Abstract
Background
Pharmacological management of subjects with Parkinson's disease (PD) is complex. Regardless of drug selection, adherence is one of the main concerns. Nonadherence is associated with poor symptomatic control and low quality of life. In general, adherence to once‐a‐day formulations is thought to be better in comparison to 3‐times‐daily dosing.
Methods
A cross‐sectional study was carried out. Consecutive uninsured subjects diagnosed with PD were treated either with an immediate‐ or extended‐release dopamine agonist formulation. Clinical and demographic data were collected. Subjects were assessed using the International Parkinson and Movement Disorder Society UPDRS. Adherence was evaluated using the Morisky‐Green test (MGT).
Results
A total of 314 (175 males and 139 females) subjects with PD were included. In regard to treatment, 188 (59.9%) were on an immediate‐release dopamine agonist and 126 (40.1%) on an extended‐release dopamine agonist. According to the MGT, 21 (6.7%) subjects were classified as nonadherent, 273 (86.9%) with a low adherence, and only 20 (6.4%) were considered with high adherence. Dopamine agonist levodopa equivalent daily dose was higher in the extended‐release group (296.6 ± 112.4 vs. 231.3 ± 133.4; P = 0.011); also, these subjects had more years of formal education (12.3 ± 5.2 vs. 9.5 ± 5.2; P = 0.630). No difference in adherence levels was found (P = 0.802) between subjects treated with an immediate‐release dopamine agonist and those receiving an extended‐release formulation.
Conclusions
Overall adherence in subjects with PD is low. Use of an extended‐release over an immediate‐release dopamine agonist formulation in this study population is not associated with a better adherence.
Keywords: Parkinson's disease, adherence, dopamine agonist, immediate‐release, extended‐release
Parkinson's disease (PD) is one of the most frequent neurodegenerative diseases, with an estimated prevalence of 2% of adults over age 60.1 Treatment of PD is symptomatic, mostly focused on the motor symptoms.
Optimum medication management typically allows subjects diagnosed with PD to remain active in most aspects of their lives. On the other hand, the natural progression of PD is accompanied by reduced drug efficacy and greater disability later in the course of the disease.
Pharmacological management of PD is complex. Several treatment strategies are available, but, regardless of the initial pharmacotherapy, adherence is one of the main concerns. Lack of adherence is associated with poor motor symptoms control, low quality of life, motor fluctuations, and dyskinesias.2
Levodopa and dopamine agonists (DAs) are arguably the best antiparkinsonian drugs for the treatment of motor symptoms. The principal advantage of DA extended‐release (ER) formulations over l‐dopa is the longer duration of their effect. The half‐life of l‐dopa is approximately 90 min; drug formulations such as pramipexole ER and rotigotine transdermal patch provide continuous delivery of drug over 24 hr.3 As a consequence, a better adherence might be expected in subjects with PD treated with a once‐a‐day dose ER DA in comparison with subjects on a 3‐times‐a‐day immediate‐release (IR) DA.
The aim of the present study was to compare the drug adherence in subjects with PD treated with an IR DA agonist versus an ER formulation.
Methods
A cross‐sectional study was carried out at the National Institute of Neurology and Neurosurgery in Mexico City. The Institute is a tertiary referral center for a population without social health insurance coverage. Consecutive subjects who fulfilled the UK Brain Bank Criteria for PD were included.4 Only subjects who were on treatment with DA, either as mono‐ or polytherapy, were included. The study was approved by both the local investigation committee and by the ethics committee. All patients signed a written informed consent.
Clinical and demographic data regarding gender, age, employment status, current comorbidities (diabetes mellitus [DM], hypertension [HTN], and dyslipidemia), age at motor symptoms onset, and current treatment and dose were collected. Socioeconomic status (SES) was determined by a standardized evaluation performed by a social worker (being 1 the lowest and 6 the highest level).5 l‐dopa equivalent daily dose (LEDD) and dopamine agonist LEDD (DA‐LEDD) were calculated, as published elsewhere.6
All subjects were evaluated by a neurologist with expertise in movement disorders using the Spanish version of the MDS‐UPDRS.7 Subjects were classified as fluctuators or nonfluctuators based on the MDS‐UPDRS part IV item 4.3 (time spent in the off state) and item 4.4 (functional impact of motor fluctuations).
