Serious Cardiovascular Events In Patients Research Articles

Dexmedetomidine: a magic bullet on its way into palliative care-a narrative review and practice recommendations.

Dexmedetomidine is a potent adrenergic alpha-2 receptor agonist. It was first approved for sedation for mechanically ventilated patients. Being a sedative medication that is not associated with respiratory depression and holding analgesic properties fosters the interest for this drug in the palliative care field. The primary objectives of this review were to identify the key indications for the real-world use of dexmedetomidine in palliative care and other disciplines. A narrative review after extensive PubMed search was performed from 1950 to present on October 21st 2021. The language of the publications was restricted to English, German, French and Italian. (I) Current dexmedetomidine use. There is a growing body of evidence that dexmedetomidine may reduce the incidence and severity of delirium, reduce opioid-consumption and postoperative nausea in intensive care settings. It is also used to facilitate withdrawal from different substances (alcohol, opioids, heroin). Concerning safety aspects of the drug, some studies reported an increased rate of serious cardiovascular events in patients with pre-existing heart conditions due to bradycardia and arterial hypo- and hypertension. Since the drug has a main hepatic metabolism, dose reduction is mandatory in patients with hepatic impairment. (II) Dexmedetomidine and palliative care. There have been sporadic case reports about the successful use of dexmedetomidine in palliative care. Indications for symptom control included sedation for hyperactive delirium, cancer pain, opioid-induced-hyperalgesia, dystonia, cough, vomiting, shivering and dyspnea. It is mainly applied via the intravenous (i.v.), subcutaneous, but also nasal and, buccal routes. Admixture ("syringe-driver") studies showed that dexmedetomidine is compatible with morphine, hydromorphone, hyoscine and haloperidol. In 2021, a first prospective cohort study became available. Here, the authors reported promising result for dexmedetomidine use in hyperactive terminal delirium for reducing delirium intensity and agitation. Especially the unique "conscious sedation" or "awake sedation" that allows patients to arouse easily under sedation and report comfort or distress was discussed by the authors. In this review, we present the main findings for dexmedetomidine from palliative care settings and other disciplines. The potential benefits and criticalities of the drug are discussed and practical recommendations for its use are provided.

Effects of GLP-1RAs on cardiovascular outcomes in patients with type 2 diabetes mellitus: review of real-world data on target populations from diabetes registry in Russian Federation

RATIONALE. Over the past 20 years the prevalence of type 2 diabetes in Russia has more than doubled and reached 4.43 million people in 2020, while the growth rate keeps increasing. Most patients with T2DM are at a higher risk of developing major adverse cardiovascular events (MACE) associated with significant mortality. There is a strong evidence base that the drugs belonging to GLP-1RA class contribute to reducing the risk of cardiovascular events and renal outcomes. At the same time, the current prescribing rates of these treatments in Russia are quite low - only about 0.1% of patients are prescribed GLP-1RAs, according to Diabetes Registry data.AIM. Review the results of several randomized clinical trials (RCTs) concerning effects of GLP-1RA treatments on prevention of primary and secondary cardiovascular events and estimate the number of diabetic target population.MATERIALS AND METHODS. We examined the data from clinical trials on GLP-1RA treatments registered in Russia and used in routine clinical practice (ELIXA, EXSCEL, LEADER, SUSTAIN-6 and REWIND) and data from two meta-analyzes published as of December 1, 2020. The task was to evaluate the inclusion criteria, patient profile, and the clinical efficacy and safety profiles of the studied therapies. Also, the analysis of clinical information from the Diabetes Registry (DR) was performed to estimate the number of target T2DM patients meeting RCTs inclusion criteria that could benefit from prescribing of GLP-1RAs.RESULTS. The reviewed clinical trials demonstrated a statistically significant reduction (p <0.05) in the risk of serious cardiovascular events in patients treated with Liraglutide [RR 0.87 (95% CI, 0.78-0.97)], Semagltuide [OP 0.74 (95% CI 0.58-0.95)] and Dulaglutide [RR 0.88 (95% CI 0.79-0.99)]. Meta-analyzes utilizing data from 6 RCTs with the total number of 56,004 T2DM patients, also, confirmed a statistically significant reduction in the risk of developing MACE (by 12%) in the studied population, and a 17% reduction in the risk of combined renal outcomes [RR 0.83 (95% CI 0.78-0.89), p <0.0001]. The DR patient population that met the RCTs inclusion criteria amounted to 538.6 thous. subjects in case of REWIND and 432.4 thous. in case of LEADER and SUSTAIN-6. The key differences between FDR patients and patients engaged in RCTs included gender and age characteristics. The DR patients were generally older and the bulk of them were women, which has to do with overall Russian demographic trends. The proportion of DR patients with established CVD was 26%, which closely matched the profile of patients from REWIND study (31.5%). According to DR data, the number of patients in whom the treatment was intensified following prescription of basal insulin was 7612 per year, which is close to a potential cohort eligible for alternative treatment with GLP-1RAs.CONCLUSION. All the drugs belonging to GLP-1RA class are clinically effective in reducing the risk of cardiovascular and renal outcomes, while demonstrating a favorable safety profile including with respect to lower risk of developing hypoglycemia. The decreased risk of complications was recorded both in patients with existing cardiovascular risks and patients with established CVD. Of all GLP-1RA treatments available in Russia at this point, the greatest clinical effectiveness is achieved by Liraglutide, Semaglutide and Dulaglutide. The estimated patient population from DR, meeting RCTs inclusion criteria and matching RCTs patient profile was over 500, 000 people with the largest number of patients meeting the REWIND criteria. The target population of patients with T2DM who may potentially benefit from the administration of GLP-1RAs is over 500, 000 people. Out of that number at least 7.5 thousand are patients, whose treatment is intensified following prescription of basal insulin (with an aim of improving glycemic control, but without consideration of cardiovascular risks).Currently, if we take the real world clinical setting in Russia, the number of patients receiving GLP-1RA treatments is substantially lower than the estimated figures (less than 1%), which requires reconsideration of the approach toward their prescribing as is recommended by state-of-the-art clinical guidelines prioritizing prevention of cardiovascular risks.

PAMPs and DAMPs as the Bridge Between Periodontitis and Atherosclerosis: The Potential Therapeutic Targets.

Atherosclerosis is a chronic artery disease characterized by plaque formation and vascular inflammation, eventually leading to myocardial infarction and stroke. Innate immunity plays an irreplaceable role in the vascular inflammatory response triggered by chronic infection. Periodontitis is a common chronic disorder that involves oral microbe-related inflammatory bone loss and local destruction of the periodontal ligament and is a risk factor for atherosclerosis. Periodontal pathogens contain numerous pathogen-associated molecular patterns (PAMPs) such as lipopolysaccharide, CpG DNA, and Peptidoglycan, that initiate the inflammatory response of the innate immunity depending on the recognition of pattern-recognition receptors (PRRs) of host cells. The immune-inflammatory response and destruction of the periodontal tissue will produce a large number of damage-associated molecular patterns (DAMPs) such as neutrophil extracellular traps (NETs), high mobility group box 1 (HMGB1), alarmins (S100 protein), and which can further affect the progression of atherosclerosis. Molecular patterns have recently become the therapeutic targets for inflammatory disease, including blocking the interaction between molecular patterns and PRRs and controlling the related signal transduction pathway. This review summarized the research progress of some representative PAMPs and DAMPs as the molecular pathological mechanism bridging periodontitis and atherosclerosis. We also discussed possible ways to prevent serious cardiovascular events in patients with periodontitis and atherosclerosis by targeting molecular patterns.

