Normal Ambulatory Blood Pressure: A Clinical-Practice- Based Analysis of Recent American Heart Association Recommendations

The American Journal of Medicine (2006) 119, 69.e13-69.e18 CLINICAL RESEARCH STUDY Normal Ambulatory Blood Pressure: A Clinical-Practice- Based Analysis of Recent American Heart Association Recommendations Iddo Z. Ben-Dov, MD, MSc, Liora Ben-Arie, Judith Mekler, MSc, Michael Bursztyn, MD, FAHA Department of Internal Medicine, Hadassah-Hebrew University Medical Center, Mount-Scopus Campus, Jerusalem, Israel. ABSTRACT PURPOSE: The American Heart Association Council on High Blood Pressure Research recently issued recommendations for blood pressure measurement in humans. According to these recommendations, normal 24-hour ambulatory blood pressure is defined as less than 130/80 mm Hg. Concurrently, normal daytime and nighttime blood pressure levels are defined as less than 135/85 mm Hg and less than 120/70 mm Hg, respectively. Our aim was to investigate the intrinsic compatibility of these blood pressure cutoffs in clinical practice. SUBJECTS AND METHODS: We analyzed 4121 consecutive ambulatory blood pressure measurement sessions. Age was 57 7 years, 53% were female, and 64% and 9% were treated for hypertension and diabetes, respectively. Body mass index was 27 4 kg/m 2, and manual blood pressure was 148 22/85 12 mm Hg. Subjects were classified as having normal 24-hour blood pressure if the corresponding value was less than 130/80 mm Hg. Normal awake-sleep blood pressure was diagnosed if awake blood pressure was less than 135/85 mm Hg and sleep blood pressure was less than 120/70 mm Hg. RESULTS: Concordance between the cutoffs was found in 92% of the subjects (kappa 0.77). Among the 8% of discordant subjects, only 1% were hypertensive applying the 24-hour (but not awake-sleep) blood pressure values, whereas 7% were hypertensive according to awake-sleep but not 24-hour blood pressure values (P.0001). CONCLUSIONS: In real-life ambulatory blood pressure measurement, a generally good agreement was found between the recently issued ambulatory blood pressure normality suggestions. However, some subjects are classified as hypertensive only according to one of these methods, more often by the awake-sleep cutoff of 135/85 and 120/70 mm Hg. This discordance may be significant in large-scale clinical blood pressure monitoring. 2006 Elsevier Inc. All rights reserved. KEYWORDS: Ambulatory blood pressure monitoring; Normality; Guidelines; AHA In cross-sectional studies, ambulatory blood pressure levels and patterns were associated with blood pressurerelated target organ damage. In prospective studies, a higher ambulatory blood pressure, sustained hypertension, and nondipping ambulatory blood pressure pattern were associated with an increased risk of subsequent cardiovascular events. 1 Furthermore, in patients with Requests for reprints should be addressed to Iddo Z. Ben-Dov, Department of Internal Medicine, Hadassah-Hebrew University Medical Center, Mount-Scopus Campus, PO Box 24035, Jerusalem, Israel, 91240. E-mail address: vp02292@netvision.net.il treated hypertension, a higher ambulatory pressure predicts cardiovascular events even after adjustment for clinic blood pressure. 2 It is remarkable, therefore, that the upper limit of normal ambulatory blood pressure has not been established. On the basis of correlations with clinical blood pressure of untreated subjects in the Pressioni Arteriose Monitorate E Loro Associazioni (PAMELA) study, Mancia and coworkers 3 calculated the cutoff point of normal ambulatory blood pressure. They suggested a 24-hour average of 120/75 mm Hg to 130/81 mm Hg as the limit. The corresponding value in elderly participants was 120/76 mm Hg. 4 In the Ohasama study, Ohkubo and 0002-9343/$ -see front matter 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.amjmed.2005.08.020

