Efficacy of Atomoxetine Versus Midodrine for the Treatment of Orthostatic Hypotension in Autonomic FailureNovelty and Significance
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.
The autonomic nervous system is responsible for maintaining blood pressure in the upright position. When this system fails, as in autonomic failure, orthostatic hypotension (OH) occurs. Severely affected patients with autonomic failure can stand only for a few minutes before developing disabling presyncopal symptoms or frank syncope. Although nonpharmacological measures, such as physical countermaneuvers and the use of compression garments, are the first step in the treatment of OH,1 these interventions may not suffice to improve standing blood pressure and control OH-related symptoms. Thus, the use of pharmacological agents often becomes necessary.2
The α1 adrenergic agonist midodrine has become the mainstay treatment in patients with autonomic failure and neurogenic OH. This drug induces direct vasoconstriction and improves upright systolic blood pressure (SBP) after acute and chronic administration.3–5The Food and Drug Administration (FDA), however, recently proposed the withdrawal of midodrine because of the lack of postmarketing studies supporting its clinical efficacy in reducing symptoms.6,7 More recently, droxidopa was approved by the FDA for the treatment of OH as a synthetic prodrug to norepinephrine and epinephrine. This drug, however, is still not commercially available, and there is no information about its long-term efficacy and safety.
We and others have reported that, even in patients with severe autonomic failure, there is some degree of residual sympathetic activity. For instance, patients with multiple systems atrophy have intact peripheral noradrenergic fibers,8 despite impairment in central autonomic pathways. In patients with pure autonomic failure, the peripheral noradrenergic denervation9 is heterogeneous and does not occur in all vascular beds.10 This raises the possibility that blockade of the norepinephrine transporter (NET), which increases the availability of norepinephrine in the synaptic gap, may be an effective therapy in autonomic failure. Indeed, our proof of concept study showed that acute administration of atomoxetine, a selective NET blocker, is an effective pressor agent in autonomic failure.11 Considering that the sympathetic nervous system is maximally activated in the upright position, the purpose of this study was to test the hypothesis that atomoxetine is better than midodrine in improving upright SBP in patients with neurogenic OH.
Patients with severe autonomic failure (pure autonomic failure, multiple systems atrophy, and Parkinson’s disease)12 were recruited from referrals to the Paden Autonomic Dysfunction Center at Vanderbilt University. The diagnosis of autonomic failure was confirmed using standardized autonomic function testing.13,14⇓ OH was defined as a decrease in SBP of ≥20 mm Hg or diastolic blood pressure (DBP) of ≥10 mm Hg within 3 minutes of standing or 60° head-up tilt.15 Patients were excluded if they had autonomic failure secondary to diabetes mellitus, amyloidosis, or paraneoplastic syndrome. All studies adhered to the principles of the Declaration of Helsinki and Title 45, US Code of Federal Regulations, Part 46, Protection of Human Subjects. The study was approved by the Vanderbilt Institutional Review Board, and studies were conducted in accordance with institutional guidelines. All subjects provided written informed consent. The study was registered at ClinicalTrials.gov under “Treatment of Orthostatic Hypotension in Autonomic Failure” (NCT00223691).
All subjects were admitted to the Vanderbilt Clinical Research Center. Patients were fed a low-monoamine, caffeine-free diet containing 150 mEq/day sodium and 60 to 80 mEq/day potassium for ≥3 days before evaluation. Medications affecting the autonomic nervous system, blood pressure, and blood volume were discontinued for ≥5 half-lives before admission.
All studies were conducted in the morning, in a postvoid state, ≥2.5 hours after breakfast to avoid the postprandial hemodynamic effects. On separate days, patients were given atomoxetine (18 mg; Eli Lilly Pharmaceuticals, Indianapolis, IN), midodrine (5–10 mg; Shire Pharmaceuticals Inc., Wayne, PA), or placebo in a randomized, single-blind, crossover fashion. Studies were conducted with the patients seated in a chair, with their feet on the floor.
During baseline, SBP, DBP, and heart rate (HR) were measured every 5 minutes for 30 minutes. Orthostatic vital signs were obtained at 1, 3, 5, and 10 minutes or until tolerated. The patients were asked to rate their OH-related symptoms using the Orthostatic Hypotension Questionnaire (OHQ).16 The study drug was then administered, and the SBP, DBP, and HR were assessed every 5 minutes for 60 minutes. We repeated the orthostatic vital signs assessment and symptom evaluation at the end of this period, as described previously. Blood pressure and HR were measured using an automated brachial sphygmomanometer (Dinamap; GE Medical Systems Information Technologies, Milwaukee, WI). Data were digitally transferred into a custom-designed database (Access; Microsoft Corporation, Bellevue, WA).
