Share this article on:

Droxidopa in the Treatment of Postural Orthostatic Tachycardia Syndrome

Ruzieh, Mohammed MD; Dasa, Osama MD; Pacenta, Ann MD; Karabin, Beverly CNP, PhD; Grubb, Blair MD

doi: 10.1097/MJT.0000000000000468
Original Articles

Background: Postural orthostatic tachycardia syndrome (POTS) is a constellation of signs and symptoms that occur when a patient is upright and relieved by recumbence. Currently, no drugs are labeled for the treatment for POTS. Droxidopa is an orally administered amino acid that is converted to norepinephrine and thought to improve both blood pressure and symptoms in patients with orthostatic intolerance.

Study Question: To appraise the effect of Droxidopa in a clinical setting in patients with POTS refractory to other forms of treatment.

Study Design: A retrospective study of patients with POTS at our Syncope and Autonomic Disorders Center. Three hundred fifty-two patients were screened, 54 of them were prescribed Droxidopa and found to be eligible to include in our study.

Measures and Outcome: Symptoms of orthostatic intolerance, side effects of therapy and response to treatment. Statistical analyses were done using SPSS software. Thirty-seven patients were included in data analysis. Patients who failed to follow up, didn't obtain Droxidopa due to insurance and cost concerns, had hypertensive response to therapy or had allergic reaction were excluded from data analysis.

Results: The most frequently reported symptom was dizziness in 91.9% of patients, followed by syncope and fatigue in 70.3% and 67.6% of patients, respectively. Symptoms of dizziness, syncope and fatigue were reported less after treatment; 75.7%, 51.4% and 40.5%, respectively. There was no statistically significant difference in standing or sitting blood pressure before and after treatment. Despite the improvement in some symptoms. Only 27% of patients reported improved quality of life after treatment. Of total, 40.5% of patients stopped the treatment either due to side effects or ineffectiveness.

Conclusion: Droxidopa appears to improve some symptoms of orthostatic intolerance in patients with POTS but has diminutive impact on quality of life and blood pressure. Further assessment in large clinical trials is needed to evaluate its efficacy.

Departments of 1Internal Medicine and

2Cardiovascular, University of Toledo Medical Center, Toledo, OH.

Address for correspondence: Departments of Internal Medicine, University of Toledo Medical Center, 3000 Arlington Ave, Toledo, OH 43615. E-mail: mohammed_ruzieh@hotmail.com

The authors have no conflicts of interest to declare.

Back to Top | Article Outline

INTRODUCTION

Postural orthostatic tachycardia syndrome (POTS) is a chronic, potentially disabling condition with no clear pathologic substrate and multiple interacting pathophysiologic mechanisms.1 It is one of the most common manifestations of orthostatic intolerance.2,3

POTS is defined as the presence of orthostatic intolerance symptoms associated with an increase heart rate of 30 bpm or more (or heart rate that exceeds 120 bpm) that takes place within the first 10 minutes of standing or upright tilt, in the absence of any other chronic debilitating conditions such as prolonged bed rest or the use of medications known to contract vascular or autonomic tone.4

The manifestations of POTS that reflect orthostatic intolerance include those of cerebral hypoperfusion and reflex sympathetic activation. Up to one-third of patients may develop secondary orthostatically triggered vasovagal (reflex, neurally mediated) syncope.5 As in all types of orthostatic intolerance, typical exacerbating factors include heat exposure, physical exertion, heavy meals, prolonged recumbency, menses, and drugs such as diuretics and vasodilators.6

The pathophysiologic mechanisms of orthostatic intolerance in POTS are multifactorial and include hypovolemia, venous pooling, hyperadrenergic states, and restricted adrenergic neuropathies in the lower limb.1

POTS management requires multidisciplinary approach and multimodality treatment, including patient education, volume restitution, physical countermaneuvers, graded exercise training, and pharmacotherapy (fludrocortisone, midodrine, β-blockers, and/or pyridostigmine). To date, no drugs are labeled for treating patients with POTS.

Recently, FDA has approved Droxidopa for treatment of neurogenic orthostatic hypotension (NOH) on Feb 2014. Four short-term, randomized, double-blind, multicenter trials have examined the efficacy of Droxidopa in patients with NOH. The primary diagnosis of patients in these studies included the following: Parkinson disease, multiple system atrophy, pure autonomic failure, dopamine b-hydroxylase deficiency, or nondiabetic autonomic neuropathy.4,7–10. Droxidopa improved symptoms such as lightheadedness, fatigue, visual disturbances; and quality of daily activities in patients with NOH.7

POTS is distinct from orthostatic hypotension, nonetheless it is similar. Earlier studies suggested that midodrine, a vasoconstrictor through its α1 adrenoceptor agonist activity, is effective in the treatment of POTS,11,12 so we hypothesized that Droxidopa would be a safe alternative treatment for patients with refractory POTS through its vasoconstrictive activity.

