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Posts Tagged ‘Lipitor’

Honesty in Drug Advertising: Some rare examples

Posted by medconsumers on May 1, 2007

“In patients with multiple risk factors for heart disease, LIPITOR REDUCES RISK OF HEART ATTACK BY 36%* If you have risk factors such as family history, high blood pressure, age, low HDL (‘good’ cholesterol) or smoking.”

The noteworthy part of this New York Times ad is the asterisk and this explanation of the 36% statistic: “That means in a large clinical study, 3% of patients taking a sugar pill or placebo had a heart attack compared to 2% of patients taking Lipitor.”

Take a moment to appreciate the significance of this rare finding of candor in one of those ubiquitous Lipitor ads featuring Dr. Robert Jarvik, “inventor of the Jarvik Artificial Heart and Lipitor user.” Most drug ads would rather proclaim a “36% reduction” and leave it at that, but this version shows exactly what it means. Take Lipitor for years and your risk of having a heart attack drops 1%. Granted, the explanation is in much smaller type than the 36%, but at least it’s there.

Another Jarvik/Lipitor Times ad proclaims: “In patients with type 2 diabetes, LIPITOR REDUCES RISK OF STROKE BY 48%* If you also have at least one other risk factor for heart disease…” The explanation: “That means in a large clinical study, 2.8% of patients taking a sugar pill or placebo had a stroke compared to 1.5% of patients taking Lipitor.”

It’s rare to see ads with drug benefits expressed in what statisticians call absolute risk terms, which are more understandable to the public as well as doctors. Tom Abrams, director of the FDA Division of Drug Marketing, Advertising and Communications, explained in a telephone interview that the FDA encourages drug companies that provide quantitative information (e.g., 36% reduced risk of heart attack) in their ads to show what it means. In other words, the ad must answer the question: 36% of what?

Whether quantitative information goes into an ad is up to the drug companies, but once it does, the FDA wants them to put in the explanation, Abrams said, though only the most egregious non-compliers get a warning letter. Why no explanation of the quantitative information in all TV versions of these ads? “This is a quicker media and companies believe that people can’t process the information?” he said.

Well, honesty in some print ads is better than nothing. The next thing to look for is the quantification of the drug’s severe adverse effects…in absolute risk terms.

Maryann Napoli, Center for Medical Consumers ©
May 2007

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Report Side-Effects of Statin Drugs

Posted by medconsumers on November 1, 2006

This is an excellent Web site for anyone who is currently on a statin drug or who has stopped taking one because of a serious adverse reaction. Although cholesterol-lowering statin drugs first went on the market 20 years ago, there are major information gaps concerning their adverse effects.

Beatrice A. Golomb, MD, PhD, who heads the UCSD Statin Study at the University of California at San Diego, has been working for years to change things by collecting information directly from the public. She has recently launched a new online survey (www.statineffects.com) “for people who have had adverse responses to statins or to other cholesterol-lowering drugs, and also [for] people who have done well on these drugs.” Statins are a class of cholesterol-lowering drugs that includes atorvastatin (Lipitor), simvastatin (Zocor), pravastatin (Pravachol) fluvastatin (Lescol), lovastatin (Mevacor), and rosuvastatin (Crestor).

The very existence of this study is tacit acknowledgment of deficiencies both in the FDA drug approval process and in its post-market surveillance system. Drug trials are designed to prove a benefit and typically do not provide a full picture of harm. Add to the mix the fact that most statin drugs are taken by older people. Many report to Dr. Golomb that their doctors attribute such problems as joint pain and memory deficits to aging and do not consider the possibility of statin side effects.

The site is more than a survey opportunity. It has information on known adverse effects divided into two sections: “Side Effects Your Doctor Will be Familiar With (muscle symptoms and changes in liver function, as noted in a blood test)” and “Lesser Known Side Effects” (e.g., peripheral neuropathy, memory loss, thinking and concentration problems), as well as a description of symptoms that should be reported immediately to your doctor.

Maryann Napoli, Center for Medical Consumers ©

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Statins: Low Odds of Benefit

Posted by medconsumers on July 1, 2006

Statin-Treatment Guidelines: 198 to 1 odds that the drug won’t help

Would you go on long-term statin drug therapy if you knew that the odds are one in 23,000 that the drug will save you from a cardiac death? How about one in 198? And are you prepared to stay on that drug for the rest of your life, though the full story on the drug’s harms is yet to be known? That is what the experts who put together the U.S. and Canadian statin-treatment guidelines expect of the public, according to an analysis published last month in the British Medical Journal.

So much of medical decision-making boils down to probabilities. What is my chance of having a heart attack? And how will this drug reduce the risk? Cholesterol drug ads, for example, proclaim a 25% reduction in heart attack. But that means nothing unless you know your personal odds of a heart attack. Always ask: 25% of what?

If, for example, you are a healthy middle-aged woman with high cholesterol but a tiny chance of having a heart attack in the next five years, then the drug offers a 25% reduction in those already miniscule odds. But, if you are a middle-aged male smoker who has already had a heart attack, then the 25% reduction offers a large benefit.

Researchers who study drug trials have another way of determining odds called number needed to treat. They frame the research question this way: How many people must take this drug every day for five years to save one person from a cardiac death? That formula is the basis of the new analysis of international guidelines for prescribing the cholesterol-lowering statin drugs that include Lipitor, Mevacor, Zocor, Pravachol, Crestor, and Lescol. It highlights some major deficiencies in the information intended to guide physician prescribing practices. And in turn, deficiencies in the information consumers need to make informed decisions.

The statin-treatment guidelines from five countries—Australia, Canada, New Zealand, the U.K., the U.S.—and several European medical societies were assessed by a team of Canadian researchers led by Douglas G. Manuel, MD, of the Institute for Clinical Evaluative Sciences in Toronto. The number needed to treat was determined by applying each set of guidelines to the same population of 6,760 Canadian men and women, aged 20 to 74 years.

