The problem of uncontrolled hypertension

(2002) 16, S3 S8 2002 Nature Publishing Group All rights reserved 0950-9240/02 $25.00 www.nature.com/jhh The problem of uncontrolled hypertension Department of Public Health and Clinical Medicine, Norrlands University Hospital, Umeå, Sweden It is well established that there is a continuous relationship between raised blood pressure and the risk of cardiovascular or cerebrovascular disease. Both systolic and diastolic hypertension are associated with increased risk, but systolic blood pressure appears to be a more important determinant of risk than diastolic blood pressure. Randomised controlled trials have clearly shown that lowering blood pressure results in significant reductions in cardiovascular mortality and morbidity, and hence current hypertension management guidelines recommend target blood pressures of below 140/90 mm Hg (135/85 mm Hg in the case of the WHO/ISH guidelines). Despite the clear evidence for the benefits of antihypertensive therapy, however, blood pressure is often not adequately controlled in clinical practice. Population surveys indicate that the pro- portion of patients achieving even conservative blood pressure targets may be only 20% or lower. A number of factors contribute to poor control of hypertension, including a focus by the physician on diastolic blood pressure, rather than the prognostically more important systolic pressure, and poor adherence to therapy by patients. Poor adherence may be largely attributable to adverse events, and there is evidence that the excellent tolerability profile of angiotensin II type 1 (AT 1 )-receptor blockers may help to increase the proportion of patients remaining on therapy. AT 1 -receptor blockers could thus make a potentially important contribution to solving the problem of uncontrolled hypertension. (2002) 16, S3 S8. doi:10.1038/sj.jhh.1001433 Keywords: AT 1 -receptor blockers; antihypertensive therapy; blood pressure; cardiovascular disease; risk factors Introduction: blood pressure and cardiovascular risk There is extensive epidemiological and clinical trial evidence that a continuous and linear relationship exists between blood pressure and risk of cardiovascular or cerebrovascular disease (Figure 1). 1,2 This relationship holds even in individuals with socalled normal blood pressure; within the normotensive range, those individuals with the lowest blood pressure show the lowest risk of cardiovascular events (Figure 1). 1,3 Both systolic hypertension and diastolic hypertension confer an increased risk of cardiovascular events. 4 Diastolic blood pressure has traditionally been regarded as the principal determinant of cardiovascular risk, but increasing evidence shows that systolic blood pressure is actually the more potent risk factor. A recent meta-analysis, which included over 15 000 patients with isolated systolic hypertension, found that, after correction for regression dilution bias, a 10 mm Hg increase in systolic blood pressure was associated with increases of nearly 10% in the risk of all fatal and non-fatal complications, except for coronary events. 5 Similarly, in a community-based case-control study performed in the UK, the adjusted odds ratio for stroke, compared Correspondence:, Department of Public Health and Clinical Medicine, Norrlands University Hospital, 901 85 Umeå, Sweden. E-mail: larsh.lindholm fammed.umu.se with non-hypertensive individuals, was 1.3 in patients who achieved a systolic blood pressure of below 140 mm Hg after antihypertensive therapy, but increased to 1.6 in those with a mean treated systolic blood pressure of 144.3 mm Hg and 3.2 in those with treated systolic blood pressures above 160 mm Hg. 6 The odds ratio in the latter patients was similar to that in untreated hypertensive patients, a finding which underlines the importance of effective blood pressure control in reducing the risk of cardiovascular or cerebrovascular disease. Benefits of antihypertensive treatment The benefits of antihypertensive therapy, in terms of reducing cardiovascular mortality and morbidity, are clearly established. The pooled data from 17 randomised trials of antihypertensive therapy show that antihypertensive treatment reduces the risk of stroke by approximately 38%, that of coronary heart disease (CHD) by 16%, and that of vascular death by 21%. 7 Furthermore, these benefits were achieved with relatively modest reductions in blood pressure, of approximately 5 6 mm Hg for diastolic blood pressure, and 10 12 mm Hg for systolic blood pressure. 7 In absolute terms, a 10/5 mm Hg reduction in blood pressure could potentially prevent 5 7 events per 1000 patient-years in medium-risk patients, and more than 10 events per 1000 patient-years in patients at highest risk; even larger benefits could be achieved with a greater reduction in blood pressure (Table 1). 3

