Chest
Volume 143, Issue 6, June 2013, Pages 1699-1708
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Original Research
Diffuse Lung Disease
Sildenafil Preserves Exercise Capacity in Patients With Idiopathic Pulmonary Fibrosis and Right-sided Ventricular Dysfunction

https://doi.org/10.1378/chest.12-1594Get rights and content

Abstract

Objective

The purpose of this study was to determine whether sildenafil improves 6-min walk distance (6MWD) in subjects with IPF and right ventricular dysfunction.

Methods

The IPFnet, a network of IPF research centers in the United States, conducted a randomized trial examining the effect of sildenafil on 6MWD in patients with advanced IPF, defined by carbon monoxide diffusing capacity < 35% predicted. A substudy examined 119 of 180 randomized subjects where echocardiograms were available for independent review by two cardiologists. Right ventricular (RV) hypertrophy (RVH), right ventricular systolic dysfunction (RVSD), and right ventricular systolic pressure (RVSP) were assessed. Multivariable linear regression models estimated the relationship between RV abnormality, sildenafil treatment, and changes in 6MWD, St. George's Respiratory Questionnaire (SGRQ), the EuroQol instrument, and SF-36 Health Survey (SF-36) from enrollment to 12 weeks.

Results

The prevalence of RVH and RVSD were 12.8% and 18.6%, respectively. RVSP was measurable in 71 of 119 (60%) subjects; mean RVSP was 42.5 mm Hg. In the subgroup of subjects with RVSD, subjects treated with sildenafil experienced less decrement in 6MWD (99.3 m; P = .01) and greater improvement in SGRQ (13.4 points; P = .005) and EuroQol visual analog scores (17.9 points; P = .04) than subjects receiving placebo. In the subgroup with RVH, sildenafil was not associated with change in 6MWD (P = .13), but was associated with greater relative improvement in SGRQ (14.8 points; P = .02) vs subjects receiving placebo. Sildenafil treatment in those with RVSD and RVH was not associated with change in SF-36.

Conclusions

Sildenafil treatment in IPF with RVSD results in better preservation of exercise capacity as compared with placebo. Sildenafil also improves quality of life in subjects with RVH and RVSD.

Section snippets

Setting and Participants

The complete STEP-IPF protocol has been previously published.6 See e-Appendix 2 for a full description of the study methods. This was a double-blind, placebo-controlled trial of sildenafil in patients with advanced IPF and was conducted at 14 IPFnet centers (e-Appendix 1). All subjects provided written informed consent. The study was approved by institutional review boards at participating institutions. Eligibility criteria included consensus criteria-defined IPF and carbon monoxide diffusing

Results

Of 180 subjects enrolled into STEP-IPF, echocardiograms from 119 were available for independent review (sildenafil, n = 56; placebo, n = 63) (Fig 1). The remaining 61 echocardiograms could not be transferred to the echocardiogram core for review due to inability of clinical centers to obtain institutional review board permission for data transfer. No significant difference was detected in the high-resolution CT image scoring or pathology scoring for patients treated with sildenafil vs placebo

Discussion

We have demonstrated that sildenafil treatment results in significantly better exercise capacity and QOL in IPF for subjects with RVSD present on echocardiogram. It has previously been demonstrated that PH results in exercise limitation in patients with IPF.14 Prior work suggests that sildenafil leads to preferential pulmonary artery vasodilation in well-ventilated lung tissue and may improve ventilation-perfusion matching and gas exchange in IPF.4 Hence, STEP-IPF hypothesized that sildenafil

Acknowledgments

Author contributions: Drs Han and Anstrom had full access to all of the data and take responsibility for the integrity and accuracy of the data analysis.

Dr Han: contributed to study conception and design; data collection, analysis, and interpretation; writing of the manuscript; and served as principal author.

Dr Bach: contributed to data analysis and interpretation, and writing of the manuscript.

Dr Hagan: contributed to data analysis and interpretation, and writing of the manuscript.

Mr Yow:

References (23)

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    A controlled trial of sildenafil in advanced idiopathic pulmonary fibrosis

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    Funding/Support: This work is supported by funding from National Institutes of Health/National Heart, Lung and Blood Institute [Grants K23 HL093351 and U10HL080509 (data coordinating center), U10HL80413, U10HL80274, U10HL80370, U10HL80371, U10HL80383, U10HL80411, U10HL80509, U10HL80510, U10HL80513, U10HL80543, U10HL80571, and U10HL80685 (clinical centers)]; by the Cowlin Fund at the Chicago Community Trust; by Pfizer Inc, which donated sildenafil and matching placebo; and by Masimo Corp, which donated pulse oximeters.

    Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details.

    *

    A complete list of study participants is located in e-Appendix 1.

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