-Caveat Lector- >>>Well! And they don't want dying people to become potheads. And I remember when kids' lip-smacking was from licking the beaters after mom made frosting. A<>E<>R <<< From http://www.washingtonian.com/health/what_you_dont_know.html }}>Begin HEALTH & MEDICINE What You Don't Know Too Little Is Known About the Long-Term Effects of the Most Popular Drugs By Thomas J. Moore For more information on this and other drug-safety issues, visit the author's Web site at www.thomasjmoore.com. Five Ways To Be Medication Smart In early April, 27,000 women discovered an important letter in their mailbox. The women had been taking part in a government-sponsored test of estrogen, a hormone replacement taken by 21 million women either alone or in combination with progesterone. The National Institutes of Health were sponsoring the study to learn the long-term effects of the most widely prescribed drug in America. The letter told the women that this first large long-term study of estrogen had turned up an embarrassing fact: The most important promised benefit of estrogen therapy for women after menopause--protection from heart attack and stroke-- apparently did not exist, at least after three years of treatment. In fact, the drug appeared to slightly increase the risk. This was contrary to pronouncements by the American College of Physicians, the National Heart, Lung, and Blood Institute, and the National Cancer Institute, all of which listed a lower risk of heart disease as an important benefit of taking estrogen. The estrogen news was the third unpleasant surprise about long-term drug benefits in one month's time. In March, another NIH study with 42,000 participants found that the blood-pressure drug Cardura--one of a family of alpha blockers taken by 1 million people--was so ineffective at preventing strokes and heart failure that patients taking Cardura needed to be switched to more effective medication. A few weeks later, Merck made a terse announcement about a long-term safety study of Vioxx, its new blockbuster arthritis drug and painkiller prescribed for more than 6 million people. Compared with users of an inexpensive generic drug called naproxen, the Vioxx patients experienced more heart attacks. While the drugs mentioned here have documented benefits in the short term, these three examples underline a fact little known to most consumers: The long- term effects of most drugs intended for lifetime use are not routinely studied and thus unknown. Although new drugs are usually studied in thousands of patients for short periods, the international standard provides that drugs intended for lifetime use should be tested only in about 100 people for periods of one year or more. Although Food and Drug Administration requirements for some drugs are stricter, US law does not provide for the long-term testing of drugs, before or after approval for marketing. Even when occasional long-term tests reveal unexpected problems, no reliable way exists to ensure that patients are promptly taken off drugs that are shown to be dangerous, weak, or ineffective. Even when lives are at stake, drug companies and other health authorities repeatedly have failed to warn doctors and patients about newly discovered problems or ensure they halt treatment or switch to a better drug. The failure to provide for long-term testing of drugs and to make wise use of the results constitutes perhaps the single most dangerous flaw in a system intended to protect patients from unnecessary harm from prescription drugs. Some other examples, each involving families of drugs taken by more than a million people: Sular. This is a blood-pressure drug in the family called calcium channel blockers. One trial found that patients with adult-onset diabetes who took the drug had a 500-percent higher risk of heart attack than those taking an ACE inhibitor, another kind of blood-pressure drug. Investigators halted the trial, unwilling to continue giving the patients Sular. But neither the manufacturer, the FDA, nor the American Diabetes Association warned the public about the risk or urged people to switch to more effective drugs. Evista. Eli Lilly's new estrogen alternative is an example of a drug that could either cause cancer or prevent it, and without long-term testing it is impossible to know. When Evista was given to laboratory mice, 38 percent developed ovarian cancer, but other evidence suggests that Evista affects a human breast-cell receptor in a manner that might help prevent breast cancer. Without much-longer studies, there's no way to say whether Evista might prevent breast cancer, cause other cancers, or both. Ritalin and Prozac. Both drugs illustrate the perils of failing to perform long- term safety studies for psychiatric drugs. Do the tremors, disfiguring tics, and other signs of neurological impairment reported in about 10 percent or more patients taking the drugs become permanent and irreversible in some cases as they do with some other psychiatric drugs? Long-term safety studies capable of detecting permanent brain damage have never been published. Zocor and Lipitor. A six-year clinical trial proved that Merck's cholesterol drug Zocor can prevent heart attacks. Similar studies have never been completed for Warner-Lambert's Lipitor, another cholesterol lowerer. As a result, there's no