Discrepancies between Office and Ambulatory Blood Pressure: Clinical Implications

CLINICAL RESEARCH STUDY

Discrepancies between Office and Ambulatory Blood Pressure: Clinical Implications José R. Banegas, MD,a,b Franz H. Messerli, MD,c Bernard Waeber, MD,d Fernando Rodríguez-Artalejo, MD,a,b Alex de la Sierra, MD,e Julián Segura, MD,f Alex Roca-Cusachs, MD,g Pedro Aranda, MD,h Luis M. Ruilope, MDf a

Department of Preventive Medicine and Public Health, Universidad Autónoma de Madrid, Spain; bCIBER en Epidemiología y Salud Pública (CIBERESP), Barcelona, Spain; cDivision of Cardiology, St. Luke’s-Roosevelt Hospital, Columbia University College of Physicians and Surgeons, New York, NY; dDivision of Clinical Pathophysiology, Centre Hospitalier Universitaire Vaudois et Université de Lausanne, Switzerland; eHypertension Unit, Clinic Hospital, Barcelona, Spain; fHypertension Unit, Doce de Octubre Hospital, Madrid, Spain; gHypertension Unit, Department of Internal Medicine, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Spain; hNephrology Department, Hospital Regional Universitario Carlos Haya, Málaga, Spain.

ABSTRACT BACKGROUND: Recent trials have documented no benefit from small reductions in blood pressure measured in the clinical office. However, ambulatory blood pressure is a better predictor of cardiovascular events than office-based blood pressure. We assessed control of ambulatory blood pressure in treated hypertensive patients at high cardiovascular risk. METHODS: We selected 4729 patients from the Spanish Ambulatory Blood Pressure Monitoring Registry. Patients were aged ⱖ55 years and presented with at least one of the following co-morbidities: coronary heart disease, stroke, and diabetes with end-organ damage. An average of 2 measures of blood pressure in the office was used for analyses. Also, 24-hour ambulatory blood pressure was recorded at 20-minute intervals with a SpaceLabs 90207 device. RESULTS: Patients had a mean age of 69.6 (⫾8.2) years, and 60.8% of them were male. Average time from the diagnosis of hypertension to recruitment into the Registry was 10.9 (⫾8.4) years. Mean blood pressure in the office was 152.3/82.3 mm Hg, and mean 24-hour ambulatory blood pressure was 133.3/72.4 mm Hg. About 60% of patients with an office-pressure of 130-139/85-89 mm Hg, 42.4% with office-pressure of 140-159/90-99 mm Hg, and 23.3% with office-pressure ⱖ160/100 mm Hg were actually normotensive, according to 24-hour ambulatory blood pressure criteria (⬍130/80 mm Hg). CONCLUSION: We suggest that the lack of benefit of antihypertensive therapy in some trials may partly be due to some patients having normal pressure at trial baseline. Ambulatory monitoring of blood pressure may allow for a better assessment of trial eligibility. © 2009 Elsevier Inc. All rights reserved. • The American Journal of Medicine (2009) 122, 1136-1141 KEYWORDS: Ambulatory blood pressure; Antihypertensive therapy; Blood pressure control; Clinical trials; Office blood pressure; Treatment goals

During the last few years, a number of randomized trials have compared “head-to-head” different antihypertensive drugs.1-7 Because most of the clinical benefits are conferred by the degree of blood pressure (BP) reduction,8-12 Funding: The main funding for the study was obtained from Lacer Spain, SA, through an unrestricted educational grant. Conflict of Interest: None. Authorship: We verify that all authors had access to the data and a role in writing the manuscript. Requests for reprints should be addressed to Luis M. Ruilope, MD, Hypertension Unit, Doce de Octubre Hospital, Av. Cordoba s/n, Madrid 28041, Spain. E-mail address: [email protected]

0002-9343/$ -see front matter © 2009 Elsevier Inc. All rights reserved. doi:10.1016/j.amjmed.2009.05.020

interpretation of the results of these trials might be difficult unless blood pressure control in the treatment arms is similar.8 Also, and somewhat astonishingly, some recent trials of antihypertensive treatment achieving a small but significant reduction in blood pressure have documented little if any benefit against placebo.13,14 Of note, in most of these studies, blood pressure at trial entry was only slightly elevated (mean systolic pressure of 140-150 mm Hg, and inclusion of normotensive individuals). Recent studies have shown that out-of-office blood pressure, as assessed by 24-hour ambulatory monitoring, predicts

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cardiovascular morbidity and mortality better than blood pres⬎125 g/m2 in men and ⬎ 110 g/m2 in women from an M15-19 sure measured in the clinical office. Marked discrepancies mode echocardiogram, or presence of electrocardiographic crihave been documented between office and ambulatory meateria (Sokolow index ⬎35 mm or Cornell index ⬎2440 mm/ surements of blood pressure;20 hypertension control is usually ms). Renal disease was defined as serum creatinine ⬎1.5 much more frequent in the out-of-office than in the office mg/dL in men and ⬎1.4 mg/dL in women, or urinary setting.21 These findings led us to protein excretion ⬎300 mg/day. hypothesize that the lack of benefit Biochemical parameters correin some trials could be partly due to sponded to the last office-based CLINICAL SIGNIFICANCE baseline blood pressure being actudetermination within the precedally lower than that recorded in the ing 3 months. ● A third of hypertensive patients considclinical office. To our knowledge, Blood pressure was measured in ered uncontrolled by office-based measures this possible explanation has not the clinical office using validated are normotensive according to 24-hour been proposed yet. In fact, officedevices, with appropriate cuff sizes, ambulatory blood pressure monitoring. based blood pressure at trial entry after a 5-minute rest and under These patients could be over-treated. plays a role, though modest, in exstandardized conditions.23-26 Speplaining benefit from antihypertencifically, the average of 2 pressure ● Lack of benefit of antihypertensive thersive drug treatment.22 readings was used for analyses. apy in some trials might be due to some This study assesses the control of Measurements were obtained by patients having normal 24-hour blood blood pressure, according to officetrained and certified staff.23-26 Qualpressure at trial entry. based and ambulatory measureity control measures included con● Ambulatory monitoring of blood presment, among high-risk treated hytinuing education activities and sure may allow for better assessment of pertensive patients. It also ascertains monthly site visits, where experipatient eligibility for clinical trials than whether ambulatory blood pressure enced independent observers ascontrol is independent of age, sex, sessed the accuracy of measureoffice-based blood pressure. and cardiovascular morbidity. ments. Reproducibility of blood pressure measures was good, with Pearson’s correlation coefficients of PATIENTS AND METHODS 0.922 for systolic blood pressure and 0.859 for diastolic blood We used data from the Spanish Ambulatory Blood Pressure pressure. Inter-observer reliability also was high; the Welch Monitoring Registry, which has been described elsestatistic was 725 (P ⬍.001) for the mean of 2 systolic blood where.20,21 Briefly, this Registry started in June 2004 and pressure measurements, and 218 (P ⬍.001) for the mean of 2 was based on a large network of physicians trained in diastolic blood pressure measurements. The Welch statistic ambulatory blood pressure monitoring, who have consecuwas 722 (P ⬍.001) for the second measurement of systolic tively recruited 51,573 hypertensive patients with indication pressure, and 215 (P ⬍.001) for the second measurement of diastolic pressure. for blood pressure monitoring across the 17 regions of Thereafter, 24-hour ambulatory blood pressure was reSpain. Both the study protocol and hypertension treatment corded at 20-minute intervals using a SpaceLabs 90207 followed international guidelines.23,24 device. Recording was considered valid when at least 80% Of all patients in the Registry, we studied 4729 essential of pressure readings during day- and nighttime (defined hypertensives currently treated with antihypertensive drugs, from patients’ diaries) fulfilled the standardized technical aged ⱖ55 years and with at least one of the following requirements.25 Valid recordings were analyzed to obtain concurrent diseases: coronary heart disease, stroke, or diabetes with end-organ damage. None of the individuals had average 24-hour, diurnal and nocturnal systolic and diaheart failure. The diagnosis of each disease was clinically stolic pressure.23,24,26 A nondipping pattern was defined 23,24 documented according to international guidelines. All when the fall in nocturnal systolic blood pressure was lower other registered clinical characteristics 23,24 are listed in than 10% of diurnal systolic pressure. Table 1. We defined dyslipidemia as total serum cholesterol Informed consent was obtained from all patients. The ⬎250 mg/dL, or low-density lipoprotein cholesterol ⬎155 study was approved by Institutional Review Boards at the mg/dL, or high-density lipoprotein cholesterol ⬍40 mg/dL coordinating centers, and was formally supported by the in men and ⬍48 mg/dL in women, or current lipid-lowering European Society of Hypertension. therapy; obesity as body mass index ⱖ30 kg/m2; diabetes Statistical Analysis mellitus as fasting blood glucose repeatedly above 126 mg/dL or current antidiabetic therapy; renal damage as Control of hypertension in the clinical office was defined serum creatinine 1.3-1.5 mg/dL in men and 1.2-1.4 mg/dL as systolic/diastolic blood pressure ⬍140/⬍90 mm Hg; in women, or microalbuminuria (average urinary albumin and control of ambulatory hypertension was defined as excretion of 30-300 mg daily); radiological evidence of 24-hour ambulatory systolic/diastolic pressure ⬍130/⬍80 atherosclerosis as carotid intima-media thickness ⱖ0.9 mm; mm Hg.23,25 Goals for diurnal and nocturnal ambulatory and left ventricular hypertrophy as a ventricular mass index blood pressure were set at systolic/diastolic pressure ⬍135/

