Introduction

Arterial blood pressure (BP) is a very useful variable in clinical practice. Its measurement is simple, inexpensive and easy; it is worth noting that BP should be accurately obtained, following the recommendations of the VI Brazilian Guidelines on Hypertension (DBH VI)¹1. Sociedade Brasileira de Cardiologia. Sociedade Brasileira de Nefrologia. Sociedade Brasileira de Hipertensão. VI Diretrizes Brasileiras de Hipertensão. Arq Bras Cardiol. 2010;95(1 supl 1):1-51..

Office BP measurement is the central parameter for the diagnosis, treatment and follow-up of systemic arterial hypertension (SAH), being directly, continuously and independently related to the risk of fatal and non-fatal cardiovascular (CV) events¹1. Sociedade Brasileira de Cardiologia. Sociedade Brasileira de Nefrologia. Sociedade Brasileira de Hipertensão. VI Diretrizes Brasileiras de Hipertensão. Arq Bras Cardiol. 2010;95(1 supl 1):1-51.

2. Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA, Izzo JL Jr, et al. The National High Blood Pressure Education Program Coordinating Committee. Seventh Report os the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Hypertension. 2003;42(6):1206-52. ^{- 3}3. Mancia G, Fagard R, Narkiewicz K, Rédon J, Zanchetti A, Böhm M, et al; Task Force Members. 2013 ESH/ESC Guidelines for the management of arterial hypertension: the Task Force for the management of arterial hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). J Hypertens. 2013;31(7):1281-357..

Thus, the consideration of BP values closer to the upper limits of normality, the so-called prehypertension (PH)²2. Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA, Izzo JL Jr, et al. The National High Blood Pressure Education Program Coordinating Committee. Seventh Report os the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Hypertension. 2003;42(6):1206-52., and intervention on those values have been emphasized over the last decade, because PH represents an important opportunity to prevent established SAH, contributing to reduce the associated CV risk.

Repeated BP measurement at the office allows the diagnosis of hypertension and normotension. To better assess BP behavior, there are methods that analyze BP by using a higher number of measurements, minimizing interferences of the environment, situation and observer. Those alternatives are as follows: 24-hour ambulatory BP monitoring (ABPM); and dwelling BP measurement [home BP monitoring (HBPM) and BP self-measurement (BPSM)]. Based on those methods, two other BP classifications were adopted: white coat hypertension (WCH) and masked hypertension (MH)¹1. Sociedade Brasileira de Cardiologia. Sociedade Brasileira de Nefrologia. Sociedade Brasileira de Hipertensão. VI Diretrizes Brasileiras de Hipertensão. Arq Bras Cardiol. 2010;95(1 supl 1):1-51. ^{, 3}3. Mancia G, Fagard R, Narkiewicz K, Rédon J, Zanchetti A, Böhm M, et al; Task Force Members. 2013 ESH/ESC Guidelines for the management of arterial hypertension: the Task Force for the management of arterial hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). J Hypertens. 2013;31(7):1281-357.

4. Sociedade Brasileira de Cardiologia, Sociedade Brasileira de Hipertensão, Sociedade Brasileira de Nefrologia. V Diretrizes Brasileiras de Monitorização Ambulatorial da Pressão Arterial (MAPA) e III Diretrizes Brasileiras de Monitorização Residencial de Pressão Arterial (MRPA). Arq Bras Cardiol. 2011;97 (3 supl.3):1-24. ^{- 5}5. O'Brien E, Parati G, Stergiou G, Asmar R, Beilin L, Bilo G, et al; European Society of Hypertension Working Group on Blood Pressure Monitoring. European Society of Hypertension position paper on ambulatory blood pressure monitoring. J Hypertens. 2013;31(9):1731-68. Erratum in J Hypertens. 2013;31(12):2467. (Figure 1).

Epidemiological and clinical studies on those conditions are still limited; however, they deserve attention because of their higher CV risk as compared with normotension⁶6. Vasan RS, Larson MG, Leip EP, Evans JC, O´Donnel CJ, Kannel WB, et al. Impact of high-normal blood pressure on the risk of cardiovascular disease. N Engl J Med. 2001;345(18):1291-7. ^{, 7}7. Conen D, Ricker PM, Buring JE, Glynn RJ. Risk of cardiovascular events among women with high normal blood pressure or blood pressure progression: prospective cohort study. BMJ. 2007;335(7617):432-40..

This document represents the position of the Brazilian Society of Cardiology Arterial Hypertension Department (DHA/SBC) on the diagnosis and non-drug and drug therapy for PH, WCH and MH, aiming at contributing to a better clinical practice.

Prehypertension

Epidemiology

The term PH was described in 2003 on the American Guideline on Arterial Hypertension¹1. Sociedade Brasileira de Cardiologia. Sociedade Brasileira de Nefrologia. Sociedade Brasileira de Hipertensão. VI Diretrizes Brasileiras de Hipertensão. Arq Bras Cardiol. 2010;95(1 supl 1):1-51. that emphasized the importance of adopting strict preventive measures in the presence of PH, considering that individuals with such characteristics have a higher incidence of SAH in the following years and greater CV risk than those with optimal BP (lower than 120/80 mm Hg)²2. Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA, Izzo JL Jr, et al. The National High Blood Pressure Education Program Coordinating Committee. Seventh Report os the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Hypertension. 2003;42(6):1206-52. ^{, 3}3. Mancia G, Fagard R, Narkiewicz K, Rédon J, Zanchetti A, Böhm M, et al; Task Force Members. 2013 ESH/ESC Guidelines for the management of arterial hypertension: the Task Force for the management of arterial hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). J Hypertens. 2013;31(7):1281-357.. A study has shown that among prehypertensive individuals aged 40-49 years, the incidence of hypertension in the following years is 80%⁸8. Moreira LB, Fuchs SC, Wiehe M, Gus M, Moraes RS, Fuchs FD. Incidence of hypertension in Porto Alegre, Brazil: a population-based study. J Hum Hypertens. 2008;22(1):48-50..

In the PURE (Prospective Urban and Rural Epidemiological) Study, assessing 153,996 individuals in 17 countries, PH prevalence was 36.8%, greater than the SAH rate (34.3%). Data on the North American adult population have shown a 40% prevalence⁹9. Lloyd-Jones D, Adams R, Carnethon M, De Simone G, Ferguson B, Flegal K, et al; American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Heart disease and stroke statistics - 2009 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation. 2009;119(3):e21-181..

Prehypertension is known to be often associated with other CV risk factors, such as obesity, insulin resistance, diabetes mellitus, dyslipidemia and other metabolic syndrome phenotypes, resulting in early vascular abnormalities and progression to atherosclerosis¹⁰10. De Marco M, de Simone G, Roman MJ, Chinalli M, Lee ET, Russel M, et al. Cardiovascular and metabolic predictors of progression of prehypertension into hypertension: the Strong Heart Study. Hypertension. 2009;54(5):974-80..

