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Clinical Update

Erectile dysfunction, sildenafil and cardiovascular risk

K Kim Chew, Bronwyn G A Stuckey and Peter L Thompson

MJA 2000; 172: 279-283

Abstract - Cardiovascular disease and erectile dysfunction - Sildenafil and erectile dysfunction - Sildenafil and adverse cardiovascular events - Did sildenafil cause or contribute to the reported deaths? - Recommendations - Disclosure - References - Authors' details
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Abstract
  • Cardiovascular risk factors are commonly associated with erectile dysfunction and should be identified and treated.
  • Patients with cardiovascular diseases should be assessed and counselled regarding their fitness for sexual activity.
  • The danger of concurrent use of sildenafil and nitrates under any circumstances, regardless of age and sex, must be highlighted at all levels of the community.
  • Sildenafil is absolutely contraindicated in patients receiving treatment with long-acting nitrates for ischaemic heart disease.
  • Patients who need sublingual short-acting nitrates infrequently should not be precluded from taking sildenafil, provided they are aware that sildenafil is not to be taken within 24 h of taking the nitrate.

There has been concern about the use of sildenafil (Viagra; Pfizer) for the treatment of erectile dysfunction (ED), particularly with regard to its possible role in the reported deaths and other serious cardiovascular events. Although sildenafil attracted considerable free media publicity in its debut in Australia and ranks as the most publicised new product this decade,1,2 consumer interest has been subdued and partly overshadowed by reports of 130 deaths involving sildenafil users in the United States between late March and mid-November 1998.3

It is therefore important that the association between sildenafil and these deaths be examined critically, so that the nature and the degree of risk may be identified and proper guidelines may evolve for the use of sildenafil.


Cardiovascular disease and erectile dysfunction
Cardiovascular disease and ED are known to be associated. In the Massachusetts Male Ageing Study,4 moderate or complete ED was 31% more prevalent among people with heart disease than in an age-matched cohort without heart disease. In a study in Perth, WA, the prevalence of complete ED among patients with hypertension, ischaemic heart disease and peripheral vascular disease was 26%, 38% and 57%, respectively, compared with 18.6% for the whole study.5 Reported ED in patients hospitalised for myocardial infarct or coronary artery surgery is of the order of 57%-64%.6,7

Conversely, in patients with severe ED, there is a 16% risk of severe, clinically occult ischaemic heart disease.8 Indeed, a statistically significant correlation has been shown between ED and the number of occluded coronary vessels.9

A significant number of patients requesting treatment for ED will have known or undiagnosed ischaemic heart disease, leading to considerable potential for adverse cardiovascular events. Moreover, many medications used for the treatment of cardiovascular disease may aggravate ED or complicate its treatment.10


Sildenafil and erectile dysfunction
Sexual stimulation leads to the release of nitric oxide in the corpus cavernosum and results in an increase of cyclic guanosine monophosphate (cGMP), which produces smooth muscle relaxation and increased blood flow. Sildenafil is a selective inhibitor of cGMP-specific type 5 phosphodiesterase (PDE), the enzyme responsible for the degradation of cGMP in the corpus cavernosum. Thus, it enhances the effects of cGMP and permits an erectile response to be achieved or sustained (Box 1). The relevant pharmacodynamic and pharmacokinetic characteristics of sildenafil are summarised in Box 2.11-13 The efficacy of sildenafil in the treatment of ED has been demonstrated in 21 randomised, double-blind, placebo-controlled trials involving more than 3000 patients aged 19-87 years with ED of various aetiology.11

Sildenafil has been studied in men with ischaemic heart disease and with a wide range of other risk factors.14 A low incidence of serious or clinically significant adverse events, including cardiovascular events, was reported, comparable to that in patients with no known history of cardiovascular disorders.

