PROVE-IT and REVERSAL: Effect of Intensive Compared With Moderate Lipid-Lowering Therapy on Progression of Coronary Atherosclerosis (REVERSAL)

From: http://www.medscape.com/viewarticle/484048_2

PROVE-IT and REVERSAL: Effect of Intensive Compared With Moderate Lipid-Lowering Therapy on Progression of Coronary Atherosclerosis (REVERSAL)

Summary
The comparative effects of a moderate (pravastatin 40 mg/dL) and intensive (atorvastatin 80 mg/dL) lipid-lowering intervention were assessed in 502 participants with coronary artery disease using intravascular ultrasound (IVUS) at baseline and after 18 months of treatment. Low-density lipoprotein (LDL) cholesterol level was reduced to <80>100 mg/dL in the pravastatin group, although reduced from baseline levels. The primary end point, percentage change in coronary atheroma volume, showed a significantly lower progression rate in the intensive therapy group. For the same percent decrease in LDL cholesterol level, atheroma volume reduction was greater in the atorvastatin group, suggesting a possible pleiotropic effect.
Rationale
Because the optimal target level for LDL cholesterol lowering by statins remains uncertain, a direct assessment of intervention with two potencies on coronary atheroma burden and progression might provide objective evidence for relative benefit. Ancillary effects on clinical outcomes could also be assessed but were not reported in this publication.
Study Design
Patients requiring coronary angiography for a clinical indication who were found to have at least one obstruction with at least a 20% narrowing were candidates. IVUS evaluation of the target vessel was obtained during coronary arteriography at baseline and 18 months. The target artery could not have had an intervention and a luminal narrowing >50%. LDL cholesterol level at entry had to be between 125 mg/dL and 210 mg/dL after a 4-10 week period to wash out any previous lipid-lowering agent effects. IVUS was obtained at 34 centers and evaluated at Nissen's core center at the Cleveland Clinic. The IVUS evaluation was obtained by controlled pullback through the target vessel with manual planimetry to evaluate the luminal and external elastic membrane (EEM) borders, taken as the boundaries of the atheroma (Figure 2). The primary end point, percentage change in atheroma volume, was obtained by calculating the sum of the differences between EEM and lumen areas across all evaluable cross sections.

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Figure 2.
Reversal of Atherosclerosis with Lipitor study results. Intravascular ultrasound images showing: A) calculation of atheroma area: subtraction of lumen area from external elastic membrane (EEM) bounded area, and; B) change in atheroma area in patient assigned to atorvastatin 80 mg/d. Atheroma area decreased by 43% and lumen area increased by 26%. Adapted with permission from JAMA. 2004;291:1071-1080.[4]© 2004 American Medical Association.
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Figure 2.
Reversal of Atherosclerosis with Lipitor study results. Intravascular ultrasound images showing: A) calculation of atheroma area: subtraction of lumen area from external elastic membrane (EEM) bounded area, and; B) change in atheroma area in patient assigned to atorvastatin 80 mg/d. Atheroma area decreased by 43% and lumen area increased by 26%. Adapted with permission from JAMA. 2004;291:1071-1080.[4]© 2004 American Medical Association.
Results
Of 654 patients receiving the study drug, 502 had evaluable IVUS at baseline and follow-up, evenly divided among the two groups. LDL cholesterol level was 150 mg/dL at baseline. In the atorvastatin group, mean LDL cholesterol level decreased to 79 mg/dL and in the pravastatin group to 110 mg/dL. The primary end point analysis, percentage change in atheroma volume, demonstrated a median regression in volume in the atorvastatin group (-0.4%; 95% confidence interval, 2.35-1.49) and showed no statistical progression compared with baseline, while there was a significant progression in the pravastatin group (+2.7%; 95% confidence interval, 0.24-4.67; p=0.001). In terms of mean percentage change, atheroma volume increased in both groups (5.4% in the pravastatin group, 4.1% in the atorvastatin group), indicating slightly more than a 1% difference. Intergroup comparisons of progression based on median values showed significant progression in the pravastatin group (p=0.02). However, no statistical analysis is found for mean values. For the secondary evaluation of atheroma change in the 10-mm vessel subsegment with greatest disease severity, both groups demonstrated regression compared with their respective baseline volumes, but the atorvastatin group regression was greater (p<0.01). A direct relationship was demonstrated for percent change in LDL cholesterol level and change in atheroma volume. However, the line reached 0 change in volume with an LDL cholesterol reduction of 45% with atorvastatin and 60% with pravastatin, indicating a more pronounced effect on atheroma volume decrease in the higher potency group for each percent decrease in LDL cholesterol level (Figure 3). Reduction in C-reactive protein (CRP) was significantly greater in the atorvastatin group (36.4%) than the pravastatin group (5.2%; p<0.01).

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Figure 3.
Reversal of Atherosclerosis with Lipitor study results. Comparison of percentage of low-density lipoprotein cholesterol reduction and change in atheroma volume. Solid line represents mean change; dashed lines represent 95% confidence limits for mean values. Adapted with permission from JAMA. 2004;291:1071-1080.[4]© 2004 American Medical Association.
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Figure 3.
Reversal of Atherosclerosis with Lipitor study results. Comparison of percentage of low-density lipoprotein cholesterol reduction and change in atheroma volume. Solid line represents mean change; dashed lines represent 95% confidence limits for mean values. Adapted with permission from JAMA. 2004;291:1071-1080.[4]© 2004 American Medical Association.
Comment
The most salient questions that should be asked about the results are: How does that translate into decrease in clinical outcome, and do the results, although statistically significant, suggest a large enough difference to be clinically relevant? Because coronary events are associated with unstable plaque and not necessarily atheroma volume, the atheroma burden cannot necessarily be translated into a high correlation for clinical events; however, we certainly have information on LDL cholesterol lowering and clinical events both in primary prevention and secondary prevention. The mean LDL cholesterol level was lowered by 40 mg/dL in the pravastatin group (27%) and 71 mg/dL (47%) in the atorvastatin group. If we assume that the rather high dropout rate (23% between baseline and 18 months) did not bias the results (the rate was equal in both groups), we would expect a decrease in LDL cholesterol levels of 40 mg/dL to correspond to a 25% reduction in coronary events in a high-risk population. Using a proportional regression line, which has been demonstrated for results of clinical trials, the 31-mg/dL difference in LDL cholesterol level lowering between groups would correspond to a 19% reduction in clinical events with more aggressive therapy. The difference in reduction of CRP was more marked between groups. The reduction of 36% with atorvastatin appears greater than results from statin interventions in secondary prevention trials (usually <20%). href="javascript:newshowcontent(">[5-8] As the editorial accompanying the report points out, it is possible that the pravastatin group's adherence to drugs may have been lower than the atorvastatin group. Further data are pending on clinical outcomes in this trial. From the results so far, there is evidence that atheroma plaque volume progression is less with aggressive statin dosage than moderate statin dosage, but the differences are not marked. Whether these differences relate to clinical outcomes awaits further study. It is possible that the marked differences in CRP reduction may indicate an important difference in effects on inflammatory processes. The IVUS technique cannot reliably assess changes in plaque stability, and thus no evaluation could be made in this regard.