ORLANDO, FLA. — Why do some individuals live well into their 90s free of heart disease despite an untreated serum cholesterol of 350 mg/dL, while on a daily basis physicians see numerous patients with normal or even low cholesterol who have advanced coronary disease at a relatively young age?
The answer appears to be that people differ in their vascular sensitivity to cholesterol. And that characteristic has major implications for treatment guidelines, which don't acknowledge these individual differences, Robert A. Vogel, M.D., said at the annual meeting of the American College of Cardiology.
This was the provocative implication of a new substudy of the previously reported Reversal of Atherosclerosis with Lipitor (REVERSAL) trial, said Dr. Vogel, professor of medicine and director of clinical vascular biology at University of Maryland, Baltimore.
The primary REVERSAL result was that intensive LDL-cholesterol lowering using 80 mg/day of atorvastatin (Lipitor) halted progression of coronary artery disease (CAD) as assessed by intravascular ultrasound during 18 months of follow-up. CAD continued to worsen in patients randomized to moderate LDL lowering with 40 mg/day of pravastatin (Pravachol). This finding paved the way for the Pravastatin or Atorvastatin Evaluation and Infection Therapy (PROVE-IT TIMI-22) trial, which showed fewer cardiovascular events with 80 mg/day of atorvastatin than with 40 mg/day of pravastatin after hospitalization for acute coronary syndrome.
The new REVERSAL substudy involved 214 participants with CAD whose endothelial function was assessed using the brachial artery flow-mediated dilation test at 21 medical centers. The purpose was to learn whether 3 months of intensive LDL lowering would improve endothelial function more than moderate LDL lowering. And, indeed, it did. Atorvastatin at 80 mg/day boosted flow-mediated dilation by 72%, while 40 mg/day of pravastatin increased it by 32%. But the substudy also yielded a completely unexpected and counterintuitive finding: Those CAD patients with the lowest pretreatment LDL-cholesterol levels had the worst baseline endothelial function. And they also responded much more dramatically to intensive LDL lowering than did patients with higher LDL levels.
“We found in the overall trial that the difference between intensive and moderate therapy was concentrated in people who started with low cholesterol. As clinicians, we tend not to look at intensive therapy when the cholesterol is low to start out with. But we found in REVERSAL that those were the patients who actually benefited to the greatest degree,” he explained.
The presence of CAD in REVERSAL participants with low baseline LDL-cholesterol levels couldn't be accounted for by an increased prevalence of any of the traditional or novel cardiovascular risk factors. These patients differed from the others only in their low LDL levels and worse endothelial dysfunction.
“We think the explanation is that we're all different and that if you get coronary disease and your LDL is low, it's because you're really sensitive to cholesterol,” he continued. “Your goal in cholesterol may be very different from my goal in cholesterol.”
This is a reality the National Cholesterol Education Program guidelines will have to find a way to acknowledge, assuming the new REVERSAL finding is confirmed. But that doesn't mean measurement of endothelial dysfunction is likely to find its way into routine clinical practice as a risk-stratification tool.
“Measuring brachial artery blood flow is a complicated technique. We've been doing this now for 13 years. We have one technician who's been doing it the whole time. That's all he does. One of the disappointments in REVERSAL is we found the variability of even well-trained centers to be more than we would have expected. That makes doing clinical trials, let alone individual decision making about patients, very, very difficult. At the present time, I don't see brachial artery ultrasound as a clinically oriented technique,” he said.