In Phase II-III studies involving 349 placebo patient-years and 693 sildenafil patient-years in randomised studies and 4220 patient-years in open-label studies, the incidence of myocardial infarction was lower in the sildenafil group than in the placebo group, although the difference was not statistically significant. The incidence of adverse events attributable to lowering of blood pressure in patients taking sildenafil was also low and no higher than in those receiving placebo. It was similar in patients taking concomitant antihypertensives and in those not taking these medications.14

There were reports of 26 deaths in about 5000 sildenafil patient-years, including 14 people with myocardial infarction and sudden death. None of the deaths was considered to be treatment related.14


Sildenafil and adverse cardiovascular events
The unprecedented hype generated by the launch of sildenafil in the United States was dampened by reports of cardiovascular events, including deaths, allegedly associated with its use. A summary of reports of death among sildenafil users was posted by the Food and Drug Administration (FDA), with the pertinent remark that, in interpreting these reports, consideration should be given to the limitations of spontaneous reporting, such as under-reporting, duplication, marketing and medicolegal factors, incomplete or inaccurate clinical information, and the assumption of a cause-effect relationship.3

An overview of the FDA's updated summary of 130 reports of death between late March and mid-November 1998 is shown in Box 3. Deaths have also been reported in the Netherlands15 and Australia.16


Did sildenafil cause or contribute to the reported deaths?
Sexual activity remains a potential trigger for myocardial infarction and sudden death may result from ischaemia or arrhythmia, although the relative and absolute risks are apparently low (Box 4).

In the US general population with an age distribution similar to that of sildenafil users, there are about 400 deaths per million per week, and about 150 of these have a cardiovascular cause.29 In Australia, there are about 250 myocardial infarctions (50 fatal) per week affecting men aged 35 to 69 years.30,31 More than 70% of the deceased subjects in the FDA summary had overt or occult cardiovascular disease. Considering the high prevalence of risk factors for sudden cardiac death in users of sildenafil, the reported 130 deaths need to be viewed in the context of patient exposure to about 50 million sildenafil tablets, or more than 6 million prescriptions, during the same period.

Pharmacologically, the action of sildenafil as a type 5 PDE inhibitor is highly specific. Potential for disaster seems to lie in the concurrent use of sildenafil and organic nitrates, as sildenafil potentiates the effect of nitrates and may lead to life-threatening hypotension (Box 1). Among the deaths reported in the FDA summary, there were 16-19 sildenafil users who had allegedly used or received glyceryl trinitrate or a nitrate-containing medication. In this subset of individuals, the concurrent use of nitrates would provide the possible causal link between sildenafil and death.

Therefore, it is not unlikely that sexual activity in a vulnerable person and adverse drug interaction caused or contributed to the reported deaths.


Recommendations
Box 5 shows the recommended strategy for treating ED. To minimise adverse consequences, it is important that a patient's fitness for sexual and physical activity be assessed when treatment of ED is considered, and that the patient be appropriately counselled if sexual activity is inadvisable. In general, sexual intercourse should be safe if a patient can perform an activity equal to 5-6 metabolic equivalents (METS), such as climbing 20 stairs in 10-15 seconds without distress.32 Postinfarction patients who reach 5-6 METS on stress testing without ischaemia or arrhythmia can resume their normal sexual activity without risk.33 In one study, patients with a negative exercise test result did not demonstrate ischaemia on Holter monitoring during sexual intercourse.26

The frequent use of short-acting nitrates and ongoing therapy with long-acting nitrates are absolute contraindications to the use of sildenafil. The only option for patients in this situation is to avoid the use of sildenafil.

A policy of refraining totally from the use of sildenafil in all patients receiving nitrates in whatever form and regardless of frequency would, of course, quarantine patients from the risk of drug interaction. Nevertheless, patients who have only an infrequent need for short-acting nitrates, such as sublingual glyceryl trinitrate, should not be precluded from the use of sildenafil. However, doctors need to ensure that patients fully understand the implications of the potential interaction of these therapies. Patients whose only exposure to nitrate therapy is infrequent use of sublingual glyceryl trinitrate tablets or spray should be advised that at least 24 hours from the last use of the short-acting nitrates should be allowed to elapse before the use of sildenafil. It is not definitely known when nitrates can be safely administered after a dose of sildenafil. Certainly, patients should be cautioned against the use of any form of nitrates for at least 24 hours after sildenafil. In elderly patients, and in those with hepatic and renal impairment or receiving medications which may inhibit the cytochrome P450 3A4 isoenzyme (eg, erythromycin, fluconazole, fluoxetine, cimetidine), consideration must be given to decreased sildenafil clearance.

