REVERSAL: Atorvastatin 80 mg halts atheroma progression, pravastatin 40 mg does not

November 12, 2003

Orlando, FL - Intensive lipid-lowering treatment with atorvastatin (Lipitor®, Pfizer) 80 mg daily completely halted the progression of atherosclerosis, whereas a moderate lipid-lowering regimen of pravastatin (Pravachol®, Bristol-Myers Squibb) 40 mg was associated with continued atherosclerosis progression in the REVERSAL study.

The study, presented at the American Heart Association Scientific Sessions today, represents the first major comparison of two statin drugs and the first major comparison of an intensive and a moderate lipid-lowering regimen. It is also the first large prospective atherosclerosis trial using intravascular ultrasound (IVUS)

Dr Steven Nissen

Lead investigator of the study, Dr Steven Nissen (Cleveland Clinic, OH), said the results support more widespread use of the 80-mg dose of atorvastatin. "You can reduce the progression rate of atherosclerosis to essentially zero, but you have to use the highest dose of a highly effective statin....We strongly believe that consideration of more intensive treatment with 80-mg atorvastatin is now warranted in secondary prevention, particularly for patients at high risk of morbid events," he said.

The REVERSAL trial randomized 654 patients with symptomatic coronary artery disease, a 20% or greater stenosis by angiography, and LDL levels between 125 mg/dL and 210 mg/dl to either pravastatin 40 mg or atorvastatin 80 mg. IVUS of a single target coronary was performed before randomization and after 18 months of treatment. Some patients withdrew, mainly because of reluctance to undergo a repeat cath for research purposes, with before and after results available for 502 patients.

As expected, the atorvastatin regimen lowered LDL levels significantly more than the pravastatin regimen.

REVERSAL: Final LDL levels and percent change

LDL level

Pravastatin 40 mg

Atorvastatin 80 mg

Final LDL level, mg/dL 110 79
% change -25.2 -46.3

 The primary end point was percent change in atheroma volume, which showed a 2.7% significant increase in the pravastatin group and a 0.4% nonsignificant reduction in the atorvastatin group. Comparison of the two cohorts showed a significant difference in progression rate (p=0.02). Secondary end points of change in total atheroma volume and change in percent obstructive volume also both showed progression in the pravastatin group but no change in the atorvastatin group.

Main primary and secondary end point results of REVERSAL

End points

Pravastatin, 40 mg (n=249)

Atorvastatin, 80 mg (n=253)

p for difference between groups

% change in atheroma volume +2.7 (progression) -0.4 (no change) 0.02
Change in total atheroma volume (mm3) +4.4 (progression) -0.9 (no change) 0.02
Change in % obstructive volume 1.6 (progression) 0.2 (no change) 0.0002

Subgroup analysis showed similar results for almost all subgroups, with progression of atheroma in most pravastatin subgroups but no change in any atorvastatin subgroup.

Did CRP reductions play a role?

CRP, which was also a secondary end point, was also reduced significantly more in the atorvastatin group.

CRP reductions in REVERSAL

CRP

Pravastatin, 40 mg (n=249)

Atorvastatin, 80 mg (n=253)

p for difference between groups

% change in CRP -5.2 -36.4 <0.0001

 

A post-hoc analysis involving just those patients in the pravastatin group who did achieve LDL levels below the NCEP guideline level of 100 mg/dL still showed significant progression of atheroma. There were 167 patients in this group, and they achieved mean LDL levels of 88 mg/dL. "Surprisingly, despite attaining a low LDL level on pravastatin, these patients showed highly significant progression for percent atheroma volume and percent obstructive volume," Nissen said. "At any LDL level, progression was less on atorvastatin than on pravastatin. When I started this study, I believed that any reduction in progression would just be due to lower LDL levels, but now I'm not so sure. This analysis suggests that it may be more than just LDLit seems to be the drug as well," he told an AHA press conference. "Yes, this is a post-hoc analysis and should be considered as 'hypothesis generating,' but I would say it is a robust finding," he added.

Nissen suggested that the superior reduction in CRP with atorvastatin might have contributed to its better effect on atheroma. "The difference in CRP reductions between the two groups was one of the biggest surprises in this study, and it may be one of the reasons behind the better effects seen with atorvastatin," he commented.

