Cardiovascular Side Effects: Theory or Clinically Relevant?
Soon after the approval of sildenafil for treatment of ED, several reports of adverse events temporarily related to use of sildenafil raised concerns regarding the safety of PDE-5 inhibitors, particularly in patients with cardiovascular disease. However, detailed statistical analyses, considering that the patient population using these agents is characterized by a high prevalence of cardiovascular risk factors, did not confirm an increased cardiovascular risk of sildenafil use. Neither prospective clinical trials nor retrospective analyses revealed an increased risk for sildenafil alone or for vardenafil or tadalafil.
Some theoretical concepts were initially suggested to explain the cardiac events in men taking PDE-5 inhibitors. Direct effects of PDE-5 inhibitors in altering myocardial contractility, altered response of the heart to adrenergic stimulation by potential inhibitory effects of increased cGMP on breakdown of cyclic adenosine monophosphate, reducing tolerance toward ischemia, increasing sympathetic tone, or the susceptibility to arrhyth-mia were some of the concepts suggested. For most of these concepts, how-ever, it appears to be crucial that significant amounts of PDE-5 are expressed in ventric-ular cardiomyocytes. However, this remains a matter of discussion. Whereas systematic investigations by Wallis et al. did not find evidence of PDE-5 expression in canine cardiomyocytes, Senzaki et al. reported evidence for expression of PDE-5 in canine cardiomyocytes. Additionally, in our laboratory, experimental data in the rabbit did not provide evidence for a reduced tolerance toward ischemia under PDE-5 inhibition or pro-motion of arrhythmia. Another hypothesis (referring to a coronary steal phenomenon) involving shifting blood from ischemic to nonischemic myocardium under the influence of sildenafil was not supported in experimental investigations. Conversely, the majority of clinical studies have suggested that tolerance toward ischemia, threshold of ischemic reactions during exercise, or parameters hinting at pro-arrhythmic tendencies are not significantly altered or even favorably influenced with PDE-5 inhibition.
Recently, animal research suggested powerful cardioprotective effects of PDE-5 inhibi-tion, resembling a preconditioning-like effect. However, these effects remain a matter of debate, and it is not clear how and to what extent they could be transferred into the clinical realm.
In summary, theoretical concepts regarding potential detrimental effects of PDE-5 inhibition in cardiovascular disease were not conclusively established, and neither retro-spective epidemiological data nor clinical studies supported any ischemia- or arrhythmia-promoting effect. Therefore, initial concerns about cardiac events after administration
of PDE-5 inhibitors appear to be most likely related to the patient population characterized by a remarkable cardiovascular risk factor profile.
Contraindications regarding drug interactions as well as other contraindications and recommendations according to the Princeton Consensus Panel should be carefully ob-served when prescribing these substances; however, there is reasonable evidence that PDE-5 inhibitors are also suitable for patients with cardiovascular disease.