Clinical Trials for Neurogenic Orthostatic Hypotension: A Comprehensive Review of Endpoints, Pitfalls, and Challenges

AbstractNeurogenic orthostatic hypotension (nOH) is among the most debilitating nonmotor features of patients with Parkinson's disease (PD) and other synucleinopathies. Patients with PD and nOH generate more hospitalizations, make more emergency room visits, create more telephone calls/mails to doctors, and have earlier mortality than those with PD but without nOH. Overall, the health-related cost in patients with PD and OH is 2.5-fold higher compared with patients with PD without OH. Hence, developing effective therapies for nOH should be a research priority. In the last few decades, improved understanding of the pathophysiology of nOH has led to the identification of therapeutic targets and the development and approval of two drugs, midodrine and droxidopa. More effective and safer therapies, however, are still needed, particularly agents that could selectively increase blood pressure only in the standing position because supine hypertension is the main limitation of available drugs. Here we review the design and conduct of nOH clinical trials in patients with PD and other synucleinopathies, summarize the results of the most recently completed and ongoing trials, and discuss challenges, bottlenecks, and potential remedies.

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Standing and Supine Blood Pressure Outcomes Associated With Droxidopa and Midodrine in Patients With Neurogenic Orthostatic Hypotension: A Bayesian Meta-analysis and Mixed Treatment Comparison of Randomized Trials

Annals of Pharmacotherapy ◽

10.1177/1060028018786954 ◽

2018 ◽

Vol 52 (12) ◽

pp. 1182-1194 ◽

Cited By ~ 7

Author(s):

Jack J. Chen ◽

Yi Han ◽

Jonathan Tang ◽

Ivan Portillo ◽

Robert A. Hauser ◽

...

Keyword(s):

Blood Pressure ◽

Orthostatic Hypotension ◽

Fixed Effects ◽

Randomized Trials ◽

Meta Analysis ◽

Mixed Treatment Comparison ◽

Neurogenic Orthostatic Hypotension ◽

Supine Hypertension ◽

Treatment Comparison ◽

Mixed Treatment

Background: The comparative effects of droxidopa and midodrine on standing systolic blood pressure (sSBP) and risk of supine hypertension in patients with neurogenic orthostatic hypotension (NOH) are unknown. Objective: To perform a Bayesian mixed-treatment comparison meta-analysis of droxidopa and midodrine in the treatment of NOH. Methods: The PubMed, CENTRAL, and EMBASE databases were searched up to November 16, 2016. Study selection consisted of randomized trials comparing droxidopa or midodrine with placebo and reporting on changes in sSBP and supine hypertension events. Data were pooled to perform a comparison among interventions in a Bayesian fixed-effects model using vague priors and Markov chain Monte Carlo simulation with Gibbs sampling, calculating pooled mean changes in sSBP and risk ratios (RRs) for supine hypertension with associated 95% credible intervals (CrIs). Results: Six studies (4 administering droxidopa and 2 administering midodrine) enrolling a total of 783 patients were included for analysis. The mean change from baseline in sSBP was significantly greater for both drugs when compared with placebo (droxidopa 6.2 mm Hg [95% CrI = 2.4-10] and midodrine 17 mm Hg [95% CrI = 11.4-23]). Comparative analysis revealed a significant credible difference between droxidopa and midodrine. The RR for supine hypertension was significantly greater for midodrine, but not droxidopa, when compared with placebo (droxidopa RR = 1.4 [95% CrI = 0.7-2.7] and midodrine RR = 5.1 [95% CrI = 1.6-24]). Conclusion and Relevance: In patients with NOH, both droxidopa and midodrine significantly increase sSBP, the latter to a greater extent. However, midodrine, but not droxidopa, significantly increases risk of supine hypertension.

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The impact of supine hypertension on target organ damage and survival in patients with synucleinopathies and neurogenic orthostatic hypotension

Parkinsonism & Related Disorders ◽

10.1016/j.parkreldis.2020.04.011 ◽

2020 ◽

Vol 75 ◽

pp. 97-104 ◽

Cited By ~ 1

Author(s):

Jose-Alberto Palma ◽

Gabriel Redel-Traub ◽

Angelo Porciuncula ◽

Daniela Samaniego-Toro ◽

Patricio Millar Vernetti ◽

...

