Number 24, 2004
Angina Pectoris

Vastarel MR: effective and safe for coronary patients treated with a phosphodiesterase type 5 inhibitor

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Giuseppe M. C. Rosano
Cardiovascular and Clinical Pharmacology Research Unit, San Raffaele H, Rome, Italy
Correspondence: Giuseppe M. C. Rosano, Cardiovascular and Clinical Pharmacology Research Unit, Department of Medical Sciences, San Raffaele H, via della Pisana 235, Roma, Italy. E-mail: giuseppe.rosano@sanraffaele.it

In middle aged and elderly men, erectile dysfunction (ED) is frequently related to a vascular problem that may be the consequence of overt atherosclerosis, the effect of cardiovascular drugs, the presence of cardiovascular risk factors that reduce endothelial function, or a combination of all these mechanisms [1–2]. The association between coronary artery disease (CAD) and ED is supported by several studies that have correlated the presence of coronary artery disease risk factors and degree of coronary atherosclerosis with difficulties in achieving and maintaining erections [1].
As vasculogenic ED is primarily related to impaired endothelial function, and as endothelial dysfunction is an early stage in the development and progression of atherosclerosis, it is clear that reduction of erectile function may manifest well before the onset of clinically manifest atherosclerosis. Indeed, it has been proposed recently that ED may precede the onset of the clinical manifestation of CAD and may therefore be, in asymptomatic patients, a marker for the presence of CAD [3–5]. Pritzker [4] have reported that, among a group of 50 men with vasculogenic ED but asymptomatic for angina, 28 had a positive exercise test response and the 20 who agreed to undergo coronary angiography were found to have significant coronary atherosclerosis. Similar findings have been reported by Montorsi et al [3], who have shown that ED may precede the clinical manifestation of angina by nearly 3 years.
The introduction of orally active phosphodiesterase type 5 (PDE5) inhibitors has changed the therapeutic approach to patients with ED. As a result, more men – including those with cardiac disease – are now seeking treatment for ED. However, there is significant concern about systemic hemodynamic effects of PDE5 inhibitors when they are associated with nitric oxide donors such as nitrates, because both drugs potentiate vasodilatation through a similar pathway and may increase the risk of potentially life-threatening hypotension [6]. The use of PDE5 inhibitors is strictly contraindicated in patients receiving any form of nitrate, as stated by the joint guidelines issued by the American College of Cardiology and the American Heart Association [6]. Several studies have shown that PDE5 inhibitors may be safely used in patients with stable CAD [7–10]. In these patients the limitation for the use of PDE5 inhibitors relates to their ability to perform the level of exercise required by sexual activity without experiencing myocardial ischemia [7,11]. It has been shown that metabolic consumption during sexual activity (when performed with the usual partner) is around 3 metabolic equivalent of task units (METs), and that patients who do not have inducible ischemia at this level of effort may safely engage in such activity [11].
The therapeutic approach for patients with CAD and ED should be directed towards drugs that may improve myocardial ischemia without a negative effect on erectile function. Patrizi et al [12] have shown that, in patients with CAD receiving atenolol, the administration of sildenafil did not impair exercise tolerance. β-Blockers and calcium channel blockers, drugs commonly used for the treatment of angina, may further impair and worsen erectile function in those patients with a moderately impaired function. Therefore there is a need for a therapeutic option that reduces myocardial ischemia and does not impair erectile function in patients with CAD.
Trimetazidine (Vastarel), a metabolic anti-ischemic agent widely used and recognized in the treatment of angina pectoris and effort-induced myocardial ischemia, directly modifies the use of energy substrates in the heart, thereby improving myocardial ischemia and angina without significant changes in heart rate, blood pressure, or rate–pressure product at rest or during exercise [13–18]. Because of its mode of action and absence of negative effects upon erectile function, trimetazidine seems to be the drug of choice for the treatment of patients with CAD and ED who require treatment with PDE5 inhibitors.
In order to find an alternative treatment for patients with CAD receiving nitrates and requiring treatment for ED, we have recently conducted a study [19] in which patients with proven myocardial ischemia were allocated randomly to groups to receive either chronic treatment with nitrates or chronic treatment with trimetazidine plus sildenafil before sexual activity, and who underwent ambulatory ECG monitoring during daily life and during sexual activity. In this study we have shown that, in patients with chronic stable CAD and documented exercise-induced myocardial ischemia, trimetazidine decreased daily life ischemic episodes to the same extent as nitrates, and that the combination of trimetazidine plus a single dose of sildenafil 100mg was superior to nitrate treatment in controlling ischemic episodes occurring during sexual activity (Figure 1). The results of this study indicate that the switch from nitrate to trimetazidine can be safely performed in patients with CAD requiring treatment with PDE5 inhibitors. Of importance, the association of sildenafil plus trimetazidine was significantly more effective than nitrates alone in controlling episodes of myocardial ischemia recorded during sexual activity.

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REFERENCES

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