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Supplements Understanding the Diagnosis, Management, and Treatment Options for Neurogenic Orthostatic Hypoten

Managed Care Approach to the Treatment of Neurogenic Orthostatic Hypotension

Stuart H. Isaacson, MD
OH is a major and independent risk factor for falls in elderly patients; in a large study of nursing home resi-dents, OH increased the risk of subsequent falls by 2.6-fold.40 In ambulatory patients who have PD, OH almost doubled the risk of falls (multivariate odds ratio 1.84; 95% CI, 1.02-3.31).26 A high incidence of fractures and trauma caused by falls has been documented in patients with severe NOH due to autonomic failure.41 The CDC has created a comprehensive fall prevention program called Stopping Elderly Accidents, Deaths and Injuries (STEADI) that has the potential to reduce morbidity from falls in patients with OH.42 It includes tools and educational materials for clinicians and an algorithm of fall risk assessment and interventions. One important component of this program is minimizing the use of drugs that increase the risk of a fall, including benzodiazepines and anticholinergic drugs. A practice guideline from the American Geriatric Society recommends that assess-ment and treatment of OH should be part of multifactorial interventions to prevent falls in elderly patients and those of any age who have gait or balance difficulties.43 This recommendation is based on results from 3 random-ized controlled trials that demonstrated a reduction in falls with multifactorial interventions, which included treatment of OH in addition to other interventions, such as medication reduction, optimization of fluids, and behavioral interventions.

Pharmacotherapy of NOH

The primary defect in NOH is the failure of sym-pathetic neurons to release norepinephrine and cause vasoconstriction. This defect is addressed directly by 2 sympathomimetic drugs approved by the FDA for the management of NOH: droxidopa and midodrine. The role of sympathomimetic drugs is to reduce orthostatic symptoms, prevent falls, and improve QOL.9 In addi-tion to sympathomimetic drugs, the mineralocorticoid fludrocortisone, which acts indirectly through volume expansion, is used off-label in NOH.10 Fludrocortisone is also considered for patients who cannot maintain plasma volume with salt and fluids alone or for those who do not get adequate symptom relief from a sympathomimetic drug.7,10 It is also an alternative for initial therapy in patients who do not have SH. Table 37,9,44-50 compares these pharmacotherapy options for NOH.

The presence of SH impacts treatment decisions for NOH (see Figure7,10,11). Uncontrolled SH induces a pressure diuresis that causes volume depletion and worsens orthostatic symptoms in the morning.9,51 Nonpharmacologic measures to manage SH include avoiding the supine posi-tion during the day and raising the head of the bed by 6 to 9 inches (>30 degrees).7 Also important for patients to know is that the increase in blood pressure from rapid water drinking is substantial enough that those with SH should avoid lying down within 2 hours afterward.52

Patients receiving pharmacotherapy for NOH should be advised to raise the head of the bed to minimize the risk of SH and to reduce nocturnal diuresis. For first-line treatment in patients with SH or heart failure, a sympathomimetic drug is preferred over fludro-cortisone. However, measures must still be taken to minimize the risk of SH with droxidopa and midodrine. Sympathomimetic drugs should be given as needed 30 to 45 minutes before patients with NOH intend to be upright.7 These drugs should not be used when patients intend to remain seated or supine. Product labeling for both droxidopa and midodrine includes a black box warning about the risk of SH; because of this risk, these drugs should not be taken at night.44,45 Specifically, the last dose of either drug should be taken at least 3 hours before bed. In addition, supine blood pressure should be monitored after dosage increases.

The 2-part Orthostatic Hypotension Questionnaire (OHQ) is used to assess symptomatic improvement of NOH in clinical trials and may be used to assess the response to pharmacotherapy in clinical practice. The 6-item Orthostatic Hypotension Symptom Assessment (OHSA) asks about dizziness/lightheadedness (OHSA item 1), vision disturbance, weakness, fatigue, trouble con-centrating, and head or neck discomfort. The Orthostatic Hypotension Daily Activity Scale (OHDAS) assesses the interference of NOH with standing and walking. Patients score items on a scale of 0 to 10. An improvement of 0.8 to 1.0 units is considered a minimal important change on the OHSA, OHDAS, and OHQ composite score.53 Ambulatory blood pressure monitoring also has a role in assessing the response to pharmacotherapy.54


Droxidopa is a synthetic amino acid prodrug that is converted to norepinephrine through decarboxylation by dopa decarboxylase. It was approved by the FDA in 2014 for the treatment of symptomatic NOH caused by primary autonomic failure, dopamine beta-hydroxylase deficiency, and nondiabetic autonomic neuropathy.44 More specifically, it was approved for orthostatic dizziness, lightheadedness, or for when a patient feels as if they may black out, (otherwise known as OHSA item 1). In a single-dose study of patients with NOH, the pressor effect of droxidopa had an onset at 1 hour and peaked 3.5 hours after the dose.47 The duration of action was 6 hours while standing and 8 hours while supine. A high-fat meal reduces peak levels by 35% and delays the time to peak levels by approximately 2 hours. Patients should be counseled to take droxidopa consistently either with or without food to account for this food effect.44

