doi: 10.1161/01.CIR.0000146906.42375.D3
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(Circulation. 2004;110:3149-3155.)
© 2004 American Heart Association, Inc.
New Drugs and Technologies |
Cardiovascular Effects of the 3 Phosphodiesterase-5 Inhibitors Approved for the Treatment of Erectile Dysfunction
From the Heart Institute, Good Samaritan Hospital, and the Division of Cardiovascular Medicine, Keck School of Medicine, University of Southern California, Los Angeles.
Correspondence to Robert A. Kloner, MD, PhD, Heart Institute, Good Samaritan Hospital, 1225 Wilshire Blvd, Los Angeles, CA 90017. E-mail rkloner{at}goodsam.org
Received May 17, 2004; revision received June 22, 2004; accepted June 22, 2004.
Within the last year, 2 new phosphodiesterase-5 (PDE5) inhibitors have been approved by the US Food and Drug Administration (FDA) for the treatment of erectile dysfunction (ED). Currently, sildenafil (Viagra), vardenafil (Levitra), and tadalafil (Cialis) are on the market. These agents have been shown to be effective in a broad population of men with ED, including patients with vascular disease, coronary artery disease, hypertension, and diabetes.1–5 Because the enzyme that they inhibit, PDE-5, is found in smooth muscle cells of the systemic arteries and veins throughout the body, these agents have mild vasodilator effects and thus, have the potential to impact the cardiovascular system.6 This fact is especially important for the patient with ED, because risk factors for ED include many of the same risk factors that are associated with coronary artery disease: lipid abnormalities, hypertension, smoking, diabetes, and lack of physical exercise.7,8 Because erection is a vascular event, endothelial dysfunction may inhibit it.9 Endothelial dysfunction, an early component of atherosclerosis, is rarely confined to the arteries supplying blood to the penis but more likely occurs throughout the vascular bed. Kaiser et al10 studied 30 men with ED and observed that brachial artery flow–mediated vasodilation and nitroglycerin-mediated vasodilation were reduced in these patients compared with men without ED. Thus, ED may be an early marker of vascular disease.10 Patients with frank coronary artery disease, known to be associated with endothelial dysfunction, and frank atherosclerosis often have ED, as we recently observed in 1 study, in which three fourths of the men with chronic stable angina also reported some degree of ED.11 Hence, the vasodilator effect of these PDE5 agents should be taken into consideration for the cardiac patient, both as a possible concern in some cases or a possible beneficial effect in others. The purpose of the present review is to describe the cardiovascular effects of the 3 available PDE5 inhibitors, the issue of nitrate interaction, differences and similarities in labeling regarding concomitant use of nitrates and 
-blockers, their effect on the QT interval, their safety in regard to cardiac events, and the concept that these agents may eventually play a role in therapies for various cardiac conditions, including pulmonary hypertension and congestive heart failure.
Effect of PDE5 Inhibitors on Blood Pressure and Heart Rate
Sildenafil
Sildenafil was approved as an effective agent for treating ED in 1998, and its cardiovascular effects have been studied in great depth. It has a half-life of 
4 hours (Table). In 1 study of 8 volunteers,12 80 mg of intravenous sildenafil reduced systolic blood pressure from 131±12 mm Hg with placebo to 122±13 mm Hg (P<0.001) with sildenafil. Diastolic blood pressure fell from 71±12 to 64±11, respectively, but heart rate did not change significantly (64±10 to 66±14 beats/min; mean±SD). Jackson et al12 gave 8 healthy male subjects 100, 150, and 200 mg of oral sildenafil. The mean maximum reduction in supine systolic/diastolic blood pressure was 10/7 mm Hg at 3 hours after dosing, with no difference in the 200-mg versus the 100-mg dose. In most subjects, blood pressure returned to baseline within 6 hours. The authors did not observe a significant orthostatic drop in blood pressure or increase in heart rate in the standing position. Sildenafil, as expected, reduced vascular resistance.
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In patients with stable ischemic heart disease 40 mg of intravenous sildenafil reduced systolic arterial pressure from 150±12 to 141±16 mm Hg (mean±SD) and diastolic blood pressure from 74±8 to 66±10 mm Hg but had no effect on heart rate. Cardiac output was 5.6±0.9 L/min at baseline and 5.2±1.1 L/min after intravenous sildenafil. Pulmonary artery pressure fell from 16.7±4.0 to 12.1±3.9 mm Hg. Subsequent studies verified that sildenafil results in small reductions in systolic and diastolic blood pressure, with little or no effect on heart rate.13–15 In addition, sildenafil was shown in numerous studies of pulmonary hypertension to reduce pulmonary vascular resistance and pulmonary artery pressure (PDE5 is rich within the pulmonary vasculature).16–18
Vardenafil
Vardenafil was the second PDE5 inhibitor to come to market in the United States, and it was approved by the FDA in 2003. It has many similarities to sildenafil; in fact, its molecular structure is very similar (Figure), and they share a half-life of 4 hours. In healthy volunteers, vardenafil caused a transient reduction in supine blood pressure with a mean maximum decrease of 7 mm Hg systolic and 8 mm Hg diastolic. Maximum reduction occurred between 1 and 4 hours after dosing.19 A 20-mg dose of vardenafil resulted in a mean maximum increase in heart rate of 4 beats/min.
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Tadalafil
Tadalafil was the third PDE5 inhibitor to come to market in the United States and was approved by the FDA at the end of 2003. Its chemical structure differs substantially from that of sildenafil and vardenafil, and it has a unique, long half-life of 17.5 hours. In healthy subjects, a single oral dose of 10 or 20 mg of tadalafil did not drop systolic blood pressure significantly compared with placebo. The decrease in systolic blood pressure with 20 mg tadalafil versus placebo was –0.2 mm Hg (95% confidence interval [CI], –7.1 to 6.6) in the standing position.20,21 The mean decrease in diastolic blood pressure compared with placebo was –4.6 mm Hg (95% CI, –7.9 to –1.2) in the standing position. Diastolic blood pressure was generally lower for 12 hours after administration of the drug, but the decrease in pressure remained small. Changes were even less marked in the supine position. Standing and supine heart rates were not significantly different from those with placebo.20
In patients with coronary artery disease, who had higher systolic blood pressures at baseline than did healthy volunteers, 10 mg tadalafil reduced standing systolic blood pressure from 134 to 127 mm Hg (–7 mm Hg) and diastolic blood pressure from 78 to 74 mm Hg (–4 mm Hg) at time to maximum plasma concentration (Tmax; 2 hours) after dosing.21
Hence, all 3 of the PDE5 inhibitors are mild vasodilators and may cause small drops in arterial pressure. However, the degree of drop in blood pressure is usually small. Although this is rarely a concern in healthy individuals, in cardiovascular patients with low blood pressure or hypotension at baseline, this could be a concern, as described in recent guidelines.22 This vasodilating property would also be a concern for patients with left ventricular outflow obstruction or aortic stenosis.22,23 This property also becomes an issue regarding the concomitant use of nitrates and -blockers, as described next.
Nitrate Interaction
PDE5 inhibitors work to improve ED by preventing the breakdown of cyclic GMP, the substance that promotes relaxation of smooth muscle cells in the arteries, arterioles, and sinusoids of the corpus cavernosum of the penis.24 Nitric oxide (NO) donors, such as nitroglycerin (short or long acting), isosorbide dinitrate, isosorbide mononitrate, and others stimulate guanylate cyclase, which increases the production of cyclic GMP. When NO donors are given at the same time as PDE5 inhibitors, there is both an increase in the production of cyclic GMP (due to the NO donor) and an inhibition of its breakdown (due to the PDE5 inhibitor) that can lead to a build-up of cyclic GMP with pronounced vasodilation and, in some patients, frank hypotension. Organic nitrates are contraindicated with all 3 PDE5 inhibitors on the market.19–21,25,26 Details of interaction studies are presented in the online supplement to this article.
Duration of PDE5 Inhibitor–Nitrate Interaction
If a patient with coronary artery disease takes a PDE5 inhibitor and then develops angina pectoris, when is it safe to administer nitroglycerin?
Sildenafil
A consensus statement from the American College of Cardiology/American Heart Association suggested that for sildenafil, 6 half-lives, or 24 hours (4 hours x 6), pass between sildenafil intake and the administration of a nitrate.22 This time frame was chosen to allow full washout of drug from the tissues. In a previous analysis,20 at 24 hours after sildenafil, there was no interaction with sublingual nitroglycerin. In a recent preliminary study of healthy individuals, the sildenafil-nitroglycerin interaction appeared to be gone as early as 4 hours.27
Vardenafil
Although a detailed time-course study of the interaction between vardenafil and nitrates is not available, 1 unpublished study19 did suggest a lack of interaction at 24 hours, consistent with a 4-hour half-life.
