Fw:Long-term effects of prescription drugs

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> MedPolPlus

> " . . . health officials seem to be

> more interested in avoiding public panic over inferior

> or unsafe medication than in warning patients. "

>

>

>

> What You Don't Know

>

> Too Little Is Known About the Long-Term Effects of the

> Most Popular Drugs

>

> By J.

>

> 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 -2 enzyme, which was

> linked to inflammation, but did not block the nearly

> identical -1 enzyme, which helps protect the

> stomach. Aspirin, ibuprofen, and naproxen all inhibit

> both -1 and -2 enzymes. Because Vioxx didn't

> affect -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 " -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. -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 -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 -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 -1/-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 -2 inhibitor claim that he took aspirin to

> get the -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 -1 and

> -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 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 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, 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 -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 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

> 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

> 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.

>

> Copyright ©2000 by Washington Magazine Inc.