S4 Figure 1 Relationship between diastolic blood pressure (DBP) and risk of coronary heart disease (CHD, left) and stroke (right). 1 Reprinted with permission from Elsevier Science (Lancet 1990; 335: 765 774). Table 1 Potential benefits of antihypertensive therapy, in terms of cardiovascular events prevented 3 Events prevented per 1000 patient-years 10/5 mm Hg 20/10 mm Hg Low-risk patients 5 9 Medium-risk patients 5 7 8 11 High-risk patients 7 10 11 17 Very high-risk patients 10 17 There is evidence that, in patients receiving antihypertensive treatment, cardiovascular risk is determined more strongly by the blood pressure achieved during treatment than by the initial blood pressure. 6,8 Thus, in the case-control study described above, 6 the risk of stroke was more than halved in patients in whom antihypertensive treatment resulted in a systolic blood pressure of less than 140 mm Hg, compared with those in whom systolic blood pressure remained above 160 mm Hg; by contrast, there was no significant association between baseline blood pressure and the risk of stroke in treated patients. Similarly, in a study of 3783 patients attending the Glasgow Blood Pressure Clinic, the lowest mortality rates in patients of all ages were seen in those in whom the greatest reductions in blood pressure were achieved (Figure 2). 8 While the benefits of antihypertensive therapy are undisputed, there is as yet no evidence that these benefits are related to any specific drug action; it appears to be the lowering of blood pressure itself that is beneficial. 3 Recent evidence for this comes from the Second Swedish Trial in Old Patients with Hypertension (STOP-Hypertension-2). 9 In this study, 6614 elderly hypertensive patients (mean age 76 years) were treated for a median of 5.3 years with one of three regimens: -blockers, diuretics, or both; calcium antagonists, with -blockers being given if necessary; angiotensin converting enzyme (ACE) inhibitors, with diuretics being given if necessary. There was no significant difference in the incidence of fatal cardiovascular events between the three groups (Figure 3). There was, however, a significantly lower incidence of fatal and non-fatal myocardial infarction in patients receiving ACE inhibitors, compared with those receiving calcium antagonists, and the incidence of congestive heart failure was also lower in the ACE inhibitor group; the outcome for heart failure was, however, not independent of that for myocardial infarction. A comparison of the mortality data in STOP- Hypertension-2 with those of the original STOP Study, 10 in which the same diuretic and -blocker regimens were compared with placebo, showed that all three regimens significantly reduced cardiovascular mortality, compared with that in the placebo group in the original STOP Study. Furthermore, a subgroup analysis in the 719 diabetic patients included in the STOP-Hypertension 2 study showed that there were no significant differences in cardiovascular mortality between the three regimens in this high-risk group of patients. The STOP-Hypertension-2 Study also provided valuable information on the incidence of cancer during antihypertensive therapy, since the availability of a comprehensive cancer registry in Sweden made it possible to compare the incidence of new cancers during the study with that expected in the general Swedish population. 11 This is an important issue in view of the controversial reports of an association between calcium antagonists and cancer. 12,13 Reassuringly, the STOP-Hypertension-2 data provided no evidence of any such association. A total of 607 patients (9%) had a history of cancer at baseline, and a further 625 cases were diagnosed during the course of the study. The number of new cases

S5 Figure 2 Relationship between mortality and achieved blood pressure in 3783 patients attending the Glasgow Blood Pressure Clinic. 8 Reproduced with permission from Isles CG et al. Mortality in patients of the Glasgow Blood Pressure Clinic. J Hypertens 1986; 4: 141 156. Figure 3 Incidence of fatal cardiovascular events in the Second Swedish Trial in Old Patients with Hypertension (STOP-Hypertension- 2). 9 Reprinted with permission from Elsevier Science (Lancet 1999; 354: 1751 1756). observed did not differ significantly from the expected number, and there was no significant difference in the incidence of new cancers between the groups. Moreover, there were no differences between the groups in the cumulative incidence of cancer or the sites of new cancers. Further evidence that the benefits of antihypertensive therapy are attributable to blood pressure lowering alone, rather than to specific drug actions, comes from a substudy of the United Kingdom Prospective Diabetes Study (UKPDS), in which 1148 hypertensive patients with type 2 diabetes were randomised to receive tight blood pressure control aimed at achieving a target blood pressure of below 150/85 mm Hg or less tight control aimed at achieving a blood pressure below 180/105 mm Hg. 14 Patients randomised to tight blood pressure control received either an ACE inhibitor or a -blocker as principal therapy, with other agents being added in a step-wise fashion as required; ACE inhibitors or blockers were not used in patients randomised to less tight control. After a median follow-up of 8.4 years, mean blood pressure was significantly lower in patients assigned to tight control than in those assigned to less tight control (mean 144/82 mm Hg vs 154/87 mm Hg, respectively, P 0.0001). This lower blood pressure was associated with a 32% reduction in diabetes-related deaths (P = 0.019), a 24% reduction in all diabetes-related end points (P = 0.0046), a 44% reduction in stroke (P = 0.013), and a 37% reduction in microvascular diabetic complications, predominantly retinal photocoagulation

