New Cholesterol Guidelines Abandon LDL Targets

November 14, 2013

WASHINGTON, DC – It's been more than a decade since the Adult Treatment Panel (ATP) issued the third report for the detection, evaluation, and treatment of elevated cholesterol and nine years since those recommendations were updated, but new guidelines from the American College of Cardiology (ACC) and American Heart Association (AHA), developed in conjunction with the National Heart, Lung, and Blood Institute (NHLBI), are now available online in both the Journal of the American College of Cardiology and Circulation[1].

And they contain some substantial changes from ATP 3.

Gone are the recommended LDL- and non-HDL–cholesterol targets, specifically those that ask physicians to treat patients with cardiovascular disease to less than 100 mg/dL or the optional goal of less than 70 mg/dL. According to the expert panel, there is simply no evidence from randomized, controlled clinical trials to support treatment to a specific target. As a result, the new guidelines make no recommendations for specific LDL-cholesterol or non-HDL targets for the primary and secondary prevention of atherosclerotic cardiovascular disease.

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. And in these four patient groups, the new guidelines make recommendations regarding the appropriate "intensity" of statin therapy in order to achieve relative reductions in LDL cholesterol.

No Evidence for Treating to Specific Targets

Dr Neil Stone (Northwestern University Feinberg School of Medicine, Chicago, IL), the chair of the expert panel who wrote the guidelines, spoke with the media during a conference call and said there were some problems with treating to goal, specifically in patients who were treated close but not exactly to target.

"In secondary prevention, what if your patient is on high-intensity statin therapy and gets an LDL-cholesterol level of 78 [mg/dL] and is adhering to an excellent lifestyle?" said Stone. "From our point of view, there is a large body of evidence that says he's actually doing as good a job as he can possibly do. If he has to get to an optional goal of under 70 [mg/dL] as some would advocate, it means adding on medicines for which there is not proven benefit."

In addition, the panel said that the use of LDL-cholesterol targets might result in the overtreatment of patients with nonstatin drugs. These other agents have not been shown to reduce the risk of atherosclerotic cardiovascular disease.

Dr Donald Lloyd-Jones (Northwestern University Feinberg School of Medicine), the cochair of the guidelines on the assessment of cardiovascular risk, which were also released today along with guidelines for the management and treatment of obesity and guidelines for lifestyle management, said the evidence for treating to target simply isn't there, but that doesn't mean repeated measurements of LDL cholesterol won't be needed.

"There have been no clinical trials in which they've taken an approach where they've titrated medication dosing to achieve a certain LDL level," said Lloyd-Jones. "We just haven't had those trials designed or performed yet. So we just couldn't endorse that kind of approach. And yet, we're not abandoning the measurement of LDL cholesterol, because it's perhaps our best marker of understanding whether patients are going to achieve as much benefit as they can for the dose of statin they can tolerate. For the clinician, it's also a very important marker of adherence."

Stone acknowledged that the old targets might be part of the "mind-set" of physicians but said the new recommendations actually simplify treatment in that doctors won't have to fuss around with additional means to lower LDL cholesterol if the patient has been treated with an appropriate dose of statin therapy.

The Four Major Statin Groups

The four major primary- and secondary-prevention patient groups who should be treated with statins were identified on the basis of randomized, controlled clinical trials showing that the benefit of treatment outweighed the risk of adverse events. The four treatment groups include:

  • Individuals with clinical atherosclerotic cardiovascular disease.

  • Individuals with LDL-cholesterol levels >190 mg/dL, such as those with familial hypercholesterolemia.

  • Individuals with diabetes aged 40 to 75 years old with LDL-cholesterol levels between 70 and 189 mg/dL and without evidence of atherosclerotic cardiovascular disease.

  • Individuals without evidence of cardiovascular disease or diabetes but who have LDL-cholesterol levels between 70 and 189 mg/dL and a 10-year risk of atherosclerotic cardiovascular disease >7.5%.

In 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.

"In the primary-prevention-therapy decisions, we insisted that the patient and the physician have a discussion to determine what the benefits and risks are specifically for that patient," said Stone. This discussion should focus on the patient's characteristics and preferences to determine the best therapy.

