Abstract
Objective
Limited evidence exists regarding real-world 3-monthly paliperidone palmitate (PP3M) treatment retention and associated factors.
Methods
We conducted a retrospective, nationwide cohort study using the Taiwan National Health Insurance Research Database between October 2017 and December 2019. Adult patients with schizophrenia initiated on PP3M were enrolled. The primary outcomes were time to PP3M discontinuation, time to psychiatric hospitalization, and the proportions of patients receiving the next PP3M dose within 120 days among first-, second-, and third-dose completers. Key covariates included prior PP1M duration and adequate PP3M initiation.
Results
The PP3M treatment retention rates were 79.7%, 66.3%, and 52.5% after 6, 12, and 24 months, respectively, with 86.4%, 90.6%, and 90.0% of respective first-, second-, and third-dose completers receiving the next PP3M dose. Adequate PP3M initiation and prior PP1M treatment duration > 180 days were associated with favorable PP3M treatment retention. In multivariate analyses, PP1M durations of 180−360 days (adjusted relative risk [aRR], 1.76) or < 180 days (aRR, 2.79) were associated with PP3M discontinuation at the second dose. Inadequate PP3M initiation was associated with discontinuation at the third dose (aRR, 2.18). Patients fully adherent to PP3M treatment in the first year had a higher probability of being free from psychiatric hospitalization (86.7% at 2 years), compared with those partially adherent or non-adherent to PP3M in the first year.
Conclusion
Prior PP1M duration and adequate PP3M initiation are major factors affecting PP3M treatment retention. Higher PP3M treatment retention is associated with a lower risk of psychiatric hospitalization.
Keywords: Paliperidone palmitate, Schizophrenia, Real-world, Treatment retention, Long-acting injectable antipsychotic, Psychiatric hospitalization
INTRODUCTION
Adequate treatment adherence to antipsychotic medication regimens is essential for the long-term recovery of patients with schizophrenia. Compared with orally administered equivalents, long-acting injectable (LAI) antipsychotics have longer half-lives and require less frequent administration, which can further promote treatment adherence and offer extra protection from relapse even if treatment is interrupted or discontinued [1]. The superior clinical effectiveness of once-monthly LAI antipsychotics over orally administered antipsychotics has been demonstrated in several randomized controlled trials [2-4] and population-based cohort studies [5-7], and the use of LAI is increasingly recommended by expert consensus and treatment guidelines for schizophrenia [8-10].
However, LAI antipsychotic treatment discontinuation remains common in real-world settings. Several population-based studies show that 60−90% of patients discontinue the use of first- or second-generation LAI antipsychotic treatments, especially during the first year of treatment [11-14]. The factors associated with treatment discontinuation are not fully understood, but poor medication adherence at baseline is a primary risk factor [15]. Studies examining treatment adherence to LAI antipsychotics have primarily examined biweekly or once- monthly treatments, and whether LAI antipsychotics with longer formulations are able to overcome these challenges remains unclear.
The 3-monthly paliperidone palmitate (PP3M) formulation is indicated for use in patients with schizophrenia who have achieved stability for at least 4 months while using once-monthly paliperidone palmitate (PP1M). PP3M is one of the longest-acting LAI formulations currently available, only requiring administration once every 3 months. Importantly, PP3M has been found to be non- inferior to PP1M in terms of efficacy and safety in the clinical trial setting [16]. Emerging evidence suggests that PP3M may be superior to PP1M in terms of treatment adherence and relapse prevention in the real-world setting [17,18]. However, few studies have explored the factors that affect PP3M treatment retention in a naturalistic setting [19].
We aimed to fill this important evidence gap by analyzing Taiwan’s nationwide claims database records to identify patients with schizophrenia who have been treated with PP3M during the post-marketing period. We hypothesized that PP3M treatment retention is influenced by the duration of prior PP1M treatment and the adequate initiation of PP3M treatment. Moreover, we hypothesized that patients with a higher degree of PP3M treatment retention in the first year also have a greater chance of being free from psychiatric hospitalization in the first year and thereafter.
METHODS
Design and Data Source
We conducted a retrospective, population-based cohort study utilizing data obtained from Taiwan’s National Health Insurance (NHI) claims database from the Health and Welfare Data Science Center. The NHI is a government-administered, insurance-based, national healthcare system that covers > 99.5% of the 23.5 million citizens in Taiwan. Joining the NHI is mandatory for all Taiwanese citizens (including patients with serious mental illnesses), and the treatment costs for PP1M, PP3M, and other psychiatric medications are fully reimbursed. Therefore, the NHI database is a great data source for studying the evolution of PP3M treatment over time.
The available dataset for the current analysis includes claims records for all reimbursed drug prescriptions and mental health services (inpatient, outpatient, and home visit) for a nationwide cohort of NHI beneficiaries between January 1, 2015, and December 31, 2019. In Taiwan, PP1M and PP3M have been reimbursed and available for prescription since February 2015 and October 2017, respectively.
Study Population
Between October 1, 2017, and December 31, 2018, all adult (> 18 years) NHI beneficiaries with a schizophrenia diagnosis and at least one PP3M claim in the database, with the first PP3M claim administered in the outpatient or home visit setting, were included in the analysis. The date of the first PP3M claim for each patient was defined as their index date. All patients included in the analysis were followed until December 31, 2019. The validity of the schizophrenia diagnosis was confirmed by both (a) the presence of a diagnostic code for schizophrenia (Interna-tional Classification of Diseases, Ninth Revision, Clinical Modification, ICD-9-CM: 295.xx; ICD-10: F20.x or F25.x) at least once in the database and (b) prescriptions for long-term antipsychotic treatment (minimum of 90 days) according to claim records for 2015−2017.
