Introduction
Parkinson’s disease (PD) is the fastest growing neurological disorder in the world [1]; it mostly affects people between 85 to 89 years old and is expected to impose an increasing socio-economic burden on aging societies [2-5]. PD is characterised by progressive degeneration of nigrostriatal dopamine neurons and depletion of dopamine in the dorsal striatum, giving rise to characteristic motor and non-motor symptoms [2,6].
Current PD medications help to ameliorate disease-associated motor deficits by increasing dopaminergic activity within the dorsal striatum [7,8]. The dopamine precursor, levodopa, forms the cornerstone of PD therapy due to its efficacy and tolerability in the early stages of the disease. However, levodopa levels in the brain will start to increasingly fluctuate, alternating re-emergence of symptoms (wearing off) with peak-dose dyskinesias associated with higher levodopa concentrations [7-10]. This situation worsens progressively with time [7,11-13]. Although adjunct therapies are available to overcome fluctuations, optimal management of PD remains an unmet need [7,14].
Safinamide is a levodopa add-on therapy that has proven efficacy in controlling PD-related motor fluctuations [14-17]. It exerts a unique dual mechanism of action, comprising selective and reversible inhibition of MAO-B and reduction of overactive glutamatergic transmission, which represent a major clinical advantage that may play a role in alleviating motor fluctuations and improving levodopa-induced dyskinesias [7,16,18-24]. A group of Spanish experts reached consensus on the benefits associated with safinamide when treating PD patients with mild to moderate, and even advanced, fluctuations [25]. Following the recommendation of the European Medicines Agency (EMA) on collecting supportive real-world data (RWD) [26], an observational drug utilisation study called SYNAPSES (StudY to observe safiNAmide safety profile and pattern of use in clinical Practice during the firSt post-commErcialization phaSe) was conducted to describe treatment patterns and the occurrence of adverse events (AEs) in PD patients treated with safinamide in real-life conditions, including special patient segments—patients over 75 years of age, with relevant comorbidities, or with concomitant psychiatric conditions [27].
Primary and secondary objectives of the present post-hoc analysis were to analyse the safety profile of safinamide within the Spanish study population compared to the European dataset, and to address if treatment with safinamide may improve motor complications in specific subgroups of patients, respectively. In addition, the longitudinal evolution of different motor fluctuations was analysed.
Patients and methods
Study design
The current report is a post-hoc analysis of the Spanish study participants of SYNAPSES (EU PAS Register Number EUPAS-13745), an observational, multinational, multicentre, retrospective-prospective cohort study where patients with confirmed diagnosis of idiopathic PD were followed for 12 months after the start of safinamide treatment (baseline) [27]. The study was approved by and compliant with local and European regulatory and institutional authorities (see parent report).
The study protocol is described in detail in the parent study report [27]. Briefly, 511 of 532 Spanish patients from 38 neurology and geriatric centres specialised in PD therapy were included in the final evaluation, after meeting the established inclusion criteria (see parent report). Eligible patients were enrolled in a consecutive order over 24 months without randomization [27]. The decision of starting the treatment with safinamide was made solely based on clinical evaluation and had to be taken before the patient’s inclusion in the study.
The patients were evaluated at baseline, and four (±1), eight (±1), and 12 (±1) months after [27]. Data collection was performed prospectively or retrospectively depending on the time of enrolment.
Measurements
The concomitant relevant comorbidities as well as the severity of AEs and their relationship with safinamide treatment were determined based on the investigators’ clinical judgement. The Unified Parkinson’s Disease Rating Scale [28] total score and UPDRS part III score during on time were used to gauge the overall severity of PD and motor complications, respectively, in safinamide treated patients at baseline and during each follow-up visit. Specific subgroups were also analysed—patients who were previously treated with rasagiline, high doses of levodopa or had safinamide as the only add-on therapy at the start of the observation period. For each patient, the total levodopa equivalent daily dose (LEDD) at baseline was calculated as the sum of levodopa equivalent doses (LED) in all ongoing medications following the calculation of LEDs according to predefined conversion factors (Table I) [29].
