Elsevier

Thrombosis Research

Volume 126, Issue 1, July 2010, Pages e51-e56
Thrombosis Research

Regular Article
Bosentan for chronic thromboembolic pulmonary hypertension: Findings from a systematic review and meta-analysis

https://doi.org/10.1016/j.thromres.2010.01.007Get rights and content

Abstract

Background

After acute pulmonary embolism, chronic thromboembolic pulmonary hypertension (CTEPH) is diagnosed in about 1% of patients. We performed a systematic review and meta-analysis aimed at assessing the effects of bosentan therapy in patients with CTEPH.

Methods

We searched in MEDLINE and Embase using the terms ‘pulmonary hypertension’ AND ‘bosentan’. Papers were included in this review if they reported on patients with objectively confirmed CTEPH treated with bosentan. Efficacy measures were the improvement in NYHA class, in 6 minute walking distance (6mwd) and in hemodynamics (cardiac index, pulmonary artery pressure, pulmonary vascular resistance). Mortality and safety were also assessed.

Results

Overall, 543 papers were found. Eight single-arm cohort studies (175 patients), one randomized double-blind study, one case-control study and one case report were included in the analysis.

A 35.9 meters weighted mean increase in 6 minute walking distance was observed after 3-6 months of treatment (9 studies, 208 patients) (95% CI 33.6 to 38.2; p < 0.001) and an additional increase of 21 meters after one year (4 studies, 80 patients). About 25% of patients had an improvement on functional NYHA class at 3-6 months. Data on hemodynamics were available in seven studies, 185 patients. The mean weighted increase in cardiac index at 3-6 months was 0.23 l/min/m2 (95% CI 0.22 to 0.25); the mean weighted decrease in pulmonary artery pressure at 3-6 months was 2.62 mmHg (95% CI 2.44 to 2.80). Three patient died within 3-6 months (1.4%) and 3 additional patients died within one year.

Conclusions

Bosentan therapy is associated with an improvement of hemodynamics and probably exercise capacity in patients with CTEPH. Controlled data on mortality and time to clinical worsening in patients with CTEPH are needed.

Introduction

Chronic thromboembolic pulmonary hypertension (CTEPH) is diagnosed in about 1% (ranging from 0.1 to 3%) of patients after acute pulmonary embolism [1]. CTEPH is currently deemed as the clinical consequence of single or recurrent pulmonary emboli that, for still unknown reasons, do not resolve completely [2] . Persistent pulmonary emboli can proceed asymptomatic or induce pulmonary hypertension (PH) leading to progressive right heart failure [3].

Pulmonary endarterectomy (PEA) is the treatment of choice for patients with CTEPH as it can reduce and sometimes cure PH [4]. The reported five-year survival rate in patients not undergoing surgery is 30% among those with a mean pulmonary artery pressure (PAP) above 40 mmHg and 10% among those with a mean PAP above 50 mmHg [5], [6].

In about 10% of patients PH persists despite the removal of significant amounts of organised thrombus. The clinical benefit of medical therapies for patients with persistent PH after PEA as well as for patients with distal lesions who are not candidates for PEA remains undefined.

Bosentan, an oral endothelin receptor antagonist currently recommended for the treatment of idiopathic pulmonary arterial hypertension, has been proposed as a potential treatment for inoperable CTEPH or persistent CTEPH after PEA.

We performed a systematic review and meta-analysis aimed at evaluating the potential clinical benefits of bosentan therapy in patients with CTEPH.

Section snippets

Identification and selection of articles

Relevant articles were identified by searching MEDLINE (1998 to present) and EMBASE (1998 to present) with the following key words: pulmonary hypertension and bosentan. Furthermore, reference lists of retrieved articles and review articles were manually reviewed to implement our search.

Papers were excluded from this review if they reported on patients with other causes of PH different from CTEPH. In the case of duplicate or redundant publications the most recent and/or most informative was

Study Selection

Overall, 543 papers were found using the search key words/terms ‘pulmonary hypertension’ AND ‘bosentan’ from January 1st 1998 to June 1st, 2009 (Fig. 1).

Fourteen studies were found where CTEPH patients had been assigned to receive bosentan therapy. Three studies were excluded as they did not exclusively include CTEPH patients and extrapolation of data on patients with CTEPH was not possible [20], [22]. Eleven studies were included in the systematic review, one was a randomized placebo

Exercise capacity

6MWD was the primary outcome in most of the selected studies. Nine studies (208 patients) reported on the 6MWD at 3-6 months from the start of bosentan therapy [14], [15], [18], [19], [22], [24], [26], [27]. The weighted mean increase in 6MWD after 3-6 months of treatment was 35.9 meters (95% CI 33.6 to 38.2; p < 0.001). The median increase in 6MWD at 3-6 months was 49 meters (range 2.9 to 92 meters).

Four studies (80 patients) reported on the 6MWD at one year from the start of bosentan therapy [14],

Meta-analysis

One randomized placebo-controlled study and one case-control study were found aimed at evaluating the clinical benefit of bosentan in patients with objectively confirmed CTEPH. PVR at rest at week 16 expressed as a percent of the baseline value or change from baseline to week 16 in 6MWD was the co-primary endpoint of the randomized study. Functional class and 6MWD were the primary end points of the case-control study.

Overall, 6MWD at 3-6 months was evaluated in 84 patients receiving bosentan and

Discussion

Our critical review shows that a three - six month bosentan therapy can obtain a benefit in exercise capacity and pulmonary hemodynamics in patients with CTEPH. With respect to exercise capacity, the critical review showed a significant improvement in the 6MWD after three-six months of therapy and a mild further increase in the 6MWD at one year in patients receiving bosentan beyond the initial 3-6 months. The improvement in 6MWD was only partially confirmed in the meta-analysis after four months

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      Oral bosentan did not show improvement in exercise capacity. A systematic review of 10 observational studies and the BENEFiT trial found that in inoperable patients with CTEPH, oral bosentan was associated with improvement in baseline exercise capacity as measured by the 6MWT, as well as decreased mPAP and increased cardiac index compared to controls.102 Given this promising data, the MERIT-1 trial with macitentan, a newer-generation endothelin receptor antagonist, is currently underway in patients with inoperable CTEPH with the primary endpoint being the change in PVR 16 weeks after therapy compared to placebo.

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      Small vessel disease in CTEPH has provided the rationale for the use of PAH-targeted medical therapy in non-operable patients with CTEPH or patients with persistent PH after PEA. Some case series or uncontrolled studies have provided evidence for improvement in exercise capacity and haemodynamics with the use of bosentan, epoprostenol, sildenafil, treprostinil [40–43]. The positive experience gained from these studies led to the first randomized, placebo-controlled trial in patients with inoperable CTEPH.

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    This review was performed without any external support.

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