Rosuvastatin and Atorvastatin Equally Regress Atherosclerosis

November 15, 2011

Updated November 15, 2011 (Orlando, Florida) — High-dose statin therapy with atorvastatin (Lipitor, Pfizer) or rosuvastatin (Crestor, AstraZeneca) resulted in a significant regression of coronary atherosclerosis, despite differential effects on LDL- and HDL-cholesterol levels with the two most popular lipid-lowering medications. Treatment with rosuvastatin 40 mg resulted in lower LDL- and higher HDL-cholesterol levels than atorvastatin 80 mg, but the effect on percent atheroma volume (PAV) measured by intravascular ultrasound (IVUS) did not significantly differ.

The Study of Coronary Atheroma by Intravascular Ultrasound: Effect of Rosuvastatin Versus Atorvastatin (SATURN) is published online November 15, 2011 in the New England Journal of Medicine to coincide with its presentation at a late-breaking clinical-trials session here at the American Heart Association 2011 Scientific Sessions.

Speaking during the morning press conference announcing the results, Dr Stephen Nicholls (Cleveland Clinic, OH) said that less than 5% of patients with stable coronary disease are treated with maximum-dose statins, and this remains one of the challenges in secondary prevention.

"We're very good at prescribing statins, we're just not so good at increasing the doses," said Nicholls. "Safety is one of the elements of it, but the other element is that people question what the added benefit is. The incremental LDL lowering is about 5% or 6% every time you double the dose. I think what we're seeing here is very reassuring for patients. Over a 24-month period, patients with largely with stable disease tolerated these agents very well at these doses. They achieved very effective levels of LDL and HDL cholesterol, and if you're looking for benefit, I see the removal of the disease from the artery wall that ultimately causes the clinical event as a very reassuring extra benefit for the doses of these agents."

Dr Darwin Labarthe (Northwestern University Feinberg School of Medicine, Chicago, IL), one of the discussants of the SATURN trial, was more cautious in his interpretation of the data and, in fact, called the results of the study "inconclusive." He said that while the intravascular ultrasound (IVUS) data do show a regression of atherosclerosis, the potential clinical impact is unknown.

"I think we have a long way to go before we know if this measure, a surrogate measure of atherosclerosis, has a direct implication for clinical practice," said Labarthe.

Head-to-Head Comparison of Two Popular Drugs

Launched in 2008, the SATURN study is a randomized, double-blind clinical trial designed to test the effectiveness of the maximum doses of rosuvastatin and atorvastatin to regress coronary atherosclerosis in 1385 patients with coronary artery disease. Prior to the study initiation, investigators hypothesized that the LDL-lowering effects of the statins would be similar but that rosuvastatin would likely raise HDL-cholesterol levels more than atorvastatin.

Over 104 weeks of therapy, treatment with rosuvastatin and atorvastatin resulted in low LDL-cholesterol levels (62.6 vs 70.2 mg/dL, respectively; p<0.001) and HDL cholesterol that approached levels considered acceptable for secondary prevention of cardiovascular events (48.6 vs 50.4 mg/dL, respectively; p=0.01).

The primary efficacy end point, PAV, decreased 0.99% in atorvastatin-treated patients and 1.22% in rosuvastatin-treated patients, a nonsignificant difference. In terms of effect on normalized total atheroma volume (TAV), a secondary end point, there was a significant reduction of 6.39 mm3 in the rosuvastatin arm compared with a 4.42-mm3 reduction in the atorvastatin arm, a between-group difference that was statistically significant (p=0.02).

Speaking during the morning press conference, Nicholls said the degree of coronary atherosclerosis regression in both arms is striking, and the largest observed in any clinical trial so far. He pointed out that 68.5% of the rosuvastatin-treated patients and 63.2% of atorvastatin-treated patients achieved some degree of regression when assessed by PAV on IVUS. For the TAV end point, 71.3% and 64.7% of the rosuvastatin- and atorvastatin-treated patients achieved disease regression.