Key Covariates
Prior PP1M treatment duration was defined as the number of days of continuous PP1M treatment before the index date. Each PP1M claim was considered 30 days of continuous treatment, and a grace period of up to 15 days was allowed when determining PP1M treatment continuity (i.e., the gap between two PP1M claims was ≤ 45 days).
According to the product label, PP3M is recommended for initiation in patients with an adequate response to PP1M for at least 4 months, with no changes in the last two PP1M doses. In addition, a 3.5-fold conversion in dose strength from PP1M to PP3M is recommended. In the current analysis, adequate PP3M initiation was defined as: (a) ≥ 1 PP1M claims within 180 days before the index date; (b) no gap > 45 days between PP1M claims within 120 days before the index date; (c) the same dose strength for the last two PP1M claims immediately prior to the index date; and (d) a correct conversion in dose strength between the last PP1M claim and the first PP3M. These criteria reflect the recommendations for PP3M administration and were used in another real-world database study of PP3M [20].
Other covariates included age, sex, employment status (based on the patients’ insurance information), history of psychiatric hospitalization during the previous 2 years, clinical settings, PP3M dosage, concomitant oral antipsychotic treatment before or after PP3M treatment initiation, and psychiatric outpatient visits within 30 days after the first PP3M dose. Based on the authors’ clinical experience, these covariates could affect PP3M treatment retention.
PP3M Treatment Retention and Treatment Patterns after PP3M Discontinuation
The probability of PP3M treatment retention over time was estimated using the Kaplan–Meier method. Each PP3M claim was considered 90 days of continuous treatment, and a grace period of 30 days was allowed when determining PP3M treatment continuity. PP3M treatment discontinuation occurred on day 91 after the last PP3M claim if no PP3M claim was identified within 120 days after the last PP3M claim, regardless of whether the patient resumed PP1M treatment during the 120-day window.
Supplementary analyses were conducted to characterize the antipsychotic treatment pattern after PP3M dis-continuation. For each 120-day time window after the first, second, and third PP3M claim, a patient’s antipsy-chotic treatment status was classified into five mutually exclusive categories using the following hierarchical order: (a) on PP3M treatment, (b) on PP1M treatment, (c) on other LAI treatment, (d) on oral paliperidone treatment, and (e) others. Patients treated with more than one treatment option during this time window were classified into the first applicable category (e.g., a patient treated with both PP3M and PP1M will be classified as having PP3M treatment). Shifts between treatment categories were visualized using a Sankey diagram. The Kaplan–Meier pro-bability of combined PP1M/PP3M treatment retention after the index date was also estimated. In this supplementary analysis, each PP3M and PP1M claim was treated as 90 and 30 days of continuous treatment, respec-tively, and a grace period of 30 days was allowed when determining PP1M/PP3M treatment continuity.
PP3M Treatment Retention and Psychiatric Hospitalization
The probability of patients’ psychiatric hospitalization- free status over the 2-year period after the initiation of PP3M treatment was estimated using the Kaplan–Meier method. When exploring the association between PP3M treatment retention and psychiatric hospitalization-free status, we used patients’ adherence status to PP3M treatment in the first year as a measure for PP3M treatment retention status. Patients’ adherence status to PP3M treatment in the first year was classified into 3 mutually exclusive categories: (a) fully adherent, (b) non-adherent, (c) partially adherent. Patients in the fully adherent group received PP3M treatment in each quarter of the first year. Patients in the non-adherent group received only the first PP3M treatment at the index date and did not receive any other PP3M treatment in the remaining of the first year. Other patients were classified as the partially adherent group.
Statistical Analysis
Descriptive statistics were used to describe the demographic and clinical characteristics of patients in the overall PP3M cohort. PP3M treatment retention over time was estimated using Kaplan–Meier survival curves, and log- rank tests were conducted to compare the treatment survival curves of patient subgroups stratified by prior PP1M treatment duration (< 180, 180−360, or > 360 days) and adequate PP3M initiation (yes or no).
To explore whether prior PP1M treatment duration and adequate PP3M initiation were associated with early PP3M treatment discontinuation, multivariate regression models were developed using the following approach. In Step 1, the clinical characteristics of patients who completed two PP3M doses were compared with those who discontinued after one dose, and the characteristics of patients who completed three PP3M doses were compared with those who discontinued after two doses. Continuous variables were examined using independent ttests (if variables were normally distributed) or Mann–Whitney U tests (if variables were not normally distributed), and categorical variables were compared using chi-square tests. Clinical factors with a pvalue < 0.10 in Step 1 were selected for analysis by univariate and multivariate regression models in Step 2. To estimate the relative risks (RR) of these clinical factors, log-binomial regression models were applied. A two-sided pvalue < 0.05 was considered statistically significant. In the sensitivity analyses, the multivariate regression models were built using the stepwise variable selection method, with significance levels of 0.15 in Step 1 for both variable entry and retention in the model.
Kaplan–Meier plots were produced to estimate the probability of psychiatric hospitalization-free status over time, and log-rank tests were conducted to compare the curves of patient subgroups stratified by prior PP1M treatment duration (< 180, 180−360, or > 360 days), adequate PP3M initiation (yes or no), and PP3M adherence status in the first year (fully adherent, partially adherent, or non-adherent). Censuring occurred at the last day of the observation period or when patients were lost to follow- up, whichever occurred earlier.
