Conference: 2017 PH Professional Network Symposium
Release Date: 10.06.2017
Presentation Type: Abstracts
File Download: 2017 PHPN Abstract 1008
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Abstract presented at the 2017 PH Professional Network Symposium held in Bethesda, MD on October 5-7, 2017
To establish the optimal washout period for switching from PDE5i to riociguat in patients with pulmonary arterial hypertension (PAH) who have an inadequate response to PDE5i.
PDE5i and the soluble guanylate cyclase (sGC) stimulator riociguat are treatments for PAH that target the nitric oxide (NO)–sGC–cyclic guanosine monophosphate (cGMP) pathway at separate molecular targets. Patients with PAH exhibit endothelial dysfunction resulting in decreased NO bioavailability and low levels of intracellular cGMP, which may render PDE5i ineffective, and many PAH patients receiving PDE5i do not reach treatment goals. Concomitant administration of PDE5i with riociguat is contraindicated, as an increased risk of side effects over the long term (particularly hypotension) and no evidence of a positive benefit:risk ratio were observed in the PATENT PLUS study (Galiè et al. Eur Respir J 2015;45:1314-1322). Riociguat stimulates sGC through an NO-independent mechanism, meaning that its mechanism of action is unaffected by the decreased NO levels characteristic of patients with PAH. Therefore, switching patients with insuff icient response to PDE5i to riociguat may optimize signaling in the NO–sGC–cGMP pathway.
We reviewed published and unpublished data for PDE5i (sildenafil and tadalafil) and riociguat, and data from PATENT PLUS to propose a washout period for patients switching between these agents.
PDE5i are contraindicated with organic nitrates, as this can cause a profound, synergistic drop in blood pressure. As pharmacodynamic data (blood pressure and heart rate) show no interaction between sildenafil and nitrates after 24 hours’ washout (six sildenafil half-lives), a 24-hour sildenafil washout period before starting nitrates is recommended. Interaction studies showed a moderate additive, but not synergistic, effect of riociguat and sildenafil on blood pressure; therefore, a 24-hour washout period should also be appropriate before starting riociguat.
Tadalafil labeling recommends a 48-hour washout before starting nitrates, derived from findings that the hypotensive tadalafil–nitrate interaction is no longer present after 48 hours. There are no available data on concomitant therapy with riociguat and tadalafil; however, based on the available evidence, a 48-hour washout period is proposed for switching from tadalafil to riociguat.
Data from the PDE5i and nitrate interaction studies indicate the effectiveness of a 24-hour (sildenafil) or 48-hour (tadalafil) washout period for reducing the interaction between PDE5i and nitrates. The use of the same washout periods for switching from PDE5i to riociguat represents an appropriate balance between safe transition and minimizing the delay during which patients may be deprived of treatment and at risk of deterioration. In line with American Thoracic Society recommendations (Hill et al. Ann Am Thorac Soc 2015;12:269-273) and the US prescribing information for riociguat, in the ongoing REPLACE study, riociguat treatment will be started after a washout period of 24 hours with previous sildenafil therapy and 48 hours with previous tadalafil therapy.