Cost effectiveness of paliperidone palmitate versus risperidone long-acting injectable and olanzapine pamoate for the treatment of patients with schizophrenia in Sweden

Figures & data

Figure 1.  Markov decision analytic model simulating the history of a cohort of multi-episode (two or more relapses) with schizophrenia. The Figure depicts the first two (of a maximum of four) treatment lines. APn, initial antipsychotic; APn+1, treatment switch; Adh., adherent; Part Adh., partial adherent; Non Adh., non-adherent; Hosp, hospitalization; No Hosp, no hospitalization; SE, side-effect.

Figure 2.  Treatment sequence. PLAI, paliperidone palmitate; RLAI, risperidone long-acting injectable; OLAI, olanzapine pamoate; ER, extended release.

Table 1.  Clinical input values.

Parameters	Value		Data/comment
Risk ratio of relapse versus placebo (1 year)
PLAI	0.33	Assumed non-inferior to RLAI (PSY-3006)23
RLAI	0.33	RLAI/quet (ConstaTRE)17 *oral typical2; quet=haloperidol (relapse)26
		= 0.44 →  0.44 × 0.76 = 0.33 Where 0.44 is the RLAI/quetiapine ratio from the ConstaTRE study17 and 0.76 is the relapse rate for haloperidol26
OLAI	0.46	Non-inferior efficacy to oral olanzapine18
Oral olanzapine	0.46	52-week probability of relapse/placebo probability of relapse2
Oral risperidone	0.63	52-week probability of relapse/placebo probability of relapse2
Oral paliperidone ER	0.37	52-week probability of relapse/placebo probability of relapse2
Perphenazine	0.76	Assumed similar to oral typical2; meta analysis19
Zuclopenthixol	0.63	Similar to oral risperidone2; meta analysis20
Clozapine	0.76	1.00 RR clozapine vs. haloperidol studies meta-analysis26; relapse prevention of ‘oral typical’ versus placebo2
Placebo	1.00	Reference
Risk ratio of relapse by level of adherence
Adherent (reference)	1.00	Probability of relapse in adherent patients, 13.5%10
Partially adherent	1.81	(Probability of relapse in, partially adherent + excess filler)/ adherent = [24.1% * 0.16 + 24.8% * 0.19)/0.35]/ 13.5%10
Non-adherent	2.59	Probability of relapse in non-adherent, 34.9%/adherent, 13.5%10
Duration of relapse
Relapse req. Hosp: Acute psychiatric ward	66.4	Days, Swedish national inpatient care statistics27
Relapse not req. Hosp: Community	30	Days, assumption
Probabilities of patients with side-effects (1-year)
EPS
PLAI	9.3%	PLAI/RLAI EPS AEs (PSY-300228 53-week data on file) *RLAI29
RLAI	12.6%	RLAI/oral olanzapine30 *annualized oral olanzapine29
OLAI	7.6%	Equal to oral olanzapine (no significant differences)31
Oral olanzapine	7.6%	Annualized oral olanzapine29 (14.7% est. 2.02 years)
Oral risperidone	18.2%	Annualized oral risperidone29 (32.2% est. 1.94 years)
Oral paliperidone ER	11.4%	OR paliperidone / OR risperidone2 *annualized oral risperidone29
Perphenazine	19.7%	Annualized oral typical29 31.4% est. 1.71 years)
Zuclopenthixol	19.7%	Annualized oral typical29 31.4% est. 1.71 years)
Clozapine	8.8%	Annualized clozapine29 (17.2% est. 2.04 years)
TD
PLAI	0.3%	PSY-300132
RLAI	1.2%	Rate at 50 weeks, open-label clinically stable patients33
OLAI	3.0%	Equal to oral olanzapine (no significant differences)31
Oral olanzapine	3.0%	Annualized oral olanzapine29 (5.9% est. 2.02 years)
Oral risperidone	4.1%	Annualized oral risperidone29 (7.8% est. 1.94 years)
Oral paliperidone ER	4.1%	Assumed equal to oral risperidone2
Perphenazine	5.2%	Annualized oral typical29 8.7 %(est. 1.71 years)
Zuclopenthixol	5.2%	Annualized oral typical29 8.7% est. 1.71 years)
Clozapine	3.1%	Annualized clozapine29 (6.2% est. 2.04 years)
Weight gain (≥7%)
PLAI	8.5%	PLAI/RLAI (PSY-300228 53-week data on file) *RLAI24
RLAI	9.1%	RLAI/oral olanzapine30 *annualized oral olanzapine29
OLAI	16.3%	Equal to oral olanzapine (no significant differences)18
Oral olanzapine	16.3%	Annualized oral olanzapine29 (30.1% est. 2.02 years)
Oral risperidone	12.0%	Annualized oral risperidone29 (22.0% est. 1.94 years)
Oral paliperidone ER	11.7%	Annualized oral paliperidone ER/annualized oral olanzapine34 *oral olanzapine29
Perphenazine	9.5%	Annualized oral typical2915.7% (est. 1.71 years)
Zuclopenthixol	9.5%	Annualized oral typical29 15.7% (est. 1.71 years); meta-analysis confirms not significantly different from other typicals
Clozapine	12.6%	Annualized clozapine29 (24.1% est. 2.04 years)
Diabetes
PLAI	1.6%	Average of (NICE diabetes2/weight gain) risk ratios *risk of weight gain (PLAI)28
RLAI	1.7%	Average of (NICE diabetes2/weight gain) risk ratios *risk of weight gain (RLAI)
OLAI	4.2%	Equal to oral olanzapine (no significant differences)18
Oral olanzapine	4.2%	Probability of diabetes – 1st year of initiation2
Oral risperidone	2.1%	Probability of diabetes – 1st year of initiation2
Oral paliperidone ER	2.1%	Probability of diabetes – 1st year of initiation2
Perphenazine	2.0%	Oral typical; probability of diabetes – 1st year of initiation2
Zuclopenthixol	2.0%	Oral typical; probability of diabetes – 1st year of initiation2
Clozapine	2.4%	Average of (NICE diabetes2/weight) ratios *weight (clozapine)