To assess the patient's degree of risk, a new global risk assessment tool was developed by the expert panel. The new cardiovascular risk score is designed to assess the risk of an initial cardiovascular event and includes participants from racially and geographically diverse cohorts such as the Framingham Heart Study (FHS), the Atherosclerosis Risk in Communities (ARIC) study, the Coronary Artery Risk Development in Young Adults (CARDIA), and the Cardiovascular Health Study (CHS). The new pooled cohort equations predict the future risk of cardiovascular disease and also stroke.

New Risk Score Raises Eyebrows

To heartwire , Dr Roger Blumenthal (Johns Hopkins Medical Institute, Baltimore, MD), who was not part of the writing committee, said he agreed with 90% of the information in the new guidelines. "To put that in perspective, I probably only agree with my wife 85% of the time," he said.

I don't even agree with my wife 100% of the time.

Namely, he is a little troubled by the new atherosclerotic risk score. Derived from FHS, ARIC, CARDIA, and CHS, it hasn't performed all that well when applied to other cohorts, such as the Multiethnic Study of Atherosclerosis (MESA) and Reasons for Geographic and Racial Differences in Stroke (REGARDS) study, he said. The risk score does not take into account family history of premature cardiovascular disease, triglycerides, waist circumference, body-mass index, lifestyle habits, and smoking history.

"In my mind, we're putting a lot of faith in this risk score," said Blumenthal. "We're probably going to be treating many more people, especially many more ethnic minorities, who get above this 7.5% threshold."

Dr Brendan Everett (Brigham and Women's Hospital, Boston, MA) told heartwire that the expert panel is going "out on a limb" a little with regard to the new risk score. He said that while a risk-prediction algorithm was used in the ATP III guidelines, a number of large statin trials have been published to date, and none of these studies used a risk score to identify patients for inclusion.

"If the model performs poorly, of course, then it's unlikely to do a good job separating patients at a higher rather than lower 10-year atherosclerotic cardiovascular disease risk, and it will thus lead to misallocation of statins," commented Everett. "Even if it does perform well, using a risk score to identify individuals who will benefit from statin therapy, regardless of the etiology of their elevated risk, is not an approach that has been tested in any clinical trial."

Will There Be Any Controversy?

The aspect of the new guidelines that will likely receive the most pushback from physicians is treating individuals with LDL-cholesterol levels ranging from 70 to 100 mg/dL, the so-called "normal" levels, simply because their risk score exceeds 7.5%. The risk score, argues Blumenthal, is dominated largely by chronological age, blood pressure, and smoking status.

"Patients could have a completely normal lipid profile, with normal triglycerides, HDL cholesterol, and LDL cholesterol, but because of what your birth certificate says, or because your blood pressure is 145 [mm Hg], the guidelines will now recommend treatment," Blumenthal told heartwire . "I think this is going to be problematic for a lot of physicians and patients because just last week you would have said their LDL-cholesterol levels of 80 or 90 [mg/dL] is optimal."

Dr Steven Nissen (Cleveland Clinic, OH) said the guidelines are a "radical change" from ATP III, but he agrees with moving away from the traditional targets. "Those goals, of less than 70 or less than 100 [mg/dL], were never based on any kind of careful scientific study," said Nissen. "They were helpful to physicians and patients because they were a target. The guideline writers threw out those goals and are working very hard to identify patients in whom statins provide benefit."

Nissen also said treating patients with a calculated risk exceeding 7.5% is a lower threshold for treatment than previous guidelines and likely expands the use of statins to millions of patients who would not have otherwise been treated under the ATP III guidelines. What will help is that the drugs are so cheap, now that all the statins, with the exception of rosuvastatin, are available as generic medications.

"I think it makes sense," said Nissen. "Statins have had a profound impact on the risk of morbid and mortal events for heart disease. They are generally very safe. The old guidelines previously emphasized the treatment of patients in older age groups. Now it's easier to look at people in their 40s or 50s and have them reach a 7.5% risk. In many ways, that's good, because if you wait until people are older to treat them, they'll already have vascular disease by the time you begin treatment. The point of treatment is to prevent disease."