S6 Blood pressure control in clinical practice (P = 0.0092). There was, however, no significant difference in diabetes-related mortality between patients in the tight control group receiving ACE inhibitor-based therapy and those receiving a blocker. How often are blood pressure targets achieved? Population studies suggest that blood pressure is often inadequately controlled in clinical practice. Indeed, the available evidence suggests that, despite the availability of effective treatment, blood pressure control can still be described by the traditional rule of halves. 3 According to this rule, only about half of all hypertensive patients are diagnosed, only half of these receive treatment, and in only half of these is blood pressure adequately controlled; thus, only about 12.5% of patients are adequately treated. In a survey of hypertension management in 10 countries worldwide, the proportion of patients in whom blood targets of below 140/90 mm Hg were achieved ranged from 27% in the US to only 6% in England, and the proportion achieving more conservative targets of below 160/90 mm Hg ranged from 2.5 22.5%. 15 Similarly, recent data from England indicate that only 32% of adults diagnosed as hypertensive (defined as systolic blood pressure 140 mm Hg or diastolic blood pressure 90 mm Hg) received treatment, and blood pressure was considered controlled in only 9%. 16 Moreover, there is evidence that blood pressure, particularly systolic blood pressure, is often not adequately controlled even in specialist hypertension clinics. In a study in six Veterans Administration hypertension clinics, diastolic blood pressures below 90 mm Hg were achieved in approximately 70% of patients, and relatively few had blood pressures of 95 mm Hg or above; by contrast, systolic pressures below 140 mm Hg were achieved only in approximately 45%, and about 20% had systolic pressures of 160 mm Hg or above (Figure 4). 17 Similarly, data from the CardioMonitor database, which includes over 17 000 patients from seven countries (Canada, France, Germany, Italy, Spain, the UK and the USA), indicate that more than 90% of patients with uncontrolled hypertension have uncontrolled systolic blood pressure, whereas only approximately 50% have uncontrolled diastolic blood pressure. 18 Most national and international hypertension management guidelines have set blood pressure targets of approximately 140/90 mm Hg, 19 although the current WHO/ISH guidelines recommend a more stringent target of 130/85 mm Hg. 3 Evidence that such targets are feasible comes from the Hypertension Optimal Treatment (HOT) Study, in which approximately 18 000 hypertensive patients were randomised to target diastolic blood pressures of 90 mm Hg, 85 mm Hg or 80 mm Hg. 20 All patients received felodipine as basic therapy and ACE inhibitors, -blockers, and hydrochlorothiazide were added as needed according to a five-step titration protocol in order to achieve the target blood pressures. Overall, 92% of patients achieved diastolic blood pressures of below 90 mm Hg. However, systolic blood pressure was less consistently controlled; while 94% of patients achieved systolic blood pressures of 160 mm Hg or below, only 46% achieved the widely advocated target of 140 mm Hg or below. Such findings suggest that, although the diastolic blood pressure targets set out in management guidelines may be feasible, in practice systolic blood pressure targets are often difficult to achieve. However, it should be noted that in this study the blood pressure targets were based solely on diastolic blood pressure, and hence management decisions also focused on diastolic blood pressure. Reasons for inadequate blood pressure control The reasons for inadequate blood pressure control are complex and arise from a combination of factors related to the way that physicians treat hypertension, poor patient adherence to therapy, and the properties of the antihypertensive drugs themselves. These factors have been investigated in the EISBERG (Evaluation and Interventions for Systolic Blood pressure Elevation Regional and Global) project, which comprises three elements: 18 a formal collection of epidemiological data to examine the relationship between systolic blood pressure and outcome; the CardioMonitor database, providing quantitative data on the management of hypertension and other cardiovascular disorders in seven countries; qualitative research to investigate attitudes to and knowledge of hypertension treatment among primary care physicians. Physician-related factors It is