treatment of graves
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The treatment of Graves’ The treatment of Graves’ disease: What we do and the disease: What we do and the
evidence behind it.evidence behind it.
Bijay VaidyaBijay Vaidya
Ali ChakeraAli Chakera
OutlineOutline
Case based discussionsCase based discussions
Review of the evidenceReview of the evidence
CasesCases1.1. Simple Graves’ diseaseSimple Graves’ disease
2.2. Graves’ disease with eye problemsGraves’ disease with eye problems
3.3. Graves’ disease and pregnancyGraves’ disease and pregnancy
Case 1Case 1
A 43A 43♀♀ presents with presents with symptoms of thyrotoxicosis.
o/e: Sinus tachycardiaSmall diffuse goitreNo evidence of thyroid eye disease
TSH <0.01mu/L FT4 45pmol/L (12-24)TSH <0.01mu/L FT4 45pmol/L (12-24)
Positive TSH receptor antibodies
What would you do?What would you do?
To discuss:To discuss:– What treatment would you offer this lady?What treatment would you offer this lady?– How long would you treat her for?How long would you treat her for?– Why have you chosen the option that you have Why have you chosen the option that you have
chosen?chosen?
What your colleagues do?What your colleagues do?
Locally:Locally:
80%
19%
0.04%0%
20%
40%
60%
80%
100%
Drugs RAI Surgery
Nationally:Nationally:
Preferred treatment options for Preferred treatment options for initial treatment of Graves’initial treatment of Graves’
Vaidya et al. Clinical Endocrinology (2008) 68, 814
What are the questions?What are the questions?
Initial treatmentInitial treatment– Drugs vs radioiodine vs surgeryDrugs vs radioiodine vs surgery
Optimal drug treamentOptimal drug treament– CBZ vs PTUCBZ vs PTU– B&R vs Dose titrationB&R vs Dose titration– Duration of treatmentDuration of treatment
On what basis should we be treating?On what basis should we be treating?– Most effective?Most effective?– Most cost-effective?Most cost-effective?– Least side-effects?Least side-effects?– Ease of therapyEase of therapy– Individualised therapyIndividualised therapy
What should we use as initial What should we use as initial treatment?treatment?
Short-term efficacyShort-term efficacy– Drugs – Cure: 30-50%Drugs – Cure: 30-50%– RAI – Cure: 85%-95%RAI – Cure: 85%-95%– Surgery – Cure: 100%Surgery – Cure: 100%
Long-term efficacyLong-term efficacy– No significant difference in QoL 14-21 years No significant difference in QoL 14-21 years
after randomisation to antithyroid drugs, RAI after randomisation to antithyroid drugs, RAI or surgeryor surgery(Abraham-Nordling et al. Thyroid. 2005; 15(11): 1279-86)(Abraham-Nordling et al. Thyroid. 2005; 15(11): 1279-86)
EfficacyEfficacy
Cost-effectivenessCost-effectiveness
Radioactive iodineRadioactive iodinePatel Patel et al.et al. Thyroid. 2006; 16(6): 593-598 Thyroid. 2006; 16(6): 593-598
135 patients with thyrotoxicosis 135 patients with thyrotoxicosis 61% - thionamide, 35% - RAI, 4% - surgery61% - thionamide, 35% - RAI, 4% - surgeryCost per ‘cure’ – thionamide (73%), surgery Cost per ‘cure’ – thionamide (73%), surgery (100%), RAI (95%)(100%), RAI (95%)
Qari Qari et al.et al. Saudi Medical Journal. 2001; 22(10): Saudi Medical Journal. 2001; 22(10): 907-9907-9
100 patients – retrospective100 patients – retrospectiveCost per ‘cure’ – thionamide (11%), surgery Cost per ‘cure’ – thionamide (11%), surgery (54%), RAI (96%)(54%), RAI (96%)
ThionamideThionamide £3763£3763
RAIRAI £1375£1375
SurgerySurgery £6551£6551
ThionamideThionamide £21800£21800
RAIRAI £275£275
SurgerySurgery £6500£6500
Side-Effects/ProblemsSide-Effects/Problems
ThionamidesThionamides– CommonCommon– AgranulocytosisAgranulocytosis– HepatitisHepatitis
RAIRAI– Short-term restrictionsShort-term restrictions– Long-term hypothyroidismLong-term hypothyroidism
SurgerySurgery– HypocalcaemiaHypocalcaemia– Larygeal nerve palsyLarygeal nerve palsy
What is the best drug What is the best drug therapy?therapy?
Medical TreatmentMedical Treatment
Which drug is bestWhich drug is best
B&R versus Dose TitrationB&R versus Dose Titration
Duration of treatmentDuration of treatment
Which drug?Which drug?
EfficacyEfficacy
Side-effectsSide-effects
Ease of regimeEase of regime
Which drug?Which drug?