Blumenthal said another limitation to the guidelines is in selecting 70 mg/dL as the threshold for treatment if their 10-year risk exceeds 7.5%. There would likely be less resistance to change if the guideline writers selected 100 mg/dL as the lower threshold for treatment in this group, he suggested. He agreed that physicians who don't advocate statin therapy in patients who have not yet had a cardiovascular event, the primary-prevention cohort, might be upset that more Americans are going to be treated with the lipid-lowering drugs.

Fire and Forget

Overall, nearly every expert consulted agreed with the shift away from specific LDL-cholesterol treatment targets given the lack of evidence and with the emphasis on using maximum tolerated statin intensity. As Everett said, "there are really no other good data in this broad population that anything works as well as a statin." He noted the previous guidelines left more room for doctors to use nonstatin agents, but none of them have been shown to reduce hard clinical end points.

Nissen told heartwire the new recommendations should generally help make treatment easier for aware physicians, in that there is a decision to treat followed by a decision on dose. He used a military term to describe the approach, "fire and forget," in that physicians won't have to titrate to goal but instead choose a statin known to achieve a given relative reduction in LDL-cholesterol levels. He adds there is the possibility of confusion among some doctors given the switch away from targets, and this might lead to treatment inertia.

Dr Michael Miller (University of Maryland, Baltimore, MD) agreed about the increased ease of use with the new guidelines. "In a way, the guidelines are easier because it's either moderate or high dose, and it knocks out other medications like fibrates, niacin, and ezetimibe unless patients are statin intolerant or they can't get the desired LDL lowering," he told heartwire . "It does bring a bit more focus in on simplifying the regimen until we get new data."

He added he was not surprised by the shift away from specific targets, adding that writing committee largely "got it right based on what we know today." The Pravastatin or Atorvastatin Evaluation and Infection Therapy (PROVE-IT) trial, for example, was a secondary-prevention study that led the way for "lower is better" in acute coronary syndrome patients, but that trial tested a moderate-intensity statin vs a high-intensity statin. It did not compare outcomes based on specific treatment targets.

"The problem I foresee now is what to do with patients we've been taking care of for a period of time," said Miller. "I have patients I've been taking care of for 20 years, and they've been doing fine on a moderate statin. Am I now going to push the envelope?"

The strongest recommendation, he believes, will be to institute moderate or intensive statin therapy in patients coming into the clinic now or for the statin-naive patient. For the patient who has not yet been maximized on an intensive statin but who has had a coronary event years ago, there is insufficient evidence to make changes, said Miller.

Other Recommendations

In addition to identifying the four statin groups, the focus on intensity rather than goals, and the new global risk assessment equations for primary prevention, the new cholesterol guidelines also make recommendations on safety and provide guidance on the role of biomarkers and other noninvasive tests.

In the new guidelines, the ACC/AHA state that in selected individuals who don't fit into any of the four groups, additional factors can be considered if the decision to start statin therapy is unclear. The factors include family history of premature atherosclerotic cardiovascular disease in a first-degree relative, high-sensitivity C-reactive protein (CRP) >2 mg/L, the presence of calcification on a coronary artery calcium (CAC) scan, and an ankle-brachial index <0.9.

The writing committee also states that the new guidelines are not intended to provide a comprehensive approach to managing lipids and that many unanswered questions remain. These future questions, such the use of non-HDL cholesterol in decision-making, the role for treating high triglycerides, and whether treating markers such as apolipoprotein B or LDL particles is useful, will hopefully be examined in future randomized trials and incorporated in future guidelines.

Stone and Lloyd-Jones report no conflicts of interest. Disclosures for the coauthors are listed in the paper. Blumenthal reports no conflicts of interest. Everett reports grant support from Roche Diagnostics, the NHLBI, and Novartis. Nissen reports consulting for all the major pharmaceutical companies, including AstraZeneca, the makers of Crestor, but does not accept financial compensation. Miller reports consulting for Amarin and GlaxoSmithKline and receives research funding from Amgen, Eli Lilly, Merck, Roche, and Takeda Pharmaceuticals.


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