Dopamine agonist therapy in early Parkinson's disease

Rebecca Stowe; Natalie Ives; Carl E Clarke; van Hilten; Joaquim Ferreira; Robert J Hawker; Laila Shah; Keith Wheatley; Richard Gray

doi:10.1002/14651858.CD006564.pub2

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Analysis 1.1

Comparison 1 Symptom control in trials of dopamine agonists versus levodopa, Outcome 1 Freezing.

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Analysis 2.1

Comparison 2 Motor complications in trials of dopamine agonists versus levodopa, Outcome 1 Dyskinesia.

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Analysis 2.2

Comparison 2 Motor complications in trials of dopamine agonists versus levodopa, Outcome 2 Dystonia.

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Analysis 2.3

Comparison 2 Motor complications in trials of dopamine agonists versus levodopa, Outcome 3 Motor Fluctuations.

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Analysis 3.1

Comparison 3 Non‐motor side‐effects in trials of dopamine agonists, Outcome 1 Oedema.

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Analysis 3.2

Comparison 3 Non‐motor side‐effects in trials of dopamine agonists, Outcome 2 Somnolence.

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Analysis 3.3

Comparison 3 Non‐motor side‐effects in trials of dopamine agonists, Outcome 3 Constipation.

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Analysis 3.4

Comparison 3 Non‐motor side‐effects in trials of dopamine agonists, Outcome 4 Dizziness.

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Analysis 3.5

Comparison 3 Non‐motor side‐effects in trials of dopamine agonists, Outcome 5 Hallucinations.

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Analysis 3.6

Comparison 3 Non‐motor side‐effects in trials of dopamine agonists, Outcome 6 Nausea.

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Analysis 3.7

Comparison 3 Non‐motor side‐effects in trials of dopamine agonists, Outcome 7 Insomnia.

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Analysis 3.8

Comparison 3 Non‐motor side‐effects in trials of dopamine agonists, Outcome 8 Headache.

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Analysis 3.9

Comparison 3 Non‐motor side‐effects in trials of dopamine agonists, Outcome 9 Vomiting.

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Analysis 3.10

Comparison 3 Non‐motor side‐effects in trials of dopamine agonists, Outcome 10 Hypotension.

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Analysis 3.11

Comparison 3 Non‐motor side‐effects in trials of dopamine agonists, Outcome 11 Anxiety.

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Analysis 3.12

Comparison 3 Non‐motor side‐effects in trials of dopamine agonists, Outcome 12 Depression.

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Analysis 4.1

Comparison 4 Levodopa dose in trials of DA + LD versus LD, Outcome 1 Levodopa Dose (mg/day).

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Analysis 5.1

Comparison 5 Mortality in trials of dopamine agonists (by randomised treatment comparison), Outcome 1 Mortality.

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Analysis 6.1

Comparison 6 Patient withdrawal in trials of dopamine agonists (by randomised treatment comparison), Outcome 1 Overall patient withdrawal.

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Analysis 6.2

Comparison 6 Patient withdrawal in trials of dopamine agonists (by randomised treatment comparison), Outcome 2 Patient withdrawal due to adverse events.

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Analysis 6.3

Comparison 6 Patient withdrawal in trials of dopamine agonists (by randomised treatment comparison), Outcome 3 Patient withdrawal due to lack of efficacy.

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Table 1. Clinician‐rated disability scale data reported in trials