69.e14 The American Journal of Medicine, Vol 119, No 1, January 2006 CLINICAL SIGNIFICANCE colleagues 5 prospectively evaluated the prognostic implications of ambulatory blood pressure. Twenty-four-hour values greater than 134/79 mm Hg were associated with increased cardiovascular mortality. The seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure did not define normal ambulatory blood pressure, but stated that awake hypertensive individuals have a mean blood pressure of more than 135/85 mm Hg and during sleep, more than 120/75 mm Hg. 6 The European Society of Hypertension (ESH) published 2 different normality definitions. According to the recommendations for conventional, ambulatory, and home blood pressure measurement, normal ambulatory blood pressure should be diagnosed if both awake blood pressure and sleep blood pressure are lower than 135/85 mm Hg and 120/70 mm Hg, respectively. 7 On the other hand, according to the ESH-European Society of Cardiology (ESC) guidelines for the management of arterial hypertension, normal 24-hour ambulatory blood pressure is defined as lower than 125/80 mm Hg. 8 We previously reported a 7% discordance rate between the 2 different ESH definitions among referred subjects. 9 In a scientific statement, the American Heart Association (AHA) issued recommendations for blood pressure measurement. 10 These recommendations include suggested values for the upper limit of normal ambulatory blood pressure, including daytime, nighttime, and 24-hour averages (Table 1). Are these values, namely, the 24-hour and the daytime-nighttime definitions, in harmony with each other? According to which of these cutoffs is an individual more likely to be classified as hypertensive? Our aim was to investigate the compatibility of the 24-hour and daytime-nighttime ambulatory blood pressure normality definitions, as recently suggested by the AHA, in real-life clinical practice. Assessing blood pressure control by ambulatory blood pressure monitoring requires appropriate normality definitions. The American Heart Association has issued two sets of definitions. One addresses 24-hour means, while the other concerns daytime-nighttime values. Using an ambulatory blood pressure monitoring database to examine the internal agreement between these two definitions, we found a generally good concordance. However, some subjects were classified discordantly by these methods. This may be significant in large-scale ambulatory blood pressure monitoring. SUBJECTS AND METHODS This is a study of data from our existing ambulatory blood pressure monitoring service database. Primary-care physicians ( 90%) and subspecialty clinics ( 10%) referred subjects for standard clinical indications (eg, evaluation for suspected hypertension or whitecoat hypertension, evaluation of treatment effects). The authors were not involved in the treatment or decision making of these subjects. We analyzed 4121 consecutive ambulatory blood pressure monitoring sessions of nonpregnant adults, performed during a 13-year period. Age was 57 7 years, 53% were female, and 64% and 9% were treated for hypertension and diabetes, respectively. Body mass index was 27 4 kg/m 2, and manual blood pressure was 148 22/85 12 mm Hg. Before 1997, 24-hour ambulatory blood pressure monitoring was performed with Accutracker II (Suntech, Raleigh, NC). Subsequently, we used Spacelab 90207 (Redmond, Wash), as previously described. 11 The monitor was mounted on the nondominant arm between 8:00 AM and 10:00 AM, and removed 24 hours later. A mercury sphygmomanometer was initially attached to the monitor through a Y-connector to ensure agreement between the 2 modes of measurement; ambulatory blood pressure monitoring was not performed if disagreement exceeded 5 mm Hg. These initial measurements, taken by a trained technician, were considered as the subject s manual blood pressure. 12 Blood pressure was measured every 20 minutes during the day and every 30 minutes at night. Measurements recorded during sleep, including afternoon naps (as logged in a diary), were analyzed as sleep blood pressure. Nighttime arousals were noted (since 1999) and analyzed along with awake blood pressure. Dipping was defined as 10% or greater sleep-related reduction in mean blood pressure. Subjects were classified as having normal 24- hour blood pressure (24h-BP) if the corresponding value was less than 130/80 mm Hg. Likewise, subjects were classified as having normal awake-sleep blood pressure if their awake blood pressure was less than 135/85 mm Hg and their sleep Table 1 Values suggested by the American Heart Association for daytime, nighttime, and 24-hour average blood pressure 10 Optimal Normal Abnormal Daytime 130/80 mm Hg 135/85 mm Hg 140/90 mm Hg Nighttime 115/65 mm Hg 120/70 mm Hg 125/75 mm Hg 24-hour 125/75 mm Hg 130/80 mm Hg 135/85 mm Hg

