Sex Differences in Response to Tadalafil in Pulmonary Arterial Hypertension

doi:10.1378/chest.14-0263

Chest

Volume 147, Issue 1, January 2015, Pages 188-197

https://doi.org/10.1378/chest.14-0263 Get rights and content

BACKGROUND

Pulmonary arterial hypertension (PAH) is a progressive disease with high rates of morbidity and mortality. Current therapies improve symptoms, functional capacity, and, in select cases, survival. Little is known about patient factors that may predict the likelihood of patient-important, clinically relevant responses to therapy such as the 6-min walk distance (6MWD) and health-related quality of life (HRQoL).

METHODS

Data from the randomized clinical trial of tadalafil in PAH were used. Adjusted logistic regression models were created to examine the relationship between baseline characteristics and odds of achieving the minimal important difference (MID) in three parameters, defined as either a > 33-m increase in 6MWD, a > 5-unit increase in physical component summary score of the Medical Outcomes Study Short Form-36 (SF-36), or a > 5-unit increase in mental component summary score of the SF-36.

RESULTS

The study included 405 subjects. Younger age, male sex, lower baseline 6MWD, and disease etiology were associated with greater odds of achieving the MID for the 6-min walk test. Active treatment, younger age, and male sex were associated with greater odds of achieving the MID for the physical component summary score. Male sex was associated with greater odds of achieving the MID for the mental component summary score.

CONCLUSIONS

Age, sex, baseline functional capacity, and disease etiology are variably associated with the likelihood of achieving clinically relevant responses in patient-important outcomes to PAH-specific therapy such as 6MWD and HRQoL. The increased likelihood of response in men compared with women is a novel finding and may reflect pathophysiologic differences between sexes.

Section snippets

Materials and Methods

The Pulmonary Arterial Hypertension and Response to Tadalafil (PHIRST) trial was a double-masked, placebo-controlled, 16-week study of 405 patients with PAH, including both treatment-naive patients and patients on background therapy with the ERA bosentan.⁵ The primary outcome was change from baseline to week 16 in 6MWD. Secondary outcome measures included HRQoL as assessed by the Medical Outcomes Study 36-item Short Form (SF-36) version 2 collected at baseline and at week 16. The 6MWT was

Results

As shown in Table 1, 405 subjects who completed the PHIRST trial were included in this analysis. The majority of subjects were white women who were, on average, 53 years of age. Most had idiopathic PAH, but approximately one-quarter had connective tissue disease (CTD)-related PAH. A minority had anorexigen-associated PAH or PAH related to congenital heart disease. At baseline, most subjects had WHO FC II or III disease and had a moderate degree of functional impairment based upon baseline 6MWT.

Discussion

In this study, we report the association between patient characteristics and treatment response in patients with PAH. To our knowledge, this is the first study to examine the relationship between baseline demographic, clinical, and functional parameters and the attainment of patient-important, clinically relevant responses to PAH-specific therapy. Our data show that immutable patient characteristics, such as age, sex, and type of disease, influence the likelihood of response to therapy.

Acknowledgments

Author contributions: S. C. M. served as principal author, drafted the manuscript, had full access to all of the data in the study, and takes responsibility for the integrity of the data and the accuracy of the data analysis. S. C. M., P. M. H., M. A. P., and R. A. W. contributed to the conception and design of the study and S. C. M., P. M. H., M. A. P., Y. Z., and R. A. W. contributed to data analysis and interpretation, and revision and final approval of the manuscript.

Financial/nonfinancial

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This study was presented in abstract form at the American Thoracic Society International Meeting 2013, May 17-22, 2013, Philadelphia, PA.

FUNDING/SUPPORT: This study was supported by the National Heart, Lung, and Blood Institute [Grant K23 HL093387 to Dr Mathai].

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

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Chest

Original Research: Pulmonary Vascular DiseaseSex Differences in Response to Tadalafil in Pulmonary Arterial Hypertension

BACKGROUND

METHODS

RESULTS

CONCLUSIONS

Section snippets

Materials and Methods

Results

Discussion

Acknowledgments

J Am Coll Cardiol

Health Qual Life Outcomes

Chest

J Am Coll Cardiol

Am J Cardiol

Chest

Chest

Chest

Am Heart J

J Am Coll Cardiol

Chest

Chest

Respir Med

Bosentan therapy for pulmonary arterial hypertension

N Engl J Med

Pulmonary veno-occlusive disease: the bête noire of pulmonary hypertension in connective tissue diseases?

Presse Med

Primary Pulmonary Hypertension Study Group A comparison of continuous intravenous epoprostenol (prostacyclin) with conventional therapy for primary pulmonary hypertension

N Engl J Med

Pulmonary Arterial Hypertension and Response to Tadalafil (PHIRST) Study Group Tadalafil therapy for pulmonary arterial hypertension

Circulation

Circulation

Sildenafil Use in Pulmonary Arterial Hypertension (SUPER) Study Group Sildenafil citrate therapy for pulmonary arterial hypertension

N Engl J Med

Treprostinil Study Group Continuous subcutaneous infusion of treprostinil, a prostacyclin analogue, in patients with pulmonary arterial hypertension: a double-blind, randomized, placebo-controlled trial

Am J Respir Crit Care Med

Tadalafil therapy and health-related quality of life in pulmonary arterial hypertension

Curr Med Res Opin

Imatinib mesylate as add-on therapy for pulmonary arterial hypertension: results of the randomized IMPRES study

Circulation

PATENT-1 Study Group Riociguat for the treatment of pulmonary arterial hypertension

N Engl J Med

Original Research: Pulmonary Vascular Disease
Sex Differences in Response to Tadalafil in Pulmonary Arterial Hypertension