PROVE-IT was a 24-month study testing the hypothesis that a lower absolute LDL cholesterol level in patients with ACS is associated with a reduced risk of CVD events, while also evaluating the efficacy and safety of aggressive LDL cholesterol lowering. The noninferiority study was designed to test the equivalence of pravastatin 40 mg daily vs atorvastatin 80 mg daily for use in preventing death or major CV events in patients following an ACS.

To address the critical "is-lower-better" question, investigators sought to compare the effect of a reduction of LDL cholesterol to approximately 100 mg/dL with pravastatin 40 mg daily or to 70 mg/dL daily with atorvastatin 80 mg daily in patients hospitalized with an acute MI and unstable angina. As expected, atorvastatin lowered LDL cholesterol more than pravastatin.

The primary composite end point of all-cause mortality, MI, documented unstable angina requiring hospitalization, revascularization requiring PCI or CABG, and stroke for patients receiving standard statin therapy with pravastatin was 26.3% compared with 22.4% in the high-dose atorvastatin arm, representing a 16% relative risk reduction favoring atorvastatin. As a result, pravastatin failed to meet the criteria for equivalence.

Cannon emphasized that the trial was designed not as a comparison between two drugs but rather to determine whether the drugs were effective in preventing cardiac death in ACS patients and, more important, whether there was an added benefit of intensive LDL cholesterol lowering compared with standard cholesterol therapy.

"The primary end point comparing the two different intensities gave us a very clear answer," said Cannon. "The more intensive lowering of LDL provided a 16% reduction in the risk of all-cause mortality of major cardiac events."

During his presentation, Cannon addressed the issue of lipid-lowering therapy in ACS patients no longer hospitalized as well as other patients who have cardiac disease or who have risk factors for disease, such as elevated cholesterol.

"I think the findings today, showing that there is a benefit of intensive lipid lowering in these high-risk patients, reemphasizes the central role of lowering LDL cholesterol as a major way of preventing mortality and morbidity in heart disease," said Cannon. "This should encourage all patients to look very carefully to see whether they are receiving current appropriate treatment."

This should encourage all patients to look very carefully to see whether they are receiving current appropriate treatment.

Dr Roger Blumenthal (Johns Hopkins University Medical Center, Baltimore, MD), who commented on the results for heartwire, said that in the study's patient populationpatients with likely plaque rupture and lipid-laden plaques that may have eroded or fissuredaggressive cholesterol lowering may help to stabilize ACS patients.

"The take-home message from this study is that it is probably a good idea to be very aggressive with LDL lowering early on," said Blumenthal. "One can always scale back a little. Unfortunately, the tendency has always been we'll start with a lower dose and then titrate up, but that doesn't happen frequently. Most patients end up staying on a very low dose of drug."

Cannon agreed, telling heartwire that one of major issues in the management of cholesterol is that patients are not receiving standard care, that is, are not being treated to target with lipid-lowering therapies.

"We want to make sure that patients receive the optimal benefits of this class of drug proven to reduce mortality, MI, and other cardiac end points," said Cannon. "I think we've seen that titrating upward does not always happen."

The finding of superiority for atorvastatin was surprising because Bristol Myers-Squibb (New York, NY), the makers of pravastatin, sponsored the trial.

Commenting on the results for heartwire, Dr Steven Nissen (Cleveland Clinic, OH), who recently published the REVERSAL study showing that atorvastatin 80 mg daily halted the progression of atherosclerosis compared with pravastatin 40 mg, took issue with the PROVE-IT study design, saying the trial was not designed to show the impressive results seen with atorvastatin.

"These results should be a huge surprise because the study, in my opinion, was carefully and cleverly designed to show no difference," said Nissen. "It's important that people who understand clinical trials be willing to say that. Companies don't usually take huge risks of losing on their own trials."

These results should be a huge surprise because the study, in my opinion, was carefully and cleverly designed to show no difference.

Nissen said the two-year study was theoretically too short in duration and lacked sufficient number of patients to detect any differences between the two drugs. Event curves, said Nissen, typically take one to two years to separate, noting there was no difference in the Cholesterol and Recurrent Events (CARE) trial between placebo and pravastatin until 18 months. In PROVE-IT, the clinical superiority of atorvastatin emerged as early as 30 days and was consistent over time.

"The power calculations were designed around showing noninferiority and made noninferiority far and away the most probable outcome," said Nissen. "Still, the difference between the two drugs was enormous and yielded a superiority finding for their competitor's drug. It's almost unprecedented to see this kind of a backfire in medicine."

Cannon admitted he was surprised by the results but said most of the study's steering committee did not expect to find such a dramatic difference between pravastatin, a "highly effective therapy," and atorvastatin that lowered LDL further. "Many people have been surprised, but on the other hand I think it fits exactly what one would expect based on the changes in LDL cholesterol."

Among the individual components of the primary end point, there was a consistent benefit favoring high-dose atorvastatin over standard-dose pravastatin, with the exception of stroke, which showed little difference. Moreover, the benefit was consistent across the prespecified subgroups, including men and women; patients with unstable angina or MI; and those with and without diabetes mellitus.

Nissen said the results were made even more impressive by the reduction in mortality seen with atorvastatin. Although the results did not achieve statistical significance, Nissen said he is not too concerned with the p value, noting the results were very close to significance.

