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?