Ben-Dov et al Ambulatory Blood Pressure Normality Cutoffs 69.e15 Table 2 Classification of subjects according to manual and ambulatory blood pressure* Normal or controlled manual blood pressure Abnormal or uncontrolled manual blood pressure Normal or controlled ambulatory blood pressure Normal blood pressure White-coat hypertension Abnormal or uncontrolled ambulatory blood pressure Masked hypertension Hypertension *For simplicity, treated and untreated were united under unifying definitions. However, for treated patients white-coat hypertension refers to isolated office uncontrolled hypertension, and masked hypertension refers to isolated ambulatory uncontrolled hypertension. blood pressure was less than 120/70 mm Hg. We assessed the compatibility between the 2 approaches in determining the normality of a subject s ambulatory blood pressure, as well as in classifying subjects according to Table 2: (1) normal blood pressure, or normal blood pressure control (henceforth, normotension), (2) white-coat hypertension, or isolated office uncontrol (henceforth, white-coat hypertension), (3) masked hypertension, or masked uncontrol (henceforth, masked hypertension), and (4) hypertension, or uncontrolled hypertension (henceforth, hypertension). This was performed by means of McNemar, chi-square, and interrater agreement (kappa) tests. Demographic and clinical differences between the stated subgroups were analyzed using analysis of variance (with Bonferroni s corrections for multiple comparisons), t test, or chisquare, as appropriate. Two-sided P values less than.05 were considered significant. RESULTS Concordance Between the Classification Methods Ambulatory blood pressure was assessed in 4121 subjects. Abnormal ambulatory blood pressure was found in 74% according to the 24h-blood pressure method, whereas 80% had ambulatory blood pressure according to awake-sleep blood pressure (P.0001). The difference in proportions was 6.3% (95% confidence interval, 5.7%-6.8%). Concordance between the two methods was found in almost 92% of the subjects. As shown in Figure 1, among the 8.1% discordant subjects, 7.2% were defined as hypertensive applying the awake-sleep blood pressure definition, but not the 24h-blood pressure definition, whereas only 0.9% were hypertensive according to the 24h-blood pressure but not the awake-sleep blood pressure definition. Concordance between the 2 cutoffs also was evaluated by an interrater agreement test; one examiner applied the 24-hour definition, whereas the other applied the awake-sleep definition. We found a kappa value of 0.77, which implies a good agreement. We further evaluated how the different ambulatory blood pressure normality definitions affect the categorization of subjects into 4 subgroups: normotension, white-coat hypertension, masked hypertension, and hypertension. As shown in Figure 2, application of the 24h-blood pressure method yielded a higher proportion of white-coat (or isolated office uncontrolled) hypertensives, whereas masked hypertension (or isolated ambulatory uncontrolled hypertension) was more common according to the awake-sleep blood pressure method (P.0001). Overall agreement was very good (weighted kappa 0.85). Characterization of the Discordant Subgroups The 2 defining methods, 24h-blood pressure and awakesleep blood pressure, generated 4 categories of subjects: normotension, hypertension, awake-sleep blood hypertension 73.1% sleep BP 62% awake-sleep BP - 7.2% awake and sleep BP 3% 24h BP 0.9% normal BP 18.8% awake BP 35% Figure 1 Co-classification of 4121 subjects according to the two normality definitions: normal 24-hour blood pressure 130/80 mm Hg, and normal awake-sleep blood pressure 135/85 mm Hg and 120/70 mm Hg, respectively (left). Subclassification of individuals with normal 24-hour blood pressure, but awake-sleep blood pressure, according to the circadian component (right). BP blood pressure.