Descriptive analyses and statistical tests were conducted using SAS version 9.4 (SAS Institute Inc.). The log-binomial regression models were conducted using the PROC GENMOD procedure. Kaplan–Meier survival curves were generated using Stata version 14.0 (Stata Co., LLC.), and the Sankey diagram was generated using the plotly package of R version 4.0.2 (R Foundation for Statistical Com-puting). A two-sided pvalue < 0.05 was considered significant.
RESULTS
Baseline Characteristics
A total of 960 patients met the PP3M cohort eligibility criteria (see Fig. 1 for the patient flowchart). The median follow-up duration was 513 days (interquartile range [IQR], 442−595). Table 1 summarizes the baseline characteristics of the overall PP3M cohort. Patients’ median age was 44 years (IQR, 36−52). Male and female patients were almost equal in number. Approximately two-thirds of patients did not experience any psychiatric hospitalization during the prior 2 years, and one-third of patients were employed in some form at the time of PP3M initiation; these factors suggest that PP3M use was primarily initiated in a group of clinically stable patients. However, a minority of patients (n = 67, 7.0%) had high levels of psychiatric inpatient service utilization at baseline (≥ 4 hospitalizations during the prior 2 years), suggesting that PP3M is sometimes used in less stable patients.
Fig. 1.
Patient flowchart.
PP1M, paliperidone palmitate 1-monthly; ICD-9-CM, International Classification of Diseases, Ninth Revision, Clinical Modification.
Table 1.
Demographics and clinical characteristics of the overall PP3M cohort
| Characteristic | Overall PP3M cohort (n = 960) |
|---|---|
| Sex | |
| Female | 478 (49.8) |
| Male | 481 (50.1) |
| Missing | 1 (0.1) |
| Age at the PP3M initiation (yr) | 44.1 ± 11.5 |
| Median (IQR) | 44 (36−52) |
| 18−39 | 332 (34.6) |
| 40−59 | 544 (56.7) |
| ≥ 60 | 84 (8.8) |
| Employment statusa at PP3M initiation | |
| Wage-based employees | 183 (19.1) |
| Self-employees, laborers, farmers, or fishers | 160 (16.7) |
| Other status | 617 (64.3) |
| Number of psychiatric hospitalization in the past 2 years (time) | 0.9 ± 1.8 |
| 0 | 616 (64.2) |
| 1−3 | 277 (28.9) |
| ≥ 4 | 67 (7.0) |
| Cumulative psychiatric bed days in the past 2 years (day) | 20.2 ± 44.7 |
| Median (IQR) | 0 (0−22) |
| Prior PP1M treatment duration (day) | 246.0 ± 126.2 |
| Median (IQR) | 315 (122−360) |
| < 180 | 352 (36.7) |
| 180−360 | 370 (38.5) |
| > 360 | 238 (24.8) |
| Concomitant oral antipsychotic use before PP3M initiation | |
| Yes | 322 (33.5) |
| No | 638 (66.5) |
| Initial treatment setting of PP3M | |
| Outpatient clinic | 766 (79.8) |
| Home visit | 194 (20.2) |
| Initial dosage of PP3M | |
| 525 mg eq. | 665 (69.3) |
| 350 mg eq. | 295 (30.7) |
| Adequate initiation of PP3M | |
| Yes | 540 (56.3) |
| No | 320 (43.7) |
| Interval between the last PP1M and first PP3M claims (day) | 49.8 ± 86.8 |
| Median (IQR) | 28 (28−35) |
| Number of PP3M claims in the first 365 days (first claim included) (claim) | 4.1 ± 1.4 |
| Median (IQR) | 5 (3−5) |
Values are presented as number (%) or mean ± standard deviation.
IQR, interquartile range; mg eq., mg equivalent; PP1M, paliperidone palmitate 1-monthly.
a“Wage-based employees” refer to NHI beneficiaries with category 1 insurance status; “Self-employees, laborers, farmers, or fishers” refer to NHI beneficiaries with category 2 or 3 insurance status. All other NHI beneficiaries are classified as “Other status”.
Initiation of PP3M Treatment
Most patients initiated PP3M treatment in the outpatient clinic setting (79.8%) with a prior PP1M treatment duration of ≤ 360 days (75.2%). The median duration of prior PP1M treatment was 315 days (10.5 months).
Adequate PP3M initiation was observed in 56.3% of patients. Patients who experienced adequate initiation were similar to patients who experienced inadequate initiation in terms of sex, age, and employment status; however, patients with inadequate initiation experienced increased psychiatric hospitalization and were more likely to use concomitant oral antipsychotic treatment before PP3M initiation (Table 2). Inadequate initiation was especially common among patients with high psychiatric inpatient service utilization at baseline (59 of 67 patients, 88.1%). The most common reason for inadequate initiation was the combination of the presence of PP1M treatment gaps within 120 days before the index date and changes in dose strength between the last 2 PP1M claims (210 of 960 patients, 21.9%).
Table 2.
