead to more PoPH patients becoming eligible for liver transplantation.
“Patients with PoPH are really contraindicated for liver transplantation. These patients have a high level of pulmonary vascular resistance and they cannot receive a liver transplantation due to the very high operative risk,” elucidated Prof Sitbon. “However, we know that some of them need a liver transplantation because they have severe cirrhosis or hepatocarcinoma. So, if we are able to decrease PVR below a certain threshold and improve cardiopulmonary haemodynamics, we can transplant those patients safely. For patients who are not candidates for liver transplantation, we can improve their quality of life as we are doing for other forms of PAH. Therefore, it is very important to have a drug that demonstrates efficacy in this patient population without any safety issues.”
Prof Sitbon also informed us of further reasons why it was so vital such a trial of PoPH patients needed to take place. While often considered a rare form of PAH, he pointed out it is more frequent than many people realise, comprising around 20% of the PAH population in France for example. Additionally, Prof Sitbon and colleagues in clinical practice have observed excellent results when using PAH drugs for PoPH; what has been lacking was a RCT demonstrating these effects.
Effect on Exercise Capacity
A less positive aspect of the study was the lack of significant improvements in symptoms and exercise capacity found between macitentan and placebo groups, measured in both World Health Organization (WHO) functional class and 6-minute walk distance (6MWD); however, Prof Sitbon believes that this could be due to factors relating to the characteristics of the patients participating in the PORTICO trial. “The baseline NT-proBNP [N-terminal pro b-type natriuretic peptide] was not very elevated because these patients are not as severe in terms of haemodynamics as we sometimes observe in idiopathic PAH and it’s difficult to demonstrate change if this level is not very high,” he said. “Regarding the walk test, we know that those patients are deconditioned, so that may be another explanation. When we waited for more time, not 3 months but 6 months and more, we observed an improvement in exercise capacity. The PORTICO trial had two phases, first was double-blind, followed by open-label, but for patients receiving macitentan from the beginning we observed a greater improvement in exercise capacity after 6 months.”
Prof Sitbon informed us that the lack of notable differences in the 6MWD and WHO functional class was the biggest source of questions posed by clinicians when the data were presented at ERS 2018. Those patients included in PORTICO will now continue to be followed and at the end of the full 24-week PORTICO study, will transition to the drug in the real world. The most common adverse events in the trial for patients receiving macitentan versus placebo were peripheral oedema and headache (25.6% versus 11.9% and 16.3% versus 16.7%, respectively).
Prof Sitbon then outlined the large focus placed upon PoPH in his department at the Université Paris-Sud. PoPH is typically diagnosed following screening for liver transplantation, which is mandatory; in patients who are not candidates for liver transplantation, screening is not mandatory and this can lead to delays in diagnosis and patient care. To improve the situation, Prof Sitbon emphasised the importance of enhanced collaboration and sharing of information between pulmonologists and hepatologists, something which he and his team have been heavily involved in at their institution. “Along with my colleague Laurent Savale we do a lot of presentations and lectures, and have a lot of conversations with our colleagues from the hepatology departments. Now they are more aware of PoPH so if a patient complains of shortness of breath they think about PoPH and screen with echocardiography. We have to create collaborations with other specialists, I think that’s absolutely key,” he stated.
Prof Sitbon gave the parallel example of the collaboration that now takes place between physicians from different specialities to improve treatment for pulmonary hypertension (PH) linked to scleroderma, including pulmonologists, internal medicine specialists, and rheumatologists. PH is a common complication of scleroderma, with around 1 in 10 patients developing the condition.4 Efforts were therefore made to improve dialogue from physicians from all specialities with expertise in these conditions. A major aspect of this has been the attendance from specialists from these different fields at conferences on the subject. This is something Prof Sitbon believes can translate to PoPH, particularly between experts in respiratory health and hepatologists. “Today when we have a conference on PH we always speak about scleroderma and I think we can try and do the same with hepatologists,” he added.
EMJ Respiratory 6.1
It was a pleasure to speak with the distinguished Prof Sitbon about the results of the PORTICO trial and related topics at the recent ERS Congress. A full review of the event will be covered in the upcoming edition of the annual EMJ Respiratory eJournal, available to read in early November. As always, the issue is open-access, and will also include reviews of abstracts presented at ERS, symposium reviews, Editorial Board interviews, and peer-reviewed papers. You can subscribe to our respiratory content as well as that from any of our other 16 therapeutic areas for free by clicking here.
- Business Wire. First Randomized Controlled Trial in Portopulmonary Hypertension Shows OPSUMIT® (macitentan) Significantly Improved Pulmonary Vascular Resistance Compared with Placebo. 2018. Available at: https://www.businesswire.com/news/home/20180916005006/en/Randomized-Controlled-Trial-Portopulmonary-Hypertension-Shows-OPSUMIT. Last accessed: 8 October 2018.
- Sitbon O et al. Efficacy and safety of macitentan in portopulmonary hypertension: the PORTICO trial. Abstract OA267. ERS International Congress, Paris, France, 15-19 September, 2018.
- Sitbon O, Morrell NW. Pathways in pulmonary arterial hypertension: The future is here. Eur Respir Rev. 2012;21(126):321-7.
- Pulmonary Hypertension News. Scleroderma-Associated Pulmonary Arterial Hypertension. 2018. Available at: https://pulmonaryhypertensionnews.com/scleroderma-associated-pah/. Last accessed: 8 October 2018.