The “winners” are the Australian and British guidelines because they are the most effective in potentially avoiding the most deaths. However, the New Zealand guidelines were deemed the most efficient because they potentially avoided almost as many deaths while recommending statin drugs to the fewest people. Based on the New Zealand guidelines, the number needed to treat is 108, or for every cardiac death prevented, 108 people must take statins for five years. (By comparison, the number needed to treat is 198 and 154, for the U.S. and Canada, respectively.)

What is most troubling about the results of this new analysis is not just that the U.S. and Canadian guidelines identify a larger pool of people as candidates for statin therapy in order to prevent one cardiac death. But it is also the fact that the crucial topic of drug-related harm was ignored by those who established the guidelines. “Treatment guidelines don’t discuss harms. I don’t know why,” said Douglas G. Manuel, MD, the lead author of the analysis, in a telephone interview.

“Harms are idiosyncratic, meaning everyone has more or less the same chance of harm. I say that with lots of caveats,” explained Dr. Manuel, a scientist and primary care physician. “But this is not so where it concerns benefits. If a person is at high risk because he has had a heart attack, then the benefit [of statin therapy] will be large. But as a person’s risk of heart disease gets lower, then I am more uncomfortable [about prescribing statins].”

The harm question was put to David Atkins, MD, medical officer at the U.S. Agency for Healthcare Research and Quality, the lead federal agency charged with improving the quality, safety, efficiency, and effectiveness of health care for all Americans. “Many guidelines about drugs skirt around the issue of harms,” he said in a telephone interview. “With anti-hypertension drugs, for example, side effects include sexual dysfunction and dry mouth, but they affect a small number of people—2-5%.” They are not addressed, Dr. Atkins explained, because it “complicates the message too much.” What’s more, he said, “Doctors tend to regard the issue of side effects as trivial in light of a heart attack.”

All of the statin-treatment guidelines are purportedly evidence based, meaning they are drawn from the same published results from clinical trials in which participants have been randomly assigned to take a statin or a placebo and followed for about five years. However, a healthy skepticism is in order where it concerns women without heart disease. A 2003 government report, Diagnosis and Treatment of Coronary Heart Disease in Women: Systematic Reviews of Evidence on Selected Topics, concluded, “There is insufficient evidence to determine whether lipid lowering [i.e., with drugs, diet or other lifestyle changes] reduces risk for any clinical outcome [e.g., heart attack, stroke].” The main reasons for the “insufficient evidence” are: women are underrepresented in statin trials and most of the trials pool the results of men and women together.

Informed decision-making about statin therapy is hampered further by another problem with medicine’s gold standard evidence—the randomized clinical trial, according to Dr. Manuel. “My expectation to get good information about harms from a randomized clinical trial is somewhat low because we are missing key parts of the information about adverse events from drugs in general, not just statins. What we need is better postmarketing surveillance,” he said, referring to mandatory reporting of adverse drug reactions after a new drug goes on the market. (Currently, reporting is voluntary and captures less than 10% of all serious adverse drug reactions.)

The FDA-required clinical trials conducted prior to approval usually have a few thousand participants at best. Only when hundreds of thousands of people begin taking a drug for years do the rare or uncommon serious adverse reactions come to light. Cardiologists are often quoted in the media saying that statins are safer than aspirin, but they are likely unaware that drug trials frequently fail to report all serious adverse reactions. (To see how common it is for drug companies to withhold information about adverse reactions suffered by clinical trial participants, see “Empirical evidence for selective reporting of outcomes in randomized trials: comparison of protocols to published articles.”)

Statin trials are a case in point. James Wright, MD, and colleagues at the University of British Columbia conducted a 2003 review of all five statin primary prevention trials and found that the serious adverse events* went unreported in three of these published trials. When Dr. Wright was asked for an update, he explained by e-mail that the serious adverse events were collected in all 12 major statin trials. However, ten of these trials have failed to report these important results (i.e., make them publicly available). Worse, the authors of these trials refused the UBC reviewers’ repeated requests for the harms data.

Treatment guidelines may be aimed at physicians, but the brunt of their deficiencies will be borne by the people who unquestioningly follow their doctors’ recommendations, especially those who are at low risk of developing heart disease. Understanding the probabilities that relate to the drug as well as your own personal risk is crucial to informed decision-making.

If your doctor says that statin therapy will reduce your odds of having a heart attack by 25% but cannot answer the question—25% of what?—here is how to do it yourself. Go to the National Heart, Lung and Blood Institute Web site for the less than perfect 10-year risk calculator. If, for example, you have a 2% chance of having a heart attack in the next ten years (two out of 100 people with exactly your risks), then the 25% reduction from statin therapy will bring your odds down to 1.5%. Predictably, the quiz, or anything else on this Web site, won’t help you understand the odds of harm or benefit from statin drugs. It is easy to see why pharmaceutical companies like to convey benefit in terms of a 25% reduction in their ads without explaining what that means or how it relates to a person’s baseline risk of having a heart attack. It is much harder to understand why information gathered and disseminated by a government agency funded with taxpayers’ money would not be more forthcoming.

Bottom Line: The new analysis of international guidelines shows a wide variation in the number needed to treat, though all are based on the same clinical trials. Harms are not addressed, possibly because there is a consensus among cardiologists that statins are safe and that serious side effects are rare. But there is also a consensus among people who study the FDA’s postmarketing surveillance system that less than 10% of all serious adverse drug reactions are reported to the agency. Inefficient guideline like those from Canada and the U.S. will send many people to statin therapy who have only a low risk for heart disease. Using the Canadian guidelines, Dr. Manuel and colleagues estimated that at least 23,000 low-risk people would have to take statins for five years to prevent one death from heart disease.

* Defined as “any untoward medical occurrence that results in death, is life-threatening, requires hospitalizations, requires prolongation of hospitalization, or results in persistent or significant disability.”

Maryann Napoli, Center for Medical Consumers ©

Controversy over U.S. Cholesterol-Treatment Guidelines

On July 12, 2004, the U.S. National Cholesterol Education Program updated its statin-treatment guidelines, greatly expanding the pool of candidates for statin drugs. They include men and women without heart disease but who have a moderately high risk of developing it, plus low-density lipoprotein (LDL) levels between 100 and 129 mg/dL; and those with heart disease and LDL levels between 70 and 100 mg/dL. The new recommendations are applied to men and women regardless of age. Overnight, millions more Americans became eligible for life-long statin therapy.

