IVUS being used to test new drug therapies

Measuring plaque burden with IVUS is effective method for monitoring atherosclerosis.

Use of intravascular ultrasonography can precisely measure plaque burden and is currently being used to test new drug therapies.

“There’s a paradigm shift going on, which will very likely lead to approval of new antiatherosclerotic agents based upon IVUS imaging trials,” said Steven E. Nissen, MD, medical director of the Cleveland Clinic Cardiovascular Coordinating Center and editorial board member of Cardiology Today’s Noninvasive Imaging section.

Nissen and Paul Schoenhagen, MD, reviewed the state of IVUS in clinical trials for a recent paper published in the Cleveland Clinic Journal of Medicine.

Plaque volume

Steve E. Nissen

“The problem is if you want to wait for morbidity and mortality trials for new classes of antiatherosclerotic drugs, let’s say HDL-raising drugs, it is going to take a long time. If you were to start a phase 3 or phase 4 trial tomorrow, you wouldn’t have data until 2012 and patients can’t wait that long,” Nissen said.

“So we’ve developed IVUS to be used along with studies of carotid intima-media thickness as a means to getting drugs approved for the indication of slowing coronary atherosclerosis.”

IVUS allows researchers to measure an artery at two different time points and determine the volume of atherosclerotic plaque.

“We recognize that it’s always better to have morbidity and mortality data when you can, but this is an intermediate step that potentially can be used by regulatory authorities,” Nissen said, adding that no drugs have been approved yet based on this outcome measure.

Several trials have used IVUS studies for quantitative volumetric analyses. In the REVERSAL trial (Reversal of Atherosclerosis with Aggressive Lipid Lowering), patients with angiographically documented CAD were randomly assigned to 18 months of treatment with 80 mg of atorvastatin (Lipitor, Pfizer) or 40 mg of pravastatin (Pravachol, Bristol-Myers Squibb).

Ultrasound measurement: Atheroma area.

The primary outcome of REVERSAL was the percent change in atheroma volume, which increased by 2.7% in the pravastatin group and decreased by 0.4% in the atorvastatin group, an effect that was independent of baseline LDL cholesterol levels.

“We determined that outcome using IVUS. Subsequently, PROVE-IT, a morbidity and mortality trial, showed that the differences that we saw by IVUS translated into big clinical advantages,” Nissen said.

Direct observation

In the APO A-I Milano trial, 47 patients were randomized to receive five weekly IV infusions of placebo or recombinant apolipoprotein A-I Milano/phospholipid complexes (ETC-216) at 15 mg/kg or 45 mg/kg in a double-blind fashion at a 1-2-2 ratio.

IVUS was performed within two weeks after an acute coronary syndrome episode and was repeated after the five weekly treatments.

“This trial showed that HDL infusion could improve the rate of progression and actually induce regression of coronary atherosclerosis, and that drug is now being developed,” Nissen said.

According to the review paper, IVUS allows direct observation of a vessel’s plaque burden rather than its lumen size. It is performed during cardiac catheterization. A small catheter (<3 French or <1.0 mm) is advanced into the coronary artery, allowing real-time intraluminal imaging of the vessel wall and measurement of the atheroma.

“We’re not trying to measure preclinical endpoints. Most of the studies we’re doing are among patients who already have the disease. What we’re trying to do is refine therapy,” Nissen said. – by Jeremy Moore

For more information:

• Schoenhagen P, Nissen SE. Intravascular ultrasonography: using imaging end points in coronary atherosclerosis trials. Cleve Clin J Med. 2005;72:487-496.