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Efficacy of atomoxetine versus midodrine for the treatment of orthostatic hypotension in autonomic failure.

ABSTRACT: The clinical presentation of autonomic failure is orthostatic hypotension. Severely affected patients require pharmacological treatment to prevent presyncopal symptoms or frank syncope. We previously reported in a proof of concept study that pediatric doses of the norepinephrine transporter blockade, atomoxetine, increases blood pressure in autonomic failure patients with residual sympathetic activity compared with placebo. Given that the sympathetic nervous system is maximally activated in the upright position, we hypothesized that atomoxetine would be superior to midodrine, a direct vasoconstrictor, in improving upright blood pressure and orthostatic hypotension-related symptoms. To test this hypothesis, we compared the effect of acute atomoxetine versus midodrine on upright systolic blood pressure and orthostatic symptom scores in 65 patients with severe autonomic failure. There were no differences in seated systolic blood pressure (means difference=0.3 mm Hg; 95% confidence [CI], -7.3 to 7.9; P=0.94). In contrast, atomoxetine produced a greater pressor response in upright systolic blood pressure (means difference=7.5 mm Hg; 95% CI, 0.6 to 15; P=0.03) compared with midodrine. Furthermore, atomoxetine (means difference=0.4; 95% CI, 0.1 to 0.8; P=0.02), but not midodrine (means difference=0.5; 95% CI, -0.1 to 1.0; P=0.08), improved orthostatic hypotension-related symptoms as compared with placebo. The results of our study suggest that atomoxetine could be a superior therapeutic option than midodrine for the treatment of orthostatic hypotension in autonomic failure.

SUBMITTER: Ramirez CE

PROVIDER: S-EPMC4231172 | biostudies-literature | 2014 Dec

REPOSITORIES: biostudies-literature

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Efficacy of atomoxetine versus midodrine for neurogenic orthostatic hypotension.

Project description:OBJECTIVE:The efficacy and safety of 1-month atomoxetine and midodrine therapies were compared. Three-month atomoxetine and combination therapies were investigated for additional benefits. METHODS:This prospective open-label randomized trial included 50 patients with symptomatic neurogenic orthostatic hypotension (nOH). The patients received either atomoxetine 18 mg daily or midodrine 5 mg twice daily and were evaluated 1 and 3 months later. Those who still met the criteria for nOH at 1 month received both midodrine and atomoxetine for an additional 2 months, and if not, they continued their initial medication. The primary outcome was an improvement in orthostatic blood pressure (BP) drop (maximum BP change from supine to 3 min after standing) at 1 month. The secondary endpoints were symptom scores, percentage of patients with nOH at 1 and 3 months. RESULTS:Patients with midodrine or atomoxetine treatment showed comparative improvement in the orthostatic BP drop, and overall only 26.2% of the patients had nOH at 1 month, which was similar between the treatment groups. Only atomoxetine resulted in significant symptomatic improvements at 1 month. For those without nOH at 1 month, there was additional symptomatic improvement at 3 months with their initial medication. For those with nOH at 1 month, the combination treatment resulted in no additional improvement. Mild-to-moderate adverse events were reported by 11.6% of the patients. INTERPRETATION:One-month atomoxetine treatment was effective and safe in nOH patients. Atomoxetine improved orthostatic BP changes as much as midodrine and was better in terms of ameliorating nOH symptoms.

| S-EPMC6952305 | biostudies-literature

Efficacy of Servo-Controlled Splanchnic Venous Compression in the Treatment of Orthostatic Hypotension: A Randomized Comparison With Midodrine.