Droxidopa, a norepinephrine prodrug, increases the amount of synaptic Norepinephrine that can bind to both alpha-2 and alpha-1 receptors, and so theoretically therefore improves both sympathetic splanchnic arterial vasoconstriction and sympathetic splanchnic venoconstriction in POTS and may represent an ideal drug to improve the orthostatic response in POTS.13 To our knowledge, no clinical trials have evaluated the response to Droxidopa in POTS.

Back to Top | Article Outline

METHODOLOGY

Study design

This was a retrospective study approved by our local institutional review board on a cohort of patients taking Droxidopa. We reviewed charts of 352 POTS patients seen at our autonomic center between January 2014 and September 2015 and found 54 patients eligible for inclusion in this study.

The primary endpoint was the improvement in symptoms and quality of life measures: palpitations, fatigue, lightheadedness, exercise intolerance, nausea, diminished concentration, tremulousness, syncope, and near syncope.

Patients were followed for up to a year. Information about the subjective symptoms and sense of well-being from each patient was collected from the patient's charts, physician communications, and direct patient inquiry. A treatment was considered successful if it provided symptomatic relief with or without a documented increase in blood pressure.

Patients were considered intolerant to Droxidopa if they developed side effects that lead to discontinuation of therapy.

Back to Top | Article Outline

Study population

Patients were drawn from those seen at the Syncope and Autonomic Disorders Center at the University of Toledo Medical Center.

We included all patients, males and females, aged 18–89, who were diagnosed with POTS, by medical history and other testing, who failed previous physical and pharmacologic therapies, and who were prescribed Droxidopa between January 2014 and September 2015 in our center as a last resort in their management.

Back to Top | Article Outline

Statistical analysis

We compared baseline characteristics for descriptive analysis. The data are observational and are presented as mean ± SD and percentages. Independent sample t test was used for continuous variables. Chi-square test was used for categorical variables. The level of significance was set at 0.05. Statistical analysis was performed using SPSS23.

Back to Top | Article Outline

Draft results

Out of 352 patients who follow at our Syncope and autonomic dysfunction clinic, 54 patients were prescribed Droxidopa, Figure 1.

FIGURE 1

FIGURE 1

Fourteen patients were excluded from the study either because of loss to follow-up or could not obtain the medication because of cost and insurance problems. Three patients were excluded from data analysis, 2 developed hypertensive reactions, and 1 developed a rash that warranted discontinuation of the treatment.

Out of the 37 patients included in the final data analysis, 15 patients stopped the medication because of the side effects or ineffectiveness.

Ten patients (27%) reported clinical and functional status improvement with treatment.

Thirty-seven patients were included in the final analysis, of which [28 (75.7%) were females], with a mean age of 48.08 ± 18.1 years, Table 1. The dose of Droxidopa ranged from 100 mg 3 times a day to 600 mg 3 times a day.

Table 1

Table 1

Back to Top | Article Outline

Effects on symptoms

The most frequently reported symptom was dizziness in 91.9% of patients, followed by syncope and fatigue in 70.3% and 67.6% of patients, respectively. Symptoms of dizziness, syncope, and fatigue were reported less after treatment; 75.7%, 51.4%, and 40.5%, respectively, Table 1.

Back to Top | Article Outline

Effects on hemodynamics

No statistically significant increase in standing or sitting blood pressure was noted in our patients before and after treatment, Table 2.

Table 2

Table 2

Back to Top | Article Outline

Side effects of therapy

The most commonly reported side effect was nausea/vomiting in 6 patients which warranted stopping therapy in all of them. Other side effects included urinary symptoms (2 patients) and chest pain/palpitations (2 patients), weight gain (1 patient), and insomnia in 1 patient, Table 3.

Table 3

Table 3

Back to Top | Article Outline

DISCUSSION

Droxidopa is an orally administered amino acid that is converted to norepinephrine14 and thought to improve both blood pressure and symptoms in patients with orthostatic intolerance.

In a double-blinded placebo-controlled trial, Droxidopa improved symptoms of NOH with maximum effect on lightheadedness and mean standing systolic blood pressure.7

Although there are limited data for the use of Droxidopa in NOH, its evidence for use in POTS is thin and lack supporting studies in the clinical settings. Accordingly, it is not approved for this purpose.

The hallmark of POTS is symptoms provoked by standing and relieved by recumbence with minimal or no change in orthostatic blood pressure15.

