Correspondence

Hemodynamic Effects of Sildenafil

N Engl J Med 2000; 343:967-968September 28, 2000

Article

To the Editor:

Herrmann et al. (June 1 issue)1 concluded that “oral sildenafil has no direct adverse cardiovascular effects in men with severe coronary artery disease.” However, they studied only a single dose of sildenafil in only 14 men, in an open-label study with no controls that was conducted after the administration of diphenhydramine and diazepam — drugs not normally used in conjunction with sildenafil for its only indication, erectile dysfunction. Moreover, there was no adjustment for the various other medications the men were taking (beta-blockers, aspirin, heparin, and angiotensin-converting–enzyme inhibitors). In this context, the authors' conclusion is overly strong.

Studies investigating adverse drug effects are more revealing when the results are shown as distributions of individual responses to treatment rather than as means and standard deviations. This can be clearly seen in Figure 1 of the article by Herrmann et al., which shows substantial changes in the average peak coronary blood velocity between base-line values and the values after the administration of sildenafil for a few of the coronary arteries, with modest changes for most of the arteries, such that the mean difference does not reflect the possibility that the change in blood velocity in a few of the men in this small study may have been sufficient to place them at risk for an adverse event. In addition, the mean values do not allow for an understanding of whether the changes occurring in affected and unaffected arteries in the same subject were in the same or the opposite direction after the administration of sildenafil.

A study of this size does not provide any assurance about the true rates of adverse events that were not observed. For example, a study of 300 subjects limits the probability of adverse events not observed — with 95 percent confidence — to about 1 percent.2 Because in this study there were only 14 men, the probability of any adverse event not observed could have been as high as 20 percent. The inability to exclude side effects occurring in up to 20 percent of patients is not reassuring for a drug that is being used by thousands of men worldwide. Until much larger studies have been done, physicians and their patients should continue to exercise caution with regard to the potential for adverse cardiovascular effects of sildenafil.

Saul Malozowski, M.D., Ph.D., M.B.A.
J. Todd Sahlroot, Ph.D.
Food and Drug Administration, Rockville, MD 20857

2 References

1. 1

   Herrmann HC, Chang G, Klugherz BD, Mahoney PD. Hemodynamic effects of sildenafil in men with severe coronary artery disease. N Engl J Med 2000;342:1622-1626
   Full Text | Web of Science | Medline

2. 2

   Jonavic BD, Levy PS. A look at the rule of three. Am Stat 1997;51:137-139
   CrossRef | Web of Science

Author/Editor Response

Dr. Herrmann replies:

To the Editor: Although we detected no adverse cardiovascular effects of oral sildenafil in men with severe coronary disease, our sample was small, and the study design was open label. We agree with Drs. Malozowski and Sahlroot that, as we stated in our article, “because of variability among individual men, sildenafil could have an adverse effect in some patients or in those with other cardiovascular conditions and different hemodynamic status.”

The results in the patients we studied, however, support our conclusion that there were no undesirable coronary, pulmonary, or systemic hemodynamic effects of sildenafil. These results should not be overinterpreted by readers as indicative of the overall safety of this agent. Rather, one should rely on data accumulated from placebo-controlled clinical trials involving men with ischemic heart disease1 and men without ischemic heart disease,2 and more than 6000 man-years of exposure to sildenafil. These data have not demonstrated an increased risk of myocardial infarction or death from any cause. Furthermore, analysis of the post-marketing data on cardiovascular events temporally associated with sildenafil use that have been reported to the Food and Drug Administration does not suggest a risk that is any higher than that which might be expected for men with erectile dysfunction.2

It is important to remember that most studies of sildenafil for the treatment of erectile dysfunction excluded patients with congestive heart failure, unstable angina, recent myocardial infarction, hypertension requiring multiple medications, obstructive cardiomyopathy, or severe valvular heart disease. In such high-risk patients, sexual activity and the use of sildenafil should be delayed until the cardiac condition has been stabilized.3 In some of these patients and in other, lower-risk patients, stress testing can be useful for both the patient and the physician to assess further the potential for ischemia with sexual activity. In low-risk patients, including those with stable coronary artery disease who are not being treated with nitrates, sildenafil appears to be safe.4

Howard C. Herrmann, M.D.
University of Pennsylvania Medical Center, Philadelphia, PA 19104

4 References

1. 1

   Conti CR, Pepine CJ, Sweeney M. Efficacy and safety of sildenafil citrate in the treatment of erectile dysfunction in patients with ischemic heart disease. Am J Cardiol 1999;83:Suppl:29C-34C
   CrossRef | Web of Science | Medline

2. 2

   Kloner RA. Cardiovascular risk and sildenafil. Am J Cardiol 2000;86:Suppl:57F-61F
   CrossRef | Web of Science | Medline

3. 3

   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 | Web of Science | Medline

4. 4

   Cheitlin MD, Hutter AM Jr, Brindis RG, et al. Use of sildenafil (Viagra) in patients with cardiovascular disease: Technology and Practice Executive Committee. Circulation 1999;99:168-177[Erratum, Circulation 1999;100:2389.]
   Web of Science | Medline

Citing Articles (6)

Citing Articles

1. 1

   David A. Calhoun. (2010) Obstructive Sleep Apnea and Hypertension. Current Hypertension Reports 12:3, 189-195
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2. 2

   Konstantinos Kontaras, Varnavas Varnavas, Zenon S Kyriakides. (2008) Does Sildenafil Cause Myocardial Infarction or Sudden Cardiac Death?. American Journal of Cardiovascular Drugs 8:1, 1-7
   CrossRef

3. 3

   John M. Dopp, Barbara J. Morgan. (2006) Cardiovascular Consequences of Sleep-disordered Breathing. Journal of Cardiopulmonary Rehabilitation 26:3, 123-130
   CrossRef

4. 4

   Alexander G. Logan, Sandra M. Perlikowski, Andrew Mente, Andras Tisler, Ruzena Tkacova, Mitra Niroumand, Richard S. T. Leung, T. Douglas Bradley. (2001) High prevalence of unrecognized sleep apnoea in drug-resistant hypertension. Journal of Hypertension 19:12, 2271-2277
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5. 5

   Donald S. Silverberg, Arie Oksenberg. (2001) Are sleep-related breathing disorders important contributing factors to the production of essential hypertension?. Current Hypertension Reports 3:3, 209-215
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6. 6

   Gordon Williams. (2001) Reply. BJU International 87:9, 907-909
   CrossRef