EDITORIAL
Orthostatic Hypotension in Parkinsonism: What Is It and How Can We Treat It? Susan H. Fox, MRCP (UK), PhD and Connie Marras, FRCPC, PhD* Morton and Gloria Shulman Movement Disorders Clinic and the Edmond J. Safra Program in Parkinson’s Disease, Toronto Western Hospital, University Health Network, Toronto, ON, Canada
Neurogenic orthostatic hypotension (nOH) can be a disabling nonmotor sign in patients with parkinsonism (advanced Parkinson disease [PD] and multiple system atrophy [MSA]) because of pathological changes resulting in autonomic failure. Both recognition of the symptoms and management can be challenging. Two publications in this issue of the Journal have focused on this problem. Diagnosing nOH in PD is not always simple. The PD patients may have a measurable postural decrease in blood pressure (BP) but do not necessarily experience classic symptoms of syncope or pre-syncope. More typically, parkinsonian patients present with nonspecific dizziness after several minutes, increased falls, fatigue, and weakness. Conversely, PD patients may report symptoms suggestive of nOH, but measuring lying and standing BP after 3 min does not reveal a symptomatic fall in BP. Also problematic is that defining what constitutes a clinically relevant change in postural BP is not reliably known in the PD population, because definitions of nOH were determined from non-PD populations. Neurogenic orthostatic hypotension in PD can also be assessed using rating scales, which currently include subscores of the Unified Parkinson’s Disease Rating Scale or the Orthostatic Hypotension Questionnaire (OHQ), which is a 10-item scale covering symptoms such as lightheadedness/feeling faint, visual disturbance, and weakness while standing and walking. The study by Palma et al.1 published in this issue set out to determine BP parameters that are associated with symptomatic nOH in PD. The study recruited 210 participants with PD and compared supine BP after 20 min and then standing BP after 3 min and correlated changes with OHQ
------------------------------------------------------------
*Correspondence to: Dr. Connie Marras, Toronto Western Hospital, University of Toronto Neurology, Movement Disorders Centre, 11-MP, 399 Bathurst Street, Toronto, Ontario, Canada, E-mail: connie.marras@ utoronto.ca
Relevant conflicts of interest/financial disclosures: Nothing to report. Full financial disclosures and author roles may be found in the online version of this article. Received: 20 November 2014; Revised: 5 January 2015; Accepted: 8 January 2015 Published online 11 March 2015 in Wiley Online Library (wileyonlinelibrary.com) DOI: 10.1002/mds.26179
to determine what constitutes a hemodynamic target for treatment of symptomatic nOH. Overall approximately half had a postural drop in BP of any magnitude, but using a postural change of 20 mm Hg systolic or 10 mmHg diastolic, only 16% were symptomatic, and using a larger 30/15 mmHg change, only 13% were symptomatic. A mean upright BP of less than 75 mmHg, compared with greater than 75 mmHg, best discriminated those with symptoms of OH from those without. Thus, PD patients with a postural decrease in BP may not be symptomatic, and the absolute low BP, when upright, is most predictive of symptoms. Treating nOH in Parkinsonism currently relies on nonpharmacological approaches, such as reducing BPlowering drugs, ensuring adequate fluids, and salt supplementation. Specific drugs to increase standing BP currently rely on the use of general pressor agents, with no level 1 randomized controlled trials (RCTs) performed in PD subjects on which to make any evidencebased medicine (EBM) conclusions.2 Safety concerns with these drugs remain an issue, including hypokalemia with fludrocortisone and worsening existing supine hypertension with midodrine. Thus, clinical trials evaluating new agents in PD are welcome. One agent evaluated for nOH in PD is the noradrenaline precursor, L-threo-3,4-dihydroxyphenylserine or droxidopa, which is the subject of a clinical trial reported in this issue.3 Droxidopa is converted to noradrenaline (NA) via dopa-decarboxylase in the periphery. Autonomic failure in idiopathic PD and MSA results in either low or normal supine levels of NA and no elevation of NA on standing. The mechanism of action of droxidopa is thus likely through elevation of peripheral NA. On average, droxidopa elevates standing systolic BP by approximately 10 mmHg. Lying systolic BP is also elevated, and thus supine hypertension is a possible side effect of this drug. Dosing is required 3 times per day because peak action is approximately 2 to 3 h after ingestion. Droxidopa has been available in Japan since 1989 and received Food and Drug Administration approval in 2014 for short-term use in nOH in primary autonomic failure, PD, MSA, and nondiabetic autonomic
