How’d we get here? If you’re confused about the latest statin and cholesterol news, this information may help...

Have you been confused about what to make of the ENHANCE trial tumult and the differing viewpoints from experts about whether or not statins save lives and if lowering cholesterol levels matters?

It’s certainly become widely believed that lowering our cholesterol levels is important to prevent heart disease and premature death — but is it?

It’s also popularly believed that statins are important for preventing premature deaths (whether or not they work by lowering cholesterol levels) — but are they?

How can we make informed, evidence-based, decisions or make sense of the conflicting things we've been hearing this week?

To begin to look at these questions, let’s turn to how we evaluate any claim that a potion or treatment works. With homeopathy or an alternative modality, for instance, we’ve learned the importance of a ‘fair test.’ In the article, “How do we know what will kill or cure us,” the core principles of true evidence-based medicine were examined. To know if something works, we can’t rely on what we believe works, but what is proven to work in a randomized, placebo-controlled clinical trial.

For a trial to be a fair and honest test, it is designed to see if a potion or treatment works better than nothing at all. Hence, the importance of a placebo or a control group, to compare to the intervention group. A randomized controlled study randomly sorts a group of people into one group that gets the treatment and another group that doesn’t (the control group). Assigning patients at random reduces the risk of bias and increases the likelihood that differences seen between the groups can be attributed to the treatment.

And the only way to scientifically overcome subjectivity in interpreting the effects of an intervention is through “double-blinding” and using outcomes (endpoints) that can be soundly measured and that matter. In other words, we look to see if a treatment affects actual clinical outcomes — important and indisputable changes, like premature deaths, eradication of a disease pathogen or fewer bone fractures. We don’t use subjective measures because of placebo and nocebo effects. And it doesn’t matter if it changes some surrogate measure, like a lab test result. No one wants to hear that “the treatment ‘worked’, but the patient died.” In other words, we are cautious of false surrogate endpoints.

As Dr. Steven Bratman, M.D., wrote in “A Major Scientific Advance of the 20th Century”:

I once took alternative medicine on faith. For decades, I practiced it on patients and myself and my family, and assumed that pretty much all of it worked. Then I learned about double-blind studies, and it was like a tornado blowing down a house of cards. I discovered that I, like most people who love alternative medicine, had made a huge (though understandable) mistake.

I had thought it was possible to know whether a treatment worked by trying it. I had also thought I could trust tradition, anecdote, and authority. I now see otherwise. The insights of the double-blind trial have cut through my wishful thinking and idealism, and turned me into a hard-nosed skeptic. Show me the double-blind studies, and I’ll pay attention. Otherwise, so far as I’m concerned, it’s little more than hot air....

The double-blind study has caused a revolution even in conventional medicine. Many old beliefs have been tossed out when double-blind studies were finally done. It’s been discovered, for example, that (as noted earlier) over-the-counter cough syrups don’t work, that immediate antibiotic treatment for ear infections is probably not necessary or even helpful in most cases, and that cartilage scraping for knee arthritis is no better than placebo.

Granted, there are certain research questions where it would be unethical to subject people to something that might cause them unnecessary harm. So, for instance, we don’t have people drink chemicals to see if they get cancer. There are also many other considerations that go into clinical trials, when they’re needed, how they’re reported and interpreted, and how we use their findings in clinical practice. In real life, the research evidence — showing the risks, potential benefits, inconvenience and costs — is used along with the clinical expertise and experience of a caregiver, and the actual clinical conditions and circumstances of each patient. Together, all of this allows patients to make informed decisions in keeping with their preferences and values.

To quote London physician, Dr. Ben Goldacre: “Evidence-based medicine is beautiful, elegant, clever and, most of all, important.”

Overall, randomized controlled clinical trials are “our current best means to evaluate the efficacy of an intervention,” wrote Doctors P.J. Devereaux and Salim Yusuf of the Canadian Institutes of health Research in a 2003 issue of the Journal of Internal Medicine. “As such, the RCT plays a central role in providing the evidence basis for evidence-based decision making about therapeutic interventions.”

FDA and drug trials

Which brings us to medicines and treatments. “Every drug must be proven safe and effective in controlled clinical trials before the Food and Drug Administration allows it to be sold in the United States,” explained Linda Bren writing for the FDA Consumer. Federal law first required controlled clinical trials in 1962 to “show evidence” that a drug is effective and safe before it could be approved. Since then, the FDA “has been the major force behind the development of good principles for the design and interpretation of controlled trials,” said Robert T. O'Neill, Ph.D., director of the FDA’s Office of Biostatistics. “We’ve promoted, fed, and cared for controlled clinical trials as a critical force in drug development, and we continue to do so today.”

This FDA article, “The Advancement of Controlled Clinical Trials,” explains the key parts of a controlled clinical trial and their importance — randomization, placebo-controlled, blinding, safety evaluations, no data fishing, counting all participants, open and transparent information, dose-response, diversity of patient populations, and use of surrogate endpoints. [Another description of the FDA’s Drug Review Process is here.]