Tadalafil
A nitrate-tadalafil interaction study was recently reported.28 In a population of patients who were healthy or had controlled hypertension or diabetes, 20 mg tadalafil or placebo was given daily for 7 days. On the seventh day, sublingual nitroglycerin was administered at 2, 4, 8, 24, 48, 72, or 96 hours. There was evidence that tadalafil augmented the nitrate-induced decrease in blood pressure within the first 24 hours of its administration. At and beyond 48 hours, the interaction was not detectable, as assessed by mean maximal falls in blood pressure or outlier criteria. Thus, the manufacturer suggests that if a patient has taken tadalafil and develops chest pain and it is deemed medically necessary that nitrates be given, at least 48 hours should elapse after the last dose of tadalafil before nitrates are given. Even then, nitrates should be given only under close medical supervision and appropriate hemodynamic monitoring.
What should a patient do if he/she develops chest pain after having taken a PDE5 inhibitor? The patient should call for emergency assistance for hospital transport29 and apprise the emergency medical technicians and emergency physicians regarding use of the PDE5 inhibitor. Organic nitrates are initially contraindicated. The American College of Cardiology/American Heart Association Consensus document22 reminds physicians that other antianginal agents can be considered in such situations. ß-Blockers, calcium channel blockers, morphine, and other anti-ischemic agents, such as oxygen, aspirin, and statins, may be safely given in the setting of a PDE5 inhibitor. Furthermore, should a patient develop a myocardial infarction while taking a PDE5 inhibitor, usual care—thrombolytics, antiplatelet agents, and percutaneous coronary intervention—is indicated. Only organic nitrates should be avoided. If a patient has taken a PDE5 inhibitor, inadvertently receives a nitrate, and becomes hypotensive, the American College of Cardiology/American Heart Association recommends common-sense measures: placing the patient in the Trendelenburg position, administering intravenous fluids and -agonists, and finally using intra-aortic balloon counterpulsation. At the present time, there are no specific antidotes to PDE5 inhibition.
Interaction With Common Antihypertensive Agents Other Than -Blockers
Several studies investigated the interactions of sildenafil, vardenafil, and tadalafil on blood pressure in patients already taking usual antihypertensive medicines, such as calcium channel blockers, diuretics, ß-blockers, angiotensin-converting-enzyme inhibitors, and angiotensin receptor blockers. In general, these studies suggested that when a PDE5 inhibitor was administered to patients already taking antihypertensive medications, small additive drops in blood pressure occurred that were roughly equivalent to or less than the drops in pressure that occurred when the PDE5 inhibitors were taken without concomitant antihypertensive agents.
Sildenafil
Webb et al25 studied men who were already receiving amlodipine for the treatment of hypertension for at least 1 month. These authors showed that 100 mg sildenafil given 2 hours after a morning dose of 5 or 10 mg amlodipine resulted in a mean maximal change from baseline blood pressure of –8 mm Hg supine systolic and –7 mm Hg supine diastolic compared with men who received placebo plus amlodipine. The differences in standing systolic and diastolic blood pressures were –10 and –8 mm Hg, respectively.
Even smaller additional reductions in blood pressure were reported when the PDE5 inhibitor sildenafil was administered to patients already taking ß-blockers, diuretics, or angiotensin-converting-enzyme inhibitors.30 There was no increase in adverse events in patients treated with sildenafil who received antihypertensive medicines, even multiple antihypertensive medicines.30–32 No increase in syncope or postural hypotension was reported when sildenafil was given to patients already taking these common antihypertensive drugs. Furthermore, the most common side effects of sildenafil (headache, flushing, dyspepsia, visual disturbance, rhinitis) were not worsened in patients on concomitant antihypertensive medicines, even if the patients were taking 2 or more antihypertensive medicines.31 The efficacy of sildenafil to improve ED remained high (72%) in hypertensive patients taking antihypertensive agents.31,32
Vardenafil
Vardenafil was associated with a small or no fall in blood pressure when administered to patients taking their usual antihypertensive medicines.33,34 Vardenafil 20 mg produced an additional fall in mean systolic/diastolic blood pressure of 6/5 mm Hg versus placebo when it was concomitantly administered with slow-release nifedipine (30 or 60 mg) in patients whose blood pressure had been controlled with this calcium channel blocker.35
Tadalafil
Kloner et al36 reported a series of studies in which 10 or 20 mg tadalafil was administered to patients with hypertension taking antihypertensive medications or to healthy individuals who received an antihypertensive medicine. In healthy individuals receiving 5 mg amlodipine daily for at least 14 days, 20 mg tadalafil had no significant additional effect with a mean change in systolic/diastolic blood pressure of –1/1 mm Hg compared with placebo. This ambulatory blood pressure monitoring study showed no interaction between 5 mg amlodipine and 20 mg tadalafil. Tadalafil 10 mg given to hypertensive patients who had been receiving the thiazide diuretic bendrofluazide was associated with an additional reduction in supine systolic/diastolic blood pressure of 6/4 mm Hg and in standing systolic/diastolic pressure of the same degree. Tadalafil 10 mg administered to patients taking metoprolol (25 to 200 mg daily) resulted in an additional mean reduction in supine systolic/diastolic blood pressure of 5/3 mm Hg and in standing systolic/diastolic blood pressure of 7/4 mm Hg. Tadalafil 10 mg administered to patients taking enalapril (10 to 20 mg per day) was associated with a mean reduction in supine systolic/diastolic blood pressure of 4/1 mm Hg and in standing systolic/diastolic blood pressure of 3/1 mm Hg. In an ambulatory BP monitoring study, 20 mg tadalafil given to patients already receiving various angiotensin receptor blockers was associated with an additional mean reduction in ambulatory systolic/diastolic blood pressure of 8/4 mm Hg. The incidence of adverse events in tadalafil-treated patients in general was similar to that in patients receiving or not receiving concomitant antihypertensive medicines, similar to observations with the other PDE5 inhibitors.
