Current Cholesterol Treatment Guidelines Don’t Reflect Medical Evidence

In the last year, three of my close relatives were prescribed statins; the class of drugs used to reduce cholesterol levels in the bloodstream. All three of my relatives had elevated readings of low-density lipoprotein (LDL) cholesterol (the bad kind) but no other risk factors for heart disease. Two of these relatives (my sister and a brother-in-law) are in their 50’s, are not overweight, maintain relatively healthy diets and exercise moderately. The third, my mother, is in her late 70’s, exercises daily and is in very good mental and physical health. No diabetes, little family history of heart disease, none are smokers.

I am not a doctor, but because I’ve written about medicine and health care for so long, people sometimes ask me for advice about medical problems and medications; most of the time I demur. But when my family members asked me what I thought about them undergoing drug therapy—potentially for many years, if not decades, in order to bring LDL cholesterol down to a target level, it was difficult to keep quiet. That’s because despite the widespread, almost reflexive, practice for doctors to prescribe statins, there is scant hard evidence that lowering cholesterol levels in otherwise healthy people will keep them from developing heart disease and extend their lives. This is especially true for women and people of both sexes who are over 65.

Questions about the wisdom of treating patients solely to achieve an LDL target are particularly important right now. A committee (the Adult Treatment Panel or ATP IV) convened by The National Heart, Blood and Lung Institute is currently revising clinical guidelines for testing and managing cholesterol. These guidelines were last released in 2002 (updated in 2004) and state that “recent clinical trials robustly show that LDL-lowering therapy reduces risk for CHD [coronary heart disease]. For these reasons, ATP III continues to identify elevated LDL cholesterol as the primary target of cholesterol-lowering therapy. As a result, the primary goals of therapy and the cutpoints for initiating treatment are stated in terms of LDL.”

Since those guidelines were released, more and more of us have been put on cholesterol-lowering drugs—current estimates are that one in four Americans over the age of 45 takes a statin daily. Heavy marketing of drugs like Lipitor (newly available in a generic form), Crestor and Zocor (available as generic simvastatin) to consumers, along with a concerted effort by drug companies to sell doctors on the relative cholesterol-lowering benefits of these drugs resulted in $17.1 billion in health care spending on just statins alone in 2009. Current spending figures are thought to exceed $20 billion. But along with this surge in treatment, there has been growing resistance among some researchers and cardiac specialists to the wholesale prescribing of statins. Studies have shown that for adults who already have heart disease, taking statins can have a clear benefit in preventing another heart attack. But for most everyone else, evidence of that clear benefit in preventing heart attacks and extending life is far less certain and can best be determined by considering an individual’s risk factors. As Rita Redberg, professor of medicine and director of women’s cardiovascular services at the University of California, San Francisco writes this week in the Wall Street Journal :

“For most healthy people, data show that statins do not prevent heart disease, nor extend life or improve quality of life. And they come with considerable side effects.” These include increased risk for developing diabetes, memory loss, muscle weakness, stomach distress, and aches and pains. “That’s why I don’t recommend giving statins to healthy people, even those with higher cholesterol,” she concludes.

Redberg is not alone in her treatment preferences. Recently, Harlan Krumholz, a professor of medicine at Yale’s School of Medicine and Rodney Hayward, professor of internal medicine at University of Michigan, wrote an open letter to the ATP IV committee members urging them to “follow a process that adheres closely to the scientific evidence, particularly the details of the clinical trials—which are abundant for lipid treatment.”

The letter, entitled “Three Reasons to Abandon Low-Density Lipoprotein Targets ” was published last week in the American Heart Association’s journal Circulation: Cardiovascular Quality and Outcomes and, according to Krumholz, is aimed at the larger physician community as well. It recommends a significant change from the 2002 guidelines:

“The evidence supports moving away from a target-based approach, a step that could launch a new era of guidelines in which treatment targets are replaced by a more tailored treatment approach (sometimes referred to as “individualized” or “personalized” care), which can improve patient outcomes while reducing harms and costs caused by overtreating low-risk/low-benefit individuals.”

