Sildenafil was the first phosphodiesterase-5 inhibitor (PDE5I) approved by the Food and Drug Administration (FDA). Sildenafil (Viagra) was patented in 1996 and approved by the FDA for use in erectile dysfunction (ED) in March, 1998. Vardenafil (Levitra) was approved by the FDA for the treatment of ED in August, 2003 and tadalafil (Cialis) in November, 2003. Avanafil (Stendra) was approved in April, 2012. Udenafil (Zydena) is not FDA approved for sale in the United States but is available in Korea, Russia, the Philippines and other countries.
The mechanism by which the PDE5I causes an erection is through local release of nitric oxide in the corpora cavernosa during sexual stimulation. Nitric oxide activates guanylate cyclase, resulting in increased levels of cGMP, which causes smooth muscle relaxation, vasodilation, and increased blood flow into the spongy tissue of the penis, thereby resulting in an erection. The ED drugs act by selectively inhibiting cGMP-specific phosphodiesterase-5 in the corpora cavernosa, an enzyme that promotes degradation of cGMP. The molecular structure of sildenafil is similar to cGMP, and it acts by binding competitively to phosphodiesterase-5, resulting in more cGMP and increased duration of erections. The half-life of sildenafil and vardenafil is 3–5 hours, whereas the half-life of tadalafil is 17.5 hours. Sildenafil also weakly inhibits phosphodiesterase-6 with an efficacy of approximately one-tenth of that for phosphodiesterase-5. Phosphodiesterase-6 is present in the photoreceptors of the retina and is an important component of the phototransduction cascade. The PDE5I can cause a transient color visual disturbance as a result of its interaction with phosphodiesterase-6.
The primary indication for sildenafil is treatment of ED. Other uses include treatment of pulmonary arterial hypertension (approved by the FDA in 2005 as Revatio), and prevention and treatment of high-altitude pulmonary edema associated with altitude sickness. Tadalafil was also approved by the FDA in 2009 for the treatment of pulmonary arterial hypertension (Adcirca), and in 2011, for the treatment of benign prostatic hyperplasia.
REVIEW OF CASE REPORTS OF ASSOCIATION BETWEEN PHOSPHODIESTERASE-5 INHIBITORS AND NONARTERITIC ANTERIOR ISCHEMIC OPTIC NEUROPATHY
The first case report of the potential association of an ocular side effect with the PDE5I involved a patient presenting with a third nerve palsy (1). The first case of nonarteritic anterior ischemic optic neuropathy (NAION) associated with sildenafil use was reported in 2000 (2), followed by a second case in 2001 (3). These reports were followed by 2 small case series reported in 2002 and 2005 (4,5). Numerous other single case reports or case series involving the use of sildenafil or tadalafil have since been published (6–23) (see Supplemental Digital Content, Table E1, http://links.lww.com/WNO/A171). There are 2 documented cases of combined retinal vascular occlusion and NAION after sildenafil ingestion (16,17). A total of 39 cases of NAION associated with PDE5I use have been reported in the peer-reviewed medical literature as of 2014, including 2 cases attributed to a Chinese herbal medicine containing sildenafil (11,13). According to the FDA Web site, 43 cases of NAION associated with PDE5I use had been reported to the FDA Adverse Event Reporting System as of 2005 (see Supplemental Digital Content, Table E2, http://links.lww.com/WNO/A172). Hundreds of cases of PDE5I-associated NAION have been reported to the FDA between 1999 and 2014 (24).
RESEARCH STUDIES INVESTIGATING THE EFFECTS OF SILDENAFIL ON OCULAR CIRCULATION
Research has been performed on healthy volunteers and on research subjects with known ED, investigating the effect of sildenafil on arterial blood supply to the eye through ophthalmic, posterior ciliary, and central retinal arteries (25–33). These studies are summarized in Supplemental Digital Content, Table E3, http://links.lww.com/WNO/A173. The effect of sildenafil on the retinal, optic disc, and choroidal arterial circulation in healthy individuals has not been significant, whereas its effect in study participants with ED was variable depending on the study. No studies were specifically directed at individuals who are at a high risk for NAION, that is, history of nocturnal hypotension, sleep apnea, history of NAION in the fellow eye, or individuals with a small cup-to-disc ratio. Therefore, there are no conclusive reports that demonstrate the deleterious effects of sildenafil on optic disc perfusion in individuals who are at risk for developing NAION.
EPIDEMIOLOGICAL STUDIES OF PHOSPHODIESTERASE-5 INHIBITOR USE AND NONARTERITIC ANTERIOR ISCHEMIC OPTIC NEUROPATHY
Margo and French (34) reported that a case–control study of PDE5I and NAION was feasible using the pharmacy of National Veterans Health Administration and clinical databases. McGwin et al (35) found a statistically significant association between PDE5I use and NAION in subjects with a history of myocardial infarction. Sobel and Cappelleri from Pfizer (36) criticized McGwin conclusions based on methodological limitations such as study biases, sample size, and statistical analysis, ultimately resulting in retraction of the McGwin study in 2011. A new study (37) used a health claims database to identify cases of NAION, which were matched with corresponding controls and correlated with the prescription of the PDE5I to estimate the likelihood of an association. The authors concluded that there was no association between PDE5I prescription and NAION. The study was limited solely to diagnostic codes and prescriptions identified in a database without identification of patient cases of NAION or direct linkage of patients to an actual prescription record of PDE5I use. Furthermore, the issuing of prescription for a PDE5I is not necessarily an indication or guarantee that such a pre-scription was either dispensed, or whether the medicine was taken by the patient, and conversely, does not account for patients who obtain the PDE5I from sources other than a physician. In summary, there is no convincing epidemiological evidence linking NAION with PDE5I use.
