Boston, MA - An analysis of one of the pivotal "lower-is-better" cholesterol trials—Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis in Myocardial Infarction (PROVE-IT TIMI 22)—suggests that the additional benefit of intensive treatment with statins compared with moderately-dosed therapy declines with decreasing baseline LDL-cholesterol levels [1]. Among patients with the lowest baseline LDL levels, in fact, there was no observable difference in outcomes among those treated with intensive therapy and those treated with conventional statin doses.

"Our major finding is that the baseline LDL cholesterol is an important predictor of the benefit of intensive compared with moderate lipid-lowering therapy administered for two years in high-risk statin-naive patients admitted with an acute coronary syndrome [ACS]," write lead investigator Dr Roberto Giraldez (Brigham and Women's Hospital, Boston, MA) and colleagues in the September 9, 2008 issue of the Journal of the American College of Cardiology.

In an editorial accompanying the published study [2], Drs Albert Bruschke and J Wouter Jukema (Leiden University Medical Center, the Netherlands) write that the findings have important clinical implications, specifically in that intensive lipid-lowering therapy with statins might be more deleterious than beneficial in patients who already have low LDL-cholesterol levels.

"The findings," write the editorialists, "indicate that there probably is an actual target LDL cholesterol to reach by lipid-lowering therapies of different intensities. . . . Aggressive lipid-lowering therapy may be warranted in certain cases, but moderation is likely indicated if baseline lipid levels so suggest."

Presented and published in 2004, the PROVE-IT TIMI 22 study was a two-year trial that randomized patients to atorvastatin 80 mg or pravastatin 40 mg within 10 days of hospitalization for ACS. Treatment with atorvastatin 80 mg was associated with a significant reduction in the composite end point of death or major adverse cardiovascular events compared with pravastatin 40 mg.

The study, along with those that followed it, contributed to the evidence that more intensive lipid-lowering therapy provided additional benefit by lowering LDL-cholesterol levels below then-currently-recommended targets. Despite the benefit observed, however, it remained unclear whether patients with low baseline LDL-cholesterol levels achieved the same benefit as those with higher LDL levels, possibly because there might be a threshold below which further LDL-cholesterol reduction did not yield further clinical benefit.

In this analysis, investigators focused only on statin-naive patients, a subset that included 72%, or 2986 patients, of the overall population. The purpose of the investigation was to determine the significance of baseline LDL-cholesterol levels in predicting which patients would benefit from intensive lipid-lowering therapy with a high-dose statin.

Among patients with the highest baseline LDL-cholesterol levels—those in quartile 4, or with LDL levels >132 mg/dL—treatment with atorvastatin 80 mg reduced the risk of death or major cardiovascular events a statistically significant 37% compared with those treated with pravastatin 40 mg. Across the quartiles of declining baseline LDL-cholesterol levels, there was a stepwise decline in the benefit of atorvastatin 80 mg over pravastatin 40 mg.

"Our results showed a decline in the superiority of atorvastatin 80 mg over pravastatin 40 mg from the highest to the lowest baseline LDL-cholesterol quartile," writes Giraldez and colleagues. The investigators add that when baseline LDL-cholesterol levels were analyzed as a continuous variable, the benefit of atorvastatin 80 mg over pravastatin 40 mg was observed at baseline LDL-cholesterol values >66 mg/dL in a multivariate model.

The reason for the reduced benefit at low baseline LDL-cholesterol levels is not known, write the investigators, adding that various placebo-controlled studies have shown different findings.

In CARE and LIPID, for example, there was a lower LDL-cholesterol threshold for benefit with statin therapy, while the 4S study found a similar benefit of simvastatin over placebo regardless of baseline LDL-cholesterol levels. The Heart Protection Study also did not identify a lower LDL boundary where the benefits of simvastatin over placebo disappeared. However, these placebo-controlled studies randomized patients with chronic coronary disease with much higher baseline LDL-cholesterol levels at a time when potent lipid-lowering agents were unavailable.

In their editorial, Bruschke and Jukema add that the Cholesterol Trialists' Collaboration also showed statin therapy reduced the incidence of major coronary events and that the relative risk reduction was related to the absolute reduction in LDL-cholesterol levels from baseline but "largely unrelated to the initial lipid profile or other presenting characteristics."

The editorialists write that the analysis by the PROVE-IT investigators does not conclusively answer the question of "if and when aggressive treatment is warranted." They note that follow-up in the trial was short, just two years, and it is not possible to extrapolate the findings from ACS patients to all patients with coronary artery disease. Moreover, the two statins differed in their effects on lipid profile and have different pleiotropic effects, making it difficult to determine whether the differences between the two regimens are explained completely by the effects on LDL cholesterol.

"However, it is unrealistic to expect that the treatment of individual patients can be fully optimized by using the same target lipid levels for all patients," they write.