Diagnosis and clinical strategies of identification

Prehypertension has been defined as office measurements of systolic blood pressure (SBP) between 120 and 139 mm Hg and/or of diastolic blood pressure (DBP) between 80 and 89 mmHg²2. Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA, Izzo JL Jr, et al. The National High Blood Pressure Education Program Coordinating Committee. Seventh Report os the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Hypertension. 2003;42(6):1206-52.. Its identification depends on regular BP measurement, which is recommended to be performed at least once a year.

The diagnosis of PH is based on BP measurement at the office, but that diagnosis can certainly be improved with 24-hour ABPM and/or HBPM. Such forms of out-of-office BP assessment have the advantage of providing a much higher number of measurements, outside sites where BP is usually taken, representing a more reliable BP registry⁴4. Sociedade Brasileira de Cardiologia, Sociedade Brasileira de Hipertensão, Sociedade Brasileira de Nefrologia. V Diretrizes Brasileiras de Monitorização Ambulatorial da Pressão Arterial (MAPA) e III Diretrizes Brasileiras de Monitorização Residencial de Pressão Arterial (MRPA). Arq Bras Cardiol. 2011;97 (3 supl.3):1-24. ^{, 5}5. O'Brien E, Parati G, Stergiou G, Asmar R, Beilin L, Bilo G, et al; European Society of Hypertension Working Group on Blood Pressure Monitoring. European Society of Hypertension position paper on ambulatory blood pressure monitoring. J Hypertens. 2013;31(9):1731-68. Erratum in J Hypertens. 2013;31(12):2467.. It is important to identify the presence of MH among prehypertensive individuals.

There is evidence that the increase in left ventricular mass (LVM) in prehypertensive individuals is a strong predictor of the development of SAH within four years, regardless of other metabolic and anthropometric factors associated. The increase in LVM might be associated with a higher daily hemodynamic load that could be detected by measuring BP at the office. Increased BP variability, lack of its drop during sleep or sustained and prolonged increased BP during wakefulness could explain higher LVM values in prehypertensive individuals. In addition, PH progression to hypertension has been associated with increased arterial stiffness¹¹11. Safar ME, Frohlich ED. (eds): Atherosclerosis, large arteries and cardiovascular risk. Adv Cardiol. Basel: Karger; 2007. p. 117-24. ^{, 12}12. Kaess BM, Rong J, Larson MG, Hamburg NM, Vita JA, Levy D, et al. Aortic stiffness, blood pressure progression, and incident hypertension. JAMA. 2012;308(9):875-81..

Prognostic value

Prehypertension is a precursor of SAH, associates with other CV risk factors, and has greater CV morbidity and mortality⁶6. Vasan RS, Larson MG, Leip EP, Evans JC, O´Donnel CJ, Kannel WB, et al. Impact of high-normal blood pressure on the risk of cardiovascular disease. N Engl J Med. 2001;345(18):1291-7. ^{, 13}13. Julius S, Nesbitt SD, Egan BM, Weber MA, Michelson EL, Kaciroti N, et al; Trial of Preventing Hypertension (TROPHY) Study Investigators. Feasibility of treating prehypertension with an angiotensin-receptor blocker. N Engl J Med. 2006;354(16):1685-97..

In the population assessed in the Framingham study, the following percentages of individuals younger than 65 years developed SAH within a four-year follow-up in the three BP strata considered normal: 5.3% of the individuals with optimal BP; 17.6% of those with normal BP; and 37.3% of those considered to have high-normal BP at the time. For individuals older than 65 years, those rates were 16%, 25.5% and 49.5%, respectively¹⁴14. Vasan RS, Larson MG, Leip EP, Kannel WB, Levy D. Assessment of frequency of progression to hypertension in non-hypertensive participants in the Framingham Heart Study: a cohort study. Lancet. 2001;358(9294):1682-6.. Data obtained from two British Health and Lifestyle Surveys conducted seven years apart have been used to form a subsample of 2,048 normotensive individuals, and have demonstrated a greater risk for developing SAH among those with higher BP levels, especially the younger ones¹⁵15. Winegarden CR. From "prehypertension" to hypertension?: additional evidence. Ann Epidemiol. 2005;15(9):720-5.. Other studies have reported that individuals older than 45 years have a 56.4% progression rate to arterial hypertension in three years (56.9% for men and 55.9% for women)¹⁶16. Kim YM, Hong KS, Choi YH, Choi MG, Jeong JY, Lee JM, et al. Rates and related factors of progression to hypertension among prehypertensive local residents aged 45 or over in Chuncheon City: hallym aging study from a community-based cross-sectional study. Korean Circ J. 2008;38(1):43-50..

A population-based study conducted in Brazil has reported that four out of five prehypertensive individuals aged 40-49 years developed SAH in ten years⁸8. Moreira LB, Fuchs SC, Wiehe M, Gus M, Moraes RS, Fuchs FD. Incidence of hypertension in Porto Alegre, Brazil: a population-based study. J Hum Hypertens. 2008;22(1):48-50..

Regarding the increased risk for CV events of patients with PH, data from longitudinal studies from the Framingham Heart Study have indicated that SBP levels between 130-139 mm Hg and DBP between 85-89 mm Hg are associated with a two-fold increase in the risk for CV diseases (CVD) as compared with 120/80 mmHg levels¹⁴14. Vasan RS, Larson MG, Leip EP, Kannel WB, Levy D. Assessment of frequency of progression to hypertension in non-hypertensive participants in the Framingham Heart Study: a cohort study. Lancet. 2001;358(9294):1682-6.. That association proved to be more significant in diabetic individuals and those with higher body mass index (BMI)¹⁷17. Kshirsagar AV, Carpenter M, Bang H, Wyatt SB, Colindres RE. Blood pressure usually considered normal is associated with an elevated risk of cardiovascular disease. Am J Med. 2006;119(2):133-41.. Individuals with PH are more prone to acute myocardial infarction (AMI) or coronary artery disease (CAD) than those considered normotensive¹⁸18. Qureshi AI, Suri MF, Kirmani JF, Divani AA, Mohammad Y. Is prehypertension a risk factor for cardiovascular diseases? Stroke. 2005;36(9):1859-63.. A Japanese study has reported a 45% increase in the risk of CV events in prehypertensive individuals as compared with normotensive ones, after adjusting for all other traditional risk factors¹⁹19. Ishikawa Y, Ishikawa J, Ishikawa S, Kayaba K, Nakamura Y, Shimada K, et al., Prevalence and determinants of prehypertension in a Japanese general population: the Jichi Medical School Cohort Study. Hypertens Res. 2008;31(7):1323-30..

