Effects of heart rate reduction with ivabradine on the international index of erectile function (IIEF-5) in patients with heart failure

The article entitled “Effects of heart rate reduction with ivabradine on the international index of erectile function (IIEF-5) in patients with heart failure” by Mert et al. [1] reported that IIEF-5 scores increased significantly after 6 months of ivabradine treatment in patients with heart failure. Therefore, we congratulate the authors for the present paper that demonstrated positive effect of ivabradine on erectile function.

In discussion section, Mert et al. cited an article of Manolis and Doumas [2], and penned that ‘sexual side effects are not experienced in the majority of patients taking beta-blockers. Studies with both metoprolol and atenolol have demonstrated neutral effects on sexual function’ [1].

Beta(β)-adrenergic blocking agents, shortly β-blockers, exert their major effects through the β-adrenoreceptors. β-receptors are found in a wide range of tissues. The two main types of β-receptors, β₁ and β₂, frequently coexist in same tissue. There is now evidence for a β₃-receptor in brown fat, which is associated with thermogenesis [3]. In the mid of 20th century, a nonselective β-blocker, propranolol, was synthesized and proved effective in treating ischemic heart disease [4]. Today, β-blockers subdivided on the basis of pharmacologic (i.e. selective and nonselective) and water solubility.

Male patients treated with β-blockers frequently complain of erectile dysfunction (ED). Metoprolol is a medication of the selective β₁-receptor blocker type. Earlier studies showed that patients on older drugs (β‐blockers, diuretics) presented with ED more frequent than patients on newer drugs (calcium antagonists, ACE inhibitors, angiotensin II receptor blockers) [5]. Small clinical studies also confirmed the findings of experimental and observational studies on sexual side effects of β-blockers [6]. In the subsequent years, more studies designed to find the highest level of evidence to answer clinical questions about β-blockers.

Brixius et al. [7] randomized a total of 50 patients as double-blind to either nebivolol (5 mg once daily for 12 weeks), followed by placebo for 2 weeks and then metoprolol succinate (95 mg once daily for 12 weeks) or metoprolol succinate (95 mg for 12 weeks), placebo for 2 weeks and then nebivolol (5 mg for 12 weeks). Brixius et al. evaluated the latter study patients with international index of erectile function (IIEF) questionnaire and a diary documented patients’ sexual function and activity. Study results proved that nebivolol and metoprolol lowered blood pressure to a similar extent. However, metoprolol significantly decreased the majority of sexual efficacy variables assessed when used to treat middle-aged hypertensive men with no evidence of prior ED, whereas there was a tendency towards an improvement in the erectile function sub-score with nebivolol [7]. Since the authors limited the confounding effects of age, they examined a middle-aged, sexually active population. Even they enrolled subjects with no history of sexual dysfunction allowed them to assess the occurrence of ED related to the medication per se and not to other factors [7].

One year later, in an animal study, Baumhakel et al. [8] determined the effects and underlying mechanisms of treatment with the same β-receptor blockers, which were used in Brixius et al.’s clinical study, nebivolol and metoprolol on penile endothelial function in apolipoprotein E (ApoE)^-/- mice. Investigators found that endothelium-dependent relaxation of the corpora cavernosa was significantly impaired in ApoE^-/- mice, which improved in nebivolol- versus metoprolol-treated mice [8].

An observational cross-sectional study of 1007 middle aged and older high-risk hypertensive patients taking β-blockers unraveled the high prevalence of sexual dysfunction in these patients and unveiled within class differences regarding sexual effects. ED was observed in 71% of studied patients (38.1% mild, 16.8% moderate, and 16.1% severe ED) [9]. Remarkably, the most important information comes from the observed differences between various beta-blockers. In particular, metoprolol and carvedilol were associated with higher rates of ED, atenolol and bisoprolol with intermediate rates, and nebivolol with the lowest rates of ED [9].

A total of 11 nonsmoking, hypertensive but otherwise healthy men with ED were studied after 8 weeks on moxonidine monotherapy and then after 8 weeks of metoprolol monotherapy in a crossover design [10]. At the end of each treatment phase, the subjects were asked about their subjective erectile capacity, and resting and stimulated (after intracavernosal injection of a mixture of alprostadil and phentolamine) penile deep artery diameters and systolic peak velocities were measured by color Doppler ultrasonography. There were no significant differences in blood pressure after either therapy. The change from earlier antihypertensive therapy, moxonidine produced significant subjective amelioration of ED in 9/11 of the men, whereas 9/11 returned to ED after crossover to metoprolol treatment. Resting and stimulated deep penile diameters and peak systolic velocities were higher after moxonidine treatment compared with metoprolol [10]. The centrally acting sympatholytic agent moxonidine seems to improve ED both subjectively and objectively and has a better effect on penile circulation compared with the peripherally acting sympatholytic agent metoprolol [10].

In order to understand if ED resulted from the disease itself or prescribed medicine, Doumas et al. [11] investigated a switch to nebivolol in 44 male patients (age range 31–65 years), 66% of whom had experienced ED during stable antihypertensive therapy with atenolol, metoprolol, or bisoprolol. At the end of 3 months, 69% of those who had experienced ED had a significant improvement from baseline in IIEF score.

Recently, Gur et al. [12] compared the effects of nebivolol and metoprolol succinate on ED in the sexually active cases (a total of 119 patients) with coronary artery bypass surgery. The authors found that the incidence of any grade ED was higher in metoprolol succinate group patients [12]. When Aldemir et al. [13] compared nebivolol with metoprolol in males undergoing coronary artery bypass graft (CABG) surgery, researchers verified that erectile function decreases when metoprolol is used, nebivolol exerts protective effects on erectile function against the disruptive effects of cardiopulmonary bypass in patients undergoing CABG.

Negative sexual side effect of metoprolol was not limited to the male patients. Ma et al. [14] evaluated the impact of felodipine with irbesartan on sexual function compared with felodipine with metoprolol in hypertensive women. Patients’ sexual function was evaluated using a female sexual function index questionnaire at baseline and after 24 and 48 weeks of therapy. Study results suggested that the felodipine–irbesartan combination regimen improved sexual function in hypertensive women, whereas felodipine–metoprolol regiment did not.

β-blockers are established agents for reducing mortality and morbidity in patients with ischemic heart disease and have shown promise in patients with heart failure. However, the detrimental role of beta blockers especially metoprolol is evident and there are data suggesting that β-blockers have been associated with ED in men using these agents for the treatment of hypertension [7,9,15].

ED is a common and important component of quality of life in men with heart failure. Some drugs applied for heart failure therapy (e.g. β-blockers and especially metoprolol) may augment ED [16]. Therefore, β-blockers should be prescribed cautiously with clear therapeutic goals and recognition of the impact on erectile function.

Disclosure statement

No potential conflict of interest was reported by the author.