Keyword(s):

Orthostatic Hypotension ◽

Target Organ Damage ◽

Organ Damage ◽

Target Organ ◽

Neurogenic Orthostatic Hypotension ◽

Supine Hypertension ◽

The Impact

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Managing supine hypertension in a patient with non-diabetic autonomic neuropathy receiving droxidopa for neurogenic orthostatic hypotension

Clinical Autonomic Research ◽

10.1007/s10286-017-0436-4 ◽

2017 ◽

Vol 27 (S1) ◽

pp. 35-37 ◽

Cited By ~ 1

Author(s):

Steven Vernino ◽

Mark Lew ◽

Daniel Kremens

Keyword(s):

Orthostatic Hypotension ◽

Autonomic Neuropathy ◽

Diabetic Autonomic Neuropathy ◽

Neurogenic Orthostatic Hypotension ◽

Supine Hypertension

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Management of supine hypertension in patients with neurogenic orthostatic hypotension

Journal of Hypertension ◽

10.1097/hjh.0000000000002078 ◽

2019 ◽

Vol 37 (8) ◽

pp. 1541-1546 ◽

Cited By ~ 16

Author(s):

Jens Jordan ◽

Alessandra Fanciulli ◽

Jens Tank ◽

Giovanna Calandra-Buonaura ◽

William P. Cheshire ◽

...

Keyword(s):

Orthostatic Hypotension ◽

Neurogenic Orthostatic Hypotension ◽

Supine Hypertension

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Management Strategies for Comorbid Supine Hypertension in Patients with Neurogenic Orthostatic Hypotension

Current Neurology and Neuroscience Reports ◽

10.1007/s11910-021-01104-3 ◽

2021 ◽

Vol 21 (4) ◽

Author(s):

Stuart H. Isaacson ◽

Khashayar Dashtipour ◽

Ali A. Mehdirad ◽

Amanda C. Peltier

Keyword(s):

Orthostatic Hypotension ◽

Treatment Approach ◽

Management Strategies ◽

Neurogenic Orthostatic Hypotension ◽

Supine Hypertension ◽

Individualized Approach ◽

Short And Long Term ◽

Cerebrovascular Risk ◽

Pharmacologic Treatments

AbstractPurpose of ReviewIn autonomic failure, neurogenic orthostatic hypotension (nOH) and neurogenic supine hypertension (nSH) are interrelated conditions characterized by postural blood pressure (BP) dysregulation. nOH results in a sustained BP drop upon standing, which can lead to symptoms that include lightheadedness, orthostatic dizziness, presyncope, and syncope. nSH is characterized by elevated BP when supine and, although often asymptomatic, may increase long-term cardiovascular and cerebrovascular risk. This article reviews the pathophysiology and clinical characteristics of nOH and nSH, and describes the management of patients with both nOH and nSH.Recent FindingsPressor medications required to treat the symptoms of nOH also increase the risk of nSH. Because nOH and nSH are hemodynamically opposed, therapies to treat one condition may exacerbate the other. The management of patients with nOH who also have nSH can be challenging and requires an individualized approach to balance the short- and long-term risks associated with these conditions.SummaryApproaches to manage neurogenic BP dysregulation include nonpharmacologic approaches and pharmacologic treatments. A stepwise treatment approach is presented to help guide neurologists in managing patients with both nOH and nSH.

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Case 40: Parkinson’s Disease with Compensated Orthostatic Hypotension

Autonomic Testing ◽

10.1093/med/9780190889227.003.0045 ◽

2019 ◽

pp. 233-236

Author(s):

Peter Novak

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Blood Flow ◽

Cerebral Blood Flow ◽

Orthostatic Hypotension ◽

Autonomic Failure ◽

Neurogenic Orthostatic Hypotension ◽

Supine Hypertension ◽

Reduced Flow

Autonomic failure manifesting as neurogenic orthostatic hypotension and supine hypertension are common manifestations of cardiovascular dysautonomia in Parkinson’s disease. Depending on the cerebral blood flow, neurogenic orthostatic hypotension can be either compensated (with stable orthostatic cerebral blood flow) and noncompensated (with reduced flow).

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