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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
In 1996, Shire received fast-track approval from the FDA to market midodrine for symptomatic OH, with 7 years of marketing exclusivity as an orphan drug. Approval was based on studies that demonstrated improvement in a surrogate outcome, 1-minute standing systolic blood pressure. The company agreed to complete additional studies to establish symptomatic efficacy.

In 2003, when marketing exclusivity ended, Shire discontinued the brand name product, leaving only generic products available. In 2010, the FDA proposed withdrawing approval of midodrine because Shire had failed to submit adequate postmarketing studies to establish symptomatic benefit. In 2012, Shire agreed to conduct 2 studies to establish the efficacy of midodrine for relieving OH symptoms.64

These studies have been completed, but not published. Preliminary results have been posted on,66 In a placebo-controlled tilt table test, the time to onset of syncope or near-syncope was significantly lon-ger with midodrine (1105.6 vs 1626.6 sec; mean difference 521 sec; 95% CI, 124.2-917.7; P = .0131).65 In a midodrine withdrawal study, 98 patients with severe OH were treat-ed with the midodrine regimen they had taken before the study. Patients were randomized to receive midodrine for 16 days or midodrine for 15 days followed by placebo on the last day. The primary outcome of the study was the percentage of patients who failed to maintain a response 30 minutes after the dose on day 16, with failure defined as either a 4-point increase on OHSA item 1 or an increase in syncopal or near-syncopal events within 15 minutes after standing. The percentage of patients who failed to maintain a response was 30.3% for midodrine and 44.1% for placebo (mean difference of 13.8%; 95% CI, −37.6 to 9.8; P = .3145).66 Patients and clinicians maintain that midodrine may have QOL and symptomatic benefits that the clinical trials have failed to identify.67 An independent systematic review evaluated symp-tom improvement and adverse effects of midodrine in clinical trials of symptomatic OH. There was high het-erogeneity (I2 = 73%) among 5 studies that were included in the analysis. The odds ratio for symptom improvement with midodrine was 3.9 (95% CI, 1.8-8.3), providing an NNT of 3 (95% CI, 2-7).68

Adverse Effects

Adverse effects reported with midodrine are related to its alpha-agonist activity. These include pilo-erection, pruritus (especially on the scalp), paresthesia, urinary reten-tion, and SH.48,69 The previously cited systematic review evaluated adverse effects with midodrine in clinical trials of symptomatic OH.63 The relative risk of a minor adverse event (primarily piloerection, paresthesias, chills, and GI discomfort) was 4.58 (95% CI, 2.03-10.37), providing an NNH of 8 (95% CI, 3-27). Based on data from 3 studies, midodrine increased the risk of SH (relative risk 5.31; 95% CI, 1.39-20.27), with an NNH of 14 (95% CI, 9-50).68 Drug Interactions Because midodrine is a direct alpha1-agonist, its effects are opposed by alpha1-antagonists.45 There is concern that co-administration of midodrine and digoxin or beta-blockers may cause bradycardia. Fludrocortisone Fludrocortisone is a mineralocorticoid that causes volume expansion by increasing renal sodium reabsorption.10 These effects normalize over time, so other mechanisms may be responsible for its effects in NOH. Unlike the sympathomimetic drugs, it has a long duration of action (biologic half-life of 18 to 36 hours).46 In addition, it had equivalent effects on standing and supine blood pressure in a study of patients with OH due to diabetic autonomic neuropathy.70 These properties raise concern about exacerbation of SH.10 Doses of 0.1 to 0.2 mg are suggested, but some patients can respond with up to 0.6 mg daily. Clinical Efficacy Clinical trials provide little evidence for the efficacy of fludrocortisone in NOH. In a double-blind crossover trial, fludrocortisone 0.1 mg twice daily improved orthostatic blood pressure measurements in 5 patients with NOH due to diabetic neuropathy.70,71 Increases in stand-ing blood pressure were reported with fludrocortisone plus head-up sleeping in an observational study of 8 patients with NOH.72 A Movement Disorder Society Task Force found insufficient evidence to evaluate the safety and efficacy of fludrocortisone for OH in PD.73 Adverse Effects Fludrocortisone can cause hypokalemia, pedal edema, SH, and glucocorticoid effects.45 In order to minimize the risk of these adverse effects, the lowest effective dose of fludrocortisone should be used. Weight gain is expected due to fluid retention; therefore, heart failure is a relative contraindication.7 To prevent hypokalemia, potassium levels should be monitored and potassium supplementa-tion provided if needed.