Project description:Splanchnic venous pooling is a major hemodynamic determinant of orthostatic hypotension, but is not specifically targeted by pressor agents, the mainstay of treatment. We developed an automated inflatable abdominal binder that provides sustained servo-controlled venous compression (40 mm?Hg) and can be activated only on standing. We tested the efficacy of this device against placebo and compared it to midodrine in 19 autonomic failure patients randomized to receive either placebo, midodrine (2.5-10 mg), or placebo combined with binder on separate days in a single-blind, crossover study. Systolic blood pressure (SBP) was measured seated and standing before and 1-hour post medication; the binder was inflated immediately before standing. Only midodrine increased seated SBP (31±5 versus 9±4 placebo and 7±5 binder, P=0.003), whereas orthostatic tolerance (defined as area under the curve of upright SBP [AUCSBP]) improved similarly with binder and midodrine (AUCSBP, 195±35 and 197±41 versus 19±38 mm?Hg×minute for placebo; P=0.003). Orthostatic symptom burden decreased with the binder (from 21.9±3.6 to 16.3±3.1, P=0.032) and midodrine (from 25.6±3.4 to 14.2±3.3, P<0.001), but not with placebo (from 19.6±3.5 to 20.1±3.3, P=0.756). We also compared the combination of midodrine and binder with midodrine alone. The combination produced a greater increase in orthostatic tolerance (AUCSBP, 326±65 versus 140±53 mm?Hg×minute for midodrine alone; P=0.028, n=21) and decreased orthostatic symptoms (from 21.8±3.2 to 12.9±2.9, P<0.001). In conclusion, servo-controlled abdominal venous compression with an automated inflatable binder is as effective as midodrine, the standard of care, in the management of orthostatic hypotension. Combining both therapies produces greater improvement in orthostatic tolerance.URL: https://www.clinicaltrials.gov. Unique identifier: NCT00223691.

| S-EPMC4945429 | biostudies-literature

Midodrine for orthostatic hypotension: a systematic review and meta-analysis of clinical trials.

Project description:ObjectiveTo perform a systematic review and meta-analysis of clinical trials evaluating the efficacy and safety of midodrine in orthostatic hypotension (OH).MethodsWe searched major databases and related conference proceedings through June 30, 2012. Two reviewers independently selected studies and extracted data. Random-effects meta-analysis was used to pool the outcome measures across studies.ResultsSeven trials were included in the efficacy analysis (enrolling 325 patients, mean age 53 years) and two additional trials were included in the safety analysis. Compared to placebo, the mean change in systolic blood pressure was 4.9 mmHg (p = 0.65) and the mean change in mean arterial pressure from supine to standing was -1.7 mmHg (p = 0.45). The change in standing systolic blood pressure before and after giving midodrine was 21.5 mmHg (p < 0.001). A significant improvement was seen in patients' and investigators' global assessment symptoms scale (a mean difference of 0.70 [95 % CI 0.30-1.09; p < 0.001] and 0.80 [95 % CI 0.76-0.85; p < 0.001], respectively). There was a significant increase in risk of piloerection, scalp pruritis, urinary hesitancy/retention, supine hypertension and scalp paresthesia after giving midodrine. The quality of evidence was limited by imprecision, heterogeneity and increased risk of bias.ConclusionThere is insufficient and low quality evidence to support the use of midodrine for OH.

| S-EPMC3797331 | biostudies-literature

Synergistic Pressor Effect of Atomoxetine and Pyridostigmine in Patients With Neurogenic Orthostatic Hypotension.

Project description:Patients with autonomic failure are characterized by disabling orthostatic hypotension because of impaired sympathetic activity, but even severely affected patients have residual sympathetic tone which can be harnessed for their treatment. For example, norepinephrine transporter blockade with atomoxetine raises blood pressure (BP) in autonomic failure patients by increasing synaptic norepinephrine concentrations; acetylcholinesterase inhibition with pyridostigmine increases BP by facilitating ganglionic cholinergic neurotransmission to increase sympathetic outflow. We tested the hypothesis that pyridostigmine will potentiate the pressor effect of atomoxetine and improve orthostatic tolerance and symptoms in patients with severe autonomic failure. Twelve patients received a single oral dose of either placebo, pyridostigmine 60 mg, atomoxetine 18 mg or the combination on separate days in a single blind, crossover study. BP was assessed seated and standing before and 1-hour postdrug. In these severely affected patients, neither pyridostigmine nor atomoxetine improved BP or orthostatic tolerance compared with placebo. The combination, however, significantly increased seated BP in a synergistic manner (133±9/80±4 versus 107±6/66±4 mm Hg for placebo, 105±5/67±3 mm Hg for atomoxetine, and 99±6/64±4 mm Hg for pyridostigmine; P<0.001); the maximal increase in seated BP with the combination was 33±8/18±3 mm Hg at 60 minutes postdrug. Only the combination showed a significant improvement of orthostatic tolerance and symptoms. In conclusion, the combination pyridostigmine and atomoxetine had a synergistic effect on seated BP which was associated with improvement in orthostatic tolerance and symptoms. This pharmacological approach could be useful in patients with severe autonomic failure but further safety and long-term efficacy studies are needed.

| S-EPMC6309809 | biostudies-literature

Ampreloxetine Versus Droxidopa in Neurogenic Orthostatic Hypotension: A Comparative Review.