Comparison of clinical characteristics between patients with adequate and inadequate PP3M initiation
| Characteristic | Adequate PP3M initiation (n = 540) | Inadequate PP3M initiation (n = 420) | pvalue |
|---|---|---|---|
| Age at the PP3M initiation (yr) | 44.1 ± 11.0 | 44.1 ± 12.0 | 0.0631a |
| Median (IQR) | 44 (37−52) | 45 (35−52.5) | - |
| Sex | |||
| Female | 281 (52.0) | 197 (46.9) | 0.1600b |
| Male | 259 (48.0) | 222 (52.9) | |
| Missing | - | 1 (0.2) | |
| Employment status at PP3M initiation | |||
| Wage-based employees | 108 (20.0) | 75 (17.9) | 0.2501b |
| Self-employees, laborers, farmers, or fishers | 97 (18.0) | 63 (15.0) | |
| Other status | 335 (62.0) | 282 (67.1) | |
| Psychiatric hospitalization in the past 2 years (time) | 0.5 ± 1.2 | 1.3 ± 2.3 | 0.0001c |
| 0 | 365 (67.6) | 251 (59.8) | < 0.0001b |
| 1−3 | 167 (30.9) | 110 (26.2) | |
| ≥ 4 | 8 (1.5) | 59 (14.0) | |
| Psychiatric hospitalization bed days in the past 2 years (day) | 13.7 ± 32.2 | 28.5 ± 55.8 | 0.0002c |
| Median (IQR) | 0 (0−14) | 0 (0−30) | |
| Prior PP1M treatment duration (day) | 296.7 ± 90.9 | 174.5 ± 134.2 | < 0.0001a,c |
| Median (IQR) | 346.0 (228−365) | 139 (31−325) | |
| Concomitant oral antipsychotics before PP3M initiation | |||
| Yes | 158 (29.3) | 164 (39.0) | 0.0014b |
| No | 382 (70.7) | 256 (61.0) | |
| Initial treatment setting of PP3M | |||
| Outpatient clinic | 404 (74.8) | 362 (86.2) | < 0.0001b |
| Home visit | 136 (25.2) | 58 (13.8) | |
| Initial dosage of PP3M | |||
| 525 mg eq. | 371 (68.7) | 294 (70.0) | 0.6658b |
| 350 mg eq. | 169 (31.3) | 126 (30.0) | |
| Interval between the last PP1M and the first PP3M claim (day) | 28.6 ± 3.3 | 78.0 ± 127.3 | < 0.0001a,c |
| Median (IQR) | 28 (28−28) | 35 (28−77) | |
| Number of PP3M claims in the first 365 days (first claim included) (claim) | 4.3 ± 1.3 | 3.8 ± 1.5 | < 0.0001c |
| Median (IQR) | 5 (4−5) | 4 (3−5) | |
| 1 | 46 (8.5) | 50 (11.9) | < 0.0001b |
| 2 | 26 (4.8) | 40 (9.5) | |
| 3 | 22 (4.1) | 61 (14.5) | |
| 4 | 68 (12.6) | 64 (15.2) | |
| 5 | 370 (68.5) | 198 (47.1) | |
| ≥ 6 | 8 (1.5) | 7 (1.7) |
Values are presented as mean ± standard deviationor number (%).
IQR, interquartile range; mg eq., mg equivalent; PP1M, paliperidone palmitate 1-monthly; -, not available.
attest, bchi-square test, cMann–Whitney U test.
PP3M Treatment Retention over Time
On average, patients received 4.1 doses of PP3M in the first year. Figure 2A shows the PP3M treatment retention rate over time for the overall PP3M cohort. The Kaplan–Meier analysis indicated that the probability of PP3M treatment retention was 79.7% after 6 months, 66.3% after 12 months, and 52.5% after 24 months. The largest decrease in PP3M treatment retention occurred between the first and second PP3M dose, and smaller retention losses were observed for subsequent PP3M doses.
Fig. 2.
Sankey diagram of antipsy-chotic treatment patterns after the first dose of PP3M.
Figure 3 shows the evolution of antipsychotic treatment patterns after the first PP3M dose. The percentages of patients who received the next PP3M dose within 120 days were 86.4% after the first dose, 90.6% after the second dose, and 90.0% after the third dose. Among patients who received a first PP3M dose, 4.5% (n = 43) received a PP1M dose instead of the second PP3M dose, although four patients eventually returned to PP3M treatment. Those who completed the second and third PP3M doses did not return to PP1M. In the supplementary analysis, the Kaplan–Meier probabilities for combined PP1M/PP3M treatment retention were 85.2% after 6 months, 72.0% after 12 months, and 58.8% after 24 months (Fig. 4A).
Fig. 3.
Sankey diagram of antipsychotic treatment patterns after the first dose of PP3M.
PP1M, paliperidone palmitate 1-monthly; PAL, paliperidone; LAI, long-acting injectable.
Fig. 4.
Kaplan–Meier probability analysis for combined PP1M/PP3M treatment retention. (A) Overall cohort. (B) By prior PP1M duration. (C) By adequate initiation of PP3M.
PP1M, paliperidone palmitate 1-monthly.
Switching to other LAI was rare among patients treated with PP1M/PP3M, occurring in < 1% of patients during any of the 120-day windows examined in this study.
Factors Associated with Early PP3M Treatment Discontinuation
Figure 2B and 2C show the Kaplan–Meier probabilities for PP3M retention stratified according to prior PP1M treatment duration and the use of adequate PP3M initiation, respectively, which were both significantly associated with PP3M treatment retention (log-rank test p < 0.0001 for both analyses). Compared with patients with a prior PP1M duration of > 360 days, patients with a prior PP1M duration of < 180 days were associated with a greater risk of PP3M treatment discontinuation (p < 0.0001), but increased discontinuation risk was not observed for patients with a prior PP1M duration of 180−360 days (p = 0.8318). Moreover, inadequate initiation with PP3M was also associated with a great risk of PP3M treatment discontinuation. These findings were replicated in the supplementary analysis for the combined PP1M/PP3M retention rate (Fig. 4B, 4C).
