Invited review
Blood pressure control based on office and ambulatory blood pressure monitoring: the European experience in hypertensive patients treated in clinical practice

Introduction The therapeutic benefits of blood pressure (BP) lowering have been demonstrated in a large number of morbidity-mortality trials [1-3]. A meta-analysis of 61 prospective observational studies involving one million adults has shown that cardiovascular risk is strongly and directly related to BP throughout middle and old age, with a doubling of cardiovascular death for every 20/10 mm Hg increase in usual BP, beginning at 115/75 mm Hg [4]. A large interventional trial including nearly 19 000 hypertensive patients, the Hypertension Optimal Treatment study, documented the lowest incidence of cardiovascular mortality at a mean achieved systolic and diastolic BP of 138.5 and 82.6 mm Hg, respectively [5]. This led international experts in the field of hypertension to recommend for the first time an intensive BP lowering in 1999, the aim being to bring BP <140/90 mm Hg in most patients [6]. This view was supported a few years later by other official guidelines, where even lower BP targets (<130/80 mm Hg) were recommended in patients with selected diseases such as renal insufficiency and/or diabetes [7-9]). According to the last 2007 guidelines for the management of hypertension prepared jointly by the European Society of hypertension and the European Society of Cardiology, BP should be reduced below 130/80 mm Hg not only in patients with diabetes or renal dysfunction, but also in those with associated clinical conditions such as stroke and myocardial infarction [10]. The 140/90 mm Hg value was actually chosen as a goal in most recent randomized morbidity-mortality trials performed in hypertensive patients [11-19]. Notably, evidence for a better cardiovascular outcome was found in patients who achieved this target BP during the trial compared with those who failed to reach it [14, 20]. Major efforts have been directed in industrialized countries over the last decades at diagnosing and treating hypertension. How successful were these efforts in this privileged part of the world where patients are presumed to have easy access to health care? The present review aims to answer this question, taking as an example the experience accumulated in several countries across Europe. We decided to focus as much as possible on surveys performed after dissemination of the hypertension guidelines promoting as the treatment goal BP values <140/90 mm Hg, i.e. after 1999. We also made the choice of addressing the issue of BP control rate in hypertensive patients followed by physicians rather than observations made in population-based surveys. This option was taken to reflect everyday clinical practice, thus illustrating how difficult it is to normalize BP in most hypertensives. This should help to identify barriers to the achievement of satisfactory BP control as well as possible strategies to improve it. Finally, we searched for studies in which the BP control rate was assessed not only conventionally in an office setting, but also in “out-of-office” conditions, using 24-h ambulatory BP monitoring. This is of critical importance as “out-of-office” BP allows a better prediction of cardiovascular events [21-25] and has been endorsed by the latest European guidelines [10].
Office blood pressure control rate in hypertensive patients Several studies performed in different European countries were selected as representative of the BP control rate currently achieved in hypertensive patients followed by physicians in everyday practice. They are reported here according to the alphabetical order of the countries.
Belgium In a prospective cross-sectional survey 253 general practitioners were asked to provide information on the first 15 men aged 55 years or older who showed up in their office [26]. Data from 3761 subjects were obtained (Table I). Out of them 74% were considered to be hypertensive (of whom 80% were on antihypertensive therapy). BP was <140/90 mm Hg in 38% of the treated patients, and in 31% of all hypertensives. The hypertensive patients were classified into the different risk categories according to the 1999 WHO/ISH guidelines [6]. This could be done in 1316 patients. The proportion of patients who were treated was 47, 56 and 86% in the medium, high and very high risk groups, respectively. Among patients on antihypertensive therapy, BP was more frequently controlled in the medium (46%) than in the high (37%) and the very high risk group (31%). The BP control rate was significantly better among treated patients (n=92) with diastolic hypertension (defined as diastolic BP ł90 mm Hg irrespective of systolic BP) than among treated patients (n=837) with isolated systolic hypertension (defined as systolic BP ł140 mm Hg and diastolic BP <90 mm Hg), at 53 and 33%, respectively [27]. Notably, patients with isolated systolic hypertension were less frequently treated (25%) than those with diastolic hypertension (75%). A prospective cross-sectional survey was recently performed in primary care with the aim of evaluating the prevalence of isolated uncontrolled systolic BP in treated hypertensive patients [28, 29]. A random sample of 770 physicians throughout Belgium included 11 562 patients on antihypertensive therapy (Table I). Table II shows the prevalence of hyper-tension types in these patients by age class. The prevalence of isolated systolic hypertension, defined as systolic BP at least 140 mm Hg and diastolic BP less than 90 mm Hg, increased with age, reaching 38.4% above the age of 80 years. The physicians in charge of the patients decided not to adapt antihypertensive therapy in 46% of patients with on-treatment isolated systolic hypertension, compared with 16% of uncontrolled patients in the other hypertension types.
