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

Stephen P Juraschek; Jiun-Ruey Hu; Jennifer L Cluett; Anthony M Ishak; Carol Mita; Lewis A Lipsitz; Lawrence J Appel; Nigel S Beckett; Ruth L Coleman; William C Cushman; Barry R Davis; Greg Grandits; Rury R Holman; Edgar R Miller, 3rd; Ruth Peters; Jan A Staessen; Addison A Taylor; Lutgarde Thijs; Jackson T Wright, Jr; Kenneth J Mukamal

doi:10.1001/jama.2023.18497

. 2023 Oct 17;330(15):1459–1471. doi: 10.1001/jama.2023.18497

Orthostatic Hypotension, Hypertension Treatment, and Cardiovascular Disease

An Individual Participant Meta-Analysis

Stephen P Juraschek ^1,^✉, Jiun-Ruey Hu ², Jennifer L Cluett ¹, Anthony M Ishak ^1,³, Carol Mita ⁴, Lewis A Lipsitz ^1,⁵, Lawrence J Appel ⁶, Nigel S Beckett ⁷, Ruth L Coleman ⁸, William C Cushman ⁹, Barry R Davis ¹⁰, Greg Grandits ¹¹, Rury R Holman ⁸, Edgar R Miller 3rd ⁶, Ruth Peters ^12,^13,¹⁴, Jan A Staessen ¹⁵, Addison A Taylor ¹⁶, Lutgarde Thijs ¹⁵, Jackson T Wright Jr ¹⁷, Kenneth J Mukamal ¹

¹Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts

²Section of Cardiovascular Medicine, Yale School of Medicine, New Haven, Connecticut

³Healthcare Associates, Beth Israel–Lahey Health System, Boston, Massachusetts

⁴Countway Library, Harvard University, Boston, Massachusetts

⁵Hebrew SeniorLife, Hinda and Arthur Marcus Institute for Aging Research and Harvard Medical School, Boston, Massachusetts

⁶Johns Hopkins University, Baltimore, Maryland

⁷Guy’s and St Thomas’ NHS Foundation Trust, London, England

⁸Diabetes Trials Unit, Radcliffe Department of Medicine, University of Oxford, Oxford, England

⁹Department of Preventive Medicine, University of Tennessee Health Science Center, Memphis

¹⁰Department of Biostatistics and Data Science, Coordinating Center for Clinical Trials, The University of Texas School of Public Health, Houston

¹¹Division of Biostatistics, School of Public Health, University of Minnesota, Minneapolis

¹²The George Institute for Global Health, Sydney, Australia

¹³Department of Biomedical Sciences, University of New South Wales, Sydney, Australia

¹⁴School of Public Health, Imperial College London, London, England

¹⁵Sint-Franciscuscollege, Heusden-Zolder, Belgium

¹⁶Michael E. DeBakey VA Medical Center and Baylor College of Medicine, Houston, Texas

¹⁷Case Western Reserve University, University Hospitals Cleveland Medical Center, Cleveland, Ohio

^✉

Corresponding Author: Stephen P. Juraschek, MD, PhD, Section for Research, Division of General Medicine, Beth Israel Deaconess Medical Center, 330 Brookline Ave, CO-1309, No. 216, Boston, MA 02215 (sjurasch@bidmc.harvard.edu).

Accepted for Publication: August 28, 2023.

Author Contributions: Dr Juraschek had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Juraschek, Hu, Cluett, Lipsitz, Cushman, Davis, Miller, Staessen, Mukamal.

Acquisition, analysis, or interpretation of data: Juraschek, Hu, Ishak, Mita, Appel, Beckett, Coleman, Davis, Grandits, Holman, Miller, Peters, Taylor, Thijs, Wright.

Drafting of the manuscript: Juraschek, Mita, Lipsitz, Beckett, Staessen.

Critical review of the manuscript for important intellectual content: Juraschek, Hu, Cluett, Ishak, Appel, Beckett, Coleman, Cushman, Davis, Grandits, Holman, Miller, Peters, Staessen, Taylor, Thijs, Wright, Mukamal.

Statistical analysis: Juraschek, Staessen.

Obtained funding: Juraschek, Beckett, Wright.

Administrative, technical, or material support: Juraschek, Ishak, Beckett, Wright.

Supervision: Davis, Staessen, Mukamal.

Conflict of Interest Disclosures: Dr Juraschek reported receipt of grants from the National Heart, Lung, and Blood Institute (NHLBI) outside the submitted work. Dr Appel reported receipt of personal fees from Wolters Kluwer for work on chapters in UpToDate. Dr Beckett reported currently being a general member of the UK National Institute for Health and Care Excellence Cardiovascular Prevention Guidelines Committee. Dr Cushman reported being a coinvestigator for a hypertension trial funded by Recor and the principal investigator for 2 hypertension trials with George Medicine. Dr Holman reported receipt of personal fees from Anji Pharmaceuticals, AstraZeneca, Novartis, and Novo Nordisk. Dr Peters reported receipt of grants from the National Health and Medical Research Council, Mindgardens Neuroscience Network, and Medical Research Future Fund. Dr Wright reported attendance at an advisory board meeting for Medtronic. Dr Mukamal reported being principal investigator of a trial with a grant to Beth Israel Deaconess Medical Center from the US Highbush Blueberry Council. No other disclosures were reported.

Funding/Support: Dr Juraschek is supported by National Institutes of Health/NHLBI grant K23HL135273. Dr Holman is an emeritus UK National Institute for Health Research senior investigator. Dr Mukamal is supported by National Institutes of Health/National Institute on Aging grant K24AG065525.

Role of the Funder/Sponsor: The study supporters had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; or decision to submit the manuscript for publication.

Data Sharing Statement: See Supplement 2.

Additional Contributions: We thank the BioLINCC repository for data from the following studies: ACCORD BP, SPRINT, and SHEP.

^✉

Corresponding author.

PMCID: PMC10582789 PMID: 37847274

Key Points

Question

Does the effect of intensive blood pressure treatment on cardiovascular disease or all-cause mortality differ based on the presence or absence of orthostatic or standing hypotension?

