Number 28, 2005
Sex and the Heart

Efficacy and safety of trimetazidine and phosphodiesterase type-5 inhibitors

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Graham Jackson
Cardiothoracic Centre, St Thomas’ Hospital, London, UK
Correspondence: Dr Graham Jackson, Consultant Cardiologist, Cardiothoracic Centre, St Thomas’ Hospital, London SE1 7EH, UK.
E-mail: gjcardiol@talk21.com

Introduction
Coronary artery disease (CAD) is a manifestation of endothelial dysfunction and is commonly associated with erectile dysfunction [1]. Vascular disease is the most common cause of erectile dysfunction, which increases in frequency with age, affecting more than 50% of men aged 40–70 years [2]. It is estimated that erectile dysfunction affects more than 150 million men worldwide [3]. It increases in incidence with age (a man older than 70 years has 3 times the incidence of a man of 40 years), and it has been estimated that, as our population ages, by the year 2025 the number of men with erectile dysfunction will have doubled to 300 million [3].
As a consequence of erectile dysfunction, distress is commonly felt by many couples, affecting not only a man's self esteem but the entire marital (or partner) relationship. In up to 20% of all relationship breakdowns, erectile dysfunction is a major contributing factor [4]. Treatment has been transformed by the phosphodiesterase type-5 (PDE-5) inhibitors (sildenafil [Viagra], tadalafil [Cialis], and vardenafil [Levitra]), with therapeutic success rates of 80–85% in nondiabetic men and 60–70% in those with diabetes [5]. PDE-5 inhibitors potentiate the action of nitric oxide by competing with PDE-5, which degrades cyclic guanosine monophosphate (cGMP), an important mediator of smooth muscle relaxation and hence erectile function [6]. cGMP is derived from the stimulation of guanylate cyclase by nitric oxide. Organic nitrates donate nitric oxide, which can lead to an accumulation of cGMP in the presence of a PDE-5 inhibitor (Figure 1). This can result in an unpredictable and significant vasodilatory interaction, leading to a profound decrease in blood pressure which may be fatal. Oral nitrate treatment is therefore an absolute contraindication to the use of a PDE-5 inhibitor. Even though some men may have no hypotensive sequelae, it is the so-called “outliers” who do determine the recommendation.

Changing treatment
In patients whose condition is stable and who are not restricted or only mildly restricted in their exercise ability, the therapy can be re-assessed. In addition, after percutaneous or surgical intervention many men are symptom free, but continue to receive nitrates for no evidence-based reason; they can therefore have their nitrates stopped. Trimetazidine (Vastarel) is a metabolic anti-ischemic agent that is widely used in the treatment of stable angina, with an efficacy that is comparable or superior to that of oral nitrate therapy [8]. As trimetazidine has no hemodynamic actions and does not exert its effects through the nitric oxide pathway, it offers an alternative approach to nitrates that would, in turn, allow for the safe use of a PDE-5 inhibitor.
Rosano and colleagues [9] studied 38 men aged 57 ± 6 years with proven CAD and stable symptoms. Their patients underwent 24-h ambulatory electrocardiographic monitoring at baseline and after 2 weeks of treatment with oral mononitrates (20 mg three times daily) and trimetazidine (also 20 mg three times a day) in a single crossover study. The study was double-blind and erectile dysfunction was not a criterion for entry. Patients engaged in sexual intercourse 1 h after sildenafil 100 mg or placebo (nitrate group) on the last day of each treatment period. Compared with baseline, the total ischemic burden decreased significantly after both trimetazidine and isosorbide mononitrate. There was a nonsignificant trend in favor of trimetazidine for decreased frequency of silent ischemic episodes. Ischemia was less during sexual intercourse with trimetazidine plus sildenafil than with nitrates plus placebo/sildenafil. No serious adverse effects were reported.
The implications of this study for men with erectile dysfunction are extremely important. Trimetazidine is a safe and effective agent as monotherapy or combination therapy for the treatment of stable angina and it has, in addition, important metabolic effects at the cellular level, leading to improved myocardial function. Given its efficacy similar to that of oral nitrates, its absence of erectile dysfunction as an adverse effect, and its potentially beneficial effects on ischemia in combination with a PDE-5 inhibitor, it represents a means of allowing men receiving nitrates to have their therapy substituted in order to allow the opportunity for PDE-5 inhibitors to improve their erectile dysfunction and relationships.

Stopping nitrates
In our unit we have recently completed a study of discontinuing oral nitrates in patients with erectile dysfunction whose condition is stable and who continued to receive treatment with a β-blocker or calcium antagonist, or both [10]. We prospectively evaluated 425 men with erectile dysfunction and cardiac disease in our outpatient cardiac sexual advice clinic, and found that 88 (21%) were using oral nitrates. Fifty-five (63%) had a good exercise ability, and their nitrates were discontinued. They were reviewed 1 week later, and only three had restarted their nitrates because of an increase in symptoms. A PDE-5 inhibitor was effective in treating erectile dysfunction in 85%, with no adverse cardiac events. Oral nitrate therapy should therefore not be an absolute barrier to prescribing PDE-5 inhibitors, but a reason for cardiovascular re-assessment and cessation of nitrate therapy if appropriate.

Conclusions
Erectile dysfunction is common in cardiac patients who are low risk as a result of modern medical and interventional management. Those with a good exercise ability and no restrictive symptoms can have their oral nitrate therapy discontinued or substituted with trimetazidine. PDE-5 inhibitors are safe and effective in carefully assessed cardiac patients whose condition is stable and who may be denied this treatment if nitrates have been prescribed. Although other treatments for erectile dysfunction are available, oral therapy is preferred by the majority of those affected.
Sex, the heart and erectile dysfunction represent an important issue for many couples and their health care professionals. Nitrates must not be allowed to prevent patients enjoying the benefits of PDE-5 inhibitors; where they appear to, a careful re-assessment of the clinic situation is indicated.

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