PROSPECTIVE STUDIES OF NONARTERITIC ANTERIOR ISCHEMIC OPTIC NEUROPATHY AND PHOSPHODIESTERASE-5 INHIBITOR USE MANDATED BY THE FOOD AND DRUG ADMINISTRATION
On July 8, 2005, the FDA mandated that the 3 pharmaceutical companies that market PDE5I should place warnings on their drug inserts regarding the potential association between NAION and PDE5I use. In addition, the FDA mandated that Pfizer, Bayer, and Eli Lilly each perform observational studies to determine whether or not there was an association between PDE5I use and NAION. The Pfizer study results are now available (38). Studies by Bayer and Eli Lilly are still ongoing (see clinicaltrials.org).
The primary outcome measure of the case-crossover retrospective study commissioned by Pfizer was the number of cases of NAION that had been exposed to a PDE5I during a one-day case window (i.e., the day before the symptomatic onset of vision loss). A case was considered “associated” if sildenafil or vardenafil was used on that day and/or the previous day, or if tadalafil was used that day and/or any of the previous 4 days because of its longer half-life. Seventy-six potential NAION cases with PDE5I exposure were identified, of which 43 were adjudicated (masked to exposure status) to be definite NAION, and 21 to be possible NAION. Of these 43, fourteen cases were exposed to the PDE5I during the day before symptom onset. Based on conditional logistic regression, an odds ratio of 2.15 (95% confidence interval (CI): 1.06–4.34, P = 0.03) was calculated for developing definite NAION the day after exposure to the PDE5I, and when considering definite or probable NAION, increased to 2.36 (95% CI: 1.33–4.19; P = 0.003). In other words, there is at least a 2-fold increase in the risk of NAION in 2 days after sildenafil or vardenafil use and during 5 days after tadalafil use. When the time window of exposure considered to be associated with the PDE5I was increased to 1 week (which would be more accurate if the effect of the PDE5I is sustained longer than it would be expected to, based on the half-life alone), the odds ratio increased to 3.61 (95% CI: 1.70–7.69; P < 0.001) for definite NAION and to 3.86 (95% CI: 2.09–7.14; P < 0.001) for definite or probable NAION. These results strongly suggest an increased risk of developing NAION after ingestion of the PDE5I, although the absolute risk is small (3 additional cases per 100,000 men 50 years or older per year). The major limitation of this study was that it relied on a retrospective recall of PDE5I use, which may have resulted in patients being more likely to overreport recent PDE5I use against more distant use. Yet, the study had measures to mitigate the recall bias, and sensitivity analyses found no evidence of recall bias. The main strength of this report was the case-crossover design that provided self matching, which controls for all personal characteristics that are essentially time invariant over the study period (e.g., smoking, diabetes status, cup-to-disc ratio, etc.).
In response to the results of the Pfizer prospective research study, the FDA mandated an update to the drug warning for the PDE5I on March 2014 (see Supplemental Digital Content, Table E4, http://links.lww.com/WNO/A174).
SUMMARY AND CONCLUSIONS
Thirty-nine cases of NAION associated with PDE5I use have been documented in peer-reviewed publications, the details of which vary significantly in terms of the frequency with which the PDE5I was ingested before onset of NAION, the dose of the drug consumed, and the time interval between last use of an ED drug and onset of NAION. Many, although not all, cases had microvascular risk factors associated with NAION. There have not been any published reports of the effect of the PDE5I on ocular circulation in individuals at risk for NAION and/or the “disc at risk,” so it is not known whether such individuals carry a higher risk for the development of NAION in association with ingestion of ED drugs. There are no convincing epidemiological studies linking NAION with PDE5I use. However, the Pfizer case-crossover study documented a 2-fold increase in risk of NAION in individuals who ingested a PDE5I within the previous 24 hours.
The following recommendations regarding NAION and PDE5I use are suggested:
When NAION is diagnosed, an inquiry should be made as to whether any PDE5I has been used for the treatment of ED (in men), pulmonary hypertension (men or women), or whether the patient has used any substance marketed for the purpose of enhancement of sexual experience, many of which have been determined by the FDA to include variable amounts of PDE5I medications among their ingredients. If so, the patient should be counseled as to 1) the future likelihood of development of NAION in the fellow eye, which is recognized by the Ischemic Optic Neuropathy Decompression trial to be approximately 15%, and 2) the possibility that continued PDE5I use may additionally increase the risk of NAION based on the 2- to 4-fold increase in the risk of NAION after recent PDE5I use seen in the Pfizer study. Patients with a previous known history of occurrence of NAION in 1 eye should be cautioned regarding the use of PDE5I for the treatment of ED or pulmonary hypertension because of the increased risk of fellow eye involvement.
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