Findings

In this individual data meta-analysis of more than 29 000 participants in 9 hypertension trials, more intensive blood pressure treatment lowered risk of cardiovascular disease or all-cause mortality regardless of whether participants had orthostatic hypotension. Moreover, effects did not differ by the presence or absence of standing hypotension.

Meaning

Asymptomatic orthostatic hypotension or standing hypotension among adults with hypertension should not be a deterrent to more intensive hypertension treatment.

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.

This individual participant data meta-analysis assesses the effect of a lower blood pressure (BP) treatment goal or active therapy vs a standard BP treatment goal or placebo on cardiovascular disease or all-cause mortality among adults with orthostatic hypotension or standing hypotension.

Introduction

Orthostatic hypotension affects as much as 10% of adults with hypertension^1,2,3 and is associated with antihypertensive medication use⁴ as well as adverse outcomes, including cardiovascular disease (CVD) events and death.⁵ These associations have informed guideline recommendations to monitor for orthostatic hypotension prior to initiation or intensification of antihypertensive treatment as well as for monitoring safety during treatment. Concerns about worsening hypotension have contributed to recommendations against more intensive blood pressure (BP) treatment, particularly among older adults,⁶ and for deprescribing antihypertensive medications as a first-line intervention to address orthostatic hypotension.⁷

Recently, we showed that intensive BP treatment^8,9 or first-line antihypertensive classes¹⁰ were not associated with orthostatic hypotension. Moreover, in an individual participant data meta-analysis of 9 hypertension trials (5 of BP treatment goals and 4 of active therapy vs placebo), comprising 31 043 participants with 275 098 orthostatic hypotension assessments, more intensive BP treatment or active therapy reduced risk of orthostatic hypotension during follow-up.¹¹ Nevertheless, whether the presence of orthostatic hypotension negates or alters the benefits of BP treatment with respect to CVD events or death among adults with hypertension among this collection of trials had not been shown.

In the present study, we performed the second prespecified aim of our individual participant data meta-analysis, to examine orthostatic hypotension and standing hypotension (≤110/≤60 mm Hg) as risk factors for CVD events or all-cause mortality among adults with hypertension. We then determined whether the relationship between more intensive or active treatment (primary exposure) with CVD events or all-cause mortality differed in strata of baseline orthostatic hypotension or hypotension status. We hypothesized that while orthostatic hypotension and standing hypotension would be crudely associated with a higher risk of CVD or all-cause mortality, the relationship between more intensive or active treatment with CVD events or all-cause mortality would not differ in those with or without baseline orthostatic hypotension or standing hypotension.

Methods

Search Strategy and Eligibility Criteria

Our search strategy was described previously and registered in the PROSPERO registry on April 28, 2020 (CRD42020153753).¹¹ Our initial search included MEDLINE/PubMed, EMBASE, and the Cochrane Central Register of Controlled Trials databases through October 7, 2019, without language restrictions; this has now been updated through May 13, 2022. Our search strategy was prepared by a research librarian (C.M.) and focused on hypertension, BP treatment, orthostatic hypotension, and randomized trials (see the eAppendix in Supplement 1). Duplicate records were removed in Endnote (Clarivate). Abstracts were screened with Covidence by 2 independent investigators (J.L.C., S.P.J.). Discrepancies were adjudicated by consensus with a third investigator (A.M.I. or K.J.M.).

The prespecified PICO (population, intervention, comparison, outcomes)¹² criteria were (1) for population, trials of at least 500 adults with elevated BP or hypertension, aged 18 years or older; (2) for intervention, randomized BP pharmacological treatment (BP goal or active agent) for at least 6 months; (3) for comparison, at least 2 BP goals (one less than the other) or placebo; and (4) for outcome, orthostatic hypotension measured during postrandomization study visits. We excluded (1) trials of pregnant women or children, (2) animal experiments (nonhuman trials), (3) reviews, (4) observational studies, and (5) self-reported or claim-based orthostatic hypotension or studies missing orthostatic BP measurement data. We made the a priori decision to pool trials by type, ie, those comparing 2 treatment goals (a more intensive goal vs a less intensive goal), placebo-controlled trials, and all trials combined. Trials comparing active treatment with placebo without a target BP were eligible.¹³ While our search focused on postrandomization orthostatic hypotension, we encountered no trials with orthostatic hypotension limited to prerandomization visits; all trials had both prerandomization and postrandomization orthostatic hypotension assessments.

Our search also included a review of the bibliography of a recent meta-analysis of trials of intensive BP control and CVD.¹⁴ We attempted to contact investigators of each trial in this review to inquire about the availability of standing BP measurements. This approach resulted in the inclusion of 1 trial not identified through our search (eFigure 1 in Supplement 1).¹⁵ There was 1 trial for which the investigators were not able to provide us their data due to restrictions related to data sharing.¹³ All trials with orthostatic hypotension identified through our search had surveillance for CVD outcomes and mortality.

Trial Outcomes

We collected information about CVD, which included coronary heart disease, stroke, and congestive heart failure, and vital status. Time to event was derived using date of randomization and event date or last visit dates when necessary. Details related to CVD definitions by trial^{15,16,17,18,19,20,21,22,23} are available in Table 1. The primary outcome of this meta-analysis was a composite of nonfatal CVD events and all-cause mortality. All-cause mortality without nonfatal CVD events was considered a secondary outcome.

Table 1. Characteristics of Included Trials.

