sildenafil-citrate and Death--Sudden--Cardiac

Sildenafil was the first oral compound to be approved for the treatment of erectile dysfunction. In this paper, we review the current knowledge of the effects of sildenafil on myocardial infarction and sudden cardiac death. The first factor we examine is the sexual activity itself. As several studies have shown, the relative risk for an acute coronary syndrome during intercourse is not very high. Several studies examining the effects of sildenafil on mortality have been published during recent years. The great majority of these studies found that sildenafil is not an extra risk factor for an acute coronary syndrome or sudden cardiac death. In 1997, the rate of myocardial infarction in men 55-64 years of age was 1542 per 1,000000 in the US. According to this, the expected number of deaths as a result of myocardial infarction in patients 55-64 years of age receiving sildenafil, in the 24-hour period after use, from late March 1997 to mid November 1998, should have been 52. Instead, the number of reported deaths were only 15. One very optimistic finding was that sildenafil not only does not increase mortality, but in fact 'preconditions' the heart and has a cardioprotective effect. Besides, many studies have shown that sildenafil does not reduce the exercise tolerance in men with known coronary artery disease. As far as BP is concerned, the differences before and after the use of sildenafil are not clinically significant. The only contraindications for sildenafil are co-administration with alpha-adrenoceptor antagonists or with nitric oxide donors. According to the most recent studies, isoform 5 of phosphodiesterase has also been detected in the myocardium and controls the soluble pool of 3', 5'-cyclic guanosine monophosphate (cGMP). Sildenafil is very specific for cGMP but it may increase cyclic adenosine monophosphate in the myocardium indirectly. This does not occur with small therapeutic doses of the drug. There is some dispute regarding the association of sildenafil with arrhythmias, where the available evidence is not clear. However, there are suspicions that sildenafil may cause sympathetic activation. The overall conclusion is that sildenafil is a safe drug and that its appropriate use does not seem to increase the risk for myocardial infarction or sudden cardiac death.

Topics: Death, Sudden, Cardiac; Erectile Dysfunction; Humans; Male; Middle Aged; Myocardial Infarction; Phosphodiesterase Inhibitors; Piperazines; Purines; Risk; Sildenafil Citrate; Sulfones; Vasodilator Agents

Sildenafil citrate is a drug commonly used to manage erectile dysfunction. It is designated chemically as 1-[[3-(6,7-dihydro-1-methyl-7-oxo-3-propyl-1H -pyrazolo[4,3-d]pyrimidin-5-yl)-4 ethoxyphenyl] sulfonyl]-4-methylpiperazine citrate (C22H30N6(O4)S). It is a highly selective inhibitor of cyclic guanine monophosphate-specific phosphodiesterase type 5. In late March through mid-November 1998, the US Food and Drug Administration (FDA) published a report on 130 confirmed deaths among men (mean age, 64 years) who received prescriptions for sildenafil citrate, a period during which >6 million outpatient prescriptions (representing about 50 million tablets) were dispensed. The US FDA recently reported that significant cardiovascular events, including sudden cardiac death, have occurred in men with erectile dysfunction who were taking sildenafil citrate. These reports have raised concerns that sildenafil citrate may increase the risk of cardiovascular events, particularly fatal arrhythmias, in patients with cardiovascular disease. In the past few years, the cardiac electrophysiological effects of sildenafil citrate have been investigated extensively in both animal and clinical studies. 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 are needed for patients with cardiovascular diseases. However, the only absolute contraindication for sildenafil citrate is the concurrent use of nitrates. This article is intended to review sildenafil citrate's cardiovascular effects, as well as current debates about its arrhythmogenic effects.

Topics: Adult; Aged; Arrhythmias, Cardiac; Blood Pressure; Cardiovascular Diseases; Death, Sudden, Cardiac; Electrophysiology; Erectile Dysfunction; Heart Rate; Humans; Male; Middle Aged; Myocardial Contraction; Phosphodiesterase Inhibitors; Piperazines; Purines; Risk Factors; Sildenafil Citrate; Sulfones; Vasodilator Agents

Despite isolated reports of myocardial infarction and sudden cardiac death in men taking sildenafil for erectile dysfunction, clinical evidence shows the drug to be safe, effective, and well tolerated in most men with coronary artery disease. Nevertheless, caution is advised in specific instances.