Adherence to DA was assessed using the Morisky‐Green test (MGT). The MGT is a short questionnaire that has been validated for its use in several chronic diseases.8 The MGT has a high specificity, high positive predictive value, and low sociocultural‐level requirements for comprehension. The MGT has the following 4 questions: (1) Do you ever forget to take your medicine?; (2) Are you careless at times about taking your medicine?; (3) When you feel better, do you sometimes stop taking the medicine?; and (4) Sometimes if you feel worse when you take the medicine, do you stop taking it? Each question is scored in a dichotomous manner (1 = yes, 0 = no).
Adherence to treatment is considered when the response to all 4 questions is negative. On the other hand, nonadherence is considered when any of the responses are positive. Additionally, adherence was classified as: high adherence (0 points); low adherence (1–2 points); and nonadherence (3–4 points).
Statistical Analysis
Demographic data were reported in terms of percentages, mean, and standard deviation. Comparison of quantitative variables between 2 groups (adherers vs. nonadherers) was performed using the independent Student t test. For multiple group analysis (levels of adherence), a one‐way analysis of variance (ANOVA) test was used for continuous variables. After ANOVA analysis, Tukey's honestly significant difference post‐hoc test was performed. Differences in proportions of categorical variables were analyzed by chi‐square test. When data were ordinal or did not fit normal distribution, nonparametric statistics were used. A significance level of <0.05 was used throughout. All statistical analyses of data were performed with SPSS software (version 17; SPSS, Inc., Chicago, IL).
Results
A total of 314 (175 males and 139 females) consecutive subjects with PD treated with a DA were included. Sociodemographic characteristics of the study sample are summarized in the Table 1. In regard to motor phenotype, a tremor‐dominant form of PD was present in 56.4% of the subjects, whereas rigid‐akinetic phenotype was present in 36.6%. Regarding antiparkinsonian treatment, 47 (15%) subjects were on monotherapy with a DA (55.4% on pramipexole IR, 34% on pramipexole ER, and 10.6% on rotigotine). A total of 222 (70.7%) subjects were on polytherapy with l‐dopa and a DA (59.1% on pramipexole IR, 21.5% on pramipexole ER, and 19.4% on rotigotine). Finally, a total of 15 subjects (4.8%) were treated with a DA and a monoamine oxidase (MAO) inhibitor, and 30 (9.5%) were receiving l‐dopa and a MAO inhibitor along with the DA. The median of different antiparkinsonian drugs per subject was 2 (range, 1–3). A total of 166 (52.8%) subjects had motor fluctuations according to the MDS‐UPDRS part IV.
Table 1.
Demographic and clinical characteristics of subjects with PD
| Variable | |
|---|---|
| Gender (%) | Male (55.7)/female (44.3) |
| Age, yr | 60.7 ± 10.8 |
| Disease duration, years | 9.4 ± 6.1 |
| Years of schooling | 10.6 ± 5.6 |
| Currently employed (%) | 100 (31.8) |
| Frequency of dyslipidemia (%) | 63 (20.1) |
| Frequency of DM type 2 (%) | 52 (16.6) |
| Frequency of HTN (%) | 102 (32.8) |
| Disease severity according to H & Y (%) | |
| Mild (H & Y 1–2) | 192 (61.1) |
| Moderate (H & Y 3) | 97 (30.9) |
| Severe (H & Y 4–5) | 25 (8.0) |
| MDS‐UPDRS evaluation | |
| Part 1 | 10.4 ± 6.7 |
| Part 2 | 14.3 ± 10.3 |
| Part 3 | 27.9 ± 17.6 |
| Part 4 | 3.4 ± 4.3 |
| Total score | 56.1 ± 31.9 |
Overall, the LEDD was 781.5 ± 436 mg, whereas the DA‐LEDD was 246.6 ± 126.6 mg.
When comparing subjects on an IR DA with those receiving an ER DA, the former had a lower disease severity. No differences were found in SES between groups (mean social work level: 2 ± 0.81). Regarding treatment, subjects treated with an ER DA had a higher DA‐LEDD. The comparison between subjects on an IR or ER DA is shown in Table 2.
Table 2.