Table 3A shows the crude and adjusted relative risks (aRRs) for factors associated with early PP3M discontinuation after the first PP3M dose. Five clinical factors were included in the regression model as factors that differentiated patients who completed the second PP3M from those who did not (Table 4). In the multivariate analysis, prior PP1M treatment durations of < 180 days (aRR, 2.79; 95% CI, 1.57−4.95) or 180−360 days (aRR, 1.76; 95% CI, 1.01−3.07) and concomitant oral antipsychotic use after PP3M initiation (aRR, 1.98; 95% CI, 1.42−2.77) remained significantly associated with PP3M discontinuation (all p < 0.05), whereas adequate PP3M initiation was no longer significant after adjustment for other factors in the model. In the supplementary stepwise regression analysis, only prior PP1M treatment duration (< 180 days, 180−360 days) and concomitant oral antipsychotic use after PP3M initiation were retained in the model (Table 5A).
Table 3.
RRs of factors associated with PP3M discontinuation after the first and second PP3M doses
| Variable | Crude RR (95% CI) | pvalue | Adjusted RR (95% CI) | pvalue |
|---|---|---|---|---|
| A. Outcome: No PP3M claim within 120 days after the first PP3M claim | ||||
| Prior PP1M treatment duration (day) | ||||
| > 360 | Ref. | - | Ref. | - |
| 180−360 | 1.73 (1.00−3.01) | 0.0501 | 1.76 (1.01−3.07) | 0.0476 |
| < 180 | 2.96 (1.76−4.97) | < 0.0001 | 2.79 (1.57−4.95) | 0.0005 |
| Adequate initiation of PP3M | ||||
| Yes | Ref. | - | Ref. | - |
| No | 1.60 (1.16−2.22) | 0.0043 | 1.19 (0.84−1.69) | 0.3336 |
| Concomitant oral antipsychotic use after PP3M initiation | ||||
| No | Ref. | - | Ref. | - |
| Yes | 1.86 (1.34−2.60) | 0.0003 | 1.98 (1.42−2.77) | < 0.0001 |
| Psychiatric hospitalization in the past 2 years | ||||
| 0 | Ref. | - | Ref. | - |
| ≥ 1 | 1.20 (0.86−1.66) | 0.2848 | 0.94 (0.67−1.31) | 0.7006 |
| Initial treatment setting of PP3M | ||||
| Outpatient clinic | Ref. | - | Ref. | - |
| Home visit | 0.65 (0.40−1.04) | 0.0692 | 0.93 (0.57−1.51) | 0.7567 |
| B. Outcome: No PP3M claim within 120 days after the second PP3M claim | ||||
| Prior PP1M treatment duration (day) | ||||
| > 360 | Ref. | - | Ref. | - |
| 180−360 | 1.32 (0.74−2.35) | 0.3479 | 1.20 (0.67−2.14) | 0.5424 |
| < 180 | 1.75 (0.99−3.07) | 0.0528 | 1.11 (0.59−2.09) | 0.7387 |
| Adequate initiation of PP3M | ||||
| Yes | Ref. | - | Ref. | - |
| No | 2.24 (1.47−3.40) | 0.0002 | 2.18 (1.36−3.50) | 0.0013 |
| Psychiatric outpatient visit within 30 days after the first PP3M dose | ||||
| No | Ref. | - | Ref. | - |
| Yes | 0.62 (0.40−0.95) | 0.0272 | 1.61 (1.04−2.50) | 0.0333 |
| Concomitant oral antipsychotic use before PP3M initiation | ||||
| No | Ref. | - | Ref. | - |
| Yes | 1.62 (1.08−2.43) | 0.0196 | 1.31 (0.85−2.02) | 0.2149 |
RR, relative risk; CI, confidence interval; PP1M, paliperidone palmitate 1-monthly; Ref., reference; -, not available.
Table 4.