The hemodynamic parameters and symptom questionnaires were evaluated at baseline and 60 minutes after drug administration, consistent with the time for active metabolites of midodrine and atomoxetine to reach their peak plasma levels.5,17,18
Assessment of Orthostatic Hypotension–Related Symptoms
The OHQ was previously validated as a tool to assess OH-related symptoms in clinical trials.16 The questionnaire consists of 6 questions (Q), each rating the intensity of the following symptoms: Q1, dizziness, lightheadedness, feeling faint, or feeling like you might black out; Q2, problems with vision (blurring, seeing spots, and tunnel vision); Q3, generalized weakness; Q4, fatigue; Q5, trouble concentrating; and Q6, head/neck discomfort. This questionnaire addresses the severity of OH-related symptoms, with the absence of a symptom being rated as 0 and a maximal severity of symptoms as 10. In the present study, we evaluated the effect of our interventions on OH-related symptoms in 2 different ways. We reported changes in the total OHQ score and in Q1 only. The latter was done because the FDA approved the drug droxidopa for the treatment of OH based on an improvement in 1 point in Q1.19
The primary end point was the post-treatment upright SBP at 1 minute. For comparison, previous studies have used the upright SBP as a surrogate biomarker for OH improvement.5 Secondary end points included post-treatment seated SBP and DBP, upright DBP and HR, and OHQ and Q1 symptom scores. The pre- and post-treatment OHQ and Q1 scores were square-rooted transformed (SQRT) to reduce skewness of its distribution.
Data are expressed as mean±SD. The analyses were performed using a random-effects model that takes into account correlation because of repeated measurements within the same subject. Post-treatment standing SBP, DBP, and HR were adjusted for each pretreatment baseline measurement, as well as age and sex.
We also performed subgroup analyses according to the seated pressor response to both midodrine and atomoxetine. Seated pressor response was defined a priori as an increase of ≥15 mm Hg in seated SBP at 60 minutes after drug administration. We determined differences in upright SBP and OH-related symptoms in the subjects who had a seated pressor response to both midodrine and atomoxetine versus those who did not. All analyses were performed using STATA 11.0 (StataCorp, College Station, TX).
Sample size calculations were performed using paired t test analysis in PS software (Version 3.0.34).20 A blinded analysis was performed on 20 random patients enrolled in this study to obtain an estimate of variance and showed an ≈22 mm Hg standard deviation of difference in upright SBP among study interventions (midodrine and atomoxetine). An increase in upright SBP of 8 mm Hg with atomoxetine versus midodrine would be a clinically meaningful difference, representing the magnitude of response achieved with other drugs that primarily increase upright blood pressure.21 Based on these data, we estimated that 65 patients would have 80% power to detect a difference in means among treatment groups.
Subject Characteristics and Autonomic Evaluation Data
Figure S1 in the online-only Data Supplement shows the study flow diagram according to Consolidated Standards of Reporting Trials (CONSORT).22 A total of 69 patients with autonomic failure and neurogenic OH participated in this trial. The clinical characteristics of these patients are shown in Table 1. All patients had a profound decrease in SBP and DBP from the supine to the upright position (−63±29 and −29±16 mm Hg, respectively) without adequate increase in HR (12±15 bpm). Norepinephrine levels were low in supine posture (126±89 pg/mL) and did not increase appropriately during upright posture (257±249 pg/mL).
The results of the autonomic function assessment are presented in Table S1. All patients had an exaggerated decrease in SBP during phase II and absence of SBP overshoot during phase IV of the Valsalva maneuver. Pressor responses to isometric handgrip and cold pressor test were also impaired, suggesting sympathetic failure. The sinus arrhythmia ratio was decreased in these patients, indicating impaired parasympathetic function.
Pressor Response to Drugs
Atomoxetine increased seated SBP by 20 mm Hg (95% confidence interval [CI], 14 to 27; P<0.001) and seated DBP by 10 mm Hg (95% CI, 7 to 13; P<0.001) compared with placebo. Similarly, midodrine increased seated SBP by 20 mm Hg (95% CI, 13 to 28; P<0.001) and seated DBP by 10 mm Hg (95% CI, 7 to 14; P<0.001) compared with placebo Figure 1. There was no difference between atomoxetine and midodrine in seated SBP (means difference=0.3 mm Hg; 95% CI, −7.3 to 7.9; P=0.94) or seated DBP (mean difference=0.4 mm Hg; 95% CI, −3.4 to 4.2; P=0.83).