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neuropathy on the basis of short-term clinical trials. Study 3014 and study 3025 included all types of autonomic failure, whereas only subjects with PD were recruited to Study 306a6 and the report in this edition of the Journal, Study 306b.3 Studies 301 and 302 had similar designs with a pre-randomization open-label optimization stage followed by randomization of responders to 7 to 14 d of treatment. The primary outcome measure used the OHQ; with Study 3014 reporting a significant change in total OHQ score at 1 week. However, subgroup analysis of PD or MSA subjects alone showed no significant changes. Thus, the significant efficacy was driven by subjects with pure autonomic failure. Study 3025 used item 1 of the OHQ (“do you have dizziness, light-headedness, feeling faint or ‘feeling like you might black out’”) as primary outcome measure and reported no significant difference between droxidopa and placebo group. Tolerability was generally good, with the main side effects being headache, dizziness, nausea, and supine hypertension in 2% to 7%. The latest study (306) evaluated 225 subjects with symptomatic OH in PD over 10 weeks. The study was a double-blind, randomized trial of droxidopa compared with placebo. Initially designed to follow participants for the primary outcome of OHQ composite score at 8 weeks, a preplanned interim analysis of the first 51 participants (designated Study 306a; n 5 516) reported no significant difference between droxidopa and placebo. This knowledge, in combination with experience from previous studies in nOH, led to a change in the primary outcome measure to change item 1 of the OHQ between baseline and week 1. The study (designated 306b) evaluating the 171 subjects recruited subsequently is published in this issue.3 Hauser et al.6 report a significant change after 1 week of 22.3 points for droxidopa vs 21.3 points for placebo. The results of this study are in agreement with studies in other causes of nOH finding short-term benefit.4,5 Changes in the OHQ item 1 from baseline to weeks 2, 4, and 8 as well as effects of droxidopa on fall rates were secondary outcomes. Mean reduction in OHQ Item 1 was larger in the droxidopa arm at weeks 2, 4, and 8 but was not statistically significant. Number of falls suggested a benefit of droxidopa, with 229 falls reported in the droxidopa group compared with 716 in the placebo. Changes in lowest systolic blood pressure were not significantly different between the two arms across the weeks but were larger in the droxidopa arm. Side effects were significant in the droxidopa group, resulting in withdrawal in 12% because of headache and dizziness compared with 6% in placebo. Supine hypertension occurred in 7% of droxidopa groups versus 4% in placebo; however, this was only seen in first 2 weeks of treatment.
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Movement Disorders, Vol. 30, No. 5, 2015
The change in outcome measure partway through this study raises questions about the validity of subsequent analyses. However, data from the first 51 participants were not used in the subsequent analyses, and as such the ‘study 306b’ can be thought of as a new study informed by the results of a pilot trial. These results do leave considerable uncertainty, however, about the effect of droxidopa on other aspects of OH beyond item 1 of the OHQ. For droxidopa to be a valuable treatment, it will be important that its effects go beyond reducing lightheadedness; improvements in function (reflected in the remainder of the OHQ) and reduction in falls would be highly desirable. Indeed the negative findings from study 306a in OHQ composite score suggest this is unlikely, but larger studies would be required to show this definitively. Regarding the apparent loss of effectiveness beyond 1 week, the authors postulate that this may be attributable to a loss of pretreatment adrenoceptor hypersensitivity with continued treatment, which potentially could be addressed with higher doses of medication, or to response shift in patient-reported lightheadedness or dizziness occurring with continued improvement, reducing the sensitivity of the OHQ question 1 to any improvement over time. The implications of these possibilities are severalfold: future studies may benefit from larger sample size, flexible dosing regimens to optimize response, and including primary outcomes that are meaningful to patients but at the same time less likely to suffer from effects such as response shifts; fall rate is an example. Based on these results, there are several issues with droxidopa for use in clinical practice: The indication for use is currently defined as per item 1 of the OHQ, that is, symptoms of dizziness, lightheadedness, feeling faint or ‘feeling like you might black out.’ Parkinson’s disease patients may not express these specific symptoms, and more exploratory questions may need to be asked to determine whether a PD patient has symptomatic OH. Droxidopa can elevate BP and therefore supine hypertension (defined in these studies as >180 mmHg systolic /110 mmHg diastolic after 10 min lying down) is still a problem and so will require management and monitoring. The labeling in the United States carries a black box warning. Co-prescribing of midodrine was disallowed in this study, and it should not be used with droxidopa. However, fludrocortisone was allowed. In clinical practice, where patients have responded partially to midodrine, clinicians will need guidance as to whether midodrine should be discontinued before trying droxidopa.