Droxidopa showed improvement in the symptoms of dizziness, syncope, and fatigue. However, only 27% of our patients reported improvement in functional status. Our review could not predict any specific patients' characteristics that can predict response to therapy.

Our analysis showed that Droxidopa tends to increase blood pressure parameters, which were consistent with what was instituted in other studies. Nonetheless, this increase was not statistically significant and did not seem to correlate with the improvement in symptoms.

Multiple side effects have been reported with the most common being gastrointestinal symptoms which in most cases justified discontinuation of therapy.

Cost is an important issue when prescribing Droxidopa, which caused many patients getting it few weeks after the first prescription or not getting it at all.

In conclusion, Droxidopa showed only modest clinical benefits in patients with refractory POTS. Nonetheless, this retrospective single-center study probably does not have the proper design or power to answer whether Droxidopa is useful in patients with POTS, and further evaluation in larger trials will be needed to evaluate its efficacy and safety.

Back to Top | Article Outline

LIMITATIONS

There are certain limitations in our study. First, our study population was small, and each patient was used as his/her own control.

The second important limitation is that, in our study population, Droxidopa was used in patients with severe POTS who were resistant to other medical therapies and those do not represent the majority of patients with POTS; further trials that would include POTS patients at less severe stages are warranted to assess efficacy in that population.

Lastly, the response rate seen in this study can be explained by the placebo effect of the medication, and a double-blinded placebo-controlled trial is warranted to answer this question.

Although this is a nonrandomized trial, its retrospective design prevented any selection bias and allowed us to study patients in the actual clinical settings.

Back to Top | Article Outline

REFERENCES

1. Benarroch EE. Postural tachycardia syndrome: a heterogeneous and multifactorial disorder. Mayo Clinic Proc. 2012;87:1214–1225.
2. Low PA, Opfer-Gehrking TL, Textor SC. Postural tachycardia syndrome (POTS). Neurology.1995;45(4 suppl 5):S19–S25.
3. Low PA, Sandroni P, Joyner M, et al Postural tachycardia syndrome (POTS). J Cardiovasc Electrophysiol. 2009;20:352–358.
4. Grubb BP, Row P, Calkins H. Postural tachycardia, orthostatic intolerance and the chronic fatigue syndrome. In: Grubb BP, Olshansky B, eds. Syncope: Mechanisms and Management 2nd ed. Malden, MA: Blackwell/uture Press; 2005:225–244.
5. Alshekhlee A, Guerch M, Ridha F, et al Postural tachycardia syndrome with asystole on head-up tilt. Clin Auton Res. 2008;18:36–39.
6. Mathias CJ, Low DA, Iodice V, et al Postural tachycardia syndrome—current experience and concepts. Nat Rev Neurol. 2011;8:22–34.
7. Kaufmann H, Freeman R, Biaggioni I, et al Droxidopa for neurogenic orthostatic hypotension: a randomized, placebo-controlled, phase 3 trial. Neurology. 2014;83:328–335.
8. Biaggioni I, Freeman R, Mathias CJ, et al Randomized withdrawal study of patients with symptomatic neurogenic orthostatic hypotension responsive to droxidopa. Hypertension. 2015;65:101–107.
9. Hauser RA, Hewitt LA, Isaacson S. Droxidopa in patients with neurogenic orthostatic hypotension associated with Parkinson's disease (NOH306A). J Parkinsons Dis. 2014;4:57–65.
10. Hauser RA, Isaacson S, Lisk JP, et al Droxidopa for the short term treatment of symptomatic neurogenic orthostatic hypotension in Parkinson's disease (nOH306B). Mov Disord. 2015;30:646–654.
11. Chen L, Wang L, Sun J, et al Midodrine hydrochloride is effective in the treatment of children with postural orthostatic tachycardia syndrome. Circ J. 2011;75:927–931.
12. Ross AJ, Ocon AJ, Medow MS, et al A double-blind placebo-controlled cross-over study of the vascular effects of midodrine in neuropathic compared with hyperadrenergic postural tachycardia syndrome. Clin Sci (lond). 2014;126:289–296.
13. Julian Stewart, New York Medical College, Droxidoba improves postural tachycardia syndrome (POTS) and postural vasovagal syncope (VVS), ClinicalTrials.gov Identifier: NCT02558972.
14. Kaufmann H, Saadia D, Voustianiouk A, et al Norepinephrine precursor therapy in neurogenic orthostatic hypotension. Circulation. 2003;108:724–728.
15. Grubb BP. Postural tachycardia syndrome. Circulation. 2008;117:2814–2817. doi: .
Keywords:

Droxidopa; POTS; autonomic dysfunction

Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved.