ORLANDO – Results from a head-to-head comparison of the two top statins on the U.S. market, rosuvastatin and atorvastatin, in more than 1,000 patients with coronary disease – a study apparently designed to more definitively prove rosuvastatin’s superiority – instead showed that atorvastatin was statistically indistinguishable from its somewhat more potent rival for the study’s primary end point.
With this finding coming just 2 weeks before atorvastatin’s expected availability as a substantially cheaper generic drug, the study – funded by AstraZeneca, the company that markets rosuvastatin (Crestor) – appeared to have the ironic consequence of convincing experts, as well as likely payers and patients, that generic atorvastatin will do just fine for most clinical situations.
And by testing maximum dosages of both drugs for 2 years of therapy and showing that both were "amazingly well tolerated" by patients, in the words of the study’s leader, Dr. Stephen J. Nicholls, the trial also added to existing evidence that intensive therapy using either agent was safe and should be accepted more readily by physicians and patients.
The results "add to the body of evidence that these two statins are safe and quite effective for reducing risk," commented Dr. Daniel J. Rader, professor of medicine and director of the preventive cardiology program at the University of Pennsylvania in Philadelphia.
"These were very high doses. Physicians don’t like to prescribe the highest doses, and patients don’t like to take them, because they don’t think they’re safe and that they don’t have added benefit. [This study] was a good opportunity to show, in more than 1,000 patients, that if you treat patients for 24 months, [these drugs] are actually very well tolerated, the safety profile looks very good, [and] you can regress disease and get very good lipid changes," said Dr. Nicholls, clinical director of the Cleveland Clinic Center for Clinical Research.
Dr. Nicholls also highlighted the "unprecedented" regression of coronary atheroma (the study’s primary efficacy measure) that was achieved in most study patients after 2 years of treatment with maximum dosages of either of the two statins. "It’s quite profound, the ability of the high doses of these therapies to remove lipid and reduce inflammation," he said at the annual scientific sessions of the American Heart Association. "It’s not a clinical marker," he acknowledged, "but it’s a reasonable surrogate, in that [coronary atheroma] is the pathology that ultimately causes events."
Until now, rosuvastatin was known to hold a modest but consistent edge over atorvastatin in its ability to lower blood levels of LDL cholesterol and also to produce a higher rise in HDL cholesterol, but the clinical meaning of these differences had not been established. Dr. Nicholls and his associates ran SATURN (Study of Coronary Atheroma by Intravascular Ultrasound: Effect of Rosuvastatin vs. Atorvastatin) to "compare the effect of maximal dosages of the most efficacious statin regimens on progression of coronary atherosclerosis," a 40-mg/day dosage or rosuvastatin and an 80-mg/day dosage of atorvastatin.
Simultaneously with Dr. Nicholls’ report at the meeting, the results appeared in an article online (N. Engl. J. Med. 2011 Nov. 15 [doi:10.1056/NEJMoa1110874]).
From January 2008 through June 2009, the researchers enrolled 1,578 patients with coronary disease at 208 centers. After randomization, patients underwent a 2-week run-in phase of treatment, receiving their assigned drug at half the study dose. This phase eliminated nearly 200 patients, although Dr. Nicholls said that most did not continue because of investigators’ inability to obtain a usable, baseline intravascular ultrasound (IVUS) image of the patient’s target artery, and not because of adverse effects of treatment. The 1,385 patients who remained in the study (691 on atorvastatin and 694 on rosuvastatin) had their dosage scaled up to the full study level and then remained on treatment for 104 weeks, after which they underwent follow-up IVUS imaging of their index coronary artery. The study’s primary end point was the change in percent atheroma volume from baseline to follow-up IVUS.
The results showed that this primary end point decreased by an average of 0.99% in the atorvastatin-treated patients, and by an average of 1.22% in those on rosuvastatin. Although each group had statistically significant atheroma shrinkage, compared with baseline, the two groups did not significantly differ from each other. The percentage of patients with atheroma shrinkage was 69% in the rosuvastatin group and 63% in the atorvastatin group, a difference that neared – but did not reach – statistical significance.
After 2 years of treatment, average LDL cholesterol levels were 70.2 mg/dL on atorvastatin and 62.6 mg/dL on rosuvastatin, a statistically significant difference. By the end of the study, the mean HDL cholesterol levels in the two groups stood at 48.6 mg/dL for those on atorvastatin and 50.4 mg/dL for those on rosuvastatin. Although this difference in HDL also was statistically significant, "we were somewhat surprised [that] the difference in HDL was not quite as large as we suspected," Dr. Nicholls said. "At the highest doses, the difference in HDL effect appears to dissipate."