Source	Demographic characteristics	Key conditions	BP eligibility requirements, mm Hg	More intensive BP treatment assignment	Less intensive BP treatment assignment	BP measurement	Length of follow-up, median, y	Definition of cardiovascular disease event or all-cause mortality
BP treatment goal trials
AASK (n = 1094)¹⁸	African American patients aged 18-70 y	Hypertensive kidney disease without diabetes	Seated DBP ≥95	Goal: MAP ≤92 mm Hg Agents: 1 of 3 first-line agents, metoprolol (50-200 mg/d), ramipril (2.5-10 mg/d), or amlodipine (5-10 mg/d)	Goal: MAP of 102-107 mm Hg	Seated: mean of the last 2 of 3 measures Standing: 1 measure after 2:45 min of standing	CVD or all-cause mortality: 3.8 All-cause mortality: 4.1	Any definite or probable cardiovascular outcomes (nonfatal myocardial infarction, stroke, heart failure) or death due to any cause
ACCORD BP (n = 4733)¹⁹	Patients aged ≥40 y	Diabetes, CVD, or CVD risk factors	Seated SBP 130-180^a	Goal: SBP <120 mm Hg Agents: First-line agent a combination of diuretic and either ACE inhibitor or β-blocker	Goal: SBP <140 mm Hg	Seated: mean of 3 measures Standing: mean of 3 measures, 1 min after standing, each measure separated by 1 min	CVD or all-cause mortality: 4.0 All-cause mortality: 4.0	Primary end point (nonfatal myocardial infarction, nonfatal stroke, or death due to cardiovascular causes), nonfatal heart failure, or death due to any cause
SPRINT (n = 9361)¹⁶	Patients aged ≥50 y	High risk for CVD without prior stroke or diabetes	Seated SBP 130-180^a and standing SBP <110	Goal: SBP <120 mm Hg Agents: Thiazide-type diuretic encouraged, loop diuretics (advanced chronic kidney disease), and β-blockers (coronary artery disease). Chlorthalidone was encouraged as the primary thiazide-type diuretic and amlodipine as the preferred calcium channel blocker	Goal: SBP <140 mm Hg	Seated: mean of 3 measures Standing: 1 measure, 1 min after standing	CVD or all-cause mortality: 3.8 All-cause mortality: 3.8	Primary end point (myocardial infarction, acute coronary syndrome, stroke, heart failure, or death due to cardiovascular causes) or death due to any cause
SPS3 (n = 3020)²⁰	Patients aged ≥30 y	Recent lacunar stroke and hypertension	Seated SBP ≥140 or seated DBP ≥90	Goal: SBP <130 mm Hg Agents: clinician-directed regimen	Goal: SBP 130-149 mm Hg	Seated: mean of 3 measures Standing: 1 measure, 2 min after standing	CVD or all-cause mortality: 3.0 All-cause mortality: 3.2	Primary end point (recurrent fatal and nonfatal stroke) or acute myocardial infarction, heart failure event, or death due to any cause
UKPDS (n = 1148)¹⁵	Patients aged 25-65 y	Diabetes and hypertension	Seated SBP ≥150 or seated DBP ≥85 (≥160/≥85 if taking medication for hypertension)	Goal: BP <150/85 mm Hg Agents: captopril (25 mg/d to 50 mg twice daily) or atenolol (50-100 mg/d) as first-line agent	Goal: BP <180/105 mm Hg	Seated: mean of last 3 of 4 measures^b Standing: 1 measure 1 min after standing	CVD or all-cause mortality: 8.1 All-cause mortality: 8.6	Any myocardial infarction, any stroke, any heart failure, or death due to any cause
Placebo-controlled trials
HYVET (n = 3845)¹⁷	Patients aged ≥80 y	Hypertension	Seated SBP 160-199, standing SBP ≥140, seated DBP 90-109^c	Goal: <150/80 mm Hg Agents: indapamide sustained release (1.5 mg/d) (first line)	Placebo	Seated: mean of 2 measures Standing: mean of 2 measures after 2 min of standing	CVD or all-cause mortality: 5.9 All-cause mortality: 5.9	Primary end point (fatal or nonfatal stroke), any myocardial infarction, any heart failure, or death due to any cause
SHEP (n = 4736)²¹	Patients aged ≥60 y	Isolated systolic hypertension	Seated SBP 160-219,^d standing SBP ≥140, seated DBP <90	Goal: if baseline SBP >180 mm Hg, goal was SBP <160 mm Hg; if baseline SBP 160-179 mm Hg, goal was 20–mm Hg reduction Agents: step 1: chlorthalidone (12.5-25 mg/d); step 2: atenolol (25-50 mg/d) or reserpine (0.05-0.1 mg/d)	Placebo	Seated: mean of 2 measures Standing: 2 measurements after 1 and 3 min of standing	CVD or all-cause mortality: 4.2 All-cause mortality: 4.3	Any stroke, any coronary heart disease, any left ventricular heart failure, or death due to any cause
SYST-EUR (n = 4695)²²	Patients aged ≥60 y	Isolated systolic hypertension	Seated SBP <220, standing SBP ≥140, seated DBP <95	Goal: SBP <150 mm Hg (reduction of ≥20 mm Hg) Agents: nitrendipine (10 mg/d to 20 mg twice daily) combined with or replaced by enalapril (5-20 mg/d), hydrochlorothiazide (12.5-25 mg/d), or both	Placebo	Seated: mean of 2 measures Standing: 2 measures after 2 min of standing	CVD or all-cause mortality: 1.9 All-cause mortality: 2.0	Nonfatal myocardial infarction, nonfatal stroke, nonfatal heart failure, or death due to any cause
TOMHS (n = 902)²³	Patients aged 45-69 y	Mild hypertension	DBP 90-99	Goal: doses doubled (or chlorthalidone/enalapril added) for DBP <95 mm Hg (over 3 successive visits) or <105 mm Hg (single visit) Agents: nutritional-hygienic intervention plus 1 of 5 groups^e: acebutolol (400-800 mg/d), amlodipine (5-10 mg/d), chlorthalidone (15-30 mg/d), doxazosin (2-4 mg/d), or enalapril (5-10 mg/d)	Nutritional-hygienic intervention plus placebo Agents: provide chlorthalidone if BP not controlled with nutritional-hygienic intervention	Seated: mean of 2 measures Standing: 1 measure 2 min after standing	CVD or all-cause mortality: 4.4 All-cause mortality: 4.4	Primary end point (major coronary heart disease events, including myocardial infarction and heart failure), nonfatal stroke, or death due to any cause

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Abbreviations: BP, blood pressure; CVD, cardiovascular disease; DBP, diastolic blood pressure; MAP, mean arterial pressure; SBP, systolic blood pressure.

