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  •   Viagra's Hidden Risks

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    Use Caution
    Invention Was an Accident
    Latest Viagra News From AP

    By John Schwartz
    Washington Post Staff Writer
    Tuesday, June 9, 1998; Page Z12

    The retired airline executive didn't get around to asking about it until the very end of the visit with internal medicine physician Lesley Wilson: Would she prescribe some Viagra for him?

    "Most of the men who ask me about Viagra, they come out with it as we're going out the door," said Wilson, who works for Kaiser Permanente in Santa Clara, Calif. "I'm sure it's what's first in their minds, but they don't get it out until they're about to lose their chance."

    The patient seemed like a good candidate for the drug. While he was 80 years old, he was in fine health, and had just passed a series of medical tests with good results all around. She went over the list of medications he was taking to make sure that he wasn't using nitroglycerin, a heart medication that can combine with Viagra to send blood pressure plummeting to fatally low levels. And then, as she had for 30 patients before him, she wrote out a routine prescription for a bottle containing six pills.

    What happened next was anything but routine. The man died while having sex with his wife the next day.

    Not For Everyone


    Viagra is one of the most successful drugs to hit the market in recent years, with more than 1 million users since its approval by the U.S. Food and Drug Administration in late March. Known generically as sildenafil citrate, it is the first effective impotence drug that can be taken orally. It enhances the body's natural system for creating erections, allowing the smooth muscles in the penis to relax and in turn allowing the organ to fill with blood. The drug has been found effective for 70 percent of men in clinical trials. Now, however, with a small but growing number of deaths reported among men who have used the drug, health care professionals are stressing that Viagra may not be for everyone.

    The death of the retired airline executive, which occurred on Saturday, May 16, came after four deaths of Viagra users from heart attack or stroke described in reports to the Food and Drug Administration and made available by the agency two weeks ago. Nine other patients taking Viagra died in the clinical trials leading up to the drug's approval. The deaths, and a few others reported in the news since then, underscore a health risk for some users of Viagra that has been previously noted both by the FDA and by manufacturer Pfizer.

    A man caught up in the enjoyment of renewed potency might exert himself beyond the limits his body can endure and have a heart attack or stroke. That risk is especially high for many sufferers of erectile dysfunction, since some of the leading underlying causes of the condition -- cardiovascular disease, diabetes, high blood pressure -- already put them at higher risk of a heart attack or stroke. In addition, people with those medical conditions tend to lead sedentary lives, raising the health risk during heavy exertion even more.

    The agency has said that the nine preapproval deaths were "plausibly not related" to the drug, and that the other incidents reported so far are not numerous enough to reach statistical significance when a drug has been prescribed for more than 1 million patients. A senior FDA official recently said that the agency "will continue our monitoring" and expects to see more cases, in part because of the drug's high profile. But he added that the number of cases reported so far "does not seem to represent a trend or a signal, or something worrisome to us at this point."

    Pfizer last week issued a statement that the drug is safe. The company does not intend to change the guidelines for usage on the label since they already include warnings about the risks of exertion and the complications associated with using nitrates, the cause of at least one death reported to the FDA.

    One Man's Story


    The earlier death reports are brief and sketchy. What follows is a fuller account of the death of a man who had taken Viagra shortly before having sex, as related by his widow; his physician, Lesley Wilson; and his son, who lives in Washington.

    The man wanted to remain vital until his last days, and like many older people detested the notion of going through a long period of debilitating illness before death. "He said, 'If that happens to me, just take me out on a boat and push me off,' " said his 74-year-old widow, who asked that the family's name not be used.

    Meanwhile, he paid close attention to health and fitness. He had given up smoking 35 years before. Ten years ago, after developing diabetes and hardening of the arteries, or arteriosclerosis, in his legs, he went on a strict low-fat diet and lost 40 pounds. The diabetes disappeared, and the leg problems stopped bothering him.

    But in recent months, he had felt a drop in his energy level. "After Christmas he began to feel really tired," his widow said. "He thought he should be able to walk further and faster."

    There was no getting around the fact that eight decades had left their mark. A few years before, he had suffered a couple of incidents of atrial fibrillation -- a rapid heartbeat. A doctor had prescribed a common heart drug, digoxin, to keep the condition under control. A doctor had also prescribed small doses of Coumadin, a blood thinner, to prevent blood clots. This year, along with the tired feeling, he was bothered by the recent gain of eight pounds and puffiness in his limbs. He and his wife visited Wilson at Kaiser, and the doctor prescribed a mild diuretic and blood pressure medication. The pounds melted away and his blood pressure returned to normal. His heart seemed strong and his cholesterol levels excellent. There was a little bit of fluid left in his lungs from the water he had taken on, but that too appeared to be clearing up. The doctor performed a few additional tests and asked him to return on Friday, May 14, for a follow-up exam.

