Reversing Atherosclerosis With Aggressive Lipid Lowering

Linda Brookes, MSc

Disclosures

December 30, 2003

Editorial Collaboration

Medscape &

Presenter: Steven E Nissen, MD, Cleveland Clinic Cardiovascular Coordinating Center, Cleveland Clinic Foundation (Cleveland, Ohio)

More intensive lipid lowering than currently recommended by the current US National Cholesterol Education Program (NCEP) guidelines may be warranted as a method of secondary prevention in patients with coronary heart disease (CHD), particularly those at high risk of morbidity and mortality, according to the results of a large study that compared the effects of 2 statins.[1]

The REVERSing Atherosclerosis with Aggressive Lipid Lowering (REVERSAL) study measured changes in atheroma burden as assessed by intravascular ultrasound (IVUS), a technique that Dr. Nissen has been at the forefront in developing and which he believes confers many advantages over other techniques such as magnetic resonance imaging in this kind of evaluation.

The design of REVERSAL was important for 2 principal reasons: (1) exclusive use of systematic IVUS assessment of atheromatous burden as the primary endpoint; and (2) the first controlled clinical trial to provide a head-to-head comparison of active treatment with 2 different statins.

REVERSAL was a double-blind, randomized study carried out at 34 community and tertiary care centers in the United States.[2] The trial, which took place between June 1999 and September 2001, enrolled 654 patients aged 35-78 years with symptomatic coronary artery disease (CAD) and ≥ 20% stenosis by coronary angiography. LDL-cholesterol in all patients was between 125 and 210 mg/dL after an 8-week washout period.

Patients were randomized to moderate lipid lowering with pravastatin 40 mg or intensive lipid lowering with atorvastatin 80 mg for 18 months. Dr. Nissen explained that the 40-mg dose of pravastatin was the highest dose approved for this drug at the start of the trial. Simvastatin could not be used, as it was not approved in the United States for slowing progression of atherosclerosis.

Measurement of atherosclerotic burden by IVUS was carried out during baseline catheterization and at study completion. A number of patients were unwilling to have a repeat catheterization and withdrew from the study, leaving 502 patients who completed the trial, 249 patients on pravastatin and 253 on atorvastatin. The 2 treatment groups were well matched: average age was 56 years, about 70% were male, and 20% were diabetic. Baseline LDL-cholesterol was 150 mg/dL in both groups, triglycerides 197 mg/dL, and C-reactive protein (CRP) approximately 3 mg/dL.

By the end of the treatment period, LDL-cholesterol was significantly lower among patients who had received atorvastatin compared with those on pravastatin (Table 1). HDL showed a slight, nonsignificant increase with pravastatin.

Table 1. REVERSAL: Final Lipid Values and Percent Changes
Lipid value
(mg/dL)
Pravastatin
(n = 249)
Atorvastatin
(n = 253)
P value*
Final value Change (%) Final value Change (%)
Total cholesterol 188 ± 32 -18.4 151 ± 39 -34.1 < .0001
LDL-cholesterol 110 ± 26 -25.2 79 ± 30 -46.3 < .0001
HDL-cholesterol 45 ± 11 +5.6 43 ± 11 +2.9 .06
Triglycerides 166 ± 92 -6.8 148 ± 95 -20.0 .0009
HDL, high-density lipoprotein; LDL, low-density lipoprotein
*Unpaired Student's T-test
Primary and Secondary Endpoints

Dr Nissen emphasized that REVERSAL was not designed to assess differences in clinical events. The primary prespecified endpoint of the trial was change in IVUS-determined atheroma volume, which showed a significant increase in the pravastatin arm compared with baseline (progression), vs no overall change in atheroma volume in patients in the atorvastatin arm (Table 2). An unpaired comparison of the treatment arms showed a significant difference in progression rate (P = .02).

Table 2. REVERSAL: Primary Endpoint
  Pravastatin
(n = 249)
Atorvastatin
(n = 253)
P value,
pravastatin
vs
atorvastatin
Change in atheroma volume (%) +2.7 -0.4 .02
P value vs baseline .001* .98*  
*Wilcoxon signed rank test
Wilcoxon rank sum test

The findings for the secondary endpoints also favored atorvastatin (Table 3). Both treatment arms showed decreases in CRP, again with a large advantage for atorvastatin.

Table 3. REVERSAL: Secondary Endpoints
Endpoints Pravastatin
(n = 249)
Atorvastatin
(n = 253)
P value,
pravastatin
vs
atorvastatin
Change in total atheroma volume (mm3) +4.4 -0.9 .02
P value vs baseline .01* .72* --
Change in percent obstructive volume (%) +1.6 +0.2 .0002
P value vs baseline .0001* .18* --
Change in CRP (%) -5.2 -36.4 < .0001
*Wilcoxon signed rank test
Wilcoxon rank sum test

The finding of significant progression in atheroma volume with pravastatin was consistent among 22 prespecified subgroups including male/female, above/below median age, prior statin/statin naive, with/without diabetes, and with/without metabolic syndrome. A finding of no differences between the 2 treatments among patients without hypertension was attributed to chance. The results were also consistent among patients with lipid and CRP levels above and below mean levels.