Topics: Contraindications; Coronary Disease; Death, Sudden, Cardiac; Drug Interactions; Erectile Dysfunction; Hemodynamics; Humans; Male; Phosphodiesterase Inhibitors; Piperazines; Purines; Sildenafil Citrate; Sulfones

Sildenafil citrate is the first oral agent approved for the treatment of erectile dysfunction (ED); other oral agents are in the process of development. Because the mechanism of action of many of these agents involves vasodilation, there is a potential for interaction with the cardiovascular system. Sildenafil inhibits phosphodiesterase-5 (PDE-5) which is found in the corpus cavernosum and in the systemic vasculature. Sildenafil causes a mild decrease in systemic arterial pressure ( approximately -8/-5.5 mm Hg); it causes a synergistic and often major decrease in systemic arterial pressure in the presence of organic nitrates (nitric oxide donors). Sildenafil is therefore contraindicated in patients taking organic nitrates. A review was made of clinical trials in populations of men with (1) erectile dysfunction; (2) chronic stable ischemic heart disease and erectile dysfunction; and (3) hypertension and erectile dysfunction. This review showed that sildenafil was effective and not associated with an increase in serious cardiovascular adverse events, myocardial infarction (MI), or death compared with placebo. Although there have been spontaneous reports of death among men using sildenafil, there are limitations to spontaneous-event reporting. In addition. the numbers of such reports are well below the expected numbers of deaths when considering the number of men who have received prescriptions for sildenafil and their age and cardiovascular risk factor profile. Because there is a small but finite risk of having a cardiac event with sexual activity, physicians should discuss with their cardiac patients the risks of sexual activity before prescribing any treatment for ED. In addition, they should evaluate their patients' cardiac status when considering the safety of administering any ED treatment that may have systemic vasodilatory properties and can potentially lower blood pressure. In some cases, exercise treadmill testing may be warranted to determine whether ED patients with coronary artery disease can achieve the physiologic workload (4-6 metabolic equivalents) associated with sexual intercourse.

Topics: Clinical Trials as Topic; Death, Sudden, Cardiac; Erectile Dysfunction; Humans; Male; Myocardial Infarction; Phosphodiesterase Inhibitors; Piperazines; Purines; Risk Factors; Sildenafil Citrate; Sulfones

Topics: Aging; Death, Sudden, Cardiac; Drug Interactions; Enzyme Inhibitors; Erectile Dysfunction; Humans; Male; Penile Erection; Piperazines; Purines; Sildenafil Citrate; Sulfones

In recent years, there has been an increase in the use of phosphodiesterase type 5 inhibitors (PDE5i) that are purchased from abroad without a doctor's diagnosis via the Internet or other means. We report six cases in which nonprescription use of PDE5i may have led to death. Among the four deceased individuals who were believed to have experienced sudden cardiac death, three (cases 1-3) had a history of cardiovascular disease, which is a contraindication, and the remaining case (case 4) involved combined use of multiple PDE5i. Sildenafil (0.063 µg/mL, 0.087 µg/mL) was detected in two of the four cases of sudden cardiac death. Tadalafil (0.096 µg/mL) was detected in one of the remaining two cases, and tadalafil (0.197 µg/mL) and vardenafil (0.011 µg/mL) were detected in the other case. Sildenafil (0.032 µg/mL), tadalafil (0.062 µg/mL), and ethanol were detected in a traffic accident case with a history of contraindications. In a case of asphyxiation by vomit aspiration, autopsy showed 90% stenosis in the anterior descending branch of the coronary artery, and sildenafil (0.063 µg/mL) was detected. To the best of our knowledge, this is the first report of postmortem blood levels of tadalafil and vardenafil likely contributing to the cause of death. Despite all the warnings about the dangers of using PDE5 inhibitors, cases of PDE5i contributing to death are still identified during autopsies. Therefore, raising public awareness of the risks of the risks associated with the imported drug use by individuals is necessary.

Topics: Adult; Aged; Aged, 80 and over; Cardiovascular Diseases; Contraindications, Drug; Death, Sudden, Cardiac; Erectile Dysfunction; Forensic Medicine; Humans; Male; Middle Aged; Phosphodiesterase 5 Inhibitors; Risk; Sexual Behavior; Sildenafil Citrate; Tadalafil; Vardenafil Dihydrochloride

Topics: Anti-Bacterial Agents; Clarithromycin; Death, Sudden, Cardiac; Dideoxynucleosides; Drug Combinations; Drug Interactions; Electrocardiography; Fatal Outcome; HIV Infections; Humans; Lamivudine; Lopinavir; Male; Middle Aged; Piperazines; Purines; Ritonavir; Sexual Behavior; Sildenafil Citrate; Sulfonamides; Vasodilator Agents

Right ventricular (RV) dysfunction, caused by severe pulmonary hypertension (PH), is associated with high mortality because of RV failure. However, some patients can suffer from sudden cardiac death (SCD). We hypothesized that severe PH can cause RV arrhythmogenesis, leading to SCD. We sought to investigate arrhythmogenesis in PH. Optical mapping analysis (OMP) with an electrophysiological study (EPS) and pathological examination were performed in a monocrotaline (MCT)-induced rat PH model. Rats were injected with MCT (60 mg/kg), and OMP was performed in isolated Langendorff-perfused hearts. OMP revealed abnormal RV conduction delays and abnormal patterns, along with elevated RV pressure. In addition, impaired action potential duration dispersion (APDd), an index of myocardial repolarization instability, was observed only in the RVs with severe PH. The EPS demonstrated that lethal arrhythmias were induced by burst pacing to the RV when deteriorated APDd became evident. This arrhythmogenesis was inhibited by combination treatment with sildenafil and beraprost (SIL + BERA). RT-PCR showed an mRNA up-regulation of Type I collagen and down-regulation of connexin-43 in the RV at 5 weeks after MCT injection. Pathological examination revealed pulmonary vascular remodeling and RV hypertrophy with interstitial fibrosis, which was substantially reduced by SIL + BERA. Immunohistochemistry also revealed connexin-43 degradation in the RVs with severe PH. In contrast, connexin-43 was well preserved, and no lethal arrhythmias were induced by burst pacing to the RV in the absence of PH after SIL + BERA. In conclusion, RV electrical remodeling, including impaired APDd, causes arrhythmogenesis in severe PH, potentially associated with SCD attributable to PH.