Atomoxetine significantly increased upright SBP by 20 mm Hg (95% CI, 13 to 27; P<0.001) and upright DBP by 11 mm Hg (95% CI, 7 to 14; P<0.001) compared with placebo. Likewise, midodrine increased upright SBP by 12 mm Hg (95% CI, 6 to 19; P<0.001) and upright DBP by 7 mm Hg (95% CI, 3 to 11; P=0.001) compared with placebo. Atomoxetine, however, improved upright SBP to a greater extent than midodrine (means difference=7.5 mm Hg; 95% CI, 0.6 to 14.5; P=0.03). Upright SBP responses to atomoxetine were variable as shown in Figure 2. Atomoxetine tended to improve upright DBP compared with midodrine (means difference=4.1 mm Hg; 95% CI, −0.05 to 8.3, P=0.05)
Heart Rate Response to Drugs
The effects of atomoxetine and midodrine on HR were also assessed after 1 minute of upright posture. Postdrug upright HR after atomoxetine administration was greater than after midodrine by 4 bpm (95% CI, 1.4 to 7.3; P=0.003). The postdrug upright HR after midodrine was lower than placebo (3 bpm; 95% CI, −4.9 to −1.1; P=0.002). Conversely, the postdrug upright HR after atomoxetine was similar to placebo (1.4 bpm; 95% CI, −1.5 to 4.2; P=0.34).
Orthostatic Hypotension–Related Symptoms
Atomoxetine significantly improved OH-related symptoms compared with placebo in the total OHQ score (0.4 SQRT; 95% CI, −0.1 to −0.8; P=0.02) and Q1 (0.6 SQRT points; 95% CI, −0.1 to 1.7; P=0.03). There was a tendency for an improvement in OH-related symptoms with midodrine versus placebo in the total OHQ score (0.5 SQRT point; 95% CI, −0.1 to 1.0; P=0.08). However, there was no improvement in Q1 (0.6 SQRT point; 95% CI, −1.6 to 0.5; P=0.29). No differences in total OHQ score or Q1 were found between atomoxetine and midodrine (P=0.9 and P=0.42, respectively; Figure 3).
Subgroup Analyses: Effect of Study Drug on Upright SBP, OHQ, and Q1 in Subjects With and Without a Seated Pressor Response to Atomoxetine and Midodrine
We performed subgroup analyses in patients who had a seated pressor response to both midodrine and atomoxetine defined a priori as an increase of ≥15 mm Hg in seated SBP, postdrug administration (n=36 patients; 52%). In these patients, atomoxetine increased upright SBP by 26 mm Hg (95% CI, 16 to 37; P<0.001) compared with placebo. Similarly, midodrine increased standing SBP by 19 mm Hg (95% CI, 9 to 29; P<0.001) compared with placebo. Compared with midodrine, atomoxetine increased upright SBP by 8 mm Hg (95% CI, −3 to 18; P=0.16). After atomoxetine administration, the OHQ score was lower than placebo by 0.7 SQRT points (95% CI, −0.2 to −1.3; P=0.013). Similarly, the OHQ score after midodrine administration was lower than placebo by 1.0 SQRT point (95% CI, −0.3 to −1.7; P=0.004). After atomoxetine administration, Q1 was lower than placebo by 1.4 SQRT points (95% CI, 0.4 to 2.5; P=0.008). Similarly, after midodrine administration, Q1 was lower than placebo by 1.8 SQRT points (95% CI, 0.6 to 2.9; P=0.004). No differences in total OHQ or Q1 were found between atomoxetine or midodrine.
In patients who failed to increase their seated SBP >15 mm Hg, atomoxetine significantly increased upright SBP by 11 mm Hg (95% CI, 2.8 to 18.7; P=0.009) compared with placebo. There was no difference in upright SBP between midodrine and placebo (means difference=4 mm Hg; 95% CI, −3.7 to 11.8; P=0.3). Similarly, there was no difference between atomoxetine and midodrine on upright SBP (means difference=7 mm Hg; 95% CI, −1.2 to 14.7; P=0.095). Furthermore, no improvement in symptoms was found with any of these interventions.