EfficacyEfficacy– No clear difference between drugs No clear difference between drugs – Nakamura et al. JCEM. 2007; 92: 2157-62 JCEM. 2007; 92: 2157-62
PTU vs MMI: MMI – normalises T4 quickerPTU vs MMI: MMI – normalises T4 quicker
Normalisation of FT4 with MMI and Normalisation of FT4 with MMI and PTUPTU
Which drug?Which drug?
Side effectsSide effects– CBZ has a more favourable side-effect profileCBZ has a more favourable side-effect profile
CBZ – rash 7%CBZ – rash 7%
Methimazole – rash 12%Methimazole – rash 12%
PTU – rash and hepatotoxicityPTU – rash and hepatotoxicity(Cochrane)(Cochrane)
– Reports of equal side effects(Cooper 1999, Pearce 2004)
– Recent concerns of hepatotoxity with PTU (Cooper 2009)
Higher side effects particularly hepatotoxicity Higher side effects particularly hepatotoxicity with PTU.with PTU.
American data re: hepatotoxicity of PTUAmerican data re: hepatotoxicity of PTU– 33 reports of severe liver failure. 33 reports of severe liver failure. – 16 liver transplants (1990-2007)16 liver transplants (1990-2007)– US est. 1-2 of 15 000 PTU users develop liver failure.US est. 1-2 of 15 000 PTU users develop liver failure.
The problems of PTUThe problems of PTU
Which drug?Which drug?
EfficacyEfficacy– No clear difference between drugsNo clear difference between drugs
Side-effectsSide-effects– CBZ has a more favourable side-effect profileCBZ has a more favourable side-effect profile
Ease of regimeEase of regime– Once daily dosage of CBZ versus PTUOnce daily dosage of CBZ versus PTU
Which regime?Which regime?
B&R versus Dose TitrationB&R versus Dose Titration(Abrahams (Abrahams et al.et al. Cochrane Reviews 2006) Cochrane Reviews 2006)
– EfficacyEfficacy– Side EffectsSide Effects– Ease/convenienceEase/convenience
Relapse rates: B&R vs TitrationRelapse rates: B&R vs Titration
Side effects: B&R vs titrationSide effects: B&R vs titration
B&R versus Dose TitrationB&R versus Dose Titration
EfficacyEfficacy– No difference in relapse rateNo difference in relapse rate
(Abrahams (Abrahams et al.et al. Cochrane Reviews 2006) Cochrane Reviews 2006)
Side EffectsSide Effects– Fewer side effects for dose titrationFewer side effects for dose titration– However large doses used in B&R trials – up However large doses used in B&R trials – up
to 100mg/dayto 100mg/day(Razvi (Razvi et alet al. Eur J Endo. 2006; 154: 1-4). Eur J Endo. 2006; 154: 1-4)
Ease/convenienceEase/convenience– Fewer blood tests with B&R. Evidence?Fewer blood tests with B&R. Evidence?
Duration of treatmentDuration of treatment
Duration of TreatmentDuration of Treatment
Dose titrationDose titration– 12 – 18 months optimum12 – 18 months optimum– Higher relapses with 6 months in one studyHigher relapses with 6 months in one study– No advantage of longer treatmentNo advantage of longer treatment
Block & replaceBlock & replace– No clear consensusNo clear consensus– 6 as good as 12 months in one study.6 as good as 12 months in one study.
((Weetman AP et al. QJM. 1994; 87(6): 337–41)
Radioactive iodine and Radioactive iodine and surgerysurgery
Radioactive IodineRadioactive Iodine
Fixed dose vs dose calculationFixed dose vs dose calculation– Studies suggest no difference in outcome Studies suggest no difference in outcome
between two options.between two options.(Leslie (Leslie et al. et al. BMJ 2007)BMJ 2007)
– Dose calculation formulae may under-treat Dose calculation formulae may under-treat Graves’Graves’(Regalbuto (Regalbuto et al. et al. JCEM. 2003)JCEM. 2003)
– Consensus emerging that fixed dose is easier Consensus emerging that fixed dose is easier and less time consuming.and less time consuming.
Radioactive IodineRadioactive Iodine
Medication peri-therapyMedication peri-therapyATD one week either side of RAI results in ATD one week either side of RAI results in higher treatment failure and lower higher treatment failure and lower hypothyroidismhypothyroidism
SurgerySurgery
Total thyroidectomy recommended over Total thyroidectomy recommended over partial surgerypartial surgeryGrade A recommendationGrade A recommendation((Stalberg et al. W J Surgery)
Hegedüs. Endo & Metab Clinic. 2009
SummarySummary
No strong evidence base for any therapy No strong evidence base for any therapy for Graves diseasefor Graves disease
RAI – most cost effective.RAI – most cost effective.
CBZ give a chance for cure without long-CBZ give a chance for cure without long-term therapyterm therapy
B&R still the ‘best’ option?B&R still the ‘best’ option?
Any thoughts?Any thoughts?
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