way to know whether it prevents heart attacks or not. Yet the heavily marketed Lipitor is prescribed twice as often as Zocor, according to IMS Health, an industry information and consulting firm. The company says 10 million people have taken Lipitor. As long as doctors and consumers fail to distinguish between proven and unproven drugs, the industry has little market incentive to conduct expensive long-term testing that might reveal its product is inferior. For treating arthritis, Merck's Vioxx and the similar Celebrex, made by G.D. Searle, were found to be about as effective as ibuprofen and naproxen, yet both became blockbusters based on a plausible but unproven claim that they might be safer. Vioxx inhibited only the Cox-2 enzyme, which was linked to inflammation, but did not block the nearly identical Cox-1 enzyme, which helps protect the stomach. Aspirin, ibuprofen, and naproxen all inhibit both Cox-1 and Cox-2 enzymes. Because Vioxx didn't affect Cox-1, researchers believed it would cause less harm to the stomach and cause fewer perforated and bleeding ulcers. Thus Merck aggressively marketed Vioxx as one of the first "Cox-2 inhibitors." Some enthusiastic news organizations even dubbed the drugs "super aspirin." But in the real world, the story did not turn out so simply. Drugs have many effects, and the effect on the protective coating of the stomach was only one. Cox-1 performed another vital function in the body--helping to create blood clots. Aspirin, by making blood clots form more slowly, was shown to prevent heart attacks and strokes; ibuprofen and naproxen likely have smaller but similar effects on blood clots. Even before Vioxx was approved, FDA safety reviewers noted that without a cardioprotective effect, a Cox-2 drug such as Vioxx might leave arthritis patients more vulnerable to stroke, heart attack, or similar problems. The first tipoff was that in testing, seven times more serious cardiovascular events were reported--a red flag for Vioxx usage--than serious gastrointestinal injuries, where Vioxx might have a safety advantage, but the numbers were small. "With available data, it is impossible to answer with complete certainty whether the risk of cardiovascular . . . events is increased in patients on [Vioxx]," the FDA safety reviewer said. Within the year, additional proof had arrived in the largest long-term study of Vioxx that Merck had yet conducted. In hopes of finally attaining evidence of greater safety than older competing painkillers, Merck had conducted a nine- month study in 8,000 patients with rheumatoid arthritis. Compared with naproxen patients, Vioxx patients did indeed suffer fewer serious gastrointestinal complications, according to Eve Slater, senior vice president for clinical and regulatory development at Merck Research. But Vioxx patients suffered more heart attacks. Because serious cardiovascular events occur more frequently than serious GI events, it seems possible that the overall risk profile of Vioxx might be unfavorable. Merck's Slater disagreed. She also attributed the difference in heart attacks to an unexpectedly powerful cardioprotective effect of naproxen, not any shortcoming in Vioxx. Nevertheless, she said that Merck plans to inform doctors and patients about the benefits of also taking aspirin if needed to lower the risk of heart attack or stroke. In fact, the inventor of the first Cox-2 inhibitor already does this. In researching a previous account about the marketing of Vioxx and Celebrex ("Cashing In on Pain," January 2000 Washingtonian), I interviewed Philip Needleman, the scientist who discovered the Cox-1/Cox-2 concept and then brought Celebrex to market as copresident of G.D. Searle, beating Vioxx by a matter of months. Late in the interview he made a peculiar admission. In addition to taking Celebrex, Needleman told me, he personally also took a full-strength Bayer aspirin every day. It seemed odd to hear the inventor of the first Cox-2 inhibitor claim that he took aspirin to get the Cox-1 enzyme inhibitor he had removed from Celebrex. Why not take just two aspirin for about 8 cents a day instead of a $2.88 pill such as Vioxx or Celebrex? I didn't print the quote at the time because it seemed like an admission he might not have intended to make. But after the Merck study, I now believe that he was trying to tell me something. In fact, patients in long-term studies of Celebrex and Vioxx are now allowed to take aspirin so they get both Cox-1 and Cox-2 effects. In the summer of 1997, the Colorado Prevention Center in Denver was testing two drugs for high blood pressure in patients with adult-onset diabetes, a group with a high risk of heart attack. The center was comparing Sular--a calcium channel blocker--with enalapril, part of a family known as ACE inhibitors. Both Sular and enalapril immediately lowered blood pressure, but would they be equally effective in preventing heart attacks and the complications of adult- onset diabetes? Bayer, the German drug company that developed Sular, was paying most of the costs, and the National Institutes of Health was contributing the rest. Like many trials, it had a catchy acronym: ABCD, or Appropriate Blood Pressure Control in Diabetes. The Colorado Prevention Center had recruited 470 patients with adult-onset diabetes and randomly assigned them to