69.e16 The American Journal of Medicine, Vol 119, No 1, January 2006 Figure 2 Categorization of 4121 subjects according to manual blood pressure and 24-hour blood pressure (left column), or awake-sleep blood pressure (right column). HTN hypertension; BP blood pressure. pressure with normal 24h-blood pressure (henceforth, awake-sleep hypertension), and a small subgroup with 24h-blood pressure but normal awake-sleep blood pressure (henceforth, 24h-hypertension). Categoric and continuous variables concerning these subgroups are depicted in Tables 3 and 4. Subjects with Abnormal 24-Hour Blood Pressure When compared with other subgroups, subjects with 24hhypertension were younger, more likely to dip during sleep, and less likely to be female, be treated for hypertension or diabetes, have manual blood pressure, and take a daytime nap. These subjects had lower manual blood pressure than hypertensive subjects. The levels of their 24h-blood pressure, ambulatory blood pressure, and sleep blood pressure were between those of normotensive and hypertensive subjects. Subjects with Abnormal Awake-Sleep Blood Pressure Subjects with awake-sleep hypertension had a lower female: male ratio than the normotensive subgroup (but higher than the hypertensive subgroup) and were more likely to take a daytime nap and less likely to dip during sleep than both normotensive and hypertensive subjects. Subjects with awake-sleep hypertension had a lower manual blood pressure than hypertensive subjects. Their heart rate was higher than that of normotensive subjects, both awake and at sleep. The levels of their 24h-blood pressure, awake blood pressure, and sleep blood pressure were between those of normotensive and hypertensive subjects. Their absolute sleep-associated blood pressure dip was smaller than that of normotensive and hypertensive subjects, and the relative dip also was smaller than in the normotensive subgroup. Table 3 Characteristics of the 4 distinct blood pressure subgroups 24-hour HTN Normotension Awake-sleep HTN HTN P value Awake-sleep blood pressure Normal Normal Abnormal Abnormal 24-hour blood pressure Abnormal Normal Normal Abnormal Number (%) 35 (0.9) 764 (18.5) 295 (7.2) 3027 (73.5) Age (y) 53.9 13.9 55.7 16.2 54.7 16.7 57.4 14.5.001* Gender, % female 43 67 58 48.0001 Treated HTN, % 46 61 62 65.05 Treated diabetes, % 0 6 8 10.001 Abnormal manual BP, % 43 41 49 81.0001 Daytime nappers, % 26 35 41 32.005 Sleep dippers, % 100 87 53 67.0001 BP blood pressure; HTN hypertension. *Significant for HTN versus normotension and for HTN versus awake-sleep HTN.

Ben-Dov et al Ambulatory Blood Pressure Normality Cutoffs 69.e17 Table 4 Ambulatory blood pressure averages in the 4 distinct blood pressure subgroups* 24-hour HTN N 35 Normotension N 764 Awake-sleep HTN N 295 HTN N 3027 P value Awake HR, beats/min 75 9 ab 71 11 b 74 12 a 73 11 a.001 Sleep HR, beats/min 62 13 ab 62 9 b 64 9 a 64 9 a.0002 Manual BP, mm Hg 135 13 a /82 8 d 134 18 a /79 10 d 136 17 a /80 10 d 154 21/88 12.0001 24-hour BP, mm Hg 128 3 a /76 6 d 119 7/69 6 125 4 a /73 6 d 145 13/81 9.0001 Awake BP, mm Hg 132 4 a /79 9 d 124 7/73 6 130 6 a /76 7 d 149 13/85 10.0001 Sleep BP, mm Hg 112 5 ab /64 6 d 107 7 a /59 6 116 9 b /65 8 d 133 17/72 10.0001 Absolute BP dip, mm Hg 18 6 ab /14 5 de 16 7 a /14 5 d 13 13 b /10 9 e 15 13 a /13 8 d.001 Relative BP dip, % 13 4 ab /19 5 de 13 6 a /18 7 d 9 9 c /14 11 f 10 9 bc /15 9 ef.0001 BP blood pressure; HTN hypertension; HR heart rate. *Superscript letters denote subgroups with values that do not differ significantly, as determined by Bonferroni s pairwise comparisons. As shown in Figure 1, the group with awake-sleep hypertension was further subdivided to better understand its nature. The characteristics of these subpopulations (excluding the few subjects with awake blood pressure and sleep blood pressure) are depicted in Table 5, along with comparison with subjects with normal ambulatory blood pressure. Individuals with isolated awake hypertension were younger, and less likely to be female and to be treated for hypertension than subjects with normal ambulatory blood pressure. They were more likely to have manual blood pressure, to take a daytime nap, and to dip at