Project description:Neurogenic orthostatic hypotension (nOH) is a disabling problem of autonomic dysfunction in patients with Parkinson's disease, which is associated with poor quality of life and higher mortality rates. The purpose of this literature review was to explore and compare the efficacy and safety of droxidopa (an existing treatment) and ampreloxetine (a newer medication) in the treatment of nOH. We used a mixed-method literature review that addresses the epidemiology, pathophysiology, and pharmacological and non-pharmacological management of nOH in Parkinson's disease in a general way, with a more exploratory approach to droxidopa- and ampreloxetine-controlled trial studies. We included a total of 10 studies of randomized controlled trials with eight studies focused on droxidopa and two studies focused on ampreloxetine. These two drugs were analyzed and compared based on the collected individual study results. Treatment of nOH in Parkinson's disease patients with droxidopa or ampreloxetine showed clinically meaningful and statistically significant improvements relative to placebo on the components of the OHSA (Orthostatic Hypotension Symptom Assessment) composite score and OHDAS (Orthostatic Hypotension Daily Activity Scale composite scores) composite score. Droxidopa had an improved effect on daily activities, with an associated increase in standing systolic blood pressure (BP), but the long-term efficacy of droxidopa has not been documented. Standing systolic BP was maintained by ampreloxetine and worsened after the withdrawal phase. This highlights the importance of conducting further research which will help us to improve the therapeutic approach for patients with nOH and Parkinson's disease.

| S-EPMC10257554 | biostudies-literature

Orthostatic hypotension and incident heart failure in community-dwelling older adults.

Project description:To examine the association of orthostatic hypotension with incident heart failure (HF) in older adults.Of the 5,273 community-dwelling adults aged 65 years and older free of baseline prevalent HF in the Cardiovascular Health Study, 937 (18%) had orthostatic hypotension, defined as ?20 mmHg drop in systolic or ?10 mmHg drop in diastolic blood pressure from supine to standing position at 3 minutes. Of the 937, 184 (20%) had symptoms of dizziness upon standing and were considered to have symptomatic orthostatic hypotension. Propensity scores for orthostatic hypotension were estimated for each of the 5,273 participants and were used to assemble a cohort of 3,510 participants (883 participants with and 2,627 participants without orthostatic hypotension) who were balanced on 40 baseline characteristics. Cox regression models were used to estimate the association of orthostatic hypotension with centrally adjudicated incident HF and other outcomes during 13 years of follow-up.Participants (n = 3,510) had a mean (±standard deviation) age of 74 (±6) years, 58% were women, and 15% nonwhite. Incident HF occurred in 25% and 21% of matched participants with and without orthostatic hypotension, respectively (hazard ratio, 1.24; 95% confidence interval, 1.06-1.45; p = .007). Among matched participants, hazard ratios for incident HF associated with symptomatic (n = 173) and asymptomatic (n = 710) orthostatic hypotension were 1.57 (95% confidence interval, 1.16-2.11; p = .003) and 1.17 (95% confidence interval, 0.99-1.39; p = .069), respectively.Community-dwelling older adults with orthostatic hypotension have higher independent risk of developing new-onset HF, which appeared to be more pronounced in those with symptomatic orthostatic hypotension.

| S-EPMC4038247 | biostudies-literature

Management of Orthostatic Hypotension.