			Favours Ctl	Favours Ctl		Favours DA	Favours DA
Study ID	Assessment Time Point	Method of analysis	P < 0.01	P: 0.05 to 0.01	No significant difference	P: 0.05 to 0.01	P < 0.01
DA versus Placebo
USA Pramipexole A	9 weeks	Observed Case			UPDRS motor (P = 0.1)		UPDRS ADL (P = 0.002)
USA / Canada PSG	10 weeks	Last Observation Carried Forward (LOCF)			UPDRS mental	UPDRS motor & ADL	UPDRS total (P < 0.005)
International Ropinirole	12 weeks	LOCF (patients with >= 1 post dose assessment)			Finger‐tap test, UPDRS ADL & mental and Hoehn & Yahr	UPDRS motor (P = 0.018)	Clinician's Global Evaluation (P = 0.008)
International Pergolide Monotherapy	12 weeks	Intention to Treat (ITT) (patients with baseline and >= 1 follow up assessment)					UPDRS total, ADL & motor, Schwab & England ADL, and Clinical Global Impression (CGI) (P < 0.001)
USA Ropinirole	6 months	ITT					UPDRS motor and CGI (P < 0.001)
USA Pramipexole B	8 months	LOCF (patients with >= 1 post dose assessment)					UPDRS ADL & motor (P < 0.001)
UKPDRG Pergolide	16 months	LOCF (patients with >= 1 efficacy measurement)			Hoehn & Yahr, ADL and UPDRS ADL & motor
Italy A	3 months	LOCF (patients with >= 1 post dose assessment)				UPDRS motor (P = 0.014)	UPDRS total, ADL & mental (P <= 0.006)
DA + LD versus Placebo + LD
European CQA 206‐291	2 months	ITT				Schwab & England ADL	UPDRS total (P < 0.01)
France Piribedil	6 months	LOCF (patients with >= 1 post dose assessment)			UPDRS ADL and Schwab & England	UPDRS motor (P = 0.04)
Italy B	6 months	ITT					Columbia University Rating Scale (CURS) and North Western University Disability Scale (NWUDS) (P <= 0.002)
Spain	44 months	ITT			UPDRS ADL and Hoehn & Yahr		UPDRS total & motor
USA Bromocriptine	48 months	ITT			CURS and ADL score
France Lisuride	60 months	LOCF			UPDRS mental and Hoehn & Yahr		UPDRS total, ADL & motor and Schwab & England (P < 0.01)
Glasgow	12 months	ITT				NWUDS (P = 0.04)
DA + LD versus LD
Europe Bromocriptine	12 months	ITT			Webster and NWUDS
Barcelona	24 months	ITT			UPDRS mental, ADL & motor
Argentina	31 months	ITT			Hoehn & Yahr and Webster
South America	36 months	ITT			Hoehn & Yahr, Webster, CURS, NWUDS and UPDRS motor
Germany / Austria PRADO	48 months	ITT			Webster and Hoehn & Yahr
DA versus LD
Canada	6 months	ITT			Hoehn & Yahr, CURS and NWUDS
USA	14 months	ITT			UPDRS total, ADL & motor
International PSG CALM‐PD	48 months	Multiple Imputation (Little & Yau)	UPDRS total & motor (P < 0.003)	UPDRS ADL (P = 0.02)	UPDRS mental (P = 0.1)
Argentina	31 months	ITT			Hoehn & Yahr and Webster
Milan	72 months	ITT			Motor score/signs
Europe PELMOPET	36 months	LOCF (patients with both a baseline and post baseline score)	UPDRS total, ADL, motor, CGI and Patient Global Impressions (P < 0.001). Schwab & England (P = 0.008)
USA Bromocriptine	48 months	ITT			UPDRS ADL & motor
International 056	60 months	LOCF (patients with >= 1 post dose assessment)			UPDRS ADL & motor
International PKDS009	60 months	ITT	UPDRS motor (P < 0.01)	UPDRS ADL	CGI
Sydney	60 months	Per Protocol		CURS and NWUDS
UK‐PDRG	108 months	ITT	At 1 year: Webster (P = 0.006)		At 9 years: Webster

Table 1. Clinician‐rated disability scale data reported in trials

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Comparison 1. Symptom control in trials of dopamine agonists versus levodopa

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Freezing Show forest plot	5	712	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.58 [1.14, 2.18]

1.1 DA + LD versus LD	3	130	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.26 [0.62, 2.56]
1.2 DA versus LD	3	582	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.67 [1.17, 2.40]

Comparison 1. Symptom control in trials of dopamine agonists versus levodopa

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Comparison 2. Motor complications in trials of dopamine agonists versus levodopa

