Correspondence
Sildenafil in the Treatment of Erectile Dysfunction
N Engl J Med 1998; 339:699-702September 3, 1998
- Article
To the Editor:
In their study of sildenafil in men with erectile dysfunction, Goldstein et al. (May 14 issue)1 found that the drug had few major side effects. I would like to bring to your attention two cases of ventricular tachycardia that occurred within one hour after ingestion of sildenafil. Patient 1 was a 52-year-old man who had a large myocardial infarction of the anterior wall 20 years ago, which resulted in an enlarged left ventricle and a severely depressed ejection fraction, but he had never had ventricular tachycardia. One hour after taking sildenafil, during sexual activity with his girlfriend, he felt short of breath and lightheaded. He waited an hour and then drove himself to the emergency department where he was noted to have rapid sustained monomorphic ventricular tachycardia. He promptly underwent cardioversion to sinus rhythm with direct-current countershock.
Patient 2 was a 71-year-old man who had an extensive myocardial infarction of the anterior wall 25 years ago, which also resulted in an enlarged left ventricle and a severely depressed ejection fraction. He had a cardioverter–defibrillator implanted four years ago because of infrequent symptomatic episodes of ventricular tachycardia. He had not received any shocks in the preceding six months. One hour after taking sildenafil, while engaging in sexual activity, he received three shocks, each a few minutes apart, after which he immediately stopped the activity. Data recovered from the implantable cardioverter–defibrillator revealed appropriate discharge of the device for a rapid, regular tachycardia consistent with the patient's known ventricular tachycardia.
Neither of the men had ever had similar episodes during sexual activity in the past, and neither was taking any nitrate-containing drugs. These cases suggest the possibility that in men at risk for serious ventricular arrhythmias, the risk may increase during sexual activity after administration of sildenafil. Caution should be exercised in prescribing sildenafil to men with a history of ventricular arrhythmias, especially if they are not already protected by an implantable cardioverter–defibrillator.
1 ReferencesP.K. Shah, M.D.
Cedars–Sinai Medical Center, Los Angeles, CA 900481
Goldstein I ,Lue TF ,Padma-Nathan H ,Rosen RC ,Steers WD ,Wicker PA . Oral sildenafil in the treatment of erectile dysfunction. N Engl J Med 1998;338:1397-1404
Full Text | Web of Science | Medline
To the Editor:
A 74-year-old man who had had a myocardial infarction two years earlier requested a prescription for sildenafil. He was not taking any nitrate-containing drugs and denied using sublingual nitroglycerin in the past two years but always carried a bottle “just in case.” After a discussion with his physician of the contraindications, side effects, associated deaths, and alternative therapies, he still demanded the drug. This case raises questions about the risk of ischemic events during coitus in patients with coronary artery disease and the potential for drug interactions when acute ischemia is being treated.
In a recent study of Holter monitoring during coitus, 31 percent of men with coronary artery disease had ischemia (7 percent symptomatic ischemia and 24 percent silent ischemia).1 Among patients who had acute myocardial infarction, 3 percent of those who were sexually active reported having coitus within 2 hours before the onset of symptoms, and 9 percent reported it within the preceding 24 hours.2 Thus, the facilitation of sexual activity by sildenafil places a patient with coronary artery disease at risk for ischemia.
Concurrent organic-nitrate therapy in any form is contraindicated in patients taking sildenafil, since sildenafil potentiates the hypotensive effects of nitrates.3 The manufacturer of sildenafil outlines the potential dangers of inadvertent administration of nitroglycerin to patients with acute chest pain in a letter to all emergency physicians in May 1998,4 but no advice was offered on how to treat acute ischemia without using nitrates when the patient is known to have taken sildenafil.
So how do we deal with our patients? The manufacturer suggests that we “consider the cardiovascular status” because of “the degree of cardiac risk associated with sexual activity.”3 Since all 31 percent of the patients with coronary artery disease who had ischemia on Holter monitoring during coitus also had ischemia during exercise testing,1 such testing offers a potential screening tool. Although the predictive value of a positive exercise test was only 50 percent, none of the patients with a negative exercise test had ischemia during coitus.1 Although this testing adds to the cost of sildenafil therapy, until there is more information about how to treat men who may need nitroglycerin “just in case,” we think it is justifiable.
