Safety and efficacy of ampreloxetine in symptomatic neurogenic orthostatic hypotension: a phase 2 trial

Purpose In neurogenic orthostatic hypotension, blood pressure falls when upright owing to impaired release of norepinephrine, leading to dizziness. Ampreloxetine, a selective norepinephrine reuptake inhibitor, increases circulating norepinephrine levels. This study explored the safety of ampreloxetine and its effect on blood pressure and symptoms in patients with neurogenic orthostatic hypotension. Methods A multicenter ascending-dose trial (range 1–20 mg, Part A) was followed by a 1 day, double-blind, randomized, placebo-controlled study (median dose 15 mg, Part B). Eligible patients then enrolled in a 20-week, open-label, steady-state extension phase (median dose 10 mg, Part C) followed by a 4-week withdrawal. Assessments included the Orthostatic Hypotension Symptom Assessment Scale (item 1), supine/seated/standing blood pressure, and safety. Results Thirty-four patients (age 66 ± 8 years, 22 men) were enrolled. Part A: The proportion of participants with a positive response (i.e., increase from baseline in seated systolic blood pressure of ≥ 10 mmHg) was greater with the 5 and 10 mg ampreloxetine doses than with placebo or other active ampreloxetine doses. Part B: Seated blood pressure increased 15.7 mmHg 4 h after ampreloxetine and decreased 14.2 mmHg after placebo [least squares mean difference (95% CI) 29.9 mmHg (7.6–52.3); P = 0.0112]. Part C: Symptoms of dizziness/lightheadedness improved 3.1 ± 3.0 points from baseline and standing systolic blood pressure increased 11 ± 12 mmHg. After 4 weeks of withdrawal, symptoms returned to pretreatment levels. The effect of ampreloxetine on supine blood pressure was minimal throughout treatment duration. Conclusion Ampreloxetine was well tolerated and improved orthostatic symptoms and seated/standing blood pressure with little change in supine blood pressure. Trial registration NCT02705755 (first posted March 10, 2016).

Neurogenic Orthostatic Hypotension: State of the Art and Therapeutic Strategies

Neurogenic orthostatic hypotension (nOH) is a subtype of orthostatic hypotension in which patients have impaired regulation of standing blood pressure due to autonomic dysfunction. Several primary and secondary causes of this disease exist. Patients may present with an array of symptoms making diagnosis difficult. This review article addresses the epidemiology, pathophysiology, causes, clinical features, and management of nOH. We highlight various pharmacological and non-pharmacological approaches to treatment, and review the recent guidelines and our approach to nOH.

Diagnostic evaluation

When a patient presents with transient loss of consciousness (T-LOC), the history, usually initially derived from a general practitioner or ambulance personnel, is most important to determine whether it is indeed T-LOC. If so, more history taking is of paramount importance to differentiate between the different forms of T-LOC: syncope, epileptic seizures, or psychogenic attacks. When T-LOC is syncope and epileptic seizures and psychogenic attacks are less likely, the initial syncope evaluation should address the different forms of syncope: reflex syncope, orthostatic hypotension, or cardiac syncope. The initial syncope evaluation consists of (1) more detailed and careful history taking, (2) a physical examination, including supine and standing blood pressure measurements, and (3) an electrocardiogram. When the initial syncope evaluation does not yield either a certain or a highly likely diagnosis, the next step is to perform risk stratification of major cardiovascular events including sudden death. The subsequent evaluation will be determined by the causal risk.

Comparison of baroreflex sensitivity with a fall and rise in blood pressure induced by the Valsalva manoeuvre

The baroreflexes are essential in maintaining standing blood pressure. In the present study, we describe and validate an accurate and relatively simple method of evaluating baroreflexes in the clinical laboratory using heart period responses to both a rise and fall in blood pressure.