Comparisons of demographic and clinical characteristics between second PP3M dose completers and non-completers, and third PP3M dose completers and non-completers
| Variable | Having the second PP3M claim within 120 days after the first PP3M claim | pvalue | Having the third PP3M claim within 120 days after the second PP3M claim | pvalue | ||
|---|---|---|---|---|---|---|
|
|
|
|||||
| Yes (n = 826) | No (n = 128) | Yes (n = 745) | No (n = 84) | |||
| Age (yr) | 44.1 ± 11.4 | 43.5 ± 11.3 | 0.8829a | 44.3 ± 11.4 | 43.4 ± 11.6 | 0.8083a |
| Male sex | 411 (49.8) | 67 (52.3) | 0.5949b | 373 (50.1) | 40 (47.6) | 0.6621b |
| Employment status at PP3M initiation | 0.4940b | 0.0753b | ||||
| Wage-based employees | 163 (19.7) | 20 (15.6) | 148 (19.9) | 15 (17.9) | ||
| Self-employees, laborers, farmers, or fishers | 135 (16.3) | 24 (18.8) | 128 (17.2) | 7 (8.3) | ||
| Other status | 528 (63.9) | 84 (65.6) | 469 (63.0) | 62 (73.8) | ||
| Cumulative psychiatric bed days in the past 2 years (day) | 18.9 ± 42.8 | 28.1 ± 55.5 | 0.1443c | 2.6 ± 5.9 | 3.7 ± 7.4 | 0.1474c |
| Psychiatric hospitalization in the past 2 years (time) | 0.8 ± 1.7 | 1.2 ± 2.1 | 0.0965c | 0.8 ± 0.7 | 1.1 ± 2.0 | 0.1014c |
| 0 | 537 (65.0) | 77 (60.2) | 0.0146b | 489 (65.6) | 48 (57.1) | 0.2068b |
| 1−3 | 238 (28.8) | 34 (26.6) | 213 (28.6) | 28 (33.3) | ||
| ≥ 4 | 51 (6.2) | 17 (13.3) | 43 (5.8) | 8 (9.5) | ||
| Initial treatment setting of PP3M | 0.0619b | 0.4252b | ||||
| Outpatient clinic | 651 (78.8) | 110 (85.9) | 584 (78.4) | 69 (82.1) | ||
| Home visit | 175 (21.2) | 18 (14.1) | 161 (21.6) | 15 (17.9) | ||
| Initial dosage of PP3M | 0.2740b | 0.6814b | ||||
| 525 mg eq. | 567 (68.6) | 94 (73.4) | 513 (68.9) | 56 (66.7) | ||
| 350 mg eq. | 259 (31.4) | 34 (26.6) | 232 (31.1) | 28 (33.3) | ||
| Adequate initiation of PP3M | 0.0039 | 0.0002 | ||||
| Yes | 480 (58.1) | 57 (44.5) | 448 (60.1) | 33 (39.3) | ||
| No | 346 (41.9) | 71 (55.5) | 297 (39.9) | 51 (60.7) | ||
| Prior PP1M duration (no gap > 45 days between PP1M doses), day | 244.1 ± 131.5 | 193.3 ± 130.2 | < 0.0001c | 248.0 ± 130.9 | 202.8 ± 133.7 | 0.0013c |
| < 180 | 278 (33.7) | 69 (53.9) | < 0.0001b | 244 (32.8) | 37 (44.0) | 0.0794b |
| 180−360 | 326 (39.5) | 43 (33.6) | 295 (39.6) | 31 (36.9) | ||
| > 360 | 222 (26.9) | 16 (12.5) | 206 (27.7) | 16 (19.0) | ||
| Concomitant oral AP use before PP3M initiation | 268 (32.4) | 50 (39.1) | 0.1395b | 231 (31.0) | 37 (44.0) | 0.0154b |
| Concomitant oral AP use after PP3M initiation | 156 (18.9) | 42 (32.8) | 0.0003b | 146 (19.6) | 21 (25.0) | 0.2419b |
| Visited psychiatric outpatient within 1 month after first dose | 0.7 ± 0.8 | 0.8 ± 1.2 | 0.6156c | 0.7 ± 0.8 | 0.9 ± 0.9 | 0.0193c |
| None (%) | 444 (53.8) | 69 (53.9) | 0.9742b | 392 (52.6) | 55 (65.5) | 0.0250b |
Values are presented as mean ± standard deviation (SD) or number (%).
IQR, interquartile range; mg eq., mg equivalent; PP1M, paliperidone palmitate 1-monthly; AP, antipsychotics.
attest, bchi-square test, cMann–Whitney U test.
Table 5.
RRs of factors associated with PP3M discontinuation after the first and second PP3M dose–stepwise regression results
| Variable | Adjusted RR (95% CI) | pvalue |
|---|---|---|
| A. Outcome: No PP3M claim within 120 days after the first PP3M claim | ||
| Prior PP1M treatment duration | ||
| > 360 days | Ref. | - |
| 180 to < 360 days | 1.94 (1.06−3.56) | 0.0315 |
| < 180 days | 3.70 (2.07−6.59) | < 0.0001 |
| Concomitant oral AP use after PP3M initiation | ||
| No | Ref. | - |
| Yes | 2.25 (1.48−3.42) | 0.0002 |
| B. Outcome: No PP3M claim within 120 days after the second PP3M claim | ||
| Adequate initiation of PP3M | ||
| Yes | Ref. | - |
| No | 2.56 (1.59−4.12) | 0.0001 |
| Psychiatric outpatient visit within 30 days after the first PP3M dose | ||
| No | Ref. | - |
| Yes | 1.93 (1.18−3.15) | 0.0088 |
RR, relative risk; CI, confidence interval; PP1M, paliperidone palmitate 1-monthly; Ref., reference; AP, antipsychotics; -, not available.
Table 3B shows the crude and adjusted RRs for factors associated with early PP3M discontinuation after the second PP3M dose. Four clinical factors were included in the regression model as factors that differentiated patients who completed the third PP3M dose from those who did not (Table 4). In the multivariate analysis, inadequate PP3M initiation (aRR, 2.18) and psychiatric outpatient visits within 30 days after PP3M initiation (aRR, 1.61) remained significantly associated with PP3M discontinuation, whereas prior PP1M treatment duration was no longer significant after adjustment for other factors in the model. In the supplementary stepwise regression analysis, only inadequate PP3M initiation and psychiatric outpatient visits within 30 days were retained in the model (Table 5B).
Association between PP3M Treatment Retention and Psychiatric Hospitalization
Figure 5A shows the Kaplan-Meier probabilities for psychiatric hospitalization-free status in the overall PP3M cohort. The probability was 87.3% after 6 months, 81.7% after 12 months, and 78.6% after 24 months.
Fig. 5.
Kaplan–Meier probability analysis of psychiatric hospitalization. (A) Overall cohort. (B) By prior PP1M duration. (C) By adequate initiation of PP3M. (D) By PP3M adherent status.
PP1M, paliperidone palmitate 1-monthly.
