Chris’s Corner: New Cholesterol and Risk Guidelines Make a Splash
When the new cholesterol guidelines (along with several others) were released just prior to the American Heart Association Scientific Sessions, they quickly became a center of attention and point of debate at the meetings. I thought I’d take the opportunity to offer a few thoughts of my own on them, which were formerly to become the National Cholesterol Education Program Adult Treatment Panel (ATP) IV.
Let’s start with the strengths: the panel worked very hard to only include only fully evidence-based recommendations, on the advice of the Institute of Medicine. This led to the very strong recommendation that statins be used for secondary prevention, due to the multitude of trials demonstrating statins’ benefits.
Indeed, the recommendation that any patient with atherosclerotic disease receive intensive statin therapy (not only the “very high-risk” as the previous ATP III Update from 2004 stated) is the least discussed aspect of the new guideline. I fully support this idea—not surprisingly, since PROVE IT was one of the five trials showing benefit of intensive statin therapy over standard dose treatment. The recommendation to treat those with extremely high LDL cholesterol and type II diabetics is also strongly evidence-based.
Perhaps the most hotly-debated issue related to the new guidelines was the introduction of a new risk calculator to identify primary prevention patients for treatment. The new calculator—which adds the ability to predict stroke and contains two calculators (one for 10-year risk, one for lifetime risk)—certainly represents a major advance. The lifetime risk feature is particularly helpful when discussing prevention with younger patients. For example, I recently saw two new patients (one in their 40s and one in their 50s) who were concerned about cardiovascular risk. I ran through the new calculator on CardioSource with them; the findings revealed 10-year risks of 4% and 9%, respectively, but their lifetime risks were 30–40%. The older patient was started on statins, while the younger patient began a lifestyle intervention program (with the promise to revisit after 6 months to discuss if statin therapy would be beneficial).
So, where is the controversy? In the details of course: the calibration of the risk calculator. My colleague Paul Ridker, MD, ran the risk model in three of his large cohorts and found that the predicted risk was substantially higher than the actual observed risk in his studies. These differences are not surprising, but the degree of difference seemed higher than one would expect. The concern is that the risk calculator’s overestimation would impact the decision to treat, and possibly lead to the overtreatment of millions of Americans, as some newspapers posited.
I imagine that many investigators with large cohorts of patients are currently running detailed assessments of the risk calculator (looking at calibration, net reclassification, etc.), and hopefully we will see results soon. In my opinion, a good next step would be for these data to be presented and published at some sort of summit. This approach worked well following the drug-eluting stent thrombosis scare in 2006, when the Food and Drug Administration held a 2-day meeting for trialists to present their data.
One aspect I found strange was that the cholesterol guideline does not include cholesterol in the indications to treat (other than if LDL is >190 mg/dL). In theory, this indication was omitted because baseline LDL didn’t seem to matter in the trials; statins were always better. However, baseline LDL was usually included in the entry criteria.... Imagine if a treatment guideline for diabetes omitted a history of diabetes from its indications, and recommended that everyone older than 70 receive antidiabetic agents—just based on a risk of cardiovascular events?!
As such, I think that we should perhaps add elevated cholesterol to cardiovascular risk assessment when deciding to treat for primary prevention. Of course, even this simple idea of adding cholesterol doesn’t account for all primary prevention trials; patients in JUPITER had lower LDL and high C-reactive protein and still had clear benefit. Perhaps a more “trial entry criteria–based” approach for determining who should be treated would be the best “evidenced-based” approach.
This brings us to another area of controversy: not checking on-treatment LDL. The guideline argues that no additional therapy has been shown to be beneficial in a large trial. We do, however, have many ongoing trials with ezetimibe, PCSK9 inhibitors, and CETP inhibitors added to statins which use LDL as an entry criterion. Another reason to check on-treatment LDL is for medication compliance. Therefore, most doctors I have spoken with (and I) will continue to monitor LDL.
The seemingly arbitrary cut-off age in the guideline is another characteristic that I find odd. The guideline recommends only standard dose statin therapy for patients older than 75 years with known vascular disease, while recommending—most strikingly—no statin treatment at all for primary prevention in the elderly. This struck me as strange since there has been no observed interaction by age in the very large evidence base supporting treatment (encompassing thousands of elderly patients in the 26 large randomized trials). It is likely that the committee believed there would be more side effects due to drug-drug interactions in this population, but it would be simple enough to reduce the dose if a patient (of any age) developed a side effect.
All told, I am happy that these guidelines finally came out into the light and that the discussions and debates can begin. They represent an opportunity to advance these guidelines, as well as to improve the preventive therapy we can offer our patients.
Keywords: Drug Interactions, Cholesterol, Risk, Life Style, United States Food and Drug Administration, Cardiovascular Diseases, Primary Prevention
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