Table I. Conversion factors for calculating L-DOPA equivalent doses (LED) for commonly used PD medications [29].
|
| |
Conversion factor
|
Duodopa
|
DD × 1.11
|
Duodopa (L-DOPA/Carbidopa gel)
|
DD × 1.11
|
L-DOPA/Carbidopa retard
|
DD × 0.5
|
Madopar® retard
|
DD × 0.5
|
Sinemet® Plus retard
|
DD × 0.5
|
Sinemet® retard
|
DD × 0.5
|
L-DOPA/Carbidopa
|
DD × 1
|
Madopar®
|
DD × 1
|
Sinemet®
|
DD × 1
|
Stalevo®
|
DD × 1
|
DD: Daily dose of a L-DOPA containing medication.
|
Statistical methods
Due to the observational nature of this real-world data study, our aim was to purely get insights into the everyday clinical use of safinamide and not to seek statistical significances between different conditions. For information regarding statistical analyses in SYNAPSES, please refer to the parent report [
27]. Patients with missing values were not excluded from the analysis, nor were their data replaced. Categorical variables are described by absolute and relative frequencies while continuous and discrete variables are expressed as means and standard deviations.
Results
Spanish and European data
Patient profile comparison
The demographic data of the parent study SYNAPSES (European data) [
27] and the present Spanish
post-hoc analysis (Spanish data) appear closely analogous as expected (Table II). However, we observed certain small but meaningful differences between the two patient populations that may have further implications. Patients with atypical parkinsonism diagnosis were treated slightly more often with safinamide among the Spanish study population (1.8%) when compared to the European population (0.8%). In addition, we observed a tendency in prescribing safinamide to less advanced PD patients in Spain. A higher proportion of the Spanish study participants were on Hoehn & Yahr stages 1 and 2 (66.2%) at baseline, whereas the corresponding proportion of the European patients was 56.2%.
Table II. Demographic data. Comparison of patient profiles in the parent study SYNAPSES (Europe) and the post-hoc analysis of the Spanish study population (Spain).
|
| |
Total number of evaluable patients
|
Patients aged >75 years
|
Patients with relevant comorbidities
|
Patients with psychiatric conditions
|
|
Spain
n = 511
(100%)
|
Europe
n = 1558
(100%)
|
Spain
n = 131
(25.6%)
|
Europe
n = 391
(25.1%)
|
Spain
n = 373
(73.0%)
|
Europe
n = 1103
(70.8%)
|
Spain
n = 249
(48.7%)
|
Europe
n = 661
(42.4%)
|
Sex (n, %)
|
Male
|
289 (56.6%)
|
961 (61.7%)
|
59 (45.0%)
|
221 (56.5%)
|
200 (53.6%)
|
665 (60.3%)
|
119 (47.8%)
|
356 (53.9%)
|
| |
Female
|