4 ReferencesIra Schwartz, M.D., Ph.D.
David McCarthy, M.D.
University of Pennsylvania School of Medicine, Philadelphia, PA 191041
Drory Y ,Shapira I ,Fisman EZ ,Pines A . Myocardial ischemia during sexual activity in patients with coronary artery disease. Am J Cardiol 1995;75:835-837
CrossRef | Web of Science | Medline2
Muller JE ,Mittleman MA ,Maclure M ,Sherwood JB ,Tofler GH . Triggering myocardial infarction by sexual activity: low absolute risk and prevention by regular physical exertion. JAMA 1996;275:1405-1409
CrossRef | Web of Science | Medline3
Viagra (sildenafil citrate). New York: Pfizer, Inc. (package insert).
4
Letter to physicians from Pfizer, Inc., May 1998. (Or see: http://www.fda.gov/medwatch/safety/1998/viagra.htm.)
To the Editor:
We describe a patient with interstitial lung disease in whom severe pulmonary hemorrhage was associated with sildenafil therapy. The patient was an 82-year-old man who sought medical attention because of a cough, hemoptysis, and dyspnea of three days' duration. He had a history of angina that was controlled with transdermal nitroglycerin, diltiazem, and aspirin. In 1996, a routine chest x-ray film revealed interstitial reticulonodular infiltrates at both lung bases, which were not further investigated. On April 25, 1998, the patient took 25 mg of sildenafil and then had sexual intercourse. He took another 25 mg the next day with no results; 1 1/2 hours later he took another 25 mg, again with no results. His pulmonary symptoms began later that day.
Physical examination was normal except for a midsystolic murmur at the apex of the heart and rales at both lung bases. He was treated with antibiotics, and the aspirin was stopped. Four days later, he was hospitalized because of increasing cough, hemoptysis, and dyspnea. He reported coughing up blood up to 20 times per day. A computed tomographic scan of the chest revealed honeycomb changes at both lung bases, with patches of filled alveoli elsewhere. The prothrombin time was 15.8 seconds (control, 11.6 seconds), and the erythrocyte-sedimentation rate was 60 mm per hour. Serologic tests for vascular disorders and various microorganisms were negative.
The patient was treated with ceftriaxone, methylprednisolone, and cyclophosphamide because of the presumption of vasculitis. The hemoglobin concentration fell to 10.8 g per deciliter from a basal value of 13.3 g per deciliter. He was given packed red cells. His respiratory status deteriorated in spite of mechanical ventilation, culminating in cardiovascular collapse and death on May 21, 1998.
A biopsy of the lung on the 10th hospital day revealed chronic interstitial fibrosis with honeycombing. Less involved areas showed extensive foci of alveolar hemorrhage. There was no evidence of vasculitis or diffuse alveolar damage. Postmortem examination of the lungs confirmed the biopsy findings and also showed pulmonary edema, oxygen toxicity, and focal bronchopneumonia.
Alveolar hemorrhage is rare in patients with interstitial fibrosis.1 In our patient, the occurrence of alveolar hemorrhage and its temporal relation to the administration of sildenafil suggest a causal connection. We speculate that a sildenafil-mediated influx of blood through a restricted pulmonary vascular bed may have underlain the alveolar hemorrhage. The effects of nitroglycerin, a drug that is contraindicated in patients taking sildenafil, and aspirin probably contributed to the bleeding. We suggest that sildenafil be used with caution in men with pulmonary interstitial fibrosis and other disorders predisposing patients to intrapulmonary bleeding.
1 ReferencesMario J. Saldana, M.D.
Columbia Cedars Medical Center, Miami, FL 33136Cesar Villaran, M.D.
Benjamin Alhalel, M.D.
