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Sildenafil Produces Significant Haemodynamic Response in Patients With Pulmonary Arterial Hypertension Treated With Bosentan: Presented at ESC

By Chris Berrie

VIENNA, AUSTRIA -- September 6, 2007 -- A single oral dose of sildenafil has beneficial haemodynamic effects when added to bosentan in patients with pulmonary arterial hypertension (PAH), according to study results presented here at the European Society of Cardiology (ESC) Congress.

Use of the phosphodiesterase type 5 inhibitor sildenafil raised no clinically relevant safety concerns and resulted in significant reductions in pulmonary vascular resistance (PVR) and total pulmonary resistance (TPR) in the international, multicentre, open-label, noncomparative, prospective Combination Bosentan and Sildenafil in PAH (COMPASS-1) study.

"Within the last 10 years, there has been a remarkable improvement in the treatment of pulmonary arterial hypertension, and there have been many different medical treatments developed," said the study's principal investigator for Germany, Ekkehard Gruenig, MD, Associate Professor and Head, Pulmonary Hypertension Unit, Thorax Clinic, University of Heidelberg, Heidelberg, Germany.

However, individually, none of these treatments normalise patients' exercise capacity, as seen on the 6-minute walking test. The next step is therefore to consider combination therapy for these patients.

However, although both sildenafil and bosentan are approved for the treatment of PAH and their combination appears to be well tolerated, mutual pharmacokinetic interactions have been reported -- bosentan decreases the plasma concentrations of sildenafil, and sildenafil increases the plasma concentrations of bosentan.

The COMPASS-1 study was designed to evaluate the effects of a single dose of sildenafil on cardiopulmonary haemodynamics in patients with PAH who were under chronic bosentan treatment. These patients received a single oral 25-mg dose of sildenafil in combination with their bosentan therapy during right heart catheterisation (RHC). RHC was performed on four occasions: baseline 1; after the vasoreactivity test with nitric oxide; prior to sildenafil administration (baseline 2); and 60 minutes after sildenafil dosing.

Main inclusion criteria were age 18 years or older, and idiopathic or familial PAH diagnosed by RHC and of World Health Organisation Functional Class (WHO FC) II-III associated with corrected congenital systemic-to-pulmonary shunts or with drugs/toxins. Other inclusion criteria were treatment with bosentan 125 mg BID monotherapy for at least 12 weeks, and a negative vasoreactive test within 2 years before the start of bosentan treatment.

The primary endpoint was reduction in PVR from baseline 2 to 60 minutes after sildenafil dosing. The secondary endpoints were reduction from baseline 2 to 60 minutes postsildenafil for both TPR and N-terminal proB-type natriuretic peptide (NT-proBNP) and a positive acute vasoreactivity test on study day.

Of 45 patients enrolled (mean age, 52.6 years; male, 24.6%), 44 received treatment and 40 were analysed per protocol. Their baseline 1 clinical characteristics included 80% with an idiopathic aetiology, while 42.2% and 57.8% had WHO FC II and III, respectively. Mean 6-MWT was 408.9 m.

The primary endpoint was satisfied, with sildenafil seen to acutely reduce PVR by 15.2% in these bosentan-treated patients (P <.0001). Similarly, there was a significant 13.3% reduction in the secondary endpoint of TPR (P <.001). However, NT-proBNP showed nonsignificant change. "This was probably due to the fact that the 60-minute time interval was too short for [significant] changes in NT-proBNP," Dr. Gruenig explained.

One patient was seen to be vasoreactive according to European Society of Cardiology (ESC) guidelines.

Two other efficacy measures that benefited significantly from sildenafil treatment were mean pulmonary arterial pressure (9.1% decrease; P <.0001), and cardiac output (5.8% increase; P =.0015).

There were no serious adverse events and there were no adverse events related to bosentan treatment. Similarly, there were no patients with a significant decrease in systemic blood pressure, although two patients did have adverse events related to sildenafil treatment.

This study thus confirms that sildenafil can have acute haemodynamic effects when added to bosentan treatment in patients with PAH, Dr. Gruenig concluded. "This study may provide the pharmacodynamic basis for adding sildenafil to bosentan when treating patients [with PAH] with combination therapy," he added.

Funding for this research was provided by Actelion Pharmaceuticals Ltd.


[Presentation title: Acute Administration of Sildenafil in Patients With Pulmonary Arterial Hypertension (PAH) Treated With Bosentan Produced a Significant Haemodynamic Response: Results of the COMPASS-1 Study. Abstract 1012]

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