Within days of the announcement, two reporters at Newsday revealed that eight of the nine physicians on the committee that established the new guidelines had strong financial ties to companies that make statin drugs.

Two months later an open letter went to the media and the heads of the National Institutes of Health (NIH) and its division, the National Cholesterol Education Program, calling for the creation of an independent review panel free of conflicts of interest to conduct another review of all the new data from the five studies that led to the updated recommendations. The letter was written by Merrill Goozner of the Center for Science in the Public Interest and signed by 36 physicians, researchers, scientists, and politicians.

The letter charged that the expanded guidelines do not reflect the evidence. Among the objections: the evidence does not support the broad use of statins in women (including those at “moderately high risk”) and people over 70 without heart disease. And there is conflicting evidence about the value of statins to people with diabetes. Additionally, the letter asked whether the lower levels of LDL are justified by the scientific evidence.

A point-by-point response came in a letter from Barbara Alving, MD, NIH acting director, which is also available on the NCEP Web site. A new panel will be formed when results of the ongoing trials are available and the guidelines require another update, wrote Dr.Alving, and future guidelines will be posted in draft form on the National Heart, Lung, and Blood Institute Web site, along with “financial disclosure information.”

Maryann Napoli, Center for Medical Consumers ©

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Do Cholesterol-Lowering Drugs Benefit Women?

Posted by medconsumers on June 1, 2004

Many doctors have come to believe that the cholesterol-lowering drugs called statins (Lipitor, Zocor, Pravachol, Mevacor, Crestor) are safer than low-dose daily aspirin. That becomes apparent whenever statins are featured in the media as a wonder drug for the prevention of heart disease. In fact, there’s a growing consensus among cardiologists that all adults should take a statin whether or not they are at high risk.

Yet women have been underrepresented in the major clinical trials in which people with and without heart disease were randomly assigned to take a statin or a placebo (dummy pill) every day for several years. Women made up less than one-third of all the study participants. Put that together with the fact that women under the age of 75 years have a low rate of heart attack and stroke. Add this disturbing bit of news from University of British Columbia researchers who conducted a thorough review of the five prevention clinical trials: only two of the five trials released their data regarding the serious adverse effects* suffered by the study participants who were taking statins. Working with what they had, that is, the data from only two of the statin trials, the researchers found that statins did not prolong life for men or women. Worse, the benefit of taking statins (a reduced rate of non-fatal heart attacks and stroke) was offset by an increase in the serious adverse events. Until all the statin trials release their serious adverse effects data, the public will not know whether these drugs are safer than low-dose aspirin.

The sparse information that people receive about cholesterol treatment was unintentionally but aptly illustrated recently by one of the country’s top medical journals. The Journal of the American Medical Association, or JAMA, regularly publishes a “patient page,” which amounts to a layman’s translation of one of the more important papers published in each issue.

The May 12, 2004 issue of JAMA contained a review of all trials in which women with high cholesterol had been randomly assigned to take a drug or a placebo. (Most of the trials involved a statin.) Judith M.E. Walsh, MD, MPH, and Michael Pignone , MD, MPH conducted the review. Their conclusion: For women without heart disease, drugs did not prolong life or reduce the odds of dying of heart disease. The drug may reduce non-fatal cardiac events (heart attack, stroke, etc.), but “current evidence is insufficient to determine this conclusively.” For women with heart disease, drugs do not affect mortality but will reduce non-fatal events.

Turn to the patient page in the same issue of JAMA, and none of this important information can be found. Instead, six sentences are devoted to statins explaining how they work; the need for regular lab tests to check for statin-induced liver damage; the possibility of muscle damage, etc. The reader will find nothing about the drugs’ effectiveness (or ineffectiveness) in preventing or treating heart disease. The rest of the page was given over to the usual information about exercise and smoking cessation. Worse, it has outdated information about the importance of a low-fat diet; despite the fact that a review of all relevant studies found that it has little effect on heart disease prevention (see below). The patient page is intended for physicians to photocopy and give to their patients.

And what about the unreported serious adverse effects of statin drugs? Not a mention in the patient page, of course, but there it was in the “comments” section of the JAMA article. At the end of their review, Drs. Walsh and Pignone discuss possible explanations for why statins do not prolong life for women with heart disease. The drugs reduce the odds of dying of heart disease, but that benefit is canceled by a higher rate of death from other causes.

“Possible explanations include chance, the limitation that not all studies reported both heart disease and total mortality… Another potential explanation might be an increase in a competing cause of mortality, for example, an increase in hemorrhagic stroke with cholesterol-lowering therapy. However, information on the causes of non-heart disease mortality is not available for all the trials, so this possibility cannot be proven. [emphasis added] Publication of cause-specific mortality for many of the larger trials could help to clarify the association between cholesterol-lowering therapy and total mortality.”

There you have it, the full story is not yet available on the safety of cholesterol-lowering drugs, though these trials were published years ago. Traditionally, researchers design trials to answer specific questions. In this case: Does this drug reduce the rate of heart attacks and strokes or the rate of cardiovascular death? But the drug itself might cause deaths from other causes, and as Drs. Walsh and Pignone wrote, not all studies reported deaths from other causes. These concerns are relevant to men, as well.

As for the doctors who say that statins are safer than aspirin, they might one day be proven correct. But it took more than 100 years to get the full story on aspirin. (In fact, there might be more to learn.) Gastrointestinal bleeding and rarely, hemorrhagic stroke are both potentially fatal side effects of chronic use of aspirin, even at low doses. And the dangers of giving aspirin to children who have flu or chicken pox have only been known to be associated with the rare risk of Reye’s syndrome for less than 30 years.

For More Information:

- Go to the Web site, sponsored by the above-mentioned University of British Columbia researchers (www.ti.ubc.ca). In the archives, locate Therapeutics Letter No. 48 “Do statins have a role in primary prevention?

