Saturday, October 1, 2011

SATURN: Is a statin a statin?

As reported on the earlier this week, preliminary results from the Study of Coronary Atheroma by Intravascular Ultrasound: Effect of Rosuvastatin Versus Atorvastatin (SATURN) trial demonstrated no significant differences between the impact of atorvastatin (Lipitor®) and rosuvastatin (Crestor®) on the study's primary endpoint, percent atheroma volume (PAV), as measured by intravascular ultrasound (IVUS). Of note, the trial was not powered to detect significant differences in clinical outcomes, such as mortality or major adverse cardiovascular events.

Unless further analysis of SATURN reveals any additional differences, I am not sure SATURN answers the question of which statin (and at what dose) is most appropriate in patients with established coronary artery disease (CAD). The trial that primarily raised thise question was the Pravastatin or Atorvastatin Evaluation and Infection Therapy–Thrombolysis in Myocardial Infarction 22 (PROVE-IT TIMI 22) investigation, which showed that atorvastatin 80 mg ("intensive" lipid-lowering therapy) was superior to pravastatin 40 mg ("standard" lipid-lowering therapy) for preventing the composite endpoint of death and other cardiovascular outcomes (e.g., myocardial infarction, stroke, need for revascularization).

As we would expect, atorvastatin 80 mg had a greater impact on low-density lipoprotein (LDL), one of the primary markers for atherosclerosis (and thus cardiovascular risk), so a question that has remained from the PROVE-IT trial is whether improvement in the primary endpoint was due primarily to a reduction in LDL, or if other (commonly called "pleiotropic") effects were at work. One of the arguments supporting the pleiotropic hypothesis was that the difference between the two agents began to emerge as early as 30 days, which is unlikely a consequence of aggressive LDL reduction. If the latter is true, was this due to differences between the individual agents themselves or was it their relative potency, i.e., does a dose threshold exist where these pleiotropic effects begin to have a clinically meaningful impact?

The difference between statins has primarily been an issue for clinicians because of their relative cost; for many of the patients we see at our institution, cost exerts significant influence on clinical decision-making. Pravastatin is generic and available on most discount prescription programs (e.g., $4 dollar lists), so we are often satisfied if patients can be discharged on any statin they can afford, even if it is not the one for which we have the best data -- especially for patients who are already stuck paying for brand-name clopidogrel (Plavix®) or prasugrel (Effient®). That being said, choosing among statins may be less of an issue when atorvastatin becomes generically available later this year.

Because rosuvastatin is even more potent than atorvastatin at the higher end of its dosing range, some might argue for its use in some patients, a decision that is not yet supported by the literature. Given the preliminary results to date, SATURN does not appear to indicate which is better, although there may not be as meaningful a difference between the two after all. Even if rosuvastatin had shown a greater impact on PAV as measured by IVUS, the use of this marker as a surrogate for clinical outcomes has not yet been established... but that's another discussion altogether.

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