PLAI, paliperidone palmitate; RLAI, risperidone long-acting injectable; ConstaTRE, Risperdal Consta Trial of Relapse Prevention and Effectiveness; OLAI, olanzapine pamoate; ER, extended release; RR, relative risk; EPS, extrapyramidal symptom; AE, adverse event; OR, odds ratio; TD, tardive dyskinesia; est, estimated mean treatment duration; NICE, National Institutes of Clinical Excellence; MTC, mixed treatment comparison; OLE, open-label extension; DOF, data on file. *means multiplication

Table 2.  Level of adherence by treatment.

Parameters	Value	Data source/comment
Risk ratio of adherence
PLAI	1.34	5% improvement factor in adherence (once-monthly versus twice-weekly LAI)36
RLAI	1.29	Ratio of retention rates (RLAI/oral atypicals)13
OLAI	1.24	Assumes 3-hour post-injection monitoring reduces adherence by 5%
Oral olanzapine	1.00	Equal to ‘other atypical’10
Oral risperidone	1.00	Equal to ‘other atypical’10
Oral paliperidone ER	1.00	Equal to ‘other atypical’10
Perphenazine	0.91	Ratio of retention rates (oral typicals/‘other atypical’)10
Zuclopenthixol	0.91	Ratio of retention rates (oral typicals/‘other atypical’)10
Clozapine	1.48	Ratio of retention rates (clozapine/‘other atypical’)10
Reference (‘other atypical’)	1.00	41% adherent10
Risk ratio of partial adherence (1 – [probability of adherence + probability of non-adherence])
PLAI	1.21
RLAI	1.23
Oral olanzapine	1.00
Oral risperidone	0.79
Oral paliperidone ER	0.79
Clozapine	0.49
Reference (‘other atypical’)	1.00
Risk ratio of non-adherence
PLAI	0.12	5% improvement factor in adherence (once-monthly versus twice-weekly LAI)
RLAI	0.17	1/HR orals versus RLAI: disc. for compliance issues35
OLAI	0.22	Assumes 3-hour post-injection monitoring reduces adherence by 5%
Oral olanzapine	1.00	Olanzapine oral HR for disc – lack of compliance29
Oral risperidone	1.31	Risperidone oral HR for disc – lack of compliance29
Oral paliperidone ER	1.31	Risperidone oral HR for disc – lack of compliance 29
Perphenazine	1.58	Oral typical HR for disc – lack of compliance29
Zuclopenthixol	1.58	Oral typical HR for disc – lack of compliance29
Clozapine	0.92	Clozapine HR for disc versus lack of compliance29
Reference (‘other atypical’)	1.00	24% non-adherent10

PLAI, paliperidone palmitate; RLAI, risperidone long-acting injectable; OLAI, olanzapine pamoate; ER, extended release; LAI, long-acting injectable; EFESO, Estudio Farmacoepidemiologico en la Esquizofrenia con Olanzapina; disc, discontinuation; HR, hazard ratio.

Table 3.  Proportion of patients switching medication by reason for discontinuation (1 year).