Topics: Animals; Arrhythmias, Cardiac; Cardiotonic Agents; Collagen Type I; Connexin 43; Death, Sudden, Cardiac; Drug Therapy, Combination; Epoprostenol; Gene Expression Regulation; Heart; Humans; Hypertension, Pulmonary; Male; Monocrotaline; Organ Culture Techniques; Piperazines; Purines; Rats; Rats, Sprague-Dawley; Sildenafil Citrate; Sulfones; Ventricular Dysfunction, Right; Ventricular Remodeling; Voltage-Sensitive Dye Imaging

Sildenafil is increasingly being marketed to younger healthcare consumers. The purpose of this study was to profile sildenafil use in commercially insured, adult beneficiaries. Annual ambulatory prescription claims data from 1998 to 2002, for a nationwide, random sample of over 5 million life-years of commercially insured adults (aged > or =18 y), were examined retrospectively. The overall prevalence of sildenafil use increased from 0.8% (1998) to 1.4% (2002), an 84% increase. While the growth in use slowed in older males, use became more pronounced in younger males and females and decreased in older females. The fastest growing segment of users was found to be males aged 18-45 y. The proportion of users who had two or more claims for a medication that is suspected of inducing erectile dysfunction (ED) and/or a marker for a suspected ED-inducing disease decreased over the study period. Our findings suggest that use may increase among younger male and female patients and those without an underlying etiologic reason for use.

Topics: Adolescent; Adult; Advertising; Age Factors; Aged; Databases, Factual; Death, Sudden, Cardiac; Drug Prescriptions; Drug Utilization; Erectile Dysfunction; Female; Humans; Insurance, Health; Male; Middle Aged; Piperazines; Purines; Retrospective Studies; Sex Factors; Sildenafil Citrate; Sulfones; United States; Vasodilator Agents

Topics: Alcohol Drinking; Clinical Trials as Topic; Death, Sudden, Cardiac; Extramarital Relations; Feeding Behavior; Humans; Male; Myocardial Infarction; Phosphodiesterase Inhibitors; Piperazines; Purines; Risk; Sexual Behavior; Sildenafil Citrate; Sulfones

A 43-year-old man was found dead in a hotel room during a sexual relation with a colleague.He was treated both for cardiovascular disease and for erectile dysfunction with VIAGRA. A pillbox was found in the room with several tablets of verapamil (Isoptine), trimetazidine (Vastarel), yohimbine and bromazepam (Lexomil). A box of VIAGRA 25mg was found in his raincoat and two tablets were missing. His wife declared during the investigation that he was also treated by trinitrine. Autopsy revealed severe coronary artery sclerosis as well as signs of previous myocardial infarctions. Blood, urine, bile, gastric content and hair and representative tissues for histology were collected for toxicological analysis. Sildenafil and yohimbine were screened with liquid chromatography/mass spectrometry (LC/MS) and trinitrine with headspace injection (HS)/GC/MS. Verapamil and trimetazidine were identified and quantified with LC/diode array detection (DAD). Sildenafil was identified in blood, urine, bile and gastric content at 105, 246, 1206 and 754ng/ml, respectively. Hair concentration was 177pg/mg. The desmethyl metabolite was quantified in urine at 143ng/ml. Blood concentrations of verapamil and trimetazidine were measured at 659 and 2133ng/ml, respectively and were above therapeutic ranges. Trinitrine and yohimbine were not identified. These results confirm the absorption of sildenafil, verapamil and trimetazidine before the death and hair analysis indicates the chronic use of sildenafil. To the author's knowledge, this is the first report of a fatal sildenafil-verapamil association, probably by hypotension and cardiac dysrhythmia.

Topics: Adult; Autopsy; Bromazepam; Cause of Death; Chromatography, Liquid; Death, Sudden, Cardiac; Drug Interactions; Gas Chromatography-Mass Spectrometry; Hair; Humans; Male; Mass Spectrometry; Myocardial Infarction; Piperazines; Purines; Sildenafil Citrate; Sulfones; Trimetazidine; Vasodilator Agents; Verapamil; Yohimbine

Topics: Cardiovascular Diseases; Contraindications; Death, Sudden, Cardiac; Erectile Dysfunction; Humans; Male; Phosphodiesterase Inhibitors; Piperazines; Purines; Sildenafil Citrate; Sulfones