^{^a}

Range varied based on baseline antihypertensive medication use: SBP 130-160 mm Hg with 0-3 antihypertensives, SBP 161-170 with 0-2 antihypertensives, or SBP 171-180 with 0-1 antihypertensives.

^{^b}

Of 4 measures, the first was discarded and the mean of the next 3 consecutive readings with a coefficient of variation below 15% was used in the study.

^{^c}

The average seated DBP was later changed to <110 mm Hg to be able to recruit participants with isolated systolic hypertension.

^{^d}

Range was 130-219 mm Hg and DBP <85 mm Hg if taking antihypertensive medications.

^{^e}

These groups were combined to represent the “intensive blood pressure treatment group” in our extended pooled meta-analysis, which included the 4 placebo-controlled studies.

Orthostatic Hypotension and Standing Hypotension

We derived the difference between standing minus seated BP for each trial. Orthostatic hypotension was defined using thresholds introduced by the consensus definition as a change in standing minus seated systolic BP (SBP) of −20 mm Hg or more extreme or diastolic BP (DBP) of −10 mm Hg or more extreme.²⁴ Seated BP was based on protocols reported by each trial (1 measurement or the average of 2 to 3 measurements, sometimes excluding the first measurement). Standing BP was also based on trial protocols, which included a varying number of measurements and measurement times (Table 1). Standing hypotension was defined as an SBP of less than 110 mm Hg or a DBP of less than 60 mm Hg, irrespective of the seated measurement. We also examined alternative definitions of orthostatic hypotension (change in SBP ≤30 mm Hg or DBP ≤10 mm Hg) and standing hypotension (SBP ≤110 mm Hg regardless of DBP, SBP ≤100 mm Hg regardless of DBP, DBP ≤60 mm Hg regardless of SBP, and DBP ≤50 mm Hg regardless of SBP). Baseline orthostatic hypotension or standing hypotension were based on the seated and standing BP measured in the visit in closest proximity and prior to or during the randomization visit.

Other Covariates

We obtained the following covariate data across trials: age, sex (women vs men), race (Black vs non-Black), prerandomization seated and standing SBP and DBP, baseline creatinine or estimated glomerular filtration rate or chronic kidney disease status, body mass index (BMI), diabetes status, prior stroke, and history of any CVD. We focused on Black vs non-Black adults (as opposed to other racial and ethnic subgroups) to assess for disparities in health outcomes that have been observed uniquely with Black adults. We defined obesity as BMI of 30 or greater (calculated as weight in kilograms divided by height in meters squared), and stage 3 chronic kidney disease as an estimated glomerular filtration rate of less than 60 mL/min/1.73 m² based on the 2021 Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) race-free creatinine equation²⁵ or self-reported history of kidney disease (SHEP trial only). Definitions of diabetes, stroke, and CVD varied between studies (eTables 1 and 2 in Supplement 1).

Statistical Analysis

Baseline and follow-up data from all trials were combined into a single analytic data set prior to pooled analyses. Analyses were restricted to trial participants with a baseline orthostatic or standing hypotension assessment (this requirement differed from our prior meta-analysis¹¹). Analyses were also restricted to BP, BMI, and estimated glomerular filtration rate measures between the 0.01st and 99.99th percentiles of measurements performed at baseline for all 9 trials to address extreme values, which was relevant for stratified analyses (described below). Population characteristics were summarized using means and proportions by baseline orthostatic hypotension and standing hypotension status (ie, prerandomization), overall, by trial type (ie, trials of BP treatment goals or placebo-controlled trials), and by individual trial.

The primary exposure was randomized treatment assignment, ie, more intensive pharmacologic treatment of hypertension (a lower BP goal or active therapy) compared with less intensive pharmacologic treatment of hypertension (a standard goal or placebo) with respect to CVD or all-cause mortality in strata of orthostatic hypotension or standing hypotension. Pooled analyses were presented by trial type (BP treatment goal or placebo-controlled trial) and overall.

Using baseline BP measurements, we characterized the continuous relationship between difference in SBP or DBP (standing minus sitting) and standing SBP or DBP with CVD or all-cause mortality, using Cox proportional hazards models and restricted cubic splines adjusted for age, sex, and study (study was modeled with dummy variables). In sensitivity analyses, we further examined unadjusted models and models adjusted for baseline resting SBP, baseline resting DBP, BMI, estimated glomerular filtration rate of less than 60 mL/min/1.73 m² or self-reported kidney disease, and history of diabetes, using the sample with complete data. We also determined the associations between orthostatic hypotension or standing hypotension and CVD or all-cause mortality, using Cox proportional hazards models adjusted for age, sex, and study for each individual study, for trials of BP treatment goals, for placebo-controlled trials, and for all trials. This was also examined by randomized assignment. All analyses were repeated for all-cause mortality alone.

We next examined the crude association between BP treatment and CVD or all-cause mortality via cumulative incidence plots in strata of baseline orthostatic hypotension and standing hypotension with follow-up censored at 5 years after randomization. We also examined the relative association between BP treatment for each individual study, for trials of BP treatment goals, for placebo-controlled trials, and for all trials by strata of baseline orthostatic hypotension and baseline standing hypotension with respect to CVD or all-cause mortality, using Cox proportional hazards models adjusted for age, sex, and study. Interaction terms of orthostatic hypotension × treatment or standing hypotension × treatment were used to assess effect modification. For standing hypotension, these models were repeated by trial type and overall using alternate definitions of standing hypotension as sensitivity analyses. We also examined the relationship between BP treatment and outcomes among adults with orthostatic hypotension or standing hypotension in strata of age (≤75 or >75 years), sex (men or women), prerandomization BP (SBP ≥140 mm Hg or DBP ≥90 mm Hg; no or yes), diabetes (no or yes), stage 3 chronic kidney disease (<60 mL/min/1.73 m² or ≥60 mL/min/1.73 m²; in SHEP, kidney disease was self-reported), and BMI (<30 or ≥30). Analyses were repeated for all-cause mortality alone.

