Experts react to the new NCEP ATP III guidelines: Many anticipate further changes down the road

July 16, 2004

Fri, 16 Jul 2004 20:30:00

Bethesda, MA - This past week, the National Cholesterol Education Program (NCEP) Adult Treatment Panel III (ATP III) published updated guidelines for cholesterol management, with significant changes in the treatment of high-risk and moderate-risk patients. Coming just two and a half years since the publication of the ATP III guidelines, the updated report is based on new evidence gleaned from five major clinical trials with statin therapy.

In the updated NCEP report, the panel took steps to address the million-dollar lipid questionthat is, "Just how low do you go with LDL lowering?" The answer, in fact, is very low, with the major message from the new guidelines being that lower is better for high-risk and moderately high-risk patients.

Still, the panel hedged a little, and instead of explicitly recommending clinicians lower LDL cholesterol in high-risk patients to levels <70 mg/dL, they left the door open for future evidence. In these very high-risk patients, lowering LDL cholesterol levels to <70 mg/dL remains a "therapeutic option," while the definitive recommendation is to lower LDL cholesterol levels to a target of <100 mg/dL.

Record between evidence and guidelines

Not surprisingly, the publication of the updated guidelines drew the attention of cardiologists, with many happy with the new recommendations and some who felt they were simply a step in the right direction.

"I think the guidelines are wonderful," Dr Christopher Cannon (Brigham and Women's Hospital, Boston, MA) told heartwire . "For one, the changes were so quickly made after PROVE-IT that I think it's an absolute record between evidence and national guidelines."

Cannon was the lead investigator of the Pravastatin or Atorvastatin Evaluation and Infection Therapy (PROVE-IT) study, one of the five trials weighed by the NCEP panel when updating the guidelines. In PROVE-IT, intensive lipid lowering with atorvastatin (Lipitor®, Pfizer) 80 mg daily provided greater protection from death and cardiovascular events compared with pravastatin (Pravachol®, Bristol-Myers Squibb) 40 mg daily in patients recently hospitalized with acute coronary syndromes (ACS).


The changes were so quickly made after PROVE-IT that I think it's an absolute record between evidence and national guidelines.


"I think the therapeutic option term is reasonable in that as far as the <70 mg/dL recommendation in high-risk patients, there has only been the one trial," said Cannon. "I think when the guidelines came out this week everybody understood that this is really the right answer in high-risk coronary patients, that they are in fact saying go to less than 70, if possible."

Cannon adds that, in terms of performance measures, the subtle wording leaves clinicians with some wiggle room for their patients who can't get to less than 70 mg/dL. Others, however, were slightly more critical, believing the guidelines need to go further in recommending clinicians aggressively lower LDL levels in these high-risk patients.

"The guidelines are starting from ATP III and the problem is that ATP III is also in the wrong place," Dr Rory Collins (Clinical Trials Unit, Oxford, UK) told heartwire . "ATP III was looking at lowering high LDL levels to so-called normal levels, which were themselves too high. By doing this interim report, I think they have almost got there, but it is still the wrong place to start from. The lessons from the Heart Protection Study [HPS] and PROVE-IT really need to be more incorporated into the report, and to do that, one would start from a different position."

Still, Collins, the principal investigator of HPS, another of the trials influencing the new recommendations, said he recognizes this is an interim report and understands the panel's desire not to completely rewrite the guidelines.

"I think the report has actually gotten a lot of things right in terms of emphasizing that what you're actually trying to do is lower LDL, and the bigger the absolute reduction the bigger the reduction in risk," he said. "Essentially, one wants to target a big absolute reduction in LDL in those who are at highest risk, and this is what the reports says, although it is written in a more complicated way than it needs to be."

A 30% to 40% reduction in LDL cholesterol

Overall, in high-risk patients, the NCEP update calls for drug therapy in those with LDL cholesterol levels between 100 and 129 mg/dL. In contrast, the ATP III guidelines set the threshold for drug therapy for high-risk patients at LDL cholesterol >130 mg/dL. Drug treatment was previously optional in those patients with LDL levels between 100 and 129 mg/dL.

Dr W Virgil Brown (Emory University, Atlanta, GA) told heartwire that the previous guidelines were problematic because they provided an upper limit of cholesterol for different levels of riskthat is, 160, 130, 100 mg/dLwithout telling clinicians to what level LDL needed to be reduced. As a result, many physicians failed to recognize these LDL levels as upper limits and have remained too comfortable with LDL cholesterol levels of 105 or 110 mg/dL in their high-risk patients, said Brown.

