These are the major findings from the Incremental Decrease in Endpoints through Aggressive Lipid Lowering (IDEAL) study presented during a late-breaking clinical-trials session at the American Heart Association (AHA) 2005 Scientific Sessions. Despite missing the primary end point, a composite of coronary death, nonfatal MI, or cardiac arrest with resuscitation, study investigators point to the reductions in secondary end points, contending that aggressively lowering LDL cholesterol (LDL-C) in patients with a previous MI can provide a benefit without an associated increase in noncardiovascular mortality or other adverse events.

Dr Terje Pedersen

According to lead investigator Dr Terje Pedersen (Ullevål University Hospital, Oslo, Norway), despite missing the primary end point in IDEAL, the collective evidence suggests that lower LDL cholesterol levels are, in fact, better.

"All the evidence is moving in the same direction," said Pedersen. "At this point, a p value of 0.07 is not going to have that large an impact on the results or the overall message. If we're looking at IDEAL as a single, randomized trial in the statin field, we might be more cautious. But put in context of the other large statin trials, with the reduction in cardiovascular disease, the IDEAL study makes a much more compelling argument."

In the study, published online today in the November 16, 2005 issue of the Journal of the American Medical Association, the IDEAL investigators point out that more intensive lowering of LDL-C in patients with a previous MI might prevent 68 first cardiovascular events (95% CI 39-97) per 1000 patients over five years.

Dr Steven Nissen

Commenting on the results of the study for heartwire, Dr Steven Nissen (Cleveland Clinic, OH) echoed the sentiment of Pedersen and the IDEAL investigators, saying the results must be viewed in context with the other statin trials.

"I think physicians are going to look at the totality of the evidence," said Nissen. "We see that in all the trials lower levels of cholesterol provide some benefits. They don't always reach statistical significance, but when you put it all together you will see a drifting toward more intensive treatment. It makes sense. The way I practice, and the way I suspect many people will practice, is that I say to my patients I'm going to try to get your cholesterol down as low as we can, as long as we can do so without an adverse event."

Dr Christopher Cannon (Brigham and Women's Hospital, Boston, MA), in an editorial to accompany the publication of the study in JAMA, writes that the IDEAL study is an important addition to the current pool of statin evidence [2]. Cannon writes that the take-home message from the IDEAL study is that "there is now considerable evidence to support the aggressive lowering of cholesterol to reduce cardiovascular events." Cannon also writes: "Physicians caring for patients with vascular disease must ensure that every patient for whom statins are appropriate receives therapy at the appropriate dose."

The IDEAL trial is one of a number of trials in the past two years addressing the "lower-is-better" hypothesis of cholesterol lowering. In the Pravastatin or Atorvastatin Evaluation and Infection Therapy (PROVE-IT TIMI-22) study of patients recently hospitalized with acute coronary syndrome, intensive lipid lowering with atorvastatin 80 mg daily provided greater protection from death and cardiovascular events than pravastatin (Pravachol, Bristol-Myers Squibb) 40 mg daily [3].

In March 2005 at the American College of Cardiology Scientific Sessions, findings from the Treating to New Targets (TNT) study showed that intensive lipid lowering with atorvastatin 80 mg daily provided greater protection from major cardiovascular events than low-dose atorvastatin in stable CHD patients [4]. Yet despite these positive findings, the Aggrastat to Zocor (A to Z) study showed disappointing results; treatment with high-dose simvastatin failed to show a significant reduction in the primary composite end point of cardiovascular death, MI, readmission for ACS, or stroke [5]. In addition, the high-dose simvastatin regimen was associated with a higher rate of myopathy and rhabdomyolysis.

In this most recent "lower-is-better" investigation, IDEAL investigators sought to compare high-dose atorvastatin with simvastatin 20 mg, a dose widely used in clinical practice. Study investigators also wanted to examine the safety profile of high-dose atorvastatin, because the TNT study reported a trend toward a higher number of deaths from noncardiovascular causes.

