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Safety of Anacetrapib in Patients with or at High Risk for Coronary Heart Disease

Christopher P. Cannon, M.D., Sukrut Shah, Ph.D., R.Ph., Hayes M. Dansky, M.D., Michael Davidson, M.D., Eliot A. Brinton, M.D., Antonio M. Gotto, Jr., M.D., D.Phil., Michael Stepanavage, M.S., Sherry Xueyu Liu, M.S., Patrice Gibbons, M.S., Tanya B. Ashraf, B.A., Jennifer Zafarino, M.S., Yale Mitchel, M.D., and Philip Barter, M.D., Ph.D. for the DEFINE Investigators

November 17, 2010 (10.1056/NEJMoa1009744)

http://www.nejm.org/doi/pdf/10…..Moa1009744

This study was designed to evaluate the overall safety profile and the effects of Anacetrapib on the lipid levels in patients with coronary heart disease or at high risk for coronary heart disease.

So what is Anacetrapib? Anacetrapib is a cholesteryl ester transfer protein (CETP) inhibitor. A plasma protein that promotes the transfer of cholesteryl esters from HDL and other lipoproteins fractions. Drugs that inhibit CETP increase HDL cholesterol, and some lower LDL cholesterol.

Why are investigators so concerned with the safety issue? To make a long story short the development of Torcetrapib, the first CETP inhibitor that was tested in a clinical outcomes trial, was terminated after the drug was shown to cause an excess of deaths and cardiovascular events. Treatment with Torcetrapib increased blood pressure and circulating aldosterone levels and altered serum electrolyte levels. Subsequent studies indicated that these adverse effects of Torcetrapib were unrelated to the inhibition of CETP and are not necessarily shared by other members of the class of CETP inhibitors.

What is spectacular about the study? By 24 weeks, the LDL cholesterol level had been reduced from 81 mg per deciliter to 45 mg per deciliter in the anacetrapib group, as compared with a reduction from 82 mg per deciliter  to 77 mg per deciliter in the placebo group (P<0.001) — a 39.8% reduction with Anacetrapib beyond that seen with placebo. In addition, the HDL cholesterol level increased from 41 mg per deciliter to 101 mg per deciliter in the Anacetrapib group, as compared with an increase from 40 mg per deciliter to 46 mg per deciliter  in the placebo group (P<0.001) — a 138.1% increase with Anacetrapib beyond that seen with placebo.

You may ask yourself are they sure that the above results have occurred because of Anacetrapib and  not because of any other concomitant drugs the patients were taking during the study (confounding variable)? Well, the answer is that the investigators were dealing with patients who are taking statins and having coronary heart disease so they cannot stop the lipid lowering drugs and their only way to control for these confounders is to use a randomized design and to make sure that the two groups (placebo and Anacetrapib) are comparable in term of baseline characteristics including confounders in both groups.

Concerning the drug safety the study revealed:

Through 76 weeks, no changes were noted in blood pressure or electrolyte or aldosterone levels with Anacetrapib as compared with placebo. Prespecified adjudicated cardiovascular events occurred in 16 patients treated with Anacetrapib (2.0%) and 21 patients receiving placebo (2.6%) (P=0.40).

A question that may cross your mind is how did they monitor the drug safety during the study if it is a double blinded study? An external, independent safety monitoring committee whose members were aware of the patients' group assignments was responsible for reviewing safety data on a regular basis throughout the study to ensure patient safety. An independent statistical group supported the safety monitoring committee by performing analyses, including those proposed by the safety monitoring committee, independently of the sponsor. 

All serious cardiovascular events and deaths from any cause were adjudicated by an external, independent adjudication committee whose members were unaware of the patients' group assignments.

What are the study shortcomings?

First, the study is too small to provide definitive results regarding the overall safety or efficacy of anacetrapib.

Second, since most of the study participants were white, additional safety data are required from patients of other races or ethnic groups, notably Asians, in whom drug metabolism of the lipid agents, such as statins, may be different.

Third, given previous uncertainty regarding the safety of extremely low levels of LDL cholesterol, the protocol mandated the discontinuation of the study drug if the LDL cholesterol level was less than 25 mg per deciliter at two consecutive measurements; thus, the study provides no information about the long-term safety of reducing LDL cholesterol to such extremely low levels. {As specified by the protocol, the study drug was discontinued in any patient who had an LDL cholesterol level of less than 25 mg per deciliter at two consecutive measurements; this occurred in 142 patients in the anacetrapib group (17.6%) and 1 patient in the placebo group (0.1%)!}

Future implications: These initial results provide a rationale for conducting a large clinical outcomes trial involving patients with cardiovascular disease who are at high risk for recurrent events.

Thought for the day: If subsequent studies supported the safety of Anacetrapib and were able to show a decrease in the mortality that will be a breakthrough and it will definitely shake the statins market!