Correlation between IR and ER DA and demographic factors
| IR DA (n = 188) | ER DA (n = 126) | P value | |
|---|---|---|---|
| Age, yr | 60.2 ± 11.6 | 61.4 ± 9.6 | 0.349 |
| Female gender (%) | 77 (41) | 62 (49.2) | 0.149 |
| Currently employed (%) | 54 (28.7) | 46 (36.5) | 0.195 |
| Years of schooling | 9.5 ± 5.2 | 12.3 ± 5.7 | <0.001 |
| Disease duration, years | 9.3 ± 5.3 | 9.6 ± 7 | 0.630 |
| Disease severity (%) | |||
| Mild | 106 (56.3) | 86 (68.2) | 0.045 |
| Moderate | 71 (37.8) | 26 (20.7) | 0.002 |
| Severe | 11 (5.9) | 14 (11.1) | 0.139 |
| MDS‐UPDRS score | 57.8 ± 31.1 | 53.5 ± 33.1 | 0.245 |
| DA monotherapy (%) | 33 (17.5) | 29 (23) | 0.233 |
| LEDD (mg) | 794.9 ± 414.9 | 761.5 ± 466.9 | 0.517 |
| DA‐LEDD (mg) | 231.3 ± 133.4 | 296.6 ± 112.4 | 0.011 |
Overall adherence using the MGT was 6.4% (n = 20). When adherence was categorized; 21 (6.7%) subjects were classified as nonadherent, 273 (86.9%) with a low adherence, and only 20 (6.4%) were considered with high adherence.
Subjects with no adherence were younger than those with a low adherence (53.8 ± 11.9 vs. 61.2 ± 10.7 yr; P = 0.009, respectively). Also, the presence of other comorbidities was associated with low or no adherence (P = 0.023).
No association between levels of adherence and gender (P = 0.135), employment status (P = 0.228), years of schooling (P = 0.654), number of comorbidities (P = 0.233), disease duration (P = 0.705), presence of motor fluctuations (P = 0.82), current use of l‐dopa (P = 0.105), MDS‐UPDRS total score (P = 0.245), LEDD (P = 0.517), or DA‐LEDD (P = 0.011) were found.
When comparing adherence between subjects with an IR versus ER DA, no differences were found (P = 0.802). Comparisons of DA formulation, dose, and drug scheme across different levels of adherence are shown in Table 3.
Table 3.
Comparison of DA formulations, drug scheme, and dosing of across different levels of adherence
| Nonadherence | Low adherence | High adherence | P value | |
|---|---|---|---|---|
| Drug scheme | ||||
| DA monotherapy (%) | 3 (14.28) | 38 (13.92) | 6 (30) | 0.150 |
| DA/LD (%) | 12 (57.16) | 198 (72.53) | 12 (60) | 0.181 |
| DA/MAOi (%) | 3 (14.28) | 11 (4.03) | 1 (5) | 0.104 |
| DA/LD/MAOi (%) | 3 (14.28) | 26 (9.52) | 1 (5) | 0.600 |
| Number of antiparkinsonian (median, range) | 2 (1–3) | 2 (1–3) | 2 (1–3) | 0.701 |
| DA formulation (%) | ||||
| IR (n = 188) | 14 (7.4) | 162 (86.2) | 12 (6.4) | 0.802 |
| ER (n = 126) | 7 (5.6) | 111 (88) | 8 (6.4) | |
| DA (%) | ||||
| Pramipexole IR (n = 188) | 14 (7.4) | 162 (86.2) | 12 (6.4) | |
| Pramipexole ER (n = 73) | 4 (5.5) | 63 (86.3) | 6 (8.2) | 0.835 |
| Rotigotine (n = 53) | 3 (5.7) | 48 (90.6) | 2 (3.7) | |
| Dopamine dosage | ||||
| LEDD | 805.2 ± 451.7 | 787.9 ± 436.7 | 669.4 ± 415.3 | 0.497 |
| DA‐LEDD | 250.6 ± 126.6 | 245.5 ± 127.7 | 257.6 ± 132.7 | 0.920 |
LD, levodopa; MAOi, MAO inhibitor.
Discussion
Adherence is one of the most important issues regarding treatment of chronic and progressive diseases. In PD, managing and controlling motor and nonmotor symptoms is the main therapeutic goal of current treatment strategies. Lack of adherence to antiparkisonian drugs may result in switching between several drugs without achieving a proper response. Davis et al. have demonstrated a difference in medical costs associated with adherence ranging from $9228 USD in the adherers to $15 826 USD in the nonadherers.9
Nevertheless, adherence in PD is usually not adequate. Marchi et al. reported nonadherence in 52.7% of their study sample.10 Conversely, Wei et al. reported that only 25% of 7583 patients with PD had a low adherence.11
In general, adherence to once‐a‐day medications is thought to be better in comparison to several takes a day.12 Schapira et al. surveyed patients receiving either IR or ER pramipexole and found that 94% of subjects with early PD and 89% with advanced PD had a strong preference for once‐a‐day rather than 3 times a day.13 Nevertheless, our study failed to show any differences in adherence between subjects on DA therapy with IR versus ER formulations.
