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Bosentan Improves Haemodynamics and Delays Time to Clinical Worsening in Patients With Mildly Symptomatic Pulmonary Arterial Hypertension: Presented at ESC

By Chris Berrie

VIENNA, AUSTRIA -- September 5, 2007 -- The dual endothelin receptor antagonist bosentan is well tolerated and can delay disease progression among patients with mildly symptomatic pulmonary arterial hypertension (PAH), researchers reported here at the European Society of Cardiology (ESC) Congress.

In their study, bosentan significant reduced pulmonary vascular resistance and plasma levels of N-terminal proB-type natriuretic peptide (NT-proBNP), and delayed trend in time to clinical worsening for patients with mildly symptomatic PAH.

These findings suggest that early treatment of patients with World Health Organisation functional class II PAH can delay disease progression, said principal investigator Nazzareno Galié, MD, Associate Professor in Cardiology, Cardiothoracic Department, Institute of Cardiology, University of Bologna, Bologna, Italy.

Dr. Galié presented the results of the prospective, randomised, double-blind, placebo-controlled, parallel-group study on behalf of the Endothelin Antagonist Trial in Mildly Symptomatic PAH Patients (EARLY) investigators.

The rationale for the study was based on the fact that bosentan is indicated for PAH in World Health Organization (WHO) functional class III in Europe and III/IV in the United States, and because prognosis appears better when treatment is started earlier, he explained in his presentation on September 2nd. Therefore, he said, the EARLY study was designed to investigate safety and efficacy of bosentan in mildly symptomatic patients with PAH.

The study included subjects who were aged 12 years or more and had WHO functional class II PAH due to various causes. They were excluded if they had severe obstructive lung disease, total lung capacity <80% of normal, symptomatic lower limb vascular disease, or PAH-specific treatment.

The two coprimary endpoints were pulmonary vascular resistance at rest and change in total distance walked during six minutes (6MWD), both at month 6 and relative to baseline. The main secondary endpoint was trend in time to clinical worsening, with others including changes in WHO functional class, Borg dyspnoea index, quality of life, and various at-rest haemodynamic parameters. A post-hoc analysis monitored change in NT-proBNP concentrations.

Definitions used for clinical worsening were death, hospitalisation for PAH, and symptomatic progression of PAH.

After the 185 patients completed 4 weeks of screening, 92 were randomised to receive placebo and 93 to receive bosentan 62.5 mg BID over 4 weeks, followed by dose escalation to bosentan 125 mg BID for the final 20 weeks. The two groups were similar in terms of age and male/female breakdowns.

Full baseline patient clinical profiles were carried out (placebo vs bosentan): time from diagnosis (3.7 vs 2.9 years); 6-MWT (431 vs 438 m); pulmonary vascular resistance (805 vs 839 dyn.s.cm-5); mean right atrial pressure (7.5 vs 6.9 mmHg); mean pulmonary arterial pressure (52.3 vs 52.5 mmHg); total pulmonary resistance (959 vs 997 dyn.s.cm-5); cardiac index (2.7 vs 2.7 L.min.m-2); mixed venous oxygen saturation (68.0 vs 66.3%); and NT-proBNP (844 vs 706 ng.L-1).

Commenting on the relatively high 6-MWD as compared with other similar trials, Dr. Galié noted, "In these patients there are no signs of right ventricular failure at rest, and this is rather a big difference as compared with other studies."

At the 6-month endpoint, placebo pulmonary vascular resistance was 107% of baseline and for bosentan, 83% of baseline, representing a significantly reduced pulmonary vascular resistance for a treatment effect of 23% in favour of bosentan (P <.0001). The 6-MWD ended at -8 m for placebo patients and +11 m for patients on bosentan, representing a beneficial trend for bosentan in the treatment effect of 19 m (P =.076).

Significance in favour of bosentan was again reached for delay in trend in time to clinical worsening (P =.0114). Within the trend in time to clinical worsening, bosentan had its main beneficial effects on symptomatic progression (placebo, 9 patients; bosentan, 1 patient) and hospitalisations for PAH (3 vs 1 patients). There was one death in each treatment group.

Of note, although bosentan only showed a slight nonsignificant increase in the proportion of patients who improved from WHO FC II to I, the proportion of patients who showed worsening from WHO FC II to III/IV was significantly reduced by bosentan over placebo, with a relative risk in favour of bosentan of 0.26 (95% CI, 0.08-0.90; P =.0285).

Similarly, for quality of life, bosentan produced a beneficial relative risk over placebo in the proportion of patients who improved (relative risk, 1.50; 95% CI, 1.07-2.10; P =.0044), while not affecting those who worsened. Finally, bosentan also significantly reduced NT-proBNP compared with placebo, producing a treatment effect of -471 ng.L-1 (P =.0003).

Bosentan was well tolerated, with a safety profile consistent with that observed in previous studies. Placebo and bosentan produced the same levels of adverse events that led to discontinuation (9.8% vs 9.7%), although placebo patients discontinued largely due to aggravated pulmonary hypertension (6.5% vs 2.2%), which was directly balanced by bosentan discontinuations due to adverse events other than pulmonary hypertension (2.2% vs 6.5%).

Dr. Galié stressed, "The EARLY results indicate that PAH is a progressive disease even in functional class II patients, underlining the need for early identification and treatment, whereby bosentan might indeed be an appropriate treatment for functional class II patients with PAH."

Funding for this research was provided by Actelion Pharmaceuticals Ltd.


[Presentation title: Bosentan Improves Haemodynamics and Delays Time to Clinical Worsening in Patients With Mildly Symptomatic Pulmonary Arterial Hypertension: Results of the EARLY Study. Abstract 1011]

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