Clinica Ricardo Palma, Lima 27, Peru1
Katzenstein AL ,Myers JL . Idiopathic pulmonary fibrosis: clinical relevance of pathologic classification. Am J Respir Crit Care Med 1998;157:1301-1315
Web of Science | Medline
To the Editor:
Since the introduction of sildenafil, we have prescribed it for approximately 100 men. To our surprise, acute cystitis has developed in 15 of the spouses of these men (women between the ages of 55 and 75 years). Thus far, all these women have been successfully treated with standard therapy. Men treated with sildenafil should be advised to tell their female sexual partners to maintain good hydration and empty their bladders immediately after intercourse. Postcoital antibiotic therapy should be considered for women with recurrent infections.1 Most important, sexual activity (and sildenafil) should be avoided when symptoms of cystitis are present.2
2 ReferencesW. Norris Little, M.D.
G. Timothy Park, M.D.
Henry M. Patton, M.D.
Newton General Hospital, Covington, GA 300141
Stapleton M ,Latham RH ,Johnson C ,Stamm WE . Postcoital antimicrobial prophylaxis for recurrent urinary tract infection: a randomized, double-blind, placebo-controlled trial. JAMA 1990;264:703-706
CrossRef | Web of Science | Medline2
Stamm WE ,Hooton TM . Management of urinary tract infections in adults. N Engl J Med 1993;329:1328-1334
Full Text | Web of Science | Medline
To the Editor:
As noted by Goldstein et al., erectile dysfunction has both organic and psychological causes. Some of the organic causes are specified in their paper, but others are not. In the Methods section, the authors describe how the men were evaluated and state that 21 percent underwent endocrine testing. The types of endocrine tests that were performed are not described, nor are we told whether men with endocrine disorders other than poorly controlled diabetes mellitus (e.g., hypogonadism) were excluded. According to a National Institutes of Health consensus statement,1 measurements of serum testosterone and prolactin should be obtained in men with erectile dysfunction. In men with testosterone deficiency, testosterone therapy improves libido and erectile function. Similarly, in men with hyperprolactinemia, appropriate treatment may restore sexual function. Correcting endocrine abnormalities first and adding sildenafil later, if needed, is preferable to prescribing sildenafil as the initial therapy.
1 ReferencesA. Wayne Meikle, M.D.
University of Utah, School of Medicine, Salt Lake City, UT 84132Stefan Arver, M.D., Ph.D.
Karolinska Hospital, SE-171 76 Stockholm, Sweden1
Impotence: NIH consensus statementJAMA 1993;270:83-90
CrossRef | Web of Science
To the Editor:
In their introduction, Goldstein et al. quote figures from the Massachusetts Male Aging Study to the effect that 39 percent of 40-year-old men and 67 percent of 70-year-old men have erectile dysfunction.1 These figures are misleading, because they include all grades of erectile dysfunction; the figures for complete erectile failure were 5 percent at the age of 40 and 15 percent at the age of 70.
The results the authors reported in their paper presumably included men with all degrees of erectile dysfunction. One would expect better results in men with mild or moderate erectile dysfunction than in those with complete erectile dysfunction, but no data are provided relating drug efficacy to the severity of erectile dysfunction. Could the authors tell us how effective sildenafil was for men in each category of erectile failure, particularly those with complete erectile dysfunction?
1 ReferencesKenneth G. Marshall, M.D.
University of Western Ontario, London ON N5Z 2C1, Canada1
Feldman HA ,Goldstein I ,Hatzichristou DG ,Krane RJ ,McKinlay JB . Impotence and its medical and psychosocial correlates: results of the Massachusetts Male Aging Study. J Urol 1994;151:54-61
Web of Science | Medline
To the Editor:
Goldstein et al. evaluated the efficacy of sildenafil using the quality of erections and the numbers of attempts at intercourse that were successful as the units of analysis. How many more men taking sildenafil than taking placebo had improved erectile function, and among those taking sildenafil, how many men had excellent or good results and how many had poor results? These data are needed for counseling a man about the likelihood of improvement of erectile dysfunction if he takes the drug.