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Dyskinesia Show forest plot	16	3404	Peto Odds Ratio (95% CI)	0.51 [0.43, 0.59]

1.1 DA + LD versus LD	8	1019	Peto Odds Ratio (95% CI)	0.74 [0.53, 1.04]
1.2 DA versus LD	10	2385	Peto Odds Ratio (95% CI)	0.45 [0.37, 0.54]
2 Dystonia Show forest plot	9	1896	Peto Odds Ratio (95% CI)	0.64 [0.51, 0.81]

2.1 DA + LD versus LD	4	203	Peto Odds Ratio (95% CI)	0.67 [0.25, 1.81]
2.2 DA versus LD	7	1693	Peto Odds Ratio (95% CI)	0.64 [0.50, 0.81]
3 Motor Fluctuations Show forest plot	11	2580	Peto Odds Ratio (95% CI)	0.75 [0.63, 0.90]

3.1 DA + LD versus LD	5	813	Peto Odds Ratio (95% CI)	0.89 [0.61, 1.28]
3.2 DA versus LD	7	1767	Peto Odds Ratio (95% CI)	0.71 [0.58, 0.87]

Comparison 2. Motor complications in trials of dopamine agonists versus levodopa

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Comparison 3. Non‐motor side‐effects in trials of dopamine agonists

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Oedema Show forest plot	6	1650	Peto Odds Ratio (Peto, Fixed, 95% CI)	3.48 [2.53, 4.79]

1.1 DA versus Placebo	1	333	Peto Odds Ratio (Peto, Fixed, 95% CI)	2.28 [0.90, 5.75]
1.2 DA (+/‐LD) versus LD	5	1317	Peto Odds Ratio (Peto, Fixed, 95% CI)	3.68 [2.62, 5.18]
2 Somnolence Show forest plot	11	2423	Peto Odds Ratio (Peto, Fixed, 95% CI)	2.18 [1.75, 2.72]

2.1 DA versus Placebo	5	1006	Peto Odds Ratio (Peto, Fixed, 95% CI)	3.68 [2.62, 5.18]
2.2 DA (+/‐LD) versus LD	6	1417	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.49 [1.12, 2.00]
3 Constipation Show forest plot	8	1961	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.80 [1.36, 2.39]

3.1 DA versus Placebo	4	944	Peto Odds Ratio (Peto, Fixed, 95% CI)	2.19 [1.39, 3.43]
3.2 DA (+/‐ LD) versus LD	4	1017	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.59 [1.11, 2.28]
4 Dizziness Show forest plot	13	2294	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.60 [1.28, 2.01]

4.1 DA versus Placebo	7	957	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.90 [1.32, 2.74]
4.2 DA (+/‐LD) versus LD	6	1337	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.45 [1.09, 1.92]
5 Hallucinations Show forest plot	14	2479	Peto Odds Ratio (Peto, Fixed, 95% CI)	2.22 [1.58, 3.12]

5.1 DA versus Placebo	5	956	Peto Odds Ratio (Peto, Fixed, 95% CI)	4.55 [2.38, 8.71]
5.2 DA (+/‐LD) versus LD	9	1523	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.69 [1.13, 2.52]
6 Nausea Show forest plot	15	2631	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.86 [1.56, 2.23]

6.1 DA versus Placebo	7	1184	Peto Odds Ratio (Peto, Fixed, 95% CI)	3.11 [2.35, 4.11]
6.2 DA (+/‐ LD) versus LD	8	1447	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.32 [1.05, 1.66]
7 Insomnia Show forest plot	10	2315	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.29 [1.02, 1.64]

7.1 DA versus Placebo	5	998	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.78 [1.20, 2.63]
7.2 DA (+/‐LD) versus LD	5	1317	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.07 [0.79, 1.44]
8 Headache Show forest plot	11	2168	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.26 [0.96, 1.67]

