Both rosuvastatin (Crestor, AstraZeneca) and atorvastin (Lipitor, Pfizer) at maximum dose lowered LDL cholesterol levels, raised HDL levels and reduced atherosclerotic plaque in the SATURN trial, the study’s lead researcher reported Nov. 15 at the 2011 American Heart Association conference. While the Phase 2 clinical trial failed to find any significant difference between the two drugs’ ability to limit or reverse progression of coronary artery disease (CAD), it did show that a high-dose regime is safe and well tolerated.
“No study has directly compared the effects of the maximum dose of the most efficacious statin regimes on the progression of coronary atherosclerosis,” Stephen J. Nicholls, MBBS, PhD, cardiovascular director at the Cleveland Clinic, said during a presentation. He added that safety at highest dosages also is a concern. “Doctors and patients tend to not use higher doses of these therapies. They are worried about the safety and they don’t know if there is any extra benefit for the patient.”
Nicholls and colleagues enrolled 1,385 patients with symptomatic CAD with angiographically confirmed stenosis of greater than 20 percent and LDL cholesterol levels of more than 80 mg/dl or, if untreated with a statin in the preceding four weeks, LDL cholesterol levels of more than 100 mg/dl. Patients were randomized into either a rosuvastatin group (694 patients who received a 40 mg dose daily) or a atorvastin group (691 patients, 80 mg daily dose).
They performed a serial intravascular ultrasound (IVUS) assessment at baseline and after 104 weeks of treatment and measured LDL-C, HDL-C and triglyceride levels at six, 12, 18 and 24 months, plus C-reactive protein at 12 and 24 months. The primary efficacy endpoint was percent of atheroma volume (PAV) and the secondary efficacy endpoint was normalized total atheroma volume (TAV).
An analysis of cholesterol levels gave the edge to rosuvastatin over atorvastatin for LDL, 62.6 vs. 70.2 mg/dl, and for HDL, 50.4 vs. 48.6 mg/dl. PAV decreased by 0.99 percent with atorvastatin and by 1.22 percent with rosuvastatin.
“The most striking finding is the degree of regression in both groups,” Nicholls said, adding that there was no significant difference between the groups. “There was a marked regression in coronary atherosclerosis [in both groups] and a much greater extent than we have ever observed in any other clinical trial.”
They found a statistically significant difference in TAV findings, with rosuvastatin at -6.39 mm 3 compared with atorvastatin at -4.42 mm 3.
The majority of patients in both groups showed disease regression: 63.2 percent with atorvastatin and 68.5 percent with rosuvastatin for PAV, and 64.7 percent with atorvastatin and 71.3 percent with rosuvastatin for TAV.
“We see that about two-thirds of the individuals treated with the highest doses of these therapies actually [had the treatment] remove plaque from the coronary artery wall,” he said.
They reported that the adverse event rate was half of that in other studies, and the low event rate was coupled with both drugs being “amazingly well tolerated,” he said.
Nicholls concluded that maximum doses of both drugs were well tolerated and promoted disease regression. “We have come a long way, but we still have a long way to go,” he concluded.
In a follow-up discussion, Darwin L. Labarthe, MD, PhD, MPH, of Northwestern University Feinberg School of Medicine in Chicago, said he found the study to be informative but inconclusive and cautioned that about 29 percent of patients were lost to follow-up.
He summarized that the primary outcome found no difference between rosuvastatin and atorvastin while the second outcome favored rosuvastatin, making it inconsistent with the first outcome. He added that outcomes for patients lost to follow-up were unknown and could change the results substantially.
“This study provides no basis to infer a differential clinical benefit between the two interventions,” he said. He added that Nicholls and his colleagues acknowledged these limitations in a paper on SATURN that was published simultaneously in the New England Journal of Medicine.
SATURN was funded by AstraZeneca.