Brian Budenholzer, M.D.
Group Health Northwest, Spokane, WA 99210-0204Author/Editor Response
The authors reply:
To the Editor: In response to the first two letters, it is known that sexual intercourse increases cardiac workload1 and that the risk of myocardial infarction increases by a factor of 2.5 in the two hours after sexual activity.2 It seems likely that the risk of cardiac arrhythmia is also increased. The men Dr. Shah describes had severely depressed left ventricular function, a major risk factor for ventricular arrhythmia and sudden death. In clinical trials, the rate of myocardial infarction was similar in men receiving sildenafil and those receiving placebo.3 We agree with Dr. Shah that physicians should closely follow the recommendations provided. The suggestion by Drs. Schwartz and McCarthy relates only to men with erectile dysfunction who have ischemic heart disease and are not prescribed nitrates in any form. In this group, additional testing before sildenafil treatment may be justified to evaluate the possibility of acute ischemia brought about by sexual activity. These cases emphasize the need for physicians to consider the cardiovascular status of men with erectile dysfunction before any treatment is prescribed.
In response to Saldana et al.: we are unaware of other reports of alveolar hemorrhage in men taking sildenafil. The administration of sildenafil does not increase the antiplatelet action of aspirin.
Little et al. draw attention to the important role of the partner, and we agree that every effort should be made to involve the man's partner early in the treatment of erectile dysfunction. This involvement should include determining the preferences of the partner as well as the man, and informing both about the nature of the sexual dysfunction, the results of diagnostic studies, and the treatment options and their potential consequences.4
In response to Drs. Meikle and Arver: serum testosterone and prolactin were measured in all men screened for the sildenafil studies, and men with low values for testosterone or elevated values for prolactin were not eligible for enrollment. We agree that these tests should be performed in all men with erectile dysfunction, because they identify readily reversible causes of the condition.4
As Dr. Marshall states, we cited combined prevalence rates for mild, moderate, and complete erectile dysfunction; these rates should reflect the expected rates in clinical practice. Our results thus represent the mean therapeutic responses of all men randomly assigned to treatment. However, Steers et al. have recently published data on the efficacy of sildenafil in men with severe erectile dysfunction.5 On the basis of end-of-treatment scores, men with severe erectile dysfunction receiving sildenafil had complete response rates of 46 percent, as compared with a rate of 8 percent for those receiving placebo (P<0.001).
In answer to Dr. Budenholzer's question: 101 of 136 men (74 percent) reported improved erections with sildenafil, as compared with 23 of 118 men (19 percent) taking placebo (P<0.001).
5 ReferencesIrwin Goldstein, M.D.
Boston Medical Center, Boston, MA 02118Raymond C. Rosen, Ph.D.
University of Medicine and Dentistry of New Jersey–, Robert Wood Johnson Medical School, Piscataway, NJ 08854William D. Steers, M.D.
University of Virginia, Charlottesville, VA 22908for the Sildenafil Study Group
1
Hellerstein HK ,Friedman EH . Sexual activity and the postcoronary patient. Arch Intern Med 1970;125:987-999
CrossRef | Web of Science | Medline2
Muller JE ,Mittleman A ,Maclure M ,Sherwood JB ,Tofler GH . Triggering myocardial infarction by sexual activity: low absolute risk and prevention by regular physical exertion. JAMA 1996;275:1405-1409
CrossRef | Web of Science | Medline3
Morales A ,Gingell C ,Collins M ,Wicker PA ,Osterloh IH . Clinical safety of oral sildenafil citrate (Viagra) in the treatment of erectile dysfunction. Int J Impot Res 1998;10:69-74
CrossRef | Web of Science | Medline4
Rosen R, Padma-Nathan H, Goldstein I. Process of care model for the management of erectile dysfunction in the primary care setting. In: Carson C, Kirby R, Goldstein I, eds. Male erectile dysfunction. Oxford, England: Isis Medical Media (in press).
5
Steers WD, Sildenafil Study Group
Web of Science
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