Adverse events

No differences were seen in adverse events or liver and muscle enzyme elevations between the two regimens, and no patient experienced myopathy. The study was not powered to examine clinical events, and with only two deaths, 12 MIs, and two strokes, no meaningful analysis of mortality or morbidity was feasible.

Generally well received

The REVERSAL results were generally well received at the AHA, and the designated discussant of the trial at the hotline session, Dr John Hodgson (Cleveland Clinic, OH), seemed even more excited about the results than Nissen himself. "Heart disease can be likened to cancer and statins to chemotherapy. The REVERSAL trial shows us that we should be using these agents aggressively to put our patients into remission," he told the meeting.

Other lipid investigators also greeted the results with enthusiasm. Among these was Dr Eugene Braunwald (Brigham and Women's Hospital, Harvard Medical School, Boston, MA). He commented to heartwire that he thought the REVERSAL results were "terrific." "I was particularly interested in the CRP observations and reassured that side effects with the 80-mg dose of atorvastatin were not a problem," he added.

Caution on extrapolating to effect on clinical events?

But what does stopping the progression of atherosclerosis really mean in terms of a reduction in clinical events? Although Nissen admitted that it was uncertain exactly how much this observation would translate into an effect on clinical events, he was very upbeat on the issue: "Everybody agrees that morbidity and mortality trials are the king of the mountain, but these will take years, and I happen to believe that stopping progression of disease is important. A 3% increase in progression seen with pravastatin over the 18 months of this trial will mean that the arteries will be a lot more narrowed over the next few years. That has to be a bad thing. But high-dose atorvastatin stopped progression in its tracks."

Dr Raymond Gibbons

Chair of the AHA's Scientific Sessions program committee, Dr Raymond Gibbons (Mayo Clinic, Rochester, MN) was more cautious. "Although very provocative, these results will not change the guidelines. We need to see clinical-outcome studies to do that." He said doctors should first concentrate on making sure that their patients are taking even moderate doses of statins. "Many patients are not even taking moderate doses of statins at presentwe're not even getting them to LDL levels of 110 mg/dL. Evidence from hard-end-point trials have shown that the statins as a class are effective at reducing clinical events and that lowering LDL to below 100 is where we should be. We should be focusing on this first of all," he commented to heartwire .

Nissen agreed that the study may not change the guidelines, but he added that it might still change clinical practice. " I don't think I can make clinical recommendations on the basis of one IVUS study, but doctors will look at the findings and make up their own minds. I already have, and I have changed my practice as a result."

Dr Chris Cannon (Brigham and Women's Hospital, Boston, MA) also voiced a cautionary note, pointing out that preventing atheroma progression was just a surrogate end point and that improving surrogate end points do not always correlate with an improvement in clinical outcomes. "We thought TIMI-3 flow was a good surrogate marker for mortality in thrombolysis trials, but then several trials came along with new drugs that improved TIMI-3 flow but did not improve mortality. REVERSAL is a mechanistic study and it has generated some fascinating results.... Reducing plaque burden is obviously not a bad thing, but we have to be careful when looking at surrogate end points."

PROVE-IT and other trials

More information on whether the REVERSAL data do have an effect on clinical outcome will become available soon, with the results of the PROVE-IT study. This trial, in which Cannon and Braunwald are both involved, is comparing the exact same two regimens in REVERSAL but in 4000 ACS patients and has a clinical outcome as the primary end point. Results are expected at the American College of Cardiology meeting next March.

Several other clinical-end-point trials comparing high-dose vs moderate- or low-dose statin treatment are also under way. These include TNT (atorvastatin 80 mg vs atorvastatin 10 mg), IDEAL (atorvastatin 80 mg vs simvastatin 20 mg), and SEARCH (low-dose vs high-dose simvastatin).

What about HDL?

Other experts commented that although high-dose statin therapy looks promising, new approaches aimed at raising HDL might be even more impressive. One study, published last week, also by Nissen's group, showed particularly exciting results with recombinant apolipoprotein (Apo) A-1 Milano, an HDL mimetic, which actually caused significant regression of coronary atherosclerosis in ACS patients. Cannon commented that: "The entire world is thrilled with the HDL story. This will probably be additive on top of LDL lowering and is the best news in the field."

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