If a patient should develop angina within 24 hours of taking sildenafil, nitrates should be totally avoided. Doctors should ensure that their patients follow this advice carefully. If necessary, an increase in the dose of alternative anti-anginal agents should be considered. If a patient requires hospital admission, non-nitrate anti-anginal preparations such as β-blockers or calcium-channel blockers can be used with due regard to the risk of hypotension. If complications should develop from the inadvertent concurrent use of a nitrate, the recommendations of the American College of Cardiology and the American Heart Association34 should be followed. These include resuscitative measures such as fluid infusion and judicious use of intravenous vasopressors to maintain blood pressure, as well as appropriate non-nitrate anti-anginal agents.

If adherence to such guidelines is difficult, the alternative is to avoid sildenafil in favour of other therapeutic options for ED. Clinical judgement and discretion must prevail over generalisation, bearing in mind the risk and benefit and the priority of the therapeutic interventions involved.

There are no established data on the safety and efficacy of sildenafil in

  • patients with myocardial infarction or life-threatening arrhythmia within the preceding six months;

  • patients with systolic blood pressure < 90 mmHg; or

  • patients with cardiac failure or coronary artery disease causing unstable angina.

Caution must be exercised in prescribing sildenafil for these patients and for patients receiving complicated multidrug antihypertensive therapy.34 Where appropriate, monitoring of blood pressure at the initiation of sildenafil therapy would identify patients with a hypotensive response to sildenafil.

An appropriate educational program will reduce the risk of drug interaction by alerting pharmacists and doctors to the potential danger. Pharmaceutical companies marketing nitrate-containing medications should specify sildenafil as a contraindication in their product information. Paramedics, nursing staff, patients and the community at large should be instructed on the danger of the concurrent use of sildenafil and nitrates, and of the undesirable practice of sharing medication with relatives and friends (Box 6).

It is important that a warning be given to every patient, regardless of sex or age. Women have been known to use sildenafil to heighten sexual arousal and young people may use amyl nitrite inhalation for recreational pursuit.

Cardiovascular diseases affect an estimated 2.3 million Australians.35 The risk of angina increases with age, affecting 12.4% of men and 11.7% of women aged 65-69 years.36 These proportions are likely to be greater among patients with ED. A request for treatment of ED provides a window of opportunity to assess the patient for cardiovascular and other risk factors, including diabetes and abnormal lipid profile. Cardiovascular risk factors, if identified, should be vigorously treated according to established guidelines.37,38

The sildenafil controversy continues.39 It has been reported that the FDA continues to believe that sildenafil remains safe.39 However, continuing postmarketing surveillance is essential for sildenafil, as for any recently marketed drug.

Disclosure B G A Stuckey has served as a principal investigator in clinical studies of sildenafil. K K Chew and B G A Stuckey have received sponsorship to attend conferences from Pfizer Aust Pty Ltd. P L Thompson serves on the international steering committee of a Pfizer-sponsored clinical trial of lipid lowering in the elderly. K K Chew, B G A Stuckey and P L Thompson have been invited to present papers at Pfizer-sponsored meetings.