222 (43.4%)
|
597 (38.3%)
|
72 (55.0%)
|
170 (43.5%)
|
173 (46.4%)
|
438 (39.7%)
|
130 (52.2%)
|
305 (46.1%)
|
Age at enrollment (years: mean ± SD)
|
|
68 ± 10.3
|
68.4 ± 9.7
|
79.9 ± 3.0
|
79.7 ± 3.1
|
70 ± 9.1
|
70.0 ± 8.7
|
68.7 ± 9.9
|
68.3 ± 9.4
|
Race
(n, %)
|
Caucasian
|
507 (99.2%)
|
1543 (99.0%)
|
131 (100%)
|
389 (99.5%)
|
369 (98.9%)
|
1094 (99.2%)
|
247 (99.2%)
|
658 (99.5%)
|
Other
|
4 (0.8%)
|
15 (1.0%)
|
0 (0.0%)
|
2 (0.5%)
|
4 (1.1%)
|
9 (0.8%)
|
2 (0.8%)
|
3 (0.5%)
|
Diagnosis
(n, %)
|
Idiopathic PD
|
500 (97.8%)
|
1542 (99.0%)
|
129 (98.5%)
|
389 (99.5%)
|
367 (98.4%)
|
1094 (99.2%)
|
243 (97.6%)
|
653 (98.8%)
|
Atypical Parkinsonism
|
9 (1.8%)
|
12 (0.8%)
|
2 (1.5%)
|
2 (0.5%)
|
5 (1.3%)
|
7 (0.6%)
|
5 (2.0%)
|
6 (0.9%)
|
Juvenile PD
|
2 (0.4%)
|
4 (0.3%)
|
0 (0.0%)
|
0 (0.0%)
|
1 (0.3%)
|
2 (0.2%)
|
1 (0.4%)
|
2 (0.3%)
|
Time from diagnosis
(years: mean ± SD)
|
|
8.1 ± 5.6
|
7.9 ± 5.3
|
8.1 ± 5.2
|
7.9 ± 5.3
|
8.0 ± 5.5
|
7.8 ± 5.3
|
8.9 ± 6.1
|
8.4 ± 5.5
|
Time from onset of symptoms
(years: mean ± SD)
|
|
8.9 ± 5.5
|
8.8 ± 5.5
|
8.8 ± 4.9
|
8.9 ± 5.5
|
8.8 ± 5.3
|
8.7 ± 5.4
|
9.5 ± 6.1
|
9.3 ± 5.5
|
Age at onset of symptoms
(years: mean ± SD)
|
|
58.6 ± 11.5
|
59.3 ± 11.0
|
71.2 ± 5.5
|
70.9 ± 6.5
|
60.9 ± 10.2
|
61.0 ± 10.1
|
58.8 ± 11.5
|
58.8 ± 10.7
|
Hoehn & Yahr stage
(n, %)
|
1
|
20 (4.2%)
|
82 (5.3%)
|
1 (0.8%)
|
5 (1.3%)
|
16 (4.5%)
|
45 (4.1%)
|
6 (2.5%)
|
21 (3.1%)
|
2
|
295 (62.0%)
|
793 (50.9%)
|
58 (48.7%)
|
143 (36.6%)
|
206 (58.4%)
|
550 49.9%)
|
129 (54.4%)
|
307 (46.4%)
|
3
|
139 (29.2%)
|
421 (27.1%)
|
52 (43.7%)
|
144 (36.9%)
|
114 (32.3%)
|
325 (29.5%)
|
85 (35.9%)
|
215 (32.5%)
|
4
|
21 (4.4%)
|
88 (5.6%)
|
8 (6.7%)
|
40 (10.2%)
|
16 (4.5%)
|
70 (6.3%)
|
17 (7.2%)
|
63 (9.5%)
|
5
|
1 (0.2%)
|
6 (0.4%)
|
0 (0.0%)
|
4 (1.0%)
|
1 (0.3%)
|
5 (0.5%)
|
0 (0.0%)
|
4 (0.6%)
|
Percentages (%) are calculated by column. n: number of patients; PD: Parkinson’s disease; SD: standard deviation.
|
One observation of potential clinical relevance was that in Spain there were more patients (30.9%) whose safinamide treatment was not compliant with its indication (i.e., off-label use). In the European study population only 16.9% of the patients were using safinamide off-label (Table III). The difference was mainly due to more frequent prescription of safinamide to patients without motor fluctuations (16.8% vs. 8.8%) and treatment initiation with doses other than 50 mg/day (14.5% vs. 7.6%) in Spain, where there is a tendency to prescribe safinamide in earlier stages, including suboptimal on state.
