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PAH therapies slashed admissions and deaths.

Barcelona--Targeted therapies for pulmonary arterial hypertension collectively reduced all-cause mortality by 43% compared with placebo, in a meta-analysis of the randomized, placebo-controlled, clinical trials conducted during the last 18 years.

Moreover, treatment reduced by 61% the hospitalization rate for pulmonary arterial hypertension (PAH), an end point with major economic and quality of life consequences, Dr. Nazzareno Galie noted at the annual congress of the European Society of Cardiology.

These findings, while highly significant both statistically and clinically, probably underestimate the true magnitude of treatment benefit in clinical practice because the meta-analysis included negative trials of drugs subsequently denied marketing approval due to lack of efficacy, such as beraprost and terbogrel, as well as studies of approved drugs in non-approved, suboptimal doses.

"This is a very, very conservative approach," said Dr. Galie, professor of cardiology and head of the pulmonary hypertension center at the University of Bologna (Italy).

The meta-analysis offers a rebuttal to critics who claim current therapies for PAH provide only marginal clinical benefit. The critics have trumpeted another meta-analysis that concluded the treatments produced "limited benefits in clinical end points" and failed to support a significant survival advantage (Am. Heart J. 2007;153:1037-47). But this was a seriously flawed meta-analysis that missed six randomized trials available at the time, according to Dr. Galie.

The 21 randomized placebo-controlled trials included in the meta-analysis involved 3,140 PAH patients followed during an average of 14.3 weeks of treatment. The trials involved endothelin-receptor antagonists, thromboxane synthase inhibitors, prostanoids, and phosphodiesterase type-5 inhibitors.

"Interestingly enough, there are four times more commentaries and editorials than there are randomized studies," the cardiologist noted.

All-cause mortality occurred in 1,5% of patients in the active treatment arms, compared with 3.8% of placebo-treated controls. That translated into a need to treat 61.2 patients for 14.3 weeks to prevent one death. The PAH hospitalization rate was 3.2% in the active treatment groups and 8.0% in controls, for a number needed to treat of 19.9.

The database was not of sufficient size to show any significant differences in efficacy for the various drug classes, according to Dr. Galie.

Six-minute walk distance improved with active treatment by a mean of 11% over baseline, or just under 36 m, in the 19 randomized trials reporting this end point.

Small to moderate improvements in various hemodynamic parameters with active treatments were also identified via right heart catheterization. Among these were a 1.84 mm Hg weighted mean reduction in right atrial pressure.

"This is the first time a statistically significant decrease in right atrial pressure has been shown. It is not all that much, but there is no single randomized controlled study with a significant reduction in right atrial pressure," Dr. Galie said.

Although this meta-analysis refutes the argument that current treatments for PAH bring little clinical benefit, Dr. Galie was nonetheless quick to point out he considers these therapies inadequate. Mortality over the intermediate and long term remains high, and many patients have extensive hemodynamic and functional impairments despite treatment.

Another avenue worth pursuing is the use of combined-drug regimens for initial treatment, he said. But regulatory agencies have frowned upon proposals for randomized trials taking this approach, and pharmaceutical companies with competing agents for PAH have been reluctant to participate.

The meta-analysis was funded by the University of Bologna. Dr. Galie disclosed having served on advisory boards for several pharmaceutical companies.
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Title Annotation:CARDIOVASCULAR MEDICINE; pulmonary arterial hypertension
Author:Jancin, Bruce
Publication:Internal Medicine News
Article Type:Report
Geographic Code:4EUSP
Date:Oct 1, 2009
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