In general, sildenafil, vardenafil, and tadalafil appear to be well tolerated and safe in patients receiving most concomitant antihypertensive agents. There appears to be no or only small additive drops in blood pressure that occur when the PDE5 inhibitor is administered in addition to the antihypertensive medicines. The 1 exception to this appears to be -blockers, as described next.
Interaction of PDE5 Inhibitors With -Blockers
Sildenafil
There were recent changes to the labeling of sildenafil regarding concomitant use in patients receiving -blockers.37 One study assessed concomitant administration of the nonselective 1-blocker doxazosin with sildenafil in patients with benign prostatic hypertrophy who had been taking -blockers for at least 8 weeks. Doxazosin is given for both hypertension and benign prostatic hypertrophy. Two of 20 patients receiving 4 mg doxazosin and 50 mg sildenafil developed symptomatic hypotension. Interestingly, no (0/20) patients receiving 4 mg doxazosin and 100 mg sildenafil had symptomatic hypotension. Also, the 25-mg dose of sildenafil, when coadministered with 4 mg doxazosin, was not associated with hypotension. The label precaution (not contraindication) now advises that 50 or 100 mg sildenafil should not be taken within a 4-hour window of -blocker administration. A 25-mg dose of sildenafil may be taken at any time in relation to an -blocker.
Vardenafil
Vardenafil is contraindicated in patients taking -blockers.19 When 10 or 20 mg vardenafil was administered to healthy volunteers either simultaneously or 6 hours after a 10-mg dose of the 1-blocker terazosin (used for both hypertension and benign prostatic hypertrophy), significant hypotension was observed. When 10 mg vardenafil was given at the same time as 10 mg terazosin, 6 of 8 volunteers developed a standing systolic blood pressure <85 mm Hg. In a study with 20 mg vardenafil, simultaneous administration of 10 mg terazosin resulted in 2 of 9 subjects dropping their standing systolic blood pressure to <85 mm Hg. When dosing was separated by 6 hours, 7 of 28 subjects dropped their standing systolic blood pressure to below 85 mm Hg. Results with tamsulosin (a selective 1a-blocker, which is more selective for prostatic tissue and mainly used to treat benign prostatic hypertrophy) also showed an interaction with vardenafil but to a lesser extent. Two of 16 subjects who received 10 mg vardenafil plus 0.4 mg tamsulosin developed a standing systolic blood pressure below 85 mm Hg. Thus, when vardenafil was released in the United States, it carried an absolute contraindication in patients taking -blockers.19 However, a recent analysis suggests that this interaction is much less marked when vardenafil is administered to patients with benign prostatic hypertrophy who have been on long-term -blocker therapy.38
Tadalafil
Tadalafil is contraindicated in patients taking -blockers except for 0.4 mg tamsulosin (1a-blocker). In 1 study,39 20 mg tadalafil augmented the hypotensive effect of 8 mg doxazosin with a mean maximal decrease in standing systolic blood pressure that was greater than placebo (mean difference of 9.8 mm Hg). The number of subjects with a standing systolic blood pressure of <85 mm Hg was greater after doxazosin plus tadalafil (28%) versus doxazosin plus placebo (6%). In a separate analysis,39 0.4 mg tamsulosin was given with 10 or 20 mg tadalafil. In subjects taking this -blocker, tadalafil produced mean maximal reductions in standing systolic blood pressure that were similar to those seen with placebo (mean difference of 1.7 mm Hg with 10 mg tadalafil and of 2.3 mm Hg with 20 mg tadalafil). Furthermore, none of the subjects receiving tamsulosin plus tadalafil dropped their standing systolic blood pressure to <85 mm Hg.
