Since the U.S. Food and Drug Administration (FDA) approved sildenafil citrate (Viagra) on March 27, 1998 to treat male erectile dysfunction, it has become one of the most popular drugs worldwide. More recently, tadalafil (Cialis) and vardenafil hydrochloride (Levitra) have been introduced for the same purpose.
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 patients who have developed non-arteritic anterior ischemic optic neuropathy (NAION) soon after the ingestion of sildenafil (1-7), and three patients who developed it after use of tadalafil (8-10). Varied opinions on the cause-and-effect relationship between these drugs and the development of NAION have been expressed by the FDA, the pharmaceutical industry, ophthalmologists, urologists, and other physicians, resulting in considerable confusion in the public mind. For example, in the New York Times, May 29, 2005, Suzanne Trevino, a spokesperson for the FDA, said “We're not able to specifically say that these 38 cases are a result of the patients taking Viagra.” The same newspaper article quoted Michael Berelowitz, MD, Pfizer's vice president, as saying, “We've studied all our databases right now, and we see no signal of causation with Viagra.” David Moskowitz, an analyst at Friedman, Billings, and Ramsey, is quoted as saying that “It may not be the drug at all; it may be just the patient population that's experiencing this blindness…We think this was an overreaction.” In the Archives of Ophthalmology, Egan and Fraunfelder (11) have stated that the connection between sildenafil use and the development of 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, the strong re-challenge data (9) suggest the drug effect may be significant.”
To understand whether there is a cause-and-effect relationship between erectile dysfunction drugs and NAION, one must consider basic scientific facts related to NAION as well as to the drugs.
BLOOD SUPPLY OF THE OPTIC NERVE HEAD
Studies on the blood supply of the optic nerve head (ONH) (13,14), as well as experimental (15), pathologic, and clinical findings, have all shown that NAION is caused by ischemia of the ONH (16). Therefore, the most important considerations in understanding the development of NAION are the factors that influence blood flow in the ONH. Evidence shows that blood flow is influenced by many factors, including systemic arterial blood pressure, endothelial-derived vasoactive agents, and autoregulation of blood flow in the ONH (17). Autoregulation is deranged by many systemic and local causes, including the aging process, arterial hypertension, diabetes mellitus, marked arterial hypotension from any cause, arteriosclerosis, atherosclerosis, hypercholesterolemia, vasospasm, and probably regional vascular endothelial disorders (17-20).
RISK FACTORS FOR NAION
My studies have shown that NAION is a multifactorial disease, with many risk factors playing a role in its development (21,22). They can be divided into predisposing and precipitating risk factors.
Predisposing Risk Factors
Predisposing risk factors are those that make a person 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 hypotension (particularly nocturnal), diabetes mellitus, hyperlipidemia, atherosclerosis, arteriosclerosis, migraine and other vasospastic disorders, defective cardiovascular autoregulation, sleep apnea, hematologic disorders, and others (22). Local risk factors include increased intraocular pressure, marked optic disc edema from any cause, location of the watershed zone of the posterior ciliary arteries in relation to the optic disc, and vascular disorders in the nutrient vessels of the ONH (22). Pomeranz et al (5) concluded that “A small cup-to-disc ratio may be a risk factor for development of NAION in association with the use of sildenafil.” Our studies have shown that an absent or small cup is simply a secondary contributing factor, once the process of NAION has started, and not a primary factor (23).
Precipitating Risk Factors
In the presence of predisposing risk factors, precipitating risk factors act as the “last straw.” In a study of 925 episodes (involving 871 eyes) of NAION (24), 73.3% had a definite history of discovering the visual loss first upon awakening or at first opportunity to use vision critically after sleeping; in the remaining episodes, time of onset was generally uncertain. This shows that nocturnal arterial hypotension acted as the precipitating factor in the vast majority. Also, 24-hour ambulatory blood pressure monitoring studies (25,26) have shown a significant correlation between progressive visual loss in NAION and nocturnal arterial hypotension. Therefore, contrary to the prevalent misconception, NAION is largely a hypotensive disorder, not an embolic or thrombotic disorder. This is in sharp contrast to other strokes, which are primarily embolic or thrombotic phenomena.
Our 24-hour ambulatory blood pressure monitoring studies in over 700 patients so far have shown the following:
1. Taking blood pressure-lowering medication in the evening or at bedtime aggravates the physiological decrease of blood pressure during sleep, resulting in nocturnal arterial hypotension (26,27)
2. Daytime blood pressure often is no guide to the nighttime blood pressure or to the extent of decrease in blood pressure during sleep. We have not infrequently seen patients with ideal daytime blood pressure who developed a marked decrease during sleep without being on any treatment (22,26)
3. Patients with “white-coat hypertension” are often treated aggressively, resulting in marked nocturnal arterial hypotension, putting them at risk for developing NAION (25)
4. There is a significant correlation between progressive visual loss in NAION and nocturnal arterial hypotension (25,26)
ERECTILE DYSFUNCTION DRUGS AND NAION
In the light of this basic scientific information on NAION, let us evaluate the role of erectile dysfunction drugs in the development of NAION.
Cardiovascular Risk Factors Are Common in These Patients
Most reported cases are from middle-aged and elderly men. Arterial hypertension, diabetes mellitus, hyperlipidemia, and other systemic cardiovascular risk factors are common in this group. As discussed above, those factors predispose them to develop NAION.