	Proportion of patients switching medication due to:
	Lack of efficacy	Intolerability/ side-effects	Lack of compliance	Patient request	Source
PLAI	7.3%	1.4%	0.7%	3.3%	RLAI values adjusted by PLAI/RLAI ratios^†
RLAI	7.3%	2.0%	0.9%	3.3%	Ratio of annualized RLAI/oral atypical discontinuation rates (per reason)35 *oral atypical discontinuation rates (per reason)29
OLAI	6.6%	2.2%	0.7%	4.0%	Equal to oral olanzapine except for discontinuation due to lack of compliance (*risk of non-compliance)
Oral olanzapine	6.6%	2.2%	3.1%	4.0%	Annualized oral olanzapine29
Oral risperidone	8.2%	3.5%	4.3%	4.3%	Annualized oral risperidone29
Oral paliperidone ER	8.2%	3.5%	4.3%	4.3%	Annualized oral risperidone29
Perphenazine	13.9%	3.6%	4.5%	6.3%	Lack of compliance: annualized perphenazine29; other reasons: annualized perphenazine/oral olanzapine discontinuation hazard ratio from CATIE data42 *oral olanzapine discontinuation rate
Zuclopenthixol	12.8%	4.6%	4.5%	6.0%	Annualized oral typical29
Clozapine	6.3%	2.5%	3.1%	2.1%	Annualized clozapine29

^†Risk of relapse ratio for discontinuation due to lack of efficacy, average of PLAI to RLAI side-effects for discontinuation due to intolerability/side-effects, risk of non-compliance for discontinuation due to lack of compliance. Assumed equivalent discontinuation due to patient request.

PLAI, paliperidone palmitate; RLAI, risperidone long-acting injectable; OLAI, olanzapine pamoate; ER, extended release; CATIE, Clinical Antipsychotic Trials of Intervention Effectiveness. *means multiplication

Table 4.  Utility scores.

Health states	Mean utility	Source
Stable (no side-effects)	0.919	Elicited from patient sample44
Relapse (not req. hospitalization)	0.762	Mid-point between utilities for stable and relapse (requiring hospitalization)
Relapse (req. hospitalization)	0.604	Elicited from patient sample44
Dead	0.000
Utility decrements for SEs
Acute EPS	0.197	Elicited from patient sample (0.919–0.722)44
TD	0.197	Assumed = EPS
Weight gain	0.094	Elicited from patient sample (0.919–0.825)44
Diabetes	0.150	Elicited from patient sample (0.919–0.769)44

SE, side-effects; EPS, extrapyramidal symptom; TD, tardive dyskinesia.

Table 5.  Mean resource use – ambulatory care for schizophrenia by health state.

Resource use	Stable over 6 months (per month)	Relapse, not requiring hospitalization over 6 months (per month)
Psychiatric visit – outpatient	1.4 (0.233)	2.1 (0.350)
Psychiatrist – home visit	2.5 (0.417)	2.3 (0.383)
Primary care physician visit	1.8 (0.300)	1.6 (0.267)
Psychiatric nurse visit	12.6 (2.100)	5.2 (0.867)
Occupational therapist	0.0	0.8 (0.133)
Social worker visit	0.1 (0.017)	0.4 (0.067)
Group therapy	0.4 (0.067)	0.1 (0.017)
Community mental health center visit	2.4 (0.400)	1.4 (0.233)
Day hospital visit	2.3 (0.383)	2.1 (0.350)

Source: Adapted from Almond et al., 200437 (mean usage/6 months, monthly rates in brackets).

Table 6.  Mean resource use for the management of side-effects.

Management of side-effects	Side-effect	Resource use
Psychiatrist – consultant	Any	1.0 (0.167 per month)
Primary care physician	Any	2.0 (0.333 per month)
Nutritionist/dietician	Weight gain	0.6 (0.1 per month)
Laboratory test for cholesterol	Weight gain	0.5 (0.083 per month)
Laboratory test for glycemia associated with diabetes	Diabetes	0.5 (0.083 per month)
Pharmacological management for EPS (days of treatment)	EPS	30
Pharmacological management for diabetes (month of treatment)	Diabetes	1

Source: Assumptions from NICE guidelines, 20102.

EPS, extrapyramidal symptoms.

Table 7.  Mean daily doses and drug cost per unit.

