Jean Luc Vachiery discusses the rationale behind combination therapies in the treatment of pulmonary arterial hypertension.
FILMED AT THE EUROPEAN SOCIETY OF CARDIOLOGY (ESC) ANNUAL MEETING, AUGUST 2016
WHAT FACTORS INFORM RISK STRATIFICATION IN PATIENTS WITH PULMONARY ARTERIAL HYPERTENSION?
00:11 – The risk stratification is critical in the management of PH. All the factors that we use can be divided in three categories. The first one is clinical where we have NYHA functional class, signs of right ventricular failure or syncope. The second one is exercise related, so functional six-minute walking distance or cardiopulmonary exercise testing. And finally, last but not least, all the markers of right ventricular strain and dysfunction whether it’s by biomarkers, echocardiography or invasive right heart catheterisations. Once we get there, we have patients in low, intermittent and high risk and then we can decide which treatment to apply.
COULD YOU TELL US ABOUT THE RATIONALE FOR USING COMBINATION THERAPIES IN PULMONARY ARTERIAL HYPERTENSION?
00:56 – Combination therapy in PH is becoming the new treatment paradigm. The reasons are multiple. One can be inspired by other disease areas, rare disease, not only but also severe disease such as cancer or heart failure, are typically treated with combination of drugs. The second one goes with the combination of compounds. Some of them might have synergistic effects, and then improve patients’ outcome better than just one of the two of the three members of the combination. And finally now we have very strong, robust clinical evidence, not only for sequential combination therapy, but also for upfront, initial combination therapy with several compounds. I mean, it’s clearly…it’s overwhelmingly demonstrated that combination therapy helps us to raise the bar of patients’ outcome in this disease.
AT WHAT TREATMENT STAGE SHOULD COMBINED THERAPY STRATEGIES BE EMPLOYED?
01:53 – Timing for combination therapy is critical. For quite a long time we did sequential, meaning that we were just waiting for the patient to go worse or to improve just not enough, to embark on sequential treatment. Right now we know that initial therapy, as soon as the patient is diagnosed, has an impact on outcome and the evidence is becoming extremely strong. So, for us, at our centre and at many expert centres, combination therapy started at…it started right at time of diagnosis.
WHAT COMBINATIONS ARE THE MOST PROMISING?
02:26 – There are several combinations that were tested. The first that has been obviously tested initially is a combination of ambrisentan and tadalafil. It’s the one and only trial called the AMBITION trial that demonstrated that this combination was highly powerful in decreasing clinical events. So we’re not talking only about improving six-minute walking distance, but really decreasing the rate of event. Some other studies demonstrated that using macitentan, an endothelin receptor antagonist, together with a background therapy, with a PDE5 was also good to lower the rate of events. And finally, a combination with selexipag, which is a prostacyclin receptor agonist that is not a prostacyclin, also from the GRIPHON trial, demonstrated some benefits. So, we have a combination with surely ambrisentan plus tadalafil at initiation of treatment, sequential with macitentan with something else, and selexipag with either PDE5 or endothelin receptor antagonist that really prove their efficacy in event-driven studies, and that’s probably what we have the most robust. Future is coming. We will have new therapies but the need to demonstrate that they are as efficacious as the other combination that we use right now.
WHAT UNMET NEEDS REMAIN IN THE FIELD OF PULMONARY ARTERIAL HYPERTENSION?
03:50 – Pulmonary arterial hypertension is an incurable disease. So clearly, the unmet needs are thousands. So we are missing really a drug that can reverse the remodelling and the narrowing of the pulmonary vessel, so even the so-called plexiform lesions which are really destructive. We are also missing drugs that stand the proof of time. So, being as efficacious at initiation as they would be a couple of years after. And finally, I mean, finding a cure for this disease clearly is something important. The unmet need that is currently met is the combination of several stakeholders in this disease, and that includes, of course, physicians, industries, but also patients and regulatory agencies.