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Show Erectile Dysfunction Drugs and Non- Arteritic Anterior Ischemic Optic Neuropathy: Is There a Cause and Effect Relationship? Sohan Singh Hayreh, MD, PhD, DSc, FRCS, FRCOphth Abstract: The recent reports of non- arteritic anterior is- Trevino, a spokesperson for the FDA, said " We're not able chemic optic neuropathy ( NAION) occurring shortly after to specifically say that these 38 cases are a result of the ingestion of erectile dysfunction agents have raised the patients taking Viagra." The same newspaper article quoted question of whether these agents have a cause- and- effect Michael Berelowitz, MD, Pfizer's vice president, as saying, relationship to NAION. The nature of optic nerve head " We've studied all our databases right now, and we see no blood flow and the various factors that influence it, the signal of causation with Viagra." David Moskowitz, an systemic vascular effects of these agents, and the clinical analyst at Friedman, Billings, and Ramsey, is quoted as features of NAION lead me to believe that these agents are saying that " It may not be the drug at all; it may be contributory factors. Patients with the appropriate risk fac- just the patient population that's experiencing this blind-tors should, therefore, be warned of this possibility and ness... We think this was an overreaction." In the Archives advised to refrain from using these agents. of Ophthalmology, Egan and Fraunfelder ( 11) have stated . . . . _ , , , , -„„_ „ „„^ „„„. that the connection between sildenafil use and the devel- ( J Neuro- Ophthalmol 2005; 25: 295- 298) t f„., m, , t t nr ., „ U 1_ opment ot NAION does not meet World Health Organization criteria for a cause- and- effect relationship ( 12) but go on to state that " Despite a lack of mechanism of action, Since the U. S. Food and Drug Administration ( FDA) the strong re- challenge data ( 9) suggest the drug effect may approved sildenafil citrate ( Viagra) on March 27, 1998 be significant." to treat male erectile dysfunction, it has become one of the To understand whether there is a cause- and- effect most popular drugs worldwide. More recently, tadalafil relationship between erectile dysfunction drugs and NAION, ( Cialis) and vardenafil hydrochloride ( Levitra) have been one must consider basic scientific facts related to NAION introduced for the same purpose. as well as to the drugs. The FDA recently reported visual loss in 38 patients after use of sildenafil and in one patient after use of vardenafil. A Medline search revealed published reports of 15 BLOOD SUPPLY OF THE OPTIC patients who have developed non- arteritic anterior ischemic JNLKVL HLAD optic neuropathy ( NAION) soon after the ingestion of sil- Studies on the blood supply of the optic nerve head denafil ( 1- 7), and three patients who developed it after use ( 0NH) ( 13,14), as well as experimental ( 15), pathologic, of tadalafil ( 8- 10). Varied opinions on the cause- and- effect and clinical findings, have all shown that NAION is caused relationship between these drugs and the development of bY ischemia of the ONH ( 16). Therefore, the most important NAION have been expressed by the FDA, the pharmaceu- considerations in understanding the development of NAION tical industry, ophthalmologists, urologists, and other physi- are t h e f a c t o r s t h a t influence blood flow in the ONH. Evi-cians, resulting in considerable confusion in the public mind. dence shows that blood flow is influenced by many factors, For example, in the New York Times, May 29, 2005, Suzanne including systemic arterial blood pressure, endothelial-derived vasoactive agents, and autoregulation of blood flow in the ONH ( 17). Autoregulation is deranged by many Department of Ophthalmology and Visual Sciences ( SSH), College of systemic and local Causes, including the aging process, arte- Medicine, University of Iowa, Iowa City, Iowa. rial hypertension; d i a b e t e s mellitUS, marked arterial hypo- Address correspondence to Sohan Singh Hayreh, MD, PhD, DSc, _ . . , , FRCS, FRCOphth, Department of Ophthalmology and Visual Sciences, t e n S 1 0 n fr° m ** CaUSe> arteriosclerosis, atherosclerosis, College of Medicine, University of Iowa, Iowa city, IA 52242; E- mail: hypercholesterolemia, vasospasm, and probably regional sohan- hayreh@ uiowa. edu vascular endothelial disorders ( 17- 20). RISK FACTORS FOR NAION patients with ideal daytime blood pressure who de- My studies have shown