Algorithm for diagnosing hypertension using out‐of‐office blood pressure measurements

Abstract The authors developed and validated a diagnostic algorithm using the optimal upper and lower cut‐off values of office and home BP at which ambulatory BP measurements need to be applied. Patients presenting with high BP (≥140/90 mm Hg) at the outpatient clinic were referred to measure office, home, and ambulatory BP. Office and home BP were divided into hypertension, intermediate (requiring diagnosis using ambulatory BP), and normotension zones. The upper and lower BP cut‐off levels of intermediate zone were determined corresponding to a level of 95% specificity and 95% sensitivity for detecting daytime ambulatory hypertension by using the receiver operator characteristic curve. A diagnostic algorithm using three methods, OBP‐ABP: office BP measurement and subsequent ambulatory BP measurements if office BP is intermediate zone; OBP‐HBP‐ABP: office BP, subsequent home BP measurement if office BP is within intermediate zone and subsequent ambulatory BP measurement if home BP is within intermediate zone; and HBP‐ABP: home BP measurement and subsequent ambulatory BP measurements if home BP is within intermediate zone, were developed and validated. In the development population (n = 256), the developed algorithm yielded better diagnostic accuracies than 75.8% (95%CI 70.1–80.9) for office BP alone and 76.2% (95%CI 70.5–81.3) for home BP alone as follows: 96.5% (95%CI: 93.4–98.4) for OBP‐ABP, 93.4% (95%CI: 89.6–96.1) for OBP‐HBP‐ABP, and 94.9% (95%CI: 91.5–97.3%) for HBP‐ABP. In the validation population (n = 399), the developed algorithm showed similarly improved diagnostic accuracy. The developed algorithm applying ambulatory BP measurement to the intermediate zone of office and home BP improves the diagnostic accuracy for hypertension.


INTRODUCTION
Compared to office blood pressure (BP), out-of-office BP has demonstrated better predictive power for hypertension-mediated organ damage and cardiovascular events. [1][2][3][4] Additionally, diagnosis and treatment of hypertension solely using office BP measurements possess an inherent risk of over-treatment of white-coat hypertension or under-treatment of masked hypertension. Therefore, recent guidelines recommend greater application of out-of-office BP measurements in the diagnosis and treatment of hypertension, particularly when whitecoat or masked hypertension is suspected. 5,6 Ambulatory BP measurement is preferred to home BP measurement because ambulatory BP provides better cardiovascular risk prediction than home BP. 3,7 However, ambulatory BP measurement is not conducted for all patients because of high cost and inconvenience.
Alternatively, home BP could be easily measured; however, ambulatory and home BP measurement methods are not interchangeable because there is a diagnostic disagreement between these two methods. [8][9][10][11] It is impractical to measure ambulatory or home BP in all patients, and it is not easy to determine which method could be most appropriately applied for the most suitable patients.
Several algorithms for the diagnosis of hypertension using ambulatory and home BP measurements have been proposed. [12][13][14][15][16][17] However, most studies focused on diagnosing white-coat hypertension, not on masked hypertension, and did not apply all available office, home, and ambulatory BP measurement methods. Moreover, existing guidelines do not clearly indicate the patients most suitable for ambulatory and home BP measurement for diagnosing hypertension, 5,6 and both are overused. 17,18 Although stage 1 hypertension and high normal BP were suggested as conditions in which out-of-office BP measurements are required, 5,6 the upper and lower BP thresholds, which necessitate out-of-office BP measurement to distinguish white-coat and masked hypertension from sustained hypertension and normotension, have not been adequately investigated. Therefore, practitioners are easily confused in determining patients where ambulatory and home BP measurements are appropriate.
In this study, we developed and validated a diagnostic algorithm by determining the optimal upper and lower cut-off BP levels at which ambulatory or home BP measurement need to be applied.

Study population
The diagnostic algorithm was developed using data from the study conducted between March 2012 and September 2013, 8,19 and validated with data of the study conducted between January 2015 and December 2019 (ClinicalTrials.gov identifier: NCT03855605). 11