Figure 5A-5D shows the Kaplan–Meier probabilities for psychiatric hospitalization-free status stratified by prior PP1M treatment duration, the use of adequate PP3M initiation and the PP3M adherence status in the first year, respectively. Compared with patients with a prior PP1M duration of > 360 days or 180−360 days, patients with a prior PP1M duration of < 180 days had a lower probability of being free from psychiatric hospitalization (log-rank test p < 0.0001 for both analyses). Patients with a prior PP1M duration of > 360 days or 180−360 days had a similar probability of psychiatric hospitalization (p = 0.3425). Moreover, patients with inadequate initiation of PP3M had a lower probability of being free from psychiatric hospitalization compared with patients with adequate initiation of PP3M (p < 0.0001).
Compared with patients who were fully adherent to PP3M in the first year, patients partially adherent or non-adherent to PP3M had a lower probability of being free from psychiatric hospitalization (p < 0.0001 for both analysis). Patients partially adherent or non-adherent to PP3M had a similar probability of psychiatric hospitalization (p = 0.1955). In patients who were fully adherent to PP3M treatment in the first year, the probability of psychiatric hospitalization-free status was 96.3% after 6 months, 89.8% after 12 months, and 86.7% after 24 months.
DISCUSSION
This population-based cohort study examined PP3M treatment retention and associated factors among patients with schizophrenia. The cohort exclusion criteria were minimized in this study to reflect real-world LAI treatment practices. A high treatment retention rate was observed for the first 2 years of PP3M treatment. A smooth transition from the first to the second dose of PP3M appears to be crucial for future treatment retention, as the largest loss in PP3M treatment retention was observed between the first and second PP3M dose. Both prior PP1M treatment duration and adequate PP3M initiation were significantly associated with PP3M treatment retention, but prior PP1M treatment duration was more strongly associated with PP3M treatment retention at the second dose, whereas adequate PP3M initiation was more strongly associated with PP3M treatment retention at the third dose. These findings may have important clinical implications for clinicians who aim to optimize PP3M patient selection and treatment strategies. Moreover, the association between the PP3M treatment retention status in the first year and the psychiatric hospitalization-free status also highlights the importance for clinicians to ensure LAI antipsychotic treatment retention to further prevent disease relapse.
Some studies have reported PP3M treatment retention rates at the population level, but few have reported retention rates beyond the first year of treatment or examined factors associated with treatment retention. In a large, retrospective claims database study in the US (n = 1,565), approximately 85% of individuals who completed the first PP3M dose and 87% of those who completed the second dose received their next dose [20]. A similar treatment retention rate was reported in smaller studies analyzing US veterans or Medicaid beneficiaries with schizophrenia who completed their first or second PP3M dose [21,22]. However, these studies did not examine factors associated with PP3M treatment retention. More recently, a retrospective, population-based cohort study in Spain reported treatment persistence (defined as the time until treatment discontinuation and transition to new treatment) and other clinical outcomes among patients with schizophrenia initiated on PP3M, which showed that PP3M treatment persistence was 86.5% after 18 months of PP3M treatment and did not differ according to age (> 40 years vs. ≤ 40 years) [23].
The optimal timing of transitioning patients from PP1M to PP3M is a clinically important issue. Some clinicians wonder whether switching to PP3M within the first year of PP1M treatment may reduce clinician–patient contacts and lead to increased treatment discontinuation and prefer to transition patients to PP3M after a prolonged PP1M treatment duration. Surprisingly, no empirical study has ad-dressed this issue to date. Our study suggested that a prior PP1M treatment duration of 180−360 days (vs. > 360 days) was associated with a higher risk of PP3M treatment discontinuation after the first dose but not after later doses. Minimal differences were observed for the Kaplan–Meier probabilities of combined PP1M/PP3M treatment retention at the time of the second PP3M dose among patients with PP1M durations > 180 days (Fig. 4B). There-fore, switching to PP3M should be considered for patients who have received PP1M treatment for 6−12 months as a potential strategy for improving long-term LAI treatment adherence.
Other lines of evidence support the initiation of PP3M within 6−12 months of PP1M treatment. First, from a pharmacokinetic perspective, 4 months of adequate PP1M treatment is sufficient for PP3M treatment initiation, forming the basis for global PP3M labeling recommen-dations. Second, adequate symptom stabilization prior to transitioning to PP3M is a key factor in ensuring a successful transition from PP1M to PP3M [24], and evidence suggests that continuous PP1M treatment beyond 6 months is not associated with additional symptom improvement [25]. Last, the treatment attrition rate for PP1M should also be considered. In Taiwan, a high PP1M attrition rate was observed during the first year in our supplementary analysis (64%, data not shown), similar to the findings of other national cohorts [12,13]. Therefore, a more aggres-sive PP3M treatment initiation strategy in accordance with the labeling recommendations is likely to benefit a substantial proportion of patients on PP1M treatment.
As expected, adequate PP3M initiation is associated with improved treatment retention. Surprisingly, no empirical study has ever addressed the clinical importance of adequate treatment initiation. In our study, after adjusting for prior PP1M treatment duration and other confounders, adequate PP3M initiation was associated with PP3M treatment retention after the second dose but not after the first dose. The positive influence of adequate PP3M initiation on treatment retention may not be immediately evident but becomes evident with a longer treatment duration. Confounding due to indication may affect some patients with inadequate PP3M initiation, as PP3M may be selected for patients with a history of poor adherence or high inpatient service utilization without ensuring proper initiation.
