Acute effects of the combination of sildenafil and inhaled treprostinil on haemodynamics and gas exchange in pulmonary hypertension

Abstract

Background

Inhaled treprostinil was recently developed for the treatment of pulmonary arterial hypertension (PAH). We investigated the safety and acute haemodynamic effects of the combination oral sildenafil and inhaled treprostinil in an open label study in patients with precapillary pulmonary hypertension.

Methods and patients

Inhaled nitric oxide (20 ppm; n=50), sildenafil (50 mg; n=50) and inhaled treprostinil (15 μg; n=25 or 30 μg; n=25) were applied in subsequent order during right heart catheter investigation to consecutive patients with pulmonary arterial hypertension (PAH; n=28), non-operable chronic thromboembolic pulmonary hypertension (CTEPH; n=17) and pulmonary fibrosis associated pulmonary hypertension (n=5).

Results

Inhaled nitric oxide reduced pulmonary vascular resistance (PVR) to 87.3±5.1% of baseline values, reduced mean pulmonary arterial pressure (PAP) to 89.7±3.5% and increased cardiac output (CO) to 102.4±2.9%. Sildenafil reduced PVR to 80.1±5.0%, mPAP to 86.5±2.9% and increased CO to 103.8±3.2%. Treprostinil, inhaled 1 h after sildenafil, reduced PVR to 66.3±3.8%, mPAP to 77.8±3.3%, and increased CO to 107.1±3.3% (mean±95% confidence interval). Subgroup analysis showed similar acute haemodynamic effects in PAH and CTEPH patients. Ventilation/perfusion distribution measurement in six patients with pre-existing gas exchange limitations was not changed by sildenafil and treprostinil. Relevant side effects were not observed.

Conclusion

The combination of sildenafil and inhaled treprostinil was well tolerated and induced additive, pulmonary selective vasodilatation in pulmonary hypertension patients. This could be of relevance also for long-term treatment of PAH and CTEPH patients.

Introduction

Pulmonary arterial hypertension (PAH) as well as non-operable chronic thromboembolic pulmonary hypertension (CTEPH) are progressive diseases with a poor prognosis if not specifically treated [1], [2]. The development of drugs that target the nitric oxide pathway (phosphodiesterase-5 inhibitors), endothelin receptors (endothelin receptor antagonists) or the prostacyclin pathway (PGI₂ analogues) has lead to significant improvement in exercise capacity, quality of life and survival of PAH patients [3], [4], [5], [6], [7], [8]. With the exception of inhaled iloprost, these drugs are not approved for treatment of pulmonary hypertension (PHT) in non-operable chronic thromboembolic disease. So far, several uncontrolled trials suggested that these drugs may also be beneficial for these patients [9], [10], [11].

Despite the therapies at hand, many patients still develop disease progression and are in need of combination therapy and finally lung transplantation [12]. Controlled clinical trials for combinations of the approved drugs are ongoing. Open label combination therapy is already widely used and resulted in better patient improvement than mono-therapy [13], [14], [15], [16], [17]. Combination therapy may be complicated by accumulating side effects and by increasing complexity of medical treatment that may lead to non-compliance of the patients. Prostanoids have been widely used for treatment of PAH with excellent results. Potent pulmonary vasodilatation, platelet inhibition and long-term anti-remodelling effects have been attributed to prostanoid therapy. The inhalation of iloprost facilitated the first effective non-parenteral prostanoid therapy for PAH, offering a reduced risk profile compared to the i.v. application [3], [13], [18], [19]. However, the frequency of six to nine inhalations per day and the relatively long inhalation time of 5–10 min restricts the early use of inhaled prostanoids in current treatment regimens. Further optimisation of inhaled prostanoid treatment should therefore aim for better patient convenience by lower inhalation frequency and quick drug application.

Treprostinil is a prostacyclin analogue with prolonged half-life that is approved for treatment of PAH via intravenous or subcutaneous infusion [8], [20], [21]. In addition to the vasodilatory effects, it was shown that treprostinil potently reduces vascular smooth muscle cell proliferation [22]. Inhaled treprostinil induces sustained pulmonary vasodilatation and therefore needs only four inhalations per day. The inhalation of up to 60 μg treprostinil with an ultrasonic nebuliser is done in less then 1 min and can be accomplished even in one single breath. It leads to pulmonary selective vasodilation without relevant systemic side effects [23], [24]. Long-term open label treatment with inhaled treprostinil was noted to be effective and without relevant side effects [23], [24], [25].

In this open label study, we addressed the safety, tolerability and haemodynamic effects of the combination of sildenafil and inhaled treprostinil.