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Is it time to expand your use of statins?

New update gives doctors the option of a lower LDL goal for patients at very high risk

From the September ACP Observer, copyright 2004 by the American College of Physicians.

By Janet Colwell

For several years, researchers have been making increasingly impressive claims about statins' ability to reduce patients' risk for coronary events. Now, physicians have new guidance to help them put that research into practice.

In July, the National Cholesterol Education Program (NCEP) released an update of guidelines for cholesterol management giving physicians a therapeutic option to use more intensive LDL-lowering therapy in very high-risk patients.

The NCEP, which is coordinated by the National Heart, Lung, and Blood Institute of the National Institutes of Health, reaffirmed its existing goal of reducing LDL levels to less than 100 mg per deciliter for patients at high risk of heart disease. For patients at the highest risk of heart disease, however, the NCEP made it a therapeutic option to reduce LDL cholesterol to less than 70 mg per deciliter.

Some observers say that about 3 million more Americans are now eligible for LDL-lowering drug therapy under the new update. The panel noted, however, that very high-risk patients who start with high LDL levels might not be able to achieve the new goals using existing drugs. In many very high-risk cases, getting LDL to 70 mg per deciliter or lower will require higher doses of statins or a combination of drugs.

While the revised recommendations are based on evidence, some physicians say they are wary of trying to convince patients to take higher drug doses or additional drugs. And others are concerned about the safety of radically dropping LDL cholesterol levels.

The latest science

The NCEP's new update comes on the heels of guidelines it released just three years ago.

The 2001 guidelines, known as Adult Treatment Panel III (ATP III), expanded the group of patients the NCEP defined as high risk. Before ATP III, high-risk patients included only those with coronary heart disease or those with non-coronary forms of atherosclerotic disease. The ATP III guidelines, however, broadened that category to include patients with diabetes and those with two or more risk factors, such as smoking and hypertension, and a 10-year risk of developing heart disease of more than 20%, based on Framingham Heart Study risk scores.

This year's guidance took ATP III recommendations a step further, revising a key recommendation on when to consider starting LDL-lowering drug therapy. Whereas ATP III said that drugs should be considered if a high-risk patient's LDL is 130 mg per deciliter or higher, with an LDL less than 100 mg per deciliter as the ultimate goal, the new guidance strongly recommends drug therapy be considered even in high-risk patients with a baseline LDL of 100-129 mg per deciliter. The recommendations say a target of less than 70 mg per deciliter is a "therapeutic option" for the subset of patients at very high risk.

This subset includes those who have had a recent heart attack, and those who have cardiovascular disease combined with either diabetes, or severe or poorly controlled risk factors (such as continued smoking), or metabolic syndrome.

While the ATP III guidelines will be formally updated when warranted by further scientific developments, NCEP officials felt compelled to release this summer's update because of news from five major clinical trials conducted since 2001. The results of several of those trials indicate that reducing LDL cholesterol to well below 100 mg per deciliter could significantly reduce heart disease risk.

In the Heart Protection Study, for instance, researchers found that LDL lowering with a daily dose of 40 mg of simvastatin significantly reduced cardiovascular mortality. The large study, which appeared in the July 6, 2002 issue of The Lancet, found that the drug reduced the risk of heart attacks and strokes by about 25% in high-risk patients, regardless of their baseline LDL levels.

Earlier this year, the results of two other influential studies added to statins' growing reputation. The REVERSAL trial, with findings published in the March 3, 2004, Journal of the American Medical Association, compared the effect of intensive and moderate lipid-lowering therapies in patients with coronary artery disease.

Researchers found that study participants showed angiographic evidence of significantly greater benefit from aggressive therapy (80 mg of atorvastatin) than moderate (40 mg of pravastatin) therapy, even when those participants had relatively low LDL levels. Researchers also found that participants benefited from having their LDL cholesterol lowered well below 100 mg per deciliter.

The second study, which appeared in the April 8 New England Journal of Medicine, similarly compared a daily dose of 40 mg of pravastatin to 80 mg of atorvastatin. However, this study, known as the Prove-It trial, looked only at patients who had recently suffered acute coronary syndromes.

While patients on moderate therapy reduced their LDL cholesterol levels to a median of 95 mg per deciliter, the intensive therapy group had less risk of major cardiac events by getting their LDL cholesterol even lower, to a median of 62 mg per deciliter.

These latest studies were also accompanied by speculation as to whether statins' benefits may extend beyond lowering LDL cholesterol. Although more research is needed, investigators claimed that statins' apparent anti-inflammatory properties may play a role in slowing the progression of heart disease.

"It turns out that what's really important is not your LDL level but your risk for having an event," said Christie M. Ballantyne, FACP, director of the Center for Cardiovascular Disease Prevention at Houston's Baylor College of Medicine. "Over a 15-year period, there's been a total change in the treatment paradigm. If someone is extremely high risk, just treat them."