O R T H O S T A T I C
The use of dopa-decarboxylase inhibitors (DDCI) such as carbidopa or benserazide in levodopa preparations theoretically could reduce efficacy of droxidopa. Study 3014 showed that subjects on DDCI did not have significant improvement in either rise in systolic BP or change in OHQ composite score compared with non-users. If patients using DDCI do not benefit, this severely limits the usefulness of droxidopa in this population. Evidence for long-term use of droxidopa is lacking, and 1-week outcomes so far in randomized controlled trials (RCTs) are far too short for clinical usefulness. However, one open-label 3-month follow-up of study reported sustained improved OHQ.7 More long-term follow-up studies are needed. Where droxidopa will fit into treatment strategies for nOH is unclear. In clinical practice, patients will likely be prescribed droxidopa only when currently available agents have been tried and failed. Further studies are needed to guide treatment decisions.
H Y P O T E N S I O N
I N
P A R K I N S O N I S M
References 1.
Palma J, Gomez-Esteban J, Kaufmann L, Martinez J, Tijero B, Berganzo K, Kaufmann H. Orthostatic hypotension in Parkinson disease: how much you fall or how low you go? Mov Disord in press.
2.
Seppi, K, Weintraub D, Coelho M, Perez-Lloret S, Fox SH, Katzenschlager R, Hametner EM, Poewe W, Rascol O, Goetz CG, Sampaio S. Movement Disorder Society evidence-based medicine review update: treatments for the non-motor symptoms of Parkinson’s disease. Mov Disord 2011;26(Suppl 3):S42-S80.
3.
Hauser R, Isaacson S, Lisk JP, Hewitt LA, Rowse G. Droxidopa for the short-term treatment of symptomatic neurogenic orthostatic hypotension in Parkinson’s disease (nOH306B). Mov Disord in press.
4.
Kaufmann H, Freeman R, Biaggioni I, et al. Droxidopa for neurogenic orthostatic hypotension: a randomized, placebo-controlled, phase 3 trial. Neurology 2014;83:328-335.
5.
.Chelsea Therapeutics. Clinical study of droxidopa in patients with neurogenic orthostatic hypotension (NOH)(NOH302) [ClinicalTrials.gov identifier NCT00633880] US National Institues of Health, ClinicalTrials.gov.2014. [Accessed 2014 November 3]. Available from: http://www.clinicaltrials.gov/ct2/show/study/ NCT00633880.
6.
Hauser RA, Hewitt LA, Isaacson S. Droxidopa in patients with neurogenic orthostatic hypotension associated with Parkinson’s disease (NOH306A). J Parkinsons Dis 2014;4:57-65.
7.
Isaacson S, Shill H, Vernino S, et al. Durability of effect with longterm, open-label droxidopa treatment in patients with symptomatic neurogenic orthostatic hypotension (NOH 303) [abstract no. 1291]. Mov Disord 2012;27(Suppl 1):S424-S425.
