During the 10 weeks of the study, the 92 droxidopa patients reported 308 falls and the 105 placebo patients reported 908 falls (Fig. 3). This translates to fall rates of 0.4 falls per patient-week in the droxidopa group and 1.05 falls per patient-week in the placebo group, a crude relative risk reduction (RR) of 62% (Fig. 4). However, the data were skewed and displayed extreme dispersion, with approximately 40% of patients experiencing no falls and some patients experiencing many falls, particularly in the placebo group (Fig. 5). The prespecified ZINB model was found inappropriate and the preplanned Wilcoxon rank sum test was conducted to assess the mean difference across groups (P = 0.704). However, this test lacks efficiency in situations where the distributions are different in shape and dispersion. A post hoc analysis using Poisson-inverse Gaussian regression showed that droxidopa reduced the number of falls (RR = 77%; P = 0.014) and the dispersion (P = 0.02). Goodness of fit was examined using residuals plots that confirmed the model was appropriate. These model-dependent findings were also supported by a nonparametric analysis based on the basic bootstrap that returned a comparable falls rate ratio of 0.38 (95% confidence interval, 0.13–0.92).
In the droxidopa group, 54 patients reported 245 days with at least 1 fall. On those days, the worst fall of the day (which could have been the only fall of the day) was associated with lightheadedness 46.5% of the time, losing consciousness 9.4% of the time, and with FOG 26.9% of the time. In the placebo group, 63 patients reported 372 days with at least 1 fall. On those days, the worst fall of the day (which could have been the only fall of the day) was associated with lightheadedness 43.5% of the time, losing consciousness 5.4% of the time, and with FOG 23.9% of the time.
Fall-related injuries are displayed in Table 3. A smaller proportion of patients receiving droxidopa reported fall-related injuries compared with placebo (19/114 [16.7%] vs 29/108 [26.9%]. In both groups, the most frequent fall-related AEs reported were contusions, skin lacerations, and excoriations; reports of these types of injuries were less common in patients receiving droxidopa than placebo (contusion 4.4% vs 11.1%; skin lacerations 4.4% vs 9.3%; and excoriations 5.3% vs 7.4%). In addition, in the placebo group, fractures (facial bones, fibula, and tooth; each n = 1 [0.9%]) and a traumatic brain injury (n = 1, 0.9%) were reported, whereas no patients in the droxidopa group reported these more severe types of injuries.
Movement Disorder Society-Unified Parkinson's Disease Rating Scale
There were no significant differences across groups in change from baseline to EoS in MDS-UPDRS motor, postural stability, or freezing scores (Table 4).
Our analysis suggests that droxidopa may reduce falls in PD patients with nOH. We hypothesize that the observed reduction in falls in the droxidopa group is due to improvement in OH, but other mechanisms such as improvement in freezing or attention are conceivable.
Although an association between OH and falling would seem logical, some studies in older adults identified such an association while others did not.14 In assessing the literature, Shaw and Claydon14 point out that differences in results could potentially be related to differences in BP assessment techniques (auscultatory, finger cuff plethysmography, arterial tonometry, intra-arterial cannula), timing of assessments (beat-to-beat, 1 minute, 3 minutes, >3 minutes), orthostatic test (sit-to-stand, lying-to-standing, head-up tilt), and OH criteria employed (1996 consensus definition,15 Fedorowski criteria,16 initial OH, delayed OH, steady-state recovery from OH). Of the 8 studies examined that used lying-to-standing BP assessments, only 3 identified a direct association between OH and falls. In contrast, both studies that used head-up tilt tests with beat-to-beat BP measurements found this association. Overall, their review and the available literature indicate that there is an association between OH and falls but that standard auscultatory BP testing supine and through 3 minutes standing may miss this association.
In our study, in the droxidopa group, the percentages of worst falls of the day reported to be associated with lightheadedness (46.5%) or syncope (9.4%) were similar to that reported in the placebo group (43.5% and 5.4%), thus failing to provide supportive evidence that droxidopa specifically reduced falls by ameliorating lightheadedness and syncope. However, this analysis is limited by the fact that a substantial percentage of individuals with falls due to syncope may not experience presyncopal symptoms and are amnestic for loss of consciousness.17,18
There is also evidence to suggest that FOG is associated with a central norepinephrine deficiency and that treatment with droxidopa might ameliorate this condition, but this has yet to be proven. In an analysis of the relationship between clinical symptoms of PD and cerebrospinal fluid monoamines, FOG was found to be associated with a reduction in cerebrospinal fluid norepinephrine.19 More recently, in an autopsy study of 46 patients who had PD, FOG was significantly associated with the degree of neuronal loss or gliosis in the locus coeruleus.20 In the 1980s, a series of small open-label studies conducted in Japan suggested that droxidopa could increase norepinephrine brain concentrations and reduce FOG, culminating in its 1989 approval in Japan for an indication that included “freezing phenomenon in PD.”21 Tohgi et al22 initially reported improvement in FOG in 3 of 6 patients and later reported23 improvement in FOG in 6 of 8 Hoehn-Yahr stage III patients and 1 of 5 stage IV patients. More recently, Fukada et al24 reported improvement in FOG in a small group of patients (n = 6) treated with droxidopa plus entacapone. Thus, it is possible that droxidopa could reduce falls by ameliorating FOG. However, in our study, the percentage of worst falls reported to be associated with freezing in the droxidopa group (26.9%) was similar to that reported in the placebo group (23.9%). In addition, change in MDS-UPDRS freezing scores was not significantly different across groups.