According to the NCEP recommendations, patients in the high risk category should aim for an LDL cholesterol level of less than 100 mg per deciliter. (The threshold for patients with less than two risk factors, however, is set much higher, at more than 160 mg per deciliter.) Based on the doses used and benefit obtained in the recent clinical trials, the NCEP now advises physicians to gauge the intensity of drug therapy to achieve at least a 30% to 40% reduction in LDL cholesterol in high-risk or moderately high-risk patients.

How low should you go?

While the NCEP update recognizes the growing body of evidence about statins' ability to reduce risk for coronary events, it also raises some key questions. For example, how low can physicians reduce their patients' LDL cholesterol levels? What is the cost-benefit ratio of aggressive statin use? And does intensive statin therapy pose any long-term side effects?

On all three questions, the evidence is murky. While most people do not suffer serious side effects from moderate statin therapy, there are no long-term data on intensive therapy, although there are concerns about the possible long-term effects of drastically reducing LDL cholesterol. The NCEP update notes that in older studies, a suggested association between very low LDL cholesterol levels and an increase in total mortality may have been due to confounding factors. No significant increase in serious side effects from LDL lowering per se has been seen in clinical trials.

Other researchers have argued that it may be safe to reduce LDL cholesterol as low as 35 to 50 mg per deciliter, the typical LDL level of a newborn. Others note that 70 mg per deciliter is probably safe because people with hypobetalipoproteinemia, who have only half the normal LDL level, seem to be less likely to die from heart disease.

There is, however, another problem: Some very high-risk patients may not be able to reduce their LDL cholesterol below 70 mg per deciliter with the drugs currently available. It is often impossible, for example, to cut LDL levels more than 50%. Nevertheless, this degree of LDL lowering will reduce risk for a coronary event by 50%—a huge benefit.

These concerns, combined with the fact that the clinical trial evidence is not yet definitive, led the NCEP to frame much of its latest advice as therapeutic options, instead of formal recommendations. The panel is waiting for the results of several trials now underway to help determine whether making the 70 mg per deciliter target an official guideline is scientifically valid. In particular, officials say, more information is needed on the benefits of lowering LDL to very low levels.

"At the moment, we are short of having the evidence to set a new guideline," said James I. Cleeman, MD, the NCEP's coordinator at the National Heart, Lung, and Blood Institute. "There are very high-risk patients in whom physicians may certainly regard it as appropriate to bring the LDL down to well below 100, but that's not a global recommendation for high-risk patients. The need for individualized therapy still exists."

A more aggressive stance

While NCEP officials are waiting for more evidence, some practicing physicians are concerned about practical issues like cost.

They say that financial issues loom large, particularly as guidelines recommend expanding the population of high-risk patients who should be taking cholesterol-lowering drugs. Many patients with multiple health issues are already taking—and paying for—several drugs; convincing them to add a statin or increase their statin dose, some physicians say, could be a hard sell.

But others are calling for an even more aggressive approach to statin therapy. Not surprisingly, cardiologists are leading the charge.

Daniel J. Rader, ACP Member, director of the University of Pennsylvania's Preventive Cardiology and Lipid Clinic, routinely goes beyond current guidelines in deciding when to initiate statin therapy and how aggressively to treat at-risk patients. He treats all very high-risk patients with statins regardless of their LDL level and routinely aims for LDL levels of less than 70 mg per deciliter in patients with heart disease.

"Statins genuinely reduce cardiovascular disease risk substantially and are underutilized," said Dr. Rader, who was a co-author of the Prove-It study. "The biggest message to get across to physicians is if someone is at very high risk, put them on a statin and don't worry about what their baseline LDL is."

Several medical organizations have also taken a more aggressive stance. Earlier this year, for example, the American Heart Association recommended that women at high risk for heart disease should receive a statin regardless of their LDL level.

And ACP recently issued a new clinical practice guideline advising physicians to treat any patient who has coronary heart disease and type 2 diabetes with statins, regardless of their LDL concentration. For more information, click here.

The College, which was one of the first groups to dispense with targets for patients at high risk of heart disease, also said that diabetics who do not have coronary heart disease but have at least one other risk factor such as hypertension, smoking or obesity should be taking a statin or gemfibrozil, especially if they have low HDL cholesterol, regardless of their LDL levels.

The American Diabetes Association (ADA), which issues new guidelines on diabetes care each January, is considering updating its lipid recommendations when its professional practice committee meets in October, according to Nathaniel Clark, ACP Member, the ADA's vice president of clinical affairs.

The ADA's current recommendations set a goal of under 100 mg per deciliter for patients with diabetes. The ADA also recommends considering statin therapy for all diabetics over age 40 with total cholesterol of more than 135 mg per deciliter to achieve a 30% LDL reduction, regardless of baseline LDL levels. The ADA committee will discuss next month whether the LDL target should be changed or whether statins should be recommended for all those with diabetes, given their high risk of cardiovascular disease.