Table III. Frequency of safinamide off-label use among the Spanish and European study populations at the start of treatment.
|
Category of off-label use
|
Spain (n, %)
|
Europe (n, %)
|
Any
|
158 (30.9%)
|
233 (16.9%)
|
Patients without motor fluctuations at the start of treatment
|
86 (16.8%)
|
121 (8.8%)
|
Patients that start safinamide with a dose other than 50 mg/day
|
74 (14.5%)
|
105 (7.6%)
|
Patients without levodopa in addition to safinamide
|
14 (2.7%)
|
21 (1.5%)
|
Patients with a diagnosis other than idiopathic PD
|
11 (2.2%)
|
16 (1.2%)
|
Patients treated concomitantly with other MAO inhibitors
|
7 (1.4%)
|
11 (0.8%)
|
Percentages (%) are computed out of the evaluable patients. MAO: monoamine oxidase; n: number of patients; PD: Parkinson’s disease.
|
Within special patient segments, we did not observe differences in the proportion of patients over 75 years of age or patients with relevant comorbidities at baseline (Table II). Interestingly, however, a higher percentage of the Spanish patients seemed to suffer from pre-existing concomitant psychiatric conditions (48.7%), mainly anxiety (21.7%) and depression (31.3%), as compared to the European sample (42.4%). Psychosis was prevalent in only 2.2% of the Spanish study population. Additionally, there were more often sleep disturbances (49.5% vs. 45.2%) and less often fatigue (19.4% vs. 25.5%) among the Spanish patients (Fig. 1a). In terms of the motor symptoms, the Spanish patients tended to suffer from tremor (66.9%) slightly more often compared to the European participants (58.3%) before starting the treatment with safinamide.
Figure 1. Prevalence of motor and non-motor symptoms (a) and use of concomitant PD and psychiatric treatments (b) at baseline in the Spanish and European study populations. Percentages are computed out of the total number of evaluable patients. A patient can have more than one motor or non-motor symptom or concomitant medication. Spain: n = 511; Europe: n = 1558.
In accordance with the higher prevalence of psychiatric comorbidities (including psychiatric conditions assessed as a diagnosis by neurologists, and psychiatric symptoms reported by patient and assessed by clinicians), the Spanish patients used more psychiatric drugs (antidepressants and other psychiatric treatments) at baseline as compared to the European sample (Fig. 1b). No marked differences in the use of PD treatments were observed between the Spanish and European study populations.
Spanish population
Effects on UPDRS scores
We observed a mean reduction of 1.6 points in the UPDRS total score (subscales I, II and III) and 1.5 points in the UPDRS part III (motor examination) score from baseline to the 12-month follow up among all Spanish study participants during
on time (Table IV). This further substantiates the earlier reported stability of disease severity over time with apparent improvements in motor symptoms after the start of safinamide therapy [
27].
Table IV. UPDRS scores during the observation period in Spanish study participants (mean ± SD).
|
| |
Baseline
|
4 months
|
8 months
|
12 months
|
Part I: Mentation, behaviour, and mood: 0-16 points
|
2.2 ± 2.2
|
2.1 ± 2.2
|
1.9 ± 2.0
|
2.0 ± 2.2
|
Part II: Activities of daily living: 0-52 points
|
11.6 ± 6.4
|
11.4 ± 6.3
|
11.0 ± 6.5
|
11.6 ± 6.8
|
Part III: Motor examination: 0-108 points
|
26.8 ± 12.1
|
24.8 ± 12.0
|
24.8 ± 12.3
|
25.3 ± 13.0
|
Part IV: Complications of therapy (in the past week): 0-23 points
|
4.0 ± 2.9
|
3.8 ± 2.6
|
3.6 ± 2.8
|
3.7 ± 2.7
|
Total Score (subscales I, II and III): 0-176 points
|
40.5 ± 17.8
|
38.8 ± 17.7
|
37.8 ± 17.8
|
38.9 ± 19.1
|
Total Score (subscales I, II, III and IV): 0-199 points
|
44.3 ± 18.6
|
42.4 ± 18.5
|
41.6 ± 18.9
|
43.0 ± 20.3
|
SD: standard deviation; UPDRS: Unified Parkinson’s disease rating scale.
|
To address the use of safinamide in certain patient subgroups, we analysed how patients treated previously with rasagiline, a high dose of levodopa (>400 mg), or safinamide as the only add-on therapy at baseline responded to safinamide adjunct therapy (Fig. 2). The proportion of patients with clinically important improvement from the baseline to the 12-month follow up (responders) was defined based on the criteria developed by Shulman, et al: a difference of more than 4.3-points in the UPDRS total score and more than 2.5 points in the UPDRS III score are considered clinically important [30].