White coat hypertension

Epidemiology

The prevalence of WCH varies because of the diversity of the diagnostic criteria involving not only aspects related to BP measurement but also to the populations studied. The mean overall prevalence of WCH, based on four population-based studies, was 13%, and reached 32% among hypertensives in those studies²⁰20. Fagard RH, Cornelissen VA. Incidence of cardiovascular events in white-coat, masked and sustained hypertension vs. true normotension: a meta-analysis. J Hypertens. 2007;25(11):2193-8.. In the general population, those values range from 10% to 20%, being more common among children and the elderly, in the female sex, and in non-smokers²¹21. Staessen JA, O'Brien ET, Amery AK, Atkins N, Baumgart P, De Cort P, et al. Ambulatory blood pressure in normotensive and hypertensive subjects: results from an international database. J Hypertens Suppl. 1994;12(7):S1-12. ^{, 22}22. Dolan E, Stanton A, Atkins N, Den Hond E, Thijs L, McCormack P, et al. Determinants of white-coat hypertension. Blood Press Monit. 2004;9(6):307-9..

The prevalence of WCH is also related to office BP measurements, its percentage being 55% among stage 1 hypertensives, and only 10% among stage 3 hypertensives²¹21. Staessen JA, O'Brien ET, Amery AK, Atkins N, Baumgart P, De Cort P, et al. Ambulatory blood pressure in normotensive and hypertensive subjects: results from an international database. J Hypertens Suppl. 1994;12(7):S1-12.. However, among individuals whose DBP at the office exceeds 105 mm Hg, WCH is an unlikely finding²³23. Angeli F, Verdecchia P, Gattobigio R, Sardone M, Reboldi G. White-coat hypertension in adults. Blood Press Monit. 2005;10(6):301-5.. That phenomenon also occurs among hypertensives undergoing treatment, being called the white coat effect. Muxfeldt et al²⁴24. Muxfeldt ES, Bloch KV, Nogueira AR, Salles GF True resistant hypertension: is it possible to be recognized in the office? Am J Hypertens. 2005;18(12 Pt 1):1534-40. have assessed uncontrolled hypertensive patients on antihypertensive treatment, of whom more than 60% were on three or more drugs and 37% had the white coat effect. In the PAMELA (Pressione Arteriose Monitorate E Loro Associazioni) study, ongoing for ten years, 42.6% of the patients with metabolic syndrome and WCH at the first consultation developed sustained arterial hypertension²⁵25. Mancia G, Bombelli M, Facchetti R, Madotto F, Quarti-Trevano F, Polo Friz H, et al. Long-term risk of sustained hypertension in white-coat or masked hypertension. Hypertension. 2009;54(2):226-32..

The greater the BMI, the higher the WCH prevalence. Helvaci et al²⁶26. Helvaci MR, Kaya H, Yalcin A, Kuvandik G. Prevalence of white coat hypertension in underweight and overweight subjects. Int Heart J. 2007;48(5):605-13., studying the BP behavior of individuals assessed at check-up clinics, have reported the following WCH prevalences: 19.6% for individuals with IMC lower than 18.5 kg/m²; 35.6% for individuals with IMC between 18.5 and 24.9 kg/m²; and 68.4% for overweight individuals (IMC between 25 and 29.9 kg/m²) ²⁶26. Helvaci MR, Kaya H, Yalcin A, Kuvandik G. Prevalence of white coat hypertension in underweight and overweight subjects. Int Heart J. 2007;48(5):605-13..

The WCH frequency increases with age, and, among individuals older than 65 years, its prevalence usually ranges from 43% to 45%²⁷27. Pickering TG, James GD, Boddie C, Harshfield GA, Blank S, Laragh JH. How common is white coat hypertension? JAMA. 1988;259(2):225-8..

In a follow-up period of up to 6.5 years, Verdecchia et al²⁸28. Verdecchia P, Palatini P, Schillaci G, Mormino P, Porcellati C, Pessina AC. Independent predictors of isolated clinic ('white-coat') hypertension. J Hypertens. 2001;19(6):1015-20. have reported a 37% risk of developing arterial hypertension in individuals with WCH. That percentage related to baseline values of ABPM rather than to office BP.

Diagnosis and clinical strategies of identification

The diagnosis of WCH requires office and out-of-office BP measurement, be it by use of ABPM or home measurements⁴4. Sociedade Brasileira de Cardiologia, Sociedade Brasileira de Hipertensão, Sociedade Brasileira de Nefrologia. V Diretrizes Brasileiras de Monitorização Ambulatorial da Pressão Arterial (MAPA) e III Diretrizes Brasileiras de Monitorização Residencial de Pressão Arterial (MRPA). Arq Bras Cardiol. 2011;97 (3 supl.3):1-24.. The thresholds recommended are those adopted at the most recent NICE²⁹29. National Institute for Health and Clinical Excellence (NICE). Hypertension: the clinical management of primary hypertension in adults. Clinical Guideline CG 127; August 2011. and 2013 ESH/ESC³3. Mancia G, Fagard R, Narkiewicz K, Rédon J, Zanchetti A, Böhm M, et al; Task Force Members. 2013 ESH/ESC Guidelines for the management of arterial hypertension: the Task Force for the management of arterial hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). J Hypertens. 2013;31(7):1281-357. guidelines, and ESH Position Paper on Ambulatory Blood Pressure Monitoring⁵5. O'Brien E, Parati G, Stergiou G, Asmar R, Beilin L, Bilo G, et al; European Society of Hypertension Working Group on Blood Pressure Monitoring. European Society of Hypertension position paper on ambulatory blood pressure monitoring. J Hypertens. 2013;31(9):1731-68. Erratum in J Hypertens. 2013;31(12):2467., which maintain the values of the JNC 7²2. Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA, Izzo JL Jr, et al. The National High Blood Pressure Education Program Coordinating Committee. Seventh Report os the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Hypertension. 2003;42(6):1206-52. and 2003 and 2007 ESH/ESC³⁰30. O'Brien E, Asmar R, Beilin L, Imai Y, Mallion JM, Mancia G, et al; European Society of Hypertension Working Group on Blood Pressure Monitoring. European Society of Hypertension recommendations for conventional, ambulatory and home blood pressure measurement. J Hypertens. 2003;21(5):821-48. ^{, 31}31. Mancia G, De Backer G, Dominiczak A, Cifkova R, Fagard R, Germano G, et al; Management of Arterial Hypertension of the European Society of Hypertension; European Society of Cardiology. 2007 Guidelines for the Management of Arterial Hypertension: the Task Force for the Management of Arterial Hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). J Hypertens. 2007;25(6):1105-87. Erratum in: J Hypertens. 2007;25(8):1749. guidelines, and were based on studies such as the IDACO (International Database on Ambulatory Blood Pressure monitoring in relation to Cardiovascular Outcomes Investigators)³²32. Kikuya M, Hansen TW, Thijs L, Bjorklund-Bodegrd K, Kuznetsova T, Ohkubo T, et al; International Database on Ambulatory Blood Pressure monitoring in relation to Cardiovascular Outcomes Investigators. Diagnostic thresholds for ambulatory blood pressure monitoring based on 10-year cardiovascular risk. Circulation. 2007;115(16):2145-52. and Ohasama Study³³33. Ohkubo T, Imai Y, Tsuji I, Nagai K, Ito S, Satoh H, et al. Reference values for 24-h ambulatory blood pressure monitoring based on a prognostic criterion: the Ohasama study. Hypertension. 1998;32(2):255-9. (table 1).