- Go to the archives of the British Medical Journal at www.bmj.com for the review of all studies assessing the heart disease prevention benefit of reduced dietary fat intake. Find the March 31, 2001 issue featuring “Dietary fat intake and prevention of cardiovascular disease: systematic review” by Lee Hooper et al.

*Serious adverse effects are any untoward medical occurrences that result in death, are life threatening, require hospitalization or prolongation of hospitalization, or results in persistent or significant liability.

Maryann Napoli, Center for Medical Consumers (C)
June 2004

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Cardiologists Poised to Give Everyone Lipitor

Posted by medconsumers on April 1, 2004

The findings were considered to be so important that The New England Journal of Medicine made the study freely available on its Web site one month earlier than the April 8 publication date. Two cholesterol-lowering statin drugs—Lipitor (atorvastatin) and Pravachol (pravastatin)—were compared in a clinical trial that involved 4,162 people who had been hospitalized for a sudden attack of chest pain due to heart disease. Lipitor proved to be more effective at reducing the rate of deaths from heart disease, heart-related problems and the need for procedures, such as bypass surgery and angioplasty. Once the news caught media attention, the reporting made the benefit appear larger than it is.

Some of the participants, all of whom had heart disease and low levels of LDL, the so-called bad cholesterol, benefited from even further reductions in their LDL with Lipitor. The finding is widely expected to lead to a lowering of what constitutes the ideal level of LDL. Currently, people are told to keep their LDL below 100 mg.

The participants had been randomly assigned to take either a higher than normal dose of Lipitor (80 mg) or the standard 40 mg dose of Pravachol each day. Because of the high stakes, drug companies rarely pit their drug against a competitor in a clinical trial. Bristol-Myers Squibb, maker of Pravachol, lost big time by sponsoring this trial. It was designed to prove that Pravachol, which had been losing market share, is just as good as the more costly high dose Lipitor.

At the time this trial was planned, Pravachol’s highest dose was 40 mg. The study is known by the catchy name of Prove It, or Pravastatin or Atorvastatin Evaluation and Infection Therapy.

Here are the differences in outcomes in the Prove It trial: After two years, the people on Pravachol had a combined rate of heart attack, bypass surgery, angioplasty, stroke and death of 26.3% compared with 22.4% for people on Lipitor. The death rate from heart disease was 1.1% for the Lipitor group compared to 1.4% for the Pravachol group. The rate of death from any cause was 2.2% for people on Lipitor and 3.2% for people on Pravachol.

These 1- 3% differences in favor of Lipitor have cardiologists across the country quite excited and ready to raise the statin dose and lower the threshold for safe LDL levels. The Prove It results would be exciting if we had the full picture on high-dose Lipitor. As is often the case, the serious adverse effects experienced by the study participants taking Lipitor were not reported.

Christopher P. Cannon, MD, who led the Prove It trial, was asked about this information gap. “We do plan a separate full publication of all the safety data soon…the journal only allows a certain amount of space for only one paper,” he responded by e-mail. “There were more liver function test abnormalities with Lipitor at 80 mg, but these were all transient and were resolved when the dose was stopped or reduced.” Still, adverse reactions caused nearly one out of every three participants to stop the drug. 3% more people in the Lipitor group stopped taking the drug. Besides liver failure, muscle pain is a known consequence of high-dose statin therapy.

Dr. Cannon said that his study found Lipitor to be better than Pravachol for both men and women, though women represented only 22% of the participants (911). The above-quoted statistics apply to all participants, and the researcher did not break things down to show how large the benefits are to women, or whether they have a higher rate of serious adverse reactions.

90% of participants were white and the rest were not specified. This leaves an information gap for everyone else. Earlier studies have shown that Asians, for example, are at a higher risk for severe muscle damage if they take any statin at daily doses of 80 mg. For unknown reasons, the drug tends to remain in the body longer in Asians, which raises their odds of this and other adverse effects. Dr. Cannon and colleagues suggest that their findings point to the need for 62 mg as the new LDL threshold for people with “established coronary heart disease.”

Judging from the media reports of Prove It trial, many cardiologists seem poised to extend its results to people without heart disease. None of the physicians quoted in the media warned that this would amount to a dangerous experiment. In all the previous clinical trials that involved people without heart disease, statin drugs were administered in doses no higher than 40 mg. Only one prevention trial involved people taking Lipitor. None lasted more than seven years.

Interestingly, the new results have revived an old controversy about whether the benefits of statins are due to their cholesterol lowering, anti-inflammatory or some other effects. “Unfortunately, we do not know the precise mechanism of action responsible for atorvastatin’s [Lipitor's] superiority,” wrote Eric J. Topol, MD, of the Cleveland Clinic in an accompanying editorial. Dr. Topol believes that “only a fraction of the patients who should be treated with a statin are actually receiving such therapy.” He sees cost as the biggest stumbling block. Lipitor, at the recommended starting dose of 10 mg, is about $900 per year. At the 80-mg dose used in the Prove It trial, Lipitor costs about $1,400 per year.

What you can do
Here are several non-drug ways to reduce your odds of having a heart attack.

  • Cut trans fatty acids from your diet because they have long been known to be damaging to the heart. Trans fatty acids are formed during the hydrogenation of either vegetable or fish oils. They are used extensively in processed foods to ensure a longer shelf life. Certain foods like donuts, potato chips and other snack foods are particularly high in trans fatty acids. Look for the words “partially hydrogenated oil” or “shortening” on the ingredients list.
  • Take niacin supplements. The Coronary Drug Project followed 3,908 men taking a placebo or niacin therapy for nine years. The niacin group had a lower rate of non-fatal heart attacks and an 11% lower rate of all-cause mortality than the men in the placebo group. A recent survey of the various types of niacin on the market found that immediate-release niacin is the least expensive and safest version to purchase (and the no-flush niacin products are useless, see HealthFacts January 2004).
  • Add heart healthy foods with omega-3 fatty acids and folic acid to your diet. Omega-3 fats can be found in fish, omega-3-enriched eggs, walnuts and flax seeds. Folic acid is in green vegetables, beans, wheat germ and certain fruits and vegetables.