France A cross-sectional study was carried out in a sample of 3153 general practitioners who were requested to give information on the first 5 hyper-tensive patients presenting in their office [29]. Data from 14 066 treated patients were available for analysis (Table I). These patients were divided into 3 groups according to the cardiovascular risk stratification proposed by the 1999 WHO/ISH guidelines [6]. BP control (<140/90 mm Hg) was seen less frequently in patients with the highest risk (27%) than in those with the medium (31%) and the lowest risk (43%). A key observation was that the high risk patients received more frequently two or more drugs (56%) than their medium (44%) and low risk counterparts (34%). Thus, patients expected to benefit the most from BP normalization were also patients who were the most difficult to treat. The BP control rate has also been evaluated in treated hypertensive patients known to have coronary heart disease [30]. A total of 1423 patients were recruited by general practitioners, and 2596 by cardiologists. Normal BP (<140/90 mm Hg) was observed more frequently among patients followed by cardiologists (40.8%) than among those followed in general practice (26.3%), and more often among patients in the lowest cardiovascular risk group (general practitioners: 26.3%, cardiologists: 32.4%). Among patients with uncontrolled hypertension, 67.4% were receiving ł2 drugs when followed in general practice, compared with 77.7% when followed in cardiological practice. In a multiple regression analysis, age, total cholesterol, obesity, current smoking, and diabetes were independently and negatively associated with hypertension control. More recently the results of an observational cross-sectional epidemiological study aiming to assess the determinants of hypertension control have been published [31]. A total of 4966 hypertensive patients aged >18 years were included, followed by 2487 practitioners (Table I). The patients had to be pharmacologically treated with the same drug(s) for more than 1 month and less than 1 year. Half of them had two or more cardiovascular risk factors in addition to hypertension. BP was <140/90 mm Hg in only a small fraction of patients (18%). Factors independently associated with poor BP control were advanced age, male gender, history of previous cardiovascular event, high heart rate and high body weight.
Germany A cross-sectional prevalence study has been conducted in a representative nationwide sample of primary care doctors (n=1912) who were asked to give information on a total of 45 093 patients [32]. 17 485 patients were considered as having hypertension (39%) and 14 647 among those diagnosed as hypertensive were treated (84.5%), using a monotherapy in 45% of cases (Table I). The fraction of patients on antihypertensive therapy who had BP <140/90 mm Hg was 31.7%. When asked to estimate the success of their treatment, however, the doctors considered hypertension as “well controlled” in 52% of their patients.