Long-term outcome of patients with invasive electrophysiology procedure related cardiac tamponade

Abstract Aims Iatrogenic cardiac tamponades are a rare but dreaded complication of invasive electrophysiology procedures (EPs). Their long-term impact on clinical outcomes is unknown. This study analyzed the risk of death or serious cardiovascular events in patients suffering from EP related cardiac tamponade requiring pericardiocentesis during long-term follow-up. Methods and results Out of 19997 invasive EPs at our university hospital between January 1998 and September 2018, all patients with EP related periprocedural cardiac tamponade were identified (n=60) and matched (1:3 ratio) to a control group (n=180). After a follow-up of 5 years, the composite primary end point - death from any cause, acute myocardial infarction, TIA/stroke and hospitalization for heart failure – occurred in significantly more patients in the tamponade than in the control group (12 patients (20.0%) vs 19 patients (10.6%); Hazard ratio (HR) 2.53 (95% CI, 1.15–5.58); p=0.021). This was mainly driven by a higher incidence of TIA/stroke in the tamponade than in the control group (HR 3.75 (95% CI, 1.01–13.97); p=0.049). Death from any cause, acute myocardial infarction and hospitalization for heart failure did not show a significant difference between the groups. Hospitalization for pericarditis occurred in significantly more patients in the tamponade than in the control group (HR 36.0 (95% CI, 4.68–276.86); p=0.001). Conclusion Patients with EP related cardiac tamponade are at higher risk for cerebrovascular events during the first two weeks and hospitalization for pericarditis during the first months after index procedure. Despite the increased risk for early complications tamponade patients have a good long-term prognosis without increased risk for mortality or other serious cardiovascular events. Funding Acknowledgement Type of funding source: Foundation. Main funding source(s): German Research Foundation

Long-term outcome of patients with invasive electrophysiology procedure-related cardiac tamponade.

Iatrogenic cardiac tamponades are a rare but dreaded complication of invasive electrophysiology procedures (EPs). Their long-term impact on clinical outcomes is unknown. This study analysed the risk of death or serious cardiovascular events in patients suffering from EP-related cardiac tamponade requiring pericardiocentesis during long-term follow-up. Out of 19997 invasive EPs at the Karolinska University Hospital between January 1998 and September 2018, all patients with EP-related periprocedural cardiac tamponade were identified (n = 60) and matched (1:3 ratio) to a control group (n = 180). After a follow-up of 5 years, the composite primary endpoint - death from any cause, acute myocardial infarction, transitory ischaemic attack (TIA)/stroke, and hospitalization for heart failure - occurred in significantly more patients in the tamponade than in the control group [12 patients (20.0%) vs. 19 patients (10.6%); hazard ratio (HR) 2.53 (95% confidence interval, CI 1.15-5.58); P = 0.021]. This was mainly driven by a higher incidence of TIA/stroke in the tamponade than in the control group [HR 3.75 (95% CI 1.01-13.97); P = 0.049]. Death from any cause, acute myocardial infarction, and hospitalization for heart failure did not show a significant difference between the groups. Hospitalization for pericarditis occurred in significantly more patients in the tamponade than in the control group [HR 36.0 (95% CI 4.68-276.86); P = 0.001]. Patients with EP-related cardiac tamponade are at higher risk for cerebrovascular events during the first 2 weeks and hospitalization for pericarditis during the first months after index procedure. Despite the increased risk for early complications tamponade patients have a good long-term prognosis without increased risk for mortality or other serious cardiovascular events.