sleep than their normotensive countersubjects. The magnitude of their dip was significantly higher. On the other hand, subjects with isolated sleep hypertension were more likely to be treated for hypertension than individuals with normal ambulatory blood pressure values and were less likely to dip (the magnitude of which was significantly smaller). Their age was younger than the average normotensive subject. Divergence from the European Society of Hypertension-European Society of Cardiology Guidelines The AHA suggestions regarding normal daytime and nighttime ambulatory blood pressure are similar to recommendations issued by the ESH. 7 However, the values stated for normal 24-hour ambulatory blood pressure differ, less than 130/80 mm Hg and less than 125/80 mm Hg, 8 respectively. Whereas 74% of our subjects had 24-hour ambulatory blood pressure according to AHA values, this number increased to 83% applying ESH-ESC guidelines (97.5% confidence interval for the difference, 8.8%-9%, kappa 0.73). The average manual blood pressure of the divergent subjects (those with 24h-blood pressure according to ESH-ESC but not AHA values) was 140 17/80 10 mm Hg. DISCUSSION Ambulatory blood pressure monitoring practice is in need of normality definitions. In accordance with this necessity, the AHA Council on High Blood Pressure Research recently issued relevant recommendations. 10 It is noteworthy, however, that 2 different sets of values were published: a 24hblood pressure normality suggestion and a daytime-nighttime recommendation. In this study, we revealed that these 2 sets are not identical, although their compatibility is good. Significantly more subjects are classified as hypertensive according to the daytime-nighttime blood pressure definition (7.2%). Nevertheless, a small subgroup of subjects with 24h-blood pressure but normal awake and sleep Table 5 Subpopulation characteristics among the awake-sleep blood pressure group Isolated awake HTN Normal BP Isolated sleep BP Number (%) 102 (2.5) 764 (18.5) 184 (4.5) Age (y) 52.0 18.4* 55.7 16.2 56.5 15.3 Gender, % female 57 67 58 Treated HTN, % 53 61 70 Abnormal manual BP, % 69 41 38 Daytime nappers, % 47 35 36 Sleep dippers, % 100 87 25 Absolute BP dip, mm Hg 26 8 /20 6 16 7/13 5 5 7 /6 5 Relative dip, % 20 6 /25 7 13 6/18 7 4 6 /8 7 BP blood pressure; HTN hypertension. *P.05; P.001; P.0001; all for the comparison with the normal BP group.

69.e18 The American Journal of Medicine, Vol 119, No 1, January 2006 values also exists (0.9%). In a related study examining recent ESH recommendations and guidelines, we found the corresponding proportions to be 2.5% and 4.5%, respectively. 9 The dissimilarity between the figures suggests that the ESH guideline regarding normal 24-hour ambulatory blood pressure ( 125/80 mm Hg) is considerably more stringent than the recent AHA suggestions (24-hour ambulatory blood pressure 130/80 mm Hg), because the recommendations regarding daytime and nighttime blood pressure are identical. One may speculate that the values issued by the ESH are more suitable, because the 2 discordant subgroups created (ie, subjects with normal ambulatory blood pressure according to 24-hour but not daytime-nighttime definitions, or vice versa) are comparable in size. Another direct consequence of the difference between the normality definitions is the higher proportion of individuals classified as having white-coat hypertension (and lower proportion of sustained hypertensive subjects) according to the 24-hour normal ambulatory blood pressure definition issued by the AHA. A considerable number of the subjects diagnosed with white-coat hypertension applying the latter definition are truly hypertensive according to the daytime-nighttime definition or the European recommendations. This might partially explain the cardiovascular dysfunction, found in some studies, in subjects with whitecoat hypertension compared with truly normotensive individuals. 