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 ©