A Randomized Crossover Trial of Ivabradine, Propranolol, and Placebo in Postural Orthostatic Tachycardia Syndrome: A Detailed Description

Postural orthostatic tachycardia syndrome (POTS) is characterized by an excessive orthostatic heart rate increase and lacks approved pharmacologic therapies. The objective of the study was to compare hemodynamic effects of ivabradine and propranolol and assess medication preferences in patients with POTS. In a randomized, placebo-controlled, crossover trial, patients with POTS completed three 4-week treatment phases (ivabradine, propranolol, and placebo). Each phase concluded with a 10-minute head-up tilt test with continuous beat-to-beat hemodynamic monitoring. Analyses included 28 participants (mean age 33 ± 9 years, 100% female). The prespecified primary outcome was delta heart rate during tilt. Head-up tilt test hemodynamics were described as minute-by-minute averages, deltas from supine baseline, and peak heart rate (HR) in the last 5 to 10 minutes. Prespecified within-participant comparisons were performed between treatments. Treatment preference was recorded at each phase end. Compared to placebo, HR was lower for ivabradine (99 ± 3 vs 118 ± 3 beats/min; P < 0.001) and propranolol (100 ± 3 vs 118 ± 3 beats/min; P < 0.001). ΔHR (standing - supine) was lower for ivabradine (27 ± 2 vs 36 ± 2 beats/min; P = 0.001) and propranolol (28 ± 2 vs 36 ± 2 beats/min; P = 0.003) vs placebo. Ivabradine showed a greater increase in Δ systolic blood pressure compared to propranolol (4.9 mm Hg vs 1.9 mm Hg; P = 0.001) but no significant difference in either HR or ΔHR between them. Among 22 preferences, all participants preferred ivabradine (P < 0.001) or propranolol (P < 0.001) over placebo, without differences between active treatments (59% vs 41%; P = 0.52). Ivabradine and propranolol reduce orthostatic tachycardia vs placebo, lowering heart rate below POTS diagnostic criteria. Ivabradine elevates systolic blood pressuremore than propranolol, supporting personalized drug selection. Importantly, heart rate lowering was consistent whereas symptom and quality-of-life effects were more selective, supporting individualized treatment.