that NAION is a multifacto- veloped a marked decrease during sleep without being rial disease, with many risk factors playing a role in its on any treatment ( 22,26) development ( 21,22). They can be divided into predispos- 3. Patients with " white- coat hypertension" are often treated ing and precipitating risk factors. aggressively, resulting in marked nocturnal arterial hypotension, putting them at risk for developing NAION ( 25) _ , . . _ . , „ ^ 4. There is a significant correlation between progressive Predisposing Risk Factors ,, • XTAT/~ » XT J * 1 * 11. * _, ,. . . , . , , , visual loss m NAION and nocturnal arterial hypoten- Predisposrng risk factors are those that make a person . o^. r) f,\ susceptible to develop NAION but do not necessarily produce it. They may be systemic or local in the ONH. Systemic risk factors include arterial hypertension, arterial ERECTILE DYSFUNCTION DRUGS hypotension ( particularly nocturnal), diabetes mellirus, hy- AND NAION perlipidemia, atherosclerosis, arteriosclerosis, migraine and In the light of this basic scientific information on other vasospastic disorders, defective cardiovascular auto- NAION, let us evaluate the role of erectile dysfunction regulation, sleep apnea, hematologic disorders, and others drugs in the development of NAION. ( 22). Local risk factors include increased intraocular pressure, marked optic disc edema from any cause, location of Cardiovascular Risk Factors Are Common in the watershed zone of the posterior ciliary arteries in These Patients relation to the optic disc, and vascular disorders in the nutrient Most reported cases are from middle- aged and el-vessels of the ONH ( 22). Pomeranz et al ( 5) concluded that derly men. Arterial hypertension, diabetes mellirus, hyper- " A small cup- to- disc ratio may be a risk factor for devel- lipidemia, and other systemic cardiovascular risk factors are opment of NAION in association with the use of sildenafil." common in this group. As discussed above, those factors Our studies have shown that an absent or small cup is predispose them to develop NAION. simply a secondary contributing factor, once the process of NAION has started, and not a primary factor ( 23). NAION Has Occurred Shortly After Drug Use In most of the reported cases of NAION after Precipitating Risk Factors ingestion of sildenafil, the patient has detected visual loss In the presence of predisposing risk factors, pre- uPo n awakening in the morning, as have most NAION cipitating risk factors act as the " last straw." In a study of patients ( 24). 925 episodes ( involving 871 eyes) of NAION ( 24), 73.3% had a definite history of discovering the visual loss first Other Contributory Drugs Are Often Used upon awakening or at first opportunity to use vision criti- Patients with arterial hypertension and other cardio-cally after sleeping; in the remaining episodes, time of onset vascular disorders invariably take beta- blockers, angiotensin-was generally uncertain. This shows that nocturnal arterial converting enzyme- inhibitors, calcium channel blockers, or hypotension acted as the precipitating factor in the vast other drugs with arterial hypotensive effect. In their study majority. Also, 24- hour ambulatory blood pressure mon- on the combination of antihypertensive therapy with sil-itoring studies ( 25,26) have shown a significant correlation denafil or placebo, Mahmud et al ( 28) stated that " The between progressive visual loss in NAION and nocturnal extent of individual maximum reductions ( in mm Hg) from arterial hypotension. Therefore, contrary to the prevalent mis- baseline in systolic ( 24 ± 10 versus 6 ± 8; P < 0.05) and conception, NAION is largely a hypotensive disorder, not diastolic blood pressure ( 8 ± 5 versus 3 ± 2; P < 0.05) an embolic or thrombotic disorder. This is in sharp contrast occurred on the sildenafil study day." Patients with benign to other strokes, which are primarily embolic or thrombotic prostatic hypertrophy are often advised to take alpha adreno-phenomena. receptor blocking agents at bedtime which can produce Our 24- hour ambulatory blood pressure monitoring nocturnal arterial hypotension ( 26,27). Erectile dysfunction studies in over 700 patients so far have shown the following: is one side effect of these and many other arterial hypo- 1. Taking blood pressure- lowering medication in the even- tensive drugs, ing or at bedtime aggravates the physiological decrease of blood pressure during sleep, resulting