Risk: benefit of treating high blood pressure in older adults

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1 British Journal of Clinical Pharmacology DOI: /j x Risk: benefit of treating high blood pressure in older adults Omar Mukhtar 1 & Stephen H. D. Jackson 2 1 Clinical Pharmacology & Therapeutics, King s Health Partners, King s College Hospital, Denmark Hill, London, UK and 2 Clinical Gerontology, King s Health Partners, King s College Hospital, Denmark Hill, London, UK Correspondence Dr Omar Mukhtar MB, ChB, King s Health Partners, King s College Hospital, Denmark Hill, London SE5 9RS, UK. Tel.: Fax: o.mukhtar@nhs.net Keywords elderly, hypertension, older adults, risk : benefit, treatment, trials Received 5 February 2012 Accepted 22 June 2012 Accepted Article Published Online 9 July 2012 Older people (those aged 65 or over) comprise over 15% of the UK s population and this cohort is growing. Whilst at greatest risk from systemic arterial hypertension (hypertension), its resultant end organ damage and clinically significant cardiovascular disease, this group was initially neglected in clinical trials and thereby denied treatment, with the lack of evidence cited as justification. However since the 1960s, when the first landmark trials in severe diastolic hypertension were published, there has been a progressive attempt to understand the pathophysiology of hypertension and to expand the evidence base for treatment in older adults. In contrast to the participants of the very first randomized trials who had a mean age of 51, the recent Hypertension in the Very Elderly Trial demonstrated significant mortality and morbidity benefits from the treatment of both mixed systolic and diastolic hypertension, as well as isolated systolic hypertension in octogenarians. This review highlights the progressive evidence base behind the relative risks and benefits of treating hypertension in older adults. Introduction Older people (those aged 65 or over) comprise over 15% of the UK s population and represent an ever growing cohort. With the prevalence of hypertension increasing with advancing age, the ensuing risk of end organ damage and clinically significant cardiovascular disease is greatest in this group. In recent a number of trials and substudies have focused on the effects of treating hypertension specifically in older adults and this review of landmark studies seeks to analyze the risks and benefits of such an approach (Table 1). The problem of systemic arterial hypertension Hypertension is a highly prevalent disease process thought to affect approximately 1 billion people worldwide [1]. Whilst it may be a consequence of inter-current renal, endocrine or respiratory disease (secondary hypertension), it is largely idiopathic, or essential, in origin (primary hypertension). A major cardiovascular risk factor, if left uncontrolled it can be responsible for end-organ damage, including chronic kidney disease, retinopathy, cerebrovascular disease, cardiac dysfunction and atrial fibrillation. Most strikingly with advancing age, comes a logarithmic increase in systolic blood pressure regardless of gender, race, ethnicity or socio-economic status (Figure 1) [1, 2]. The pathophysiology of hypertension in older adults The evident increase in (systolic) blood pressure observed with ageing is believed to be multi-factorial in origin. Pathophysiological changes in the arterial media are thought to render large and medium sized vessels, particularly the aorta, less distensible [3]. These changes include increased fracturing of elastin, collagen deposition, calcification and increased exposure to circulating and endothelium derived vaso-active mediators e.g. endothelin-1 and norepinephrine [4 6]. In turn, arterial stiffness is increased, causing systolic blood pressure (SBP) augmentation, increased myocardial oxygen demand and reduced organ perfusion [7, 8]. 36 / Br J Clin Pharmacol / 75:1 / The Authors British Journal of Clinical Pharmacology 2012 The British Pharmacological Society

