Impact of Dual Lipid-Lowering Strategy With Ezetimibe and Atorvastatin on Coronary Plaque Regression in Patients With Percutaneous Coronary Intervention: The Multicenter Randomized Controlled PRECISE-IVUS Trial

Tsujita K, Sugiyama S, Sumida H, et al; PRECISE–IVUS Investigators
J Am Coll Cardiol. 2015 Aug 4;66(5):495-507. doi: 10.1016/j.jacc.2015.05.065

Background

IMPROVE–IT (Improved Reduction of Outcomes: Vytorin Efficacy International Trial) assessed the effect of simvastatin plus placebo vs. simvastatin plus ezetimibe on CV endpoints. Simvastatin lowers LDL-c levels through blocking hepatic cholesterol synthesis, while ezetimibe inhibits cholesterol absorption through inhibition of the Niemann-Pick C1like1 protein. After addition of ezetimibe to statin therapy, a lower incidence of CV death, myocardial infarction (MI), rehospitalisation for unstable angina, coronary revascularisation or stroke was seen [1].
It is unknown whether the additional LDL-c lowering achieved with addition of a nonstatin agent to standard statin therapy will also lead to stronger coronary plaque regression. Also, it is unclear whether a dual lipid-lowering strategy (combined inhibition of cholesterol synthesis and absorption) modifies plaque progression and/or regression.
The prospective, randomised assessor-blind PRECISE-IVUS (Plaque Regression With Cholesterol Absorption Inhibitor or Synthesis Inhibitor Evaluated by Intravascular Ultrasound) trial therefore compares the effects of ezetimibe added to atorvastatin (LZ group, n=100) with atorvastatin monotherapy (L group, n=102) on coronary plaque regression and change in the lipid profile in Japanese patients with CAD undergoing PCI, during 9-12 months of follow-up. Coronary artery atheroma volume was measured by IVUS. Half of the patients were assigned to an acute coronary syndrome (ACS) cohort (51% STEMI) and the remainder to a stable angina pectoris (SAP) cohort.

Main results

• Dual lipid-lowering strategy showed a larger reduction of LDL-c level than atorvastatin monotherapy (LZ: -40%+18 mg/dL vs. L: -29+24 mg/dL, P<0.001).
• LDL-c to HDL-c ratio was lower in the LZ group (1.45+0.45) than in the L-group (1.77+0.55, P<0.001), and more patients in the LZ group achieved LDL-c target of <70 mg/dL (72% vs. 47%, P<0.001).
• The primary IVUS endpoint of non-inferiority of the LZ to the L group in absolute change in percent atheroma volume (PAV) was met, with a mean difference between the groups of -1.538% (95%CI: -3.079 to 0.003%).
  For superiority, the absolute change in PAV was reduced by -1.4% (95%CI: -3.4 to -0.1%) in the LZ group and by -0.3% (-1.9 to 0.9%) in the L group (P<0.001).
• A secondary IVUS endpoint total atheroma volume (TAV)normalised, showed a larger effect in the LZ group (-6.6, 95%CI: -12.6 to 0.2%) than in the L group (-1.4%, 95%CI: -6.7 to 4.4%, P<0.001). More patients in the LZ group showed disease regression with regard to TAVnormalised (75% vs. 58%, P=0.02).
• The plaque regression effect in the LZ vs. L group was greater in the ACS cohort than in the SAP group (both with regard to absolute change in PAV and percent change in TAVnormalised), and analysis of correlations between lipid biomarkers and absolute change in PAV suggested plaque regression reversibility in ACS patients.

Conclusion

The dual lipid-lowering strategy that combines inhibition cholesterol synthesis and absorption (atorvastatin and ezetimibe) yielded a more remarkable lowering of LDL-c than atorvastatin monotherapy, with evidence of suppression of the compensatory enhancement of cholesterol absorption. In addition, volumetric IVUS analysis revealed the non-inferiority of the combination therapy with regard to absolute change in PAV, as well as the superiority with respect to coronary plaque regression with negative vascular remodelling in the analysed segment. The ACS cohort showed a more pronounced benefit of the dual lipid-lowering approach than did the stable angina pectoris group.


Find this article online at J Am Coll Cardiol

Editorial comment [2]

In the PRECISE-IVUS study, “at first glance, the lower mean LDL-C level achieved with combination therapy than with monotherapy (63.2 mg/dl vs. 73.3 mg/dl) seems to account for the enhanced regression associated with the former. However, linear regression analysis failed to show an association between achieved LDL-C levels and PAV changes.” However, in the SATURN study lower LDL-c levels were achieved but no detectable PAV reduction. “Thus, cholesterol lowering itself does not seem to explain the greater reduction of PAV with combination therapy versus monotherapy observed in the PRECISE-IVUS trial.” The anti-inflammatory effect of ezetimibe is unlikely to be the cause either, since reduction of C-reactive protein was similar for both treatments.
Crea and Niccoli see a role for sterols other than cholesterol, since in PRECISE-IVUS lathosterol, campesterol and sitosterol and their ratio to cholesterol decreased with the combination therapy, but increased with monotherapy. “Interestingly, the campesterol-to-cholesterol ratio reduction was significantly and positively related to a reduction in PAV.” (…) “Only a prospective interventional trial to analyse the effects of plant sterol–enriched food on the incidence of cardiovascular events can exclude a potential cardiovascular risk linked with their excess.” The authors of the editorial also mention a possible role for other pleiotropic effects unrelated to cholesterol lowering and effects on reduction of cholesterol crystals in ezetimibe-related potentiation of plaque regression. They conclude by saying that “The molecular mechanisms driving the additional benefit of ezetemibe on plaque progression  compared with statin monotherapy need to be further investigated.”

References

1. Cannon C. IMPROVE-IT trial: a comparison of ezetimibe/simvastatin versus simvastatin monotherapy on cardiovascular outcomes after acute coronary syndromes. Presented at: Annual Scientific Sessions of the American Heart Association, Chicago, IL, November 17, 2014.
2. Crea F, Niccoli G. Ezetimibe and plaque regression: cholesterol-lowering or pleiotropic effects? J Am Coll Cardiol. 2015 Vol 66 (5): 508-10.