At the 2017 European Society of Cardiology (ESC) Congress in Barcelona, physicians, researchers, and technologists gave presentations upon an expansive set of topics. Every cardiac indication was represented at the conference, including rare ones such as pulmonary arterial hypertension (PAH).
PAH is a fatal cardiopulmonary disease with a global annual mortality rate of 15%. The pathology of PAH has been attributed mainly to endothelial dysfunction and vascular remodeling, although increasing evidence indicates that the disease has more of an inflammatory proliferative nature.
Over the years, three mechanistic pathways have been implicated for the development of therapeutic treatments for PAH. These approaches to treatment can be classified broadly into those that inhibit vasoconstriction (the narrowing of blood vessels) and those that enhance vasodilation (the widening of blood vessels).
The third day of the 2017 ESC Congress was highlighted by Dr. Stephan Rosenkranz, who delivered presentation 'PAH – Triple Combination in a Timely Manner'.
When discussing prescribing patterns of physicians who treat PAH patients, Dr. Rosenkranz noted: “We are currently targeting three different pathways.”
The three pathways are the nitric oxide pathway, which is targeted by phosphodiesterase type 5 (PDE5) inhibitors and soluble guanylate cyclase (sGC) stimulators; the prostacyclin (IP) pathway, which is targeted by IP analogs and IP receptor agonists; and the endothelin pathway, which is targeted by endothelin receptor antagonists.
Dr. Rosenkranz emphasised that targeting multiple pathways is an important therapeutic option, stating: “in PAH, there is a strong rationale for the concomitant use of drugs acting on different pathways.”
Current PAH treatment guidelines recommend targeting multiple pathways using a combination of drugs.
Dr. Rosenkranz added: “The treatment guidelines are based on the individual risk of our patients.
"The current risk stratification strategy divides the patient population into low, medium, and high-risk categories.
"If we look at combination therapies in treatment-naïve patients, initial oral combination therapy is recommended. In high-risk patients, initial combination therapy including an intravenous prostanoid is recommended by the guidelines. If there is an inadequate response, then another therapy should be added, which is called a triple sequential combination therapy.”
Patients continue to experience disease progression despite dual combination therapy, whether sequential or upfront, according to data collected from the SERAPHIN (sequential) and AMBITION (upfront) studies.
Sequential combination therapies involve patients who have not responded well to monotherapies and are given another treatment in addition to their current prescription. Upfront combination therapies are multiple treatments being simultaneously prescribed upon diagnosis. According to the guidelines: “for patients not achieving a low-risk status, the addition of a third therapy may be adequate in order to improve long-term prognosis of patients.”
Dr. Rosenkranz polled the audience to see how many people in attendance used a sequential or upfront triple combination regimen to treat their PAH patients. Of audience members, 55% responded that they do use a sequential or upfront triple combination regimen. He presented patient record data from Europe, the US, Argentina, and Japan. The data showed a maximum of 5% of patients from each of the countries were on triple combination therapy.
Rosenkranz noted: “Despite the availability of treatment options targeting these pathways in PAH, the use of triple combination therapy is rare.”
The COMPERA registry enrolled patients from seven European countries with a major contribution from German centres. It showed that triple combination therapy was not widely used at inclusion, with only 3% of patients prescribed.
Dr. Rosenkranz added: “We have to admit that there are no randomised controlled trials in the context of combination therapy showing that survival is really improved by IV [intravenous] prostanoids, but yet we have data that clearly indicates that from clinical practice.”
Dr. Rosenkranz then presented data from the REVEAL registry, showing that parenteral prostanoids are underused. A total of 44.1% of PAH patients at the time of PAH-related death were not receiving a parenteral prostanoid, and almost one-third of functional class (FC) IV patients were not receiving a parenteral prostanoid.
To provide some evidence regarding the efficacy of triple combination therapy, Dr. Rosenkranz noted that data from the GRIPHON trial indirectly provided the PAH community with insight regarding long-term outcomes in PAH patients on triple therapy.
The GRIPHON trial is a Phase III study that assessed the long-term efficacy and safety of Actelion’s Uptravi (selexipag) in PAH patients. It showed that Uptravi reduced the risk of a morbidity or mortality event by 40%. At baseline, 80% of all patients were already on a background therapy, with 32.5% of patients already on a dual combination therapy of an endothelin receptor antagonist (ERA) and a PDE5 inhibitor at baseline.
Patients on triple combination therapy consisting of selexipag + ERA + PDE5 inhibitor had the risk of a morbidity or mortality event reduced by 37% compared to triple therapy with placebo + ERA + PDE5 inhibitor.
Rosenkranz noted: “If selexipag is effective on top of dual combination therapy, perhaps we can use an upfront triple combination therapy at baseline.”
The current TRITON study is a Phase IIIb trial that compares the efficacy and safety of an initial triple oral treatment regimen of macitentan + tadalafil + selexipag versus an initial oral treatment regimen of macitentan + tadalafil + placebo in newly diagnosed, treatment-naïve PAH patients. The primary endpoint of the trial is change of pulmonary vascular resistance (PVR) from baseline to Week 26, as measured by right heart catheterisation (RHC).
Dr. Rosenkranz concluded that patients with progressive PAH who responded inadequately to maximal therapy including dual and triple combination regimens should be considered for lung transplantation, a recommendation mentioned in the 2015 ESC guidelines. As with any transplantation case, timely referrals are crucial. Any delay could potentially result in increased waiting list mortality and clinical severity at time of transplantation.
Dr. Rosenkranz summarised his presentation by stating that triple combination therapy should be considered for patients who are high-risk and treatment-naïve, patients who are intermediate-risk and on an ERA + PDE5 inhibitor / sGC stimulator dual therapy who do not achieve a low-risk status, and patients who are deteriorating on an oral combination therapy.
Evidence is still being gathered to evaluate whether inhaled iloprost or oral / inhaled treprostinil may serve as alternatives in a triple combination therapy, or if treatment-naïve patients at low to intermediate risk should immediately begin a triple therapy regimen. Patients failing to respond to triple combination therapy should be considered for lung transplantation.
The PAH community is highly anticipating the results of the TRITON study to see if upfront triple combination therapy is more efficacious for treatment-naïve patients of low to intermediate-risk status.
According to key opinion leaders interviewed by GlobalData, many physicians treating PAH patients have already made the transition of initiating PAH patients on upfront dual combination therapy. However, more clinical trial data on the efficacy and safety of triple combination therapies are warranted before physicians will become convinced to adopt a more upfront triple combination therapy approach.