Maryann Napoli, April 2004

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Statins Drugs: How Safe? How Effective?

Posted by medconsumers on November 1, 2003

(Almost) Everything You Need to Know About Statin Drugs

Though the first of the statins went on the market over 17 years ago, they unofficially reached miracle drug status last summer when these cholesterol-lowering medicines made the front cover of Newsweek. The magazine’s breathless coverage started with the inevitable anecdote about a middle-aged man who was unable to lower his total cholesterol level of 290 through diet and exercise alone.

Six months of trying, and his level dropped a mere 27 points, so his doctor put him on “one of the class of powerful cholesterol-lowering drugs,” Lipitor. “He knows he should try harder to eat right,” continued the Newsweek article, “but he also knows he doesn’t have to worry about cholesterol as long as he takes that little pill every day. ‘It’s better living through chemistry,’ he says. Or perhaps more to the point, longer living.”

Well, that just about sums up the current rosy view of statins. It is also indicative of the unrealistically optimistic, one-sided information consumers get about these drugs from their doctors, the media and drug industry advertising. Too often, people get little more than this from their doctors: “Your cholesterol is too high, take this drug.” Or, if pressed for more information, a doctor might say: “Take this drug, it will reduce your chances of dying from a heart attack.”

Statins are intended as a lifelong treatment. Any drug taken by a healthy person every day for the rest of his or her life should be backed with clear evidence from carefully conducted studies that the benefits outweigh the risks. Such studies should have included people just like you, be they older women whose only risk factor is high cholesterol or middle-aged men with high cholesterol and several other risk factors for heart disease.

A Critical Look is Needed
This article will address such questions as: Are statins safe and effective for everyone? What exactly have they been proven to do? Will they increase longevity, as the Newsweek article implies? It will also describe a new analysis of all statin studies, which contradicts the prevailing belief that these drugs are of great preventive benefit to most older people. You will learn that the case for statin therapy is stronger for people with heart disease and/or diabetes than it is for healthy people with high cholesterol and another risk factor or two.

When statins were first introduced, they were prescribed primarily to people with heart disease. In time, they became an appropriate prescription for all older people. Lest you think that’s an exaggeration, recall the news out of England in the summer of 2003, when a respected team of researchers proposed the “ polypill ” for all adults over the age of 55, with a statin as one of six chosen lifesaving components (along with aspirin, folic acid, and three anti-hypertensive drugs at half dose).

The polypill might not have caught on yet, but the idea that just about every middle-aged and older person is a candidate for statin therapy certainly has. In fact, you needn’t have high cholesterol to get a prescription. And for older women, statins have begun to replace postmenopausal hormones as the drug of choice to prevent heart disease.

Advertised Widely
One can hardly make it through the TV evening news without viewing at least one statin ad, usually conveying the idea that diet and exercise are not enough to lower cholesterol in most people. (True enough, but more on that later.) The most egregious statin ad, however, is Pfizer’s campaign in Canada where, ironically, it is against the law to advertise prescription drugs to consumers.

Pfizer Canada gets around the law by not mentioning the name of its drug (a familiar tactic used in the U.S. to circumvent the mandated requirement of describing side effects). In what is known as a “heart disease awareness” ad, Canadians are encouraged to ask their doctors for a cholesterol test. The ad shows the bare feet of a corpse on a morgue drawer with a toe tag that reads: Male, age 42; cause of death: heart attack. The ad’s headline: “What would you rather have, a cholesterol test or a final exam?”

Six statin drugs are now available: atorvastatin (Lipitor), fluvastatin (Lescol), lovastatin (Mevacor), pravastatin (Pravachol), rosuvastatin (Crestor) and simvastatin (Zocor). Altogether statins drive a $20 billion a year world-wide market, with Lipitor No. 1– of all prescription drugs–in retail sales in the U.S. No head-to-head comparison has ever been conducted to determine whether one is superior to the others.

Statins are widely regarded as safe, and perhaps the safest of all cholesterol-lowering drugs, though no one has done a study comparing them against their older counterparts. The acknowledged side effects of statins include muscle pain and weakness, suppression of the body’s formation of Co-enzyme Q10 and, rarely, a potentially fatal muscle-wasting disorder called rhabdomyolysis. One statin, Baycol, has been withdrawn because it was linked to 31 deaths from rhabdomyolysis. The other statins still pose a rare risk for this disorder, especially at doses of 80 mg/daily. Another rare side effect is peripheral neuropathy, which is nerve damage that causes numbness or tingling in the hands and feet. Chief among the unacknowledged side effects are memory loss and other cognitive problems, which have been reported anecdotally by people who were not in clinical trials.

There is a controversy among researchers over the very real possibility that the benefit of statins has less to do with cholesterol reduction than the drugs’ other biochemical effects, most notably anti-inflammatory properties. Atherosclerosis is thought to be due to an inflammatory response to arterial injury–an injury caused by high blood pressure, smoking or other risk factors.

Cholesterol as a Disease:
To understand today’s obsession with cholesterol, it helps to have a little background regarding this particular risk factor and how it came to be treated as if it were a disease. High blood levels of cholesterol emerged as a risk factor for heart disease in the Framingham Heart Study, whose results have been misrepresented, according to some researchers. Begun in 1948, it followed 5,000 healthy men and women living in Framingham, Massachusetts, to determine which factors distinguished those who eventually suffered a heart attack.

Cholesterol was identified as one, but only one of 240 risk factors that included short stature, male baldness, creased ear lobes, and being married to a highly educated woman. Research focused on cholesterol because it is a modifiable risk factor (translation: drug industry opportunity). Though the Framingham Study found a strong association between blood levels of cholesterol and heart disease only in young and middle-aged men, the entire population was, in time, instructed to fear this particular risk factor.

Contrary to conventional medical wisdom, the Framingham study did not find that a high-fat diet doomed people to a heart attack. A subgroup of Framingham participants was assessed for their intake of saturated fats, dietary cholesterol and overall calories. None had any effect on the development of heart disease.

