Selective serotonin reuptake inhibitor use and outcomes in pulmonary arterial hypertension

Abstract

Background

Pulmonary arterial hypertension (PAH) is characterized by elevated pulmonary vascular resistance which leads to right ventricular failure. Serotonin and the serotonin transporter play an important role in animal and human studies of PAH. We therefore hypothesized that PAH patients treated with high-affinity selective serotonin reuptake inhibitors (SSRIs) would have a reduced risk of death compared to PAH patients not treated with SSRIs.

Methods

We performed a retrospective cohort study of 84 consecutive adult PAH patients who underwent initial evaluation from January 1994 to June 2002 at the Pulmonary Hypertension Center of the New York Presbyterian Hospital. Patient–time while receiving high-affinity SSRIs (K_d<1 nmol) (paroxetine, sertraline, or fluoxetine) was considered “exposed”. Patient–time while receiving tricyclic, atypical, or no antidepressants was considered “unexposed”.

Results

Thirteen of the 84 patients (15%) used high-affinity SSRIs during the study period. Five patients were taking high-affinity SSRIs at baseline and 8 initiated high-affinity SSRIs during the follow-up period. The median time from baseline evaluation until initiation of high-affinity SSRIs was 125 (0–1227) days. The median duration of high-affinity SSRI use was 482 (110–1624) days and the total at-risk time on high-affinity SSRIs was 18.1 person-years. Seventy-nine (94%) patients were treated with warfarin; 38 (45%) received continuous intravenous epoprostenol; 12 (14%) received continuous subcutaneous treprostinil, and 23 (27%) were treated with oral bosentan. The median follow-up was 764 days. Twenty-four patients died and one underwent lung transplantation during the study period.

There were no differences in age, gender, diagnosis, hemodynamics, or incidence of acute vasoreactivity between SSRI users and non-users. The risk of death for high-affinity SSRI users was lower but not statistically significantly different from that of non-users (hazard ratio=0.53, 95% CI 0.07 to 3.9, $p=0.53$). Adjustment for demographics, diagnosis, hemodynamics, or other therapies did not significantly change this result.

Conclusions

SSRI use was associated with a 50% reduction in the risk of death in a cohort of PAH patients which was not statistically significant. Larger cohort studies may better define this relationship; an adequately powered trial of high-affinity SSRIs in PAH patients may be warranted.

Introduction

Pulmonary arterial hypertension (PAH) is characterized by elevated pulmonary vascular resistance and right ventricular failure. Many studies support a role for serotonin in the pathophysiology of PAH. Patients with PAH have increased free plasma serotonin levels, which persist beyond explantation of the diseased lungs [1]. Overexpression of the gene for the serotonin transporter (SERT), which brings serotonin into cells, results in increased pulmonary artery pressure [2]. Hypoxia- and monocrotaline-induced pulmonary hypertension in animal models is inhibited by fluoxetine, a selective serotonin reuptake inhibitor (SSRI) that blocks the SERT [3], [4]. Studies have also suggested a protective effect of SSRI use in coronary artery disease [5], [6], [7]. Although these findings provide a rationale for randomized controlled trials of SSRIs in PAH, there are no published clinical data regarding SSRI use in PAH patients, making a clinical trial premature. We hypothesized that PAH patients treated with high-affinity SSRIs would have a reduced risk of death compared to PAH patients not treated with SSRIs.