2 Risk: benefit of treating high blood pressure in older adults A Stroke mortality (floating absolute risk and 95% Cl) Systolic blood pressure Age at risk: B Stroke mortality (floating absolute risk and 95% Cl) Diastolic blood pressure Age at risk: Usual systolic blood pressure (mm Hg) Usual diastolic blood pressure (mm Hg) Figure 1 Absolute risk of stroke mortality in relation to blood pressure [38]. Reproduced with permission Advancing age is also associated with a decline in plasma renin and aldosterone activity. Older adults with hypertension, when compared with their younger counterparts, are found to have lower concentrations of plasma renin [9, 10]. This may be related to the age-associated nephrosclerosis observed in the juxtaglomerular apparatus, causing a decline in GFR and potentially explaining the increased risk of hyperkalemia amongst this cohort [10]. However, whether these changes in the renin-angiotensinaldosterone system are mediated directly via dysregulation of the autonomic nervous system remains to be established [9 12]. Furthermore, it is postulated that the hypertension observed amongst older adults may partly be a consequence of altered renal homeostasis. With declining renal mass, particularly affecting the renal cortex, a 20 25% reduction in GFR is observed between the ages of 30 and 85 [13]. Coupled with this, progressive glomerulosclerosis and interstitial fibrosis are seen with advancing age, as well as dysfunction of the membrane sodium/ potassium-adenosine triphosphatase [13, 14]. Thus, hypertension is, in part, fostered via increased intracellular sodium concentrations, reduced sodium calcium exchange and volume expansion in older adults [13, 14]. The consequences of hypertension in older adults Aside from its malignant phase, hypertension is largely an asymptomatic disease, resulting in it being described as a silent killer. It is a risk factor for ischaemic stroke, cerebral haemorrhage, vascular dementia and Alzheimer s disease. Relative to the myocardium it has been implicated in the pathogenesis of coronary artery disease (myocardial infarction and angina pectoris), left ventricular dysfunction (left ventricular hypertrophy and heart failure) and rhythm disorders (atrial fibrillation and sudden death). Within the eye, it is a risk factor for the development of hypertensive retinopathy, retinal artery occlusion, non-arteritic anterior ischaemic optic neuropathy and age-related macular degeneration. Elsewhere in the body, it is associated with aortic and peripheral arterial disease (including aneurysmal disease, large vessel dissection and occlusive disease), as well as chronic kidney disease. Functionally, hypertension amongst older adults may be associated with a decline in quality of life (QoL).There is a large body of evidence supporting the notion that the end-organ damage associated with hypertension, be it cerebrovascular events, cardiac failure or chronic renal impairment, is associated with a reduction in QoL. However, reported declines in QoL observed with mild to moderate hypertension amongst older adults have not consistently been reproduced the relationship is frequently clouded by the effect of advancing age on QoL [15]. Another pathophysiological factor of note in older people is orthostatic hypotension (a decrease in systolic blood pressure of 20 mmhg on standing). This has consistently been associated with negative outcomes both in terms of QoL and mortality. Data from the Honolulu Heart Program demonstrates that orthostatic hypotension is an independent predictor of 4 year all-cause mortality Br J Clin Pharmacol / 75:1 / 37

3 O. Mukhtar & S. H. D. Jackson amongst adults aged between 71 and 93 (relative risk 1.64; 95% CI 1.19, 2.26) [16]. The benefits of treating hypertension in older adults Pre-HYpertension in the Very Elderly Trial (HYVET) In 1963, the Veteran s Administration (VA) commenced the first double-blind, placebo-controlled, multicentre trial to determine the value, if any, of treating non-malignant hypertension. Reporting its results in 1967, from a group of 143 male hypertensive patients with diastolic blood pressures averaging between 115 and 129 mmhg, it had assigned them to either active (hydrochlorothiazide plus reserpine and hydralazine) treatment or placebo. With twenty-seven severe hypertension-related complications and four mortalities arising in the placebo arm, compared with two complications and no deaths in the active group, the authors had demonstrated the benefits of antihypertensive therapy in non-malignant hypertension [17]. However, with a mean age of 51, a new question would emerge was this benefit, seen with the treatment of severe diastolic hypertension, applicable to all age groups with all forms of hypertension? In 1979 the Hypertension Detection and Follow-up Program (HDFP) published its results, having elected to recruit patients between the ages of 30 and 69. Comparing stepped care (antihypertensive therapy in specialist centres, increased stepwise to achieve and maintain reduction of BP to or below set goals) with referred care (treatment via their usual source), the investigators found a 17% reduction in 5 year all-cause mortality between the two arms (6.4 vs. 7.7 per 100; P < 