Measurements for office, home, and ambulatory BP
BP measurement schedule ( Figure S1 in the supplementary material) was also described elsewhere, 8,11,19 and it did not differ significantly between the studies. Participants were asked to avoid smoking, caffeine-containing beverages, and exercise within 30 min preceding the measurements. Three readings of office BP after 5 min of seated rest in a quiet room and at 1-min intervals were obtained at each visit using an appropriate cuff size. In the development study population, the office BP were measured trice from both arms on the first visit, and the arm with higher BP was determined and designated as the index arm. During the second and third visits, office BP was measured from the index arm. In the validation population, office BP was measured from both arms simultaneously three times during every three visits. The BPs of both arms were averaged, and the BP of the arm with the higher averaged BP was used as the office BP of the index arm.
Home BP was measured with validated oscillometric device (WatchBP Home; Microlife, Taiwan) in both studies. Participants were instructed to take triplicate measurements at 1 min intervals every morning (between 07:00 h or waking and 09:00 h) and every evening (between 21:00 h and 23:00 h or before bedtime) for seven consecutive days. In the validation study, home BP measurements for 9 days were allowed if the participants desired. Participants were instructed to measure BP in the morning after micturition or defecation, and before showering and breakfast. On the last day of home BP measurement, participants measured the last morning home BP and visited the clinical trial centers (second visit). Based on our previous findings, a valid measurement of home BP was defined as at least 5 days of morning and evening duplicate measurements. 19 The home BP measured on the evening of the first day and on the morning of the second day were discarded, and the first and second readings of each session were averaged (the third reading was discarded). 19 At the second visit, ambulatory BP monitoring over 25 h was performed on the non-dominant arm using an automated, noninvasive oscillometric device (Mobil-O-Graph, I.E.M GmbH, Germany), with a measurement interval of 30 min. Participants were instructed to continue normal daily activities during the day. A valid measurement was defined as valid readings for > 70% of the total measurement attempts, and at least 14 measurements during the daytime (10:00 to 20:00 h for development population, 09:00 to 21:00 for validation population) and at least seven measurements during the nighttime (00:00 to 06:00 h).
A blood sample for hematologic and biochemical analysis was obtained after at least 8 h of overnight fasting.

Diagnostic accuracy of algorithm
The diagnostic sensitivities and specificities of the three arms were more than 95% and 86%, respectively. AUCs were more than 0.9 (

Validation of diagnostic algorithm
The prevalence of white-coat and masked hypertension in the intermediate zone were not different from those of the development population (  Figure 2). As in the development population, the diagnostic sensitivity was also improved significantly, excluding individuals in the intermediate zone of office and home BP ( Table 3). The diagnostic sensitivity, specificity, and accuracies of each arm in the validation population were similar to those in the development population (Table 4).

Twenty-four hour ambulatory BP as a reference standard for the diagnosis of hypertension
The algorithm using 24-h ambulatory BP as a reference standard for the diagnosis of hypertension showed similar results with the algorithm using daytime ambulatory BP. The majority of masked and white coat hypertension was distributed in the intermediate zone, and diagnostic accuracy in the validation population also had good consistency to the development population, with accuracies exceeding 95% (Tables   S2-S4, and Figures S2 and S3 in the supplementary material). Discrimination of white-coat hypertension from sustained hypertension is crucial to avoid unnecessary antihypertensive medication.
Also, it is crucial to identify masked hypertension due to the similar or greater cardiovascular risk, compared to sustained hypertension. 20,21 Several studies and recent guidelines provided diagnostic algorithm to detect masked hypertension but did not provide an upper threshold BP to detect white-coat hypertension. 5  There are limitations to this study. First, we determined daytime ambulatory BP as confirming diagnosis, rather than 24-h ambulatory BP. Daytime ambulatory BP does not reflect nighttime BP. However, daytime ambulatory BP has the advantage of more effectively reflecting real office and home BP during the waking period while having the same diagnostic threshold as home BP in current guidelines. 5 Second, office BP in our study was measured using the standardized technique recommended in the hypertension guidelines, 5,6 which may be different from those measured by a physician in routine clinical practice. Therefore, education regarding standardized office BP measurement techniques for healthcare providers may be required. The advantage of our algorithm is that we provided an alternative method to use home BP measurements instead of office BP measurements in controlled condition.
In conclusions, we proposed a diagnostic algorithm for hypertension using the intermediate zone of office BP, home BP, and both, followed by confirmation with ambulatory BP measurements. This algorithm may have an advantage in efficacy for the detection of masked and white coat hypertension.

FUNDING
The study of development population was funded by Dong-A ST Co.
Ltd., Seoul, Korea. The sponsor was not involved in study design, study conduction, data interpretation, and the writing of the manuscript. The study of validation population was not funded.

AUTHOR CONTRIBUTIONS
All authors have read the manuscript and have approved this manuscript. All authors made substantial contributions to conception and design, acquisition of data, or analysis and interpretation of data; took part in drafting the review paper or revising it critically for important intellectual content; agreed on the journal to which the review paper will be submitted; gave final approval of the version of the review paper; and agreed to take responsibility and be accountable for all aspects of the work.