White coat hypertension is characterized as follows: 1) increased office BP levels (SBP ≥ 140 mmHg and/or DBP ≥ 90 mmHg); and 2) normal out-of-office BP levels (< 135/85 mmHg) measured on ABPM during wakefulness, or at home (HBPM or BPSM), as shown in table 1 and figures 1 and 2. The European Society of Hypertension recommends that, on ABPM, the diagnosis of WCH requires normal mean values of 24-hour BP and of nocturnal BP⁵5. O'Brien E, Parati G, Stergiou G, Asmar R, Beilin L, Bilo G, et al; European Society of Hypertension Working Group on Blood Pressure Monitoring. European Society of Hypertension position paper on ambulatory blood pressure monitoring. J Hypertens. 2013;31(9):1731-68. Erratum in J Hypertens. 2013;31(12):2467..

Under such conditions, the diagnosis of office arterial hypertension changes to WCH. Individuals with stage 1-2 office hypertension, with neither co-morbidities nor target organ lesions, should undergo complementary assessment by BP measurement outside the office (figure 3).

The white coat effect is defined as an increase in SBP and DBP ≥ 20 mm Hg and 10 mm Hg, respectively³⁴34. Myers MG, Haynes RB, Rabkin SW. Canadian Hypertension Society guidelines for ambulatory blood pressure monitoring. Am J Hypertens. 1999;12(11 Pt 1):1149-57. Erratum in Am J Hypertens 2000;13(2):219., between office BP measurement and the mean BP on ABPM during wakefulness or home measurements, with no change in the diagnosis of normotension or hypertension.

The use of the term 'home measurements' should increase, replacing the terms HBPM and BPSM. Thus, BPSM should be encouraged with validated equipment, cuffs applied to arm, and periodically tested calibration. It differs mainly from HBPM because of the use of a determined protocol, characterizing that both methods have more similarities than differences and can be used together³⁵35. Gomes MA, Paiva AM. MAPA e MRPA: o valor das medidas de pressão arterial fora do consultório. Revista Norte Nordeste de Cardiologia. 2013;3(2):10-20..

Prognostic value

Cardiovascular outcomes related to WCH are still controversial. Studies have suggested that WCH has lower risk, similar to that of normotensive individuals, and that risk tends to increase over time. Meta-analysis carried out with 7,030 individuals has evidenced the existence of increasing CV risk from normotension, to WCH, to MH, and finally, to hypertension²⁰20. Fagard RH, Cornelissen VA. Incidence of cardiovascular events in white-coat, masked and sustained hypertension vs. true normotension: a meta-analysis. J Hypertens. 2007;25(11):2193-8. ^{, 36}36. Verdecchia P, Reboldi GP, Angeli F, Schillaci G, Schwartz JE, Pickering TG, et al. Short and long-term incidence of stroke in white coat hypertension. Hypertension. 2005;45(2):203-8.

37. Pierdomenico SD, Cuccurullo F. Prognostic value of white-coat and masked hypertension diagnosed by ambulatory monitoring in initially untreated subjects: an update meta-analysis. Am J Hypertens. 2011;24(1):52-8.

38. Franklin SS, Thijs L, Hansen TW, Li Y, Boggia J, Kikuya M, et al; International Database on Ambulatory Blood Pressure in Relation to Cardiovascular Outcomes Investigators. Significance of white-coat hypertension in older persons with isolated systolic hypertension: a meta-analysis using the International Database on Ambulatory Blood Pressure Monitoring in Relation to Cardiovascular Outcomes population. Hypertension. 2012;59(3):564-71. ^{- 39}39. Hansen TW, Kikuya M, Thijs L, Bjorklund Bodegard K, Kuznetsova T, Ohkubo T, et al. Prognostic superiority of daytime ambulatory over conventional blood pressure in four populations: a meta-analysis of 7030 individuals. J Hypertens. 2007;25(8):1554-64..

Regarding the risk of developing hypertension, the PAMELA study has shown that a significantly higher proportion of individuals previously diagnosed with WCH or MH, after ten years were diagnosed with sustained hypertension as compared with previously normotensive individuals²⁵25. Mancia G, Bombelli M, Facchetti R, Madotto F, Quarti-Trevano F, Polo Friz H, et al. Long-term risk of sustained hypertension in white-coat or masked hypertension. Hypertension. 2009;54(2):226-32..

Masked hypertension

Epidemiology

Masked hypertension is characterized by normal BP values at the office and abnormal out-of-office BP values, on either ambulatory or dwelling BP measurements (ABPM, HBPM or BPSM)⁴⁰40. Pickering TG, Davidson K, Gerin W, Schwartz JE. Masked hypertension. Hypertension. 2002;40(6):795-6..

The prevalence of MH is estimated to range from 8% to 20% among adults with no treatment, and to be at least 50% among individuals on drug treatment⁴¹41. Bobrie G, Clerson P, Menard J, Postel-Vinay N, Chatellier G, Plouin PF. Masked hypertension: a systematic review. J Hypertens. 2008;26(9):1715-25.. A meta-analysis involving 28 studies has estimated a 16.8% MH prevalence in the general population. Among children, the estimated MH prevalence is 7%⁴²42. Verberk WJ, Kessels AG, de Leeuw PW. Prevalence, causes, and consequences of masked hypertension: a meta-analysis. Am J Hypertens. 2008;21(9):969-75.. Higher MH prevalence has been observed when office BP is in the high-normal range⁴¹41. Bobrie G, Clerson P, Menard J, Postel-Vinay N, Chatellier G, Plouin PF. Masked hypertension: a systematic review. J Hypertens. 2008;26(9):1715-25.. Office BP within the normal range as compared to abnormal ambulatory values has been attributed, among other factors, to the "regression toward the mean" phenomenon⁴⁰40. Pickering TG, Davidson K, Gerin W, Schwartz JE. Masked hypertension. Hypertension. 2002;40(6):795-6.. Other factors have also correlated with MH³⁰30. O'Brien E, Asmar R, Beilin L, Imai Y, Mallion JM, Mancia G, et al; European Society of Hypertension Working Group on Blood Pressure Monitoring. European Society of Hypertension recommendations for conventional, ambulatory and home blood pressure measurement. J Hypertens. 2003;21(5):821-48. ^{, 40}40. Pickering TG, Davidson K, Gerin W, Schwartz JE. Masked hypertension. Hypertension. 2002;40(6):795-6. ^{, 43}43. Ogedegbe G. Causal mechanisms of masked hypertension: socio-psychological aspects. Blood Press Monit. 2010;15(2):90-2.

44. Aksoy I, Deinum J, Lenders JW, Thien T. Does masked hypertension exist in healthy volunteers and apparently well-controlled hypertensive patients? Neth J Med. 2006;64(3):72-7.