In our analysis, no significant associations with PP3M treatment retention were observed for age, sex, employment status, clinical setting, PP3M dosage, concomitant antipsychotic use before PP3M initiation, or history of psychiatric hospitalization. A prior population-based study in Spain also found that age was not associated with PP3M treatment persistence [23]. However, a UK study reported that female sex and younger age were associated with PP3M discontinuation [19]. In our cohort, female patients were well represented, which added to the strength of our findings, and sex was not identified as a significant factor associated with PP1M treatment retention in our supplementary analysis (data not shown).
Concomitant oral antipsychotic use and psychiatric outpatient visits after PP3M initiation were associated with reduced PP3M retention rates after the first and second doses, respectively. These factors may reflect clinical instability after PP3M initiation, increasing the subsequent risk of PP3M discontinuation.
In our study, a high proportion of PP3M-treated patients remained free of psychiatric hospitalization, especially among patients with a prior PP1M treatment duration of > 180 days, with adequate initiation of PP3M, or who were fully adherent to PP3M treatment in the first year. In general, our finding is consistent with other recently published observational studies, which demonstrate the high clinical effectiveness of PP3M in the real-world clinical practice setting [23,26]. In the UK, Taylor and colleagues reported the 2-year clinical outcomes of 111 non-elderly patients with schizophrenia treated with PP3M in the South London and the Maudsley NHS Foundation Trust. The mean duration of prior PP1M treatment in their cohort was 33.6 months, and 7% of the patients experienced relapses (defined as a step-up in clinical care) while on PP3M treatment [26]. In our study, a nationally representative patient cohort was analyzed, and the mean duration of prior PP1M treatment was much shorter (8 months). The outcome definition was different. Moreover, patients who discontinued PP3M treatment were not censored in our Kaplan-Meier analyses. These factors might account for the slight difference in the reported outcomes between our study and theirs. In another retrospective, population-based observational study conducted in Spain, the comparative clinical outcomes of patients treated with second-generation LAIs were reported. In their PP3M cohort, the Kaplan-Meier probability of patients free from psychiatric hospitalization was 92.0% at 12 months and 88.4% at 18 months [23]. Compared with their finding, a numerically higher probability of psychiatric hospitalization was observed in our PP3M cohort, which might be due to the high service accessibility and utilization of inpatient psychiatric service in Taiwan under the universal health insurance coverage [27].
To our knowledge, this study is the first study to examine factors associated with PP3M treatment retention based on a nationally representative sample. However, our study also has several limitations. First, the reasons for PP3M discontinuation were not available in the claim records. In other PP3M cohorts, patient refusal rather than side effects was the most common reason for treatment discontinuation [19,28]. Second, some clinical factors known to be associated with LAI treatment retention, such as clinical disease severity and disease insight, were also not available from the claim records [24]. Third, LAI treatment retention is affected by the mental health care system infrastructure, limiting the generalizability of our study findings to other health care systems. Despite these limitations, we feel that the whole population-based analysis and real-world nature of our data add to the overall strengths of our study findings.
In conclusion, our study demonstrates a high PP3M treatment retention rate in Taiwan’s health care setting during the first 2 years of treatment. Prior PP1M treatment duration and adequate PP3M initiation are major factors affecting PP3M treatment retention. Patients with a prior PP1M duration of 180−360 days can benefit from PP3M treatment at a similar rate as patients with a prior PP1M duration of > 360 days, although additional attention and intervention may remain necessary to ensure treatment retention between the first and second dose. Favor-able treatment retention of PP3M in the first year is associated with a higher chance for patients to be able to be free from psychiatric hospitalization - an important step toward disease remission and recovery.
Acknowledgements
This study was performed using data from the Health and Welfare Data Science Center, Ministry of Health and Welfare, Taiwan. The interpretations and conclusions contained herein do not represent those of the Health and Welfare Data Science Center, Ministry of Health and Welfare, Taiwan.
Funding Statement
Funding This study was supported by Johnson & Johnson, Taiwan, Ltd. The funding body played no role in the study design or data analysis and interpretation in this paper.
Footnotes
Conflicts of Interest
Chih-Lin Chiang was employed at Johnson & Johnson, Taiwan, Ltd during the conduct of the study and is currently employed at Janssen, Japan. Yi-Wen Chen is employed at Johnson & Johnson, Taiwan, Ltd. Yan-Fang Liu is employed at Janssen, USA. Other authors declare no conflicts of interest.
Author Contributions
Conceptualization: Chien-Heng Lin, Huang-Li Lin, Chih-Lin Chiang, Yi-Wen Chen, Yan-Fang Liu, Yen- Kuang Yang, Chao-Hsiun Tang. Data acquisition: Chien- Heng Lin, Huang-Li Lin, Chih-Lin Chiang, Yi-Wen Chen, Chao-Hsiun Tang. Formal analysis: Chih-Lin Chiang, Yi- Wen Chen, Chao-Hsiun Tang. Funding: Chih-Lin Chiang, Yi-Wen Chen. Project administration: Chih-Lin Chiang, Yi-Wen Chen. Data visualization: Chih-Lin Chiang, Yi-Wen Chen. Supervision: Yan-Fang Liu, Yen-Kuang Yang, Chao-Hsiun Tang. Validation: Chao-Hsiun Tang. Writing—original draft: Chien-Heng Lin, Huang-Li Lin, Chih-Lin Chiang, Yi-Wen Chen. Writing—review & editing: Yan-Fang Liu, Yen-Kuang Yang, Chao-Hsiun Tang.
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