Orthostatic Hypotension, Hypertension Treatment, and Cardiovascular Disease: An Individual Participant Meta-Analysis

Abstract

Importance: There are ongoing concerns about the benefits of intensive vs standard blood pressure (BP) treatment among adults with orthostatic hypotension or standing hypotension.

Objective: To determine the effect of a lower BP treatment goal or active therapy vs a standard BP treatment goal or placebo on cardiovascular disease (CVD) or all-cause mortality in strata of baseline orthostatic hypotension or baseline standing hypotension.

Data sources: Individual participant data meta-analysis based on a systematic review of MEDLINE, EMBASE, and CENTRAL databases through May 13, 2022.

Study selection: Randomized trials of BP pharmacologic treatment (more intensive BP goal or active agent) with orthostatic hypotension assessments.

Data extraction and synthesis: Individual participant data meta-analysis extracted following PRISMA guidelines. Effects were determined using Cox proportional hazard models using a single-stage approach.

Main outcomes and measures: Main outcomes were CVD or all-cause mortality. Orthostatic hypotension was defined as a decrease in systolic BP of at least 20 mm Hg and/or diastolic BP of at least 10 mm Hg after changing position from sitting to standing. Standing hypotension was defined as a standing systolic BP of 110 mm Hg or less or standing diastolic BP of 60 mm Hg or less.

Results: The 9 trials included 29 235 participants followed up for a median of 4 years (mean age, 69.0 [SD, 10.9] years; 48% women). There were 9% with orthostatic hypotension and 5% with standing hypotension at baseline. More intensive BP treatment or active therapy lowered risk of CVD or all-cause mortality among those without baseline orthostatic hypotension (hazard ratio [HR], 0.81; 95% CI, 0.76-0.86) similarly to those with baseline orthostatic hypotension (HR, 0.83; 95% CI, 0.70-1.00; P = .68 for interaction of treatment with baseline orthostatic hypotension). More intensive BP treatment or active therapy lowered risk of CVD or all-cause mortality among those without baseline standing hypotension (HR, 0.80; 95% CI, 0.75-0.85), and nonsignificantly among those with baseline standing hypotension (HR, 0.94; 95% CI, 0.75-1.18). Effects did not differ by baseline standing hypotension (P = .16 for interaction of treatment with baseline standing hypotension).

Conclusions and relevance: In this population of hypertension trial participants, intensive therapy reduced risk of CVD or all-cause mortality regardless of orthostatic hypotension without evidence for different effects among those with standing hypotension.

Figure 1.. Association of Change in SBP or Standing SBP With CVD or All-Cause Mortality

Adjusted hazard ratios by treatment status for change in systolic blood pressure (SBP) with (A) cardiovascular disease (CVD) or all-cause mortality or (B) all-cause mortality, as well as for standing SBP with (C) CVD or all-cause mortality or (D) all-cause mortality, using a restricted cubic spline with 4 knots determined by the Harrell method. Figures are based on data from all 9 trials. Shading represents 95% CIs. Both models were expressed relative to the median value and were truncated at the 2.5th and 97.5th percentiles. Models were adjusted for age, sex, and study. Hazard ratios are shown on a natural log scale. Included are kernel density plots representing the distribution of change in SBP or standing SBP by treatment and by outcome status: low goal/active treatment, no outcome; low goal/active treatment, with outcome; standard goal/placebo, no outcome; and standard goal/placebo, with outcome. In Supplement 1, see eTable 7 for the event numbers and denominators for this figure and eFigures 6-8 for similar representations by diastolic blood pressure and additional modeling.

Figure 2.. Treatment Assignment and Outcomes in Strata of Orthostatic Hypotension for Cardiovascular Disease or All-Cause Mortality and All-Cause Mortality by Trial

HR indicates hazard ratio; NA, not applicable (not calculable). The HRs in strata of orthostatic hypotension are pooled by trial type (trial of blood pressure [BP] goal or placebo-controlled trial) and overall. Point estimates (circles) were generated with Cox models adjusted for age and sex. Pooled estimates (diamonds) were also adjusted for study. Point estimate sizes are weighted by number of participants as a proportion of the total in the pooled population. Whiskers represent 95% CIs. P values for interaction are comparisons of point estimates across strata. Orthostatic hypotension is defined as a change in systolic BP on standing of −20 mm Hg or more extreme or diastolic BP of −10 mm Hg or more extreme. Corresponding numbers are available in eTable 14 in Supplement 1. ^aP = .04.

Figure 3.. Treatment Assignment and Outcomes in Strata of Standing Hypotension for Cardiovascular Disease or All-Cause Mortality and All-Cause Mortality by Trial

HR indicates hazard ratio; NA, not applicable (not calculable). The HRs in strata of standing are pooled by trial type (trial of blood pressure [BP] goal or placebo-controlled trial) and overall. Trial point estimates (circles) were generated with Cox models, with adjustment for age and sex. Pooled estimates (diamonds) were also adjusted for study. Point estimate sizes are weighted by number of participants as a proportion of the total number in the pooled population. Whiskers represent 95% CIs. P values for interaction are comparisons of point estimates across strata. Standing hypotension is defined as a systolic BP of ≤110 mm Hg or a diastolic BP of ≤60 mm Hg. Corresponding numbers are available in eTable 15 in Supplement 1.