8.1 DA versus Placebo	5	789	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.11 [0.68, 1.79]
8.2 DA (+/‐LD) versus LD	6	1379	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.35 [0.96, 1.90]
9 Vomiting Show forest plot	7	998	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.30 [0.78, 2.18]

9.1 DA versus Placebo	4	624	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.37 [0.61, 3.05]
9.2 DA (+/‐LD) versus LD	3	374	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.26 [0.64, 2.46]
10 Hypotension Show forest plot	10	1866	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.25 [0.88, 1.78]

10.1 DA versus Placebo	3	451	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.73 [0.90, 3.35]
10.2 DA (+/‐LD) versus LD	7	1415	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.11 [0.73, 1.67]
11 Anxiety Show forest plot	5	1113	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.14 [0.75, 1.73]

11.1 DA versus Placebo	1	105	Peto Odds Ratio (Peto, Fixed, 95% CI)	7.39 [0.46, 119.79]
11.2 DA (+/‐LD) versus LD	4	1008	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.09 [0.72, 1.66]
12 Depression Show forest plot	6	1628	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.91 [0.68, 1.22]

12.1 DA versus Placebo	2	347	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.48 [0.20, 1.14]
12.2 DA (+/‐LD) versus LD	4	1281	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.99 [0.72, 1.34]

Comparison 3. Non‐motor side‐effects in trials of dopamine agonists

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Comparison 4. Levodopa dose in trials of DA + LD versus LD

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Levodopa Dose (mg/day) Show forest plot	7	455	Mean Difference (IV, Fixed, 95% CI)	‐82.21 [‐110.13, ‐54.29]

Comparison 4. Levodopa dose in trials of DA + LD versus LD

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Comparison 5. Mortality in trials of dopamine agonists (by randomised treatment comparison)

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Mortality Show forest plot	11	3228	Peto Odds Ratio (95% CI)	1.05 [0.86, 1.28]

1.1 DA versus Placebo	1	264	Peto Odds Ratio (95% CI)	0.0 [0.0, 0.0]
1.2 DA + LD versus LD	2	637	Peto Odds Ratio (95% CI)	0.45 [0.21, 0.97]
1.3 DA versus LD	8	2327	Peto Odds Ratio (95% CI)	1.11 [0.91, 1.37]

Comparison 5. Mortality in trials of dopamine agonists (by randomised treatment comparison)

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Comparison 6. Patient withdrawal in trials of dopamine agonists (by randomised treatment comparison)

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Overall patient withdrawal Show forest plot	27		Peto Odds Ratio (Peto, Fixed, 95% CI)	Subtotals only

1.1 DA versus Placebo	8	1293	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.43 [1.06, 1.93]
1.2 DA + LD versus LD	11	1348	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.85 [0.66, 1.10]
1.3 DA versus LD	10	2388	Peto Odds Ratio (Peto, Fixed, 95% CI)	2.02 [1.70, 2.40]
2 Patient withdrawal due to adverse events Show forest plot	23	4719	Peto Odds Ratio (Peto, Fixed, 95% CI)	2.49 [2.08, 2.98]

2.1 DA versus Placebo	8	1293	Peto Odds Ratio (Peto, Fixed, 95% CI)	2.43 [1.60, 3.68]
2.2 DA + LD versus LD	9	1220	Peto Odds Ratio (Peto, Fixed, 95% CI)	2.62 [1.74, 3.93]
2.3 DA versus LD	8	2206	Peto Odds Ratio (Peto, Fixed, 95% CI)	2.47 [1.96, 3.11]
3 Patient withdrawal due to lack of efficacy Show forest plot	18		Peto Odds Ratio (Peto, Fixed, 95% CI)	Subtotals only

3.1 DA versus Placebo	6	946	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.28 [0.11, 0.70]
3.2 DA + LD versus LD	9	1021	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.26 [0.14, 0.47]
3.3 DA versus LD	5	1151	Peto Odds Ratio (Peto, Fixed, 95% CI)	2.93 [1.94, 4.42]

Comparison 6. Patient withdrawal in trials of dopamine agonists (by randomised treatment comparison)

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