	Mean dose per day (mg)*	Cost per unit (SEK/mg)	Source/comment
PLAI	2.5	44.33	Assumed to have the same price/mg as RLAI^†
RLAI	2.7	44.33	Derived from price for 37.5 mg RLAI^†
OLAI	10.0	7.82	Average of unit prices for OLAI 210 mg, 300 mg and 405 mg
Oral olanzapine	10.0	4.47	Derived from price for 10 mg, 56 tablets package^†
Oral risperidone	5.0	2.78	Average unit prices derived from prices of 60 tablet packages of 2 mg and 3 mg risperidone^†
Oral paliperidone ER	6.0	5.90	Derived from price for 6 mg, 56 tablets package^†
Perphenazine	30.0	0.36	Average of unit prices derived from prices of 100 tablet packages with 2 mg and 8 mg^†
Zuclopenthixol	30.0	0.23	Average of unit prices derived from prices of 100 tablet packages with 2 mg, 10 mg and 25 mg^†
Clozapine	300	0.06	Average of unit prices derived from prices of 100 tablet packages with 25 mg and 100 mg^†

*World Health Organization defined daily dose, available at http://www.whocc.no/atc_ddd_index/47.

^†All prices per unit are derived from official published prices on the TLV website, except PLAI which was assumed to have the same price/unit as RLAI.

PLAI, paliperidone palmitate; RLAI, risperidone long acting injectable; OLAI, olanzapine pamoate; ER, extended release.

Table 8.  Resource use unit costs (direct medical perspective).

Services	Unit cost (in SEK 2009)	Inflation rate (%)
Inpatient care
Acute psychiatric ward (per day)^a	6112
Ambulatory care
Psychiatrist – outpatient^b	2114	4.46
Psychiatrist – home visit^c	4230	0.00
Primary care physician^b	878	4.46
Psychiatric nurse^b	1391	4.46
Occupational therapist^b	1155	0.00
Social worker^c	358	4.46
Group therapy^c	1666	0.00
Sheltered workshop^d	572	0.00
Community mental health center visit^d	572	0.00
Day care center visits^d	572	0.00
Home help/care worker^b	358	4.46
General medical ward (days)^b	4438	4.46
Day hospital visit^e	1923	0.00
Management of side-effects
Nutritionist/dietician	1961^c	—
Laboratory tests for cholesterol associated with weight gain^e	47	0.00
Laboratory test for glycemia associated with diabetes^e	18	0.00
Pharmacological management for acute EPS (day of treatment)^e	2.67	0.00
Pharmacological management for diabetes without complications (month of treatment)^f	225.50	0.00

Data sourced from: ^aSödra sjukvårdsregionen, Price list for University Hospital in Malmö 2006 (+3.4% inflation); ^bRegional prices and reimbursement for the Southern Health Care region 2008. Division 7, Psychiatry Lund (+4.46%); ^cRegional prislista för Uppsala-Örebroregionen 2009; ^dLandstinget Dalarna, Prislista 2009; ^eRegionala priser och ersättningar för Södra sjukvårdsregionen 2009; ^fRingborg et al., 200750.

EPS, extrapyramidal symptoms.

Table 9.  QALYs and costs (SEK, %) per patient over 5 years.

Values per patient over 5 years	PLAI	RLAI	OLAI
Antipsychotic acquisition costs; SEK (%)	160,011 (17.5)	168,389 (18.0)	114,481 (11.8)
Schizophrenia-related costs; SEK (%)
Stable	380,281 (41.7)	379,602 (40.7)	374,671 (38.7)
Relapse	4633 (0.5)	4793 (0.5)	5952 (0.6)
Side-effects costs; SEK (%)	1989 (0.2)	2349 (0.3)	3088 (0.3)
Hospitalization costs; SEK (%)	365,805 (40.1)	378,449 (40.5)	470,370 (48.6)
Total; SEK	912,719	933,581	968,591
Total costs, SEK discounted (3%)	858,830	878,461	911,556
QALYs, discounted 3% (base case)	3.92	3.84	3.76
QALYs, per patient, undiscounted (sensitivity analysis)	4.15	4.06	3.98
QALYs, discounted 5% (sensitivity analysis)	3.78	3.70	3.68
Relapses, discounted 3% (base case)	1.37	1.41	1.76
Relapses, per patient, undiscounted (sensitivity analysis)	1.46	1.51	1.87
Relapses, discounted 5% (sensitivity analysis)	1.31	1.36	1.69

PLAI, paliperidone palmitate; RLAI, risperidone long-acting injectable; OLAI, olanzapine pamoate.

QALY, quality-adjusted life-year.

Figure 3.  Cost-effectiveness plane (QALYs gained and relapses avoided), PLAI versus RLAI. Solid lines depict the 95% confidence interval; solid triangles depict the base-case values. QALY, quality-adjusted-life-year; PLAI, paliperidone palmitate; RLAI, risperidone long-acting injectable.

Figure 4.  Cost-effectiveness plane (QALYs gained and relapses avoided), PLAI versus OLAI. Solid lines depict the 95% confidence interval; solid triangles depict the base-case values. QALY, quality-adjusted-life-year; PLAI, paliperidone palmitate; OLAI, olanzapine long-acting injectable.

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