45. Obara T, Ohkubo T, Kikuya M, Asayama K, Metoki H, Inoue R, et al; J-HOME Study Group. Prevalence of masked uncontrolled and treated white-coat hypertension defined according to the average of morning and evening home blood pressure value: from the Japan Home Versus Office Measurement Evaluation Study. Blood Press Monit. 2005;10(6):311-6.

46. Ogedegbe G, Pickering TG, Clemow L, Chaplin W, Spruill TM, Albanese GM, et al. The misdiagnosis of hypertension: the role of patient anxiety. Arch Intern Med. 2008;168(22):2459-65.

47. Wang GL, Li Y, Staessen JA, Lu L, Wang JG. Anthropometric and lifestyle factors associated with white-coat, masked and sustained hypertension in a Chinese population. J Hypertens. 2007;25(12):2398-405. ^{- 48}48. Baguet JP, Hammer L, Levy P, Pierre H, Rossini E, Mouret S, et al. Night-time and diastolic hypertension are common and underestimated conditions in newly diagnosed apnoeic patients. J Hypertens. 2005;23(3):521-7., as shown in Chart 1. In a study involving 3,400 treated hypertensives, the major factors associated with MH were overweight (1.38; 95% CI: 1.09-1.75) and regular alcohol consumption (OR, 1.37; 95% CI: 1.09-1.72)⁴²42. Verberk WJ, Kessels AG, de Leeuw PW. Prevalence, causes, and consequences of masked hypertension: a meta-analysis. Am J Hypertens. 2008;21(9):969-75.. In another study, the risk for MH was higher among men than among women [relative risk (RR), 1.14; 95% CI: 1.01-1.28] and among smokers (RR, 1.16; 95% CI: 1.04-1.30)⁴⁹49. Ungar A, Pepe G, Monami M, Lambertucci L, Torrini M, Baldasseroni S, et al. Isolated ambulatory hypertension is common in outpatients referred to a hypertension center. J Hum Hypertens. 2004;18(12):897-903.. Another study has shown that women were less prone than men to have MH (OR, 0.39; 95% CI: 0.22- 0.68)⁴⁷47. Wang GL, Li Y, Staessen JA, Lu L, Wang JG. Anthropometric and lifestyle factors associated with white-coat, masked and sustained hypertension in a Chinese population. J Hypertens. 2007;25(12):2398-405..

Classically, the presence of MH occurs among untreated individuals. Recently, the literature has emphasized the occurrence of normal office BP and elevated out-of-office BP values in treated individuals. Lower levels of anxiety and the use of antihypertensive drugs only before the medical consultation, with a drug action peak at the time of medical examination, has also been listed as causing factors⁴⁴44. Aksoy I, Deinum J, Lenders JW, Thien T. Does masked hypertension exist in healthy volunteers and apparently well-controlled hypertensive patients? Neth J Med. 2006;64(3):72-7. ^{, 46}46. Ogedegbe G, Pickering TG, Clemow L, Chaplin W, Spruill TM, Albanese GM, et al. The misdiagnosis of hypertension: the role of patient anxiety. Arch Intern Med. 2008;168(22):2459-65. ^{, 50}50. Ogedegbe G, Agyemang C, Ravenell JE. Masked hypertension: evidence of the need to treat. Curr Hypertens Rep. 2010;12(5):349-55..

Diagnosis and clinical strategies of identification

Masked hypertension refers to untreated patients with systematically normal office BP measurements (BP < 140/90 mm Hg) and elevated BP on ABPM or at home measurements - mean BP during wakefulness or mean home BP ≥ 135/85 mm Hg⁵¹51. Pickering T, Eguchi K, Kario K. Masked hypertension: a review. Hypertens Res. 2007;30(6):479-88. ^{, 52}52. Terawaki H, Metoki H, Nakayama M, Ohkubo T, Kikuya M, Asayama K, et al. Masked hypertension determined by self-measured blood pressure at home and chronic kidney disease in the Japanese general population: the Ohasama study. Hypertens Res. 2008;31(12):2129-35. (table 1 and figures 1 and 4). It is worth noting the position of the European Society of Hypertension for ABPM, which has also considered the elevated means of 24-hour and nocturnal BP measurements as criteria for MH diagnosis, even with normal mean BP during wakefulness⁵5. O'Brien E, Parati G, Stergiou G, Asmar R, Beilin L, Bilo G, et al; European Society of Hypertension Working Group on Blood Pressure Monitoring. European Society of Hypertension position paper on ambulatory blood pressure monitoring. J Hypertens. 2013;31(9):1731-68. Erratum in J Hypertens. 2013;31(12):2467..

The conditions listed on Chart 1 are related to MH, and, when present, the diagnosis of MH can be suspected, and ABPM should be considered for a more adequate analysis of the actual BP behavior. The presence of target-organ lesions and the report of repeated high out-of-office BP measurements should raise suspicion of MH¹1. Sociedade Brasileira de Cardiologia. Sociedade Brasileira de Nefrologia. Sociedade Brasileira de Hipertensão. VI Diretrizes Brasileiras de Hipertensão. Arq Bras Cardiol. 2010;95(1 supl 1):1-51. ^{, 3}3. Mancia G, Fagard R, Narkiewicz K, Rédon J, Zanchetti A, Böhm M, et al; Task Force Members. 2013 ESH/ESC Guidelines for the management of arterial hypertension: the Task Force for the management of arterial hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). J Hypertens. 2013;31(7):1281-357.

4. Sociedade Brasileira de Cardiologia, Sociedade Brasileira de Hipertensão, Sociedade Brasileira de Nefrologia. V Diretrizes Brasileiras de Monitorização Ambulatorial da Pressão Arterial (MAPA) e III Diretrizes Brasileiras de Monitorização Residencial de Pressão Arterial (MRPA). Arq Bras Cardiol. 2011;97 (3 supl.3):1-24. ^{- 5}5. O'Brien E, Parati G, Stergiou G, Asmar R, Beilin L, Bilo G, et al; European Society of Hypertension Working Group on Blood Pressure Monitoring. European Society of Hypertension position paper on ambulatory blood pressure monitoring. J Hypertens. 2013;31(9):1731-68. Erratum in J Hypertens. 2013;31(12):2467. ^{, 48}48. Baguet JP, Hammer L, Levy P, Pierre H, Rossini E, Mouret S, et al. Night-time and diastolic hypertension are common and underestimated conditions in newly diagnosed apnoeic patients. J Hypertens. 2005;23(3):521-7. ^{, 53}53. Kawano Y, Horio T, Matayoshi T, Kamide K. Masked hypertension: subtypes and target organ damage. Clin Exp Hypertens. 2008;30(3):289-96. ^{, 54}54. Mallion JM, Genes N, Vaur L, Clerson P, Vaisse B, Bobrie G, et al. Detection of masked hypertension by home blood pressure measurement: is the number of measurements an important issue? Blood Press Monit. 2004;9(6):301-5..

