Overdosed America (23 page)

Most should. Clearly, the people with the highest risk of heart attack are those who already have CHD. This is the situation in which statins are most helpful (called secondary prevention). The results of three large randomized controlled studies of statin drugs in secondary prevention were incorporated into the 2001 guidelines: the
4S
study of Zocor, and the CARE and
LIPID
studies of Pravachol. The primary difference among them is the
average LDL cholesterol levels
of the people in the studies.

In the
4S
and
LIPID
studies, LDL cholesterol levels averaged 188 and 150 mg/dL, respectively. In both of these studies, treatment with a statin significantly reduced the risk of another heart attack, the risk of dying of coronary heart disease, and the overall mortality rate. In the
CARE
study, LDL cholesterol levels averaged 139 mg/dL—very close to the average for people who develop coronary heart disease (140 mg/dL)—and the results were not quite as impressive: there was a significant decrease in the risk of heart disease but no significant reduction in the risk of death from heart disease or the overall risk of death.

Just how many heart attacks are prevented by treating people who already have heart disease with a statin drug? In the
CARE
and
LIPID
studies, the reduction in fatal and nonfatal heart attacks in the people treated with Pravachol was 0.6 percent each year. This means that 166 people need to be treated for a full year to prevent one heart attack. If my patient is that 1 out of 166, I certainly want him or her to be taking a statin; yet given all the media hype about statin drugs, it is easy to be misled into believing that statins will help everybody or almost everybody who has already had a heart attack.

The guidelines refer to the three major clinical trials of secondary prevention to support the statement that statin therapy effectively reduces the risk of recurrent CHD in women. The
4S
study shows that treatment with a statin does decrease the risk of recurrent CHD for women but does not decrease the risk of death from CHD. Furthermore, the overall death rate was actually 12 percent
higher
in the women who took the statins compared with the women who took the placebo (not statistically significant). The
CARE
study similarly showed that statins significantly reduce the risk of recurrent heart attack, but not the risk of death from coronary heart disease in women, and not the risk of death from all causes in the study population as a whole. The
LIPID
study failed to show a significant reduction in the risk of recurrent CHD in women and did not present mortality data for women. At best, these studies show that statins probably lower the risk of recurrent CHD in women with coronary heart disease, but do not appear to lower their overall mortality rate.

Wouldn’t it be interesting to be able to test the recommendations of the 2001 cholesterol guidelines against the older standard of care to see how much benefit would actually result from tripling the number of Americans taking statins? Of course this would be completely impractical, requiring another large, costly, many-year clinical trial. Even more of an obstacle is the fact that such a study would be highly unethical—volunteers assigned to receive treatment according to the old standards would receive therapy that was less than the best medical care currently being recommended.

In a remarkable coincidence, the findings of almost exactly such a study were published in JAMA about a year and a half after the 2001 guidelines were released.
The ALLHAT study
had been designed in the early 1990s in a way that fortuitously turned out to be a good test of the expanded use of statin drugs recommended in the 2001 guidelines.

Starting in 1994, the ALLHAT study enrolled more than
10,000 patients at high risk
of coronary heart disease—equal numbers of men and women age 55 and older whose risk factors for heart disease would have qualified about 90 percent of the men and 75 percent of the women for statin therapy according to the new guidelines. The patients were randomly assigned to take a statin drug (Pravachol) or simply to receive the usual care from their own doctors and let the chips fall where they may with regard to drug therapy. By the end of the study, 83 percent of the group assigned to take Pravachol were still taking a statin and 26 percent of the “usual care” group had been started on cholesterol-lowering therapy by their own doctors—a perfect test to see how much more heart disease could be prevented if the number of Americans being treated with statins were tripled.

The study found that tripling the number of people on statins neither prevented heart disease nor decreased the overall risk of death. There was no benefit to increasing the number of patients taking statins beyond the community norm of the mid-1990s: not for people age 55 to 64 or 65 and older, not for men or women, not for those with or without diabetes, not for those with or without heart disease, and not for those with LDL cholesterol higher or lower than 130 mg/dL. The only group that derived any significant benefit from more statins were African Americans who had fewer episodes of heart disease but no fewer deaths.

These findings should have been major news. Yet the
Wall Street Journal
was the only major newspaper that I could find that carried the story; otherwise there seemed to be a virtual press blackout. Within the medical journals, the study findings were largely rejected by experts on the basis that so many of the people in the usual-care group had been put on statins that the difference in cholesterol levels between the Pravachol and usual-care groups was not enough to show the benefit of statins. But that was
exactly
the point of the study. High-risk patients treated by their own doctors according to the prevailing standards of the mid-1990s were already getting the maximum benefit of statin therapy. Tripling the number of people taking statins—coincidentally, almost exactly in line with the recommendations of the new guidelines—provided no further benefit.

Dr. Richard C. Pasternak, the cardiologist who wrote the editorial that accompanied the publication of the ALLHAT study results in JAMA, concluded,
“Physicians might be tempted
to conclude that this large study demonstrates that statins do not work; however, it is well known that they do.” So much for evidence-based medicine. From my perspective, Pasternak was wrong. The study did not tempt me to think that statins don’t work—it just made me think that tripling the number of people on statins doesn’t provide any additional benefit. Dr. Pasternak was one of the original 14 authors of the 2001 cholesterol guidelines. He declared financial relationships with nine drug companies in the
“financial disclosures”
that accompanied his editorial in JAMA.