References
  1. Kiely M. Viagra saturates media. Marketing Globe. Marketing 1998; Dec: 58.
  2. Jones A. When the thrill has gone. Business Rev Weekly 1999; June 25: 90-95.
  3. US Department of Health, Food and Drug Administration. Postmarketing safety of sildenafil citrate (Viagra) and summary of reports of death in Viagra users received from marketing (late March through mid-November 1988). 24 November 1988.
  4. Feldman HA, McKinlay JB, Goldstein I, Longcope C. Erectile dysfunction, cardiovascular disease and cardiovascular risk factors: prospective results in a large random sample of Massachusetts men. J Urol 1998; 159 Suppl 5: 91 abstract 347.
  5. Chew KK, Earle CM, Stuckey BGA, et al. Erectile dysfunction in general medical practice: prevalence and clinical correlates. Int J Impot Res 2000; 12: 1-5.
  6. Wabrek AJ, Burchell RC. Male sexual dysfunction associated with coronary heart disease. Arch Sex Behav 1980; 9: 69-75.
  7. Gundle MJ, Reeves BR, Tate S, et al. Psychosocial outcome after aortocoronary artery surgery. Am J Psychiatry 1980; 137: 1591-1594.
  8. Anderson M, Nicholson B, Louie E, Mulhall JP. An analysis of vasculogenic erectile dysfunction as a potential predictor of occult cardiac disease. J Urol 1998; 159 Suppl 5: 30 abstract 118.
  9. Greenstein A, Chen J, Miller H, et al. Does severity of ischaemic coronary disease correlate with erectile function? Int J Impot Res 1997; 9: 123-126.
  10. Slag MF, Morley JE, Elson MK, et al. Impotence in medical clinic outpatients. JAMA 1983; 249: 1736-1740.
  11. Morales A, Gingell G, Collins M, et al. Clinical safety of sildenafil citrate (Viagra) in the treatment of erectile dysfunction. Int J Impot Res 1998; 10: 69-74.
  12. Viagra -- approved product information. Pfizer, 1998.
  13. Boolell M, Allen MJ, Ballard SA, et al. Sildenafil: an orally active type 5 cyclic GMP-specific phosphodiesterase inhibitor for the treatment of penile erectile dysfunction. Int J Impot Res 1996; 8: 47-52.
  14. Zusman RM, editor. Cardiovascular data on sildenafil citrate. Am J Cardiol 1999; 83(5A).
  15. Feenstra J, van Drie-Pierik RJHM, Lacle CF, Stricker BHC. Acute myocardial infarction associated with sildenafil. Lancet 1998; 352: 957-958.
  16. Viagra is here! Australian Adverse Drug Reactions Bulletin 1998; 17(4).
  17. Hellerstein HK, Friedman EH. Sexual activity and the postcoronary patient. Arch Intern Med 1970; 125: 987-999.
  18. Bohlen Y, Held JP, Sanderson MO, Paterson RP. Heart rate, rate-pressure product, and oxygen uptake during four sexual activities. Arch Intern Med 1974; 144: 1745-1748.
  19. Willich SN, Klatt S, Arntz HR. Circadian variation and triggers of acute coronary syndromes. Eur Heart J 1998; 19 Suppl C: C12-23.
  20. Nalbangtil I, Yigitbasi O, Kiliccioglu B. Sudden death in sexual activity. Am Heart J 1976; 91: 405-406.
  21. Ueno M. The so-called coital death. Jpn J Legal Med 1963; 17: 330-340.
  22. Renshaw DC, Karstaedt A. Is there (sex) life after coronary bypass? Comp Ther 1988; 14: 61-66.
  23. Lecomte D, Fornes P, Nicolas G. Stressful events as a trigger of sudden death: a study of 43 medico-legal autopsy cases. Forensic Sci Int 1996; 79: 1-10.
  24. Muller JE, Mittleman MA, Maclure M, et al. Triggering myocardial infarction by sexual activity. JAMA 1996; 275: 1405-1409.
  25. Johnston BL, Fletcher GF. Dynamic electrocardiographic recording during sexual activity in recent post-myocardial infarction and revascularization patients. Am Heart J 1979; 98: 736-741.
  26. Drory Y, Shapira I, Fisman EZ, Pines A. Myocardial ischaemia during sexual activity in patients with coronary artery disease. Am J Cardiol 1995; 75: 835-837.
  27. Kavanagh T, Shephard RJ. Sexual activity after myocardial infarction CMAJ 1977; 116: 1250-1253.
  28. Paolillo V, Marra S, Spadaccini F, Angelino PF. Dynamic electrocardiographic recording during sexual activity in recent post-myocardial infarction and revascularization patients [letter]. Am Heart J 1980; 100: 763.
  29. Health United States. 1998. Hyattsville, Maryland: US National Center for Health Statistics, 1998.
  30. Australian Institute of Health and Welfare. Heart, stroke and vascular diseases, Australian facts. Canberra: AIHW and the Heart Foundation of Australia, 1999. (Cardiovascular Disease Series No. 10. AIHW Cat. No. CVD 7.)
  31. Australian Bureau of Statistics. Causes of death, Australia. Canberra: ABS, 1997. (Cat No. 3303.0.)
  32. Cardiac rehabilitation: sex after a heart attack. In: Zaret BL, Moser M, Cohen LS, editors. Yale University School of Medicine Heart Book. New York: Hearst Books, 1992; 351.
  33. Tardif GS. Sexual activity after a myocardial infarction. Arch Phys Med Rehabil 1989; 70: 763-766.
  34. Summary statement of the American College of Cardiology and the American Heart Association on the use of sildenafil (Viagra) in patients at clinical risk from cardiovascular effects. 10 August 1998. <http://www.americanheart.org/ Whats_News/AHA_Science_Advisories/viagra.html>. Accessed 18 February 2000.
  35. Fact sheet for prevention of myocardial infarction. National Heart Foundation of Australia. Curr Ther 1999; 39: 52.
  36. Fact sheet for angina. National Heart Foundation of Australia. Curr Ther 1999; 39: 63.
  37. Grundy SM, Balady GJ, Criqui MH, et al. Guide to primary prevention of cardiovascular diseases. A statement for healthcare professionals from the Task Force on Risk Reduction. Circulation 1997; 95: 2329-2331.
  38. Heart Foundation of Australia. Guide for the use of lipid lowering drugs in adults. Canberra: Heart Foundation of Australia, 1999. Available at <http://www. heartfoundation.com.au/include/defaultStory.asp?OwnerUID=200&Content Type=tblcategory>.
  39. Mitka M. Some men who take Viagra die -- why? [news]. JAMA 2000; 283(5). <http://jama.ama-assn.org/issues/v283n5/full/jmn0202-2.html>. Accessed 18 February 2000.

