Anacetrapib, an inhibitor of Cholesteryl Ester Transfer Protein (CETP) activity, lowers the risk of heart attack and related cardiovascular complications among patients who are receiving intensive statin treatment. These are the conclusions from a major randomized controlled trial of 30,000 participants led by researchers in the Clinical Trial Service Unit at the University of Oxford.
Unveiling the key findings at the European Society of Cardiology Congress today, the trial’s co-principal investigator Professor Martin Landray said:
“The REVEAL trial has shown for the first time that adding anacetrapib to intensive statin therapy reduces the incidence of cardiovascular events for high risk patients. The treatment was very well tolerated and there were no major safety concerns.
“These findings are in marked contrast to the disappointing results of previous trials of other CETP inhibitors. The reduction in the risk of cardiovascular events is in line with the effects of other drugs that lower LDL cholesterol levels, such as statins. The large increase in HDL cholesterol levels produced by anacetrapib did not appear to have much impact on risk.”
The Randomized EValuation of the Effects of Anacetrapib through Lipid Modification (REVEAL) trial involved over 30,000 men and women who had some form of vascular disease, such as heart attack or stroke. They were recruited from more than 400 hospitals in the UK, USA, Canada, China, Germany, Italy, and Scandinavia. All participants were given intensive treatment with atorvastatin (a commonly prescribed statin drug) to ensure good control of LDL (“bad”) cholesterol. Participants also received anacetrapib, an investigational CETP inhibitor, or a matching placebo for an average of 4 years. Information was recorded on cardiovascular events, death, cancer, reasons for hospital admission, and a wide range of other health-related outcomes relevant to understanding the safety and efficacy of anacetrapib.
The REVEAL study results are summarized below:
- Adding anacetrapib to statin therapy reduced the blood level of LDL cholesterol by around 20% and doubled the level of HDL cholesterol.
- Adding anacetrapib to intensive statin treatment produced a 9% proportional reduction in the risk of the composite outcome of heart attack, death from heart disease, or coronary revascularization (i.e. coronary artery stenting or bypass surgery).
- In a subsidiary analysis, anacetrapib significantly reduced the composite outcome of coronary death or myocardial infarction. There was no significant effect on ischaemic stroke.
- Anacetrapib was well tolerated and, as has been found previously, the levels of anacetrapib in body fat continued to increase while treatment continued.
- Anacetrapib produced a small reduction in the risk of developing diabetes mellitus.
- There were no major safety signals and no increase in death, cancer or other serious medical events, but there was a small increase in blood pressure and a small reduction in kidney function.
The main results are published in more detail in the New England Journal of Medicine today.
The positive results of the REVEAL trial of 4 years of anacetrapib treatment contrast with the results of previous trials of other CETP inhibitors, all of which were stopped after about 2 years of follow-up due to either unexpected hazards or apparent lack of efficacy.
Dr Louise Bowman, the other co-principal investigator of REVEAL, explained:
“The REVEAL trial has a number of strengths which allow reliable assessments of both efficacy and safety. It recruited around twice as many participants as any previous trial of a CETP inhibitor; it collected information on double the number of cardiovascular events; and the CETP inhibitor treatment continued for twice as long.
“The full effects of anacetrapib did not appear to emerge until beyond the first year of treatment. A similar pattern has been observed in randomized trials of other LDL-cholesterol lowering treatments, such as statins. Consequently, previous trials of CETP inhibitors that were stopped after only about 2 years may have been too short for any benefits to emerge.”
The REVEAL trial was designed and conducted by independent investigators (supported by the British Heart Foundation and Medical Research Council) in the Clinical Trial Service Unit at the University of Oxford, Oxford, UK, in collaboration with the Thrombolysis in Myocardial Infarction (TIMI) Study Group at Brigham and Women’s Hospital and Harvard Medical School in Boston, USA, along with other members of the independent academic Steering Committee and MSD (known as Merck in the USA and Canada). MSD also funded the trial and provided the study drugs.
Professor Landray acknowledged all those who contributed to the success of the study:
“We would particularly like to thank the 30,000 patient volunteers who participated in REVEAL. It would also not have been possible without the efforts of hundreds of clinicians and researchers from around the world. Together they have made it possible to demonstrate that heart disease risks can be reduced further by adding anacetrapib to current therapy.”