Midodrine Efficacy in Orthostatic Hypotension

Abstract

feel obligated to comment on several deficiencies of this work. Unfortunately, the article was published under the Mayo Clinic name by former trainees without expert supervision, since none of the autonomic experts at Mayo who author this letter were in any way involved in conducting the study or guiding its interpretation. The deficiencies are major and reflect poorly on Mayo Clinic investigators. Furthermore, this article needs rectification-both of content and interpretation-to avoid potential damage to the future of the first US Food and Drug Administration (FDA)-approved and arguably single most efficient pharmacologic intervention for orthostatic hypotension (OH) to date.First, the article has a main focus on the effect of midodrine on the orthostatic change in blood pressure (delta BP from supine to standing). This focus reflects an apparent misconception of autonomic pharmacology. Midodrine is a prodrug that is hydrolyzed to its active metabolite desglymidodrine, a pure alpha-1 agonist, resulting in arteriolar and venular constriction, which has the same effect on supine and standing BP. 1 It is NOT expected to selectively increase standing BP (or affect delta BP), which has never been used as primary trial endpoint, and therefore cannot be used as a primary focus of a meta-analysis.Second, meta-analyses are typically undertaken when a treatment of interest has been studied, but the findings are equivocal or negative. The rationale is that a combination of comparable studies might improve power. In this paper, the studies are far from comparable. Nine studies are included in this meta-analysis. The studies range from small open-label case series to large double-blind, placebo-controlled multicenter trials. Trial design ranges from simple pre-post assessments, parallel group design, and crossover trials to pharmacologic dose-response studies. The studies are inhomogeneous in terms of primary endpoints, orthostatic challenge (45-degree head-up tilt versus active standing), patient population (young familial dysautonomia cohort versus neurodegenerative patient cohorts), as well as definition of OH. Those data simply cannot be meaningfully pooled.Third, the four double-blind, placebo-controlled trials on midodrine in OH were pooled for an assessment of the actual variable of interest, the effect on standing BP. In spite of the different trial designs, all four trials reported midodrine to significantly increase standing BP in patients with neurogenic OH (all p < 0.002). [2][3][4][5] Due to "significant heterogeneity" of the effect, the evidence for midodrine improving standing BP was rated as "low." When marked trial design differences exist (trials with 171 versus trials with eight patients; parallel-group versus cross-over studies; differences in dosing; differences in timing of effect assessment-three trials assess the drug-effect one hour after administration, while one trial averages hourly measurements throughout the day without specific timing relative to administration), it would be most adequate to ...

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