NAION Has Occurred Shortly After Drug Use
In most of the reported cases of NAION after ingestion of sildenafil, the patient has detected visual loss upon awakening in the morning, as have most NAION patients (24).
Other Contributory Drugs Are Often Used
Patients with arterial hypertension and other cardiovascular disorders invariably take beta-blockers, angiotensin-converting enzyme-inhibitors, calcium channel blockers, or other drugs with arterial hypotensive effect. In their study on the combination of antihypertensive therapy with sildenafil or placebo, Mahmud et al (28) stated that “The extent of individual maximum reductions (in mm Hg) from baseline in systolic (24 ± 10 versus 6 ± 8; P < 0.05) and diastolic blood pressure (8 ± 5 versus 3 ± 2; P < 0.05) occurred on the sildenafil study day.” Patients with benign prostatic hypertrophy are often advised to take alpha adrenoreceptor blocking agents at bedtime which can produce nocturnal arterial hypotension (26,27). Erectile dysfunction is one side effect of these and many other arterial hypotensive drugs.
Erectile Dysfunction Drugs Cause Systemic Hypotension
It is well established that sildenafil use is associated with a decrease in blood pressure (28-30). Our 24-hour ambulatory blood pressure monitoring studies (26,27,31) have shown that arterial hypotensive medication taken in the evening or bedtime aggravates the normal physiological decrease of blood pressure during sleep, resulting in marked nocturnal arterial hypotension. Erectile dysfunction drugs are taken most often in the evening or before going to bed so that their arterial hypotensive effect is likely to aggravate physiologic nocturnal hypotension, especially if the patient takes other drugs with hypotensive effects.
Erectile Dysfunction Drugs Stimulate Release of Vasoconstrictors
Phillips et al (32) showed that sildenafil causes an increase in plasma norepinephrine levels by 31% ± 5% (P = 0.004) and concluded that sympathetic activation may have implications for understanding cardiovascular events associated with sildenafil use. It is well known that norepinephrine is a potent vasoconstrictor. In malignant arterial hypertension, ONH ischemia and NAION may be the result of diffusion of vasoconstrictor agents from the peripapillary choroid into the ONH (18). This phenomenon may be yet another contributory factor in development of NAION after sildenafil use.
Stroke and NAION May Follow Rechallenge with Erectile Dysfunction Drugs
Morgan et al (33) describe a patient who suffered a transient ischemic attack followed by a stroke in the same distribution six days later, with each event being associated with sildenafil use. In another study (34), Humphrey perimetry performed after ingestion of 200 mg sildenafil in a healthy young woman showed bilateral superior and inferonasal visual field depression. A critical review of all the reported cases shows a close temporal relationship between the ingestion of these drugs and the onset of NAION.
This evidence indicates that a cause-and-effect relationship between the drugs and development of NAION is likely. Skeptics may use the arguments that follow to dispute this point.
NAION Seems to Occur in Patients Using Erectile Dysfunction Drugs Who Have No Evident Systemic or Vascular Predisposing Risk Factors
Having studied more than a thousand patients with spontaneously-occurring NAION, I can confirm that many patients seem perfectly healthy by the usual standards. But there are serious limitations in our ability to detect NAION risk factors. For example, a patient may be having marked nocturnal arterial hypotension when the daytime blood pressure is absolutely ideal. Whereas it is always assumed that atherosclerosis is a disease of the elderly, atherosclerotic plaques in the coronary arteries have been seen among young (average age, 22 years), healthy American soldiers killed in the Korean War (35). Also, in humans, we have no means to determine the local risk factors in the ONH mentioned above (17,36).
Erectile Dysfunction Drugs Have Been Used for a Long Time before NAION Develops
Whereas it is true that many cases of NAION have occurred in patients who have been using erectile dysfunction drugs for a long time, it may be that a critical decrease in blood pressure is required to produce the degree of hypoperfusion of the ONH to cause NAION in susceptible persons. The requisite combination of factors to cause threshold perfusion failure in the ONH may not be present after every use of erectile dysfunction drugs. This is well illustrated by the fact that patients suffer successive attacks of NAION in the same eye (37) or the other eye (38) days, months, or even years apart.
Erectile Dysfunction Drugs Do Not Lower Perfusion of the Optic Nerve Head
Pomeranz and Bhavsar (7) have stated that Grunwald et al (39) found no significant change in the ONH blood flow with sildenafil as compared with placebo use. However, Grunwald et al (39) measured ONH blood flow with the laser Doppler flowmeter, a device that does not measure ONH blood flow reliably (40). Results based on this method may not be valid (41).
Despite these points, I believe that there is sufficient evidence to support a cause-and-effect relationship between the ingestion of erectile dysfunction drugs and the development of NAION. Most probably, the incidence of NAION after use of these drugs is much higher than is apparent from the reports because patients are not always forthcoming to physicians about their use of these drugs, owing to embarrassment or their belief that this is not relevant information. Given the information I have presented, patients with cardiovascular risk factors, diabetes mellitus, those who take arterial hypotensive drugs, and those who have a history of previous NAION should be advised against the use of erectile dysfunction drugs.
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