The IDEAL study was a prospective, randomized, open-label, blinded-end-point evaluation trial conducted in 190 ambulatory cardiology-care and specialist practices in northern Europe between March 1999 and March 2005. In total, 8888 patients aged 80 years or younger with a history of acute MI were included in the study and followed for a median of 4.8 years. Patients previously treated with statins qualified if they had been titrated to a dose no higher than the equivalent of simvastatin 20 mg.

Patients in the simvastatin study arm not taking a statin before randomization had, on average, a 33% reduction in LDL cholesterol after 12 weeks compared with the 49% reduction in LDL cholesterol in statin-naïve patients treated with atorvastatin. During treatment, mean LDL-C levels were 104 mg/dL in the simvastatin group and 81 mg/dL in the atorvastatin group.

The primary end point of coronary death, acute MI, or cardiac arrest with resuscitation occurred in 463 patients (10.4%) in the simvastatin group and in 411 patients (9.3%) in the atorvastatin group and was not statistically significantly different between the two study arms.

The composite secondary end point of a major cardiovascular event, defined as major coronary events and stroke, was significantly reduced in patients treated with atorvastatin. Similarly, there were reductions in the risk of nonfatal MI, any CHD event, and any cardiovascular event. The risk of death from any cause was similar in both study groups. There were no significant differences in noncardiovascular deaths between the treatment groups.

Regarding safety, death from noncardiovascular causes was higher in the simvastatin study arm. There were more nonserious adverse events resulting in drug discontinuation in the atorvastatin group and a greater proportion of patients developing liver-enzyme elevation with atorvastatin 80 mg. Serious myopathy and rhabdomyolysis were rare in both groups.

Dr James de Lemos (University of Texas Southwestern Medical Center, Dallas), who commented on the results of IDEAL for heartwire, agreed with Pedersen, Nissen, and Cannon, saying he doesn't interpret the study as a failed trial. Compared with the other high-dose statin studies, including trials looking specifically at atorvastatin 80 mg, the results show that intensive lipid-lowering therapy is safe and effective at the highest doses.

Dr Roger Blumenthal (Johns Hopkins University Medical Center, Baltimore, MD) also views the results of IDEAL in a positive light. For him, the results send a clear message that clinicians should aim for LDL-cholesterol levels of 80 mg/dL or less in stable coronary patients. "The study is not quite a home run, but it is at the very least a stand-up double," said Blumenthal.

Blumenthal pointed out, however, that most patients in the simvastatin study arm "did pretty darn well." With a higher incidence of liver-enzyme elevations in patients treated with atorvastatin 80 mg, the study also suggests that there is no need to push patients to stay on a high dose of atorvastatin.

"The general thinking had been that you were doing the patients a grave disservice if you were not giving them 80 mg of atorvastatin," said Blumenthal. "In this study, patients treated with the comparator drug simvastatin, 20 mg or 40 mg, did nearly as well, and it was better tolerated."

For de Lemos, the most salient take-home message from IDEAL is a refocusing on the importance of low levels of LDL cholesterol. When the TNT study is compared with the IDEAL trial, for example, de Lemos pointed out that both trials had near-identical reductions in LDL cholesterol and similar reductions in event rates. Because TNT compared high-dose atorvastatin with low-dose atorvastatin and IDEAL compared high-dose atorvastatin with low-dose simvastatin, the studies suggest that the different statins reduce events proportionally to their LDL-lowering properties. If the event-rate reduction was different between these two trials, it could be argued that differences between statins' pleiotropic effects were at work, he said.

Nothing magical seems to happen here that would make us shift our focus away from LDL-lowering effects. The important point is to lower LDL cholesterol to sufficiently low levels to provide incremental benefit.

"Nothing magical seems to happen here that would make us shift our focus away from LDL-lowering effects," said de Lemos. "The important point is to lower LDL cholesterol to sufficiently low levels to provide incremental benefit."