QT Interval
Vardenafil was associated with small increases in QTc in 1 study19,40 and carries the label warning that it should be avoided in patients with congenital QT prolongation and patients taking class IA (eg, quinidine, procainamide) or class III (eg, amiodarone, sotalol) antiarrhythmic medications. Tadalafil20,41 and sildenafil37 do not carry this statement. To date, there have been no known cases of torsade de pointes in patients receiving PDE5 inhibitors. In our experimental animal studies of acute coronary artery occlusion, administration of sildenafil was not associated with an increase in ventricular arrhythmia.42 Additional details on QT interval may be found in the online supplement to this article.
Do the PDE5 Inhibitors Exacerbate Ischemia?
Studies with sildenafil, vardenafil, and tadalafil showed that when these agents were given to patients with coronary artery disease during exercise stress testing, there was no exacerbation of ischemia compared with placebo.43–46 A very important aspect of these studies was that the level of exercise was similar to or exceeded that achieved during sexual intercourse. In a few of these studies, sildenafil43 and vardenafil45 actually appeared to have a beneficial effect on exercise-induced ischemia. A study performed in the cardiac catheterization laboratory by Hermann et al14 observed that when oral sildenafil was administered to patients with severe coronary artery disease, it had no adverse effects on coronary artery diameter or coronary artery flow velocity and actually improved coronary artery vasodilator reserve induced by adenosine. Halcox et al47 demonstrated a slight vasodilating effect of sildenafil on epicardial coronary arteries. The effects of vardenafil and tadalafil on coronary artery hemodynamics are unknown at this time.
Do PDE5 Inhibitors Cause Myocardial Infarction or Death?
After the initial release of sildenafil, there were anecdotal reports of myocardial infarction and death. However, sexual activity itself may be associated with a small but definite increase in risk of myocardial infarction.48 Patients with ED are more likely to have risk factors for coronary artery disease (such as age 
45, smoking, lipid abnormalities, diabetes, hypertension, and lack of physical activity) or have frank heart disease.6–8,49 Analysis of double-blind, randomized, controlled studies and open-label studies did not show an increase in the rates of myocardial infarction or death in patients receiving sildenafil versus placebo or when compared with age-matched expected events.2,50–55 Similar results have been reported with tadalafil20,21 and vardenafil.56 Postmarketing surveys in the United Kingdom54 and in the United States, including 1 by the FDA,52 did not show a rate of myocardial infarction, ischemic heart disease, or mortality in men who took sildenafil to be greater than expected than in an age-matched population. In fact, death rates tended to be less in the population taking sildenafil (perhaps suggesting that healthier men were receiving the drug). Postmarketing data regarding cardiovascular event rates in men taking vardenafil or tadalafil have yet to be reported and will be important.
Other Cardiovascular Effects
PDE5 inhibitors have potential therapeutic use for a number of cardiovascular disorders, including pulmonary hypertension, congestive heart failure, hypertension, and endothelial dysfunction. Details are described in the online supplement.
Summary
There are currently 3 PDE5 inhibitors available for the treatment of ED. All are effective in patients with organically based ED, including ED due to vascular disease. Sildenafil and vardenafil have relatively short half-lives of 4 hours, whereas the half-life of tadalafil is 17.5 hours. These agents are all mild vasodilators and have minimal effects on blood pressure. Sildenafil, vardenafil, and tadalafil are all contraindicated with nitrate use. Should a patient develop chest pain while taking sildenafil or vardenafil, nitrate may be administered under supervision at 24 hours (and possibly earlier); should a patient take tadalafil and develop chest pain, nitrate may not be given until at least 48 hours after the tadalafil dose and then again, only under close monitoring. -Blockers are a contraindication to the use of vardenafil. Except for 0.4 mg tamsulosin, -blockers are a contraindication to the use of tadalafil. Sildenafil >25 mg should not be given within 4 hours of an -blocker. Doses of sildenafil of 25 mg may be administered at any time in relation to an -blocker. Vardenafil should not be administered to patients taking class IA or III antiarrhythmic drugs or to patients with congenital QT prolongation. The PDE5 inhibitors do not adversely affect total exercise time or time to ischemia during exercise stress testing. The PDE5 inhibitors are safe to administer to patients taking antihypertensive medicines (except for the -blockers, as described earlier). The PDE5 inhibitors are effective for the treatment of ED in patients with cardiac disease, including patients with chronic coronary artery disease57 and hypertension. Data from controlled clinical trials do not suggest an increase in myocardial infarction or death rates in patients taking PDE5 inhibitors. These agents appear safe and effective in most patient populations but have not been studied extensively in patients with baseline severe or unstable cardiac conditions.
