Presented at the AHA congress 2014 by: Christopher P Cannon (Brigham and Women's Hospital, Boston, MA, VS)
LBCT.02 - Anti-Lipid Therapy and Prevention of CAD

Background

Lowering LDL-cholesterol levels is the mainstay of cardiovascular (CV) prevention. Evidence mainly comes from statin trials, which showed a reduction in morbidity and mortality, and high doses have more effect on non-fatal CV events than lower doses. Thus far, no other lipid-modifying therapy, like fibrates, niacin and CETP-inhibitors, has been shown to have clinical benefit in addition to statins. Despite statin treatment, patients remain at high risk of CV events, thus other lipid-modifying agents are still warranted.
Ezetimibe inhibits the Niemann-Pick C1-like 1 (NPC1L1) protein, which is mostly localised in the epithelium of the gastrointestinal tract. Ezetimibe inhibits cholesterol absorption and gives 20% extra LDL-c lowering when given in addition to statins. It has recently been shown that polymorphisms in the NPC1L1 gene are associated with lower LDL-c levels and a lower CV risk.
The IMPROVE-IT study was set up to compare the clinical efficacy and safety of the combination of ezetime and simvastatin (EZ/Simva) with simvastatin alone. Patients who were admitted to the hospital for STEMI, NSTEMI of unstable angina (UA) in the past 10 days were included, of 50 years or older and with at least one high risk factor, and LDL-c 50-125 mg/dL, or 50-100 mg/dL if they had already received lipid-lowering therapy. Patients were randomised to EZ/Simva or Simva and followed for at least 2.5 years. The primary endpoint was CV mortality, myocardial infarction (MI), hospital admission for UA, coronairey revascularisation (> 30 days after randomisation) or stroke.

Main results

• Patients on EZ/Simva showed consistently lower LDL-c levels during the study period. After a year patients randomised to simvastatin had on average 69.9 mg/dL as compared with 53.2 mg/dL in patients on EZ/Simva.
• The primary endpoint occurred significantly less often after 7 years of follow-up in patients randomised to EZ/Simva (22572 events, 32.7%), as compared to patients on Simva alone (2742 events, 34.7%, HR: 0.936, 95%CI: 0.887-0.988, P=0.016, NNT=50).
• For the primary endpoint and thre prespecified secondary endpoints after 7 years in the intention-to-treat analysis, EZ/Simva also showed statistiscally significant benefit as compared with Simva alone.

• Of the individual CV endpoints, EZ/Simva protected significantly against MI (13.1% vs. 14.8% after 7 years, HR: 0.87, P=0.002), ischaemic stroke (3.4% vs. 4.1%, HR: 0.79, P=0.008) and the combination of CVD/MI/stroke (20.4% vs. 22.2%, HR: 0.90, P=0.003).

• In prespecified subgroups, a different effect was only seen between patients with or without diabetes, such that patients with diabetes benefitted more from the EZ/Simva combination.
• With regard to safety, no significant differences were observed in the intention-to-treat group in the incidence of cancer, muscle or gal bladder-related events.

Conclusion

The IMPROVE-IT trial was the first study that shows that extra clinical benefit can be obtained when another therapy than statins, namely ezetimibe, is added to statin therapy. This implies that LDL-c lowering with an agent other than statins indeed reduces CV events and that even lower LDL-c levels are indeed even better. Ezetimibe was safe for patients.
This study thus confirms the LDL-c hypothesis that lowering LDL-c levels can prevent CV disease. These findings should be considered when writing updated guidelines.
In an AHA comment, Loris Mosca, Professor of Medicine in Colombia University Medical Center en Director of Preventive Cardiology in het New York Presbyterian Hospital says: “These results are consistent with decades of research in high-risk ACS patients affirming the central role of aggressive LDL reduction in the prevention of recurrent heart disease. They further suggest that we should consider setting the LDL bar even lower among our high-risk patients to achieve maximum benefit to prevent recurrent heart disease and stroke.“

Also read the results of the on-treatment analysis of IMPROVE-IT:
News • 20-11-2014

IMPROVE-IT on-treatment analysis confirms advantage of adding ezetimibe to statins

AHA 2014  The on-treatment analyses show an even larger clinical treatment effect of ezetimibe addition to statins, as compared with the intention-to-treat analyses.