Masked hypertension can also be identified based on repeated BP measurements in the morning and afternoon with proper sensitivity and specificity⁷7. Conen D, Ricker PM, Buring JE, Glynn RJ. Risk of cardiovascular events among women with high normal blood pressure or blood pressure progression: prospective cohort study. BMJ. 2007;335(7617):432-40.. However, several authors have questioned the reproducibility in the long run of the measurements obtained in that way⁵⁵55. Head GA, McGrath BP, Mihailidou AS, Nelson MR, Schlaich MP, Stowasser M, et al. Ambulatory blood pressure monitoring in Australia: 2011 consensus position statement. J Hypertens. 2012;30(3):253-66..

Prognostic value

The prognostic value of MH is controversial; while some studies have confirmed its greater CV risk, others have failed to show such relationship. Several authors have reported that ABPM and home BP measurements of hypertensives are better independent predictors of both target-organ lesions⁵⁶56. Verdecchia P, Porcellati C, Schillaci G, Borgioni C, Ciucci A, Battistelli M, et al. Ambulatory blood pressure: an independent predictor of prognosis in essential hypertension. Hypertension. 1994;24(6):793-801. ^{, 57}57. Liu JE, Roman MJ, Pini R, Schwartz JE, Pickering TG, Devereux RB. Cardiac and arterial target organ damage in adults with elevated ambulatory and normal office blood pressure. Ann Intern Med. 1999;131(8):564-72. and CV risk⁵⁸58. Bobrie G, Chatellier G, Genes N, Clerson P, Vaur L, Vaisse B, et al. Cardiovascular prognosis of "masked hypertension" detected by blood pressure self-measurement in elderly treated hypertensive patients. JAMA. 2004;291(11):1342-9. than office BP measurement. However, Cuspidi et al⁵⁹59. Cuspidi C, Negri F, Sala C, Mancia G. Masked hypertension and echocardiographic left ventricular hypertrophy: an updated overview. Blood Press Monit. 2012;17(1):8-13., analyzing 13 studies in an attempt to relate MH and left ventricular hypertrophy (LVH), have concluded that the relationship between MH and the development of LVH was limited⁵⁹59. Cuspidi C, Negri F, Sala C, Mancia G. Masked hypertension and echocardiographic left ventricular hypertrophy: an updated overview. Blood Press Monit. 2012;17(1):8-13..

On the other hand, concentric remodeling and LVH, thickening of the intima-media layer, carotid atherosclerotic plaques and microalbuminuria were more prevalent in MH than in the normotensive population⁵⁶56. Verdecchia P, Porcellati C, Schillaci G, Borgioni C, Ciucci A, Battistelli M, et al. Ambulatory blood pressure: an independent predictor of prognosis in essential hypertension. Hypertension. 1994;24(6):793-801..

Hanninen et al⁶⁰60. Hanninen MR, Niiranen TJ, Puukka PJ, Johansson J, Jula AM. Prognostic significance of masked and white-coat hypertension in the general population: the Finn-Home Study. J Hypertens. 2012;30(4):705-12., assessing the prognostic value of MH in a general population sample in Finland, have included 2,046 normotensive and hypertensive individuals with different CV risk factors. Those authors have reported that, assessing the CV risk by measuring home BP, patients with MH have a higher CV risk adjusted for age as compared with that of normotensive individuals. However, MH was not an independent predictor of CV risk when the baseline home BP measurement was adjusted for other traditional risk factors. They have concluded that home BP values associated with other traditional risk factors are sufficient for CV risk stratification.

Meta-analyses of prospective studies have indicated a two fold increase in the risk for CV events in MH as compared with true normotension, an incidence similar to that observed in true SAH. The non-detection of MH and the consequent lack of treatment might have contributed to that result²⁰20. Fagard RH, Cornelissen VA. Incidence of cardiovascular events in white-coat, masked and sustained hypertension vs. true normotension: a meta-analysis. J Hypertens. 2007;25(11):2193-8. ^{, 37}37. Pierdomenico SD, Cuccurullo F. Prognostic value of white-coat and masked hypertension diagnosed by ambulatory monitoring in initially untreated subjects: an update meta-analysis. Am J Hypertens. 2011;24(1):52-8. ^{, 41}41. Bobrie G, Clerson P, Menard J, Postel-Vinay N, Chatellier G, Plouin PF. Masked hypertension: a systematic review. J Hypertens. 2008;26(9):1715-25..

Non-drug treatment for prehypertension, white coat hypertension and masked hypertension: efficacy and difficulties for implementation

There is no doubt about the benefits obtained with changes in lifestyle (CLS) for individuals with SAH and prehypertension, and there are good indications that they extend to those with WCH, as well as to those with MH¹1. Sociedade Brasileira de Cardiologia. Sociedade Brasileira de Nefrologia. Sociedade Brasileira de Hipertensão. VI Diretrizes Brasileiras de Hipertensão. Arq Bras Cardiol. 2010;95(1 supl 1):1-51. ^{, 3}3. Mancia G, Fagard R, Narkiewicz K, Rédon J, Zanchetti A, Böhm M, et al; Task Force Members. 2013 ESH/ESC Guidelines for the management of arterial hypertension: the Task Force for the management of arterial hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). J Hypertens. 2013;31(7):1281-357..

The major CLS aimed at that purpose are as follows: weight control; change to the DASH diet (rich in fruits, vegetables, fibers, minerals and low-fat dairy products); reduced salt intake; reduced alcohol consumption; smoking cessation; physical exercise practice; and psychosocial stress control¹1. Sociedade Brasileira de Cardiologia. Sociedade Brasileira de Nefrologia. Sociedade Brasileira de Hipertensão. VI Diretrizes Brasileiras de Hipertensão. Arq Bras Cardiol. 2010;95(1 supl 1):1-51. ^{, 3}3. Mancia G, Fagard R, Narkiewicz K, Rédon J, Zanchetti A, Böhm M, et al; Task Force Members. 2013 ESH/ESC Guidelines for the management of arterial hypertension: the Task Force for the management of arterial hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). J Hypertens. 2013;31(7):1281-357..

Several clinical studies assessing those measures have shown a significant BP reduction in hypertensive and prehypertensive individuals, and a delay in the appearance of SAH in the latter⁶¹61. Effects of weight loss and sodium reduction intervention on blood pressure and hypertension incidence in overweight people with high-normal blood pressure. The Trials of Hypertension Prevention, phase II. The Trials of Hypertension Prevention Collaborative Research Group. Arch Intern Med. 1997;157(6):657-67.

62. Appel LJ, Moore TJ, Obarzanek E, Wollmer WM, Svetkey LP, Sacks FM, et al. A clinical trial of the effects of dietary patterns on blood pressure. DASH Collaborative Research Group. N Engl J Med. 1997;336 (16):1117-24.

63. Sacks FM, Svetkey LP, Vollmer WM, Appel LJ, Bray GA, Harsha D, et al. Effects on blood pressure of reduced dietary sodium and the Dietary Approaches to Stop Hypertension (DASH) diet. DASH-Sodium Collaborative Research Group. N Engl J Med. 2001;344(1):3-10.