Acknowledgments
Disclosure
Dr Kloner is a compensated speaker for and consultant to Pfizer, Bayer-GSK, and Lilly ICOS, and receives research support from Lilly ICOS.
Footnotes
An online-only Data Supplement is available at http://www.circulationaha.org
References
1. Goldstein I, Lue TF, Padma-Nathan H, et al. Oral sildenafil in the treatment of erectile dysfunction. N Engl J Med. 1998; 338: 1397–1404.
2. Padma-Nathan H. Sildenafil citrate (Viagra) and erectile dysfunction: a comprehensive four year update on efficacy, safety, and management options. Urology. 2002; 60 (suppl): 1–90.[Medline] [Order article via Infotrieve]
3. Hellstrom WJG, Gittleman M, Karlin G, et al. Vardenafil for treatment of men with erectile dysfunction: efficacy and safety in a randomized double-blind, placebo-controlled trial. J Androl. 2002; 23: 763–771.
4. Brock GB, McMahon CG, Chen KK, et al. Efficacy and safety of tadalafil for the treatment of erectile dysfunction: results of an integrated analysis. J Urol. 2001; 168: 1322–1336.[CrossRef]
5. Gresser U, Gleiter OH. Erectile dysfunction: comparison of efficacy and side effects of the PDE5 inhibitors sildenafil, vardenafil and tadalafil. Eur J Med Res. 2002; 7: 435–446.[Medline] [Order article via Infotrieve]
6. Kloner RA, Jarow JP. Erectile dysfunction and sildenafil citrate and cardiologists. Am J Cardiol. 1999; 83: 576–582.[CrossRef][Medline] [Order article via Infotrieve]
7. Feldman HA, Goldstein I, Hatzichristou DG, et al. Impotence and its medical and psychological correlates: results of the Massachusetts Male Aging Study. J Urol. 1994; 151: 54–61.[Medline] [Order article via Infotrieve]
8. Feldman HA, Johannes CB Derby CA, et al. Erectile dysfunction and coronary risk factors: prospective results from the Massachusetts Male Aging Study. Prev Med. 2000; 30: 328–338.[CrossRef][Medline] [Order article via Infotrieve]
9. Azadzoi KM, Siroky MB, Goldstein I. Study of etiologic relationship of arterial atherosclerosis to corporal veno-occlusive dysfunction in the rabbit. J Urol. 1996; 155: 1795–1800.[CrossRef][Medline] [Order article via Infotrieve]
10. Kaiser DR, Billups K, Mason C, et al. Impaired brachial artery endothelium- dependent and -independent vasodilation in men with erectile dysfunction and no other clinical cardiovascular disease. J Am Coll Cardiol. 2004; 43: 179–184.
11. Kloner RA, Mullin SH, Shook T, et al. Erectile dysfunction in the cardiac patient: how common and should we treat? J Urol. 2003; 170: S46–S50.[CrossRef][Medline] [Order article via Infotrieve]
12. Jackson G, Benjamin N, Jackson N, et al. Effects of sildenafil citrate on human hemodynamics. Am J Cardiol. 1999; 83: 13C–20C.[Medline] [Order article via Infotrieve]
13. Zusman RM, Morales A, Glasser DB, et al. Overall cardiovascular profile of sildenafil citrate. Am J Cardiol. 1999; 83: 35C–44C.[CrossRef][Medline] [Order article via Infotrieve]
14. Hermann HC, Chang G, Klugherz BD, et al. Hemodynamic effects of sildenafil in men with severe coronary artery disease. N Engl J Med. 2000; 342: 1622–1626.
15. Kloner RA. Sex and the patient with cardiovascular risk factors: focus on sildenafil. Am J Med. 2000; 109 (suppl 9A): 13S–21S.[CrossRef][Medline] [Order article via Infotrieve]
16. Zhao L, Mason NA, Morrell N, et al. Sildenafil inhibits hypoxia-induced pulmonary hypertension. Circulation. 2001; 104: 424–428.
17. Prasad S. Wilkinson J, Gatzoulis MA. Sildenafil in primary pulmonary hypertension. N Engl J Med. 2000; 343: 1342.
18. Wilkens H, Guth A, Konig J, et al. Effect of inhaled iloprost plus oral sildenafil in patients with primary pulmonary hypertension. Circulation. 2001; 104: 1218–1222.
