Association Between Orthostatic Hypertension and Frailty Among Older Patients With Hypertension

The data that support the findings of this study are available from the corresponding author upon reasonable request.

This is an analysis of the study participants of the HOWOLD-BP trial (How to Optimize Elderly Systolic Blood Pressure), which was a prospective, multicenter, open-label randomized clinical trial to compare the optimal target blood pressure for older Korean patients with hypertension.⁸ We included patients aged ≥65 years with hypertension who were already taking antihypertensive medications or treatment-naïve patients with a clinic SBP of 140 to 180 mm Hg. All patients enrolled in this study were independent in their activities of daily living. Patients were excluded if they had secondary hypertension, resistant hypertension, or symptomatic orthostatic hypotension (1-minute standing SBP of <110 mm Hg) at screening. Patients with a history of acute coronary syndrome, cardiac surgery, urgent coronary intervention, or stroke within 3 months, and patients with concomitant systolic heart failure or other significant structural heart diseases were excluded. Furthermore, patients with uncontrolled diabetes (hemoglobin A1c ≥10%), end-stage renal disease (on hemodialysis or estimated glomerular filtration rate <15 mL/min per 1.73 m²), severe liver function abnormality (liver enzyme levels >3× the upper normal range), uncontrolled thyroid dysfunction, and moderate to severe retinopathy were also excluded.

The participants were recruited from 12 University hospitals in Korea. We collected blood pressure data measured at the clinic in the supine and standing positions along with home blood pressure monitoring data, laboratory findings, frailty assessments (gait speed, questionnaire, and handgrip strength), cognitive function, and quality of life (QOL). The study protocol was approved by the ethics committee of each participating center. This study was registered with the Clinical Research Information Service (KCT0003787; https://cris.nih.go.kr/). All participants provided written informed consent.

Blood pressure and pulse rate were measured at the heart level in a seated position using a professional digital blood pressure monitor (HEM7080-IC, Omron Healthcare, Lake Forest, IL). To evaluate orthostatic blood pressure changes, we measured supine blood pressures after a 5-minute rest. The participant was then asked to stand with the arm supported, and blood pressures were measured 3 minutes after the participant’s feet touched the ground. While standing, participants were asked about symptoms of hypotension. Changes in blood pressure after standing were assessed at baseline. Orthostatic blood pressure increase was calculated as the mean blood pressure measurement while standing minus the blood pressure measured in the supine position. Orthostatic hypotension was defined as a decrease in SBP of ≥20 mm Hg or a decrease in DBP of ≥10 mm Hg within 3 minutes of standing.⁹ Orthostatic hypertension was defined as an increase in SBP of ≥20 mm Hg within 3 minutes of standing and upright SBP ≥140 mm Hg.¹⁰

Trained clinical research coordinators assessed frailty using the Korean version of the FRAIL (K-FRAIL) questionnaire, which includes a simple 5-item questionnaire regarding fatigue, resistance, ambulation, illnesses, and loss of weight. Frail scale scores range from 0 to 5 (1 point for each component, where 0 indicates the best and 5 the worst). A score of ≥3 is categorized as frail, 1 to 2 as prefrail, and 0 as robust.¹¹ In addition, gait speed and handgrip strength were measured to evaluate frailty. Gait speed was measured by taking the time to complete a 4-m course at the usual walking speed. The handgrip strength was measured twice in both arms using a TKK-5401 GRIPD instrument (Takei, Niigata, Japan). The maximum handgrip strengths of both hands were recorded. Slow gait speed was defined as <1 m/s, and low muscle strength was defined as handgrip strength <28 kg for men and <18 kg for women, as recommended by the Asian Working Group for Sarcopenia.¹² Cognitive function was assessed using the Korean version of the Montreal Cognitive Assessment (range, 0–30; with lower scores indicating worse function). A MoCA cutoff score of <23 points was applied for detecting mild cognitive impairment or dementia.^13,14 Evaluation of health-related QOL was performed using the Korean version of the EQ-5D.¹⁵ This measure comprises 5 dimensions (mobility, self-care, usual activities, pain or discomfort, and anxiety or depression), each of which was rated at 3 levels (no problem, some problems, severe problems).

