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Responder analysis


PAH to CTEPH but add: ‘nonetheless this analysis is the first evaluation of the treatment response of patients with CTEPH using these commonly applied parameters and indicates the efficacy of riociguat in patients with inoperable CTEPH or persistent/recurrent PH after PEA’.1


PAH and PATENT-1 analysis A similar analysis was undertaken with patients with PAH in the 12-week Phase III PATENT-1 study (excluding those on the 1.5mg maximum three times a day dose of riociguat).3,4 At week 12, 49% of treatment-naïve


patients (n=221) and 37% of patients given background PAH-targeted therapy (n=225: 194 were receiving prior treatment with endothelin receptor antagonists (ERAs), and 31 were receiving prior treatment with non-intravenous prostanoids) showed an increase in 6MWD of ≥40m, compared with 20% and 27%, respectively in patients who received


and 47%, respectively at baseline. The proportion of placebo-treated treatment- naïve patients with a cardiac index of ≥2.5l/min/m2


showed a fall from 44% at


baseline to 42% at week 12 compared with a decrease from 53% to 47% among those on background PAH-targeted therapy receiving placebo.


Three-quarters of treatment-naïve, and 72% of patients on background PAH- targeted therapy, had SVO2


≥65% after 12


weeks of riociguat treatment. In contrast the proportion of treatment-naïve and background PAH-targeted therapy patients who received placebo showed a drop of 14% (from 67% to 53% and 55% to 41%, respectively) from baseline to week 12.


The proportion of patients with RAP <8mmHg showed a small rise in patients treated with riociguat (61% to 66% for treatment-naïve patients; 53% to 56% for background PAH-targeted therapy patients) and a fall among those who received placebo from baseline to week 12


“Analysis of PATENT-1 demonstrates that riociguat treatment increases the proportion of patients achieving a range of clinically relevant responder threshold criteria”


placebo (n=126). More patients receiving prior prostanoids (50%) than those receiving ERAs (35%) responded to riociguat. A 21% increase in the proportion of treatment-naïve patients and 15% increase in the proportion of patients on background PAH-targeted therapy with 6MWD ≥380m was seen at week 12. Patients receiving placebo showed a drop of 2% and 5% among those who were treatment-naïve and receiving background PAH-targeted therapy, respectively.


The proportion of treatment-naïve patients treated with riociguat with WHO FC I/II status rose from 55% at baseline to 67% at week 12 compared with no change (59%) among those receiving placebo. The proportion of patients on background PAH-targeted therapy with WHO FC I/II status treated with riociguat increased from 34% to 53% whereas placebo-treated patients in that group rose from 42% to 47% over the same period. A cardiac index of ≥2.5l/min/m2


at


week 12 was recorded by 72% of treatment-naïve and 81% of background PAH-targeted therapy patients treated with riociguat at week 12 – up from 43%


of the study (60% to 47% for treatment- naïve patients; 58% to 51% for background PAH-targeted therapy patients).


Similarly, the proportion of patients with a NT-proBNP level of <1800pg/ml rose from baseline to week 12 in riociguat- treated individuals from baseline to week 12 compared with falls over the same timescale among those receiving placebo. Among treatment-naïve patients receiving riociguat, the proportion rose from 79% at baseline to 89% at week 12, whereas for patients who had received background PAH-targeted therapy, the proportion with NT-proBNP level of <1800pg/ml rose from 84% to 90% over the same period. Equivalent proportions for treatment-naïve and background PAH-targeted therapy patients given placebo were 78% to 72% and 81% to 73%, respectively. Finally, a combined measure


(including 6MWD ≥380m, WHO FC I/II, cardiac index ≥2.5l/min/m2


, NT-proBNP <1800pg/ml, and SvO2 ≥65%) was seen in


15% of riociguat-treated (n=193) and 13% of placebo-treated (n=93) patients at baseline. At 12 weeks the proportions rose


to 34% and 16%, respectively. The authors mention the study has several limitations. For example, ‘the responder thresholds of 6MWD ≥40m, NT-proBNP <1800pg/ml, and SvO2


≥65%


have not been validated in independent studies and do not form part of the current treatment goals for patients with PAH. Additionally, although the responder analyses were pre-planned for the total population, the analyses for the sub-groups were post hoc. These analyses are descriptive only, and firm conclusions regarding the significance of the observed differences are speculative only’.3 They conclude: ‘analysis of PATENT-1 demonstrates that riociguat treatment increases the proportion of patients achieving a range of clinically relevant responder threshold criteria. These improvements were consistent in treatment-naïve patients and patients receiving background therapy with ERAs or prostanoids, highlighting the consistent efficacy of riociguat in these different patient populations’. They add that ‘data from the ongoing long-term extension study, PATENT-2, are expected to help establish whether these responder criteria correlate with improved long-term outcomes’.3,5


Conclusions


For the first time, clinical response criteria have been applied to data for patients with inoperable CTEPH or persistent or recurrent PH after PEA who received placebo or riociguat. The analyses, along with a similar exercise in a group of patients with pulmonary hypertension, provide further insight into the efficacy of riociguat. l


References 1. D’Armini AM et al. Use of responder threshold criteria to evaluate the response to treatment in the Phase III CHEST-1 study. J Heart Lung Transplant 2015;34:348–55.


2. Ghofrani HA et al. Riociguat for the treatment of chronic thromboembolic pulmonary hypertension. N Engl J Med 2013;369:319–29.


3. Langleben D et al. Use of clinically relevant responder threshold criteria to evaluate the response to treatment in the Phase III PATENT-1 study. J Heart Lung Transplant 2015;34:338–47.


4. Ghofrani HA et al. Riociguat for the treatment of pulmonary arterial hypertension. N Engl J Med 2013;369:330–40.


5. Rubin LJ et al. Riociguat for the treatment of pulmonary arterial hypertension: a long-term extension study (PATENT-2). Eur Resp J 2015;45:130–13.


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