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Michael O'Riordan

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
[1]
in both the Journal of the American College of Cardiology and Circulation .
And they contain some substantial changes from ATP 3.
Gone are the recommended LDL- and non-HDLcholesterol 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:

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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 therapysuch as rosuvastatin (Crestor,
AstraZeneca) 20 to 40 mg or atorvastatin 80 mgshould 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

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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,

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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.
References

1. Stone NJ, Robinson J, Lichtenstein AH, et al. 2013 ACC/AHA guideline on the treatment of blood cholesterol to
reduce atherosclerotic cardiovascular risk in adults: A report of the American College of Cardiology/American
Heart Association. J Am Coll Cardiol 2013. Article. Circulation 2013. Article.

Heartwire 2013

Cite this article: Michael O'Riordan. New Cholesterol Guidelines Abandon LDL Targets. Medscape. Nov 12, 2013.

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