ORLANDO -- Optimal treatment with potent statin drugs significantly regresses coronary plaque as evidenced by intravascular ultrasound procedures, researchers said here at the American Heart Association (AHA) meeting.
Stephen Nicholls, MBBS, PhD, medical director of intravascular ultrasound at the Cleveland Clinic, reported that in patients treated with high-dose (40 mg) rosuvastatin (Crestor), plaque burden decreased 1.22% (P<0.001) from baseline. The study was sponsored by AstraZeneca, the marketer of rosuvastatin.
Nicholls also reported that in patients treated with soon-to-be-generic atorvastatin 80 mg (Lipitor), plaque regression was 0.99% (P<0.001) from baseline. Atorvastatin will become a generically available drug this month.
However, there was no statistical difference (P=0.17) between treatment with atorvastatin when compared with rosuvastatin, Nicholls said.
A secondary efficacy endpoint, normalized total atheroma volume, favored rosuvastatin with a reduction of 6.4 cubic mm versus 4.4 cubic mm in the atorvastatin arm (P=0.01), Nicholls said. He added, however, that emphasis must be placed on the primary endpoint, which showed no statistical difference between the two drugs.
The findings were published online by the New England Journal of Medicine at the same time as the results were discussed in a press briefing sponsored by the AHA.
"Both groups did amazingly well, with more regression than we have ever seen with intravascular ultrasound," said Steven Nissen, MD, director of cardiovascular medicine at the Cleveland Clinic and one of the co-investigators of the Study of Coronary Atheroma by Intravascular Ultrasound: Effect of Rosuvastatin versus Atorvastatin (SATURN) trial.
Nissen was also the principal investigator of the 2004 REVERSAL trial in which high dose atorvastatin was compared with placebo in an attempt to reverse plaque. But while the result in REVERSAL showed no progression of atherosclerosis in the atorvastatin arm, the treatment failed to show a reversal of the coronary blockages.
"REVERSAL was an 18-month trial," Nissen told MedPage Today, "while SATURN ran for 102 weeks. We also have made better progress in other medicines and in getting patients to stop smoking which may have reduced inflammation in the SATURN patients." He said that the reduced inflammation levels may have allowed the statins in SATURN to better regress plaque.
In the trial, the 520 patients taking rosuvastatin over the course of two years achieved mean low density lipoprotein cholesterol levels of 62.6 mg/dL versus 70.2 mg/dL in the atorvastatin arm (P<0.001), and the high density lipoprotein cholesterol increase was likewise greater with rosuvastatin, for a mean of 50 mg/dL versus 49 mg/dL (P=0.02).
"These values resulted in a lower ratio of LDL cholesterol to HDL cholesterol during treatment with rosuvastatin (1.30±0.02 versus 1.50±0.02 with atorvastatin; P<0.001), a greater proportion of rosuvastatin-treated patients in whole LDL cholesterol levels below 70 mg per deciliter (1.81 mmol per liter) were achieved (72.1% versus 56.1% with atorvastatin; P <0.001), and a smaller proportion of rosuvastatin-treated patients whose LDL cholesterol levels remained higher than the current treatment goal of 100 mg per deciliter (2.6 mmol per liter) (4.6% versus 7.7% with atorvastatin; P =0.04)," the researchers reported in the journal.
The average age of patients was 57, more than 70% were men, and roughly 95% were white.
Stephen Nicholls noted that "Doctors have been reluctant to use high doses of statins, but in this study the drugs were safe, well-tolerated, and had a profound impact on lipid levels, the amount of plaque in vessel walls, and the number of cardiovascular events."
Safety was, in fact, better than expected with "not a single case of rhabdomyolysis," Nissen noted. There were a handful of atorvastatin patients -- 17 -- who had measurable increases in liver enzymes, and five patients -- four in the atorvastatin arm -- had creatine kinase levels more than 10 times the upper limit of normal, but those were isolated readings.
The researchers noted limitations of the study, including the lack of a placebo group to measure plaque progression. Moreover, since all patients were undergoing clinically indicated angiography, it "remains uncertain whether our findings apply to primary prevention in asymptomatic patients."
Also, 25% of patients did not undergo the final intravascular ultrasound assessment, and those patients may have had different rates of progression, the researchers said. These patients were not included in the report.
The invited discussant of the study, Darwin Labarthe, MD PhD, professor of preventive medicine at Northwestern University Feinberg School of Medicine, said those missing people in the study cast doubt on whether there was difference between the drugs -- and even whether there a difference in regression at all.
"All we can say about this study is that it is inconclusive," Labarthe told MedPage Today. "This is too large a fraction -- which I calculate as 29% of the patient cohort -- where results are unknown, to be ignored. We really don't have any idea what happened with these patients."
He said these unknown outcomes could easily have tipped the balance in favor or either drug.
Christopher Cannon, MD, associate professor of medicine at Brigham & Women's Hospital/Harvard Medical School, Boston, who was not a participant in the trial, suggested that SATURN did "have the regression over the two-year period that we would be hoping for."
He told MedPage Today the study also "provides some safety data on the 40-mg dose of rosuvastatin. We rarely use that high dose but sometimes we need that in people with sky-high LDLs. Now we have a study to show that generally it worked out okay.
"For 90% of the people, the study shows that atorvastatin will give you the same impact for much less cost," Cannon said. "I would think that in the post-generic age, rosuvastatin will find a place at both ends of the spectrum – high LDLs and those with muscle aches and pains. Those in between should be able to use atorvastatin."
The study was sponsored by AstraZeneca.
Nicholls disclosed commercial interests with Eli Lilly, AstraZeneca, Novartis, Resverlogix, Roche, Anthera, LipoScience, Merck, Takeda, CSL Behring, sanofi-aventis, Omthera, Boehringer Ingelheim and Abbott. Other co-investigators also noted commercial interests with Bristol-Myers Squibb, diaDexus, GlaxoSmithKline, Kowa, Sanofi-Synthelabo, Adnexus, Amylin, Esperion, Genentech,Idera Pharma, Resverlogix, Pfizer, ProNova and Sigma-Tau. Co-authors are also employees of AstraZeneca.
Dr. Nissen reports that the Cleveland Clinic Center for Clinical Research has received funding perform clinical trials from Pfizer, AstraZeneca, Novartis, Karo Bio, Takeda, Resverlogix and Eli Lilly.
Cannon disclosed commercial interests with Novartis, Bristol-Myers Squibb, Alnylam, Automedics Medical Systems, AstraZeneca, Merck, Accumetrics, GlaxoSmithKline, Takeda, Intekrin and Pfizer.
Labarthe had no disclosures.
- Reviewed by Robert Jasmer, MD Associate Clinical Professor of Medicine, University of California, San Francisco and Dorothy Caputo, MA, RN, BC-ADM, CDE, Nurse Planner
American Heart Association Scientific SessionsSource Reference: Nicholls S, et al "Comparison of the progression of coronary atherosclerosis for two high efficacy statin regimens with different HDL effects: SATURN Study Results" AHA 2011; Abstract LBCT.04.