take Sular, the calcium channel blocker, or enalapril, the generic ACE inhibitor. The pills looked identical and were distributed in bottles labeled only with code numbers so that neither patients nor investigators knew which drug was being taken. The trial was to last five years--not just the few months of study required for Sular's earlier FDA approval--with every participant receiving checkups and being monitored for heart attacks and other adverse events. This ongoing flow of data went to a special Data and Safety Monitoring Committee, the only group with access to the codes identifying the medication taken by each patient. If the safety committee concludes that one of the groups of patients is being harmed or simply denied what is clearly a better treatment, it is ethically obligated to bring the trial to a halt. In July 1997 the Data and Safety Monitoring Committee of the ABCD trial voted to halt the study, according to Raymond Estacio, the study's medical director. A striking difference had emerged between the two drugs after four of the planned five years. Patients taking the calcium channel blocker Sular were five times more likely to experience a heart attack than those taking the generic ACE inhibitor, enalapril. Clearly, it was unethical to continue the experiment knowing Sular patients would experience heart attacks that could be prevented by giving them the ACE inhibitor. But what about the approximately 1 million patients with diabetes who were already taking Sular or similar calcium channel blockers? Shouldn't they be switched to the more effective ACE inhibitor? This was considered in a telephone conference call in fall 1997. The participants included representatives from the trial researchers, the National Institutes of Health, and the Food and Drug Administration. The issue was whether to make a public announcement to warn patients, especially those with diabetes. Of the 15 people taking part, Estacio says, just one wanted to make a public announcement. A lower-key option--to use a special fast-track mechanism to obtain speedy publication in a major medical journal--was also rejected. "In fact, it was pretty carefully discussed about how to present the data so there wouldn't be a widespread panic," says Howard Hutchinson, executive medical director of Astra-Zeneca, the company that sells Sular in the United Sates. Another six months would pass before the ABCD trial findings were published in the New England Journal of Medicine. The article triggered a single day of news stories before the issue largely disappeared. The FDA never issued a warning or press release. Astra-Zeneca never notified doctors to avoid using the drug in patients with diabetes. The American Diabetes Association never made a statement. But there's no doubt among experts that people with adult-onset diabetes should not unnecessarily risk heart attack by taking a calcium channel blocker rather than an ACE inhibitor. Estacio, the trial director, says he would switch any of his own diabetes patients taking calcium channel blockers to an ACE inhibitor. The company that sells Sular agrees. "Probably the ACE inhibitor is the better choice in the diabetic patient," says Hutchinson. Asked why his company didn't communicate this finding to doctors, Hutchinson replied, "Does that mean we have to go overboard and put people in a panic about their medication?" Sular, he noted, had not been proven harmful, merely less effective in preventing heart attacks. At the American Diabetes Association, Richard Kahn, chief scientific and medical officer, also agrees that patients should be switched to ACE inhibitors. "We haven't said this officially," he says, "but people taking other [blood pressure] drugs need to talk to their doctors about whether they should switch to an ACE inhibitor." The FDA would not even provide an official to discuss why it had never issued a warning to diabetes patients or required Astra-Zeneca to warn doctors. Under fire for favoring industry, the agency has curtailed press access to its medical experts. With other drugs, too, health officials seem to be more interested in avoiding public panic over inferior or unsafe medication than in warning patients. In the case of estrogen and heart disease, NIH's National Heart, Lung, and Blood Institute made no public announcement. But its media managers anticipated that if 27,000 letters were sent to women in the estrogen trial, one of the letters was going to end up in the news media. Thus, a statement with a few details about estrogen was prepared and made available only to reporters who asked for it. > Reporters who requested specifics couldn't get them because the heart institute refused to disclose additional information and had no plans to make this landmark scientific data available to doctors and experts through a medical journal. The institute's logic in withholding this scientific data? According to Jacques Rossouw, the NIH researcher directing the huge women's trial, "providing numbers now could be misleading and could be used by others not fully familiar with all the trends . . . to draw unwarranted conclusions about the continuation of the trial." Legally and ethically, the NIH had to inform the women in the trial of the findings because their treatment with estrogen could be increasing their risk of