Peri-operative Antithrombotic Therapy in Hair Transplantation

1. Kuniyoshi Yagyu, MD, FISHRS (nhttkyo11{at}kioicho.jp) 1. Tokyo, Japan Patients under antithrombotic therapy sometimes visit our clinic for hair transplantation. Antithrombotic therapy is of critical importance to prevent serious cardiovascular events in patients with a mechanical heart

OS 12-02 SLEEP APNEA CARDIOVASCULAR ENDPOINTS (SAVE) STUDY

Abstract There is uncertainty over whether treatment of obstructive sleep apnea (OSA) can prevent serious cardiovascular (CV) events. SAVE (NCT00738179; ACTRN12608000409370) was designed to determine whether treatment of OSA with CPAP reduces the risk of serious CV events in patients with established CV disease. Participants were centrally randomised to CPAP treatment or usual care between 2008 and 2013,with follow-up completed late 2015 and the results will be announced in August 2016. The primary endpoint is a composite of CV death, myocardial infarction, stroke, hospitalisation for heart failure, and hospitalisation for either an acute ischemic cardiac event or transient ischemic event (TIA). Sample size was set at 2500 to provide 90% power (alpha 0.05) to detect a 25% relative risk reduction in the primary endpoint in the CPAP group compared with the usual care group. This international, prospective, open, randomised controlled clinical trial of CPAP for the prevention of major and minor CV events recruited 2717 participants with co-existing CV disease and moderate to severe OSA from clinics in Australia and New Zealand, China, India, Spain, and the USA. The main results will be presented at the conference. SAVE will determine whether treatment of OSA in patiens with CV disease can prevent secondary major CV events, the results of which will have significant impact on clinical practice.

The association of serum vitamin D concentration with serious complications after noncardiac surgery.

Vitamin D deficiency is a global health problem. Epidemiological studies demonstrate that vitamin D is both cardioprotective and neuroprotective. Vitamin D also plays a substantial role in innate and acquired immunity. Our goal was to evaluate the association of serum vitamin D concentration on serious postoperative complications and death in noncardiac surgical patients. We retrospectively analyzed the data of 3509 patients who had noncardiac surgery at the Cleveland Clinic Main Campus and had a serum vitamin D measurement. The relationship between serum vitamin D concentration and all-cause in-hospital mortality, in-hospital cardiovascular morbidity, and serious in-hospital infections was assessed as a common effect odds ratio (OR) by using a multivariate generalized estimating equation model with adjustment for demographic, medical history variables, and type and duration of surgery. Higher vitamin D concentrations were associated with decreased odds of in-hospital mortality/morbidity (P = 0.003). There was a linear reduction of the corresponding common effect odds ratio (OR 0.93, 95% confidence interval, 0.88-0.97) for severe in-hospital outcomes for each 5 ng/mL increase in vitamin D concentration over the range from 4 to 44 ng/mL. In addition, we found that the odds versus patients with vitamin D <13 ng/mL (i.e., 1st quintile) were significantly lower in patients with vitamin D 13-20, 20-27, 27-36, and > 36 ng/mL (i.e., 2nd-5th quintiles); the corresponding estimated ORs were 0.65 (99% confidence interval, 0.43-0.98), 0.53 (0.35-0.80), 0.44 (0.28-0.70), and 0.49 (0.31-0.78), respectively. However, there was no statistically significant difference among individual quintiles >13 ng/mL. Vitamin D concentrations were associated with a composite of in-hospital death, serious infections, and serious cardiovascular events in patients recovering from noncardiac surgery. While causality cannot be determined from our retrospective analysis, the association suggests that a large randomized trial of preoperative vitamin D supplementation and postoperative outcomes is warranted.

The relation between total joint arthroplasty and risk for serious cardiovascular events in patients with moderate-severe osteoarthritis: propensity score matched landmark analysis

Objective To examine whether total joint arthroplasty of the hip and knee reduces the risk for serious cardiovascular events in patients with moderate-severe osteoarthritis.Design Propensity score matched landmark analysis.Setting Ontario,...

The sleep apnea cardiovascular endpoints (SAVE) trial: Rationale and start-up phase.