in nocturnal Erectile Dysfunction Drugs Cause arterial hypotension ( 26,27) Systemic Hypotension 2. Daytime blood pressure often is no guide to the night- It is well established that sildenafil use is associated time blood pressure or to the extent of decrease in blood with a decrease in blood pressure ( 28- 30). Our 24- hour pressure during sleep. We have not infrequently seen ambulatory blood pressure monitoring studies ( 26,27,31) have shown that arterial hypotensive medication taken in young ( average age, 22 years), healthy American soldiers the evening or bedtime aggravates the normal physiological killed in the Korean War ( 35). Also, in humans, we have no decrease of blood pressure during sleep, resulting in marked means to determine the local risk factors in the ONH nocturnal arterial hypotension. Erectile dysfunction drugs mentioned above ( 17,36). are taken most often in the evening or before going to bed so that their arterial hypotensive effect is likely to aggravate Erectile Dysfunction Drugs Have Been Used for physiologic nocturnal hypotension, especially if the patient a Long Time before NAION Develops takes other drugs with hypotensive effects. Whereas it is true that many cases of NAION have occurred in patients who have been using erectile dys- Erectile Dysfunction Drugs Stimulate Release function drugs for a long time, it may be that a critical of Vasoconstrictors decrease in blood pressure is required to produce the degree Phillips et al ( 32) showed that sildenafil causes an in- of hypoperfusion of the ONH to cause NAION in sus-crease in plasma norepinephrine levels by 31% ± 5% ( P = ceptible persons. The requisite combination of factors to 0.004) and concluded that sympathetic activation may have cause threshold perfusion failure in the ONH may not be implications for understanding cardiovascular events present after every use of erectile dysfunction drugs. This is associated with sildenafil use. It is well known that nor- well illustrated by the fact that patients suffer successive epinephrine is a potent vasoconstrictor. In malignant arterial attacks of NAION in the same eye ( 37) or the other eye ( 38) hypertension, ONH ischemia and NAION may be the result days, months, or even years apart, of diffusion of vasoconstrictor agents from the peripapillary choroid into the ONH ( 18). This phenomenon may be yet Erectile Dysfunction Drugs Do Not Lower another contributory factor in development of NAION after Perfusion of the Optic Nerve Head sildenafil use. Pomeranz and Bhavsar ( 7) have stated that Grunwald et al ( 39) found no significant change in the ONH blood Stroke and NAION May Follow Rechallenge flow with sildenafil as compared with placebo use. How-with Erectile Dysfunction Drugs ever, Grunwald et al ( 39) measured ONH blood flow with Morgan et al ( 33) describe a patient who suffered the laser Doppler flowmeter, a device that does not measure a transient ischemic attack followed by a stroke in the same ONH blood flow reliably ( 40). Results based on this distribution six days later, with each event being associated method may not be valid ( 41). with sildenafil use. In another study ( 34), Humphrey Despite these points, I believe that there is sufficient perimetry performed after ingestion of 200 mg sildenafil in evidence to support a cause- and- effect relationship between a healthy young woman showed bilateral superior and the ingestion of erectile dysfunction drugs and the develop-inferonasal visual field depression. A critical review of all ment of NAION. Most probably, the incidence of NAION the reported cases shows a close temporal relationship after use of these drugs is much higher than is apparent between the ingestion of these drugs and the onset of from the reports because patients are not always forthcom- NAION. ing to physicians about their use of these drugs, owing to This evidence indicates that a cause- and- effect re- embarrassment or their belief that this is not relevant lationship between the drugs and development of NAION information. Given the information I have presented, is likely. Skeptics may use the arguments that follow to patients with cardiovascular risk factors, diabetes mellirus, dispute this point. those who take arterial hypotensive drugs, and those who have a history of previous NAION should be advised NAION Seems to Occur in Patients Using against the use of erectile dysfunction drugs. 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