Movement Disorders, Vol. 30, No. 5, 2015
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Orthostatic Hypotension in Parkinsonism: What Is It and How Can We Treat It? Susan H. Fox, MRCP (UK), PhD and Connie Marras, FRCPC, PhD* Morton and Gloria Shulman Movement Disorders Clinic and the Edmond J. Safra Program in Parkinson’s Disease, Toronto Western Hospital, University Health Network, Toronto, ON, Canada
Neurogenic orthostatic hypotension (nOH) can be a disabling nonmotor sign in patients with parkinsonism (advanced Parkinson disease [PD] and multiple system atrophy [MSA]) because of pathological changes resulting in autonomic failure. Both recognition of the symptoms and management can be challenging. Two publications in this issue of the Journal have focused on this problem. Diagnosing nOH in PD is not always simple. The PD patients may have a measurable postural decrease in blood pressure (BP) but do not necessarily experience classic symptoms of syncope or pre-syncope. More typically, parkinsonian patients present with nonspecific dizziness after several minutes, increased falls, fatigue, and weakness. Conversely, PD patients may report symptoms suggestive of nOH, but measuring lying and standing BP after 3 min does not reveal a symptomatic fall in BP. Also problematic is that defining what constitutes a clinically relevant change in postural BP is not reliably known in the PD population, because definitions of nOH were determined from non-PD populations. Neurogenic orthostatic hypotension in PD can also be assessed using rating scales, which currently include subscores of the Unified Parkinson’s Disease Rating Scale or the Orthostatic Hypotension Questionnaire (OHQ), which is a 10-item scale covering symptoms such as lightheadedness/feeling faint, visual disturbance, and weakness while standing and walking. The study by Palma et al.1 published in this issue set out to determine BP parameters that are associated with symptomatic nOH in PD. The study recruited 210 participants with PD and compared supine BP after 20 min and then standing BP after 3 min and correlated changes with OHQ
------------------------------------------------------------
*Correspondence to: Dr. Connie Marras, Toronto Western Hospital, University of Toronto Neurology, Movement Disorders Centre, 11-MP, 399 Bathurst Street, Toronto, Ontario, Canada, E-mail: connie.marras@ utoronto.ca
Relevant conflicts of interest/financial disclosures: Nothing to report. Full financial disclosures and author roles may be found in the online version of this article. Received: 20 November 2014; Revised: 5 January 2015; Accepted: 8 January 2015 Published online 11 March 2015 in Wiley Online Library (wileyonlinelibrary.com) DOI: 10.1002/mds.26179
to determine what constitutes a hemodynamic target for treatment of symptomatic nOH. Overall approximately half had a postural drop in BP of any magnitude, but using a postural change of 20 mm Hg systolic or 10 mmHg diastolic, only 16% were symptomatic, and using a larger 30/15 mmHg change, only 13% were symptomatic. A mean upright BP of less than 75 mmHg, compared with greater than 75 mmHg, best discriminated those with symptoms of OH from those without. Thus, PD patients with a postural decrease in BP may not be symptomatic, and the absolute low BP, when upright, is most predictive of symptoms. Treating nOH in Parkinsonism currently relies on nonpharmacological approaches, such as reducing BPlowering drugs, ensuring adequate fluids, and salt supplementation. Specific drugs to increase standing BP currently rely on the use of general pressor agents, with no level 1 randomized controlled trials (RCTs) performed in PD subjects on which to make any evidencebased medicine (EBM) conclusions.2 Safety concerns with these drugs remain an issue, including hypokalemia with fludrocortisone and worsening existing supine hypertension with midodrine. Thus, clinical