64. Stevens VJ, Obarzanek E, Cook NR, Lee IM, Appel LJ, West DS, et al. Long-term weight loss and changes in blood pressure: results of the Trials of Hypertension Prevention, phase II. Ann Intern Med. 2001;134(1):1-11.

65. Cook NR, Cutler JA, Obarzanek E, Buring JE, Rexrode KM, Kumanyika SK, et al. Long term effects of dietary sodium reduction on cardiovascular disease outcomes: observational follow-up of the trials of hypertension prevention (TOHP). BMJ. 2007;334(7599):885-8.

66. Appel LJ, Champagne CM, Harsha DW, Cooper LS, Obarzanek E, Elmer PJ, et al. Effects of comprehensive lifestyle modification on blood pressure control: main results of the PREMIER clinical trial. JAMA. 2003;289(16):2083-93.

67. Elmer PJ, Obarzanek E, Vollmer WM, Simons-Morton D, Stevens VJ, Young DR, et al. Effects of comprehensive lifestyle modification on diet, weight, physical fitness, and blood pressure control: 18-month results of a randomized trial. Ann Intern Med. 2006;144 (7):485-95. ^{- 68}68. Park S, Rink LD, Wallace JP. Accumulation of physical activity leads to a greater blood pressure reduction than a single continuous session, in prehypertension. J Hypertens. 2006;24(9):1761-70..

Regarding WCH, the encouragement of CLS is based on the following reasons: WCH is not harmless, because individuals with WCH can have changes in target organs; CLS should be the initial strategy to reduce BP in any type of BP behavior change; CLS are recommended as an important strategy to prevent or delay the appearance of SAH in the general population; patients with WCH are more likely to develop sustained SAH; CLS have clear benefits to other CV risk factors; the drug treatment of WCH is still controversial¹1. Sociedade Brasileira de Cardiologia. Sociedade Brasileira de Nefrologia. Sociedade Brasileira de Hipertensão. VI Diretrizes Brasileiras de Hipertensão. Arq Bras Cardiol. 2010;95(1 supl 1):1-51. ^{, 3}3. Mancia G, Fagard R, Narkiewicz K, Rédon J, Zanchetti A, Böhm M, et al; Task Force Members. 2013 ESH/ESC Guidelines for the management of arterial hypertension: the Task Force for the management of arterial hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). J Hypertens. 2013;31(7):1281-357. ^{, 20}20. Fagard RH, Cornelissen VA. Incidence of cardiovascular events in white-coat, masked and sustained hypertension vs. true normotension: a meta-analysis. J Hypertens. 2007;25(11):2193-8..

In masked hypertension, the recommendations can be more specific according to the period of the day in which BP increases, such as morning, daytime and nocturnal hypertension⁶⁹69. Kawano Y. Lifestyle modification for masked hypertension. Curr Hypertens Rev. 2011;7(1):9-12..

The reduction in alcohol consumption and in physical and mental stress is recommended for patients with morning hypertension⁷⁰70. Leary AC, Struthers AC, Donnan PT, MacDonald TM, Murphy MB. The morning surge in blood pressure and heart rate is dependent on physical activity after waking. J Hypertens. 2002;20(5):865-70.. Regarding hypertension during wakefulness, smoking cessation is necessary, as well as physical and mental stress control⁷¹71. Verdecchia P, Schilatti G, Borgioni C, Ciucci A, Zampi I, Battistelli M, et al. Cigarette smoking, ambulatory blood pressure and cardiac hypertrophy in essential hypertension. J Hypertens. 1995;13(10):1209-15.. Those with hypertension during sleep should undergo salt restriction, because that type of hypertension is more often observed in salt-sensitive individuals⁷²72. Uzu T, Nakao K, Kume S, Araki H, Isshiki K, Araki S, et al. High sodium intake is associated with masked hypertension in Japanese patients with type 2 diabetes and treated hypertension. Am J Hypertens. 2012;25(11):1170-4., as well as weight reduction, especially the obese individuals with obstructive sleep apnea syndrome⁷³73. Baguet JP, Lévy P, Barone-Rochette G, Tamisier R, Pierre H, Peeters M, et al. Masked hypertension in obstructive sleep apnea syndrome. J Hypertens. 2008;26(5):885-92..

In addition to close follow-up by a medical professional, the multiprofessional team plays a fundamental role, motivating adherence to treatment and assuring that changes are permanent¹1. Sociedade Brasileira de Cardiologia. Sociedade Brasileira de Nefrologia. Sociedade Brasileira de Hipertensão. VI Diretrizes Brasileiras de Hipertensão. Arq Bras Cardiol. 2010;95(1 supl 1):1-51. ^{, 3}3. Mancia G, Fagard R, Narkiewicz K, Rédon J, Zanchetti A, Böhm M, et al; Task Force Members. 2013 ESH/ESC Guidelines for the management of arterial hypertension: the Task Force for the management of arterial hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). J Hypertens. 2013;31(7):1281-357. ^{, 74}74. Tsai J, Liu J, Kao C, Tomlinson B, Kao P, Chen J, et al. Beneficial effects on blood pressure and lipid profile of programmed exercise training in subjects with white coat hypertension. Am J Hypertens. 2002;15(6):571-6.

75. Lima AS, Zanetti ML, Miyar LO, Machado MP. Fatores facilitadores / dificultadores para a implementação de um programa educativo por equipe multidisciplinar. Arq Bras Endocrinol Metab. 2003;47(5):568-78. ^{- 76}76. Margolius D, Wong J, Goldman ML, Rouse-Iniguez J, Bodenheimer T. Delegating responsibility from clinicians to nonprofessional personnel: the example of hypertension control. J Am Board Fam Med. 2012;25(2):209-15..

Despite evidence, the great limitation and reason of distrust is the effectiveness of those CLS measures out of the context of clinical trials. In real life, even the most motivated individuals face difficulties to sustain CLS, pressed by cultural forces, deep-rooted habits, society rules and commercial interests that encourage sedentary lifestyle, improper diet, and excessive caloric intake⁷⁷77. Appel LJ; American Society of Hypertension Writing Group. ASH position paper: dietary approaches to lower blood pressure. J Am Soc Hypertens. 2009;3(5):321-31.. This raises expectations about the potential of drug alternatives to face those situations⁷⁸78. Hooper L, Bartlett C, Davey Smith G, Ebrahim S. Systematic review of long term effects of advice to reduce dietary salt in adults. BMJ. 2002;325(7365):628. ^{, 79}79. Fuchs FD, Gus M, Moreira WD, Moraes RS, Rosito GA, Sorucco A, et al. Blood pressure effects of antyhypertensive drugs and lifestyle modification in a Brazilian hypertensive cohort. J Hypertens. 1997;15:783-792..