The idea that a low-fat diet prevents heart disease lives on, despite a 2001 review of all relevant clinical trials. The combined results showed that reducing or modifying dietary fat intake had no effect on heart disease mortality or total mortality (Hooper et al. British Medical Journal, 3/31/01).

However, modest reductions in non-fatal cardiovascular “events” (e.g., strokes, heart attacks) were shown in the few trials in which the participants remained on the diet for more than two years.

Several books have been written about the overrated importance of cholesterol (both dietary and blood levels) in the development of heart disease, most notably Heart Failure (1989) by Thomas J. Moore, The Cholesterol Myths (2000) by Uffe Ravnskov , MD, PhD, and Tales from the Other Drug Wars (1999: Chapter on Lipid-Lowering Drugs by Isabelle Savoie www.chspr.ubc.ca/misc/drugwars2.pdf) Such skeptics are usually fond of pointing out that half of all heart attacks occur in people who have normal cholesterol levels.

Lifestyle Changes Often have Small Effect
Once a person’s blood test shows high cholesterol, a low-fat diet is recommended, along with the admonition to get regular exercise. Most people will find that these two lifestyle changes bring only minimal reductions in cholesterol, making statin therapy the inevitable next step.

Given the emphasis on cholesterol “numbers,” it is easy to lose sight of the fact that the ultimate goal of drug therapy is not to lower cholesterol but to reduce the odds of dying of a heart attack or stroke. A pharmaceutical company seeking approval from the FDA, however, need only prove its drug can lower cholesterol. The more important, long-term studies are initiated many years later.

When researchers began conducting clinical trials to prove that lowering cholesterol will prevent cardiac deaths, they ran into some major snags over the course of several decades. Despite millions of dollars spent on clinical trials, researchers simply could not prove that lowering people’s cholesterol had any effect on life expectancy. Whether the study participants lowered their cholesterol with diet, exercise, smoking cessation, and/or drugs, the heart disease death rate went down but the over-all death rate, that is, the death rate from all causes, went up. In other words, their total death rate was no different from that of the people who did not lower their cholesterol.

Statins are Different…or are They?
Proof that statin drugs can benefit people without heart disease comes from five clinical trials in which the participants had been randomly assigned to take a statin or a placebo daily. Altogether about 40,000 healthy but high-risk people, aged 55 to 82 years, participated in these clinical trials, with the statin doses ranging from 10 mg to 40 mg a day. Participants were primarily males with high cholesterol and other risk factors, such as smoking and angina (chest pain caused by constrictions in the coronary arteries). In one trial, the men and women had either normal or borderline levels of cholesterol. Several reviews of the five clinical trials came to the conclusion that statins can reduce the rate of non-fatal heart attacks and strokes. The drugs also reduce cardiovascular mortality, but they did not reduce all-overall mortality.

Conveying the Benefit to the Public:
Interestingly, the Newsweek article devoted only one sentence to the critical question of what has been proven regarding statins. Without further explanation, the article says a large study “showed that cholesterol-lowering drugs reduced the risk of heart attack and stroke by at least one quarter for those at highest risk.” While this is roughly accurate, it appears more impressive than the reality. The one-quarter reduction refers to the difference in the rate of heart attack between the study participants taking statins and those on the placebo.

What makes the statistic misleading is the fact that healthy people–even those with high cholesterol–have a low risk of having a heart attack to begin with. And reducing their odds of having a heart attack by one-fourth simply means that 3% of the statin-treated study participants had a heart attack or stroke, as compared to 4% of the untreated participants (the placebo group). Or put another way: There were 1% fewer statin-treated people had heart attacks. The studies lasted only about five years so these statistics apply to taking the drug only for that length of time. (See Web sites listed at the end of this article for help in understanding risk assessment.)

It is not unusual for reviewers to look at the same trials and come to different conclusions about what has been proven. This is what happened when a Canadian team of researchers conducted its own review of the five statin trials. This new analysis took issue with the generally agreed upon conclusion that these five trials proved that the benefit of statins far outweigh the risks.

The New Analysis:
The analysis of the five trials was conducted by a team of researchers at the University of British Columbia led by James M. Wright, PhD, who came to the alarming conclusion that statins harm as many people as they help. True, the combined results of the five trials did, in fact, show a lower rate of non-fatal heart attack and stroke. However, once serious adverse events* were taken into account, the results were not so positive. The statin users did have 1.4% lower rate of heart attack within the next five years, compared with untreated people, but that small benefit was offset by a 1.8% rate of serious adverse events associated with the drug.

Dr. Wright and colleagues might be the first reviewers to step back and look at the big picture–assessing the serious risks as well as the benefits of statins. Only two of the five trials reported serious adverse events. “Based on the two trials, we are suspicious that some serious adverse events are being increased by statins and that this appears to be canceling the benefit of the reduction in heart attacks and strokes,” Dr. Wright wrote in an e-mail interview. The new analysis was published in the April-June 2003 issue of Therapeutics Initiative, an evidence-based drug therapy newsletter (“Do Statins Have a Role in Primary Prevention?” Available free at www.ti.ubc.ca).

Dr. Wright is associated with the Cochrane Collaboration, an international network of experts who conduct systematic reviews of the supporting evidence for drugs and other medical, surgical or behavioral interventions. In a move that distinguishes many Cochrane reviewers, Dr. Wright and his colleagues at the University of British Columbia contacted the authors of the three trials that did not publish the number of serious adverse events suffered by their study participants. The reviewers have yet to receive the requested data.

Yet to be Proved for Women:
In the e-mail interview, Dr. Wright was asked about statins’ proven benefit specifically to women–something omitted from the analysis as it appeared in Therapeutics Initiative. To answer this question, Dr. Wright did a separate analysis of women who participated in four of the five primary prevention trials, emphasizing that they made up only 28% of all the study participants. “Combined results of all trials do not support the use of statins by women without heart disease,” concluded Dr. Wright. This is explained by the fact that women were not only underrepresented in the trials, but also, as a group, have a very low risk of having a heart attack in a five-year period.