    That morning he told his wife that there was no need for her to accompany him, and that he wanted to return to the doctor's office on his own. What she did not know was that he intended to ask the doctor for some Viagra.

    She said she still doesn't understand why. "I don't really know what they classify as impotence," she said with some exasperation. She and her husband had continued to have intercourse, she said, and enjoyed it. The loss of energy, and perhaps the medications he was taking, made an erection less of a sure thing than in the past, and sex didn't last quite as long. Maybe it wasn't like the sex of earlier days, but she said "I didn't have a problem with it." She sighed. "You know how men are about their performance," she said. "They relate it to their worth, or something. I give him credit for wanting to do something."

    Sex and the Heart


    The man was careful -- and his family believes that he wouldn't have taken a new medication without researching its risks. But in those first weeks after the FDA approval of Viagra, risks were rarely discussed. The warnings from the FDA and Pfizer that some patients might not be physically prepared for the exertion involved in physical activity were largely glossed over in news reports.

    Sex can be hard work, said Randall M. Zusman, associate professor of medicine at the Harvard Medical School and director of the division of hypertension and vascular medicine at Massachusetts General Hospital. Intercourse can send the heart rate up from 70 beats a minute to more than 100, and blood pressure during sex can shoot up from normal levels of about 140 millimeters of mercury to 300. Zusman, an adviser to Pfizer on the drug, believes that it is safe for "the vast majority of patients," but he added that "the prescription of Viagra is obviously not one that can be made without some thought."

    Cardiovascular disease can rob people of energy and stamina, leading them to more sedentary lives. This, in turn, raises the risk of heart attack even further with sudden exertion.

    James E. Muller, director of the Gill Heart Institute at the University of Kentucky, has studied the risk of heart attack triggered by sex and found it is actually very low in the general population -- a two-in-a-million chance per hour, double the risk of having a heart attack at any time but still comfortingly low, Muller said. Patients who have had heart attacks increase their risk of another heart attack during sex tenfold. But even that only raises the chance of a subsequent heart attack to 20 chances per million, according to Muller's research.

    At the same time, Muller estimates that the risk of a heart attack during intercourse for people who do not exercise and who have untreated cardiovascular disease could come closer to one in a thousand, the kind of risk that patients and doctors take seriously.

    Both the FDA and Pfizer have urged patients to get a full checkup, and to discuss honestly with their doctors whether the drug is right for them. "You've got to make sure that when you talk with your physician about this that indeed you are capable of engaging in a physical activity that might involve more exertion than you've been able to engage in lately," said a senior FDA official.

    'Are You Okay?'


    After the appointment with the doctor, the retired airline executive "came home and he was quite pleased," his widow recalled. He went outside to mow the front lawn, and afterward they went to a potluck dinner. They came back home and went to bed.

    The next morning began as every morning did: He woke up first and brought her her morning coffee in bed. He sat on the side of the bed next to her as they discussed what they would do with their day: He planned to mow the back yard.

    "Then we had sex," she said. "It was okay, I must say." But things went wrong at the end. "All of a sudden he just -- I shouldn't say he collapsed on me, but his full weight went 'pow!' " she said. "He gave a grunt -- 'Hunh!' It was like snapping your fingers, like that. I grabbed his face with both hands."

    She recalled shouting his name over and over, and recalled asking " 'Are you okay?' I was screaming at him, practically."

    Her husband only weighed 140 pounds, but his full weight was enough to pin her. "I got one arm out from under, one leg out from under," and was able to roll him over. She attempted mouth-to-mouth resuscitation, but he didn't respond; she called 911 and was guided through the same procedure she had just performed.

    Suddenly paramedics were banging on her door, dispatched while she was still on the line. "They were there instantaneously," she said. As they spent the next 10 minutes trying to resuscitate her husband, she slipped into the closet to dress and called her nearest child, a daughter in San Jose. She rode in the ambulance to the hospital and was ushered into a small waiting room.

    "A doctor came in and told me that he didn't make it to the hospital," she said; that in fact, her husband was probably dead the moment he collapsed. She asked the hospital to inform her family doctor and began the endless round of funeral arrangements and phone calls with family and friends.

    Early Monday morning, Wilson, the physician, called. "She was totally shocked," the widow recalled. But after hearing the description of the heart attack, the doctor somberly said, "You know, he asked me for a prescription for Viagra."

    "I did not know it until then," the widow said.

    The doctor agreed to help collect all the medical facts and to help piece together the puzzle of the man's death. The widow also called Pfizer directly and was connected with the company's safety department. The company representatives "took lots and lots of information," she said.

    When her son arrived from Washington, she asked him to go through his father's papers. There, in the lower right desk drawer, was the bottle with little blue pills. The prescription was for six pills; there were five left. She believes that her husband had intended to surprise her; to show off his renewed potency and then to reveal his secret afterward.