THE SLEEP APNEA CARDIOVASCULAR ENDPOINTS (SAVE) STUDY (CLINICAL TRIALS REGISTRATION NUMBER: NCT00738170) is an academic initiated and conducted, multinational, open, blinded endpoint, randomised controlled trial designed to determine whether treatment of obstructive sleep apnea (OSA) with continuous positive airways pressure (CPAP) can reduce the incidence of serious cardiovascular events in patients with established cardiovascular disease. The answer to this question is of major importance to populations undergoing ageing and lifestyle changes all over the world. The SAVE study brings together respiratory, sleep and cardiovascular clinician-scientists in a unique interdisciplinary collaborative effort with industry sponsors to conduct the largest and most ambitious clinical trial yet conducted in the field of sleep apnea, with a global recruitment target of 5000 patients. Following its launch in Australia and China in late 2008, SAVE has now entered a phase of international expansion with new recruitment networks being established in New Zealand, India and Latin America. This article describes the rationale for the SAVE study, the considerations behind its design, and progress thus far in establishing the recruitment network. The report emphasises the important role that Chinese sleep and cardiovascular investigators have played in the start-up phase of this landmark international project.

Atherosclerotic Plaque Regression: Fact or Fiction?

Coronary artery disease is the major cause of death in the western world. The formation and rapid progression of atheromatous plaques can lead to serious cardiovascular events in patients with atherosclerosis. The better understanding, in recent years, of the mechanisms leading to atheromatous plaque growth and disruption and the availability of powerful HMG CoA-reductase inhibitors (statins) has permitted the consideration of plaque regression as a realistic therapeutic goal. This article reviews the existing evidence underpinning current therapeutic strategies aimed at achieving atherosclerotic plaque regression. In this review we also discuss imaging modalities for the assessment of plaque regression, predictors of regression and whether plaque regression is associated with a survival benefit.

Myocardial infarction in a young athlete with non-obstructive hypertrophic cardiomyopathy and normal coronary arteries

We describe an acute myocardial infarction in a young athlete with non-obstructive hypertrophic cardiomyopathy (HCM) and normal coronary arteries. A 18 year old athlete came to our attention for dispnoea and chest pain during effort. Echocardiography showed non-obstructive HCM, with restrictive physiology. Cardiac catheterization and coronary angiography showed elevated pulmonary artery pressure and normal coronary arteries. He was discharged on sotalol and diuretics. Nine months later, he was resuscitated from a cardiac arrest during mild effort. The ECG revealed a high rate of atrial fibrillation with significant ST-T changes, and echocardiography an akinesia of interventricular septum. Cardiac enzymes were elevated. The coronary angiogram showed normal coronary arteries. This case is important as a reminder that acute myocardial infarction is not only due to coronary artery disease, and that atrial fibrillation may represent a trigger of serious cardiovascular events in patients with HCM.

Hemodynamic and oxidative stress profile after exercise in type 2 diabetes

This study investigated the effect of an acute bout of exercise (>85% V O 2 Max ) on biochemical, hemodynamic and oxidative stress variables in sedentary and physically active subjects with type 2 diabetes (T2D). Blood measurements were taken before and after a treadmill test on 12 sedentary non-diabetes subjects (ND), 12 sedentary type 2 diabetes (T2S) and 9 physically active T2D subjects (T2DA). T2DS subjects before and after the treadmill test showed a higher plasma glucose (123.2 ± 19.0 mg/dL versus 108.9 ± 16.8 mg/dL, p < 0.001), HbA 1C (8.7 ± 2.4% versus 7.3 ± 1.2%, p < 0.001) and body fat% (21.3 ± 5.7% versus 34.6 ± 4.5%, p < 0.001) than T2DA subjects. T2DA had higher V O 2 Max (37.7 ± 3.5 versus 29.5 ± 3.2, p < 0.05), time on treadmill (22.3 ± 2.1 min versus 16.1 ± 2.1 min, p < 0.05), hemoglobin (17.9 ± 0.9 g/dL, p < 0.05) and lower blood pressure levels in comparison to ND and T2DS subjects. Thiobarbituric acid substances (TBARS) in T2DS were higher than in T2DA subjects (0.27 ± 0.1 nmol/mL versus 0.21 ± 0.1 nmol/mL, p < 0.05). Glutathione (GSH) levels were similar among the groups. Physically active type 2 diabetes subjects had a more favorable biochemical, hemodynamic and oxidative stress profile than sedentary subjects. The coexistence of a poor cardiopulmonary performance and high oxidative stress environment can determine a profile of high risk for serious cardiovascular events in patients with diabetes.