clear that hypertension is not managed aggressively enough and that physicians are often conservative in their approach, not making alterations to therapy even if blood pressure remains elevated. The problem of under-treatment may be exacerbated by the number and complexity of management guidelines, so that many doctors may be unfamiliar with recommended treatment strategies. The EISBERG project found that diastolic blood pressure remains the focus of antihypertensive treatment for many physicians, despite the proven prognostic significance of systolic blood pressure; mean diastolic blood pressure decreased progressively between 1992 and 1997, whereas mean systolic blood pressure was almost unchanged. Moreover, many physicians, particularly those who qualified more than 11 years prior to the survey, were sceptical about the value of treating raised systolic blood pressure. Reasons for focusing on diastolic blood pressure included the belief that

S7 Figure 4 Diastolic (a) and systolic (b) blood pressures achieved in patients treated at six Veterans Administration hypertension clinics. 17 Reproduced with permission from Perry HM Jr et al. Antihypertensive efficacy of treatment regimens used in Veterans Administration hypertension clinics. Department of Veterans Affairs Cooperative Study Group on Antihypertensive Agents. Hypertension 1998; 31: 771 779. systolic blood pressure is too variable to be a reliable indicator of cardiovascular risk, or a mistaken belief that systolic blood pressure is harder to control when diastolic blood pressure is normal. 18 The most common reasons for changing therapy were poor efficacy or adverse events. 18 Patient age was found to be the major factor influencing treatment decisions; in general, patients over 65 years of age were likely to be treated later and less aggressively than younger patients. Most physicians initiated treatment at a blood pressure threshold of 160/95 mm Hg in younger patients, whereas in older patients the majority used a threshold of 170/100 mm Hg. This is not consistent with current guidelines, which recommend lower thresholds for intervention in older patients than in younger patients. 18 Patient adherence to therapy It is widely recognised that patients adherence to antihypertensive therapy is often poor, 21 and this is frequently cited by physicians as a leading cause of treatment failure. For example, CardioMonitor data included in the EISBERG project show that approximately 70% of primary care physicians believed that poor adherence to therapy was responsible for failure to achieve blood pressure targets. By contrast, there is evidence that patients tend to over-estimate their adherence to therapy, and consider poor efficacy or adverse effects to be the major causes of treatment failure. In one survey, for example, approximately 80 90% of patients considered their adherence to therapy to be good or complete, whereas only 20 30% of physicians considered their patients adherence to be good. 22 Drug-related factors Several studies have shown that persistence with therapy varies between different classes of antihyper- tensive drugs. 23,24 A recent study, for example, examined persistence with medication at 6-month intervals after initiation of therapy in almost 25 000 patients included in a Canadian database. 24 Patients were regarded as persistent if the original prescription was refilled within 21 days of the target month. After 6 months, persistence with therapy was significantly higher among patients receiving angiotensin II type 1 (AT 1 )-receptor blockers than in those receiving other antihypertensive agents (69% vs 32 55%, P 0.001), and this difference was maintained throughout the study; by 24 months, 75% of patients treated with AT 1 -receptor blockers were still receiving treatment, compared with only 21 42% of patients receiving other antihypertensive therapy (Figure 5). One factor that may contribute to the greater persistence seen with AT 1 -receptor blockers, compared with other antihypertensive therapies, is the excellent tolerability of these agents. Clinical trials with AT 1 -receptor blockers have consistently shown adverse event profiles comparable with those in placebo-treated patients. 25 Conclusions Despite the clear benefits of antihypertensive therapy in reducing cardiovascular morbidity and mortality, hypertension remains poorly controlled in clinical practice and few patients achieve even conservative blood pressure targets. While there may be many reasons for this situation, it seems likely that poor adherence to therapy plays a central role. It is therefore important to find the right drug (or combination of drugs), in terms of tolerability, convenience and efficacy, for each individual patient. AT 1 -receptor blockers such as candesartan cilexetil, with their placebo-like tolerability, may offer significant advantages in many patients. These agents can thus potentially make an important contribution to addressing the problem of uncontrolled hypertension.

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