Time to benefit varies among clinical trials of lipid-lowering therapies
Variations in Time to Benefit Among Clinical Trials of Cholesterol-Lowering Drugs
Literature - Barter PJ, and Waters DD. - J Clin Lipidol 2018; published online ahead of printIntroduction and methods
Time to benefit (TTB) is important because it may help understand how a treatment works, it helps deciding whether or not, and when, to stop a clinical trial because of futility, and it supports the decision of whether to treat elderly patients with multiple diseases and a reduced life expectancy
Large, randomized, controlled, double blind, cardiovascular clinical outcome trials with statins have been completed, as well as several studies with other lipid-lowering drugs, including cholestyramine, gemfibrozil, ezetimibe, evolocumab, alirocumab and anacetrapib. The objective of this analysis was to compare the TTBs of 24 clinical studies with lipid-lowering drugs. For this purpose, benefit curves were created by subtracting the placebo or comparator drug curves from the active treatment curves. TTB was determined by visual inspection of the outcome curves for the primary endpoint.
Main results
- TTB varied from 1-36 (mean: 13.1) months across all 24 trials, averaging 11.1 months in statin versus placebo trials (N=14), 10.3 months in all statin trials (N=17), and 20.0 months in non-statin trials (N=7). TTB was 12 months in the 2 PCSK9 inhibitor trials.
- Each mmol/L (38.6 mg/dL) reduction in low density lipoprotein cholesterol (LDL-c) corresponds in statin trials to a 22% reduction in events [1]. In statin versus no statin trials, the reduction in CV events is 9% in the first year and 22-28% in subsequent years, per mmol/L reduction in LDL-c.
- If there is no history of an acute coronary syndrome, TTB appears to be similar in patients with or without known coronary artery disease.
- Atorvastatin appears to be associated with a shorter TTB compared with other statins. The average TTB in the 6 atorvastatin trials was 4.75 months, compared to 13.4 months in the 11 trials with other statins. Some evidence suggests that atorvastatin has an active metabolite that functions as an antioxidant and has a favorable effect on lipoproteins [2-4].
Conclusion
TTB varies among lipid-lowering therapies. In some studies, particularly those with atorvastatin, benefit was obvious within the first year, but early benefit should not be expected with all LDL-c lowering drugs. Eventual benefit cannot be precluded, even if the outcome curves do not separate before 30 months of treatment. The results of this analysis should be of interest to those who design, or evaluate the design of clinical trials of cholesterol-lowering drugs.
References
1. Collins R, Reith C, Emberson J, et al. Interpretation of the evidence for the efficacy and safety of statin therapy. Lancet 2016;388:2532-61.
2. Mason RP, Walter MF, Day CA, et al. Active metabolite of atorvastatin inhibits membrane cholesterol domain formation by an antioxidant mechanism. J Biol Chem 2006;281:9337-45.
3. Jacob RF, Walter MF, Self-Medlin Y, et al. Atorvastatin active metabolite inhibits oxidative modification of small dense low-density lipoprotein. J Cardiovasc Pharmacol 2013;62:160.
4. Mason RP, Sherratt SCR, Jacob RF. Eicosapentaenoic acid inhibits oxidation of apoBcontaining lipoprotein particles of different size in vitro when administered alone or in combination with atorvastatin active metabolite compared with other triglyceride-lowering agents. J Cardiovasc Pharmacol 2016;68:33-40.
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