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Revision as of 03:38, 20 September 2013
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DEFINE Trial On the Web |
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: : Rim Halaby, M.D. [2]
Objective
The objective of this trial is to study the therapeutic and adverse effect of anacetrapib, a CETP inhibitor, alone and with statin.[1]
Timeline
Start Date
April 2008
Methods
- Phase III trial
- Prospective, randomized, multicenter, placebo-controlled double-blind clinical trial that recuited 1,623 patients.
- Run-in phase: 2 weeks
- Two arms of the study: anacetrapib 100 mg daily or placebo for 76 weeks
Inclusion Criteria
- Age between 18-80 years
- LDL-C < 100 mg/dL and coronary heart disease or risk equivalent
- Patient receiving statin therapy with or without other anti-lipidemics
- HDL < 60 mg/dL
- Triglycerides < 400 mg/dL
- Abstinence or use of at least 2 effective contraceptive methods
- Be at least 75% compliant during run-in phase
Exclusion Criteria
- NYHA class III or IV heart failure
- Any of the following events within 3 months:
- Uncontrolled arrhythmias
- Myocardial infarction
- Percutaneous coronary intervention
- Coronary artery bypass graft
- Unstable angina
- Stroke
- LDL-C<50 mg/dL
- Uncontrolled hypertension defined as SBP ≥ 160 mmHg / DBP≥ 100 mmHg for non-diabetics or SBP ≥ 150 mmHg / DBP ≥ 90 mmHg for diabetics
- CPK or liver function tests twice the upper normal limit
- Active or chronic hepatic or biliary disease
- Renal failure with eGFR < 30 mL/min/1.73 m2
- Diabetes mellitus diagnosed within 3 months or HbA1c > 8.5%
- TSH below or 20% above normal limit
- Homozygous familial hypercholesterolemia
- Type I and type II hyperlipidemia
- Currently on warfarin, systemic corticosteroids, anabolic steroids, or any drug that potently affects CYP3A4.
Outcomes
- Primary end points: Percent change in LDL after 24 weeks, adverse experiences including cardiovascular end points, other lab values, ECG changes, vital sign and physical examination assessments after 76 weeks of treatment.
- Secondary end points: Change in HDL, total cholesterol, triglyceride, CRP apo A-I, A-II, B, C-III, and E, lipoprotein(a) and ratios of total cholesterol/HDL, LDL/HDL, apo B/ apo A-I, and LDL/apo B after 24 and 76 weeks of treatment *
- Cardiovascular end points are defined as cardiovascular death, myocardial infarction, stroke, and hospitalization for unstable angina.
Results
- 17.6% of patients on anacetrapib vs. only 0.1% of placebo were discontinued due to LDL < 25 mg/dL at 2 consecutive visits.
- With respect to LDL reduction and HDL elevation, anacetrapib showed significant changes: 39.8% and 138.1% change, respectively at 24 weeks. LDL was approximately halved from 81 to 45 mg/dL and HDL increased from 41 to 101 mg/dL. Change in HDL was further accentuated in patients with baseline low HDL < 40 mg/dL, with an increase of 152% in this sub-population.
- Similarly, a significant decrease in apoB, non-HDL-C, lipoprotein, and triglycerides, and an increase in ApoA-I were all seen with anacetrapib at 24 and 76 weeks.
- In the reversal phage, 1398 patients were enrolled. Significant reduction in LDL, non-HDL, apo-B and an increase in HDL and apo A-I persisted during that period for patients on anacetrapib, who continued to have trace concentrations of the medication. These alterations reached 50-60% of values observed during on-medication trial period.
- Anacetrapib had no effect on adverse events during the trial or the reversal phase, but had a significantly lower number of patients with liver function test disturbances by the end of the trial (p=0.02).
- In comparison to placebo, Post-hoc analysis revealed that patients on anacetrapib had significantly less revascularization procedures (p=0.001) and cardiovascular end points (p=0.048).[2]
Additional Publications from DEFINE Trial
Safety of anacetrapib in patients with or at high risk for coronary heart disease
Objective
To evaluate the safety profile and list of side effects of anacetrapib, a CETP inhibitor, in 1623 patients with coronary heart disease or its risk factors.
Results
After balancing proportions, the percentage of patients who discontinued the study due to 2 consecutive LDL-C levels < 25 mg/dL was 14.6% in patients receiving anacetrapib and 17.4% in patients receiving placebo.
The decrease in LDL levels after 24 weeks of treatment was significant in patients receiving anacetrapib compared to those on placebo. The LDL in the former group was reduced from 81 mg/dL to 45 mg/dL, where was it was only reduced from 82 mg/dL to 77 mg/dL in the latter (p<0.001). The percent change of LDL in anacetrapib group was a 39.8% reduction. Similarly, HDL increased 138.1%, from 41 mg/dL to 101 mg/dL in anacetrapib group, also significantly different from placebo that only raised HDL from 40 mg/dL to 46 mg/dL after 24 weeks (p<0.001).
There was a 44.7% increaase in apo A-1 and a 21% decrease in apo B among patients receiving anacetrapib (p<0.001).
Changes associated with anacetrapib were maintained throughout 76 weeks of follow-up.
No adverse event was significantly associated with anacetrapib alone when compared to placebo. Common adverse events in both groups included: elevation in systolic and diastolic blood pressures, electrolyte disturbances, elevation in creatinine kinase, and myalgias. Significantly, there was a 0.96mmol/L decrease in sodium in patients on anacetrapib vs. a 1.2 mmol/L in patients on placebo (p=0.02). The rates of liver function tests increase to three times above upper normal limit was in fact significantly less in patients on anacetrapib (p=0.02).
Conclusion
Anacetrapib is associated with a significant increase in HDL and decrease in LDL with a tolerable side effect probile. Further clinical trials are required to prove the beneficial effects of increasing HDL levels in preventing adverse cardiovascular events in high risk patients.
Conclusion
Anacetrapib causes a significant increase in HDL with no alteration in other biochemical levels with sustained effects. Unlike torcetrapib, anacetrapib is not associated with cardiovascular events.[2]
References
- ↑ Cannon CP, Dansky HM, Davidson M, Gotto AM, Brinton EA, Gould AL; et al. (2009). "Design of the DEFINE trial: determining the EFficacy and tolerability of CETP INhibition with AnacEtrapib". Am Heart J. 158 (4): 513–519.e3. doi:10.1016/j.ahj.2009.07.028. PMID 19781408.
- ↑ 2.0 2.1 Davidson M, Liu SX, Barter P, Brinton EA, Cannon CP, Gotto AM; et al. (2013). "Measurement of LDL-C after treatment with the CETP inhibitor anacetrapib". J Lipid Res. 54 (2): 467–72. doi:10.1194/jlr.M032615. PMC 3588873. PMID 23172660.