Polypharmacy or monotherapy in the first 5 years of PD- which is the best approach?

Dr Nin BajajClinical Director NPF Centre of Excellence in PD,

University of Nottingham

The Issues

• 60-80% of dopaminergic neurones are lost at initial diagnosis

• Internal audit data at RDH (2002-2011)• Of the 238 PD patients having FP-CIT at

presentation, 27.7% were grade 1, 43.3% grade 2 and 29% grade 3

• This equates to a moderate-severe dopa deficit in almost 3/4 of patients- in part motor, in part non-motor

Audit of Grade of FP-CIT abnormality at presentation in 238 PD patients

Grade 1

Grade 2

Grade 3

0 5 10 15 20 25 30 35 40 45

Series2Series1

The Issues

• The first year is all about reversing this huge dopa deficit

• This means using larg(ish) doses of dopamine agonists and clinically realistic doses of Ldopa in year 1

• After you’ve made up the deficit, it’s all coasting there-on- until they dement…

The Issues

• ADAGIO suggests early treatment might be neuroprotective

• DATATOP may also show this• Similar trials with pramipexole (PROUD) have

failed to demonstrate a class effect• STRIDE has also failed to show a beneficial

effect of dopa plus entacapone early on (polypharmacy failure?)

The Issues- early v late Rx; the case of neuroprotection

• Immediate Rx would add an estimate extra £3.2 million to an annual PD meds bill of £100 million (2008 data; Clarke et al Mov Dis 2011)

• Earlier Rx might expose patients to a greater life-time risk of ICD with dopamine agonists or dyskinesia/wearing off with Ldopa

• Selegiline was implicated in some trials with increased mortality rate (?cardiac)

DATATOP

• second randomization showed that patients treated with selegiline for up to 7 years experienced slower decline in UPDRS (2.3 total UPDRS units) compared with patients who were changed to a placebo after about 5 years of treatment

• Perhaps prolonged Rx course better than short for selegiline

• Is this neuroprotection or just symptomatic improvement?

TEMPO Trial- Rasagaline- 404 patients

2mg/day all along>>delayed 2mg (UPDRS 2.3)(p=0.01); immediate 1mg/day

just>delayed 2mg (UPDRS 1.8)(p=0.05)

2mg/day delayed

6/12

2mg/day1mg/day

Problems- only mildest patients enter a delayed start trial; there is a high drop-out rate in the delayed start arm; some studies suggest 8 UPDRS points is clinically meaningful, especially in early PD but perhaps a cumulative effect on UPDRS is meaningful

ADAGIO- 1176 patients1mg immediate>1mg delayed (UPDRS 1.7)

(p=0.02) BUT no sig diff 2mg arms

1mg/daily 18 months

2mg/daily for 18/122mg/daily delayed until 9/12

1mg/daily delayed until 9/12

Perhaps 2mg treatment effect masks neuroprotective effect at higher UPDRS; sub-group analysis showed this to be true but only at borderline significance

1mg looks good in ADAGIO; 2mg better in TEMPO

CALM-PD

REAL-PETPROUD

Issues- which agent should go first- dopa or DA’s?

CALM-PD

N=151

Pramipexole 0.5mg tds

Weeks 11-23 open label

N=150Ldopa equivalent to

125mg tds

Weeks 11-23 open label

CALM-PD

Motor complication in favour of pramipexole

(p<0.001)

UPDRS favoured Ldopa group (p<0.001)

Somnolence greater in pramipexole group

Ldopa group showed greater decline in B-CIT

(25% v 20%)(p=0.15)

Month 23.5

CALM-PD- 6 year follow-up

N=151

pramipexole

Ldopa or other

N=150

ldopa

Other PD Med

CALM-PD- 6 year follow-up

ADL no different (p=0.19)

Motor complications (dyskinesia,

wearing off, on-off) in favour DA

(p=0.002)

ESS favours Ldopa (p=0.002)

UPDRS no difference (p=0.11)

REAL-PET

N=68

• Requip group• Putaminal Ki -14%

N=59

• Ldopa group• Putaminal Ki -23%

18F PET putaminal Ki primary outcome

measure

• Less decline with requip (p<0.001)

PROUD-pramipexole

Immediate 1.5mg/daily pramixole

Delayed 1.5mg/daily pramipexole

6-9/12

UPDRSNo sig diff

p=0.65

Issues- is LCE polypharmacy better than LC?

Stride PD, N=747

Ldopa/carbidopa qds Ldopa/carbidopa/entacapone qds

LCE group develop dyskinesia sooner and more frequently; no difference in motor scores

Issues- is early Rx better than late-PD-LIFE

PDQ39 of earlier Rx patients

stable; those untreated declined

61 patients left untreated

at 9/12 FU

198 early PD patients

53 patients Rx at 9/12 FU

But no randomisation to early or no Rx and some of the untreated group showed faster deterioration at 9/12 than Rx group

The Issues- putting all of this together…

• But what we are suggesting is not so much early treatment, but clinically effective treatment, not under-dosing and not ignoring functional disability- these are different (albeit related) themes

• And the later we leave Ldopa Rx, the more denervated the striatum, and the greater the Ldopa related side-effects

The issues- polypharmacy is better than monotherapy

• Several trials suggest early Rx is better than late- PD-LIFE, ELLDOPA, ADAGIO, TEMPO, DATATOP

• DA trials show DA have fewer motor complications than dopa as first line Rx

• ELLDOPA shows high incidence of motor complications related to dopa dose BUT DA trials show higher efficacy for dopa

Putting it all together- Chronologically Young

• DA best first line; MAOI do not have the efficacy given the moderate-severe deficit of most patients

• Ldopa second add-in if motor deficit not reversed- otherwise MAOI

• COMPT third line add in• Polypharmacy in 5 years avoids functional

disability and ICD

Putting it all together- Chronologically Old

• Ldopa best first line; MAOI do not have the efficacy given the moderate-severe deficit of most patients; DA too many side-effects

• Low dose DA second add-in if motor deficit not reversed, e.g. low dose adjuvant rotigotine- otherwise COMPT

• MAOI third line add in• Polypharmacy in 5 years avoids high dose dopa

The Issues- if polypharmacy is good, how do we deliver it?

• Should we be using a polypill? • Probably not given the STRIDE Data- but

rasagaline plus dopa? Dopa plus nocturnal rotigotine for the non-motor stuff?

Polypill-V1

All PD patient>70 as first treatment

Rasagiline

Ldopa

No titration issue- standard dose of rasagline in all tablets

Polypill-V2

All PD <70

Sinemet CR +

Entacapone nocte

Long acting Dopamine

Agonist nocte

No titration issue wrt sinemet/entacapone dosage

Polypill-V3

All PD >70

Coenzyme Q10

LdopaCoQ10 may have a beneficial effect on mitochondrial function

Polypharmacy-V1

PD patients>70; rotigotine for the

nocturnal off

Rotigotine 2-4mg

Ldopa

Polypharmacy

PDD or DLBD

Ldopa

Rivastigmine