The University of British Columbia researchers are not the first to notice that the benefit of statin therapy to women remains an open question. High cholesterol has never been proven to be an important risk factor for women. At every stage of life, women tend to have higher blood levels of cholesterol than men of the same age; yet they are about 15 years older then men at the age of a first heart attack.

Statins have begun to replace postmenopausal hormones as the all-purpose drug to prescribe to healthy older women whose only risk factor is high cholesterol. It is noteworthy that many of the additional benefits claimed for statins–beyond cholesterol reduction–are similar to those made prematurely for estrogen. For example, some women are told that statins will also reduce their risk of Alzheimer’s disease and osteoporosis. The latter has been disproved, and the former comes only from preliminary studies.

More cases of breast cancer have shown up among statin users in three trials. In all three, the finding was described as “not statistically significant.” One trial involving people with heart disease who either took a placebo or 40 mg of Pravachol daily found that breast cancer developed in 12 out of 286 women taking the drug, compared to one out of 290 on the placebo.

People over 70
Whether high cholesterol is a problem for elderly people has been the subject of a long-running controversy. So has the question of whether cholesterol-lowering drugs can provide any benefit to this age group. The controversy was theoretically settled by a large multi-center European trial published in 2002 when The Lancet published a major trial, known by the acronym PROSPER. It showed that statins lowered the incidence of coronary events but had no effect on longevity. The PROSPER trial, however, lasted only three years.

The participants, aged 70-82 years either had heart disease (44%) or had risk factors for heart disease (56%). The PROSPER results showed an ominous increase in the frequency of new cancer diagnoses in the people taking Pravachol, which was dismissed as a “chance finding” by the authors. In response to the PROSPER trial three of five letters to the editor of The Lancet took issue with the description of “chance finding.” One letter noted that the cancer incidence over three years was 6.8% in the placebo group and 8.5% in the people taking Pravachol.

Another letter to the editor expressed concern that the PROSPER will encourage the use of statins in elderly people: “Surely one relevant statistic is that by treating 5,804 high-risk patients with pravastatin [Pravachol] or a placebo, the overall death rate [sic] was reduced from 306 to 298 over three years. This was achieved at what cost to the perception of good health, comfort, or anxiety among the participants?” wrote Peter J. Little of New Zealand (Lancet, 2/1/03). Such critics recently gained support from the new analysis by the University of British Columbia researchers who concluded that the cardiovascular benefit shown in the PROSPER trial was offset by serious risks.

Reaction to the New Analysis
The new analysis met with criticism from cardiologists in Canada, but it has been largely ignored in the U.S. The criticism centers on the fact that the University of British Columbia research team came to entirely different conclusions about statins than virtually all other medical organizations that have reviewed the same studies. In a recent article for the Toronto Globe & Mail, Dr. Ruth McPherson dismissed the research team because it did not include specialists in cholesterol metabolism and treatment. Furthermore, the findings were published in Therapeutics Initiative (TI) which “does not have the status of a peer-reviewed journal.”

TI, which is based at the University of British Columbia, is a newsletter that is peer-reviewed, according to its Web site, by family physicians, specialists, academic researchers, pharmacologists, pharmacists and epidemiologists. TI is funded by the Canadian Government to help doctors make evidence-based treatment choices. The average practicing physician does not have the time to pick through each statin trial to determine, say, whether women are represented in large enough numbers, or whether the odds of being harmed by a drug are equal to its odds of a benefit.

People with Heart Disease or Diabetes
Statins clearly benefit diabetics and people with heart disease who want to avoid a heart attack or stroke, as well as those who have already suffered one and want to prevent another. Such people are more likely to benefit from statin therapy because their odds of having a heart attack or stroke are so high. Pravachol and Zocor are the best assessed statins for people who have diabetes and/or heart disease. Altogether more than 35,000 people who fit this profile took part in trials that compared a statin with a placebo.

The most recently published large trial was conducted in the United Kingdom; 25% of the participants were women and 46% were over age 65 years. All had been randomly assigned to take Zocor or a placebo for five years. Results showed that the participants who took Zocor decreased their odds of overall mortality by 1.8% in the next five years, compared to those who were untreated (placebo group). Coronary deaths were reduced by 1.2% among statin users within five years. The reductions were higher for people who have already had a heart attack or angina and for diabetics. Contrary to expectations, Zocor showed no beneficial effect on fractures or dementia. As for the cancer-related concerns, Zocor did not alter the overall incidence of cancer ( Prescrire International, 8/03). No separate analysis has been done for women.

As for the importance of reducing fat intake, this particular lifestyle change has more relevance to people who have heart disease than it does to healthy people. Combined results of seven clinical trials involving participants with heart disease showed that dietary changes provided a 6.6% lower incidence of heart attacks and/or cardiovascular deaths than those who did not reduce fat intake.

Web Sites for Understanding Risk

www.besttreatments.org/risk This Web site in the United Kingdom helps you understand percentages as in: Take aspirin daily because studies show your risk of heart attack will be halved. Here’s another way to present the same thing: 2% of people like you will have a heart attack in the next ten years, compared to 1% of those who took aspirin daily. Examples, such as this one, are given to help you question your doctor whenever percentages are quoted in relation to a proposed medical treatment. To understand what “halve your risk of heart attack” means, one would have to know his or her risk of having a heart attack without taking the drug.

www.icru.no/hippo/cholesterol As the above example shows, people can make different decisions according to how the information is presented. This Web site in Norway consists of a quiz developed by researchers who are exploring different ways to communicate risk information to consumers. You can contribute (and become better informed about risk assessment) by taking the quiz which involves the decision whether or not to take a cholesterol-lowering drug.

hin.nhlbi.nih.gov/atpiii/calculator.asp The U.S. National Cholesterol Education Program offers this quick quiz for assessing your odds of having a heart attack in the next ten years. Unfortunately, the calculation is too brief, leaving out such important cardiovascular risk factors as diabetes and family history of early heart attacks.

Maryann Napoli is the associate director of the Center for Medical Consumers in New York City.
November 2003.