trials evaluating new agents in PD are welcome. One agent evaluated for nOH in PD is the noradrenaline precursor, L-threo-3,4-dihydroxyphenylserine or droxidopa, which is the subject of a clinical trial reported in this issue.3 Droxidopa is converted to noradrenaline (NA) via dopa-decarboxylase in the periphery. Autonomic failure in idiopathic PD and MSA results in either low or normal supine levels of NA and no elevation of NA on standing. The mechanism of action of droxidopa is thus likely through elevation of peripheral NA. On average, droxidopa elevates standing systolic BP by approximately 10 mmHg. Lying systolic BP is also elevated, and thus supine hypertension is a possible side effect of this drug. Dosing is required 3 times per day because peak action is approximately 2 to 3 h after ingestion. Droxidopa has been available in Japan since 1989 and received Food and Drug Administration approval in 2014 for short-term use in nOH in primary autonomic failure, PD, MSA, and nondiabetic autonomic
Movement Disorders, Vol. 30, No. 5, 2015
601
F O X
A N D
M A R R A S
neuropathy on the basis of short-term clinical trials. Study 3014 and study 3025 included all types of autonomic failure, whereas only subjects with PD were recruited to Study 306a6 and the report in this edition of the Journal, Study 306b.3 Studies 301 and 302 had similar designs with a pre-randomization open-label optimization stage followed by randomization of responders to 7 to 14 d of treatment. The primary outcome measure used the OHQ; with Study 3014 reporting a significant change in total OHQ score at 1 week. However, subgroup analysis of PD or MSA subjects alone showed no significant changes. Thus, the significant efficacy was driven by subjects with pure autonomic failure. Study 3025 used item 1 of the OHQ (“do you have dizziness, light-headedness, feeling faint or ‘feeling like you might black out’”) as primary outcome measure and reported no significant difference between droxidopa and placebo group. Tolerability was generally good, with the main side effects being headache, dizziness, nausea, and supine hypertension in 2% to 7%. The latest study (306) evaluated 225 subjects with symptomatic OH in PD over 10 weeks. The study was a double-blind, randomized trial of droxidopa compared with placebo. Initially designed to follow participants for the primary outcome of OHQ composite score at 8 weeks, a preplanned interim analysis of the first 51 participants (designated Study 306a; n 5 516) reported no significant difference between droxidopa and placebo. This knowledge, in combination with experience from previous studies in nOH, led to a change in the primary outcome measure to change item 1 of the OHQ between baseline and week 1. The study (designated 306b) evaluating the 171 subjects recruited subsequently is published in this issue.3 Hauser et al.6 report a significant change after 1 week of 22.3 points for droxidopa vs 21.3 points for placebo. The results of this study are in agreement with studies in other causes of nOH finding short-term benefit.4,5 Changes in the OHQ item 1 from baseline to weeks 2, 4, and 8 as well as effects of droxidopa on fall rates were secondary outcomes. Mean reduction in OHQ Item 1 was larger in the droxidopa arm at weeks 2, 4, and 8 but was not statistically significant. Number of falls suggested a benefit of droxidopa, with 229 falls reported in the droxidopa group compared with 716 in the placebo. Changes in lowest systolic blood pressure were not significantly different between the two arms across the weeks but were larger in the droxidopa arm. Side effects were significant in the droxidopa group, resulting in withdrawal in 12% because of headache and dizziness compared with 6% in placebo. Supine hypertension occurred in 7% of droxidopa groups versus 4% in placebo; however, this was only seen in first 2 weeks of treatment.