Clinical Efficacy

Droxidopa was evaluated in 3 phase 3 studies (301, 302, 306). Two of these trials (301, 302) enrolled patients with NOH due to PD, pure autonomic failure, MSA, nondiabetic autonomic neuropathy, or dopamine-beta-hydroxylase deficiency.55,56 The third trial (306) enrolled only patients with NOH caused by PD.57,58

Study 302 (the first phase 3 trial performed) had an open-label dose-optimization phase to identify droxi-dopa responders, followed by a 7-day open-label phase in which responders continued droxidopa treatment. Patients were then randomized to a 14-day double-blind withdrawal phase where they received droxidopa or placebo. Droxidopa was not more effective than placebo for the primary end point, OHSA item 1; however, a post hoc analysis found that the mean change in the OHQ composite score was significantly lower with droxidopa than with placebo (0.11 ± 2.18 vs 1.22 ± 2.39; P = .013).56

Study 301 (the second phase 3 trial performed) began with a dose-optimization phase to identify patients who responded to and tolerated droxidopa (n = 263). After a 7-day washout phase, responders received double-blind treatment with droxidopa (n = 82) or placebo (n = 80) for 1 week. The change in composite OHQ score from random-ization to week 1, the primary outcome, was −1.83 for droxi-dopa and −0.93 for placebo (treatment difference of 0.9; 95% CI, 0.30-1.48; P = .003). More patients had an improvement in the composite OHQ score of at least 3 units with droxi-dopa than with placebo (27.2% vs 11.4%; P = .016). Standing blood pressure also improved with droxidopa.55 The results of Study 301 led to a subsequent trial in patients with PD.

In study 306, which was the third phase 3 trial per-formed, patients initially entered a randomized double-blind dose-optimization phase in which they received droxidopa or placebo for up to 2 weeks before entering an 8-week treatment phase.58,59 After a planned interim analysis of the first 51 participants found no significant difference between droxidopa and placebo in the ini-tial primary end point of OHQ composite score, that analysis was designated as study 306a because of poten-tial unblinding. After discussion with the FDA, the pri-mary outcome was switched to a change in OHSA item 1 between baseline and week 1 and the subsequent 171 patients to enter the study were designated as study 306b,which became the pivotal trial supporting FDA approv-al.59 In Study 306b, the mean change in OHSA item 1 from randomization to week 1 was −2.3 for droxidopa and −1.3 for placebo (P <.05).58 Standing supine blood pressure also was significant over placebo at week 1.

Based on pooled data from studies 301 and 306, the number needed to treat (NNT) for at least 50% improve-ment in OSHA item 1 at 1 week was 5 (95% CI, 3-11). The number needed to harm (NNH) for development of hypertension was 28 (95% CI, 16-95). For discontinuation due to an adverse event, the NNH was 34. A response to droxidopa was 6.8 times more likely than an adverse event leading to discontinuation.60

The long-term efficacy of droxidopa has been evaluated in a 1-year open-label extension study (study 303) that enrolled 102 patients from studies 301 and 302. Patients received droxidopa for 3 months and then were randomized to receive droxidopa (n = 38) or placebo (n = 37) for 2 weeks. There was no significant difference between groups in the primary end point, mean change in composite OHQ score from baseline.43 However, after more than 1 year of open-label treatment with droxi-dopa, the changes from baseline in OHSA item 1 and OHQ composite scores were maintained.61,62 Droxidopa has demonstrated efficacy only in studies lasting less than 2 weeks.55,58 Product labeling recommends that patients be evaluated periodically to determine whether they con-tinue to benefit from droxidopa.44

Adverse Effects

The most commonly reported adverse effects with droxidopa in premarketing clinical trials were headache, dizziness, nausea, and hypertension.44 Adverse effects most often leading to discontinuation of droxidopa included hypertension and nausea. In Japan, where drox-idopa has been available since 1989, a symptom complex similar to neuroleptic malignant syndrome has been reported, but rarely.44,59

Drug Interactions

Many patients with PD receive carbidopa, a dopa decarboxylase inhibitor, in order to prevent conversion of levodopa to dopamine in the peripheral nervous system. A high single dose of carbidopa (200 mg) has been shown to inhibit the conversion of droxidopa to norepinephrine and abolish its pressor effect.47 Analysis of clinical trial data has not resolved the question of whether lower doses of carbidopa impair the efficacy of droxidopa.55 Droxidopa product labeling advises that dosage adjustment of droxidopa may be necessary if it is co-administered with carbidopa, and because of concerns about additive effects on SH, the product labeling recommends against co-administration of midodrine.43 Droxidopa has been given with fludrocortisone in some clinical trials; approximately 20% of patients in the droxi-dopa pivotal trials also used fludrocortisone.57,58


Droxidopa is considered a specialty drug that the manufacturer has made available through a specialty pharmacy distribution network.63 The prescriber and patient must complete prescription forms to obtain the drug. In order for patients to receive a trial of droxidopa, prior authorization procedures may require documenta-tion that the patient has not responded to or tolerated other drugs for NOH.


Midodrine is a direct alpha1-agonist that increases blood pressure by vasoconstriction. It is a prodrug that is metabolized to an active metabolite, desglymidodrine.38 Midodrine acts periph

Clinical Efficacy

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