We also performed a 2-step meta-analysis via a random-effects model weighted by the inverse variance. We assessed for heterogeneity between studies using the I² statistic, which provides the proportion of total variation in study estimates that is due to heterogeneity.²⁶ We also assessed for small study effects via the Egger test and funnel plots.²⁷ The Cox proportional hazards assumption was assessed via log-log plots (adjusted for age, sex, and study) for the association of orthostatic hypotension or standing hypotension with both outcomes using data from all trials. Log-log plots were also evaluated for treatment assignment in strata of baseline orthostatic hypotension or baseline standing hypotension. All plots of treatment assignment were crudely similar. Log-log plots of observational analyses associating orthostatic hypotension with outcomes were also crudely similar; however, there were some differences between standing hypotension and all-cause mortality. All statistical analyses were performed using Stata version 15.1 (StataCorp).

Results

Population Characteristics

Of the 29 235 participants included in this individual participant data meta-analysis, the mean age was 69.0 (SD, 10.9) years, with 31% older than 75 years; 48% were women (eTable 3 in Supplement 1). Prior to randomization, mean seated SBP was 155.1 (SD, 21.4) mm Hg and mean seated DBP was 81.9 (SD, 11.6) mm Hg, while mean standing SBP was 153.0 (SD, 21.1) mm Hg and mean standing DBP was 84.1 (SD, 12.0) mm Hg. At the time of randomization, 9% of participants had orthostatic hypotension and 5% had standing hypotension. See Table 2 for participant characteristics by orthostatic hypotension or standing hypotension status, eTable 3 in Supplement 1 for participant characteristics by trial type (trial of BP treatment goal or placebo-controlled trial), eTable 4 in Supplement 1 for a cross-tabulation of orthostatic hypotension with standing hypotension, eTables 5 and 6 in Supplement 1 for population characteristics by trial, and eTable 7 in Supplement 1 for a distribution of BP changes and standing BP measurements within all 9 trials. An update of the original meta-analysis focusing on orthostatic hypotension is available in eFigure 2 in Supplement 1.

Table 2. Participant Characteristics by Orthostatic Hypotension and by Standing Hypotension (N = 29 235)^a.

Characteristics	Orthostatic hypotension^b		Standing hypotension^b
Characteristics	Yes (n = 2592)	No (n = 26 643)	Yes (n = 1307)	No (n = 27 928)
Demographic information
Age, mean (SD), y	69.5 (11.1)	69.0 (10.8)	69.6 (11.2)	69.0 (10.8)
Age >75 y, No. (%)	873 (33.7)	8184 (30.7)	479 (36.6)	8578 (30.7)
Sex, No. (%)
Female	1312 (50.6)	12 808 (48.1)	563 (43.1)	13 557 (48.5)
Male	1280 (49.4)	13 835 (51.9)	744 (56.9)	14 371 (51.5)
Black race, No./total (%)^c	414/1923 (21.5)	5103/18 779 (27.2)	330/1270 (26.0)	5187/19 432 (26.7)
Medical conditions
Diabetes, No. (%)	539 (20.8)	4278/26 639 (16.1)	232 (17.8)	4585/27 924 (16.4)
Prior stroke, No./total (%)	302/2391 (12.6)	2510/24 427 (10.3)	201/1137 (17.7)	2611/25 681 (10.2)
History of cardiovascular disease, No./total (%)	353/2492 (14.2)	3304/25 642 (12.9)	297/1223 (24.3)	3360/26 911 (12.5)
BP measures
Prerandomization seated SBP, mean (SD), mm Hg	161.4 (21.3)	154.5 (21.3)	131.7 (22.1)	156.2 (20.8)
Prerandomization seated DBP, mean (SD), mm Hg	83.5 (12.3)	81.8 (11.5)	64.6 (11.0)	82.7 (11.0)
Prerandomization standing SBP, mean (SD), mm Hg	141.8 (21.9)	154.1 (20.7)	121.5 (22.9)	154.5 (19.8)
Prerandomization standing DBP, mean (SD), mm Hg	76.9 (13.5)	84.9 (11.6)	61.0 (9.8)	85.2 (10.9)
Prerandomization postural change in SBP, mean (SD), mm Hg^d	−19.6 (11.0)	−0.4 (9.8)	−10.2 (12.8)	−1.7 (11.1)
Prerandomization postural change in DBP, mean (SD), mm Hg^d	−6.6 (8.8)	3.1 (6.7)	−3.7 (9.0)	2.5 (7.2)
Prerandomization seated BP ≥130/≥80 mm Hg, No. (%)	2464 (95.1)	23 824 (89.4)	674 (51.6)	25 614 (91.7)
Prerandomization orthostatic hypotension, No. (%)	2592 (100)	0	427 (32.7)	2165 (7.8)
Prerandomization standing SBP ≤110 mm Hg or DBP ≤60 mm Hg, No. (%)	427 (16.5)	880 (3.3)	1307 (100)	0
Physical measures and laboratory values
Body mass index, mean (SD)^e	27.9 (5.3) [n = 2573]	28.5 (5.5) [n = 26 481]	28.6 (5.5) [n = 1302]	28.4 (5.5) [n = 27 752]
Obese, No./total (%)	734/2573 (28.5)	8551/26 481 (32.3)	428/1302 (32.9)	8857/27 752 (31.9)
eGFR, mean (SD), mL/min/1.73 m²^f	67.7 (20.6) [n = 1808]	70.2 (19.5) [n = 21 326]	65.0 (22.0) [n = 1099]	70.3 (19.5) [n = 22 035]
Stage 3 chronic kidney disease (eGFR <60 mL/min/1.73 m²), No./total (%)^f	845/2531 (33.4)	7992/26 188 (30.5)	511/1276 (40.0)	8326/27 443 (30.3)

Open in a new tab

Abbreviations: BP, blood pressure; DBP, diastolic blood pressure; eGFR, estimated glomerular filtration rate; SBP, systolic blood pressure.

^{^a}

See eTable 3 in Supplement 1 for participant characteristics in treatment goal and placebo-controlled trials.

^{^b}

Orthostatic hypotension is defined as a change on standing in SBP of −20 mm Hg or more extreme or in DBP of −10 mm Hg or more extreme. Standing hypotension is defined as an SBP of ≤110 mm Hg or a DBP of ≤60 mm Hg.