602
Movement Disorders, Vol. 30, No. 5, 2015
The change in outcome measure partway through this study raises questions about the validity of subsequent analyses. However, data from the first 51 participants were not used in the subsequent analyses, and as such the ‘study 306b’ can be thought of as a new study informed by the results of a pilot trial. These results do leave considerable uncertainty, however, about the effect of droxidopa on other aspects of OH beyond item 1 of the OHQ. For droxidopa to be a valuable treatment, it will be important that its effects go beyond reducing lightheadedness; improvements in function (reflected in the remainder of the OHQ) and reduction in falls would be highly desirable. Indeed the negative findings from study 306a in OHQ composite score suggest this is unlikely, but larger studies would be required to show this definitively. Regarding the apparent loss of effectiveness beyond 1 week, the authors postulate that this may be attributable to a loss of pretreatment adrenoceptor hypersensitivity with continued treatment, which potentially could be addressed with higher doses of medication, or to response shift in patient-reported lightheadedness or dizziness occurring with continued improvement, reducing the sensitivity of the OHQ question 1 to any improvement over time. The implications of these possibilities are severalfold: future studies may benefit from larger sample size, flexible dosing regimens to optimize response, and including primary outcomes that are meaningful to patients but at the same time less likely to suffer from effects such as response shifts; fall rate is an example. Based on these results, there are several issues with droxidopa for use in clinical practice: The indication for use is currently defined as per item 1 of the OHQ, that is, symptoms of dizziness, lightheadedness, feeling faint or ‘feeling like you might black out.’ Parkinson’s disease patients may not express these specific symptoms, and more exploratory questions may need to be asked to determine whether a PD patient has symptomatic OH. Droxidopa can elevate BP and therefore supine hypertension (defined in these studies as >180 mmHg systolic /110 mmHg diastolic after 10 min lying down) is still a problem and so will require management and monitoring. The labeling in the United States carries a black box warning. Co-prescribing of midodrine was disallowed in this study, and it should not be used with droxidopa. However, fludrocortisone was allowed. In clinical practice, where patients have responded partially to midodrine, clinicians will need guidance as to whether midodrine should be discontinued before trying droxidopa.
O R T H O S T A T I C
The use of dopa-decarboxylase inhibitors (DDCI) such as carbidopa or benserazide in levodopa preparations theoretically could reduce efficacy of droxidopa. Study 3014 showed that subjects on DDCI did not have significant improvement in either rise in systolic BP or change in OHQ composite score compared with non-users. If patients using DDCI do not benefit, this severely limits the usefulness of droxidopa in this population. Evidence for long-term use of droxidopa is lacking, and 1-week outcomes so far in randomized controlled trials (RCTs) are far too short for clinical usefulness. However, one open-label 3-month follow-up of study reported sustained improved OHQ.7 More long-term follow-up studies are needed. Where droxidopa will fit into treatment strategies for nOH is unclear. In clinical practice, patients will likely be prescribed droxidopa only when currently available agents have been tried and failed. Further studies are needed to guide treatment decisions.
H Y P O T E N S I O N
I N
P A R K I N S O N I S M
References 1.
Palma J, Gomez-Esteban J, Kaufmann L, Martinez J, Tijero B, Berganzo K, Kaufmann H. Orthostatic hypotension in Parkinson disease: how much you fall or how low you go? Mov Disord in press.
2.
Seppi, K, Weintraub D, Coelho M, Perez-Lloret S, Fox SH, Katzenschlager R, Hametner EM, Poewe W, Rascol O, Goetz CG, Sampaio S. Movement Disorder Society evidence-based medicine review update: treatments for the non-motor symptoms of Parkinson’s disease. Mov Disord 2011;26(Suppl 3):S42-S80.
3.
Hauser R, Isaacson S, Lisk JP, Hewitt LA, Rowse G. Droxidopa for the short-term treatment of symptomatic neurogenic orthostatic hypotension in Parkinson’s disease (nOH306B). Mov Disord in press.
4.
Kaufmann H, Freeman R, Biaggioni I, et al. Droxidopa for neurogenic orthostatic hypotension: a randomized, placebo-controlled, phase 3 trial. Neurology 2014;83:328-335.
5.
.Chelsea Therapeutics. Clinical study of droxidopa in patients with neurogenic orthostatic hypotension (NOH)(NOH302) [ClinicalTrials.gov identifier NCT00633880] US National Institues of Health, ClinicalTrials.gov.2014. [Accessed 2014 November 3]. Available from: http://www.clinicaltrials.gov/ct2/show/study/ NCT00633880.
6.
Hauser RA, Hewitt LA, Isaacson S. Droxidopa in patients with neurogenic orthostatic hypotension associated with Parkinson’s disease (NOH306A). J Parkinsons Dis 2014;4:57-65.
7.
Isaacson S, Shill H, Vernino S, et al. Durability of effect with longterm, open-label droxidopa treatment in patients with symptomatic neurogenic orthostatic hypotension (NOH 303) [abstract no. 1291]. Mov Disord 2012;27(Suppl 1):S424-S425.
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