Droxidopa for neurogenic orthostatic hypotension

Abstract

Objective:To determine whether droxidopa, an oral norepinephrine precursor, improves symptomatic neurogenic orthostatic hypotension (nOH).Methods:Patients with symptomatic nOH due to Parkinson disease, multiple system atrophy, pure autonomic failure, or nondiabetic autonomic neuropathy underwent open-label droxidopa dose optimization (100–600 mg 3 times daily), followed, in responders, by 7-day washout and then a 7-day double-blind trial of droxidopa vs placebo. Outcome measures included patient self-ratings on the Orthostatic Hypotension Questionnaire (OHQ), a validated, nOH-specific tool that assesses symptom severity and symptom impact on daily activities.Results:From randomization to endpoint (n = 162), improvement in mean OHQ composite score favored droxidopa over placebo by 0.90 units (p = 0.003). Improvement in OHQ symptom subscore favored droxidopa by 0.73 units (p = 0.010), with maximum change in “dizziness/lightheadedness.” Improvement in symptom-impact subscore favored droxidopa by 1.06 units (p = 0.003), with maximum change for “standing a long time.” Mean standing systolic blood pressure (BP) increased by 11.2 vs 3.9 mm Hg (p < 0.001), and mean supine systolic BP by 7.6 vs 0.8 mm Hg (p < 0.001). At endpoint, supine systolic BP >180 mm Hg was observed in 4.9% of droxidopa and 2.5% of placebo recipients. Adverse events reported in ≥3% of double-blind droxidopa recipients were headache (7.4%) and dizziness (3.7%). No patients discontinued double-blind treatment because of adverse events.Conclusions:In patients with symptomatic nOH, droxidopa improved symptoms and symptom impact on daily activities, with an associated increase in standing systolic BP, and was generally well tolerated.Classification of evidence:This study provides Class I evidence that in patients with symptomatic nOH who respond to open-label droxidopa, droxidopa improves subjective and objective manifestation of nOH at 7 days.

Safety and Durability of Effect with Long-Term, Open-Label Droxidopa Treatment in Patients with Symptomatic Neurogenic Orthostatic Hypotension (NOH303)

“…A decrease in symptom severity of approximately 50% was observed after 1 month of treatment with droxidopa and was sustained through 12 months of patient follow-up (among patients available for analysis at each time point). These results are consistent with the findings of shorter-term studies and extend previous reports by demonstrating a durability of effect for droxidopa lasting through 1 year of treatment [7][8][9][10]. Additionally, although dose adjustments and concomitant medications for the treatment of nOH were allowed per the study protocol, there was no marked trend for increased dosing of droxidopa or increased use of fludrocortisone over time, further suggesting maintenance of droxidopa efficacy.…”

“…This open-label extension patient population reflects the common clinical scenario where patients who demonstrate initial symptomatic benefit typically remain on treatment. The pattern of AEs observed was qualitatively consistent with the safety and tolerability profile demonstrated for droxidopa in short-term clinical studies [7,8,10], and there were no new or unexpected safety signals. The low incidence of supine hypertension, defined as SBP >180 mmHg, (3.8% to 12.3%) observed through 12 months of follow-up in our study was comparable to the 7.9% and 10.9% incidences previously reported in similar study populations ≤2 weeks of treatment with droxidopa [8,10].…”

“…To date, randomized clinical studies demonstrating the efficacy of droxidopa for the treatment of nOH have been short term, with a maximum duration of exposure of 10 weeks [7][8][9][10]. This 12-month open-label extension study assessed the long-term safety and durability of efficacy of droxidopa in one of the largest long-term cohorts to date of patients with nOH.…”

“…All patients had previously reported an improvement of symptoms (with or without a blood pressure response) during the open-label dose-optimization period of 1 of 2 previous droxidopa studies (NOH301 [NCT00782340] [7] or NOH302 [NCT00633880] [10]). Key exclusion criteria were current use of vasoconstrictor agents (eg, midodrine), long-acting antihypertensive drugs, or norepinephrine reuptake inhibitors; preexisting sustained severe hypertension (seated blood pressure ≥180/110 mmHg); significant systemic, hepatic, cardiac, or renal disorders; known or suspected malignancy; a history of closed-angle glaucoma; or diabetes mellitus or diabetes insipidus.…”

“…The conversion of droxidopa, a synthetic amino acid analog, into norepinephrine by dopadecarboxylase is thought to underlie its efficacy; norepinephrine increases blood pressure by inducing vasoconstriction [6]. Results of 2 short-term, randomized controlled clinical studies have demonstrated the tolerability of droxidopa and suggest that it is effective in providing relief of nOH symptoms [7][8][9].…”