Dear Editor,

RE: Non-arteritic anterior ischaemic optic neuropathy and the treatment of erectile dysfunction.

McGwin et al.[1] suggest that treatment of erectile dysfunction with sildenafil (Viagra®) or tadalafil (Cialis®), two phosphodiesterase inhibitors (PDE5-I), may increase the odds of non-arteritic anterior ischaemic optic neuropathy (NAION) in men with a history of myocardial infarction (MI) or hypertension (HTN). We believe, however, that this study is fraught with significant limitations (as the authors acknowledge) that preclude drawing any conclusions about this relationship.

Case-control studies are susceptible to several biases that must be carefully considered and controlled for in the study design, implementation, and analysis.[2] For example, accurate and complete ascertainment of exposure is critical in a retrospective case-control study because both disease and exposure occur prior to study initiation. The authors note that the interviewers were not blinded to the case or control status of the patient, making it possible that the interviewer may, even unconsciously, probe cases differently from controls for exposure to a PDE5-I (interviewer bias). Another obstacle is that patients were not consistently interviewed at the time of NAION event (or index date for controls) about their PDE5-I usage. Hence, NAION patients may have been more likely to remember drug usage (recall bias). Furthermore, exposure misclassification may have occurred as timing, dose, and duration of drug use relative to event onset were not captured (exposure bias). This information is crucial for drugs used as needed such as PDE5-I and particularly for short half-life drugs like sildenafil.

Perhaps, the most troublesome weakness of the study was the limited sample size and differential participation rates of cases and controls, likely resulting in selection bias that distorts the conclusion. The authors note that almost one-fifth of the cases and one-third of the controls refused to participate. The baseline cardiovascular characteristics, while not significantly different (with the exception of MI) between cases and controls, were consistently more prevalent in the NAION group. This finding is not surprising given that these cardiovascular conditions, especially in combination, are also risk factors for NAION.[3] Thus, the MI and HTN subgroup analyses presented in Table 3 should be interpreted with skepticism.

Exacerbating the inherent problems are subgroup analyses that had no a priori hypothesis. The dangers of unplanned subgroup analyses in research are well documented.[4] Compounding matters is the sparse number of patients, reflected in the exceptionally wide confidence intervals (Table 3). The robustness of such extremely small cell numbers must also be questioned, as the observed statistical significance for patients with MI can be eliminated if only one or two patients are switched to an alternative category. The authors also did not provide individual patient totals by exposure group with and without MI, rendering it impossible to replicate their results. Furthermore, there appear to be errors in the numbers/percentages and crude odds ratios presented in Table 2.

In summary, the methodological limitations call into serious question the authors’ conclusions. For men with a history of MI or HTN, therefore, this study does not provide any valid evidence that the use of Viagra or Cialis may increase the risk of NAION.

Rachel E. Sobel, MPH,
Pfizer Inc,
150 E 42nd St., MS#150-3-72,
New York, NY 10017.
Rachel.Sobel@pfizer.com

Joseph C. Cappelleri, PhD, MPH,
Pfizer Inc,
Global Research and Development,
Groton, CT.

References

1 McGwin G, Vaphiades MS, Hall TA, Owsley C. Non-arteritic anterior ischaemic optic neuropathy and the treatment of erectile dysfunction. Br J Ophthalmol 2006; 90:154-157.

2 Rothman KJ, Greenland S. Modern Epidemiology. Philadelphia, PA: Lippincott-Raven Publishers, 1998.

3 Hatzichristou, D. Phosphodiesterase 5 Inhibitors and Nonarteritic Anterior Ischemic Optic Neuropathy (NAION): Coincidence or Causality? J Sex Med 2005; 2:751–758.

4 Assman SF, Pocock SJ, Enos LE, Kasten LE. Subgroup analysis and other (mis)uses of baseline data in clinical trials. Lancet 2000; 35:1064- 1069.

Keywords: NAION, phosphodiesterase-5 inhibitors.