Italy The BP control achieved in patients managed by specialist physicians has been studied in 131 outpatient centres located in northern (34.5%), central (28.1%) and southern (37.4%) Italy [33]. Each centre had the task of recruiting a minimum of 20 consecutive patients attending a routine visit (Table I). A total of 2775 patients with a mean age of 61 years were included. 36.9% were receiving monotherapy and the remainder combination therapy. The prevalence of BP <140/90 mm Hg was 37.5%. The control of systolic BP only was less frequent (40.2%) than the control of diastolic BP only (64.4%). The total cardiovascular risk profile was calculated according to the 2003 ESH/ESC guidelines [9]. Low-medium risk, high risk and very high risk patients accounted for 37.3, 34.2 and 28.5% of the study population, respectively. The BP control rate (BP <140/90 mm Hg) was better in low-medium risk patients (43.2%) than in high (33.2%) and very high risk patients (34.9%). The BP control rate increased from the initial visit (41.2%) to the 6- and 12-month visits (46.2 and 52.3%, respectively). This improvement could hardly be explained by an intensification of drug consumption as the treatment remained unchanged during the 12-month follow-up in 78.3% of the patients, was stepped up in only 15.3% of the patients, and was even stepped down in 6.4% of the patients. Enhanced compliance with the prescribed treatment might have contributed to the better therapeutic effects observed with time. According to the latest ESH/ESC hypertension guidelines, target BP should be <130/80 mm Hg in high and very high risk patients [10]. Notably, such a low BP target was observed at the end of the 12-month follow-up in only a small fraction of high risk (16.3%) and very high risk patients (17.7%). An observational study was performed by 1800 general practitioners who were asked to recruit 10 consecutive patients aged 54 to 84 years [34]. The diagnosis of hypertension was based on BP ł140/90 mm Hg or the current use of antihy-pertensive drugs. A total of 12 792 patients were included in the study (5280 were untreated and 7512 treated). Overall BP control in treated patients occurred in 18.4% of subjects (Table I). Among treated hypertensives, 23.1% had diabetes. BP was <140/90 mm Hg and <130/80 mm Hg in 14.9 and 3.0% of these patients, respectively. Figure 1 depicts the classification of the patients on anti-hypertensive therapy according to the BP criteria of the ESH/ESC hypertension guidelines [9]. The majority of patients had grade 1 hypertension, meaning that their BP ranged from 140 to 159 mm Hg for systolic and/or 90 to 99 mm Hg for diastolic.
Spain A study was carried out to assess the BP control rate among special subgroups of hypertensives treated in 47 hospital-based hypertension units nationwide [35]. Out of the 4049 analyzed patients, 48% were on monotherapy and 42% had BP <140/90 mm Hg (Table I). The presence of diabetes, renal failure and proteinuria was observed in 893, 669 and 1757 patients, respectively. In these high risk patients, it is recommended to pursue the lowering of BP below 130/80 mm Hg [9]. This target was reached in only 10% of diabetics, 12% of pa- tients with renal failure and 12% of proteinuric patients. Table III shows the physicians’ management behaviour with regard to uncon-trolled hypertension. Clinical inertia was a prominent finding, as it was observed in 56% of low or medium risk patients with BP ł140/90 mm Hg, and 61% of high or very high risk patients with BP ł130/85 mm Hg.
Sweden In a cross-sectional survey 6537 patients on antihypertensive therapy were recruited by 264 primary care physicians from across Sweden (187 men and 77 women) [36]. Blood pressure was normalized (<140/90 mm Hg) in a significantly greater fraction of patients when they were treated by a female (31.0%) than a male (26.6%) physician (Table I). The gender of the physician had no influence on BP control in hypertensive men. Significantly (P<0.001) more hypertensive women however reached the target BP when treated by a female physician (32.2%) rather than by a male physician (23.7%).