heart attack. But unless they follow the news fairly carefully, the rest of American women are left to fend for themselves until some time after 2005 when the trial is completed and all results prepared for publication. Similar considerations were in evidence with the newly discovered risks of Vioxx, the arthritis drug. Merck was legally and ethically responsible for informing people in its ongoing clinical trials of the higher heart-attack risks discovered for its drug than for naproxen. It also allowed participants to take low-dose aspirin, thus replacing the Cox-1 inhibitor that was removed from Vioxx. But the company made the briefest possible announcement in a release that had to be requested from the company's press office. At the same time, Merck's marketing machine was waging a multimillion-dollar sales campaign to ensure that doctors and consumers heard good things about Vioxx. The FDA meanwhile indicates that an independent evaluation of Vioxx's newly confirmed disadvantages is months away. Even when warnings are issued, many patients aren't switched to safer or better treatments. In 1989, it was discovered that two drugs for irregular heartbeat, Tambocor and Enkaid, were causing cardiac arrest in about 7 percent of the heart-attack survivors taking them. Literally tens of thousands of heart patients had died from these and similar drugs. The FDA warned that the whole family of ten drugs was suspect and urged doctors to discontinue their use by patients with mild rhythm disturbances. In this case, the word did reach doctors via several routes. A later study showed that many doctors stopped prescribing the drugs for new patients but apparently didn't want to face the potential problems of contacting existing patients to tell them to stop. Even though a large majority of cardiologists knew about the risks, 81 percent did not take their patients off these potentially lethal heart drugs, one survey found. In the case of Cardura, the alpha blocker removed from the NIH blood-pressure trial on March 8, the system still failed even when individual parts of it performed well. When the Cardura patients had to be taken off the drug, the National Heart, Lung, and Blood Institute issued a press release that included the most newsworthy particulars. One week later, Curt Furberg, the chair of the study, made a detailed presentation at the annual meeting of the American College of Cardiology in California. Although cardiologists are only a minority of those doctors who prescribe blood-pressure medication, they are a pivotal and influential group of experts. The American College of Cardiology took the finding a step further, issuing a press statement urging doctors "to discontinue use" of Cardura and other alpha blockers for treating high blood pressure. This seemed to be one of the clearest drug warnings ever issued by an expert medical group. But only hours later, the American College of Cardiology was saying that it had made a mistake and was not in fact urging doctors to discontinue the drug. The college had intended only to urge doctors to "reassess" use of alpha blockers, according to Melanie Caudron, director of communications. "Discontinue" was a staff error, she said. The offending word was removed from the copy of the press release posted to the Web site the next day. The biggest impact of all this was on Pfizer, which sells Cardura, a drug prescribed for an estimated 800,000 patients both to reduce blood pressure and to relieve the symptoms of an enlarged prostate. Pfizer, in turn, is one of the four largest contributors to the American College of Cardiology, giving $512,000 last year. (The other three largest contributors were also drug companies--all placed in the college's "platinum heart" category of donors.) Even though it was unclear whether any major news organization had printed the contents of the press release with the word "discontinue," Pfizer asked the college to issue a new release, making it clear that it was not urging doctors to discontinue use of the drug. The cardiology group agreed, according to both Pfizer and Caudron. Pfizer then made the new press release available to its sales force to use when talking to doctors who might now express concern about Cardura, says Michael Widlitz, medical group director for Pfizer. Widlitz says Pfizer agreed with and supported the findings of the NIH study. Cardura should not be a first-choice or principal blood-pressure drug, he says. He added that it could be used in combination with other drugs, and that's how Pfizer marketed the drug. But Widlitz concedes that the company had issued no warning letter to doctors about the findings, had prepared no brochure, and had not put anything in the product's package labeling. More than two months after the warning about Cardura, there is no evidence that the new findings had any measurable effect on medical practice. Cardura's sales were unchanged throughout the period, according to data from IMS Health. News coverage was minimal. And the one clear warning from the American College of Cardiology had become garbled. The greatest problem with drug testing may be the major risks that have never been adequately studied. Brain damage and cancer develop only over the long term, and neither has been carefully studied despite warning flags from adverse