*Serious adverse events includes “any medical occurrence that results in death, is life-threatening, requires hospitalization or prolongation of hospitalization, or results in persistent or significant liability.”

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C-Reactive Protein Testing For Heart Disease

Posted by medconsumers on December 22, 2002

Should You Be Tested For C-Reactive Protein?
By Maryann Napoli

The revised view of heart disease got a boost recently. Over the last ten years, a research case has been building for the possibility that chronic inflammation within the coronary artery walls plays a strong role in the development of heart disease. This hypothesis received some support from a new study showing that inflammation is a better predictor of who will have a heart attack than high cholesterol (The New England Journal of Medicine, 11/14/02). Nearly 28,000 healthy women were tested and followed for eight years; those whose blood tests showed high levels of C-reactive protein (CRP), an indicator of inflammation, were twice as likely to have a heart attack or a stroke as the women with high levels of LDL cholesterol, also known as the “bad cholesterol.” Similar findings are showing up in an ongoing study of 22,000 men.

Media reporting of this study generally gave the impression that many doctors did not think people should seek CRP testing, though it is readily available. And the leading guidelines-setting organizations like the American Heart Association have yet to take an official position about whether the CRP test should become part of the standard battery of tests routinely administered to all adults. But a New York Times editorial was downright enthusiastic, “The test could be a boon, if not for every American then at least for all those whose weight, age, smoking or other factors make them wonder about their cardiovascular prospects.”

It would be premature to start screening all adults for CRP, according to Lori Mosca, MD, who is the Director of Preventive Cardiology at New York Presbyterian Hospital. “We don’t yet know how to use this information, even though we do know that statistically CRP has been shown to predict cardiovascular events-just like 300 other risk markers for heart disease.” Dr. Mosca wrote the editorial that accompanied the new study, entitled, C-Reactive Protein-to Screen or Not to Screen? “People are calling my office to ask, ‘should I have a stress test or an angiogram’ because their CRP is elevated. I think there’s a real risk that this information is going to be misused,” she warned in a telephone interview. “And until science can figure what to do with the information, I think that screening every American is not appropriate at this point.” What’s more, gingivitis, bronchitis and many other possibilities can raise CRP levels.

That view was seconded by David Atkins, MD, chief medical officer at the Center for Practice and Technology Assessment at the U.S. Agency for Heathcare Research & Quality. To Dr. Atkins, the known major risk factors for heart disease-high blood pressure, diabetes, smoking, being overweight or obese, high LDL, and a sedentary lifestyle-already allow doctors to do a good job at identifying the people who should be treated with drugs. “Taken together these risk factors can probably catch the large majority [of people headed for] heart attacks,” said Dr. Atkins in a telephone interview.

After doing a call-in show for National Public Radio, Dr. Mosca worried that people got the wrong impression from news reports. “Consumers might misinterpret this new study to mean that LDL cholesterol is not important because it has been shown statistically that CRP is a little bit better predictor,” she said. “Well, we can say the same thing about hundreds of other risk factors. But LDL reduction has been shown to reduce death and disability, and CRP reduction has not.”

But half of all heart attacks occur in people with normal cholesterol levels-doesn’t that suggest high cholesterol isn’t such an important risk factor? “The reason why so many people with heart disease have so-called normal cholesterol levels is that normal is too high in the U.S.,” answered Dr. Mosca. “If our LDLs were cut in half [to the level] they are in Asia, we wouldn’t have so much heart disease,” she emphasized. “There is virtually no heart disease in countries where the total cholesterol is less than 150.”

The point that cholesterol levels shouldn’t be viewed in isolation was underscored by Dr. Atkins. “People hear that half of all heart attacks occur in people with normal cholesterol levels and think ‘that could be me,’ but the reality is that many of those people have diabetes, they smoke, or have hypertension,” he explained. “Only a very small percentage of heart attacks occur in people who don’t have multiple cardiac risk factors.” Dr. Atkins is concerned that most doctors still focus too narrowly on elevated cholesterol levels, when they should step back and look at the big picture-that is, the full range of major established risk factors for heart disease-and then target the intensity of the therapy accordingly.

Statins are the cholesterol-lowering drugs of choice. Lipitor and Zocor, the two top-selling statins, accounted for $4.5 billion and $2.7 billion in retail sales, respectively, in 2001 and the largest increase in prescription drug sales for that year. Low-dose aspirin therapy is another, far less expensive, standard drug recommended for heart attack prevention. There’s pretty good evidence that both drugs are effective even in people without high cholesterol, explained Dr. Atkins. Aspirin’s anti-inflammatory effect may account-at least, in part-for its success as a heart attack preventive, and statins have an anti-inflammatory effect as well as a cholesterol-lowering effect.

Learning that a person has elevated CRP levels isn’t-in most cases-going to change the treatment plan once a doctor assesses the patient’s other risk factors. “If the person is at low risk, it is unlikely that the CRP results will change our recommendations to the patient, we would still recommend exercise, maintaining weight, avoiding smoking, eating well, etc.,” said Dr. Mosca.

“For the very high-risk individual, that is, the person with heart disease, we already know they should be on statin and aspirin therapy, unless it’s contraindicated,” she continued. “For the middle-risk individual, the decision to test should rest on whether or not the treatment is going to be altered by the results,” she continued. “I’ve certainly screened some patients for CRP when I’m on the border for using certain kinds of therapy–after I have got them as good as I can in terms of lifestyle.”

Dr. Mosca said that after the New England Journal of Medicine published her editorial advising against routinely screening all adults for CRP, she received many congratulatory calls and e-mails from cardiologists around the country. All are concerned that CRP testing will be used routinely before research proves its worth.

“Look at hormone therapy,” said Dr. Mosca, referring to the trial that was stopped last summer because the combination of estrogen and progestin was deleterious to the health of older women. “Hormones became the standard of care for the prevention of heart disease, and when the clinical trial showed that the drugs not only didn’t prevent heart disease but caused heart disease in some women, we still have doctors who refuse to believe the information. We need to wait for the clinical trials before we make general public health recommendations to screen every American.”

(December 2002)

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