Such a sweeping guideline—which would affect virtually all patients with diabetes—may help get more at-risk people on statins, Dr. Clark said. Currently, studies indicate that less than half of diabetics achieve the goal of getting their LDL level under 100 mg per deciliter.

"The concept that if you have diabetes, you should be on a statin is not really part of current medical practice, and it's a conceptual change for physicians who have been used to focusing on targets," Dr. Clark said. "If the guideline were to say, 'If someone has diabetes, put them on this drug,' that's a lot easier than checking lab tests—and the percentage of patients receiving needed treatment would increase significantly."

While groups like ACP and the ADA may be ready to dispense with LDL thresholds for certain categories of patients, the NCEP's Dr. Cleeman is concerned about adopting blanket policies that ignore LDL levels.

"A very important point is that the LDL paradigm is alive and well and that's the one that should guide therapy," he said. "It is not optimal to take a standard dose of anything and apply it equally to all patients in a category. You have to know the LDL level, in addition to the risk category, in order to decide how intensively to treat."

To back up that point, the NCEP panel cited instances where LDL levels should drive physician decision-making. For example, in the Heart Protection Study, the risk reduction for a first coronary event was only marginally significant for diabetics with an initial LDL cholesterol level of less than 116 mg per deciliter. "Thus," the update stated, "whether to start an LDL-lowering drug when LDL-C is <100 mg per deciliter in this category of patient must be left to clinical judgment."

Convincing patients

While experts may not yet agree on exactly who should receive LDL-lowering drugs and when, there is a bigger issue: Many people who should be taking the drugs according to any guideline are not. Despite the weight of recommendations like NCEP's, patients—particularly those who feel fine—resist signing up for a lifetime supply of a new drug.

"It's hard to get the message out because [being at risk for heart disease] is asymptomatic," said Dr. Ballantyne, who runs the lipid clinic at Baylor. "These are chronic conditions that, unfortunately for a lot of people, don't get their attention until they have the first event."

The patients who slip under physicians' radar are often those who have relatively low cholesterol but are nonetheless at high risk for heart disease, he added. While one person with high cholesterol may not need a statin because of a low absolute risk, another with relatively low cholesterol may benefit from treatment due to other risk factors, such as high blood pressure, high triglycerides and metabolic syndrome.

"We spent so much time educating about cholesterol that people think if they're under 200 [total cholesterol], they don't have to worry," said Dr. Ballantyne. "We need to get the message out to patients that their risk for heart disease may go up with age, and that it's a much more preventable disease than something like cancer."

The information included herein should never be used as a substitute for clinical judgment and does not represent an official position of ACP.

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Should statins be sold OTC?

The same research findings that led the National Cholesterol Education Program to publish a new update this summer pushed the British government to take a much more radical step: approve over-the-counter (OTC) sales of 10 mg simvastatin (Zocor). While that decision was criticized by medical organizations and physicians, it has nonetheless sparked renewed drug company interest in getting OTC statins approved in the United States.

In 2000, the FDA rejected OTC sales of pravastatin (Pravachol) and lovastatin (Mevacor) because of doubts about whether the drugs could be safely used without physician oversight. The federal agency is now considering an application by Johnson & Johnson-Merck Consumer Pharmaceuticals Co. to sell a low-dose OTC version of Mevacor.

Some physicians worry that patients are ill-equipped to manage the long-term use of statins on their own.

"Allergies or gastroesophageal reflux, which have medications available OTC, are very different from lifelong hypercholesterolemia," said Robert A. Kreisberg, MACP, vice president for medical affairs and dean of the college of medicine at the University of South Alabama in Mobile. "I'm concerned that some people who buy OTC will require more intensive therapy, but they won't go to their doctor because they believe they're treating it on their own."

An editorial in the May 22, 2004, issue of The Lancet harshly criticized the British government's decision to approve OTC simvastatin sales. The editors pointed out that there are no trials of OTC statins for primary heart disease prevention and no data on compliance with OTC statins.

They also questioned whether pharmacists will take the time to determine an individual's risk of developing heart disease and to give lifestyle advice to lower patients' cholesterol.

Allowing OTC sales might encourage low-risk individuals to be proactive about reducing cholesterol on their own, resulting in a shift of some preventive costs from the health care system to consumers, pointed out Christie M. Ballantyne, FACP, director of the Center for Cardiovascular Disease Prevention at Baylor College of Medicine in Houston. However, potential problems outweigh the benefits.

"Patients who treat themselves with a statin will not undergo appropriate evaluation for secondary causes of hyperlipidemia and cases of hypothyroidism or other disorders," said Dr. Ballantyne. "Patients are better off working with their physicians in a prevention program than trying to do this themselves."

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