How would treatment be determined under this “personalized approach?” First of all, most clinicians agree that lifestyle changes like following a low-fat, healthy diet and exercising—even moderately—can reduce the risk of heart disease significantly and should always be the first line of treatment. For those who have already had a heart attack, evidence does supports the use of a statin along with these lifestyle changes. But for all others, there is “an entire spectrum of risk factors” that need to be considered, says Krumholz—including whether a person is overweight, has diabetes, smokes, has a strong family history of heart disease, etc. Once a person’s risk of heart attack is better quantified, the next step is for a doctor to provide his patient with enough information to be able to make a decision about treatment.

Here we get to the heart of informed decision making. A key part of this process is providing patients with an important figure called “number needed to treat.” In his ground-breaking Business Week article on the cholesterol controversy , John Carey explains how this figure illustrates the relative benefits of statins. In the small print of Lipitor’s own ad is the following statement: “[I]n a large clinical study, 3% of patients taking a sugar pill or placebo had a heart attack compared to 2% of patients taking Lipitor.”

What this really means, according to Carey, is that even in an industry-sponsored study where many participants had risks factors like high blood pressure or were smokers, there was only one fewer heart attack per 100 people among those taking Lipitor. “So to spare one person a heart attack, 100 people had to take Lipitor for more than three years. The other 99 got no measurable benefit. Or to put it in terms of a little-known but useful statistic, the number needed to treat (or NNT) for one person to benefit is 100.”

Evidence from other studies puts the number needed to treat for statins at 250 and up for lower-risk patients even if they take it upwards of five years. In the Business Week article Dr. Jerome R. Hoffman, professor of clinical medicine at the University of California at Los Angeles asks; “What if you put 250 people in a room and told them they would each pay $1,000 a year for a drug they would have to take every day, that many would get diarrhea and muscle pain, and that 249 would have no benefit? And that they could do just as well by exercising? How many would take that?”

Moving the national cholesterol treatment guidelines away from a strictly LDL target approach (i.e. drug therapy starts when LDL cholesterol is above a certain level) and towards a less mechanistic, more risk-based one would have a number of positive effects. First of all, it will prevent overtreatment, reducing harmful side-effects like diabetes, memory loss and muscle pain while also saving health care dollars. Secondly, according to Krumholz, it will avoid under-treatment of patients who have high cardiovascular risk factors but low LDL. This could save lives.

Finally, measuring the effectiveness of a drug only by how well it reduces LDL cholesterol leads to the approval and sale of expensive new therapies that have little benefit in preventing heart attacks or death. Take the case of Vytorin, a combination of an off-patent statin and another cholesterol-lowering drug called Zestia that is sold by Merck-Schering Plough. Vytorin, which had $4.6 million in sales in 2009 and is covered by Medicare, costs four times more than a generic statin, yet has never proven more effective in preventing heart attacks or death. What it did do is lower LDL cholesterol 20% more in some patients than the generic statin. I wrote about how Merck-Schering Plough buried negative studies about Vytorin, paid cardiovascular experts to tout the drug, and is “relentlessly pursuing positive trial results” in a post for HealthBeat. These results, which will indicate whether Vytorin is better at preventing heart disease than a generic statin aren’t expected until at least 2014.

In the end, the idea that lowering cholesterol to a target level will help prevent heart disease and death in all people is not supported by scientific evidence. The case is building for a more nuanced national guideline that considers risk and a personalized approach to treatment that, according to Krumholz, “is estimated to save about 100,000 more quality-adjusted life years annually while having fewer people on high doses of statins than a treat-to-target approach.”

Right now, this message is not getting through to most physicians. After all, they are following the recommendations of the National Cholesterol Education Program. But for me, it’s hard to keep quiet when my mother calls me, her voice filled with worry, and tells me that her cholesterol is high and her new doctor wants to put her on a statin. I tell her, “you’re 79, you exercise regularly, your diet is very healthy, your mother and father lived to 90 and 86 respectively, and this is the first time a doctor has ever been concerned about your cholesterol.” I send her articles from science journals and the popular media. I advise her to bring this material to her doctor and discuss her real risk of heart disease. I wonder what kind of arrangement her doctor’s practice has with drug companies; I tell her “this is your choice, make an informed decision.”

Let’s hope the national cholesterol treatment committee moves toward recommending just this kind of what Krumholz calls a “simple, tailored treatment approach” to drug therapy that “is based on a person’s overall 5- to 10-year cardiovascular risk regardless of LDL level.” Not only does this approach reflect the best medical evidence, but it promises to reduce overtreatment and excess health care costs while moving treatment into the realm of patient-centered care.