International surveys A large survey was performed in 2004 to explore international differences in hypertension treatment. It included 21 053 hypertensive patients followed by 291 cardiologists and 1284 primary care physicians in 5 western European countries (France, Germany, Italy, Spain, United Kingdom) and the United States [37]. The data were collected using identical procedures, allowing valid comparisons between countries. The left panel of Figure 2 depicts the percentage of treated hypertensive patients who had BP <140/90 mm Hg. Large differences were observed across some countries. The best BP control rate was observed in the United States, where the use of combination therapy was highest (64 vs. 44-59% across European countries). Notably, only a small fraction of patients with inadequately controlled BP had their treatment intensified during the visit, indicating that physicians’ inertia may account for the persistence of high BP in many patients on antihypertensive therapy (Figure 2B). Physicians in the United States were clearly more prompt in modifying the treatment (38 vs. 15-28% across European countries). Finally, the results of a survey aiming to investigate in hypertensive patients the cardiome-tabolic profile according to the control of BP have been published very recently [38]. A total of 3370 hypertensive patients were included in this observational, cross-sectional survey which was carried out in 12 European countries (Belgium, Germany, Hungary, Italy, the Netherlands, Norway, Portugal, Slovenia, Spain, Sweden, Turkey and the United Kingdom) by 289 physicians (general practitioners: 61%, internists: 24%, cardio-logists: 14%, hypertension specialists: 1%). Blood pressure was controlled (<140/90 mm Hg) in 28.1% of patients. Metabolic syndrome and type 2 diabetes were seen in 57.8 and 25.6% of the total population, respectively, whereas metabolic syndrome and type 2 diabetes co-existed in 25.6% of the patients. Notably, the prevalence of metabolic syndrome was significantly (P<0.001) greater in patients with uncontrolled hypertension (66.5%) than in those with controlled hypertension (35.5%). This was also true regarding the prevalence of type 2 diabetes (41.1 vs. 9.8%, P<0.001). Most patients received only monotherapy (29.5 and 28.4% of patients with controlled and uncontrolled BP, respectively). The surveys described above provide an overview of the current management of hypertension in European countries with well developed health systems. Several points should be emphasized: • the control of BP in treated hypertensive patients remains unsatisfactory, • it is more difficult to normalize BP in patients with higher than in those with lower cardiovascular risk, • the control of systolic BP is more difficult to achieve than that of diastolic BP, • BP control is achieved with greater difficulty in older than in younger patients, • BP is difficult to control in patients with metabolic syndrome and type 2 diabetes, • combination therapy is required in most patients to normalize BP, • poor compliance with the prescribed drug regimen may contribute to the unsatisfactory BP seen in the community, • clinical inertia is a major cause of unsatisfactory BP control.
Office versus “out-of-office” blood pressure control The BP control rates achieved either conventionally (i.e. using office BP as a criterion) or relying on ambulatory BP monitoring have been compared in 12 897 hypertensive patients, recruited by 1124 physicians from 210 primary healthcare clinics, as part of a nationwide project developed by the Spanish Society of Hypertension [39]. Observations were sent to a central database from June 2004 to July 2005. There was less than 1 month interval between the office BP measu-rements and the 24-h ambulatory BP moni-toring. Office BP was controlled (<140/90 mm Hg) in 23.6% of patients (Table IV). The daytime ambulatory BP control rate (<135/85 mm Hg) was 51.5%. Among patients who had daytime ambulatory BP ł135/85 mm Hg, only 5.4% had their office BP controlled. These findings indicate that the BP control rate in treated hypertensives is substantially better when relying on BP readings taken outside the medical setting rather than on standard office-based measurements. This is important since ambulatory BP is known to reflect more closely cardiovascular risk than BP determined in a medical setting [21-24, 40].
Conclusions
There is strong evidence that tight BP control in hypertensive patients allows maximal protection against cardiovascular and renal diseases [1-3]. The BP control rate observed today in everyday practice is improving, but remains unsatisfactory. In order to normalize BP in most hypertensive patients, it appears necessary to extend the use of drug combinations. This is especially true in older patients and in those at high cardiovascular risk, in whom it is particularly difficult to bring BP under control.

References
1. Staessen JA, Wang JG, Thijs L. Cardiovascular prevention and blood pressure reduction: a quantitative overview updated until 1 March 2003. J Hypertens 2003; 21: 1055-76.
2. Williams B. Recent hypertension trials: implications and controversies. J Am Coll Cardiol 2005; 45: 813-27.
3. Turnbull F, Neal B, Algert C, et al.; Blood Pressure Lowering Treatment Trialists’ Collaboration. Effects of different blood pressure-lowering regimens on major cardiovascular events in individuals with and without diabetes mellitus: results of prospectively designed overviews of randomized trials. Arch Intern Med 2005; 165: 1410-9.
4. Lewington S, Clarke R, Qizilbash N, Peto R, Collins R; Prospective Studies Collaboration. Age-specific relevance of usual blood pressure to vascular mortality: a meta-analysis of individual data for one million adults in 61 prospective studies. Lancet 2002; 360: 1903-13.
