Cholesterol Guidelines Still Stirring Debate 1 Year Later

November 16, 2014

CHICAGO, IL – It's been a full 365 days since the American College of Cardiology (ACC) and American Heart Association (AHA) presented their "paradigm-shifting" clinical guidelines for the management of patients with elevated cholesterol.

Despite their full year in the sun, the new recommendations are still being debated, with one expert arguing that physicians should be titrating statin treatment to specific cholesterol targets.

In a packed clinical lipidology-update session at the American Heart Association (AHA) 2014 Scientific Sessions, a session that saw attendees lined two- and three-deep against the walls, Dr Virgil Brown (Emory University School of Medicine, Atlanta, GA) debated Dr Jennifer Robinson (University of Iowa, Iowa City), one of the chairs of the new cholesterol guidelines and a coauthor of the guidelines for assessing cardiovascular risk, on the relative merits of abandoning the LDL- cholesterol targets.

Brown said the new cholesterol guidelines provide "very good" guidance on statin treatment because they recommend physicians treat patients vigorously with high-dose statin therapy. However, he criticized the guideline writers for an overly strict adherence to the clinical-trial data, noting the committee relied on 26 clinical trials to formulate its conclusion that the data were insufficient to support treating to a specific LDL-cholesterol goal.

In addition, he emphasized that previous clinical guidelines—those that recommended treatment targets of <100 mg/dL or <70 mg/dL—did not have a lower LDL-cholesterol limit established and that data from multiple analyses, including the Cholesterol Treatment Trialists' (CTT) collaboration, have shown that lower levels of LDL cholesterol provide greater protection against cardiovascular events.

Most important, Brown stressed that the art of medicine requires conversations with a patient and that the LDL-cholesterol target provided a means to track patient progress. After the patient has been treated, they want to know whether treatment is working, said Brown, "and without a goal, what do you tell them ?"

"In medical practice," he said, "physicians must choose what to treat and select targets, often several. They must explain the objective to the patient, which is to prevent heart attacks and stroke, and they must explain how they plan to do it. They're going to define what they're treating and they've got to set goals, in my opinion."

"These are important issues that you need to settle with your patient," said Brown. "My argument today is that in practicing the art of medicine, randomized, double-blind, controlled clinical trials with only one intervention—that is, a statin—are not appropriate for scientifically setting targets of therapy or for setting the goals of that therapy."

What Do The Guidelines Say?

Launched last year at the AHA Scientific Sessions and published simultaneously in the Journal of the American College of Cardiology and Circulation, the new guidelines departed significantly from previous iterations by abandoning the traditional LDL- and non-HDL–cholesterol targets. In the newest guidelines, which were reported extensively by heartwire , physicians are no longer asked to treat patients with cardiovascular disease to less than 100 mg/dL or the optional goal of less than 70 mg/dL.

Instead, the new guidelines identify four groups of primary- and secondary-prevention patients in whom physicians should focus their efforts to reduce cardiovascular-disease events. Depending on the type of patient, physicians should choose the appropriate "intensity" of statin therapy to achieve relative reductions in LDL cholesterol.

Briefly, the clinical guidelines currently state that for those with atherosclerotic cardiovascular disease, high-intensity statin therapy—such as rosuvastatin (Crestor, AstraZeneca) 20 to 40 mg or atorvastatin 80 mg—should be used to achieve at least a 50% reduction in LDL cholesterol unless otherwise contraindicated or when statin-associated adverse events are present. In that case, doctors should use a moderate-intensity statin. Similarly, for those with LDL-cholesterol levels >190 mg/dL, a high-intensity statin should be used with the goal of achieving at least a 50% reduction in LDL-cholesterol levels.

For those with diabetes aged 40 to 75 years of age, a moderate-intensity statin, defined as a drug that lowers LDL cholesterol 30% to 49%, should be used, whereas a high-intensity statin is a reasonable choice if the patient also has a 10-year risk of atherosclerotic cardiovascular disease exceeding 7.5%. For the individual aged 40 to 75 years without cardiovascular disease or diabetes but who has a 10-year risk of clinical events >7.5% and an LDL-cholesterol level anywhere from 70 to 189 mg/dL, the panel recommends treatment with a moderate- or high-intensity statin.

Robinson for the Guidelines

Speaking during the debate, Robinson said the new guidelines relied on a systematic review of the randomized, controlled, clinical data and attempted to avoid expert opinion, where possible. "It was really an attempt to avoid bias," said Robinson, "and to make sure we considered all of the evidence and not just our favorite studies."

While abandoning LDL-cholesterol targets, the new guidelines are not a "shoot-and-forget" option for physicians. Physicians are still asked to regularly monitor treatment after the initiation of a statin, particularly as it pertains to adherence of drug therapy and the maintenance of a heart-healthy lifestyle, said Robinson.

For primary and secondary prevention, Robinson said there are no randomized clinical trials that titrated treatment to a specific LDL-cholesterol target or compared LDL-cholesterol targets. "At that point, we really could not make an evidence-based recommendation to continue to use LDL targets. . . . We did, however, find extensive, strong evidence that high-intensity statins reduce atherosclerotic risk more than moderate-intensity statins and that moderate-intensity statins reduce risk more than placebo."

For this reason, the guideline committee chose not to "perpetuate" the concept of lowering to LDL-cholesterol goals. The process, she said, took many years, as the committee bounced around the idea of abandoning treatment targets—it was not a decision made without thought, said Robinson.

There was also concern that by strictly adhering to the LDL-treatment goals, physicians might use other means to lower LDL-cholesterol levels, particularly in combining a moderate-intensity or low-intensity statin with an additional agent. Estrogen, for example, lowers LDL-cholesterol levels but also causes MI and strokes, she said, and there are few data supporting the use of ezetimibe (Zetia, Merck/Schering-Plough). "You could give your patient an inadequate, and not evidence-based, dose of statin," she said of treating to targets. "Even if you maximized the high-intensity statin, we have no evidence of the incremental benefit of adding a nonstatin."

Finally, she agreed with Brown that there is excellent epidemiology data showing a relationship between LDL-cholesterol levels and atherosclerotic risk, but "it's just that when you start using drugs [to lower LDL] it gets a little more complicated. It's not clear what the target should actually be."

Agreeing to Disagree

During the debate, Robinson said that when writing the guidelines the committee was aware of patients on suboptimal therapy. Data have shown that even when the cholesterol targets existed, half of post-ACS patients aren't even taking a statin at one year and just 15% are taking a high-intensity statin. "That's what you get when you're treating to targets," she said. "We think more focus should be on the intensity, on maximizing the statin dose."

Brown said that he often encounters difficulties in explaining randomized, controlled, clinical-trial data to his patient. He said the patient wants to know what the goal of treatment is, just like blood-pressure targets. "The goals we had we admittedly weren't achieving in everybody," said Brown.

One of the elephants in the room was the looming IMPROVE-IT trial, a study of 18 000 post-ACS patients with a baseline LDL-cholesterol level <100 mg/dL. In that trial, researchers are testing whether the addition of ezetimibe, which will further reduce LDL cholesterol beyond what is capable with simvastatin 40 mg, results in a significant reduction in cardiovascular events.

The full results of IMPROVE-IT will be presented during the late-breaking clinical trials session tomorrow.

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