Figure 2. Evolution of UPDRS scores from baseline to the 12-month follow up among the Spanish study population. The percentage of evaluable patients classified as ‘responders’ according to the Schulman criteria (reduction in UPDRS total > 4.3, dark bars; or UPDRS III >2.5, light bars) is shown separately for all evaluable patients (Overall) and patient categories treated previously with rasagiline (Prior rasagiline), having LED > 400 mg at baseline, or having safinamide as the only add-on therapy at baseline. n = 163-207 (UPDRS was not evaluated in every patient). A patient can belong to more than one category.
Noteworthily, we observed that 57.4% and 53.7% of patients receiving safinamide as the only add-on reduced UPDRS total score by more than 4.3 points and UPDRS III score by more than 2.5 points, respectively (Fig. 2). Only 44.1% of patients with additional adjunct therapies reduced the UPDRS total score by more than 4.3 points, and 42.8% reduced the UPDRS III score by more than 2.5 points. Thus, the clinically relevant improvement seemed more common among patients receiving safinamide as the only add-on, compared to those who also used other adjunct therapies. Equally interestingly, 55.1% of patients previously treated with rasagiline but switched to safinamide responded to the new treatment with a clinically relevant improvement in the UPDRS total score.
After 12 months of safinamide treatment, we did not observe major differences in the clinically relevant improvement between the groups of patients receiving high or low doses of levodopa at baseline (Fig. 2). However, there seemed to be a tendency of greater average reduction in both UPDRS III and UPDRS total scores in patients treated with low doses of levodopa (≤400 mg) (mean ± SD: –2.6 ± 9.1 and –2.3 ± 12.7, respectively) compared to those treated with higher doses (>400 mg) (mean ± SD: –0.7 ± 9.6 and –1.3 ± 11.7, respectively) (data not shown).
Effects on motor complications
Despite the more common off-label use of safinamide among the Spanish participants, the number of patients with motor complication was reduced from 83.2% to 63.3% after one year of treatment with safinamide (Fig. 3). The most pronounced improvements were seen in wearing off, which reduced from 62.2% to 47.8%, and dyskinesias, which reduced from 39.1% to 28.9%.
Figure 3. Proportion of patients with different motor complications in the Spanish study population during the follow up. The percentages are calculated separately from all evaluable patients at each of the observation time points. A patient can have more than one motor complication. Baseline: n = 511; at 4 months: n = 454; at 8 months: n = 436; at 12 months: n = 439.
As expected, we observed a higher percentage of patients having motor complications, especially wearing off and dyskinesias, among those taking >400 mg daily dose of levodopa at the baseline than those with lower doses (Fig. 4a). Importantly, safinamide treatment reduced the number of patients with motor complications during the 12-month follow up period in both categories. Safinamide as the only add-on therapy seemed to reduce the proportion of patients with any motor complication to a greater extent than when combined with other adjunct treatments (Fig. 4b).
Figure 4. Proportion of the Spanish study participants with different motor complications at baseline and at the 12-month follow up. The percentages of patients with complications are shown separately for those treated with levodopa ≤400 mg or >400 mg at baseline (a), and those having safinamide as the only add-on therapy or in combination with other add-on therapies at baseline (b). A patient can have more than one motor complication. n = 497 (at baseline).
Safety
In Spain, AEs and adverse drug reactions (ADRs) were reported more often (54.8% and 32.9% of the participants, respectively) during the observation period as compared to the European dataset (45.8% and 27.7%, respectively, data not shown). The major contributor to differences in AEs was the incidence of nervous system disorders (39.4% vs. 33.4%, Spanish and European datasets respectively, data not shown). Interestingly, however, there were less serious adverse events (SAEs) and serious adverse drug reactions (SADRs) despite the more common off-label use of safinamide among the Spanish study population (SAEs: 7.4% vs. 9.2%, and SADRs: 1.6% vs. 2.3% of the participants, data not shown). In line, AEs were more often characterised as mild among the Spanish patients (69.3%) compared to the European participants (61.9%).