(Received 8 Oct 1999, accepted 14 Feb 2000)

Authors' details Keogh Institute for Medical Research, Perth, WA.
K Kim Chew, FRCP(Edin), FRCP(Glas), Senior Clinical Fellow;
Bronwyn G A Stuckey, MB BS, FRACP, Medical Director, and Consultant Endocrinologist, Department of Endocrinology and Diabetes, Sir Charles Gairdner Hospital, Perth, WA.

University of Western Australia, Perth, WA.
Peter L Thompson, FRACP, FACP, Clinical Professor of Medicine, University of Western Australia, and Consultant Cardiologist, Sir Charles Gairdner Hospital, Perth, WA.

Reprints will not be available from the authors.
Correspondence: Dr B G A Stuckey, Keogh Institute for Medical Research, 3rd Floor A Block, Queen Elizabeth II Medical Centre, 2 Verdun Street, Nedlands, WA 6009.
rmriATwt.com.au

©MJA 2000
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Box 1
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2: Pharmacodynamic and pharmacokinetic characteristics of sildenafil 11-13

  • Sildenafil is about 4000-fold more selective for type 5 phosphodiesterase (PDE5) than for PDE3, which is involved in cardiac contractility.

  • In healthy volunteers, sildenafil produced a modest decrease in blood pressure (up to 8.4 mmHg systolic and 5.5 mmHg diastolic), but no consistent orthostatic effects and no clinically relevant electrocardiographic changes.

  • In patients receiving medications containing nitrates, the hypotensive effects of sildenafil can be severe. In a US study with isosorbide mononitrate 20 mg twice daily, 50 mg sildenafil produced maximal blood pressure reductions of 40.9 mmHg systolic sitting and 51.6 mmHg systolic standing, and 25.8 mmHg diastolic sitting and 29.3 mmHg diastolic standing, about one hour after dosing and lasting up to 6 h. Similar haemodynamic interaction occurred for about two hours after a dose of 500 µg sublingual glyceryl trinitrate (maximum reductions: systolic, 36.0 mmHg sitting; diastolic, 20.5 mmHg sitting).