N-Terminal pro-B-Type Natriuretic Peptide in Risk Stratification after Acute Myocardial Infarction in Patients on Long-Term Beta-Adrenergic Receptor Blocker Therapy

Background: N-terminal pro-B-type natriuretic peptide (NT-proBNP) appears to be a strong risk marker of mortality in patients with acute coronary syndrome. However, little information is available on NT-proBNP as a predictor of long-term serious cardiovascular events beyond that of left ventricular ejection fraction in patients with acute myocardial infarction (AMI), most of them treated with an early invasive strategy and on a uniform optimal secondary preventive medication including long-term beta-adrenergic receptor blockade. Objective: To assess the prognostic impact of plasma NT-proBNP in patients with AMI who received optimal medical treatment including long-term beta-adrenergic receptor blockade. Methods: Plasma NT-proBNP was measured in 219 patients (age range 31–80 years) with AMI at baseline, and then followed for a median duration of 1.63 years. The first occurrences of a serious cardiovascular event including cardiac mortality, nonfatal MI, and congestive heart failure were registered. Results: Ninety serious cardiovascular events occurred. Left ventricular ejection fraction and reperfusion therapy with thrombolysis or percutaneous coronary intervention were identified as confounders. When adjusting for these factors in multivariate analysis, NT-proBNP was a strong predictor of serious cardiovascular events in patients with a plasma NT-proBNP of >162.2 pmol/l and aged <60 years (p = 0.001). The incidence rate was related to increasing NT-proBNP (p = 0.0017). The risk of serious cardiovascular events was higher in patients with NT-proBNP levels in the highest quartile (≧162.2 pmol/l) than in those with levels in the three lowest quartiles (rate ratio = 2.5, 95% confidence interval = 1.6–3.9, p = 0.0001). Conclusion: AMI patients with high plasma NT-proBNP seem to be at an increased risk of serious cardiovascular events, but only those ≤60 years of age.

An update on nonsteroidal anti-inflammatory drugs and cyclooxygenase-2 inhibitors

Selective inhibitors of the cyclooxygenase-2 enzyme were developed to treat pain and inflammation while reducing the risk of the serious gastrointestinal side effects seen with nonselective nonsteroidal anti-inflammatory drugs (NSAIDs). The results of several clinical trials have demonstrated an apparent increased risk of serious cardiovascular events in patients taking the COX-2-selective inhibitors. Although the risk was observed originally with trials conducted with rofecoxib, it was attributed generally to the entire class of COX-2-selective drugs based on a similar mechanism of action and a hypothesis that predicted the possibility of a prothrombotic effect of the drugs compared with nonselective NSAIDs. Subsequent studies have demonstrated that elevated cardiovascular risk is not limited to the use of COX-2-specific inhibitors. An increase in cardiovascular risk actually has been seen with anti-inflammatory drugs of the NSAID class, regardless of whether they are selective or nonselective inhibitors. The US Food and Drug Administration has recommended that all such drugs carry a black box warning for gastrointestinal and cardiovascular risks.

