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

Abstract

Neurogenic 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.

Evaluation and management of orthostatic hypotension: Limited data, limitless opportunity

“…Step 3 is drug treatment. Despite the absence of high-quality evidence to support their use, 13,14 the cornerstone drugs are fl udrocortisone, midodrine, and droxidopa; pyridostigmine and atomoxetine are used less often. Table 2 summarizes relevant pharmacologic and clinical features of these agents.…”

The Pathogenesis and Treatment of Cardiovascular Autonomic Dysfunction in Parkinson’s Disease: What We Know and Where to Go

“…Among them, about 16 to 20% of PD patients have symptomatic OH [ 10 , 11 ]. The symptoms of OH are mainly caused by insufficient perfusion of target organs [ 12 , 13 ]. For example, patients with cerebral hypoperfusion may show light-headedness, dizziness, vision loss, pre-syncope, or even syncope [ 14 - 16 ], whereas, patients with hypoperfusion within lung area may result in “coat hanger” pain or orthostatic dyspnea [ 17 , 18 ].…”

The 2021 Nobel Prize in Medicine and its relevance to autonomic medicine—and other updates on recent autonomic research

“…While looking at changes in orthostatic blood pressure instead may appear more reasonable, the health authorities, including the Food and Drug Administration, prioritize patient-reported outcomes, including symptoms and disability. Hence, the widespread use of the OHQ in clinical trials of nOH [14]. Theravance enrolled 195 patients with nOH caused by pure autonomic failure (PAF), Parkinson disease (PD), dementia with Lewy bodies (DLB), or MSA.…”