October 21, 2014
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PDE5 inhibition improved cardiac remodeling, performance in meta-analysis

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Long-term, continuous administration of phosphodiesterase type 5 inhibitors may be a safe and effective treatment for CVD, according to a new report in BMC Medicine.

Researchers conducted a meta-analysis of randomized, placebo-controlled trials that assessed the impact of phosphodiesterase type 5 (PDE5) inhibitors on cardiac morphology and function. Included trials were published from March 2012 to December 2013 and studied continuous, daily or alternate-day administration of PDE5 inhibitors and reported CV-related outcomes related to cardiac geometry, performance and hemodynamic/endothelial parameters.

“For many years, the use of selective PDE5 inhibitors has been limited to on-demand administration for erectile dysfunction,” Elisa Giannetta, MD, PhD, from the department of experimental medicine, Sapienza University of Rome, and colleagues wrote. The drugs have also been shown in clinical and preclinical studies to have a potential effect on hemodynamics, right ventricular performance and oxygenation in patients with pulmonary arterial hypertension; lower urinary tract symptoms; angina relief; ischemia/reperfusion injury, MI, doxorubicin-induced cardiotoxicity, hypertrophic cardiac remodeling and HF. “The potential role of PDE5 inhibitors in non-urological fields continued to attract interest,” the researchers wrote.

The new analysis included 1,622 patients across 24 trials who were randomly assigned to PDE5 inhibition (n=954) or placebo (n=772). Patients received sildenafil (Viagra, Revatio; Pfizer) in 18 trials (n=694), tadalafil (Adcirca, Lilly) in four trials (n=54) and vardenafil (Levitra, Staxyn; Bayer HealthCare) in two trials (n=218).

Effects of PDE5 inhibition

Results from the meta-analysis demonstrated a reduction in left ventricular mass index among patients with LV hypertrophy who received sustained PDE5 inhibition (–12.21 g/m2; P<.001), but not in the full study population across five trials. Sustained inhibition was also associated with increased end-diastolic volume (5 mL/m2; P<.001) among patients without LV hypertrophy, but no significant change was observed in the main analysis across four trials.

The researchers observed no significant differences between PDE5 inhibition and placebo in interventricular septum or ventricular transverse diameter in two studies with evaluable data.

Across seven studies of 520 patients, patients who received PDE5 inhibition with sildenafil or vardenafil exhibited a significant increase in cardiac index (0.3 L/min/m2) compared with placebo. Results of a subgroup analysis indicated that these effects were present among patients without LV hypertrophy (0.354 L/min/m2) and those with left (0.298 L/min/m2) or right heart disease (0.309 L/min/m2; P<.001 for all).

Data on ejection fraction were available in six studies of 286 patients. In this population, patients who received sildenafil had a 3.56% increase in ejection fraction compared with placebo (P<.001), with a larger impact observed in patients with LV hypertrophy (4.382%; P<.001).

N-terminal-pro brain natriuretic peptide (NT-proBNP) did not change significantly in the main analysis of 407 patients across six trials. However, NT-proBNP declined significantly in a subanalysis of patients assigned PDE5 inhibition who had severe LV hypertrophy (–486.7 pg/mL; P<.001). Flow-mediated vasodilation increased significantly after PDE5 inhibition in four studies (3.306%; P=.02). This difference was more pronounced among patients who received tadalafil but did not have cardiac disease (3.953%; P=.004), and in patients older than 60 years (3.558%; P=.03).

Adverse events

The most commonly reported adverse events included epistaxis (RR=4.701; 95% CI, 1.314-16.821), gastric symptoms (RR=4.138; 95% CI, 1.564-10.946), flushing/rash (RR=3.406; 95% CI, 1.628-7.126) and headache (RR=2.507; 95% CI, 1.416-4.439). The incidence of serious adverse events, including symptomatic hypotension, did not differ significantly between patients assigned placebo or PDE5 inhibition.

“We showed that in select cohorts, long-term continuous [PDE5 inhibitor] administration can produce clinically meaningful improvements in cardiac remodeling and performance with an excellent CV safety and tolerability profile, even in older patients and under prolonged use,” Giannetta and colleagues concluded. “… On the basis of these encouraging findings, large clinical trials are urgently needed on the long-term effects of continuous [PDE5 inhibitor] administration, focusing on CV outcomes and sex-specific response in these patients.”

Disclosure: The researchers report no relevant financial disclosures.