Evidence of Plaque Regression Bolsters Case for Combining Ezetimibe With Statin

On the heels of the IMPROVE-IT trial, which supported adding ezetimibe to statin therapy in ACS patients, a new study shows the combination not only has beneficial effects on cholesterol levels in both ACS and stable angina patients but also induces a corresponding regression of coronary plaque. The study was published in the August 4, 2015, issue of the Journal of the American College of Cardiology. 

From June 2010 through April 2013, Kenichi Tsujita, MD, PhD, of Kumamoto University (Kumamoto, Japan), and the PRECISE-IVUS investigators randomized Japanese patients (78% men) who had undergone angiography and/or PCI for ACS or stable angina to atorvastatin alone (n = 122; Lipitor; Pfizer) or in combination with 10 mg of ezetimibe (n = 124; Zetia; Merck) daily at 17 centers. All patients had a baseline LDL level above 100 mg/dL.

Combination Therapy Bests Monotherapy

Atheroma burden was measured in 202 patients with volumetric IVUS at baseline and at 9 to 12 months. Demographic characteristics and baseline medication use were similar between the treatment groups, except for more occurrences of stroke in the combination therapy group and higher nitrate use in the monotherapy group.

Within the IVUS cohort, patients randomized to combination therapy achieved lower LDL levels at follow-up than those on statin monotherapy despite having had comparable baseline levels. Additionally, those in the combination therapy group had a lower ratio of LDL to HDL during treatment and were more likely to achieve target LDL levels of < 70 mg/dL. Furthermore, more patients demonstrated evidence of coronary plaque regression with ezetimibe added than with statin monotherapy (table 1).

While there was no difference between the treatment groups related to change in high-sensitivity C-reactive protein levels, several cholesterol absorption markers decreased with combination therapy but increased with monotherapy.

The ezetimibe combination proved noninferior to monotherapy for the absolute change in percent atheroma volume (primary endpoint), with a mean difference of drug effects of -1.538% (95% CI -3.079% to 0.003%). Percent change in total atheroma volume, a secondary IVUS endpoint, was greater in the combination vs monotherapy group (-6.6% vs -1.4%; P < .001). When the study authors looked at between-group differences in patients with ACS or stable angina, the ACS cohort seemed to reap a greater benefit from the combination therapy in terms of both endpoints.

Both treatment strategies were well tolerated, with similar frequency of cardiovascular events, low rates of abnormal laboratory values, and similar rates of TLR or TVR.

Potential for Guideline Change?

The IMPROVE-IT trial, presented at the 2014 American Heart Association (AHA) Scientific Sessions and published recently the New England Journal of Medicine, was the first to show the clinical benefit of adding a nonstatin agent to standard statin therapy. According to the authors, PRECISE-IVUS confirms superior plaque regression with atorvastatin/ezetimibe over atorvastatin alone and suggests that the IMPROVE-IT findings “might be derived from the suppression effect of coronary atherosclerotic development by dual lipid lowering.”

However, Dr. Tsujita and colleagues say, ezetimibe may also be helping to suppress the compensatory enhancement of cholesterol absorption that can occur with atorvastatin alone, since PRECISE-IVUS found a positive correlation between the suppression of cholesterol absorption markers and coronary plaque regression.

Importantly, the PRECISE-IVUS results “could lead to an early reevaluation of the new [American College of Cardiology/AHA] lipid management guidelines that endorses statins as the only recommended drugs for treating cholesterol-related CV risk,” the study authors suggest.

A combination regimen could be an attractive option in patients unable to tolerate high-dose statins, those who may better tolerate a combination of low-dose statin plus ezetimibe, and those who cannot achieve adequate LDL lowering despite high-dose statin therapy, they say. It may also be of use, the researchers add, in “vulnerable patients with a high risk of CAD (eg, individuals with high baseline LDL-C values, diabetes, established CV disease, or familial hypercholesterolemia).”

Many Possible Mechanisms  

In an editorial accompanying the study, Filippo Crea, MD, and Giampaolo Niccoli, MD, PhD, both of Catholic University of the Sacred Heart (Rome, Italy), caution against jumping to the conclusion that LDL lowering is solely responsible for the plaque regression. They note that in the study, linear regression analysis did not demonstrate an association between achieved LDL levels and percent atheroma volume changes. They also express doubt that the anti-inflammatory properties of ezetimibe explain the decreased plaque.

Instead, Drs. Crea and Niccoli hypothesize that ezetimibe’s positive effect may stem from inhibiting absorption of not only cholesterol but also plant sterols. High plasma levels of these sterols have been implicated by some studies in increasing the risk of cardiovascular events, they note. Other potential “pleiotropic effects” of ezetimibe that may contribute to plaque regression include:

• Modulation of genes related to inflammation and/or oxidative stress 
• Inhibition of monocyte and/or macrophage differentiation 
• Inhibition of smooth muscle cell proliferation 

“Furthermore, ezetimibe inhibits platelet aggregation and activation and seems to modulate atherosclerotic plaque composition with reduction of cholesterol crystals that, in turn, are associated with inflammasome activation, plaque growth, and vulnerability,” the editorialists add. “Ezetimibe and statins might have additive effects on cholesterol crystallization.”

Sources: 
1. Tsujita K, Sugiyama S, Sumida H, et al. 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. J Am Coll Cardiol. 2015;66:495-507.
2. Crea F, Niccoli G. Ezetimibe and plaque regression: cholesterol lowering or pleiotropic effects [editorial]? J Am Coll Cardiol. 2015;66:508-510. 

Disclosures:

• The study was supported by grants from the Ministry of Education, Science, and Culture of Japan.  
• Drs. Tsujita, Crea, and Niccoli report no relevant conflicts of interest. 

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