Transcript Use of the Thyroid Hormone Analogue Eprotirome in Statin

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. 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.
Lipoproteins
• Central core hydrophobic lipid
• Hydrophilic coat of polar phospholipid, free
cholesterol and apolipoprotein
• HDL
• LDL
• VLDL
• Chylomicrons
• VLDL and LDL transport cholesterol and triglycerides to the tissues
• HDL absorbs cholesterol and returns it to LDL or VLDL
• Atherosclerosis is strongly associated with a specific type of LDL Lipoprotein (a)
• Statins reduce circulating LDL by inhibiting endogenous cholesterol
synthesis
• Thyroid hormones increase excretion of LDL in bile acids and
activity of HDL
Treatment 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 MI
• Statins - secondary prevention - reduction in all-cause
mortality, CVD mortality, coronary heart disease (CHD)
mortality, fatal myocardial infarction (MI), and coronary
revascularization
• Limited evidence for other lipid modifying drugs - bile
acid sequestrants, ezetimibe, fibrates, nicotinic acid
Study design
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Randomised, placebo controlled
Double blind, double dummy (?)
4 week dietary lead in
12 weeks treatment Placebo or Eprotirome
Monitored 4 weeks after discontinuation
Primary efficacy (outcome) variable – change in
serum LDL
• Secondary efficacy (outcome) variables –
levels/ratios of other lipids
Double Dummy
• A technique for retaining the blind when
administering supplies in a clinical trial,
when the two treatments cannot be made
identical.
• Comparing surgery with medical treatment
• Group 1: Surgery then placebo
• Group 2: Sham surgery then medication
Study patients
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18-65
≤ Simvastatin 40mg
≤ Atorvastatin 20mg
LDL cholesterol ≥ 3.0 mmol/L
Long list of exclusions
329 screened, 189 included, 5 no data,
184 included in efficacy analysis, 168
completed the trial.
Statistics
• Sample size aimed to detect mean decrease of
LDL of 0.5 mmol/L
• Two 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
Statistics
• F test compares the variance (spread) of two groups, giving
the F statistic
• The 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 samples
• Last-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.
Results
Results
Discussion
• Addition 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 alone
• Small reduction in HDL adversely affect CV risk?
• No evidence that reduction in Lp(a) reduces CV risk despite
being associated with atherosclerosis
• Unknown thyromimetic effects or effect of suppressing TSH
• 12 weeks insufficient time to assess possible adverse effects
• Mildly deranged LFTs
Possible problems
• Drug company sponsored, all authors heavily sponsored. New drug,
so likely to be pressure to find positive results
• Reasons for drop outs not given in main article
• No statistical comparison of placebo to study groups
• Long list of exclusions would imply largely patients on primary
prevention, who are treated differently to secondary prevention
• Eprotirome 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 instead
• Proof of reduction in LDL does not prove clinical benefit