Diabetes was defined as the fulfillment of at least one of the following criteria: fasting plasma glucose ≥126 mg/dL, hemoglobin A1c ≥6.5%, or use of glucose-lowering drugs. Similarly, dyslipidemia was defined as cholesterol ≥240 mg/dL or current treatment with cholesterol-lowering agents. Information regarding cardiovascular diseases, such as congestive heart failure, revascularization, myocardial infarction, stroke, atrial fibrillation, peripheral artery disease, or lifestyle (exercise, smoking, and alcohol consumption) was also assessed. Blood and urine tests, including complete blood counts, liver enzymes, kidney function, and spot urine microalbumin levels, were performed at an accredited institution.

Statistical analyses were performed using SPSS 21.0 (IBM-SPSS, Chicago, IL). Continuous variables were expressed as mean±SD and compared using the unpaired Student t test for comparison between normal and orthostatic hypertension groups and 1-way ANOVA for comparison between 3 groups. Categorical variables were expressed as numbers and percentages, and the χ² test was used to compare proportions. Multivariable logistic models were used to identify factors affecting orthostatic hypertension. Furthermore, independent variables were selected based on significant values or factors related to orthostatic hypertension in previous studies. All statistical analyses were 2-tailed, and P<0.05 were considered statistically significant.

From the 2085 participants, we excluded 17 who did not undergo postural blood pressure measurements and 3 who did not undergo physical frailty evaluation. Hence, we analyzed data from 2065 participants. The mean age was 73.2±5.6 years, and 52.0% were females. The mean SBP and DBP were 137.1±14.9 and 75.1±9.7 mm Hg, respectively. Mean orthostatic changes of SBP is 1.95±10.7 mm Hg, and mean DBP changes after standing is 3.12±6.7 mm Hg (Figure S1).

Among the participants, 1886 (91.3%) had a normal response after standing, but 94 (4.6%) had orthostatic hypertension, and 85 (4.1%) had orthostatic hypotension after standing. More specifically, 101 patients showed exaggerated orthostatic SBP increase of ≥20 mm Hg. Among these 101 patients, 66 patients showed isolated orthostatic hypertension (supine SBP <140 mm Hg but standing SBP ≥140 mm Hg and SBP increase ≥20 mm Hg), 28 patients, who had supine SBP ≥140 mm Hg, showed further SBP increase of ≥20 mm Hg after standing, and 7 patients showed only exaggerated orthostatic response (SBP increase ≥20 mm Hg after standing, but final SBP <140 mm Hg). The mean number of pill counts of antihypertensive medications per patient was 1.98±0.8. A total of 1488 (72.1%) patients were treated with combined antihypertensive medications, and 567 (27.5%) were treated with a single agent.

The baseline characteristics according to postural blood pressure patterns are presented in Table 1. Compared with the participants with normal responses after standing, those with orthostatic hypertension were older, predominantly female, had a higher body mass index and SBP in the sitting position. However, there were no significant differences in cardiovascular risk factors or lifestyle parameters. SBP and DBP were higher in the patients with orthostatic hypertension or orthostatic hypotension compared with participants with normal response after standing. There was no significant difference in the number of prescribed antihypertensive medications or the class of antihypertensive medications between the participants with normal response and orthostatic hypertension.

Patients with orthostatic hypertension were more likely to have frailty, as evaluated by the K-FRAIL questionnaire, grip strength, and gait speed than participants with normal responses. Frailty status as assessed by the K-FRAIL questionnaire revealed that robust, prefrail, and frail older adults were 73.2%, 23.1%, and 3.7%, respectively, among the participants with normal response and 54.3%, 38.3%, and 7.4%, respectively among the patients with orthostatic hypertension (Figure 1). The proportion of patients with frailty or prefrailty was significantly higher in the orthostatic hypertension group compared with the robust group (P<0.001). Additionally, the proportion of patients with physical frailty (slow gait speed or weak grip strength) was higher in the orthostatic hypertension group (P=0.024). More specifically, 15.1% of the participants with normal responses showed both slow gait speed and weak grip strength, but 25.5% of the patients with orthostatic hypertension had both slow gait speed and weak grip strength (Figure 2). There was no significant difference in cognitive impairment (mild cognitive impairment or dementia) between participants (24.8%) with a normal response and those with orthostatic hypertension (30.1%; P=0.249). However, the MoCA scores were significantly lower in patients with orthostatic hypertension than in participants with normal response (23.1±5.3 versus 24.4±4.6; P=0.017).