    The Unanswered Question


    The autopsy report came back on Friday, May 28. It showed no great abnormality in the heart or lung, she said, although there were sites of old scar tissue, possibly a sign of a "silent" heart attack -- a minor event that had gone unnoticed.

    Did Viagra have anything to do with this death?

    It is impossible to say, with so little information available so far. It might simply have been his time.

    Wilson said that she has no idea what caused her patient's death, an incident that leaves her voice shaking when discussing it. "I just don't know if it is a fluke, or a one-in-a-million, or whether there's going to be a pattern of this type of occurrence in a certain set of patients who take this drug," she said. She promptly reported the incident to Pfizer.

    The FDA's MedWatch reporting system for drug and device side effects also collects incidents like these so that patterns can be discerned. This is the way such mysteries can be solved, she said.

    But one of the man's sons said he believes the drug had to be involved. Although he does not have a medical background, he believes his father's death cannot be fully explained as just a reasonably predictable result of exertion. "A drug that makes blood go to some part of your body that's not your heart has got to have some kind of impact," he said.

    Wilson continues to prescribe Viagra, but with more warnings than ever. "I'm careful to discuss the possible problems, and I have even referred to this case in my discussions with other patients," she said. "I've told them to go slow, take half a dose, try a dry run. Anything you could do to introduce it more slowly might be helpful."

    Geriatric specialists also recommend a go-slow approach. "The actual amount of exertion that's required" for sex "need not be great -- you don't need to act like a 19-year-old," advises Robert N. Butler, co-author of "Love and Sex After 60" and a professor of geriatrics at the Mount Sinai School of Medicine. "If you can walk a city block or you can walk up a flight of stairs, you could moderate your sexual activity in that same range."

    Heart specialist Muller said that those who want to return to sexual activity might want to condition for the challenge. "Cardiac patients who have been sedentary and want to get on Viagra ought to get in a rehab [cardiac rehabilitation] program first," Muller said.

    The widow is still sorting out her life. She and her family agreed to talk about the details of this personal tragedy in case the drug is involved, so that others can receive a warning delivered in human terms. "He was so into finding out everything about health," his wife said, "I know that he would want any facts that are helpful, or constructive -- or even critical -- he would want them to be out there."

    She is exhausted by the never-ending round of telephone calls from family and friends, as well as the continuing need to tie up her husband's affairs and move on. There's comfort in the many conversations -- and, she said, humor as well.

    "A couple of my friends said, 'Boy, that's the way most men would like to go.' "

    More Information:
    Taking Viagra? Proceed With Caution


    If you're thinking of taking Viagra to treat impotence:

    See a urologist and, if possible, one who is a specialist in erectile dysfunction. These specialists will review your therapy options to see if Viagra is the best treatment for you.

    Seek a full work-up from your doctor to determine whether your erectile dysfunction is the result of underlying heart disease, diabetes, high blood pressure or other medical conditions. Your doctor may want to prescribe additional treatment for these ailments.

    If you have been leading a fairly sedentary life, be prepared to embark on a program of cardiac rehabilitation before resuming sexual activity.

    Do not take Viagra if you are taking nitroglycerin or other nitrate medications. The combination of nitrate drugs and Viagra can send blood pressure to dangerously low levels.

    Do not use "poppers," the nitrate-based recreational inhalants used by some people to enhance sexual pleasure.

    If you take Viagra and have health problems after sex, be sure to tell the emergency care physicians that you have taken the drug. It will keep them from administering drugs that could interact with Viagra and make your condition worse.

    More Information:
    Viagra's Discovery Was an Accident


    Viagra's discovery as an impotence therapy was a happy accident. The manufacturer Pfizer Inc. initially tested the drug as a heart medicine. It turned out to be ineffective for that use, but many of the participants in the study noted a surprising side effect. Men who were impotent were able to have erections.

    Before the drug was approved by the Food and Drug Administration in late March, studies were conducted on 4,000 men with erectile dysfunction, caused by a variety of medical as well as psychological conditions. Results showed that 64 percent to 72 percent completed intercourse after taking Viagra, compared with 23 percent of men taking a dummy pill. Men were instructed to take the drug about an hour before intercourse.

    Common side effects include flushing in the face, headache and upset stomach. Some men reported a blue tinge to their vision while taking the drug. Men are warned not to take Viagra if they are also taking nitrate heart drugs, such as nitroglycerin.

    The drug, which goes by the generic name sildenafil citrate, works by causing the release of a chemical found largely in the penis, cyclic guanosine monophosphate (cyclic GMP), that in turn causes the smooth muscle of the penis to relax, allowing the organ to fill with blood and become erect. The drug also suppresses an enzyme that breaks down cyclic GMP, extending the duration of erection.

    Viagra is not the only treatment for impotence, though it is the first effective oral medication. Other therapies include drugs that can be injected or inserted directly into the penis. Another oral medication, apomorphine, is being tested and could be available in about a year.

    © Copyright 1998 The Washington Post Company

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