Project description:PURPOSE OF REVIEW:This article reviews the management of orthostatic hypotension with emphasis on neurogenic orthostatic hypotension. RECENT FINDINGS:Establishing whether the cause of orthostatic hypotension is a pathologic lesion in sympathetic neurons (ie, neurogenic orthostatic hypotension) or secondary to other medical causes (ie, non-neurogenic orthostatic hypotension) can be achieved by measuring blood pressure and heart rate at the bedside. Whereas fludrocortisone has been extensively used as first-line treatment in the past, it is associated with adverse events including renal and cardiac failure and increased risk of all-cause hospitalization. Distinguishing whether neurogenic orthostatic hypotension is caused by central or peripheral dysfunction has therapeutic implications. Patients with peripheral sympathetic denervation respond better to norepinephrine agonists/precursors such as droxidopa, whereas patients with central autonomic dysfunction respond better to norepinephrine reuptake inhibitors. SUMMARY:Management of orthostatic hypotension is aimed at improving quality of life and reducing symptoms rather than at normalizing blood pressure. Nonpharmacologic measures are the key to success. Pharmacologic options include volume expansion with fludrocortisone and sympathetic enhancement with midodrine, droxidopa, and norepinephrine reuptake inhibitors. Neurogenic supine hypertension complicates management of orthostatic hypotension and is primarily ameliorated by avoiding the supine position and sleeping with the head of the bed elevated.

| S-EPMC7339914 | biostudies-literature

The efficacy of nonpharmacologic intervention for orthostatic hypotension associated with aging.

Project description:ObjectiveTo determine the efficacy and safety of nonpharmacologic interventions for orthostatic hypotension (OH) secondary to aging.MethodsA total of 150 orthostatic challenges were performed in 25 older people (age 60-92 years) to determine cardiovascular responses to bolus water drinking, compression stockings, abdominal compression, and physical countermaneuvers. Primary outcome was response rate as assessed by proportion of participants whose systolic blood pressure (SBP) drop improved by ≥10 mm Hg.ResultsThe response rate to bolus water drinking was 56% (95% confidence interval [CI] 36.7-74.2), with standing SBP increasing by 12 mm Hg (95% CI 4-20). Physical countermaneuvers were efficacious in 44% (95% CI 25.8-63.3) but had little effect on standing SBP (+7.5 mm Hg [95% CI -1 to 16]). Abdominal compression was efficacious in 52% (95% CI 32.9-70.7) and improved standing SBP (+10 mm Hg [95% CI 2-18]). Compression stockings were the least efficacious therapy (32% [95% CI 16.1-51.4]) and had little effect on standing SBP (+6 mm Hg [95% CI -1, 13]). No intervention improved symptoms during standing. There were no adverse events.ConclusionsBolus water drinking should become the standard first-line nonpharmacologic intervention, whereas compression stockings should be disregarded in this population.Classification of evidenceThis study provides Class III evidence that for older people with OH, bolus water drinking is superior to other nonpharmacologic interventions in decreasing SBP drop.

| S-EPMC6105042 | biostudies-literature

Orthostatic Headaches Associated With Spontaneous Intracranial Hypotension and Autonomic Dysfunction-A Case Series in Young Patients.

Project description:Background: Orthostatic headaches can be noted in spontaneous intracranial hypotension and orthostatic intolerance. We present a case series of young patients diagnosed with spontaneous intracranial hypotension and were treated for the same but subsequently developed orthostatic intolerance. Methods: We retrospectively reviewed charts for seven young patients with orthostatic headaches related to spontaneous intracranial hypotension and orthostatic intolerance. Results: Patients were diagnosed with spontaneous intracranial hypotension. Diagnosis was confirmed by identifying epidural contrast leakage and three of seven patients were noted to have early renal contrast excretion on computerized tomography myelography. Patients were treated with epidural blood patches. All patients showed persistent symptoms of autonomic dysfunction after treatment of spontaneous intracranial hypotension and orthostatic intolerance was confirmed with head-up tilt table test. Conclusions: Patients with spontaneous intracranial hypotension failing to improve following epidural blood patching should be evaluated for orthostatic intolerance.

| S-EPMC8619734 | biostudies-literature

Orthostatic Hypotension in Parkinson Disease.

Project description:Orthostatic hypotension (OH) is a sustained fall in blood pressure on standing that can cause symptoms of organ hypoperfusion. OH is associated with increased morbidity and mortality and leads to a significant number of hospital admissions. OH can be caused by volume depletion, blood loss, cardiac pump failure, large varicose veins, medications, or defective activation of sympathetic nerves and reduced norepinephrine release upon standing. Neurogenic OH is a frequent and disabling problem in patients with synucleinopathies such as Parkinson disease, multiple system atrophy, and pure autonomic failure, and it is commonly associated with supine hypertension. Several therapeutic options are available.

| S-EPMC7029426 | biostudies-literature

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