Like the ALLHAT study,
the PROSPER study
(Pravastatin in Elderly Individuals at Risk of Vascular Disease), published in
The Lancet
in 2002 also got very little press coverage—no news of breakthroughs or paradigm shifts, though in a negative way it, too, should have contributed to both. The study tested the effect of statin therapy in high-risk elderly patients between the ages of 70 and 82. For those who did not already have heart disease, statin therapy did not reduce their risk of developing heart disease or stroke. It did, however, significantly increase their risk of developing cancer (
p
= .02). This risk increased each year these elderly patients took the statin, so that by the fourth year of the study there was more than 1 extra case of cancer for every 100 people taking a statin
each year
.

The 2001 cholesterol guidelines were reassuring about statins’ not causing cancer: “
There is no evidence
that currently used cholesterol-lowering drugs promote development of cancer.. . .” However, a paper titled
“Carcinogenicity of Lipid-Lowering Drugs,”
published in JAMA in 1996, was apparently overlooked. This paper pointed out that statins cause cancer in laboratory animals at blood levels only three to four times those typically achieved in cholesterol-lowering therapy for people. The authors raised the possibility that increases in the risk of cancer caused by statins
could take many years
to be detected, and therefore would not be evident in the large studies that had been done to date. (The average duration of the studies is about five years, and the average age of patients is less than 60.) We cannot know whether statins will turn out to increase the risk of cancer when used long term, nor can we know from one study whether older people might be particularly susceptible. The one thing we can know is that the denials of the evidence of such a relationship in the 2001 cholesterol guidelines and by the authors of the PROSPER article (sponsored by Bristol-Myers Squibb) suggest that the principle “First do no harm,” which should be fresh in our minds from the increased rate of breast cancer caused by HRT, seems, once again, to have been forgotten.

Also published subsequent to the 2001 guidelines were two randomized controlled clinical trials that supported the guidelines’ target of reducing LDL cholesterol below 100 mg/dL in people who already have heart disease (the Heart Protection Study and the Prove It study). This leaves unanswered the question why some studies show no benefit to cholesterol-lowering in heart patients whose LDL cholesterol level is less than 125 mg/dL, while other studies support the lower target. The only conclusion we can draw about the optimal level of LDL cholesterol in people who already have heart disease is that it is still to be determined.

The disparity between the recommendations of the 2001 guidelines and the subsequent findings of the PROSPER and ALLHAT studies cannot be dismissed as simply due to the normal zigs and zags of science. The findings of these two studies directly contradict the guidelines’ recommendations, but they don’t contradict the best scientific evidence that was available at the time the guidelines were formulated. The guidelines’ interpretation of the scientific evidence stretches credulity beyond reasonable limits to recommend statin therapy for primary prevention of heart disease in women, people over 65, and men with only moderately elevated cholesterol levels. The experts must have believed that future studies would validate their assertions regarding statin therapy, but the results of the studies that came out the following year did just the opposite. Even when the contradictory results were published, the response of many recognized experts in the field seemed to focus more on damage control to protect statin sales than on unbiased evaluation of the scientific evidence.

Why do doctors accept such obvious distortions and commercial intrusions into what ought to be the inviolable standards of medical science and medical care? There are several reasons: Practicing doctors are far too busy to do this kind of research for themselves and, as we have seen, the drug companies play a large role in determining how doctors are “educated” about the new developments in medicine (including all the “good news” about the benefits of statins). Another reason is that significant conflicts of interest have become a normal part of American medicine today.
Dr. Scott Grundy
, the chair of the panel that created the latest cholesterol guidelines, told the
Wall Street Journal,
“You can have the experts involved, or you could have people who are purists and impartial judges, but you don’t have the expertise.” Unfortunately, in American medicine that expertise is now virtually inseparable from financial ties to industry. When asked why a more balanced approach to heart disease prevention gets pushed aside by these guidelines,
Dr. Walter Willett
, professor of epidemiology and nutrition at the Harvard School of Public Health, said, “Drug companies are extremely powerful. They put huge efforts into promoting the benefits of these drugs. It’s easier for everyone to go in this direction. There’s no huge industry promoting smoking cessation or healthy food.”

The ultimate impact of the 2001 cholesterol guidelines is this: competent and caring physicians trying to provide the best possible care for their patients are being misled—and are misleading their patients. As shown in
Chapter 13
, inexpensive, easily accessible, and often more effective interventions to prevent heart disease and improve overall health are being abandoned in favor of expensive drugs. This issue highlights the question of whether our society ought to or needs to tolerate medical care that serves the interests of the drug companies and medical industry before it serves the health of the American people. The 2001 cholesterol guidelines provide one important example of just how far the pendulum has swung toward the interests of the drug companies.

The obvious question is this: Who will benefit from expanding the number of Americans on statins from 13 million to 36 million? The most honest answer (though admittedly taken out of context) probably comes from the
Morgan Stanley Dean Witter newsletter
: “Who will benefit most from an expanding [statin] market? We have identified three likely incremental winners in the 2006 statin market—AstraZeneca, Schering-Plough, and an undisclosed marketing partner for Crestor.” The newsletter continues: “there are not likely to be any outright losers.” No mention is made of the patients and the doctors who are more concerned about their own and others’ health and well-being than about pharmaceutical company profits. We are the losers.

And so it’s
come to this: The American public can no longer blindly trust that its vaunted medical journals and world-class medical experts put the interests of patients first. Naturally, this makes us want to take matters into our own hands. This is a healthy instinct. Becoming well informed and reclaiming personal responsibility are the best antidote to a fundamentally flawed system.