The FDA makes one exception to drug company trials having to show an actual benefit in clinical outcomes: “for life-threatening conditions.” For life-threatening diseases, the faster a product can get to a patient, the more likely it might give that patient a fighting chance. Since the 1970s, the FDA has allowed the use of investigational new drugs in very ill patients who had no good alternatives. And in 1992, the FDA enacted an accelerated approval regulation that allows the FDA to rely on surrogate markers to expedite access to new treatments for life-threatening diseases.

A surrogate endpoint is a laboratory measurement or physical sign used as a substitute for a clinically meaningful endpoint when they were “reasonably likely” to predict an actual clinical benefit, according to the FDA. “The approval is conditional — controlled clinical trials to verify the benefits to participants must be completed after approval. If the trials fail to show a benefit, or benefits appear not to outweigh risks, the FDA can withdraw the drug from the market.”

The importance of this need had become apparent, said the FDA, when AIDS began taking the lives of thousands of Americans and “it became clear that AIDS patients could not be maintained on two- to three-year trials,” said Dr. Rachel Behrman, M.D., an FDA infectious disease specialist. This shortcut was necessary because it was “a public health crisis” and “wasn't business as usual and we had to be a more active participant in clinical trial design,” she explained.

Okay, all of this sounds good, right?

So why all of the confusion with statins and cholesterol-lowering drugs? Why are the large clinical trials not showing significant and consistent benefits in reducing premature deaths among people who take them, even when they lower LDL-cholesterol levels?

The answer may shock you:

The basic premise of sound research evidence for drug approval — the randomized controlled clinical trial — has been neglected when it came to statins, whether they're used as a primary or secondary preventative. It is the exact same story as we’ve seen with drugs for weight loss and the ‘metabolic syndrome.’

Somehow, the FDA has allowed itself to be convinced that heart disease, like obesity, is so life-threatening and such a public health crisis that the drug companies shouldn’t have to prove a benefit in actual clinical outcome — like premature death — to get their drugs approved.

Yes, you read that correctly. Statins (like weight loss drugs) have not had to show they actually save lives or extend lives of patients. They have been given approval based solely on false surrogate endpoints. “We’ve approved drugs because they lower LDL-cholesterol without specific evidence that they decreased the rate of heart disease,” said Dr. Robert Temple, M.D., director of the FDA’s Office of Medical Policy. The problem is that, as the ENHANCE trial demonstrated, this surrogate endpoint, like so many others, is not proving to be predictive of, or a substitute measure for, clinically meaningful outcomes.

As the New York Times reported just this morning:

Because the link between excessive LDL cholesterol and cardiovascular disease has been so widely accepted, the Food and Drug Administration generally has not required drug companies to prove that cholesterol medicines actually reduce heart attacks before approval.

They have not had to conduct so-called outcome or events trials beforehand, which are expensive studies that involve thousands of patients and track whether episodes like heart attacks are reduced. So far, proof that a drug lowers LDL cholesterol has generally been enough to lead to approval. Only then does the drug’s maker begin an events trial. And until the results of that trial are available, a process that can take several years, doctors and patients must accept the medicine’s benefits largely on faith.

But it gets more concerning. The FDA has also been convinced that the drugs don’t have to show that they work better than nothing at all to be approved.

Yes, you read that correctly. Statins and diet drugs have not had to show that they actually work better than a placebo... they haven’t had to use a placebo control group.

As Ron Winslow explained just yesterday in the Wall Street Journal:

Merck, Bristol-Myers and Pfizer have already made that case resoundingly for the statin class, it’s unethical for a company to run a placebo-controlled trial in most people with heart disease.

The belief is that statins are so life-saving that it would be unethical to deny them to patients — and they’ve managed to convince the FDA and the public of that. So, drug companies can merely pit their statin or cholesterol-lowering drug against another brand’s and never test it against a placebo control group to demonstrate the point to them at all. [Just as diet drugs are pitted against other weight loss interventions ('standard of care'), and their effects ‘proven’ only by measuring temporary false surrogate endpoints.]

This is a troubling disregard of the value of evidence-based medicine. It appears that abandoning two of the foundations of randomized controlled clinical trial evidence — a placebo control group and hard-core clinical outcomes rather than surrogate endpoints — is the source of consumers and healthcare professionals having, what the New York Times described as, little more than “faith” to go on when it comes to statins.

© 2008 Sandy Szwarc

Follow-up

So why are so many experts intent on keeping people on a drug that’s never been shown to be of benefit? Dr. Roy M. Poses, M.D., at Healthcare Renewal examined this phenomenon yesterday as he tried to sort through the different opinions on the ENHANCE trial that were being quoted in the news. The American Heart Association and American College of Cardiology had both issued public statements yesterday saying they continue to recommend statins for lowering cholesterol and warning doctors to not discontinue Zetia based on the ENHANCE trial. Dr. Poses’ article is insightful in showing that the experts on the side of statins, as well as on the expert panel that created the 204 National Cholesterol Education Panel guidelines calling for lowering of treatable cholesterol levels, have all had financial ties to the statin pharmaceutical companies. But when we read and hear these experts in the news, we are almost never told of their potential conflicts of interest. “I’m not suggesting that these experts have opinions for sale,” he wrote. “The problem is that when data are conflicting, wishful thinking and commercial interests may supplant a rational consideration of the facts.”

Please remember, only you and your doctor can make clinical decisions best for you.