The tendency to use safinamide more frequently off-label in Spain did not lead to increased safety concerns in any of the special patient segments. The rates of reported SAEs or SADRs (at least one) in patients over 75 years of age, with relevant comorbidities or with concomitant psychiatric conditions, seemed to be even slightly lower in Spain as compared to the European data. Noteworthily, we did not detect significant differences in the frequency of reported AEs, SAEs, ADRs or SADRs between the off-label and appropriate use of safinamide in the Spanish population (Fig. 5). This underpins safinamide’s favourable safety profile even amongst the patients under off-label use. However, the prescription of safinamide to patients with cognitive impairment should be evaluated, since there is a certain tendency to experience a slightly higher frequency of AEs (60% vs. 56.5%), SAEs (10.9% vs. 7.9%), ADRs (36.4% vs. 31.6%) and SADRs (1.8% vs. 1.1%) when compared to cognitively normal patients.
Figure 5. Proportion of the Spanish study participants who reported at least one adverse event (AE), adverse drug reaction (ADR), serious adverse event (SAE) or serious adverse drug reaction (SADR) during the observation period. The percentages are calculated separately for patients using safinamide in accordance with the summary of product characteristics (appropriate use, light bars) and for those using it off-label (dark bars). Appropriate use: n = 353; off-label use: n = 158.
Discussion
A post-hoc analysis was conducted to explore whether safinamide had a favourable safety profile also within the Spanish study population where the drug was more often prescribed to patients with psychiatric conditions and where its off-label use was more common as compared with the European study population. Despite that AEs and ADRs were more often reported during the observation period, SAEs and SADRs seemed to be less common in the Spanish study population. AEs also seemed to be milder among the Spanish patients. Of note, significant differences were not detected in the frequency of reported AEs, SAEs, ADRs or SADRs between the off-label and appropriate use of safinamide. Furthermore, frequent off-label use of safinamide by the Spanish population did not lead to increased safety concerns in any of the special patient segments.
To gain a deeper insight, we also evaluate whether specific patient subgroups could benefit from safinamide treatment by getting clinically relevant improvement in UPDRS scores. Patients previously treated with rasagiline benefited from safinamide treatment more often in terms of UPDRS total score as compared to those who had not used rasagiline before. Safinamide also proved to be efficacious regardless of the daily dose of levodopa. Safinamide as the only add-on therapy seemed to reduce the proportion of patients with motor fluctuation to a greater extent than concomitant administration with other adjunct treatments. These observations support the value of safinamide as the initial adjunct therapy and may warrant further consideration when amending future PD therapeutic guidelines.
Analysis of Spanish and European datasets
In a European Delphi Consensus, a panel of specialists in movement disorders from across Europe was surveyed about the performance of safinamide in PD [31]. Strong consensus was reached for all the statements regarding the efficacy of safinamide on motor symptoms, motor fluctuations, quality of life and safety. Positive consensus was achieved for non-motor symptoms; however, there was lack of agreement on the efficacy of safinamide in improving cognition, urinary and sexual functions. Similarly, no agreement was reached on the tolerability of the compound in patients with hallucinations or regarding orthostatic hypotension. Regarding targeted populations, panellists agreed on safinamide as a valid therapeutic option in the early stages of fluctuations and in patients with advanced PD [31].
In the present study, when Spanish and European datasets were analysed, meaningful differences in the concomitant medications between the two study populations were unseen, highlighting the consistency in usage of PD therapies across Europe and in accordance with the European Delphi Consensus [27,31]. However, some aspects with potential clinical relevance were detected within the Spanish population—higher off-label prescription of safinamide, higher proportion of patients suffering from concomitant psychiatric conditions and receiving an increased amount of psychiatric medication.