19. Product monograph for Levitra (vardenafil HCL). Bayer Health Care, Glaxo SmithKline; 2003.
20. Emmick JT, Stuewe SR, Mitchell M. Overview of the cardiovascular effects of tadalafil. Eur Heart J Suppl. 2002; 4 (suppl H): H32–H47.[Abstract]
21. Kloner RA, Mitchell M, Emmick JT. Cardiovascular effects of tadalafil. Am J Cardiol. 2003; 92 (suppl): 37M–46M.[CrossRef][Medline] [Order article via Infotrieve]
22. Cheitlin MD, Hutter AM Jr, Brindis RG, et al. ACC/AHA expert consensus document use of sildenafil (Viagra) in patients with cardiovascular disease. American College of Cardiology/American Heart Association. J Am Coll Cardiol. 1999; 33: 273–282.
23. DeBusk R, Drory Y, Goldstein I, et al. Management of sexual dysfunction in patients with cardiovascular disease: recommendations of the Princeton Consensus Panel. Am J Cardiol. 2000; 86: 175–181.[CrossRef][Medline] [Order article via Infotrieve]
24. Rosen RC, Kostis JB. Overview of phosphodiesterase 5 inhibition in erectile dysfunction. Am J Cardiol. 2003; 92 (suppl): 9M–18M.[Medline] [Order article via Infotrieve]
25. Webb DJ, Freestone S, Allen MJ, et al. Sildenafil citrate and blood-pressure-lowering drugs: results of drug interaction studies with an organic nitrate and a calcium antagonist. Am J Cardiol. 1999; 83: 21C–28C.[Medline] [Order article via Infotrieve]
26. Webb DJ, Muirhead GJ, Wolff M, et al. Sildenafil citrate potentiates the hypotensive effects of nitric oxide donor drugs in male patients with stable angina. J Am Coll Cardiol. 2000; 36: 25–31.
27. Oliver JJ, Bell K, Leekie SM, et al. Interaction between glyceryl trinitrate and sildenafil citrate (Viagra) may last less than four hours. Int J Impot Res. 2002; 14 (suppl 3): S22–S28.[CrossRef][Medline] [Order article via Infotrieve]
28. Kloner RA, Hutter AM, Emmick JT, et al. Time course of the interaction between tadalafil and nitrates. J Am Coll Cardiol. 2003; 42: 1855–1860.
29. DeBusk RF. Sexual activity in patients with angina. JAMA. 2003; 290: 3129–3132.
30. Zusman RM, Prisant LM, Brown MJ. Effect of sildenafil citrate on blood pressure and heart rate in men with erectile dysfunction taking concomitant antihypertensive medication. Sildenafil Study Group. J Hypertens. 2000; 18: 1865–1869.[CrossRef][Medline] [Order article via Infotrieve]
31. Kloner RA, Brown M, Prisant LM, et al for the Sildenafil Study Group. Effect of sildenafil in patients with erectile dysfunction taking antihypertensive therapy. Am J Hypertens. 2001; 14: 70–73.[CrossRef][Medline] [Order article via Infotrieve]
32. Pickering TG, Mancia G, Glasser DB, et al. Safety of Viagra (sildenafil citrate) in men with erectile dysfunction and arterial hypertension who are taking multiple antihypertensive treatments. Am J Hypertens. 2002; 15 (suppl 1): A55–A56.
33. Kloner RA, Mohan P, Segerson T, et al. Cardiovascular safety of vardenafil in patients receiving antihypertensive medications: a post-hoc analysis of five placebo-controlled trials. J Am Coll Cardiol. 2003; 41 (suppl A): 276A–277A.
34. Padma-Nathan H, Porst H, Eardley I, et al. Efficacy and safety of vardenafil, a selective phosphodiesterase 5 inhibitor, in men with erectile dysfunction on antihypertensive therapy. Presented at the American Society of Hypertension 17th Annual Scientific Meeting. New York, NY, 2002.
35. Rohde G, Jordan P. Influence of vardenafil on blood pressure and pharmacokinetics in hypertensive patients on nifedipine therapy. Pharmacotherapy. 2002; 22: 418. Abstract.
36. Kloner RA, Mitchell M, Emmick JT. Cardiovascular effects of tadalafil in patients on common antihypertensive therapies. Am J Cardiol. 2003; 92 (suppl): 47M–57M.[Medline] [Order article via Infotrieve]
37. Sildenafil prescribing information. New York, NY: Pfizer; 2004.
38. Auerbach S, Gittelman M, Mazzu A, et al. Coadministered vardenafil (for erectile dysfunction) and tamsulosin do not induce hypotension in patients with benign prostatic hypertrophy. Am J Hypertens. 2004; 17: 16A. Abstract.