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Table 1 Characteristics of Treated High-risk* Hypertensive Patients (n ⫽ 4729) Variable Age, years ⱖ60 years, % Males, % Body mass index, kg/m2 Body mass index ⱖ30 kg/m2, % Tobacco smoking, % Dyslipidemia, % Diabetes, % Family history of premature CVD, % Target organ damage, % Left ventricular hypertrophy, % Radiological evidence of atherosclerosis, % Renal damage, % Established cardiovascular or renal disease, % Coronary heart disease, % Heart failure, % Stroke, % Renal disease, % Office systolic blood pressure, mm Hg Office diastolic blood pressure, mm Hg Blood pressure taken in the morning, % 24-hour systolic blood pressure, mm Hg 24-hour diastolic blood pressure, mm Hg Daytime systolic blood pressure, mm Hg Daytime diastolic blood pressure, mm Hg Nighttime systolic blood pressure, mm Hg Nighttime diastolic blood pressure, mm Hg Night/day systolic blood pressure ratio Night/day diastolic blood pressure ratio Dipper, % Duration of hypertension, years No. antihypertensive drugs 1, % ⱖ2, % Time of drug taking, % Once daily Twice daily

69.6 86.7 60.8 29.5 40.5 10.8 62.1 51.0 15.0 59.6 26.9 25.0 20.7 79.4 46.9 0.0 31.9 6.6 152.3 82.3 74.1 133.3 72.4 135.1 74.5 128.5 67.0 0.95 0.90 28.2 10.9 2.5 11.9 88.1

(8.2)

(4.4)

centages across categories of office BP. The Kappa statistic was used to assess agreement between office and ambulatory BP. Odds ratios (OR) with their 95% confidence intervals (CI), obtained from multiple logistic regression, were used to summarize the relationship between ambulatory BP control and office BP; logistic models were adjusted for sociodemographic and clinical characteristics. Statistical significance was set at P ⬍.05. The SPSS for Windows version 13.0 software (SPSS Inc., Chicago, Ill) was used for statistical analysis.

RESULTS

(21.8) (12.2) (16.3) (9.7) (16.5) (10.1) (18.8) (10.4) (0.09) (0.09) (8.4) (1.2)

82.9 17.1

Continuous values are shown as mean (SD). *For high-risk definition, see Methods.

⬍85 mm Hg and ⬍120/⬍70 mm Hg, respectively.23,25 Different cutoffs were selected for office and for ambulatory hypertension control because, in population studies, office values of 140/90 mm Hg correspond to average 24-hour values of 125-130/80 mm Hg; the corresponding average diurnal and nocturnal values are 130-135/85 and 120/70 mm Hg.23,25 Sensitivity analyses were conducted to examine whether ambulatory blood pressure control varied with sex and concurrent coronary heart disease, stroke, diabetes, or heart failure. Differences in the distribution of clinical characteristics were assessed with the Student’s t test for continuous variables, and the chi-squared test for categorical variables. A P-value for trend was calculated to test differences in per-

