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Treat risk and not LDL-cholesterol targets, new perspective argues January 19, 2012 Michael O'Riordan

Ann Arbor, MI and New Haven, CT - In an open letter to the writing committee of the upcoming cholesterol guidelines, two physicians are calling for the abandonment of treating to LDL-cholesterol targets and instead recommending that the new guidelines focus on a more tailored treatment approach that takes into account overall cardiovascular risk [1]. In focusing on global risk, rather than LDL-cholesterol levels, doctors would improve patient outcomes and reduce adverse effects and costs that result from treating low-risk, low-benefit patients.

"In creating the new guidelines, I think it's time to reflect on what the evidence really tells us," Dr Harlan Krumholz (Yale University School of Medicine, New Haven, CT), one of the authors of the new perspective, said in an interview with heartwire. "Even though this might represent a paradigm shift in the approach to patients, it adheres more closely to the evidence that's been generated. And this recommendation in no way impugns the cholesterol hypothesis. It's not about that. What we know is that statins reduce risk, but they ought to be concentrated in people at higher risk. Focusing on targets can lead to a misallocation of the intervention to patients who are less likely to benefit and missing those patients who are more likely to benefit."

"We should be thinking about [statins] as a risk-reduction medications rather than lipid-lowering drugs."

In the perspective, published online January 17, 2012 in Circulation: Cardiovascular Quality and Outcomes, Krumholz and Dr Rodney Hayward (University of Michigan, Ann Arbor) argue that the embedded wisdom of focusing on treating patients to LDL targets with lipid-lowering drugs is not the right approach. Since statin therapy lowers the risk of cardiovascular disease regardless of baseline LDL-cholesterol levels, they urge the writing committee of the National Cholesterol Education Program (NCEP) Adult Treatment Panel (ATP) IV guidelines, which are expected to be published sometime this year, to recommend treatment based on patient risk profile.

"The only things that will determine how much benefit a patient gets from treatment are the statin you choose-how potent it is-and the patient's overall risk," Hayward told heartwire.

Making the case for risk, not LDL cholesterol

In their perspective, as well as to heartwire, Krumholz and Hayward point out that no major randomized clinical trial has studied outcomes in treating patients to LDL-cholesterol targets. Instead, the clinical trials tested fixed doses of drugs in specific patient populations, with statin trials showing a significant reduction in risk while other drugs have not yet been tested, such as ezetimibe (Vytorin, Merck/Schering-Plough). They also note that the safety of treating to LDL-cholesterol targets has not been proven and that the target-based approach can lead to the treatment of patients at low risk for cardiovascular events-a problem, since there are side effects with statins and drug-drug interactions.

"Given that it's fairly well accepted that statins lower your risk no matter what your cholesterol is, we should be thinking about them as a risk-reduction medication rather than lipid-lowering drugs," said Krumholz. "If they can lower risk, then their value is primarily based on what the baseline risk is. If the risk is high, you're going to get more benefit, and if the baseline risk is low, the relative reduction in risk is not going to buy you much."

Hayward and Krumholz argue that a tailored treatment approach that focuses on the patient's 10-year cardiovascular risk profile is a "simpler, safer, more effective, more evidence-based approach" that has the potential to result in a significant increase in quality-adjusted life-years while treating fewer patients with high-dose statins. Hayward told heartwire that most of the treatment benefit with statins comes from initiating therapy. An increase in dose can result in a large relative reduction in risk in patients at high risk for cardiovascular disease, but might result in "net harm" in lower-risk patients.

Hayward also noted that undertreating patients when LDL-cholesterol levels are low but overall cardiovascular risk is high is a problem. He added that while clinicians might rely on LDL-cholesterol levels alone, it is relatively easy to enter information into the Framingham Risk Score (FHS) or other risk calculators. "We have the ability to dramatically reduce heart disease with minimal polypharmacy," said Hayward.

"LDL is an imperfect predictor of risk, and when you predicate treatment on LDL-cholesterol levels alone, you end up treating some patients with modestly elevated LDL levels but who are at low risk for cardiovascular disease or losing some patients who have low LDL levels who are at a substantially higher risk of heart disease," added Krumholz.

Reducing heart disease with fewer drugs

Hayward and Krumholz agree that moving away from cholesterol targets would represent a sea change in the guidelines, but the ATP III guidelines were partially based on patient risk. The highest-risk patients were treated to an LDL-cholesterol target of <70 mg/dL, while other high-risk patients had an LDL-cholesterol target of <100 mg/dL, for example. ATP IV would have to go even further, say the clinicians, making treatment based entirely on risk and not baseline LDL-cholesterol levels.

"If cholesterol is markedly elevated, if you have familial hypercholesterolemia, then obviously at that level of cholesterol you're at high risk," said Krumholz. "It's not saying you never pay attention to cholesterol. If the cholesterol is 500 [mg/dL], you're at high risk and you would treat those patients anyway. But if the patient has a cholesterol level of 125, 130, or 140 [mg/dL], with no other risk factors, you might not treat them."

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