Compared with participants with a normal response after standing, patients with orthostatic hypertension showed a poor QOL. Similarly, the EQ-5D index scores were significantly lower in patients with orthostatic hypertension than in the participants with normal response after standing (0.89±0.11 versus 0.94±0.09; P<0.001). Notably, more impairments in the dimension of mobility, usual activities, and pain or discomfort components were observed in patients with orthostatic hypertension than in those with normal response (Figure 3). However, there was no significant difference in instrumental activities of daily living dependency between the 2 groups (2.3% in the participants with normal response versus 4.3% in patients with orthostatic hypertension; P=0.237).

We performed a multivariable analysis to identify independent factors associated with orthostatic hypertension. Among the variables, the K-FRAIL group, body mass index, and SBP were independently associated with orthostatic hypertension (Table 2). However, there was no significant associations between other variables and orthostatic hypertension. Considering the multicollinearity among K-FRAIL, gait speed, and cognitive function groups, a restricted covariate model was constructed. Included variables in the model were age, sex, K-FRAIL, gait speed group, cognitive function group, myocardial infarction, stroke and SBP. The model showed a slightly lower area under the receiver operating characteristic curve (0.656) compared with the original full model (area under the receiver operating characteristic curve, 0.677). The results of the model constructed by K-FRAIL, gait speed, and cognitive function groups separately were presented in Tables S1 through S3.

First, we excluded hypertensive patients with symptomatic orthostatic hypotension in our study. Therefore, the prevalence of orthostatic hypotension in the present study was lower than the expected values. Moreover, the characteristics of the participants with orthostatic hypotension in this study may not represent those of patients with orthostatic hypotension in daily clinical practice. Second, there is controversy in defining orthostatic hypertension using the DBP increase during postural change. An increase in the DBP after standing can be a normal response. Some studies have adopted the definition of orthostatic hypertension as a ≥10-mm Hg increase in DBP within 3 minutes of standing; however, we only used the exaggerated change in SBP in accordance with the recent guideline. This may affect the generalizability of our study. Third, the measurement of positional blood pressure changes from the supine to upright positions is challenging in daily practice. However, a previous consensus statement defined orthostatic hypertension using blood pressure changes from the supine to standing positions.¹⁰ Thus, we applied the standard of orthostatic blood pressure measurement. Further studies are required to compare the significance of orthostatic blood pressure differences from supine to standing and from sitting to standing. Last, because we conducted only 1 session of orthostatic blood pressure measurements over 3 minutes, our findings may not be optimal for defining orthostatic hypo- or hypertension in an older adult cohort. However, we are collecting annual follow-up data on clinical outcomes and orthostatic blood pressure change among the study participants, which can provide more information regarding the relationship between orthostatic blood pressure response and long-term clinical outcomes.

Orthostatic hypertension is associated with frailty, cognitive impairment, and low QOL among older hypertensive patients. Evaluation of orthostatic blood pressure changes to confirm orthostatic hypertension or hypotension in frail older adults will serve as an important diagnostic procedure in vulnerable patients. Further pathophysiological and longitudinal research is needed to identify the underlying mechanisms and clinical characteristics of this association.

J.-Y. Choi, D.R. Ryu, Y. Hong, S.K. Park, and K.-i. Kim have full access to the study data and take responsibility for the integrity of the data and the accuracy of the data analysis. H.-Y. Lee, C.-H. Kim, M.-C. Cho, J.-Y. Choi, J.-H. Lee, and K.-i. Kim were responsible for the study concept. Y. Hong, S.K. Park, J.H. Lee, S.-J. Hwang, D.R. Ryu, K.H. Kim, S.H. Lee, S.Y. Kim, J.-H. Park, S.-H. Kim, H.-L. Kim. and K.-i. Kim were responsible for data curation. All authors were responsible for protocol writing and investigation. Y. Hong, S.K. Park, and K.-i. Kim conducted the data analysis. All authors interpreted the data. K.-i. Kim drafted the original article, which was reviewed and edited by all authors. K.-i. Kim was responsible for data visualization. M.-C. Cho and K.-i. Kim acquired the funding for the study. K.-i. Kim supervised the project. K.-i. Kim was responsible for the decision to submit the article. All authors gave final approval of the version to be published.