Effect of safinamide on UPDRS scores and motor complications
Safinamide as an add-on therapy has extensively proven to successfully manage motor complications [31-37] by reducing the time spent in off and required doses of levodopa (<400 mg) [31,33,35], which are associated with a reduced risk of troublesome peak-dose dyskinesias and wearing-off, and a satisfactory clinical control of PD [38-40]. In this analysis, the use of safinamide showed stronger clinical benefit (mean reduction in UPDRS scores and amount of motor complications) when initiated in conjunction with low doses of levodopa, and despite higher off-label use. Additionally, greater average reduction in UPDRS scores was observed in those individuals who experienced a clinically relevant benefit from safinamide and had LED ≤400 mg. For this reason, future research addressing differential diagnoses and/or clinical observation reports to identify those patients who could derive the best benefit from safinamide as an adjuvant therapy may help exploit its full therapeutic potential.
Switching from rasagiline
It is quite common for PD patients under levodopa treatment to start experiencing fluctuations in the relief of their symptoms [40-42]. To approach this issue, the use of MAOB inhibitors (MAOB-I) has proven to be a useful add-on to levodopa in patients experiencing motor fluctuations [41,43,44]. Rasagiline belongs to a group of drugs that increase the bioavailability of dopamine by irreversibly preventing its MAOB-dependent metabolism [41,45]. Previous studies have suggested that PD patients may benefit from switching to safinamide, not only from rasagiline, but also from other MAOB-Is [32,33,41,46], due to significant improvement in motor fluctuations and motor symptoms, reflected in a reduction of the Wearing-Off-Questionnaire-19 score [32,41]. Specifically, high doses of safinamide had stronger efficacy than rasagiline on daily OFF time, fluctuations and dyskinesia, and may reduce required levodopa doses when used concomitantly [33,41,47]. In the present sub-analysis, 55.1% of patients who were previously treated with rasagiline but switched to safinamide responded to the new treatment with a clinically relevant improvement in the UPDRS total score, thus, suggesting added benefits when switching from rasagiline to safinamide.
Safinamide safety profile within the Spanish population
Multiple studies have evaluated the safety of safinamide in different contexts [31,36,47-50]. Some studies have targeted its use in patients aged more than 75 years [48,49], where safinamide was found to be safe, efficacious and well tolerated at doses of 50-100 mg, in agreement with the European Delphi Consensus [31,48]. Other studies, such as the SADness-PD study, confirmed the efficacy and safety of safinamide in patients under antidepressant treatment, which is a common concomitant medication in PD [50]. Of note, co-administration of safinamide with antidepressants remains both well tolerated and useful for the treatment of motor symptoms and motor complications [49-51].
In the present study, although AEs and ADRs were reported more often by Spanish patients than European patients, these were milder and less serious within the Spanish study population. Notably, off-label use of safinamide was revealed to be higher in Spain, mostly due to frequent prescription of safinamide to patients without motor fluctuations and treatment initiation with doses other than 50 mg/day. However, significant differences in the frequency of reported AEs, SAEs, ADRs or SADRs were neither detected in general nor in any of the special segments, as compared to appropriate use of safinamide. This confirms the favourable safety profile of safinamide, even when prescribed outside its approved indication.
Regarding patients with cognitive impairment, the use of safinamide led to slightly higher frequencies of adverse events and adverse reactions, which is consistent with a study report where a 20% withdrawal from safinamide due to AEs were of patients presenting cognitive impairment at baseline [47]. However, the overall safety profile of safinamide as an adjunct therapy for patients with cognitive impairment was supported by 89% of the panellists of the European Delphi Consensus [31], suggesting that the higher risk of AEs in this special population could be associated with a more fragile health condition rather than with tolerability to safinamide. Another point for consideration is the absence of information regarding the number of patients having cognitive impairment prescribed with safinamide in the European dataset. Higher frequencies of AEs and ADRs could be attributed to higher prescription frequencies in Spain.