5. Hansson L, Zanchetti A, Carruthers SG, et al. Effects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension: principal results of the Hypertension Optimal Treatment (HOT) randomised trial. HOT Study Group. Lancet 1998; 351: 1755-62.
6. 1999 World Health Organization-International Society of Hypertension. Guidelines for the Management of Hypertension. J Hypertens 1999; 17: 151-83.
7. Chobanian AV, Bakris GL, Black HR, et al. Seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Hypertension 2003; 42: 1206-52.
8. Whitworth JA; World Health Organization, International Society of Hypertension Writing Group. 2003 World Health Organization (WHO)/International Society of Hypertension (ISH) statement on management of hypertension. J Hypertens 2003; 21: 1983-92.
9. European Society of Hypertension-European Society of Cardiology Guidelines Committee. 2003 European Society of Hypertension-European Society of Cardiology guidelines for the management of arterial hypertension. J Hypertens 2003; 21: 1011-53.
10. Mancia G, De Backer G, Dominiczak A, et al. 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: 1105-87.
11. Brown MJ, Palmer CR, Castaigne A, et al. Morbidity and mortality in patients randomised to double-blind treatment with a long-acting calcium-channel blocker or diuretic in the International Nifedipine GITS study: Intervention as a Goal in Hypertension Treatment (INSIGHT). Lancet 2000; 356: 366-72.
12. Dahlöf B, Devereux RB, Kjeldsen SE, et al. Cardiovascular morbidity and mortality in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol. Lancet 2002; 359: 995-1003.
13. Wing LM, Reid CM, Ryan P, et al.; Second Australian National Blood Pressure Study Group. A comparison of outcomes with angiotensin-converting-enzyme inhibitors and diuretics for hypertension in the elderly. N Engl J Med 2003; 348: 583-92.
14. Julius S, Kjeldsen SE, Weber M, et al. Outcomes in hypertensive patients at high cardiovascular risk treated with regimens based on valsartan or amlodipine: the VALUE randomised trial. Lancet 2004; 363: 2022-31.
15. Black HR, Elliott WJ, Grandits G, et al.; CONVINCE Research Group. Principal results of the Controlled Onset Verapamil Investigation of Cardiovascular End Points (CONVINCE) trial. JAMA 2003; 289: 2073-82.
16. Dahlöf B, Sever PS, Poulter NR, et al. Prevention of cardiovascular events with an antihypertensive regimen of amlodipine adding perindopril as required versus atenolol adding bendroflumethiazide as required, in the Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm (ASCOT-BPLA): a multicentre randomised controlled trial. Lancet 2005; 366: 895-906.
17. Yusuf S, Teo KK, Pogue J, et al. Telmisartan, ramipril, or both in patients at high risk for vascular events. N Engl J Med 2008; 358: 1547-59.
18. Pepine CJ, Handberg EM, Cooper-DeHoff RM, et al. A calcium antagonist vs a non-calcium antagonist hypertension treatment strategy for patients with coronary artery disease. The International Verapamil-Trandolapril Study (INVEST): a randomized controlled trial. JAMA 2003; 290: 2805-16.
19. The ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. Major outcomes in high-risk hypertensive patients randomized to angiotensin- converting enzyme inhibitor or calcium channel blocker vs. diuretic. JAMA 2002; 288: 2977-81.
20. Mancia G, Messerli F, Bakris G, Zhou Q, Champion A, Pepine CJ. Blood pressure control and improved cardiovascular outcomes in the International Verapamil SR-Trandolapril Study. Hypertension 2007; 50: 299-305.
21. 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: 2407-15.
22. Kikuya M, Ohkubo T, Asayama K, et al. Ambulatory blood pressure and 10-year risk of cardiovascular and noncardiovascular mortality: the Ohasama study. Hypertension 2005; 45: 240-5.
23. Dolan E, Stanton A, Thijs L, et al. Superiority of ambulatory over clinic blood pressure measurement in predicting mortality: the Dublin outcome study. Hypertension 2005; 46: 156-61.
24. Hansen TW, Jeppesen J, Rasmussen S, Ibsen H, Torp-Pedersen C. Ambulatory blood pressure and mortality: a population-based study. Hypertension 2005; 45: 499-504.
