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.

Keywords: atomoxetine; autonomic failure; midodrine; orthostatic hypotension.

Figure 1

Post-drug seated SBP [A] and DBP [B]. Boxes and whiskers plot displays unadjusted data. The P-values were generated by comparing post-drug seated SBP [A] and DBP [B] using random-effects model. The model was adjusted for baseline seated SBP or DBP, age, and gender.

Figure 2

[A] Post-drug standing SBP. Boxes and whiskers plot displays unadjusted post-drug standing SBP. P-values were generated by comparing post-drug standing SBP using random-effects model. The model was adjusted for pre-drug standing SBP, age, and gender. [B] Scatter plot showing individual values for the changes in standing SBP from baseline values.

Figure 3

Total OHQ [A] and Q1 [B]. Boxes and whiskers plots displays unadjusted scores. The P-values were generated by comparing the squared root of the post-drug OHQ or Q1 using random-effects model. The model was adjusted for baseline squared rooted OHQ or Q1, age, and gender.