^{^c}

Self-reported. These data are limited, particularly among international trials, in which race was not consistently reported.

^{^d}

Standing minus seated BP. Because orthostatic hypotension is defined based on either systolic or diastolic thresholds, the means for SBP and DBP are less extreme than the orthostatic hypotension threshold of −20 mm Hg or −10 mm Hg.

^{^e}

Calculated as weight in kilograms divided by height in meters squared.

^{^f}

Based on the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) 2021 race-free creatinine equation. eGFR was not available from UKPDS or SHEP. UKPDS provides stage 3 chronic kidney disease categories based on the 2021 CKD-EPI equation. For SHEP, we relied on a self-reported history of kidney disease.

Orthostatic Hypotension, Standing Hypotension, and CVD or All-Cause Mortality

Baseline orthostatic hypotension was significantly associated with the composite of CVD or all-cause mortality (hazard ratio [HR], 1.14; 95% CI, 1.04-1.26) and with all-cause mortality (HR, 1.24; 95% CI, 1.09-1.41) (eTable 8 in Supplement 1). Similarly, baseline standing hypotension was associated with both the composite of CVD or all-cause mortality (HR, 1.39; 95% CI, 1.24-1.57) and all-cause mortality (HR, 1.38; 95% CI, 1.14-1.66) (eTable 9 in Supplement 1). Associations were similar in more robustly adjusted models (eTables 10 and 11 in Supplement 1) and in strata of treatment assignment (P > .05 for interactions) (eTables 12 and 13 in Supplement 1).

BP Treatment Assignment and CVD or All-Cause Mortality

Cumulative incidence plots showed a greater risk of CVD or all-cause mortality among those assigned to standard therapy or placebo with orthostatic hypotension and lower risk among participants assigned to lower BP goals or active therapy without orthostatic hypotension (eFigure 3 in Supplement 1). Similarly, cumulative incidence plots showed greater risk of CVD or all-cause mortality and all-cause mortality among those assigned to standard therapy or placebo with standing hypotension and lower risk among participants assigned to lower BP goals or active therapy without standing hypotension (eFigure 4 in Supplement 1).

Visualization of continuous differences in BP (ie, standing minus seated SBP or DBP) revealed virtually identical patterns of association with CVD or all-cause mortality for both BP treatment assignments (Figure 1; eFigure 5-7 in Supplement 1). Notably, change in SBP followed a U-shaped pattern, while standing SBP was more J-shaped, with higher risk of CVD or all-cause mortality at higher values. In contrast, change in DBP was inversely associated with risk of CVD or all-cause mortality, following a linear pattern, while standing DBP followed a U-shaped pattern.

Figure 1. — 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.

More intensive BP treatment lowered risk of CVD or all-cause mortality among participants with orthostatic hypotension (HR, 0.83; 95% CI, 0.70-1.00) and without orthostatic hypotension (HR, 0.81; 95% CI, 0.76-0.86) prior to randomization, without evidence of a significant difference by orthostatic hypotension status (P = .68 for interaction) (Figure 2). More intensive BP treatment did not significantly lower risk of all-cause mortality among participants with orthostatic hypotension (HR, 0.92; 95% CI, 0.72-1.18), but did so among participants without orthostatic hypotension (HR, 0.84; 95% CI, 0.76-0.92), and the effect sizes did not statistically differ by orthostatic hypotension status (P = .49 for interaction).

Figure 2. — 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.

With respect to baseline standing hypotension, more intensive BP treatment significantly lowered risk of CVD or all-cause mortality among participants without standing hypotension (HR, 0.80; 95% CI, 0.75-0.85), and this effect did not differ significantly from those with standing hypotension (HR, 0.94; 95% CI, 0.75-1.18) despite few cases (P = .16 for interaction) (Figure 3). A similar pattern was observed for all-cause mortality. There was a significant reduction among participants without standing hypotension (HR, 0.84; 95% CI, 0.77-0.92) and a nonsignificant reduction among participants with standing hypotension (HR, 0.89; 95% CI, 0.62-1.27), with no evidence of an interaction between categories (P = .75 for interaction). Associations were similar in unadjusted models (eTables 14 and 15 in Supplement 1) and more robustly adjusted models (eTables 16 and 17 in Supplement 1).

Figure 3. — 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.

Sensitivity Analyses

Findings were similar when a 2-stage meta-analysis was performed (eFigures 8-11 in Supplement 1) and with alternate definitions of orthostatic hypotension (eTables 18 and 19 in Supplement 1) or standing hypotension (eTable 20 in Supplement 1). There was no evidence that effects of treatment on outcomes differed by baseline characteristics (eTable 21 in Supplement 1).

Discussion

In this individual-level meta-analysis of 29 235 participants of hypertension trials, both baseline orthostatic hypotension and baseline standing hypotension were associated with a higher risk of CVD or all-cause mortality. However, these associations did not differ by assignment to a standard vs more intensive BP goal. Furthermore, a more intensive BP treatment goal lowered risk of CVD or all-cause mortality regardless of orthostatic hypotension status prior to treatment. These findings suggest that orthostatic hypotension alone (ie, without symptoms) and standing hypotension measured prior to intensification of BP treatment should not deter adoption of more intensive BP treatment in adults with hypertension.

Multiple studies have demonstrated a relationship between orthostatic hypotension and risk of CVD events and all-cause mortality.^5,28 While hypoperfusion related to decreased BP upon standing has been thought to be a major driver of adverse outcomes, low standing BP has been less directly linked with CVD and mortality.²⁹ Indeed, some definitions of orthostatic hypotension have included low standing BP as an equivalent state to orthostatic hypotension.³⁰ Our study is consistent with the literature in that orthostatic hypotension or standing hypotension were each associated with CVD or all-cause mortality in this population of adults with hypertension.