Descriptive data of the study participants are presented in Table 1. Mean age was 69.6 (⫾8.2) years, and 60.8% of patients were male. Mean time from diagnosis of hypertension to recruitment into the Registry was 10.9 (⫾8.4) years. Among the 4729 treated patients, mean blood pressure in the office was 152.3/82.3 mm Hg, and mean 24-hour ambulatory blood pressure was 133.3/72.4 mm Hg. In total, 88.1% of patients were treated with 2 or more antihypertensive drugs. More than half of patients had associated risk factors and target-organ damage, and most of them had cardiovascular disease. About 60% of patients with office pressure of 130-139/ 85-89 mm Hg, 42.4% with office pressure of 140-159/90-99 mm Hg, and 23.3% with office pressure ⱖ160/100 mm Hg were actually normotensive, according to 24-hour ambulatory blood pressure criteria (⬍130/80 mm Hg) (Table 2). This pattern of decreasing control of ambulatory blood pressure with increasing office pressure also held when ambulatory diurnal or nocturnal pressure was considered, although, as expected, hypertension control was lower during the night (Table 2). Results were similar when using the second measure of office blood pressure, or the average of the first and second measure of office pressure (data not shown). Results showed the same trend of decreasing control of ambulatory hypertension with increasing blood pressure in the office regardless of sex or the presence of coronary heart disease, stroke, or diabetes (Table 3). In addition, when only systolic pressure was considered, 40.8% of patients whose office pressure was 140-159 mm Hg, and 55.3% of those with an office pressure of 130-139 mm Hg had their ambulatory systolic blood pressure controlled. Overall, ambulatory blood pressure control (41.8%) was much higher than office-based control of blood pressure (24.7%) (Table 4). Inter-method Kappa statistic was 0.34, showing a poor agreement between office and ambulatory blood pressure control. After adjusting for age, sex, cardiovascular risk factors, and target-organ damage in logistic regression analysis, control of 24-hour ambulatory blood pressure was less likely in those with an office-based normal pressure (OR 0.45, 95% CI, 0.30-0.69), high-normal pressure (OR 0.25, 95% CI, 0.18-0.36), stage 1 hypertension (OR 0.12,

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Table 2 Number and Percentage of Treated High-risk Hypertensive Patients whose Ambulatory Blood Pressure is Controlled, According to Criteria for Office-based and Ambulatory Blood Pressure 24-h Ambulatory Blood Pressure ⬍130/80 mm Hg

Daytime Ambulatory Blood Pressure ⬍135/85 mm Hg

Nighttime Ambulatory Blood Pressure ⬍120/70 mm Hg

Office Blood Pressure, mm Hg

n % (95% CI)

n % (95% CI)

n % (95% CI)

⬍120/80 120-129/80-84 130-139/85-89 140-149/90-94 150-159/94-99 ⱖ160/100 Total P for trend

19885.3 23073.5 37259.5 43048.1 34336.9 40523.3 197841.8 ⬍.001

21190.9 26083.1 44571.2 51757.8 44347.6 52930.5 240550.9 ⬍.001

13859.5 16051.1 25440.6 35339.5 26828.8 30117.3 147431.2 ⬍.001

(80.7-89.9) (68.6-78.4) (55.7-63.3) (44.9-51.4) (33.8-40.0) (21.3-25.3) (40.4-43.2)

(87.2-94.6) (78.9-87.3) (67.7-74.8) (54.6-61.0) (44.4-50.8) (28.3-32.7) (49.5-52.3)

(53.2-65.8) (45.6-56.6) (36.8-44.5) (36.3-42.7) (25.9-31.7) (15.5-19.1) (29.9-32.5)

95% CI ⫽ 95% confidence interval.

95% CI, 0.08-0.17), and stage 2 hypertension (OR 0.05, 95% CI, 0.04-0.07), as compared with those with an office-based optimal pressure (Table 5).

DISCUSSION The main findings of the present study are that almost half of all patients with office-based systolic blood pressure 130-159 mm Hg had a 24-hour ambulatory blood pressure of ⬍130/80 mm Hg. Similarly, a third of “uncontrolled” patients according to office blood pressure (ⱖ140/90 mm Hg) were actually controlled by ambulatory measurements. Even at an office blood pressure 160/100 mm Hg or higher, actual control of ambulatory pressure was substantial (23.3%). This indicates that 1 of 4 patients who are deemed to be frankly uncontrolled by office measures is indeed normotensive, and therefore could be over-treated. Because of the known continuous relationship between

blood pressure and cardiovascular risk, antihypertensive therapy also provides less benefit in mild hypertensive or normotensive patients than in those with very high blood pressure. Our data are consistent with the small substudy of 38 patients in the Heart Outcomes and Prevention Evaluation trial (HOPE), in which 24-hour ambulatory blood pressure monitoring showed that clinical blood pressure underestimated the blood pressure reduction with ramipril.27 Our study has some limitations. First, it included patients with similar selection criteria to those in the Telmisartan Randomized Assessment Study in ACE Intolerant Subjects with Cardiovascular Disease (TRANSCEND) trial,13 but our study sample was on average at a slightly higher cardiovascular risk. Second, like in many clinical trials,1 in this study, 2 blood pressure readings from a single visit were averaged, and the gap between ambu-

Table 3 Number and Percentage of Treated High-risk* Hypertensive Patients whose 24-h Ambulatory Blood Pressure is Controlled (⬍130/80 mm Hg), According to Office Blood Pressure, Sex, and Type of Associated Disease Office Blood Pressure, mm Hg

