September 11th, 2013

A New Standard For Pulmonary Hypertension Trials

Recently the New England Journal of Medicine published the SERAPHIN trial studying the effects of macitentan, a new endothelin receptor antagonist, in pulmonary arterial hypertension (PAH). This was a well-conducted study in 742 patients with PAH randomized to placebo, a low dose of macitentan (3mg once a day) and a high dose of macitentan (10mg once a day). When compared to placebo, both doses decreased time to the first event related to PAH, a composite endpoint of worsening of PAH, initiation of prostanoids, lung transplantation, atrial septostomy or death.

The primary outcome in the clinical trials of PAH for currently approved therapies has remained the 6-minute walk (6MW) distance since the first randomized controlled trial (RCT) for PAH in 1990. At the time of the design of that study (NEJM 1996), because a survival endpoint would require a much large, long trial, the sponsor and steering committee chose the 6MW test as the primary outcome. Subsequently, almost every trial in PAH has used the 6MW test as the primary outcome. Most of these therapies produce a similar increase in 6MW distance, approximately 30-50 meters. There has been no relationship observed between changes in 6MW distance and mortality, hospitalization for pulmonary hypertension, lung transplantation or escalation of pulmonary hypertension therapy. In fact, 6MW distance may be more reflective of abnormalities and changes in the peripheral vasculature than the pulmonary hemodynamics. In the SERAPHIN study, by choosing a composite clinical endpoint, the authors have broken the mold in PAH trials and introduced a new outcome, which has been proposed for many years (the recent IMPRESS trial used time to clinical worsening as the primary outcome). This represents an important sea change in how PAH trials are conducted.

An important aspect of this trial is where macitentan will fall in terms of clinical options of PAH. In general, most current PAH practice introduces ERAs or PDE5 inhibitors as the first oral options (if patients are not responders to calcium channel blockers) unless there is overt RV failure, where the recommendations are to start prostacyclins. Bosentan and ambrisentan are the most commonly used ERAs. Bosentan is a twice-a-day drug and requires monthly LFTs measurement. Ambrisentan is a once-a-day drug and does not require LFT measurements. In the first bosentan trial (NEJM 2002), elevated LFTs occurred in 4-14% of patients treated with bosentan, depending on the dose used. In the landmark ambrisentan trial (Circulation 2008), no patient receiving ambrisentan developed increased LFTs. In the SERAPHIN study, 3.6% of macitentan patients developed increased LFTs, compared to 4.5% of patients receiving placebo. When it comes to approval and clinical introduction of this agent, what will be important is whether LFT checks will be required in patients once macitentan is initiated. If LFT checks are not required for this agent, then macitentan will be a once a day ERA, akin to ambrisentan but with a more clinical relevant study endpoint.

Whether this composite end point will be enough to change the prescribing patterns of PAH physicians will be interesting to follow, as will be to see if the SERAPHIN study represents a new standard for PAH trials.

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