BARCELONA (FRONTLINE MEDICAL NEWS) – Off-label use of the phosphodiesterase-5 inhibitor sildenafil to treat residual pulmonary hypertension after successful correction of valvular heart disease is not merely ineffective, it’s counterproductive, according to the results of the randomized, placebo-controlled SIOVAC study.

“We believe based upon our results that off-label use of sildenafil in patients with left heart disease-pulmonary hypertension due to valvular disease should be discouraged,” Javier Bermejo, MD, declared at the annual congress of the European Society of Cardiology.

Sildenafil is approved with a solid, evidence-based indication for treating some other types of pulmonary hypertension. Many cardiologists also prescribe the drug off label for residual pulmonary hypertension in patients with corrected valve disease, hoping that it will be of benefit, since there is currently no approved treatment for this common and serious condition associated with increased mortality. But because the anecdotal literature on sildenafil for this specific type of pulmonary hypertension is mixed, Dr. Bermejo and his coinvestigators in the Spanish Network Center for Cardiovascular Research decided to conduct a multicenter randomized trial.

SIOVAC (Sildenafil for Improving Clinical Outcomes After Valvular Correction) comprised 200 patients with residual pulmonary hypertension after corrected valvular heart disease at 17 Spanish general hospitals. The patients were randomized to receive sildenafil at 40 mg t.i.d. or placebo for 6 months in this double-blind trial.

The primary endpoint was a standardized composite clinical score widely used in heart failure trials. It consists of all-cause mortality, hospital admission for heart failure, worsening exercise tolerance, and deterioration in a global self-assessment rating.

The shocker for the investigators – who had expected a positive study – was that 33% of patients in the sildenafil group worsened significantly on the composite clinical score at 6 months, compared with 14% of placebo-treated controls, said Dr. Bermejo, a cardiologist at Gregorio Marañón University Hospital in Madrid.

Moreover, only 27% of the sildenafil group improved, compared with 44% of controls. About one-third of patients in both groups remained unchanged over the course of the 6-month trial.

Dr. Bermejo noted that valvular disease is considered the next cardiac epidemic because of its strong association with advancing age and the rapid aging of the population worldwide. Pulmonary hypertension occurs is virtually all patients with severe mitral disease and in up to two-thirds of those with asymptomatic aortic stenosis. Regression of the pulmonary hypertension is often incomplete after successful surgical or transcatheter correction of the valvular lesion.

Discussant Irene M. Lang, MD, called SIOVAC “a very clear study.” It convincingly establishes that sildenafil – a vasodilator – is ineffective for the treatment of what the current ESC/European Respiratory Society guidelines on pulmonary hypertension call isolated post-capillary pulmonary hypertension, a condition defined hemodynamically by a diastolic pulmonary vascular pressure gradient of less than 7 mm Hg and/or a pulmonary vascular resistance below 3 Wood units (Eur Heart J. 2016 Jan 1;37[1]:67-119.)

The SIOVAC findings underscore the strong IIIC recommendation in the European guidelines that the use of approved therapies for pulmonary arterial hypertension is not recommended in patients with left heart disease-pulmonary hypertension, added Dr. Lang, a coauthor of the guidelines and professor of vascular biology at the Medical University of Vienna.

The Spanish government funded SIOVAC. Dr. Bermejo reported having no financial conflicts of interest.