Dal-OUTCOMES Trial
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Official Title
A Randomized, Double-blind, Placebo-controlled Study Assessing the Effect of RO4607381 on Cardiovascular Mortality and Morbidity in Clinically Stable Patients With a Recent Acute Coronary Syndrome
Objective
The objective of this trial is to study the effect of dalcetrapib on cardiovascular mortality and morbidity in patients with recent acute coronary syndrome in patients on statin therapy.[1]
Timeline
Study Description
| Start Date | April 1, 2008 |
| Run-in period: 4-12 weeks | |
| End Date | Ongoing |
| Condition | Completed |
| Study Type | Interventional |
| Study Phase | Phase III |
| Allocation | Randomized |
| Endpoint | Safety/Efficacy Study |
| Interventional Model | Parallel Assignment |
| Masking | Double Blind |
| Primary Purpose | Treatment |
| Condition | Coronary Heart Disease |
| Intervention | Dalcetrapib (600mg po daily) |
| Study Arms | Dalcetrapib 600 mg daily Placebo |
| Population Size | 15865 |
Methods
- A 72-week prospective, randomized, multicenter, placebo-controlled double-blind clinical trial that recuited 15,871 patients followed by a 12-week reversal phase .
- Acute coronary syndrome defined as: cardiac biomarkers above upper normal limits with symptoms of acute myocardial ischemia, ECG signs of ischemia that were not presumed to be present previously, or loss of viable myocardium on imaging.
- Randomization stratified according to country and whether cardiac biomarker levels are elevated or not.
Inclusion Criteria
- Patients older than 45 years
- Patients on any statin therapy at any dose, previous hospitalization for acute coronary syndrome
- Patients with no cardiac biomarker elevation but with ECG changes that were not presumed to be previously present, or evidence of obstructive coronary disease, patients with myocardial infarction who underwent percutaneous coronary intervention
- Patients with symptomatic congestive heart failure but LVEF > 40%
Exclusion criteria
- Triglyceride level above 400 mg/dL
- Pregnant or breast-feeding females
- Females with child-bearing potential who are not on effective contraception
- Symptomatic congestive heart failure by end of run-in period
- Hemoglobin ≤ 10 g/dL at end of run-in period
- Uncontrolled hypertension (SBP ≥ 180 mmHg or DBP ≥ 110 mmHg)
- HbA1c > 10 on second visit
- Renal insufficiency with creatinine > 2.2 mg/dL or clinically apparent liver disease or liver function tests > 1.5 above upper normal limit at end of run-in period
- CPK > 3 times upper normal limit at 2nd visit
- Use of other anti-lipidemic agents except Ezetimibe or fish oil
- Use of other medications that increase HDL-C, previous exposure to CETP inhibitors
- Malignancy within 3 years
- Short life expectancy
- Alcohol or drug abuse within 5 years
- Hypersensitivity reactions to trial medications of components in placebo
- Other significant clinical and investigational conditions that the investigator finds important
Outcomes
Primary Outcomes
Death from coronary heart disease, coronary events that are listed as myocardial infarction, unstable angina with evidence of acute myocardial ischemia, cardiac arrest with resuscitation, and stroke.
Secondary Outcomes
Unexpected coronary revascularization that does not include restenosis revascularization, death from any cause, change of lipoprotein and inflammatory markers levels.
Results
- 21% and 19% of patients on dalcetrapib and on placebo respectively were discontinued for unrelated reasons.
- At least 80% adherence was documented in 89% of both study groups.
- HDL increased 31-40% from baseline in dalcetrapib vs. 4-11% from baseline in placebo.
- Dalcetrapib had a minimal effect on LDL, fasting plasma glucose, or HbA1c.
- After 3 months of treatment, triglyceride increased 6-17% in placebo vs. 4-10% in dalcetrapib (p<0.001).
- Dalcetrapib had no significant effect on primary end point or the frequency of any primary end point component with a hazard ratio of 1.04 only.
- No association between primary end point and either baseline HDL levels or the HDL change after 1 month following treatment. Similar non-significant results were documented for apolipoprotein A1 levels in both groups.
- After 3 months of treatment, there is a significant 18% in CRP difference between dalcetrapib and placebo; whereby CRP levels were 1.6 mg/L in dalcetrapib and 1.4 mg/L in placebo (p<0.001).
- Higher blood pressure values by 0.6 mm Hg and diarrhea were more commonly seen in the dalcetrapib group (p<0.001).[2]
Conclusion
Dalcetrapib can increase HDL levels but has no effect on decreasing rate of recurring cardiovascular events in patients with recent history of acute coronary syndrome.[2]
References
- ↑ Schwartz GG, Olsson AG, Ballantyne CM, Barter PJ, Holme IM, Kallend D; et al. (2009). "Rationale and design of the dal-OUTCOMES trial: efficacy and safety of dalcetrapib in patients with recent acute coronary syndrome". Am Heart J. 158 (6): 896–901.e3. doi:10.1016/j.ahj.2009.09.017. PMID 19958854.
- ↑ 2.0 2.1 Schwartz GG, Olsson AG, Abt M, Ballantyne CM, Barter PJ, Brumm J; et al. (2012). "Effects of dalcetrapib in patients with a recent acute coronary syndrome". N Engl J Med. 367 (22): 2089–99. doi:10.1056/NEJMoa1206797. PMID 23126252.