In addition to a lower fall rate, we observed a lower incidence of fall-associated injuries in the droxidopa group compared with the placebo group. There were cases of a facial fracture, a fibula fracture, and a traumatic brain injury in the placebo group with no similar injuries in the droxidopa group. These observations suggest that the lower rate of falls in the droxidopa group was clinically relevant and may have important health implications.
Our study has important limitations. Although falls were a key secondary outcome in the NOH306 trial, they were not the primary outcome. In addition, falls data were not collected before randomization and patients were not stratified based on fall status or possible fall-related risk factors. Inspection of baseline characteristics indicates that 34.1% of droxidopa patients were Hoehn-Yahr stage 3 or higher, compared with 48.6% of placebo patients. Furthermore, in this study, falls were patient reported and could potentially be affected by recall bias, different interpretations of what constitutes a fall (despite receiving instructions regarding a standard definition of a fall), and syncope-related amnesia. In future studies, electronic monitoring for falls may help standardize the assessment of falls. Fall-associated symptoms were also patient reported and only given for the worst fall of the day. Furthermore, we made the assumption that traumatic injuries reported the day of or the day after a fall were related to the fall. Although the small group of placebo patients who reported a larger number of falls was influential on the results, these findings were not identified as model departures.
In study NOH306, improvements in OH symptomatology (eg, lightheadedness) and BP were significant for droxidopa versus placebo only through the first week of double-blind treatment. Nonetheless, numeric changes favored droxidopa for the full 10 weeks of treatment (dizziness/lightheadedness improvement, P = 0.077 at week 10), and group scores can mask robust individual responses. Thus, it remains possible that fall rates in the droxidopa group could have been reduced throughout the study owing to improvements in OH.
Overall, falls were very common in this group of PD patients with nOH. Notably, we observed a substantially lower fall rate in patients treated with droxidopa compared with placebo. This observation needs to be confirmed in future studies. Such studies might ideally include a period of falls assessment before initiation of the intervention, randomization stratification based on frequency of falls, and electronic monitoring to identify falls. Clinicians should be aware of the potential for OH to cause falls and understand that patients may not report lightheadedness (presyncope) or may be amnestic for syncope. Careful evaluation of orthostatic BP is indicated in patients with unexplained falls.
The data were derived from clinical trials and post hoc analyses funded by Lundbeck. In the past 36 months, R.A.H. has received personal fees from Acadia Pharmaceuticals, Auspex Pharmaceuticals, Acorda Therapeutics, AstraZeneca, Civitas Therapeutics (now Acorda Therapeutics), Cowen Group, Allergan Neuroscience, AbbVie, Biotie Therapies, Chelsea Therapeutics (now Lundbeck NA Ltd), Cynapsus Therapeutics, Eli Lilly and Company, Impax Laboratories, Lundbeck Pharmaceuticals, the Michael J. Fox Foundation for Parkinson's Research, Neurocrine Biosciences, Novartis, Pfizer, Inc, Sarepta Therapeutics, Teva Pharmaceuticals, National Institute of Neurological Disorders and Stroke, Orion, ProPhase, UCB BioSciences, Inc, and US WorldMeds. R.A.H. is employed by the University of South Florida (Florida) and is supported in part by a Center of Excellence grant from the National Parkinson Foundation. L.A.H. is an employee of Lundbeck. G.J.R. was an employee of Lundbeck at the time of the studies and manuscript development. S.H.I. has received honoraria in the past 12 months from AbbVie, Acadia, Acorda, Adamas, Addex, Allergan, Amarantus, Auspex, Biotie, Britannia, Cynapsus, Eisai, GE Healthcare, GlaxoSmithKline, Impax, Ipsen, Kyowa, Lundbeck, Medtronic, Merz, the Michael J. Fox Foundation for Parkinson's Research, Neurocrine, National Institute of Neurological Disorders and Stroke/National Institute of Health, Parkinson Study Group, Pfizer, Pharma2B, Roche, Santhera, Serono, Shire, Teva, UCB, US WorldMeds, and Xenoport for continuing medical education, consultant services, research grants, and/or promotional speaking. The authors received editorial assistance from CHC Group (North Wales, PA), which was supported by Lundbeck LLC.
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Keywords:Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved.
droxidopa; falls; Parkinson disease; neurogenic orthostatic hypotension; treatment