"The old guidelines, for those patients at highest riskthe coronary patient, the diabetic patientwere based on a trigger at 130 mg/dL," said Brown. "In other words, you should be using drugs, unless there is a contraindication, if you're above 130 mg/dL, and you would aim to get below 100 mg/dL. Now they're saying that even in that range, 100 to 129, you may well want to treat your high-risk patients and you want to treat them significantly, by lowering a further 30% to 40%."

He added the publication of recent clinical trials forced the panel to address the findings from these studies within the new guidelines. With regard to high-risk patients, both HPS and PROVE-IT helped better define the degree of reduction, he said.

"In both PROVE-IT and the Heart Protection Study, the 100 mg/dL cutoff didn't seem quite good enough," said Brown. "Leaving people at 99 mg/dL, which would have satisfied the guidelines, still leaves people at risk. We've now demonstrated benefit in going well below that number, so the panel felt compelled to say that 100 mg/dL is not adequate. But if something below that is needed, what is it? That has always been the immediate question. With the update, that is now defined for us."

In moderate-risk patientsthose with two or more risk factors for CHD (10% to 20% risk of CHD within 10 years), the NCEP target remains LDL cholesterol <130 mg/dL but gives clinicians a new therapeutic option to treat to <100 mg/dL.

"The moderate-risk group is the biggest, in terms of numbers of patients, and everybody seems to shy away from estimating just how many of these patients there are," said Cannon, adding that he has heard some say there are at least 10 million patients in the US, a number he agrees with. "This is where, by sheer numbers alone, the biggest impact will be. These changes that were made to the guidelines are fully supported by the ASCOT data, and I'm really quite happy with them."

Not going far enough

Some cardiologists, however, were not quite as enthusiastic with the new guidelines, especially the "therapeutic-option" designation.

"I don't think they went far enough," Dr Eric Topol (Cleveland Clinic, OH) told heartwire . "I understand that they may be waiting for some of the bigger trials, such as TNT and SEARCH, but we have to treat patients today."

In the NCEP update, the expert panel said that until further trials are completed, HPS and PROVE-IT shouldn't be taken as the final word on the benefit of reducing LDL cholesterol levels to well below 100 mg/dL. Until further studies are completed, such as TNT, SEARCH, and IDEAL, prudence requires that setting an LDL cholesterol goal of <70 mg/dL must be left as an option, whereas a goal of <100 mg/dL can be retained as a strong recommendation.

Topol, however, disagrees, noting that for high-risk ACS patients, PROVE-IT provided powerful and definitive results. Even in HPS, the ACS patients with LDL cholesterol levels of 100 mg/dL that were further reduced 30% had a 20% to 30% lowering in the relative risk of CHD, notes Topol. Hedging the guidelines with "preferred therapeutic options" will only make it more difficult for the NCEP panel to get this message out, especially when it is difficult enough to get patients on statins and treated to goal, he said.

Waiting for the big trials

Like the NCEP panel, many cardiologists are awaiting the publication of a number of major statin therapy trials in stable CHD patients. The large clinical-end-point trials are each comparing high-dose vs moderate- or low-dose statin treatment:

The Treating to New Targets (TNT) trial enrolled approximately 10000 CHD patients and should be completed in December 2004 and will likely be presented at the 2005 American College of Cardiology Scientific Sessions. In this trial, patients are treated to different goals to compare the conventional NCEP guideline of an LDL cholesterol goal of less than 100 mg/dL with a more aggressive LDL cholesterol goal of less than 75 mg/dL.

The Study of the Effectiveness of Additional Reduction in Cholesterol and Homocysteine with Simvastatin and Folic Acid/Vitamin B 12 (SEARCH) compares the intensity of lipid lowering, rather than specific goals, in 12000 subjects who have had a prior MI. The lipid-lowering interventions tested are simvastatin (Zocor®, Merck) 20 mg vs simvastatin 80 mg. In addition, SEARCH is testing the homocysteine hypothesis by the use of 2 mg of folic acid and 1 mg of vitamin B12.

The Incremental Decrease in Endpoints through Aggressive Lipid Lowering (IDEAL) trial is a 7600-patient study investigating whether additional clinical benefits can be achieved by greater percentage reductions in LDL-cholesterol levels with atorvastatin 80 mg than those seen with usual care (simvastatin 20 mg to 40 mg) in patients with existing CHD.

Dr Roger Blumenthal (Johns Hopkins University Medical Center) agreed that the recommendations in the guidelines could have been written more strongly. Since PROVE-IT, as well as HPS, many clinicians will likely be striving to bring LDL cholesterol levels down below 70 mg/dL anyway, he said.


