The DEFINE ( Determining the EFficacy and Tolerability of CETP INhibition with AnacEtrapib ) trial was an 18-month study in more than 1,600 patients with or at high risk for coronary heart disease ( CHD ) who were already receiving statins and were at guideline-established LDL-C goal. The study was designed to assess the lipid-modifying efficacy, safety and tolerability of Anacetrapib 100 mg daily added to ongoing statin therapy with or without other lipid-modifying agents.

There were no significant differences between the Anacetrapib and placebo-treated patients in mean change from baseline in systolic ( 0.2 mmHg, p=0.83 ) or diastolic blood pressure ( 0.0 mmHg, p=0.96 ), nor in the percentage of patients reported to have increased blood pressure. The number of patients with clinically important changes in serum electrolytes ( sodium, potassium, chloride and bicarbonate ) was not significantly different between those who received Anacetrapib and those given placebo during the 76-week treatment period ( p value range 0.25 to 0.99 ), nor was there any difference in mean change from baseline in aldosterone levels between the two groups over 76 weeks ( 20.4 pg/mL vs 18.4 pg/mL, respectively ). In addition, there were no cases of rhabdomyolysis in either the Anacetrapib or the placebo treatment groups. There was one case of elevated liver enzymes ( two consecutive values greater than or equal to three times the upper limit of normal ) in the Anacetrapib-treated patients compared to eight cases in patients given placebo.

An early member of the CETP inhibitor class, Torcetrapib, was found to cause an excess of deaths and cardiovascular events. In the DEFINE study, all cardiovascular serious adverse events and deaths from any cause were adjudicated by a blinded, external, independent adjudication committee. Reports of revascularization and heart failure were collected and adjudicated, but were not part of the pre-specified cardiovascular composite endpoint. In DEFINE, pre-specified adjudicated cardiovascular events occurred in 16 patients given Anacetrapib ( 2.0% ) compared with 21 patients who received placebo ( 2.6% ) ( p=0.40 ), coronary revascularization was carried out in significantly fewer people given Anacetrapib compared with those taking placebo ( 8 vs 28, respectively, p<0.001 ), and death from any cause occurred in 11 patients taking Anacetrapib and in eight patients given placebo ( p=0.5 ).

Rates of drug-related adverse experiences ( Aes ), serious AEs, and drug-related serious AEs were similar between the Anacetrapib and placebo groups ( 11.4% vs 10.7%, 15.2% vs 14.8%, and 0.2% vs 0.5%, respectively ). Clinical and drug-related AEs leading to discontinuation were also similar in patients taking Anacetrapib and those given placebo ( 5.4% vs 5.7% and 2.7% vs 2.2%, respectively ).

At 24 weeks, treatment with Anacetrapib resulted in a placebo-subtracted 40 percent reduction in mean LDL-C ( from 81 to 45 mg/dl vs 82 to 77 mg/dl for placebo, p<0.001 ) and a 138% increase in mean HDL-C ( from 40 to 101 mg/dl vs. 40 to 46 mg/dl for placebo, p<0.001 ). Compared to placebo, Anacetrapib also raised mean apolipoprotein (apo) A-1 ( a major protein component of HDL particles ) by 45%, lowered mean apo B ( a major protein component of atherogenic lipoprotein particles, including LDL ) by 21% and reduced mean non-HDL-C by 32% ( p<0.001 for all measures ). Anacetrapib reduced median Lp(a) ( an LDL-like particle ) by 36% compared to placebo. All changes in lipids were sustained throughout the 76-week treatment period. There were no significant differences between the treatment groups in C-reactive protein ( CRP ). There was a pre-specified discontinuation rule for patients whose LDL-C fell below 25 mg/dL, which occurred in 18% of patients treated with Anacetrapib and in one patient in the placebo group.

Source: Merck, 2010

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