Haemodynamic effects of riociguat in inoperable/recurrent chronic thromboembolic pulmonary hypertension

Abstract

Objective: We compared the haemodynamic effects of riociguat in patients with inoperable chronic thromboembolic pulmonary hypertension (CTEPH) or persistent/recurrent CTEPH after pulmonary endarterectomy in the Chronic Thromboembolic Pulmonary Hypertension Soluble Guanylate Cyclase-Stimulator Trial 1 study.

Methods: Patients with inoperable or persistent/recurrent CTEPH (n=261; mean± SD age 59±14 years; 66% women) were randomised to riociguat (up to 2.5 mg three times daily) or placebo. Haemodynamic parameters were assessed at baseline and week 16.

Results: Riociguat decreased pulmonary vascular resistance (PVR) in inoperable (n=189; least-squares mean difference: -285 dyn s/cm5 (95% CI -357 to -213); p<0.0001) and persistent/recurrent (n=72; -131 dyn s/cm5 (95% CI -214 to -48); p=0.0025) patients. Cardiac index improved in inoperable patients by a least-squares mean difference of +0.6 L/min/m2 (95% CI 0.4 to 0.7; p<0.0001), while in persistent/recurrent patients the change was +0.2 L/min/m2 (95% CI -0.1 to 0.5; p=0.17). Mean pulmonary artery pressure decreased in inoperable and persistent/recurrent patients(-4.7 mm Hg (95% CI -6.9 to -2.6; p<0.0001 and -4.8 mm Hg (-8.2 to -1.5; p=0.0055), respectively). For all patients, changes in 6 min walk distance correlated with changes in PVR (r=-0.29 (95% CI -0.41 to -0.17); p<0.0001) and cardiac index (r=0.23 (95% CI 0.10 to 0.35); p=0.0004).

Conclusions: Riociguat improved haemodynamics in patients with inoperable CTEPH or persistent/recurrent CTEPH.

Trial registration number: NCT00855465.

Conflict of interest statement

Competing interests: NHK reports personal fees and non-financial support from Bayer HealthCare Pharmaceuticals; grants and personal fees from Actelion; grants from Gilead, Lung LLC and United Therapeutics. AMD'A reports personal fees from Bayer HealthCare Pharmaceuticals and personal fees from Actelion. FG reports grants, personal fees and non-financial support from Bayer HealthCare Pharmaceuticals and personal fees from Actelion, Lilly, Novartis and Pfizer. EG reports grants, personal fees and non-financial support from Bayer HealthCare Pharmaceuticals, grants and personal fees from Actelion, GSK, Lilly and Pfizer, non-financial support from Alexion and personal fees from Miltenyi, Novartis and United Therapeutics. MMH reports grants, personal fees and non-financial support from Bayer HealthCare Pharmaceuticals and personal fees from Actelion, GSK, Lilly, Novartis and Pfizer. PJ, an investigator for Actelion, reports grants, personal fees and non-financial support from Bayer HealthCare Pharmaceuticals and personal fees from AOP. EM reports personal fees and non-financial support from Bayer HealthCare Pharmaceuticals and personal fees from Actelion, GSK and Pfizer. CN reports grants, personal fees and non-financial support from Bayer HealthCare Pharmaceuticals and personal fees from Actelion, GSK, Novartis and Pfizer. GS reports grants, personal fees and non-financial support from Bayer HealthCare Pharmaceuticals, Actelion, GSK, Lilly and Pfizer and personal fees and non-financial support from Novartis. AT reports grants, personal fees and non-financial support from Bayer HealthCare Pharmaceuticals and grants and personal fees from Actelion, GSK and AOP. CW has nothing to report. AF is an employee of Bayer Pharma AG. ND is an employee of Bayer Pharma AG. H-AG reports grants from Actelion, Bayer HealthCare Pharmaceuticals, Ergonex and Pfizer and personal fees from Actelion, Bayer HealthCare Pharmaceuticals, Ergonex, Gilead, GSK, Merck, Novartis and Pfizer.

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Figures

Figure 1

Boxplots for pulmonary vascular resistance (PVR) at baseline (BL) and CHEST-1 week 16 in the overall population and the inoperable CTEPH and persistent/recurrent PH after PEA subgroups. LS mean treatment effect (95% CI) was determined using ANCOVA. Box: 25th to 75th percentile; horizontal line: median; cross: arithmetic mean; vertical lines extend from the box to a distance of at most 1.5 IQRs; percentages refer to change from baseline in arithmetic mean. Outliers are plotted separately. ANCOVA, analysis of covariance; CHEST-1, Chronic Thromboembolic Pulmonary Hypertension Soluble Guanylate Cyclase–Stimulator Trial 1;CTEPH, chronic thromboembolic pulmonary hypertension; LS, least-squares; PEA, pulmonary endarterectomy; PH, pulmonary hypertension.

Figure 2

Boxplots for cardiac index at baseline (BL) and CHEST-1 week 16 in the overall population and the inoperable CTEPH and persistent/recurrent PH after PEA subgroups. LS mean treatment effect (95% CI) was determined using ANCOVA. Box: 25th to 75th percentile; horizontal line: median; cross: arithmetic mean; vertical lines extend from the box to a distance of at most 1.5 IQRs; percentages refer to change from baseline in arithmetic mean. Outliers are plotted separately. ANCOVA, analysis of covariance; CHEST-1, Chronic Thromboembolic Pulmonary Hypertension Soluble Guanylate Cyclase–Stimulator Trial 1; CTEPH, chronic thromboembolic pulmonary hypertension; LS, least-squares; PEA, pulmonary endarterectomy; PH, pulmonary hypertension.

Figure 3

Correlation scatter plots showing change from baseline to week 16 in (A) 6MWD and PVR and (B) 6MWD and cardiac index. Correlation was assessed using a Spearman's rank analysis. The line of best fit was determined using a linear regression analysis. 6MWD, 6 min walk distance; PVR, pulmonary vascular resistance.