25. Ohkubo T, Imai Y, Tsuji I, et al. Home blood pressure measurement has a stronger predictive power for mortality than does screening blood pressure measurement: a population-based observation in Ohasama, Japan. J Hypertens 1998; 16: 971-5.
26. Fagard RH, Van den Enden M, Leeman M, Warling X. Survey on treatment of hypertension and implementation of World Health Organization/International Society of Hypertension risk stratification in primary care in Belgium. J Hypertension 2002; 20: 1297-302.
27. Fagard RH, Van den Enden M. Treatment and blood pressure control in isolated systolic hypertension vs diastolic hypertension in primary care. J Hum Hypertens 2003; 17: 681-7.
28. Van der Niepen P, Giot C, van de Borne P. Prevalence of isolated uncontrolled systolic blood pressure among treated hypertensive patients in primary care in Belgium: results of the I-inSYST survey. J Hypertens 2008; 26: 2057-63.
29. Amar J, Vaur L, Perret M, Bailleau C, Etienne S, Cha- montin B. Hypertension in high-risk patients: beware of the under use of effective combination therapy (results of the PRATIK study). J Hypertension 2002; 20: 779-84.
30. Amar J, Chamontin B, Genes N, Cantet C, Salvador M, Cambou JP. Why is hypertension so frequently uncontrolled in secondary prevention? J Hypertension 2003; 21: 1199-205.
31. Roux O, Chapellier M, Czernichow S, Nisse-Durgeat S, Safar ME, Blacher J. Determinants of hypertension control in a large French population of treated hypertensive subjects. Blood Pressure 2006; 15: 6-13.
32. Steckelings UM, Stoppelhaar M, Sharma AM, et al. HYDRA: possible determinants of unsatisfactory hypertension control in German primary care patients. Blood Press 2004; 13: 80-8.
33. Mancia G, Pessina AC, Trimarco B, Grassi G; SILVIA (Studio Italiano Longitudinale sulla Valutazione della Ipertensione Arteriosa nel 2000) Study Group. Blood pressure control according to new guidelines targets in low- to high-risk hypertensives managed in specialist practice. J Hyper-tens 2004; 22: 2387-96.
34. Mancia G, Ambrosioni E, Rosei EA, Leonetti G, Trimarco B, Volpe M; ForLife study group. Blood pressure control and risk of stroke in untreated and treated hypertensive patients screened from clinical practice: results of the ForLife study. J Hypertension 2005; 23: 1575-81.
35. Banegas JR, Segura J, Ruilope LM, et al.; CLUE Study Group Investigators. Blood pressure control and physician management of hypertension in hospital hypertension units in Spain. Hypertens 2004; 43: 1338-44.
36. Journath G, Hellénius ML, Manhem K, Kjellgren KI, Nilsson PM; Hyper-Q Study Group, Sweden. Association of physician’s sex with risk factor control in treated hypertensive patients from Swedish primary healthcare. J Hypertension 2008; 26: 2050-6.
37. Wang YR, Alexander GC, Stafford RS. Outpatient hypertension treatment, treatment intensification, and control in Western Europe and the United States. Arch Intern Med 2007; 167: 141-7.
38. Kjeldsen SE, Naditch-Brule L, Perlini S, Zidek W, Farsang C. Increased prevalence of metabolic syndrome in uncontrolled hypertension across Europe: the Global Cardiometabolic Risk Profile in Patients with hypertension disease survey. J Hypertens 2008; 26: 2064-70.
39. Banegas JR, Segura J, Sobrino J, et al. Spanish Society of Hypertension Ambulatory Blood Pressure Monitoring Registry Investigators. Effectiveness of blood pressure control outside the medical setting. Hypertension 2007; 49: 62-8.
40. Sega R, Facchetti R, Bombelli M, et al. Prognostic value of ambulatory and home blood pressures compared with office blood pressure in the general population: follow-up results from the Pressioni Arteriose Monitorate e Loro Associazioni (PAMELA) study. Circulation 2005; 111: 1777-83.