Sub-analysis limitations
A direct comparison between the Spanish and European study populations could be considered sub-optimal since the Spanish dataset remained included in the European dataset. Although masking of interesting differences could be claimed, it was clear from the SYNAPSES analyses that safinamide presented a favourable overall safety profile, even after noticing higher off-label use and psychiatric issues among Spanish PD patients. However, such differences in clinical practice merit a deeper and more careful investigation, leading to confirmation of safinamide’s safety profile within the Spanish study population.
Finally, data collection among different recruiting centres presented some inconsistencies. For this reason, some datasets may have been perceived as incomplete due to patient withdrawal, when it was due to absence of a normalised methodology to acquire treatment-related information.
Conclusions
The present post-hoc analysis confirms that the Spanish study population from the SYNAPSES observational approach responded to add-on safinamide in a similar way as the overall European study population. Interestingly, although certain differences in clinical practice were observed among the participating European countries, such as higher use of safinamide in noncompliance with its indication in Spain, no impact on the good safety and tolerability profile of the drug was observed. Moreover, when used as adjunct therapy to treat either fluctuating PD patients or any of the predefined groups of interest, similar benefits around motor complications and motor scores with long-termed clinically significant results were seen. However, slight differences registered in cognitive impaired subjects regarding side effects suggest that safinamide should be used with caution in this sub-population. In summary, our results further support the use of safinamide as a safe and efficacious option for the management of motor fluctuations in levodopa-treated patients.
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SYNAPSES. Estudio observacional europeo para evaluar la seguridad y la efectividad de la safinamida en la práctica clínica habitual: análisis post hoc de la población española del estudio
Introducción. La enfermedad de Parkinson (EP) es una afección neurodegenerativa progresiva relacionada con la edad que requiere nuevas alternativas terapéuticas. La safinamida, un nuevo tratamiento complementario de la levodopa, afecta positivamente a las fluctuaciones de esta enfermedad al modular los sistemas dopaminérgico y glutamatérgico. Para investigar más a fondo el uso de la safinamida en la práctica clínica rutinaria europea, el presente análisis post hoc tiene como objetivo comprender el perfil de seguridad de la safinamida dentro de la población española del estudio.
Pacientes y métodos. Se evaluó a 511 pacientes españoles con EP al inicio, cuatro (±1), ocho (±1) y 12 (±1) meses después de iniciar el tratamiento con safinamida. Se utilizaron la puntuación total de la escala unificada de puntuación de la enfermedad de Parkinson (UPDRS) y la puntuación de la UPDRS III, durante el tiempo en on para medir la gravedad general de la EP y las complicaciones motoras, respectivamente, mientras que la gravedad de los acontecimientos adversos se evaluó siguiendo los criterios de los investigadores.
Resultados. La safinamida mostró un perfil de seguridad favorable en la población española del estudio, aunque la prescripción a pacientes con enfermedades psiquiátricas y el uso para indicaciones no autorizadas fueron más frecuentes que en la población europea del estudio. En España se observaron mejoras clínicamente significativas en las puntuaciones de la UPDRS cuando se utilizó la safinamida como único tratamiento complementario a la levodopa (el 57,4 y el 53,7% de los pacientes) y cuando se venía de administrar rasagilina (el 55,1% de los pacientes). Las complicaciones motoras se redujeron del 83,2 al 63,3% tras el período de estudio. No se detectaron mayores problemas de seguridad en ningún subgrupo de pacientes, aunque los pacientes con deterioro cognitivo mostraron una frecuencia algo superior de acontecimientos adversos.
Conclusiones. Este subanálisis respalda el uso de la safinamida como opción segura y eficaz para el tratamiento de las fluctuaciones motoras en diferentes subgrupos de pacientes tratados con levodopa. Sin embargo, la safinamida debe utilizarse con precaución en pacientes con deterioro cognitivo.
Palabras clave. Complicaciones motoras. Complicaciones no motoras. Discinesias. Enfermedad de Parkinson. Levodopa. Safinamida.
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