Orthostatic hypotension is a common finding among adults with hypertension.^1,2,3 This is driven in part by the fact that the magnitude of changes used in definitions of orthostatic hypotension are more likely to be observed among adults with hypertension.^31,32 In fact, this is one of the reasons some consensus guidelines have suggested an SBP decrease of 30 mm Hg be used to define orthostatic hypotension among adults with hypertension. There is also substantial evidence that hypertension contributes to BP variability,³³ with pressure natriuresis in the supine position being a major driver of BP lability.^34,35,36 Despite these physiologic links between hypertension and orthostatic hypotension, hypertension treatment is often a focus of concern when orthostatic hypotension is discovered in adults with hypertension. Indeed, many advocate for discontinuation of antihypertensive agents to prevent falls and fractures.⁷ Along these lines, the American College of Cardiology/American Heart Association 2017 high BP management guidelines recommended screening for orthostatic hypotension as part of a comprehensive patient evaluation prior to the initiation of antihypertensive treatment and in the setting of ongoing safety monitoring.³⁷ However, evidence in support of these recommendations is lacking.

In a series of examinations of orthostatic hypotension and outcomes in individual trials, we found that orthostatic hypotension prior to randomization did not alter the relationship between treatment and CVD events in both the AASK and SPRINT trials, results that we now extend to a larger and more diverse pool of studies,^8,9 although we did not examine standing hypotension in earlier work. In the present meta-analysis, we confirmed that more intensive treatment lowered the risk of CVD events regardless of orthostatic hypotension status. Moreover, beyond baseline orthostatic hypotension, we found that the effects of more intensive treatment on CVD or all-cause mortality were not significantly modified by standing hypotension, which was itself rare. These findings suggest that screening for orthostatic hypotension or standing hypotension may not be relevant for determining the benefits of more intensive BP treatment.

While there is some overlap between standing hypotension and orthostatic hypotension, it is possible that adults with controlled hypertension and normal or low seated BP could have standing hypotension without orthostatic hypotension. This condition is relevant in the context of safety monitoring, as a low standing BP may motivate clinicians to deintensify or withdraw treatment out of concern for standing hypotension. Although our study was limited by small numbers, we did not observe a difference in risk from low standing BP between treatment assignments. While this finding questions the utility of screening for standing BP in the context of BP treatment, a direct examination of the impact of deprescribing among this population is needed.

Our study has a number of strengths. It is the largest analysis to date examining the effect of orthostatic hypotension and standing hypotension on the relationship between more intensive BP treatment and CVD events or all-cause mortality. Second, the meta-analysis was performed at the individual participant level, which allowed for data harmonization and standardization of definitions across studies. Third, statistical heterogeneity was limited, suggesting common effects across trials. Fourth, risk of bias was minimal across the trials included in this meta-analysis.¹¹

Our study has clinical implications. Some have critiqued the generalizability of trials like SPRINT for excluding adults with standing hypotension and severe orthostatic hypotension,³⁸ suggesting that the prevalence of these conditions is likely higher among older adults. As a result, many have advocated for screening for these conditions, and some even recommend deescalating antihypertensive therapy in the setting of orthostatic hypotension and standing hypotension.^7,37 However, our study questions this assumption. Although orthostatic hypotension and standing hypotension were associated with adverse prognoses, more intensive BP therapy lowered risk with no significant effect modification by the presence or absence of orthostatic hypotension, and likewise the presence or absence of standing hypotension. These findings do not support current practice guidelines with respect to orthostatic hypotension screening in the context of antihypertensive treatment. It is reasonable to adjust antihypertensive agents or other drugs in the presence of symptoms of standing hypotension, but not necessarily to modify intensive BP goals.

Limitations

Our study has limitations. First, our study was limited to the hypertension trials that we identified and that provided outcome data. There may be other trials with these data that did not respond to our initial inquiry, and there was one trial for which sharing individual-level data was not permitted. Nevertheless, our population was quite large and, to our knowledge, represents the largest collection of orthostatic hypotension and hypertension trial outcome data in the literature, such that the addition of further studies, unless very large, would be unlikely to change our findings.

Second, trials differed in their study populations, BP measurement procedures, interventions, duration, and CVD outcomes ascertainment processes and definitions. While we observed a similar pattern of effect by type of trial and type of outcome, eg, when the outcome was restricted to all-cause mortality, the overall pooled summaries do not have as clear a causal interpretation as the trial-specific results.

Third, some trials excluded adults with low standing SBP,^16,17 limiting the number of participants with standing hypotension. This seemed especially apparent with the fewer numbers observed when more extreme definitions of standing hypotension were used. These exclusions may underestimate the number of patients with standing hypotension in our population and attenuate its association with adverse events. Similarly, these trials did not focus on enrolling adults with neurogenic orthostatic hypotension, which would limit the generalizability of these findings to adults with more severe orthostatic hypotension as well as adults with hypotension-related falls and syncope. Of note, the ages of participants with and without orthostatic hypotension were similar, which may suggest that older adults with orthostatic hypotension were not represented in this population.

Fourth, orthostatic hypotension was based on a seated-to-standing protocol. Supine-to-standing protocols are more sensitive than seated-to-standing protocols and may not be interchangeable.³⁹ In addition, most of the orthostatic hypotension protocols did not involve standing for 3 minutes or require repeat orthostatic hypotension assessments to establish reproducibility. Thus, it is possible that clinically relevant orthostatic hypotension was missed.

Fifth, medications used in the trials may not reflect current medicine practice or include agents thought to be more likely to affect orthostatic hypotension and falls.⁴⁰ Moreover, the trials’ entry criteria may limit generalizability, particularly if trials excluded or did not enroll frail individuals. In addition, those with orthostatic hypotension or standing hypotension were not necessarily symptomatic. This distinction may be important when applying these results in clinical practice, especially in the setting of symptomatic orthostatic hypotension or standing hypotension.

Sixth, it is possible that participants were treated differently during the study when orthostatic hypotension was identified; for example, participants with orthostatic hypotension may have received less intensive treatment. However, the net impact of this possibility on outcomes is unclear, as orthostatic hypotension was more frequent among the less intensive treatment group and withholding therapy might have also contributed to poor BP control.

Seventh, we did not have information on autonomic etiologies of orthostatic hypotension or heart rate, which has utility for identifying autonomic dysfunction.