13,14 Among the demographic and clinical differences found between our subpopulations, is it noteworthy that the subgroup with isolated sleep hypertension had a higher proportion of men and treated subjects than the subgroup with normal blood pressure. This might suggest that medical treatment in hypertensive men is less effective in lowering sleep blood pressure. On the other hand, isolated awake hypertensive subjects were younger but also more likely to be male than normotensive individuals. They were all dippers. Collectively, these findings may imply a role for increased daytime (physical) activity as a cause for isolated awake hypertension. Abnormal 24h-blood pressure with normal awake values may result from false calculation of measurements taken during daytime naps as part of the daytime average. However, this bias was avoided in the current study because of a routine analysis that accounts for actual sleeping hours and does not rely on arbitrary day-night definitions. 15 This study is limited by the nature of our population. Referred subjects, both treated and untreated, might not represent the general population. However, in real-life practice, these are the individuals in need for normality definitions, which we investigated in this report. In conclusion, this study of more than 4000 ambulatory blood pressure monitoring sessions found a generally good agreement between the sets of values recently suggested by the AHA as representing normal 24-hour, daytime, and nighttime ambulatory blood pressure. However, discordant classification was found in approximately 8%, which translates to 5.2 million Americans, assuming universal ambulatory blood pressure monitoring implementation among hypertensive subjects. Furthermore, white-coat hypertension or masked hypertension may be erroneously diagnosed in 2 million subjects, the consequences of which can only be determined by large-scale outcome studies. References 1. Appel L, Robinson K, Guallar E. Utility of Blood Pressure Monitoring Outside of the Clinic Setting. Evidence Report/Technology Assessment No. 63. AHRQ Publication No. 03-E004. Rockville, MD: Agency for Healthcare Research and Quality; November 2002. 2. Clement DL, De Buyzere ML, De Bacquer DA, et al. Prognostic value of ambulatory blood-pressure recordings in patients with treated hypertension. N Engl J Med. 2003;348:2407-2415. 3. Mancia G, Sega R, Bravi C, et al. Ambulatory blood pressure normality: results from the PAMELA study. J Hypertens. 1995;13:1377-1390. 4. Sega R, Cesana G, Milesi C, et al. Ambulatory and home blood pressure normality in the elderly: data from the PAMELA population. Hypertension. 1997;30:1-6. 5. Ohkubo T, Imai Y, Tsuji I, et al. Reference values for 24-hour ambulatory blood pressure monitoring based on a prognostic criterion: the Ohasama Study. Hypertension. 1998;32:255-259. 6. Chobanian AV, Bakris GL, Black HR, et al. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report. JAMA. 2003; 289:2560-2572. 7. O Brien E, Asmar R, Beilin L, et al. European Society of Hypertension recommendations for conventional, ambulatory and home blood pressure measurement. J Hypertens. 2003;21:821-848. 8. 2003 European Society of Hypertension-European Society of Cardiology Guidelines for the Management of Arterial Hypertension. J Hypertens. 2003;21:1011-1053. 9. Ben-Dov IZ, Ben-Arie L, Mekler J, Bursztyn M. Normal ambulatory blood pressure: a clinical-practice-based comparison of two recently published definitions. J Hum Hypertens. 2005;19:565-567. 10. Pickering TG, Hall JE, Appel LJ, et al. Recommendations for blood pressure measurement in humans and experimental animals. Part 1: Blood pressure measurement in humans. Circulation. 2005;111:697-716. 11. Perk G, Mekler J, Bursztyn M. Ambulatory pulse pressure is a relatively sleep independent variable. J Hypertens. 2003;21:723-728. 12. Owens P, Atkins N, O Brien E. Diagnosis of white coat hypertension by ambulatory blood pressure monitoring. Hypertension. 1999;34:267-272. 13. Glen SK, Elliott HL, Curzio JL, et al. White-coat hypertension as a cause of cardiovascular dysfunction.lancet. 1996;348(9028):654-657. 14. Verdecchia P, Reboldi GP, Angeli F, et al. Short- and long-term incidence of stroke in white-coat hypertension. Hypertension. 2005; 45:203-208. 15. Bursztyn M, Mekler J, Wachtel N, Ben-Ishay D. The siesta and ambulatory blood pressure monitoring. Comparability of the afternoon nap and night sleep.am J Hypertens. 1994;7:217-221.