  • Sildenafil has a half-life of about 4 h. After an oral dose of 100 mg, the plasma level peaks at about 440 ng/mL within 30-120 min, and drops to about 2 ng/mL at 24 h.

  • Sildenafil is predominantly metabolised in the liver by the cytochrome P450 3A4 system, and 18% of the dose is excreted in the urine. Increased plasma levels may result from concomitant use of a cytochrome P450 3A4 inhibitor (eg, erythromycin, fluconazole, fluoxetine, cimetidine) or reduced clearance in elderly persons (>65 years) and in those with significant hepatic and renal impairment (creatine clearance <30 mL/min).
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3: US Food and Drug Administration summary of reports of death in sildenafil users
 
Number of deaths reported130
Number with cause not mentioned or unknown48
Number from homicide or drowning2
Number from stroke3
Number from cardiovascular events
  Definite or suspected myocardial infarction
  Cardiac arrest
  Cardiac symptoms
  Coronary artery disease		77
41
27
6
3
Use of nitrates
  Took or were administered a nitrate medication
  Found with nitrate in their possession		16
3
Time of death after use of sildenafil
  Not stated or unknown
  Within 4-5 hours of using sildenafil
   (includes 27 during or immediately after sexual intercourse)
  Later the same day
  Next day
  Two days later
  Three to seven days later		61
44
 
6
8
5
4
Cardiovascular risk factors
  One or more risk factors
  No identified risk factors, but severe coronary artery disease found at autopsy
  No history of cardiac disease or risk factors
  No risk factors and no sexual activity
  Not specified		 
90
3
12
2
23
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4: Sexual activity and adverse cardiovascular events

Sexual activity, like any other physical effort, increases cardiac work and myocardial oxygen demand. 17 Heart rate and blood pressure rise to an energy expenditure of 2.0-5.4 metabolic equivalents. 18

Sexual activity may trigger an adverse cardiovascular event. 19,20 Coital death has been reported to account for 0.6% of sudden deaths, 21 although it is said to be rare in a stable sexual relationship. 22 In a study of 43 cases, sudden death was found to occur primarily in patients with severe heart disease, especially coronary heart disease, and in only three cases was sexual activity involved. 23 In another study, 9% of patients reported having had sexual activity in the 24 hours, and 3% in the two hours, preceding myocardial infarction. The relative risk of myocardial infarction occurring in the two hours after sexual activity was estimated to be 2.5, and was not increased in patients with a history of previous angina pectoris or myocardial infarction. The absolute risk increase was low, at one chance in a million for a healthy individual. 24

Electrocardiographic abnormalities during sexual activity have been reported in 12 of 24 patients with recent myocardial infarction or revascularisation. 25 In another study, 31% of men with ischaemic heart disease had ischaemia on Holter monitoring during sexual intercourse, although only 7% were symptomatic. 26 However, the frequency of angina pectoris and ventricular premature beats is less during sexual intercourse than during standard laboratory exercise, and sexual relations are thought to carry no special risk for the average postinfarction patient. 27 Sexual activity in the early posthospital phase of myocardial infarction is not a stronger stimulus than other activities for cardiac electrical instability. 28 Anxious sexual preoccupation, frustration and avoidance may actually be greater risk factors than coitus or coital alternatives. 22
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Box 5
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6: Messages for the patient with erectile dysfunction

  • Problems with erection are often associated with problems in other areas, including heart disease, and should be investigated.

  • Sildenafil can be useful to treat erectile problems, but, if combined with some medications containing nitrates (eg, for angina), dangerous side effects can occur.

  • Tell any medical attendant or your pharmacist what tablets you are taking, especially if you are taking Viagra or angina medication.

  • Do not share any medications, including Viagra, with relatives or friends.
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