Major depression with ischemic heart disease: effects of paroxetine and nortriptyline on long-term heart rate variability measures

Background Studies have linked depression to sudden death and serious cardiovascular events in patients with preexisting cardiac illness. Recent studies have shown decreased vagal function in cardiac patients with depression and depressed patients without cardiac illness. Methods We compared 20-hour, sleeping, and awake heart period variability measures using spectral analysis, fractal dimension, and symbolic dynamics in two patient groups with major depression and ischemic heart disease (mean age 59–60 years) before and after 6 weeks of paroxetine or nortriptyline treatment. Results Spectral measures showed decreases in awake and sleeping total power (TP: 0.0–0.5 Hz), ultra low frequency power (ULF: 0–0.0033 Hz), very low frequency power (VLF: 0.0033–0.04 Hz), and low-frequency power (LF: 0.04–0.15 Hz) for nortriptyline condition and a decrease in high-frequency power (HF: 0.15–0.5 Hz) for the awake condition in patients who received nortriptyline. A measure of nonlinear complexity, WC-100, significantly increased after paroxetine during the awake condition. Conclusions These findings suggest that nortriptyline has stronger vagolytic effects on cardiac autonomic function compared with paroxetine, which is in agreement with previous clinical and preclinical reports. Paroxetine may have some cardio-protective effects, especially in cardiac patients.

Diminished chaos of heart rate time series in patients with major depression

Background: Depression and anxiety have been linked to serious cardiovascular events in patients with preexisting cardiac illness. A decrease in cardiac vagal function as suggested by a decrease in heart rate (HR) variability has been linked to sudden death. Methods: We compared LLE and nonlinearity scores of the unfiltered (UF) and filtered time series (very low, low, and high frequency; VLF, LF and HF) of HR between patients with depression ( n = 14) and healthy control subjects ( n = 18). Results: We found significantly lower LLE of the unfiltered series in either posture, and HF series in patients with major depression in supine posture ( p < .002). LLE (LF/UF), which may indicate relative sympathetic activity was also significantly higher in supine and standing postures in patients ( p < .05); LF/HF (LLE) was also higher in patients ( p < .05) in either posture. Conclusions: These findings suggest that major depression is associated with decreased cardiac vagal function and a relative increase in sympathetic function, which may be related to the higher risk of cardiovascular mortality in this group and illustrates the usefulness of nonlinear measures of chaos such as LLE in addition to the commonly used spectral measures.

Sex and the patient with cardiovascular risk factors: focus on sildenafil

Erectile dysfunction (ED) is common in men with cardiovascular disease. The introduction of sildenafil citrate, the first oral agent for the treatment of this disorder, has increased awareness about the risks of sexual activity in cardiac patients and raised concerns about the safety of sildenafil in patients being treated for coronary disease. Sildenafil is a potent and selective inhibitor of phosphodiesterase type 5 (PDE5), the enzyme responsible for the degradation of cyclic guanosine monophosphate (cGMP). Sildenafil acts along the same general pathway as nitric oxide donors to increase cGMP levels and enhance erections. Sildenafil is a modest vasodilator that causes small decreases in systemic arterial pressure and mild preload and afterload reductions. It does not cause major decreases in blood pressure when administered with one or more standard antihypertensive agents. Because PDE5 is also present in small amounts in the systemic vasculature, sildenafil can cause a synergistic and major decrease in pressure when combined with organic nitrates. Use of organic nitrates is the only contraindication to sildenafil use. Data on sildenafil in patients with recent (less than 6 months) myocardial infarction (MI), unstable angina, stroke, and recent life-threatening arrhythmias are not available, so the drug should be used with caution in patients with unstable cardiac conditions. Placebo-controlled and open-label phase 2/3 trials including men with ischemic heart disease did not show an increase in MI or serious cardiovascular events in patients treated with sildenafil versus placebo. None of the serious cardiovascular events reported in these trials were considered treatment related by the investigators. There is a small but finite increased risk of developing ischemia or infarction with sexual activity. Therefore, before prescribing sildenafil or any current or future treatment for ED to patients with known cardiac disease or multiple cardiovascular risk factors, physicians should discuss the potential cardiac risk of sexual activity and perform a complete medical assessment, including an exercise stress test if appropriate.