Presentation on theme: "Use of the Thyroid Hormone Analogue Eprotirome in Statin-Treated Dyslipidemia N Engl J Med. 2010 Mar 11;362(10):906-16. Paul W. Ladenson, M.D., Jens D."— Presentation transcript:
1Use of the Thyroid Hormone Analogue Eprotirome in Statin-Treated Dyslipidemia N Engl J Med Mar 11;362(10):Paul W. Ladenson, M.D., Jens D. Kristensen, M.D., Ph.D., E. Chester Ridgway, M.D., Anders G. Olsson, M.D., Ph.D., Bo Carlsson, M.Sc., Irwin Klein, M.D., John D. Baxter, M.D., and Bo Angelin, M.D., Ph.D.
2Lipoproteins Central core hydrophobic lipid Hydrophilic coat of polar phospholipid, free cholesterol and apolipoproteinHDLLDLVLDLChylomicrons
3VLDL and LDL transport cholesterol and triglycerides to the tissues HDL absorbs cholesterol and returns it to LDL or VLDLAtherosclerosis is strongly associated with a specific type of LDL - Lipoprotein (a)Statins reduce circulating LDL by inhibiting endogenous cholesterol synthesisThyroid hormones increase excretion of LDL in bile acids and activity of HDL
4Treatment of dyslipidaemia Statins - primary prevention - significant reduction in the risk of all-cause mortality, fatal and non-fatal MI, stable angina, and a composite endpoint of coronary heart disease (CHD) death plus non-fatal MIStatins - secondary prevention - reduction in all-cause mortality, CVD mortality, coronary heart disease (CHD) mortality, fatal myocardial infarction (MI), and coronary revascularizationLimited evidence for other lipid modifying drugs - bile acid sequestrants, ezetimibe, fibrates, nicotinic acid
5Study design Randomised, placebo controlled Double blind, double dummy (?)4 week dietary lead in12 weeks treatment Placebo or EprotiromeMonitored 4 weeks after discontinuationPrimary efficacy (outcome) variable – change in serum LDLSecondary efficacy (outcome) variables – levels/ratios of other lipids
7Double DummyA technique for retaining the blind when administering supplies in a clinical trial, when the two treatments cannot be made identical.Comparing surgery with medical treatmentGroup 1: Surgery then placeboGroup 2: Sham surgery then medication
9Study patients 18-65 ≤ Simvastatin 40mg ≤ Atorvastatin 20mg LDL cholesterol ≥ 3.0 mmol/LLong list of exclusions329 screened, 189 included, 5 no data, 184 included in efficacy analysis, 168 completed the trial.
10StatisticsSample size aimed to detect mean decrease of LDL of 0.5 mmol/LTwo sided type I error rate (α) of < 0.05 [p<0.05]172 patients for statistical power of 80% [Type II error rate β = 0.2. Power = 1- β = 0.8]Analysis based on absolute change in LDL cholesterol levels between baseline and week 12
11StatisticsF test compares the variance (spread) of two groups, giving the F statisticThe Jonckheere-Terpstra test used to measure dose related response. It tests for ordered differences among groups assumed to be arranged ordinally, and tests for differences among several independent samplesLast-observation-carried-forward method allows inclusion of dropouts. It assumes that the patients improve gradually from the start of the study until the end, so that carrying forward an intermediate value is a conservative estimate of how well the person would have done had he or she remained in the study.
14DiscussionAddition of eprotirome to statin therapy resulted in substantial further reductions in levels of LDL, non HDL and Apolipoprotein B“Larger reductions that would be expected by doubling statin dose”Better reductions in triglycerides and Lp(a) than statin aloneSmall reduction in HDL adversely affect CV risk?No evidence that reduction in Lp(a) reduces CV risk despite being associated with atherosclerosisUnknown thyromimetic effects or effect of suppressing TSH12 weeks insufficient time to assess possible adverse effectsMildly deranged LFTs
15Possible problemsDrug company sponsored, all authors heavily sponsored. New drug, so likely to be pressure to find positive resultsReasons for drop outs not given in main articleNo statistical comparison of placebo to study groupsLong list of exclusions would imply largely patients on primary prevention, who are treated differently to secondary preventionEprotirome added to moderate statin dose, not to patients on maximum treatment. To be valuable, should be compared to current best treatment.Graphs plot main data points at top of CI for no obvious reason – is this to graphically exaggerate the results?No confidence intervals given for main results - standard deviations given insteadProof of reduction in LDL does not prove clinical benefit