In looking at the data, de Lemos suspects the IDEAL investigators may have slightly overestimated the benefit they expected to see with reductions in LDL cholesterol. Moreover, the observed reductions in LDL cholesterol were not as large as the investigators anticipated, affecting the power of the study. He added that the IDEAL study was not too dissimilar from the A to Z trial, in which he was involved. Both LDL-lowering trials missed their primary end point, but modest treatment effects were still observed.

De Lemos told heartwire that clinicians and researchers are moving toward important changes in the dynamic of measuring outcomes with the high-intensity statin therapies. The low levels of LDL cholesterol are reducing important clinical-event outcomes, such as unstable angina or nonfatal MI, rather than resulting in reductions in mortality. For de Lemos, however, there is no further need for mortality trials, as the benefits of statins, including high-dose statin therapy, have already been proven.

Pedersen agreed, saying, "I think we are beginning to see the bottom level of what can actually be achieved with modern therapies, as we can apply only so much prevention to these patients. I think it will be very hard for any future trials to demonstrate reductions in cardiovascular mortality."

Dr Scott Grundy (University of Texas Southwestern Medical Center, Dallas), the discussant for IDEAL during the late-breaking clinical trials session, said that as cardiovascular medicine is moving more and more toward incremental therapies, it is difficult to observe mortality benefits between the different drug regimens. In this case, it might be appropriate to use softer composite end points, such as the major coronary event end point used in the IDEAL trial.

In his editorial, Cannon, the lead author of the PROVE-IT TIMI 22 trial, points out that despite not meeting the primary end point, the results of the IDEAL study support the findings from previous statin trials. For example, when IDEAL investigators used the primary end point of the TNT study, which included stroke, there was a statistically significant 13% reduction in risk with atorvastatin 80 mg. When the primary end point of PROVE-IT was used—any cardiovascular event including revascularization—there was a statistically significant 16% reduction, identical to that of PROVE-IT.

Cannon adds that it is now expected that the National Cholesterol Education Panel (NCEP) guideline committee will review the new evidence, including data from the recently published Cholesterol Treatment Trialists (CTT) collaboration, TNT, and IDEAL, to consider fully adopting as formal recommendations the therapeutic options suggested in its 2004 update [6]. On the basis of PROVE-IT and data from the Heart Protection Study (HPS), the NCEP Adult Treatment Panel III (ATP III) updated the guidelines for cholesterol management, introducing a more aggressive, but optional, LDL-cholesterol goal of <70 mg/dL for patients at very high risk for CHD, even if baseline LDL cholesterol was <100 mg/dL.

Saying that it is difficult is not saying that we shouldn't try. . . .  What the guidelines are really telling clinicians is to get the LDL cholesterol down as low as you safely can.

According to Grundy, an author of the updated NCEP ATP III report, the IDEAL and TNT studies strengthen the case for the recommendation of LDL cholesterol goals <70 mg/dL in high-risk patients.

"Both trials showed incremental benefit for composite CVD end points with very low LDL-cholesterol levels, well below 100 mg/dL," said Grundy. "TNT further significantly reduced major coronary events. Moreover, both trials confirmed the safety of statin therapy. On the other hand, neither trial reduced CVD deaths or total mortality. High-dose statins also carry somewhat of an increased cost over standard therapy. But I predict that, in spite of these limitations, efforts to achieve very low LDL cholesterol levels will be increasingly accepted as standard therapy in secondary prevention."

Asked about the difficulties in getting patients to such low levels of LDL cholesterol, experts agreed it is not easy. Even in a clinical-trial setting, many patients are unable to go this low.

"Saying that it is difficult is not saying that we shouldn't try," said Nissen. "I think that what the NCEP target is saying is that there is good enough evidence for these very-high-risk patients that we should try to get there. Even if we only get a 25% or 35% LDL reduction, that's good. What the guidelines are really telling clinicians is to get the LDL cholesterol down as low as you safely can. We do have combination therapies available and we do have additional agents we can add to a statin. We're going to be pushing our patients and ourselves to go to lower LDL levels because there is additional benefit. But it will be difficult, no question about it."