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Post-marketing surveillance data after the approval of sildenafil citrate by the US FDA revealed significant cardiovascular problems, including sudden cardiac death, related to the use of sildenafil citrate (4).

As of February 1999, the US FDA had received 401 reports of death among men who had received a prescription for sildenafil citrate over the prior 10 to 11 months.

These included 219 cardiovascular events (MI, arrhythmia, cardiac arrest, collapse), 140 sudden deaths, and 18 cerebrovascular accidents.

The reporting period represented about 4 million to 5 million men and approximately 9 million prescriptions, which translates to approximately 8.5 deaths per million men per month (4).

However, it was determined from an analysis of adverse events reported to the FDA between March 1998 and August 1999 that important data were missing from these reports, such as medical histories, cause of death and sildenafil citrate dosing (42). As of September 30, 2001, Pfizer's clinical safety database contained information on the extent of exposure to sildenafil citrate from 124 completed and ongoing double-blind and open-label clinical trials involving 5054 placebo-treated and 6896 sildenafil citrate-treated patients, representing 2593 PY of observation (43).

Analysis of these data revealed that the overall MI incidence rate was similar in placebo-treated (0.95/100 PY) and sildenafil citrate-treated patients (0.85/100 PY; P = 0.801). For the open-label studies, analysis of data from patients representing 10,859 PY of sildenafil citrate exposure demonstrated an MI incidence rate of 0.53/100 PY. The overall MI rate for double-blind and open-label sildenafil citrate-treated patients was 0.58/100 PY.

Similar rates have been reported in a number of epidemiologic studies (44). The database also contains (as of September 30, 2001) reports of 5 deaths (from all causes) among double-blind placebo-treated patients and 9 deaths among sildenafil citrate-treated patients.

This corresponds to all-cause mortality rates of 0.53/100 PY and 0.55/100 PY, respectively (P = 0.945). The overall (double-blind and open-label) mortality rate among sildenafil citrate-treated patients was 0.37/100 PY, which is lower than that (0.66/100 PY) calculated for men aged 40 to 64 years in the US for 1999.

These results clearly show that the incidences of MI and all-cause mortality among patients who received double-blind and/or open-label sildenafil citrate treatment are similar to those observed among patients who received placebo, or in men in the same age cohort of the general population (43).

Carson III (45) reported that the incidence of adverse cardiovascular events in patients taking sildenafil does not differ from that for the general population.

Cardiac electrophysiological effects of sildenafil citrate. In the past few years, the cardiac electrophysiological effects of sildenafil citrate have been investigated extensively (46).

Geelen and colleagues (46) demonstrated that sildenafil citrate induces a dose-dependent block of the rapid component of the delayed rectifier potassium current ( I Kr ). They also reported that sildenafil citrate can have an action similar to that of class III antiarrhythmic drugs (46).

These effects are observed at concentrations that may be found in conditions of impaired drug elimination such as renal or hepatic insufficiency, during co-administration of another CYP3A4 inhibitor, or after drug overdose (11).

Prolonged cardiac repolarization caused by sildenafil citrate could result in malignant ventricular arrhythmias and lead to sudden cardiac death in some of these patients (11).

Swissa and colleagues (47) demonstrated that a combination of sildenafil citrate and a nitric oxide donor increases ventricular tachyarrhythmia/VF vulnerability in the normal right ventricle of swine. Although many reports have demonstrated the arrhythmogenic effects of sildenafil citrate, some studies have reported otherwise.

Vardi and colleagues (48) showed that sildenafil citrate does not alter the hemodynamic responses to exercise or change the incidence of ventricular arrhythmias in men with cardiovascular disease and ED.

Chiang and colleagues (49) found that sildenafil citrate at concentrations up to 30 µM has no significant effect on either the rapid ( I Kr ) or the slow ( I Ks ) components of the delayed rectifier potassium currents in guinea pig ventricular myocytes. They also found that sildenafil citrate dose-dependently blocks L-type Ca 2+ currents ( I Ca,L ), but has no effect on persistent Na + currents. They concluded that sildenafil citrate does not prolong cardiac repolarization.

Instead, in supra-therapeutic concentrations, it accelerates cardiac repolarization, presumably via its blocking effect on I Ca,L (49). Recent studies have also demonstrated that oral administration of 50 mg sildenafil citrate does not affect QT dynamic properties (50).

Furthermore, Nagy and colleagues (51) recently reported that sildenafil citrate reduces arrhythmia generic viagra united states severity during ischemia 24 h after oral administration in dogs.

Ischemic preconditioning results in powerful cardioprotective effects (52).

Repeated brief episodes of ischemia initiate a cascade of intracellular signaling events which help prevent future myocardial infraction and stunning (52).

After initial observation, this phenomenon, termed "myocardial preconditioning", was studied intensively to try to understand its cellular mechanisms and apply this knowledge towards protection of the human heart from ischemic heart disease.

Current data suggest that sildenafil citrate has a preconditioning-like cardioprotective effect in the rabbit, rat and mouse heart (53). Das and colleagues (54) reported that sildenafil citrate at a much lower dose (0.05 mg/kg) provides significant cardioprotection in isolated perfused rat hearts following global ischemic-reperfusion. They observed an improved post-ischemic recovery of ventricular function, a reduction in the incidence of VF, and a decrease in MI.

At higher doses, sildenafil caused a significant increase in the incidence of VF, while at very low doses it had no effect on cardiac function (54).

However, a study by Reffelmann and Kloner (55) demonstrated otherwise.

In their report, they did not find a decrease in myocardial necrosis following ischemia-reperfusion in a rabbit model.

The reason for these negative results was not clear.

The only noticeable difference in the experimental procedure was a considerably longer drug infusion time ( 5 min) in the study by Reffelmann and Kloner (55) as compared to that used by Ockaili and colleagues (56) ( 1 min), which could potentially affect the hemodynamic response prior to ischemia.

Signaling mechanisms in sildenafil-induced cardioprotection.

Although sildenafil citrate has been shown to have a powerful preconditioning-like cardioprotective effects in animal models of ischemia-reperfusion injury, the precise cellular mechanism underlying these effects remains unclear.

The sildenafil citrate-induced cardioprotective effect against ischemia-reperfusion injury is dependent upon the opening of mitochondrial ATP-sensitive potassium channels (mitoK ATP channels) in rabbits (56).

It has been proposed that the vasodilatory action of sildenafil citrate could potentially cause the release of endogenous mediators of preconditioning, such as adenosine or bradykinin from endothelial cells, which may trigger a signaling cascade (through the action of kinases) and the release of nitric oxide (56). Generation of nitric oxide could potentially activate guanylate cyclase, resulting in an enhanced formation of cGMP (57).

cGMP may activate protein kinase G, which could then open mitoK ATP channels, resulting in both acute and delayed cardioprotective effects (58). Mitochondria are known to play an essential role in cell survival via ATP synthesis and maintenance of Ca 2+ homeostasis (59).

Opening mitoK ATP channels partially compensates the membrane potential, which enables additional protons to be pumped out to form an H + electrochemical gradient to drive both ATP synthesis and Ca 2+ transport. Recently, Das and colleagues (60) reported that protein kinase C also plays an essential role in sildenafil-induced cardioprotection in rabbits. We conclude that, in view of the increasing incidence of sudden cardiac death in ED patients treated with sildenafil citrate, it is essential to understand how this discount sale viagra drug affects the entire cardiovascular system, especially the heart.

According to extensive data available to date, sildenafil citrate has been shown to pose minimal cardiovascular risks to healthy people taking this drug. Some precautions, however, are needed for patients with cardiovascular disease.

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