The main finding of this study is that the NET blocker atomoxetine preferentially improves upright blood pressure to a greater extent than midodrine, the current standard of care, in patients with severe autonomic failure. In addition, only atomoxetine improved OH-related symptoms as shown by a decrease in the total OHQ and Q1 scores compared with placebo. These findings suggest that atomoxetine, when given at a pediatric dose, may be an alternative therapy for patients who do not experience symptom relief with midodrine. NET blockers, and atomoxetine in particular, are approved for the treatment of attention deficit/hyperactivity disorder and are prescribed chronically in 7 million patients with this condition.23 Repurposing atomoxetine for the treatment of autonomic failure would be of major advantage because this medication is already commercially available, and therefore, its cardiovascular safety has been assessed in postmarketing studies, as well as in a large pharmacoepidemiology study.24
The treatment of neurogenic OH is challenging. A stepwise approach is recommended based on the severity of the symptoms.9 The first step includes the use of nonpharmacological treatment, such as custom-fitted compression stocking, abdominal binders, and physiological counter maneuvers, and these measures are aimed at reducing venous pooling in the lower body and, thereby, improving cardiac output on standing. The first step includes the use of nonpharmacological approaches to decrease venous pooling, avoid volume depletion, or increase plasma volume. In most patients, however, nonpharmacological measures are unable to control symptoms or reduce syncope and falls. Therefore, the use of pharmacological agents, such as short acting pressor agents, is often needed. Pressor agents will increase blood pressure for 2 to 3 hours at a time and are best given as needed, to be taken 30 to 45 minutes before upright activities.25 Evening doses should be avoided because of increased risk of supine hypertension.
Since its approval by the FDA in 1995, the α1 adrenergic agonist, midodrine, has been the current standard of care for the treatment of OH. The efficacy of midodrine in improving 1-minute upright SBP has been demonstrated in double-blind, placebo-controlled trials.3,4,26 The use of midodrine, however, is limited in some patients by adverse effects, such as pilomotor reactions, pruritus of the scalp, urinary urgency or retention, and supine hypertension.4,27 Furthermore, previous reports have described that midodrine may not work in a subgroup of patients with autonomic failure. In the present study, ≈36% of patients did not experience an increase in seated blood pressure or improvement in OH-related symptoms, despite receiving therapeutic doses of midodrine. Of note, we recently reported poor treatment adherence with midodrine in elderly patients with neurogenic OH enrolled in the Tennessee Medicare Program (TENNCARE).28 In this context, our findings suggest that atomoxetine could be an alternative therapeutic agent for treatment of patients who do not respond or develop side effects to midodrine.
In patients with autonomic failure, the decline in blood pressure on standing induces a reduction in cerebral blood flow,29 which in turn translates into presyncopal symptoms and even syncope. Cerebral blood flow could be preserved with the use of systemic pressor agents, such as midodrine.30 Indeed, midodrine did not improve OH-related symptoms when the entire cohort was analyzed; however, in our subgroup analysis, midodrine improved symptoms in patients who had an increase in seated SBP of ≥15 mm Hg. Atomoxetine may improve OH-related symptoms not only through its effect on systemic blood pressure but also locally by directly modulating cerebral blood flow. Atomoxetine crosses the blood–brain barrier and has been shown to increase cerebral blood flow in areas of high norepinephrine transporter density in healthy individuals.31
The effect of atomoxetine on upright HR is worth discussing. A normal baroreflex-mediated response to blood pressure changes leads to a compensatory increase or decrease in HR. This response is impaired in patients with autonomic failure because of impairment of baroreflex-mediated efferents.32 When a pressor agent is administered, however, the increase in blood pressure attenuates the increase in HR, otherwise seen during OH, thus suggesting that baroreflex failure is not complete in patients with autonomic failure. Indeed, in our study, midodrine significantly decreased upright HR by 4 bpm compared with placebo. In contrast, atomoxetine did not decrease upright HR compared with placebo. This finding suggests that atomoxetine has a different mechanism of action that might be explained by an indirect stimulation of β1 adrenergic receptors in the heart by increasing plasma norepinephrine in the synaptic junction, where the synaptic cleft width is narrow.33
