Effects of Anti-Hypertensive Agents on Orthostatic Changes: Secondary Analysis of the Treatment of Mild Hypertension Study (TOMHS)

Background Orthostatic hypotension (OH) and orthostatic hypertension (OHT) are common among adults with hypertension and may complicate antihypertensive treatment selection. However, the impact of specific antihypertensive agents on orthostatic blood pressure (BP) responses and risk of OH or OHT remains incompletely characterized. Methods We performed a secondary analysis of the Treatment of Mild Hypertension Study (TOMHS), a multicenter randomized clinical trial (1987-1993). A total of 902 adults aged 45-69 years with diastolic BP 90-99 mmHg were randomized to acebutolol, amlodipine, chlorthalidone, doxazosin, enalapril, or placebo. Orthostatic BP change (standing minus seated BP) was assessed at randomization, 1 month, and every 3 months up to 54 months. OH was defined as a systolic BP decrease ≥20 mmHg or diastolic BP decrease ≥10 mmHg; OHT was defined as a systolic BP increase ≥20 mmHg or diastolic BP increase ≥10 mmHg. Generalized estimating equations evaluated associations between agents and orthostatic BP changes overall, by baseline BP, and over time. Results Among 897 participants with orthostatic BP measurements (mean age 54.8 years; 38.5% female; 19.6% Black), doxazosin increased odds of OH (OR 1.45; 95% CI, 1.05-2.02) and reduced odds of OHT (OR 0.66; 95% CI, 0.51-0.86) versus placebo. Chlorthalidone reduced OHT among participants with baseline OHT (P=0.018). Amlodipine and doxazosin attenuated orthostatic systolic BP changes across baseline orthostatic BP change strata. Over time, amlodipine and chlorthalidone reduced odds of OH (P=0.001, 0.044). Conclusions Specific antihypertensive agents demonstrated distinct effects on orthostatic BP regulation. Consideration of orthostatic effects during antihypertensive selection may help individualize therapy, improve hemodynamic stability, and optimize treatment for patients at risk of orthostatic dysregulation.