39. Kloner RA, Jackson G, Emmick JT, et al. Interaction between the phosphodiesterase 5 inhibitor, tadalafil, and the two -blockers doxazosin and tamsulosin in healthy normotensive men. J Urol. In press.
40. Data on file. Food and Drug Administration Cardiovascular and Renal Drugs Advisory Committee: LEVITRA tablets. Available at http://www.fda.gov/ohrms/dockets/ac/03/slides/3956 S1-03-Bayer.ppt. Accessed September 5, 2003.
41. Cialis (tadalafil) prescribing information. Indianapolis, Ind/Bothell, Wash: Lilly ICOS LLC; 2003.
42. Reffelmann T, Kloner RA. Effects of sildenafil on myocardial infarct size, microvascular function, and acute ischemic ventricular dilatation. Cardiovasc Res. 2003; 59: 441–449.
43. Fox KM, Thadani U, Ma PTS, et al, on behalf of the CAESAR 1 (Clinical American and European Studies of Angina And Revascularization) Investigators. Sildenafil citrate does not reduce exercise tolerance in men with erectile dysfunction and chronic stable angina. Eur Heart J. 2003; 24: 2206–2212.
44. Arruda-Olson AM, Mahoney DW, Nehra A, et al. Cardiovascular effects of sildenafil during exercise in men with known or probable coronary artery disease: a randomized crossover trial. JAMA. 2002; 287: 719–725.
45. Thadani U, Smith W, Nash S, et al. The effect of vardenafil, a potent and highly selective phosphodiesterase-5 inhibitor for the treatment of erectile dysfunction on the cardiovascular response to exercise in patients with coronary artery disease. J Am Coll Cardiol. 2002; 40: 2006–2012.
46. Patterson D, MacDonald TM, Effron MB, et al. Tadalafil does not affect time to ischemia during exercise stress testing in patients with coronary artery disease. Circulation. 2002; (suppl II): 106: II-330.
47. Halcox JPJ, Nour KRA, Zalos G, et al. The effect of sildenafil on human vascular function, platelet activation, and myocardial ischemia. J Am Coll Cardiol. 2002; 40: 1232–1240.
48. Muller JE, Mittleman A, Maclure M, et al. Triggering myocardial infarction by sexual activity: low absolute risk and prevention by regular physical exertion. JAMA. 1996; 275: 1405–1409.
49. Kloner RA. Introduction: erectile dysfunction and cardiovascular risk factors. Am J Cardiol. 2003; 92 (suppl): 1M–2M.
50. Morales A, Gingell C, Collins M, et al. Clinical safety of oral sildenafil citrate (Viagra) in the treatment of ED. Int J Impot Res. 1998; 10: 69–74.[CrossRef][Medline] [Order article via Infotrieve]
51. Conti CR, Pepine CJ, Sweeney M. Efficacy and safety of sildenafil citrate in the treatment of ED in patients with ischemic heart disease. Am J Cardiol. 1999; 83 (suppl 5A): 29C–34C.[CrossRef][Medline] [Order article via Infotrieve]
52. Wysowski DK, Farinas E, Swartz L. Comparison of reported and expected deaths in sildenafil (Viagra) users. Am J Cardiol. 2002; 89: 1331–1334.[CrossRef][Medline] [Order article via Infotrieve]
53. Mittleman MA, Glasser DB, Orazem J. Clinical trials of sildenafil citrate (Viagra) demonstrate no increase in risk of myocardial infarction and cardiovascular death compared with placebo. Int J Clin Pract. 2003; 57: 597–600.[Medline] [Order article via Infotrieve]
54. Shakir SAW, Wilton LV, Boshier A, et al. Cardiovascular events in users of sildenafil: results from first phase of prescription event monitoring in England. BMJ. 2001; 322: 651–652.
55. Kloner RA. Cardiovascular risk and sildenafil. Am J Cardiol. 2000; 86 (suppl): 57F–61F.[Medline] [Order article via Infotrieve]
56. Kloner RA, Mohan P, Norenberg C, et al. Cardiovascular safety of vardenafil, a potent, highly selective PDE5 inhibitor in patients with erectile dysfunction: analysis of five controlled clinical trials. Pharmacol Ther. 2002; 22: 1371.
57. DeBusk RF, Pepine CJ, Glasser DB, et al. Efficacy and safety of sildenafil citrate in men with erectile dysfunction and stable coronary artery disease. Am J Cardiol. 2004; 93: 147–153.[CrossRef][Medline] [Order article via Infotrieve]
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