"When we put this all together with studies that have been performed over the past decade, it really is quite a striking story," said Nicholls. "There is a clear relationship between achieved levels of LDL cholesterol and disease progression. Now we are able to consistently demonstrate that if you are able to get your LDL-cholesterol level well below 70 mg/dL, you can regress disease."

Labarthe, who was present during the press conference, said that IVUS studies are inherently flawed, given that they are designed to assess an end point, in this case, PAV, when it is known that patients will be lost to follow-up. For example, in SATURN, 29% of those randomized to treatment did not return at two years for an IVUS assessment, and as a result it is difficult to make firm conclusions about the trial.

Nevertheless, the results provide "no basis to infer a differential clinical benefit" between atorvastatin and rosuvastatin, said Labarthe.

Results Differ From Other Clinical Trials

Commenting on the results of the study for heartwire , Dr Roger Blumenthal (Johns Hopkins University School of Medicine, Baltimore, MD) pointed out that there are some inconsistencies with IVUS-based studies. For example, the REVERSAL study showed that atorvastatin 80 mg halted the progression of atherosclerosis, but it did not result in disease regression, despite more than 60% of patients in SATURN having some degree of regression with the same drug dose. He added that it is still unknown if disease regression is needed to reduce the risk of clinical events.

"The reason I say we don't know is because if you go back to the carotid intima-media thickness [IMT] studies with rosuvastatin, we didn't see a regression there, just a slowing of progression, and yet we know that rosuvastatin worked in JUPITER," said Blumenthal. "So this whole emphasis on achieving regression might not be necessary or the right target."

He added that rosuvastatin underperformed in SATURN, failing to increase HDL-cholesterol levels as much had been expected. In ASTEROID, for example, where rosuvastatin 40 mg for two years resulted in a significant decrease in mean PAV, HDL cholesterol increased 15%.

"There are definitely a lot of questions about the IVUS technique and whether reversal is really the holy grail or not, but I think the main lesson is that either strategy you use, 60% to 65% of patients get some modest reversal of disease."

Also speaking with heartwire , Dr William Zoghbi (Methodist Hospital, Houston, TX) said the SATURN trial confirms that atorvastatin and rosuvastatin can be tolerated at high doses but that the doses aren't for everybody. While he will titrate statin doses to achieve an LDL treatment target of <70 mg/dL in patients with coronary disease, not all patients can handle the maximum doses. In this setting, Zoghbi will use a drug combination to get patients to target. SATURN, he said, does not truly assess safety, but the results are positive showing the regression of atherosclerosis and a lack of significant adverse events in the treatment arms.

Investigators say the side-effect profile was "acceptable," with a low incidence of laboratory abnormalities and cardiovascular events. There was a higher incidence of elevated alanine aminotransferase levels observed in the atorvastatin group, 2.0% vs 0.7%, compared with rosuvastatin (p=0.04), and a higher incidence of proteinuria reported in the rosuvastatin arm (3.8% vs 1.7%; p=0.2). Overall, glycated hemoglobin levels did not change in either treatment arm.

Nicholls has received support for travel to meetings and fees for participation in review activities from AstraZeneca; consulted for Abbott, Adnexus, Amarin, Amylin, AstraZeneca, Bristol-Myers Squibb, Esperion, Genentech, GlaxoSmithKline, Idera Pharma, Kowa, Merck, Novartis, Omthera, Resverlogix, Roche, Sanofi-Synthelabo, and Takeda; participated in speaker's bureaus for Abbott, AstraZeneca, GlaxoSmithKline, and Merck; and received honoraria from Abbott, Adnexus, Amarin, Amylin, AstraZeneca, Bristol-Myers Squibb, Esperion, Genentech, GlaxoSmithKline, Idera Pharma, Kowa, Merck, Novartis, Omthera, Resverlogix, Roche, Sanofi-Synthelabo, and Takeda. Disclosures for coauthors are listed on the journal website.


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