We previously reported that atomoxetine preferentially increases seated SBP in patients with central autonomic failure, but not in those with peripheral autonomic failure.11 In this study, we did not perform a subgroup analysis based on patient diagnosis because our cohort included a large number of patients, in whom the precise subtype of primary autonomic failure was undetermined. We observed heterogeneity in the upright pressor response to atomoxetine, which suggests that residual sympathetic tone differs among severe autonomic failure patients. Previous observations by our group showed that residual sympathetic tone can be regulated by α2 receptors. For instance, clonidine lowers blood pressure in autonomic failure patients.34 However, we have not observed a clonidine-like effect of atomoxetine in our proof of concept study.11 We think that the best explanation for this apparent discrepancy could be that, even though postsynaptic α2 receptors are intact and able to regulate residual sympathetic tone, it is likely that presynaptic norepinephrine fibers are depleted, and therefore, NET blockade is devoid of a clonidine-like effect that would lower blood pressure in these patients. In support of this, previous studies have shown that patients with multiple systems atrophy and other primary autonomic disorders, such as Parkinson’ disease and pure autonomic failure, have marked central norepinephrine deficiency as shown by a decrease in dihydroxyphenylglycol, the main neuronal metabolite of norepinephrine in their cerebral spinal fluid,35 and by the depletion of catecholamine neurons in the rostral ventrolateral medulla.36 Hence, the histological and neurohormonal evidence of norepinephrine depletion in the brain of patients with severe autonomic failure may prevent a hypotensive response secondary to NET blockade. Nevertheless, a clonidine-like reaction with paradoxical hypotension cannot be excluded in patients with mild autonomic failure. Thus, clinicians should consider testing the pressor response to atomoxetine when considering its use for the treatment of OH.
Our study has some potential limitations. First, autonomic failure patients were enrolled at a tertiary care center for autonomic disorders, which may not reflect the broader and less severe disease population. Second, we did not assess supine blood pressure during the study because of the risk of supine hypertension; we designed our study to comply with standard of care in patients with autonomic failure in whom we recommend as a routine clinical practice not to lay down after receiving pressor agents. We did not monitor blood pressure beyond 1 hour after drug administration. It is possible that some patients may have prolonged pressor responses, particularly those who are poor metabolizers of cytochrome P450 CYP2D6, which metabolizes atomoxetine.37,38 Finally, our study only addressed the effect of acute administration of atomoxetine on blood pressure and OH-related symptoms; it would be important to assess in future studies the long-term efficacy of this drug for the treatment of OH.
Atomoxetine, a selective NET blocker, increases upright blood pressure and improves OH-related symptoms to a greater extent than midodrine, the current standard of care. Atomoxetine could be a new therapeutic alternative for the treatment of OH in patients with autonomic failure. Additional studies are required to address its long-term efficacy. Atomoxetine is not FDA-approved for the treatment of OH.
Sources of Funding
This work was supported in part by grant P01 HL056693, Autonomic Rare Diseases Clinical Research Consortium Grant U54 NS065736, the Vanderbilt Clinical and Translational Science Award grant UL1 RR024975 from the National Center for Research Resources and the National Institutes of Health. Cyndya A. Shibao is supported by grant K23 HL103976 from the National Institutes of Health, PhRMA Foundation Career Development Award, and grant 10CRP4310026 from the American Heart Association Clinical Research Program.
The online-only Data Supplement is available with this article at http://hyper.ahajournals.org/lookup/suppl/doi:10.1161/HYPERTENSIONAHA.114.04225/-/DC1.
- Received July 8, 2014.
- Revision received July 18, 2014.
- Accepted August 11, 2014.
- © 2014 American Heart Association, Inc.
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Novelty and Significance
What Is New?
We show that pediatric doses of atomoxetine improve upright systolic blood pressure and presyncopal symptoms in patients with primary forms of autonomic failure to a greater extent than the standard of care, midodrine.
What Is Relevant?
Patients with autonomic failure often develop disabling orthostatic hypotension. Midodrine is the current standard of care for this condition. However, some patients may not respond to this medication or develop intolerable side effects. Our study provides an alternative therapeutic option for these challenging patients.
The NET blocker atomoxetine improves upright blood pressure to a greater extent than midodrine, the current standard of care, in patients with severe autonomic failure. Only atomoxetine improved orthostatic hypotension–related symptoms compared with placebo. These findings suggest that atomoxetine, when given at a pediatric dose, could be an alternative therapy for patients who do not experience symptom relief with midodrine. Atomoxetine is not Food and Drug Administration–approved for the treatment of OH, and further studies are required to address its long-term efficacy.