Additional Pharmacotherapy Options

Other drugs have been evaluated for treatment of NOH, but they do not have a well-defined role in management. These include non-steroidal anti-inflamma-tory drugs (primarily indomethacin), erythropoietin in patients with anemia, and desmopressin in patients with nocturnal polyuria.74-76 Octreotide and acarbose have been evaluated for postprandial hypotension.77,78

Atomoxetine inhibits norepinephrine reuptake by inhibiting the pre-synaptic norepinephrine transporter. In patients with NOH due to autonomic failure who have residual sympathetic activity, this has the potential to raise blood pressure by increasing synaptic nor-epinephrine levels.7 Atomoxetine displayed a pressor effect only in patients with central autonomic failure in a study that compared its effects in patients with central and peripheral autonomic failure.79 A placebo-controlled crossover study compared single doses of atomoxetine and midodrine in 65 patients with severe autonomic failure and NOH.80

At 1 minute, upright systolic blood pressure was significantly higher with atomoxetine than midodrine (means difference 7.5 mm Hg; 95% CI, 0.6-15; P = .03). Change in the OHQ total score was significantly greater with atomoxetine than placebo (0.4 points; 95% CI, −0.1 to −0.8; P = .02). The OHQ total score with midodrine was not significantly different from placebo (0.5 points; 95% CI, −0.1 to 1.0; P = .08). Further study is necessary to define the role of atomoxetine in NOH. The cholinesterase inhibitor pyridostigmine may increase standing blood pressure by increasing choliner-gic transmission in the autonomic ganglia.10 A potential advantage of pyridostigmine is that it has demonstrated little potential to cause SH. A randomized controlled trial evaluated a single dose of pyridostigmine alone or in combination with midodrine in 60 patients with NOH.81 It caused a modest increase in standing blood pressure that was associated with symptom improvement. A sur-vey reported moderate to marked symptom improvement in 17 of 20 patients who continued long-term treatment with pyridostigmine after the single-dose study.82 In a sec-ond study of patients with NOH and autonomic failure, pyridostigmine did not improve standing blood pressure or symptoms.83 Cholinergic adverse effects can limit the use of pyridostigmine in NOH.10

Author affiliation: Parkinson’s Disease and Movement Disorders Center of Boca Raton, Florida International University Herbert Wertheim College of Medicine.

Funding source: This activity is supported by an educational grant from Lundbeck, LLC.

Author disclosure: Dr. Isaacson has the following relevant commer-cial financial relationships or affiliations to disclose:

Grant/Research Support: Abbvie, Acadia, Acorda, Adamas, Addex, Amarantus, Auspex, Biotie, Cynapsus, Eisai, GE Healthcare, Ipsen, Kyowa, Lundbeck, Merz, Novartis, Neurocrine, Pfizer, Pharma2B, Roche, Santhera, Serono, Shire, Teva, UCB, US World Meds,

Xenoport Consultant: Acadia, Acorda, Allergan, Amarantus, Auspex, Biotie, Britannia, Cynapsus, Eisai, GE Healthcare, Impax, Ipsen, Kyowa, Lundbeck, Teva, UCB, US World Meds, Xenoport

Speaker’s Bureau: Abbvie, Acadia, Allergan, GE Healthcare, Impax, Lundbeck, Teva, UCB, US World Meds, Xenoport

Authorship information: Concept and design, acquisition of data, analysis and interpretation of data, drafting of the manuscript, and critical revision of the manuscript for important intellectual content.

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