Drug treatment

Prehypertension

Prehypertension represents an intermediate stage for established SAH, and its conversion to sustained arterial hypertension is more accelerated in black individuals⁸8. Moreira LB, Fuchs SC, Wiehe M, Gus M, Moraes RS, Fuchs FD. Incidence of hypertension in Porto Alegre, Brazil: a population-based study. J Hum Hypertens. 2008;22(1):48-50. ^{, 80}80. Selassie A, Wagner CS, Laken ML, Ferguson ML, Ferdinand KC, Egan BM. Progression is accelerated from prehypertension to hypertension in blacks. Hypertension. 2011;58(4):579-87.. The renin-angiotensin-aldosterone system (RAAS) is frequently activated in prehypertensive individuals⁸¹81. Fink GD, Arthur C. Corcoran Memorial Lecture. Sympathetic activity, vascular capacitance, and long-term regulation of arterial pressure. Hypertension. 2009;53(2)307-12.. That suggests that the early intervention with drugs might reduce the incidence of sustained hypertension and prevent the progression of CVD.

The Trial of Preventing Hypertension (TROPHY)¹³13. Julius S, Nesbitt SD, Egan BM, Weber MA, Michelson EL, Kaciroti N, et al; Trial of Preventing Hypertension (TROPHY) Study Investigators. Feasibility of treating prehypertension with an angiotensin-receptor blocker. N Engl J Med. 2006;354(16):1685-97. and the Prevention of Hypertension with the Angiotensin Converting Enzyme Inhibitor Ramipril in Patients with High-Normal Blood Pressure (PHARAO) Study⁸²82. Luders S, Schrader J, Berger J, Unger T, Zidek W, Bohm M, et al. The PHARAO study: prevention of hypertension with the angiotensin-converting enzyme inhibitor ramipril in patients with high-normal blood pressure - a prospective, randomized, controlled prevention trial of the German Hypertension League. J Hypertens. 2008;26(7):1487-96. were the first to show that RAAS inhibitors reduce the incidence of hypertension. The TROPHY study has assessed 772 individuals with BP of 130-139/85-89 mm Hg, randomized to receive either placebo or candesartan (16 mg/day - intervention group). All individuals were instructed about CLS. After four years, a lower incidence of SAH (9.8%) was observed in the intervention group, with a 16% reduction in RR and number necessary to treat (NNT) of 11¹³13. Julius S, Nesbitt SD, Egan BM, Weber MA, Michelson EL, Kaciroti N, et al; Trial of Preventing Hypertension (TROPHY) Study Investigators. Feasibility of treating prehypertension with an angiotensin-receptor blocker. N Engl J Med. 2006;354(16):1685-97.. That study has been questioned regarding some methodological aspects, which might have overvalued its results. The PHARAO study has assessed 1,008 prehypertensive individuals with BP of 130-139/85-89 mm Hg, for three years, who have been randomly allocated to receive 5 mg/day of ramipril or placebo. The ramipril group showed a 34% reduction in RR in the incidence of SAH assessed by using office BP (NNT = 9) and ABPM (32.5% vs. 53.0%), with an increase in the incidence of cough (4.8% vs. 0.4%)⁸²82. Luders S, Schrader J, Berger J, Unger T, Zidek W, Bohm M, et al. The PHARAO study: prevention of hypertension with the angiotensin-converting enzyme inhibitor ramipril in patients with high-normal blood pressure - a prospective, randomized, controlled prevention trial of the German Hypertension League. J Hypertens. 2008;26(7):1487-96.. However, if those are long term benefits, if they prevent CV events and are cost-effective is yet to be clarified.

Current guidelines recommend CLS to all prehypertensive individuals, and drug intervention only to those with normal high BP values at high risk, with CVD or established kidney disease, metabolic syndrome or diabetes¹1. Sociedade Brasileira de Cardiologia. Sociedade Brasileira de Nefrologia. Sociedade Brasileira de Hipertensão. VI Diretrizes Brasileiras de Hipertensão. Arq Bras Cardiol. 2010;95(1 supl 1):1-51., at medical discretion. It is worth noting that so far there is only evidence for the use of RAAS blockers. Recent European guidelines on hypertension have highlighted the lack of sufficient scientific evidence supporting the beginning of drug treatment for normal-high BP levels.

In face of the evidence above and the low effectiveness of CLS in the long run, the use of low doses of antihypertensive drugs to prehypertensive individuals with no CVD, but at high risk to develop sustained arterial hypertension, should be considered⁸³83. Fuchs FD, Fuchs SC, Moreira LB, Gus M, Nóbrega AC, Poli-de-Figueiredo CE, et al. Prevention of hypertension in patients with pre-hypertension: protocol for the PREVER-prevent trial. Trials. 2011;12:65.

84. McInnes G. Pre-hypertension: how low to go and do drugs have a role. Br J Clin Pharmacol. 2012;73(2):187-93. ^{- 85}85. Thompson AM, Hu T, Eshelbrenner CL, Reynolds K, He J, Bazzano LA. Antihypertensive treatment and secondary prevention of cardiovascular disease events among persons without hypertension: a meta-analysis. JAMA. 2011;305(9):913-22..

White-coat hypertension (WCH)

The benefit of drug treatment to WCH remains undefined, because there has never been a clinical trial specifically designed to test that hypothesis. In addition, large clinical studies designed to show target-organ protection with antihypertensive treatment have never used ABPM or home BP measurements, except in small subgroups, with a small number of CV events, which have not yielded definitive conclusions.

In the lack of direct evidence, and in the presence of high or very high CV risk (concomitance of CVD or kidney disease, target-organ lesions, metabolic syndrome or diabetes), antihypertensive treatment can be considered for WCH. Thus, assessing CV risk factors and determining the risk of individuals with WCH are required for customized decision making about their antihypertensive treatment⁸⁶86. Mancia G, Bombelli M, Seravalle G, Grassi G. Diagnosis and management of patients with white-coat and masked hypertension. Nat Rev Cardiol. 2011;8(12):686-93..

Those patients should be followed up by using ABPM or home BP measurements.

Masked hypertension (MH)

There is plenty of scientific evidence of the negative impact of MH on CV morbidity and mortality that justify identifying and treating those patients similarly to office hypertensive patients⁴²42. Verberk WJ, Kessels AG, de Leeuw PW. Prevalence, causes, and consequences of masked hypertension: a meta-analysis. Am J Hypertens. 2008;21(9):969-75..

Clinical studies on patients with MH demonstrating the relationship between BP decrease and CV risk reduction still lack. The beginning of drug treatment for patients with MH is based on the fact that they actually have out of office hypertension, with CV risk similar to that of untreated hypertensives⁵⁰50. Ogedegbe G, Agyemang C, Ravenell JE. Masked hypertension: evidence of the need to treat. Curr Hypertens Rep. 2010;12(5):349-55. ^{, 87}87. Phillips RA. Controversies in blood pressure goal guidelines and masked hypertension. Ann NY Acad Sci. 2012;1254:115-22..

Patients with MH should be stratified and treated similarly to conventional hypertensives⁵⁰50. Ogedegbe G, Agyemang C, Ravenell JE. Masked hypertension: evidence of the need to treat. Curr Hypertens Rep. 2010;12(5):349-55.. The efficacy of antihypertensive treatment should be assessed by using out-of-office BP measurement.

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