"We now know that lower is better and our current guidelines of 100 are artificially high and are not where they should be," said Nissen. "Not only did the more aggressive therapy result in a reduction in the primary end point, but there was a 28% reduction in mortality. How many therapies do we have for post-MI patients that show such an impressive reduction in mortality? Not too many."

How many therapies do we have for post-MI patients that show such an impressive reduction in mortality? Not too many.

Rates of discontinuation for adverse events, patient preference, or other reasons were not statistically different between the two study arms at 12 months or at 24 months. The percentage of patients who developed abnormal liver elevations, defined as alanine aminotransferase (ALT)>3 times the upper limit of normal, were 1.1% for pravastatin and 3.3% for atorvastatin (p<0.001).

"When implementing data from any of these trials, we need to look at how these benefits would be balanced by any safety issues," said Cannon. "We did see a higher incidence of blood-test abnormalities, but overall, it is a very safe approach."

Blumenthal agreed, saying the side-effect profile was quite similar between the two drugs, with the exception of elevations in liver enzymes, and most physicians should be able to manage the side effects easily.

Despite both PROVE-IT and REVERSAL demonstrating the superiority of atorvastatin, the two studies reported disparate results with regard to C-reactive protein (CRP) reduction. In REVERSAL, involving a patient population with stable CAD, there was a marked difference in CRP lowering between the two drugs, with atorvastatin reducing CRP 36% compared with just 5% with pravastatin.

While there was relatively little difference in CRP lowering between the two statin regimens in PROVE-IT, Cannon said there was a difference in the achieved CRP levels between the two study arms (1.3 mg/L atorvastatin vs 2.1 mg/L pravastatin). Cannon said these "profound differences" are likely related to the effect of LDL lowering. He added the study was not designed to determine the mechanism for atorvastatin's clinical benefit but noted that in addition to the differences in LDL lowering, non-lipid-related pleiotropic effects should not be excluded.

Nissen told heartwire, however, that he disagrees with the PROVE-IT investigators' interpretation, saying he believes the superiority of atorvastatin is attributed not only to the amount of LDL lowering but also due to differences in drug profile.

In the REVERSAL study, he said, LDL cholesterol reduction alone did not explain the differences in efficacy between the two statins. In linear regression analyses, Nissen said that despite parallel regression lines between the two drugs, the progression rate at any level of LDL cholesterol reduction was lower with atorvastatin compared with pravastatin.

Cannon disagreed, saying, "Since 1987, we have been unable to find a published report of any difference in outcomes between the different agents. It's an interesting hypothesis that has existed for 17 years but nobody has been able to identify differences between the types of statins. On the other hand, there have been two or three decades of research emphasizing the benefits of the changes in the LDL cholesterol, and the changes that we saw in LDL cholesterol fully explain the clinical benefit as compared with all the other prior trials."

Blumenthal said the results of PROVE-IT and REVERSAL make for an interesting debate, one unlikely to yield substantial answers.

"Pfizer is going to want to say that the results are because of the drug, but the most we can say is that this area needs more study. The drugs have different profilesatorvastatin is lipophilic, pravastatin is notand have different effects on CRP. At the present time we don't know what effect the differences have on outcomes, with the exception of LDL lowering."

In an accompanying editorial published in the New England Journal of Medicine, Dr Eric J Topol (Cleveland Clinic, OH) writes the findings herald a shake-up in the field of cardiovascular prevention.2

"The implications of this turning pointthat is, of the new era of intensive statin therapyare profound. Even today, only a fraction of the patients who should be treated with a statin are actually receiving such therapy," says Topol, noting that more than 200 million people worldwide meet the criteria for treatment, but fewer than 25 million take statins.

Moreover, the REVERSAL and PROVE-IT studies strongly reinforce the need for more head-to-head trials of drugs within the same class. Taken together, the results from these studies will bring about a sea change in the prevention and management of atherosclerotic vascular disease, he predicts.

"The proportional reduction in major clinical outcomes that results from aggressive statin therapy is of the same order of magnitude as that seen when statins were compared with placebo in controlled trials," concludes Topol. "Intensive therapy with statins, monitored by means of measurements of LDL cholesterol or biologic markers of inflammation, is likely to result in even greater steps toward actualizing the full benefit of this remarkable class of medicines."

Interestingly, with the publication of the PROVE-IT results, intravascular ultrasound (IVUS) now moves closer to legitimacy as a surrogate marker in lipid- and plaque-modification therapies.

In his editorial, Topol writes that the combination of a clinical outcomes trial, PROVE-IT, and an imaging study, REVERSAL, yields a compelling validation of IVUS as a surrogate measure of clinical benefit with atherosclerotic agents.

This is a wonderful time for new lipid therapies.

"The superiority of atorvastatin over pravastatin seen in PROVE-IT tells us that the 3% difference in the atherosclerosis progression rate, the primary end point in REVERSAL, translates into major morbidity and mortality benefits," adds Nissen. "We now can use IVUS to develop new antiatherosclerotic therapies."

Cannon agreed, saying, the two studies, taken together, suggest that IVUS can track the progression of atherosclerotic disease and the progression does translate into clinical events.

"I think this study does validate IVUS," Cannon told heartwire. "But to change clinical practice, you need hard clinical end points. Still, this is a wonderful time for new lipid therapies, as we'll soon be able to enter into an era where we use IVUS to track progression in conjunction with trials using clinical end points."