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Switching Therapies for Pulmonary Arterial Hypertension and Challenges in Going from "Famine to Feast"


Ryan Davey, MD, FRCPC, FACC
London Health Sciences Centre
London, ON, Canada
Ryan.Davey@lhsc.on.ca



Who would have thought that even a few short years ago we, as practitioners, would be relatively spoilt for choice in deciding which pulmonary vasodilator therapy we should select for our pulmonary hypertension patients? We certainly are far from the days of "calcium antagonism or bust" but recent years have seen the PH treatment paradigm further moved on to pressing and relevant questions such as whether to use upfront combination therapy and the how to integrate oral prostacyclin agents into our practices.

Perhaps one of the agents that can cause many PH care providers considerable pause is when, how and in which PAH patients to use the soluble guanylate cyclase (sGC) stimulator, riociguat. By means of introduction for the uninitiated, riociguat acts to induce vasodilation in smooth muscle by both sensitizing the sGC enzyme to endogenous nitric oxide (NO) and also by direct stimulation of the enzyme. The resultant vasodilation appears potent and results in significant decreases in pulmonary vascular resistance (PVR) [1] and concomitant increases in cardiac output (CO).

Indeed, the vasodilatory effects from riociguat appear significant enough that its combination with phosphodiesterase-5 inhibitors (PDE5i) such as sildenafil or tadalafil may result in significant symptomatic drops in systemic blood pressure [2]. This presents the practitioner with a binary option: PDE5i or riociguat, which to choose?

At ISHLT 2016, data from a single center experience converting PAH patients from PDE5i to riociguat showed there was a significant drop in PVR and increase in cardiac index (CI) of 0.4 L/min/m2 in patients switched from PDE5i to riociguat. The RESPITE study, which has completed enrollment and whose final results are soon to be published, was designed to answer the question of the efficacy of switching from PDE5i to riociguat in stable but persistently symptomatic PAH patients not on prostacyclin therapy. Stay tuned in the coming weeks!

Prostacyclin therapies have also evolved from the somewhat onerous, short half-life parenteral formulations of epoprostenol through to inhaled and now on to oral prostacyclin analogs, including the most recently FDA and Health Canada approved prostacyclin receptor agonist: selexipag. The GRIPHON study, recently published in the NEJM by Sitbon et al., looked almost exclusively at WHO Functional Class II-III who were already on non-prostacyclin based regimens for PAH and showed a marked positive difference in the primary composite endpoint of time to first morbidity/mortality event [4].

Again, patients and clinicians may indeed wonder about transitioning from inhaled or parenteral agents to newer oral therapies - especially in those felt to be at high risk of complications inherent to intravenous or subcutaneous delivery of the drug. Although there are some anecdotal discussions and centre-specific protocols for the interconversion of prostacyclin formulations, there has yet to be a rigorously critiqued and widely accepted method for this process and certainly, most practitioners would advise caution in attempting this transition with the newest oral formulations. New data for the transition from inhaled treprostinil or selexipag should soon be available from the TRANSIT-1 study which has completed enrollment.

Ongoing collaboration will be crucial to the successful incorporation of all these therapies and also to the determination of their interchangeability. This is certainly true for any new drugs but especially for rare disease entities like PAH. ■

Disclosure Statement: The author has no conflicts of interest to disclose.


References:

  1. Ghofrani HA, Grimminger F, et al. Riociguat for chronic thromboembolic pulmonary hypertension and pulmonary arterial hypertension: a phase II study. Eur Respir J 2010; 36(4):792-9.
  2. Galiè N, Grünig E, et al. PATENT PLUS: a blinded, randomised and extension study of riociguat plus sildenafil in pulmonary arterial hypertension. Eur Respir J 2015; 45(5):1314-22.
  3. Davey RA, Raina A, Benza RL, et al. Change in PH Therapy from PDE5i to Riociguat Is Associated with Significant Incremental Increase in Cardiac Index, Decrease in Pulmonary Vascular Resistance and Mean Arterial Pressure. JHLT 2016; 35(4):S361.
  4. Sitbon O, McLaughlin VV, et al. Selexipag for the Treatment of Pulmonary Arterial Hypertension. N Engl J Med 2015; 373(26):2522-33.



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