Clinical Laboratory Strategies: June 11, 2009

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Moving Targets for Coronary Artery Disease
Study Supports Tighter Control of LDL-C and Blood Pressure

By Bill Malone

The medical community has known for decades that controlling LDL-C and blood pressure can help patients with atherosclerotic coronary artery disease, but questions remain about just how low clinicians and patients should attempt to drive these numbers. A new study shows that very low LDL-C and normal systolic blood pressure together might offer the best risk-reduction strategy. This issue of Strategies examines those findings.

Separately, both blood pressure and LDL-C and their relationship with coronary artery disease (CAD) have been studied extensively. Clinical trials demonstrated that statins lower LDL-C and prevent cardiovascular events, while epidemiological studies show that cardiovascular event rates increase with blood pressure greater than 115/75-mm Hg. However, the effect of simultaneous and intensive control of both factors isn’t well-defined. At the same time, more recent evidence suggests that treating patients more aggressively to lower LDL-C can bring additional benefit.

Seeking to better understand how these separate risk factors work together, researchers at the Cleveland Clinic in Ohio studied changes in atheroma burden, or plaque, as monitored by intravascular ultrasound in 3,437 patients with CAD (JACC 2009;53:1110-1115). The patients were stratified based on LDL-C greater or less than 70 mg/dL and systolic blood pressure greater or less than 120-mm Hg. They looked at four measures of plaque progression: percent atheroma volume, total atheroma volume, percent of patients with significant plaque progression, and percent of patients with significant plaque regression. For all of these variables, disease progressed the least in patients who had the lowest LDL-C and blood pressure.

"What we looked at with this study was really the combination, to see if there was an added benefit to getting both LDL-C and blood pressure to fairly low levels," said Stephen Nicholls, MBBS, PhD, assistant professor of molecular medicine at the Cleveland Clinic and a co-author of the study. "And that’s exactly what we saw, that the patients that clearly did the best—had the least growth of plaque in their arteries—were those patients who got their LDL less than 70 mg/dL and their systolic blood pressure below 120-mm Hg." This study is the first to demonstrate that normal blood pressure and very low LDL-C in combination are associated with less CAD progression in humans, supporting the idea that modifying global risk can slow CAD progression, even when risk factors are near normal ranges, the authors note.

More to the Story

Though researchers and clinicians remain confident that lowering cholesterol is key to treating patients with CAD, the problem remains that many patients who experience CAD-related events have lab values that fall below National Cholesterol Education Program (NCEP) guidelines. Conversely, many with quite high cholesterol never experience an event. Approaching CAD with an idea of global risk—putting more attention on hypertension, for example—may complete the picture, said Nicholls.

"This is not a disease with one cause, and it’s not a disease with just one treatment that’s going to cure it. So this study demonstrates that it’s not just about one risk factor, but you get a greater benefit from aggressively treating multiple perspectives, even when they’re near the normal range. This is an important finding because it’s not just about cholesterol, blood pressure, or diabetes. CAD results from a number of causes, and a number of causes often in the one patient. So ultimately, the best way to treat our patients will be treating their overall risk, rather than just focusing on one risk factor or another."

Time for More Aggressive Targets?

According to guidelines, patients with CAD should aim to reduce their blood pressure to below 140-mm Hg, but more recent evidence increasingly points to there being risk for pre-hypertensives (120-140-mm Hg), a notion reinforced by their study, said Nicholls. "If you can get your blood pressure below 120, you do much better. And if you can get it in combination with getting your LDL cholesterol down, you do even better on top of that."

In the article, the authors note that patients with pre-hypertension have twice as many events as those with normal blood pressure. However, guidelines from the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC-7) do not recommend blood pressure lowering drugs in pre-hypertensive patients with CAD.

Similarly, Nicholls predicted that as his study and others offer more evidence that lower LDL-C targets do make a difference, LDL-C levels laid out in guidelines and treatment goals will start to come down. But we still have a long way to go in meeting even modest targets. In fact, only 40% to 50% of patients achieve LDL-C targets in the U.S. and Europe, according to the authors.


At the end of the day, it’s ultimately more important whether a person dies or whether they have a clinical event than whether they are observed to have greater plaque progression or hypertension. So this is always one of the limitations in an imaging study that does not consider outcomes, said Nicholls. This observational study used pooled data from clinical trials, and so the authors can’t make suggestions about specific treatment strategies to lower LDL-C or blood pressure.

"While it shows us the effects of the disease, it’s not an outcome study. That being said, this is the disease that causes the outcome. And we believe that there is a very strong link between the progression of the disease on a number of different types of imaging and outcomes," explained Nicholls. "So I think the story is fairly clear that there is a relationship whereby therapies that have a benefit on the disease, also have a benefit on outcome."

Until a more definitive clinical trial that assesses the effect of different treatment strategies on clinical events can be assembled and analyzed, the new data suggests that very low LDL-C and normal systolic blood pressure offer a very good risk-reduction strategy for patients with CAD, Nicholls concluded.

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