Clinical benefit of midodrine hydrochloride in symptomatic orthostatic hypotension: a phase 4, double-blind, placebo-controlled, randomized, tilt-table study

Abstract

ObjectiveMidodrine hydrochloride is a short-acting pressor agent that raises blood pressure in the upright position in patients with orthostatic hypotension. The US Food and Drug Administration’s Subpart H approval, under which midodrine was initially approved, requires post-marketing studies to confirm midodrine’s clinical benefit in this indication. The purpose of this study was to evaluate the clinical benefit of midodrine with regard to symptom response.MethodsThis was a double-blind, placebo-controlled, randomized, crossover, multicenter study (NCT01518946). Following screening, patients aged ≥18 years with severe symptomatic orthostatic hypotension and on a stable dose of midodrine for at least 3 months were randomized to treatment with either their previous midodrine dose or placebo on day 1 and the respective alternate treatment on day 2. The primary endpoint measured time to syncopal symptoms or near-syncope using a 45-min tilt-table test at 1 h post-dose.ResultsThirty-three patients were screened for inclusion: 19 received at least one dose of midodrine and had at least one post-dose measurement of the primary endpoint. The least-squares mean time to syncopal symptoms or near-syncope after tilt-table initiation (mean ± standard error) was 1626.6 ± 186.8 s for midodrine and 1105.6 ± 186.8 s for placebo (difference, 521.0 s; 95 % confidence interval 124.2–971.7 s; p = 0.0131). There were 15 adverse events in 10 patients; all of these were mild or moderate in severity, with none considered by the investigators to be related to midodrine.InterpretationMidodrine is a well-tolerated and clinically effective treatment for symptomatic orthostatic hypotension.

Epidemiology, Diagnosis, and Management of Neurogenic Orthostatic Hypotension

“…Trials were randomized, double blind, and parallel‐design, and they enrolled patients with OH of different etiologies with supine‐to‐standing fall of systolic BP of at least 15 mm Hg accompanied by at least moderate dizziness/lightheadedness. A phase IV randomized, double‐blind, placebo‐controlled trial confirmed that midodrine also improves symptoms of OH …”

“…A phase IV randomized, double-blind, placebocontrolled trial confirmed that midodrine also improves symptoms of OH. 62 Administration of midodrine raises standing, sitting, and supine systolic and diastolic BP in patients with nOH. Standing systolic BP increases by 10 mm Hg to 30 mm Hg 1 h after a 10-mg dose of midodrine, with some effect persisting for 2 to 3 h. Treatment should begin with a 2.5-or 5-mg dose, which can then be increased up to 10 mg to be taken up to 3 times a day.…”

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

“…Indeed, a phase 4 tilt-table placebo-controlled trial with midodrine used time to symptoms of syncope or presyncope during passive head-up tilt as the main outcome measure. 41 As discussed earlier, this is a patient-reported outcome that represents a straightforward functional improvement.…”

“…Finally, some trials of nOH used the "time to symptoms after standing" as a patient-reported endpoint. 41 The primary outcome was the time since the tilt table is positioned in the 60-degree angle until the patient experiences symptoms of syncope or near syncope and asks to be tilted down. This endpoint has obvious advantages.…”

Leitlinienorientierte Diagnostik autonomer Störungen – vom Symptom zur Therapie

“…Allerdings ist Midodrin auch mit dem Auftreten einer Liegendhypertonie assoziiert und wird daher nicht bei Patienten empfohlen, die vor Beginn der Therapie im Liegen einen Blutdruck von über 170 mm Hg systolisch aufweisen. Wirksam ist Midodrin nahezu unabhängig von der, der orthostatischen Hypotonie zugrunde liegende Erkrankung [37]. ▶tab 2 Medikamente, die eine orthostatische Hypotonie auslösen oder verschlechtern können (basiert auf [33]…”