effects and other short-term indicators for some widely used drugs. For Ritalin in children and Prozac and other drugs for depression, the warning flag is the frequent occurrence of tremors and other involuntary movements that prove the drugs are impairing the brain. The most frequent tremors are mild, but effects can range upward to include disfiguring tics, uncontrollable lip smacking, or the inability to stop the tongue from darting out of the mouth. For Prozac, Paxil, and Zoloft, tremors are reported in 8 to 11 percent of patients in studies that last six to eight weeks. Medical studies of Ritalin show movement disorders observed in 9 to 58 percent of children. (The large range is explained partly by different methods and definitions.) In occasional reported cases, the lip smacking and other movement disorders in children taking Ritalin were not reversed when the drug was discontinued. The unanswered question is whether these movement disorders become more severe, more frequent, or irreversible after years of therapy. This is what occurred with the most powerful psychiatric drugs--called neuroleptics--used to combat schizophrenia and the most extreme related behaviors such as delusions, hearing of voices, violence, and self-injury. "After decades of denial, it finally became apparent that neuroleptic drugs cause irreversible brain damage and abnormal movements in most patients who take these drugs for many years," notes Bethesda psychiatrist Peter Breggin, who has written widely about the dangers of psychiatric drugs. "We also know that stimulant drugs [such as Ritalin] can produce irreversible neurological damage, but there has been too much professional denial and too little research. Now we're finding that Prozac and similar drugs commonly cause tremors and less frequently cause a variety of other abnormal movements similar to the neuroleptics. We need a great deal of caution and a lot more research on these dangers." Novartis, the manufacturer of Ritalin, declares that "sufficient data on the safety and efficacy of long-term use of Ritalin in children are not yet available." For the antidepressant drugs, some year-long studies of relapses in depression have been published--but without systematic evaluations of patients for movement disorders, sexual dysfunction, or cognitive impairment. The cancer risk of prescription drugs can be detected primarily in two ways: in animal studies and in human studies that last more than five years. What the animal studies show is that about half of recently approved drugs caused cancer when tested in rats or mice over a rodent lifetime of two to three years. Implicated are many cholesterol-lowering drugs, some blood-pressure medication, and about 40 percent of psychiatric drugs. In addition, many drugs used to treat cancer also cause cancer. But the meaning of these findings is not clear. Though the drugs known to cause cancer in people showed some problems in animal studies, the opposite remains unknown: Do all chemicals that cause cancer in animals also create a risk in humans? The alternative estrogen Evista is a provocative case: Not only was the cancer- causing effect in animals clear, but other evidence suggested a protective effect against breast cancer. It could turn out that like many cancer chemotherapy drugs, Evista is simultaneously capable of both causing and preventing cancer. But which effect is larger remains to be determined, as well as whether its risks are higher or lower than the equine estrogen taken by 21 million US women. Because long-term studies in the five-to-ten-year range with systematic collection of data on cancer are practically unheard of, the carcinogenic properties of prescription drugs will remain guesswork. A system so rife with examples of drugs that fail to deliver on their promises is a system in crisis. Add the fact that so many who take these drugs are exposed to unnecessary risks of major events such as heart attack and stroke, and the need for reform is clear. The FDA does a reasonably good job in ensuring that drugs, before approval, are thoroughly tested for the short term. But no procedure is now in place to deal with the frequent revelations that approved drugs taken by millions of people do not work as the experts believed. Instead we have drug companies that openly admit the facts and then do nothing, hoping that few will notice. We need a system to assure the long-term testing of drugs intended for lifetime use and new ways to alert the public of the findings. n Five Ways To Be Medication Smart Educate yourself. Read all you can about the benefits and risks of each drug you take. Be alert to side effects. Usually they can be eliminated or minimized by a change in medication or dose. Some drugs such as those for high blood pressure can be hazardous if stopped suddenly and should be tapered off with the help of your doctor. Know whether the drugs you're taking require that you undergo regular lab tests to assure you're not being harmed, and know what the test results mean. Work with a medical professional, but remember: The final decision on whether to take a drug is yours. Top of page Subscribe Site Index About the Washingtonian Reprints Contact Us Feedback Advertise Copyright �2000 by Washington Magazine Inc. 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