Males

Females

CHD

Stroke

Diabetes

⬍120/80

145 85.8% 148 69.8% 235 57.2% 457 40.8% 217 22.5% 1192 41.4% ⬍.001

53 84.1% 82 81.2% 137 64.0% 326 45.7% 188 24.4% 786 42.4% ⬍.001

129 88.4% 130 75.6% 224 65.1% 401 45.2% 205 25.3% 1089 46.1% ⬍.001

68 82.9% 90 73.2% 123 59.7% 260 43.0% 126 23.7% 667 43.1% ⬍.001

144 81.8% 228 74.3% 408 57.1% 1142 43.2% 624 22.3% 2546 38.3% ⬍.001

120-9/80-4 130-9/85-9 140-59/90-9 ⱖ160/100 Total P for trend

CHD ⫽ coronary heart disease. *For high-risk definition, see Methods.

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Table 4 Control of Blood Pressure among Treated High-risk* Hypertensives, According to Criteria for Office and Ambulatory Blood Pressure† 24-h Ambulatory Blood Pressure Office Blood Pressure

Controlled (⬍130/80 mm Hg)

Uncontrolled (ⱖ130/80 mm Hg)

Total

Controlled (⬍140/90 mm Hg)

800 16.9% (15.8%-17.9%) 1178 24.9% (23.7%-26.1%) 1978 41.8 (40.4%-43.2%)

370 7.8% (7.0%-8.5%) 2381 50.4% (48.8%-51.7%) 2751 58.2% (56.8-59.6%)

1170 24.7% (23.5%-25.9%) 3559 75.3% (74.1%-76.5%) 4729 (100%)

Uncontrolled (ⱖ140/90 mm Hg) Total

*For high-risk definition, see Methods. †Data correspond to number and percentage (95% confidence interval) of patients.

latory and office control of hypertension might have been smaller if multiple visits had been used. However, some studies have reported that hypertension control is similar when a single measure of blood pressure was taken at one visit and when the average of several measures on different occasions was used.28 Third, there is still some debate about the level of ambulatory blood pressure, which is equivalent to an office value of 140/90 mm Hg.23 Finally, we did not know the duration of antihypertensive treatment of the patients. It is open to debate whether the findings of our study, showing that many patients judged to be hypertensive by office measurements are indeed normotensive, can explain some of the puzzling findings of recent hypertension drug trials. But it should be noted that, for instance, in the TRANSCEND trial, most patients were treated at trial entry

Table 5 Predictors of 24-h Ambulatory Blood Pressure Control (⬍130/80 mm Hg) from Multivariate Logistic Regression Predictors Office blood pressure categories (120-129/80-84 mm Hg vs ⬍120/80 mm Hg) (130-139/85-89 mm Hg vs ⬍120/80 mm Hg) (140-159/90-99 mm Hg vs ⬍120/80 mm Hg) (ⱖ160/100 mm Hg vs ⬍120/80 mm Hg) Age (years) Sex (male vs female) Smoking (no vs yes) Dyslipidemia (no vs yes) Body mass index (⬍30 kg/m2 vs ⱖ30 kg/m2) Target organ damage (no vs yes)

Odds Ratio (95% Confidence Interval)

P Value

0.45 (0.30-0.69)

⬍.001

0.25 (0.18-0.36)

⬍.001

0.12 (0.08-0.17)

⬍.001

0.05 (0.04-0.07)

⬍.001

0.99 0.79 1.29 1.08 1.21

(0.99-1.00) (0.69-0.89) (1.06-1.57) (0.96-1.22) (1.07-1.37)

.116 ⬍.001 .012 .223 .002

1.27 (1.13-1.43)

⬍.001

and, in all likelihood, a good percentage of them were normotensive by ambulatory blood pressure monitoring. In conclusion, we suggest that the lack of benefit of antihypertensive therapy in some trials might be due to some patients having normal blood pressure at trial entry. Enrollment of patients into clinical trials based on officebased blood pressure alone might no longer be appropriate. Ambulatory monitoring of blood pressure may allow for a better assessment of trial eligibility. Moreover, it identifies the individuals with lowest actual blood pressure who, thus, are at higher risk of adverse effects of treatment.29

ACKNOWLEDGMENTS We thank all those physicians (members of the Spanish Society of Hypertension Ambulatory Blood Pressure Monitoring Registry) who participated in this study. The Registry is supported by an unrestricted educational grant from LACER pharmaceuticals in Spain, which had no role in study design, analysis and interpretation of data, writing the report, or the decision to submit the article for publication.

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