A posthoc analysis among the 167 patients treated with pravastatin who reached LDL-cholesterol levels below the NCEP guideline level of 100 mg/dL (mean 88 mg/dL) surprisingly showed that they had highly significant atheroma progression for total atheroma volume and percent obstructive volume. Although posthoc, this result was scientifically important and hypothesis generating, Dr. Nissen believes.

Although no net regression of atheroma was found for the atorvastatin group, individual patients in this group experienced significant regression, leading Dr. Nissen and his coinvestigators to conclude that in certain patients at least, intensive lipid lowering can induce regression.

Adverse Events

Both regimens were well tolerated, with no differences in adverse events between the 2 regimens. No patients experienced myopathy.

Limitations of the Trial

While the clinical endpoints of morbidity and mortality are always the preferred efficacy measures in clinical trials, comparison of 2 statins in such a trial would require enrollment of > 8000 patients for a follow-up duration of ≥ 5 years, Dr. Nissen pointed out. He and his colleagues are confident that a highly consistent relationship exists between atherosclerosis progression rates and major vascular events and that morbidity and mortality trials will confirm the results of REVERSAL.

No Such Thing as Too Low LDL-cholesterol

The results of REVERSAL appear to show that there is no such thing as too low a level of LDL-cholesterol, Dr. Nissen stated. However, he cautioned against extrapolating the results of REVERSAL into other populations, such as for primary prevention.

Mechanism of Action

The REVERSAL investigators have speculated that the differences between the 2 drugs might be due, at least in part, to the greater reduction in CRP with atorvastatin (-36.4% vs -5.2%; P < .0001). Additional studies will be made of the trial database to study this further.

Interventional Cardiology Viewpoint

As the AHA's officially designated trial discussant, John Hodgson, MD, Heart and Vascular Center, MetroHealth Medical Center (Cleveland, Ohio), an interventional cardiologist, predicted that on the basis of an increasing number of positive trials, tomographic atheroma imaging using both IVUS and noninvasive techniques will become the standard for atheroma detection and therapeutic monitoring.

Dr. Hodgson noted that while REVERSAL used a surrogate endpoint for clinical efficacy, aggressive statin therapy achieving LDL levels below NCEP goal has been clearly associated with clinical benefit in clinical trials in a wide range of primary and secondary prevention with atorvastatin at all levels of disease severity. He noted that the reduction in CRP reduction (and in other anti-inflammatory markers shown in other studies) is an important effect that needs further study.

He cautioned, however, that usual care must improve, describing reported compliance rates of < 20% for patients with established coronary disease as shameful, and emphasized that NCEP goals must be achieved.

According to Dr. Hodgson, the REVERSAL data are so compelling that all cardiologists should consider themselves interventionalists as they work to put atherosclerotic patients into remission.

Future Trials of Aggressive vs Moderate Lipid Lowering

More data comparing aggressive vs moderate LDL-cholesterol lowering are likely to become available soon from a trial using the same drugs as REVERSAL. The PRavastatin Or atorVastatin Evaluation and Infection Therapy trial (PROVE-IT; TIMI 22), has been carried out in patients with acute coronary syndromes (ACS). The results of PROVE-IT are expected to be presented at the annual scientific sessions of the American College of Cardiology in 2004.

Similar comparative studies still under way include:

  • IDEAL – The Incremental Decrease in Endpoints through Aggressive Lipid Lowering trial, which is comparing atorvastatin 80 mg/day vs simvastatin 20-40 mg/day in patients with an acute MI or history of MI

  • TNT – The Treating to New Targets study, which is comparing atorvastatin 80 mg/day with atorvastatin 10 mg/day in patients with clinically evident CHD

  • SEARCH – The Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine tests, which is comparing simvastatin 20 mg vs 80 mg in CHD patients

The results of IDEAL and TNT are expected in 2005 and those of SEARCH in 2004/2005.

Combination Strategy of Lowering LDL and Raising HDL Cholesterol

Dr. Nissen revealed that trials are planned to investigate combining LDL-cholesterol lowering with a drug that raises HDL, possibly the recombinant ApoA-I Milano/phospholipid complex, ETC-216, an HDL mimetic. Dr. Nissen and coinvestigators in the United States and Japan recently reported regression of atheroma, as measured by IVUS, after intravenous administration of ETC-216 in patients with ACS.[3] If both types of drugs are given simultaneously, progression in atheroma volume might be reversed, Dr. Nissen believes.

References
  1. Nissen S. (REVERSAL) A prospective, randomized, double blind, multi-center study comparing the effects of atorvastatin vs. pravastatin on the progression of coronary atherosclerotic lesions as measured by intravascular ultrasound. American Heart Association Scientific Sessions 2003; November 9-12, 2003; Orlando, Florida. Plenary Session XI: Late Breaking Clinical Trials.

  2. Nissen S., for The REVERSAL Investigators. Assessing the effects of statins on atherosclerosis progression using intravascular ultrasound: rationale and design of the REVERSAL study. Atherosclerosis. 2001;2:51-52.

  3. Nissen SE, Tsunoda T, Tuzcu EM, et al. Effect of recombinant ApoA-I Milano on coronary atherosclerosis in patients with acute coronary syndromes. A randomized controlled trial. JAMA. 2003;290:2292-2300.

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