In the present study, a high proportion of subjects were nonadherent to antiparkinsonian therapy. When categorizing adherence, 87% of our sample had a low adherence. A previous study by our group reported an adherence of only 35.9% in a small sample of 64 Mexican subjects with PD. In that study, the main factors associated with nonadherence were current age and employment.14 Other known factors associated with nonadherence in PD include cognitive impairment, failure to control motor symptoms, poor quality of life, and younger age.15 Conversely, the ADHESION study reported that high adherence is associated with a greater knowledge of the disease, married status, and higher income.16
In the present study, no association between current employment status was found, although younger age remained a risk factor for nonadherence. MDS‐UPDRS was also similar between ER and IR groups, as well as between levels of adherence groups.
It should be emphasized that our study population did not have social or private insurance coverage. Therefore, patients had to pay for their prescription drugs. It should also be highlighted that by the time the study was carried out, there was no generic pramipexole available in Mexico.
Polytherapy is one of the main factors known to have a negative impact on adherence. The complexity of a drug regimen is inversely related to compliance not only in PD, but also in other medical conditions.17 Moreover, it has been estimated that more than half of the subjects with PD are treated with l‐dopa plus another drug, resulting in up to 4 or 5 drug takes in the day.18 In our study sample, polytherapy was not associated with drug adherence. Also, no difference in the frequency of polytherapy was found between subjects on an ER or IR DA. Nevertheless, it should be noticed that the monotherpy subgroup was relatively small (around 20% of the sample) and might be underpowered to allow proper conclusions on this matter.
On the other hand, the presence of a chronic comorbidity had a negative impact on antiparkisonian drug adherence; this may be related to a greater number of drugs taken.
LEDD has also been associated with poor adherence. It has been reported that adherence is inversely proportional to the daily dose; for every 100‐mg increase in l‐dopa dose, the risk of adherence failure is increased by 1.86 times.19 In our study, no association of LEDD or DA‐LEDD with adherence was found. Similar to polytherapy, both the ER and IR DA group had similar LEDD. It should be highlighted that DA‐LEDD was higher in the ER group; also, these subjects had more years of formal education. Given that all subjects had a similar SES, differences in monetary income cannot be accounted as the cause of this difference. Further prospective studies addressing these associations are needed to rule out chance or confounding. In addition, subjects with a moderate disease severity (H & Y 3) used more frequently an ER formulation. Nevertheless, as mentioned before, there was no difference in drug adherence.
The present study has several limitations. First, our study sample was hospital instead of population based. Likewise, the hospital is a tertiary center prone to referral bias. Subjects included had a low SES and no social health security benefits; consequently, it is more likely that they have difficulties buying their antiparkinsonian drugs. Generalization of our results to other populations with a higher income or social health security is not possible. Second, the possibility that participants had been switched from 1 formulation to another before the cross‐sectional evaluation was performed was not addressed in the study design. Consequently, we cannot rule out this possibility, which can lead to bias.
Another drawback is the fact that quality of life or clinical global impression were not assessed in our study.
For future research, we suggest including a more heterogeneous population in terms of SES, as well as subjects with health insurance benefits. Outcomes such as health‐related quality of life, clinical global impression, and caregiver burden will be of great value to fully understand the consequences of drug adherence. Finally, cost‐utility and cost‐benefit analyses are needed.
In conclusion, PD subjects without health insurance showed a low adherence to antiparkinsonian treatment. No difference in adherence was found between subjects treated with an ER or IR DA. Overall, a younger age and presence of comorbidities were the only factors associated with poor adherence, but they appear to be independent of the DA formulation.
Author Roles
(1) Research Project: A. Conception, B. Organization, C. Execution; (2) Statistical Analysis: A. Design, B. Execution, C. Review and Critique; (3) Manuscript Preparation: A. Writing of the First Draft, B. Review and Critique.
L.B.‐R.: 1A, 1B, 2B, 2C, 3A, 3B
A.C.‐A.: 1A, 1B, 2B, 2C, 3A, 3B
R.L.‐A.: 1C, 3B
H.C.‐F.: 1C, 3B
M.R.‐V.: 1A, 1B, 3A, 3B
Disclosures
Funding Sources and Conflicts of Interest: The authors report no sources of funding and no conflicts of interest.
Financial Disclosures for previous 12 months: A.C.‐A. has received travel grant support from Boehringer Ingelheim and UCB. M.R.‐V. has received honoraria from UCB, Boehringer Ingelheim, Teva, Vanquish, Ever Pharma, Novartis, Medtronic, and the MDS. R.L.‐A. became medical science liaison for UCB Mexico in March 2015.
Relevant disclosures and conflicts of interest are listed at the end of this article.
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