If a patient is able to tolerate the drug, there is no reason why we shouldn't be pushing for lower and lower LDL numbers.


"I think even in patients with moderate to extensive coronary disease, no matter what the lipids are, many clinicians are going to be starting patients with a stronger statin with the intention of bringing LDL levels lower than 70 mg/dL," Blumenthal told heartwire . "If a patient is able to tolerate the drug, there is no reason why we shouldn't be pushing for lower and lower LDL numbers."

Blumenthal added, however, that he understands the panel's need to be cautious with the new guidelines. A number of trials are currently investigating the "How low should you go?" question and, it is hoped, will be able to answer it in stable CHD patients, he said.

"Although PROVE-IT provided a definitive answer with unstable ACS patients, it is still undecided as to how low the LDL levels should be in stable coronary patients," said Blumenthal. "So I can understand where the panel is coming from with the new guidelines. But I think we're going to start seeing a shift, even in stable patients, and especially if TNT, SEARCH, and IDEAL are positive, or even slightly positive, in that clinicians will start treating LDL cholesterol a lot more aggressively."

Brown agreed, saying he believes the recommendations reflect some anxiety about being caught flat-footed, simply because the existing data set is based on high-risk patients in special circumstances. The HPS data was based on a subgroup analysis, while PROVE-IT was studying a very-high-risk subset of unstable patients treated within the first 10 days after an infarct or hospitalization with unstable angina.

"The data we have are not broad and comprehensive, yet they are trying to make comprehensive guidelines out of them," said Brown. "This is also being done in the setting of having three huge trials currently under way looking at the stable patientTNT, SEARCH, and IDEAL. We are soon going to be getting a flow of data on this subject, so whatever the NCEP panel says now is going to have be reexamined in light of this new data involving some 30000 patients."

Dr Thomas Pearson (University of Rochester, NY) echoes the sentiments of others, saying that he believes the guidelines reflect the lack of definitiveness the data merit. He added, however, that despite not recommending that physicians treat to LDL levels <70 mg/dL and 100 mg/dL in high-risk and moderate-risk patients, the updated report will ultimately serve a purpose.

"The recommendations will be a wake-up call for some physicians," Pearson told heartwire . "There are many out there who have looked at the data and are starting to treat to lower targets. But there are still some clinicians who are willing to settle for an LDL of 130 in the coronary patient or 150 in the diabetic patient. This should be a wake-up call to let them know that they're not even close."

Should the changes have waited?

Brown told heartwire that he would have preferred to have the panel update the ATP III guidelines after the publication of these upcoming trials, with the results being available very shortly.


The data we have are not broad and comprehensive, yet they are trying to make comprehensive guidelines out of them.


"My concern is that the current update may need an additional modification based on the findings in these studies," he said. "Guidelines should have some stability; otherwise, the clinician never catches up. It takes a period of time to educate and debate and adopt. We were still in that process with the ATP III initial pronouncements."

"At the present time, the guidelines match the evidence," Cannon added. "Unfortunately, it does take time for physicians to adopt the recommendations, but I think many of them are starting to get the message that lower is better. Many people are now becoming more aggressive in treating patients."

Despite not explicitly calling for reductions of LDL to <70 mg/dL in very high-risk patients, most of those interviewed by heartwire believe the message is getting out. Collins said HPS drew attention to the very high probability that lower was better within the then-acceptable LDL cholesterol ranges, while PROVE-IT reinforced that message.

"I think what is coming through with the NCEP report is that how aggressive you are in lowering LDL depends on how high the risk is," said Collins. "They've chosen to categorize that, and I think it's a complicated way of saying that we should forget the LDL level, and depending on somebody's estimate of risk, be more or less aggressive with LDL lowering. Still, this report is a very big step toward a simplification of the guidelines, and the more we learn, the more we'll able to simplify them further."

Related links

1. [HeartWire > Atherosclerosis; Jul 12, 2004]

2. [HeartWire > Atherosclerosis; Mar 8, 2004]

3. [HeartWire > Atherosclerosis; Mar 8, 2004]

4. [HeartWire > Atherosclerosis; Mar 02, 2004]

5. [HeartWire > News; Apr 2, 2003]

6. [HeartWire > News; Dec 17, 2002]

7. [HeartWire > News; Nov 18, 2002]

8. [HeartWire > News; Jul 4, 2002]

9. [HeartWire > News; Nov 13, 2001]


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