Last, dizziness, falls, and syncope were not a focus of the current review and not ascertained by many of the trials in our review. This limits our ability to evaluate nonfatal adverse events related to orthostatic hypotension. Notably, a systematic review focused on secondary outcomes did not find intensive BP treatment to be associated with falls but did find it to be related to syncope.⁴¹ The role of orthostatic hypotension with respect to safety end points should be a focus of subsequent research.

Conclusions

In conclusion, in this large, individual participant-level synthesis of BP treatment trials, while both orthostatic hypotension and standing hypotension were crudely associated with CVD or all-cause mortality, these prerandomization BP phenotypes did not significantly modify the inverse relationship between more intensive BP treatment and CVD or all-cause mortality.

Educational Objective: To identify the key insights or developments described in this article.

Why did the authors undertake this individual participant data meta-analysis of blood pressure control in patients with orthostatic or standing hypotension?
1. Intensive blood pressure treatment and first-line antihypertensive classes have both been shown to be associated with orthostatic hypotension.
2. More than 50% of adults have intermittent orthostatic hypotension, which makes the relationship between orthostatic hypotension and cardiovascular disease essential to understand.
3. Whether the presence of orthostatic hypotension alters the benefits of blood pressure treatment had not been shown.
What were the results of the analysis for the primary outcome of cardiovascular disease events and all-cause mortality?
1. Among patients with orthostatic hypotension, compared with the group without baseline orthostatic hypotension, more intensive blood pressure treatment increased risk of the primary outcome.
2. More intensive blood pressure treatment significantly lowered risk of the primary outcome for patients with baseline standing hypotension compared with those without baseline standing hypotension, although there were few cases.
3. Neither baseline orthostatic hypotension nor baseline standing hypotension were associated with the composite outcome.
The authors suggest that what clinical implications follow from the study findings?
1. Asymptomatic orthostatic hypotension and standing hypotension measured prior to intensification of treatment should not deter adoption of intensive blood pressure treatment in adults with hypertension.
2. Blood pressure targets should be relaxed and antihypertensives reduced in patients who develop orthostatic or standing blood pressure during treatment.
3. Orthostatic hypotension, but not standing hypotension, measured prior to initiation of blood pressure treatment should spur reconsideration of blood pressure control.

Supplement 1.

eAppendix. Details of search strategies

eFigure 1. PRISMA diagram of the updated systematic review

eFigure 2. Updated meta-analysis of the effects of hypertension treatment on orthostatic hypotension

eFigure 3. Cumulative incidence of cardiovascular disease or all-cause mortality by treatment assignment and orthostatic hypotension status

eFigure 4. Cumulative incidence of cardiovascular disease or all-cause mortality by treatment assignment and standing hypotension status

eFigure 5. Restricted cubic spline of difference in diastolic blood pressure or standing blood pressure

eFigure 6. Fully adjusted splines of difference in systolic blood pressure or standing blood pressure

eFigure 7. Fully adjusted splines of difference in diastolic blood pressure or standing blood pressure

eFigure 8. Two-stage meta-analysis, orthostatic hypotension and cardiovascular disease or all-cause mortality

eFigure 9. Two-stage meta-analysis, orthostatic hypotension and all-cause mortality

eFigure 10. Two-stage meta-analysis, standing hypotension and cardiovascular disease or all-cause mortality

eFigure 11. Two-stage meta-analysis, standing hypotension and all-cause mortality

eTable 1. Comparison of covariate definitions across blood pressure treatment goal trials

eTable 2. Comparison of covariate definitions across placebo-controlled trials

eTable 3. Participant characteristics for all trials, trials of blood pressure treatment goal, and placebo-controlled trials

eTable 4. Cross-tabulation of orthostatic hypotension and standing hypotension

eTable 5. Baseline characteristics of each blood pressure treatment goal trial

eTable 6. Baseline characteristics of each placebo-controlled trial

eTable 7. Number of participants by blood pressure distribution

eTable 8. Association of baseline orthostatic hypotension with cardiovascular disease or all-cause mortality

eTable 9. Association of baseline standing hypotension with cardiovascular disease or all-cause mortality

eTable 10. Association of baseline orthostatic hypotension with cardiovascular disease or all-cause mortality adjusted for additional cardiovascular risk factors

eTable 11. Association of baseline standing hypotension with cardiovascular disease or all-cause mortality adjusted for additional cardiovascular risk factors

eTable 12. Association between orthostatic or standing hypotension and outcomes among those assigned a more intensive blood pressure goal or active treatment

eTable 13. Association between orthostatic or standing hypotension and outcomes among those assigned a standard blood pressure goal or placebo

eTable 14. Treatment effects on cardiovascular disease or all-cause mortality by baseline orthostatic hypotension, unadjusted

eTable 15. Treatment effects on cardiovascular disease or all-cause mortality by baseline standing hypotension, unadjusted

eTable 16. Treatment effects on cardiovascular disease or all-cause mortality by baseline orthostatic hypotension, adjusted for additional cardiovascular risk factors

eTable 17. Treatment effects on cardiovascular disease or all-cause mortality by baseline standing hypotension, adjusted for additional cardiovascular risk factors

eTable 18. Association of baseline orthostatic hypotension with cardiovascular disease or all-cause mortality, using an alternate definition of orthostatic hypotension based on a drop in systolic blood pressure of at least 30 mm Hg or a drop in diastolic blood pressure of at least 10 mm Hg

eTable 19. Treatment effects on cardiovascular disease or all-cause mortality by baseline orthostatic hypotension, using an alternate definition of orthostatic hypotension based on a drop in systolic blood pressure of at least 30 mm Hg or a drop in diastolic blood pressure of at least 10 mm Hg

eTable 20. Treatment effects on cardiovascular disease or all-cause mortality by baseline standing hypotension, defined using distinct thresholds for systolic or diastolic blood pressure

eTable 21. Treatment effects among participants with baseline orthostatic hypotension or baseline standing hypotension in strata of baseline characteristics

Click here for additional data file.^{(1.4MB, pdf)}

Supplement 2.

Data Sharing Statement

Click here for additional data file.^{(24.2KB, pdf)}

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