0.01). However, the mean age of the patients was again 50.8 [18]. Sub-group analysis by age (n = 2376) did not demonstrate any significant difference in effect amongst the older cohort (aged ). Stepped care was associated with a 5 year all-cause mortality of 12.7%, compared with 15.2% amongst those receiving referred care [19]. In a specific effort to determine the value of treating hypertension in older adults, the European Working Party on High Blood Pressure in the Elderly (EWPHE) recruited 840 men and women over the age of 60 with both systolic and diastolic hypertension (systolic BP mmhg, diastolic BP mmhg). A double-blind, placebo-controlled trial was commenced with active treatment consisting of 25 mg hydrochlorothiazide and 50 mg triamterene, which could be doubled as required. With an average baseline blood pressure of 183/101 mmhg, a 21/10 mmhg difference in blood pressure was observed between the two trial arms at 5, in favour of active treatment. Active treatment was also associated with reduced cardiovascular mortality (-38%; P = 0.023). This comprised a 38% reduction (P = 0.036) in cardiac mortality and a non-significant decrease in cerebrovascular mortality (-32%; P = 0.16). However this reduction in cardiac mortality was associated with increased rates of non-fatal MI amongst those receiving active treatment. This contrasted with the data in terms of cerebrovascular disease. Whilst a non-significant decrease in cerebrovascular mortality was observed, non-terminal cerebrovascular events were significantly reduced (-52%; P = 0.026). Nonetheless, with an age range of 72 8, the trialists had demonstrated that treatment of severe systolic and diastolic hypertension amongst older adults had significant cardiac mortality benefit [20]. In 1984 the Systolic Hypertension in the Elderly Program (SHEP) was commenced in the United States. Rather than extending the age boundary, this trial sought to evaluate whether treating older patients ( 60, mean age 71.6 ) with grade 2 isolated systolic hypertension (systolic blood pressure >160 mmhg; diastolic blood pressure <90 mmhg) would be beneficial, harmful or make no difference. Again a randomized, double-blind, placebo-controlled trial, the study cohort consisted of almost 5000 subjects, who were commenced on either a placebo or active therapy (initially utilizing the diuretic chlorthalidone, with atenolol 25 mg or reserpine 0.05 mg available as adjuncts). With a mean blood pressure of 170/ 76 mmhg in both trial arms at baseline, the 5 year average blood pressure was 143/68 mmhg amongst those who were actively treated. A decline in blood pressure was also observed amongst the placebo group, largely due to a drop in effect, whereby patients assigned to placebo were started on open label active therapy by their personal physicians.amongst this cohort the 5 year average blood pressure was 155/72 mmhg [21]. With regard to the primary endpoint of stroke (nonfatal or fatal), a 36% reduction was observed amongst those assigned active therapy (P = ), the absolute benefit of treatment estimated at 5 being 30 events per 1000 participants. In addition to this, active therapy was associated with a reduction in risk for coronary heart disease (RR 0.75; 95% CI 0.60, 0.94), congestive heart failure (RR 0.36; 95% CI 0.60, 0.94) and cardiovascular disease (RR 0.68; 95% CI 0.58, 0.79); a non-statistically significant trend in favour of reduced all cause mortality was also observed. However, these benefits were associated with significant adverse effects, as described later [21]. A year after the results from SHEP were published, the Medical Research Council (MRC) published data from its placebo-controlled, single-blind trial of hypertension treatment in older adults. Having recruited 4396 UK-based subjects, aged between 65 and 74, the MRC working party randomized them to one of four trial arms; (i) a potassium sparing diuretic regimen (hydrocholorothiazide 25 mg or 50 mg plus amiloride 2.5 mg or 5 mg daily), (ii) matching placebo tablets, c) the b-adrenoreceptor antagonist, atenolol, 50 mg daily or d) a matched placebo. Inclusion and exclusion criteria meant that subjects had mean 38 / 75:1 / Br J Clin Pharmacol

4 Risk: benefit of treating high blood pressure in older adults systolic pressures of mmhg and mean diastolic pressures of <115 mmhg during an 8 week run in, whilst not taking anti-hypertensive treatment [22]. The primary endpoints were defined as all cause mortality, mortality and morbidity due to stroke and mortality and morbidity due to coronary heart disease. The secondary aims were to compare the effects of the two active drugs and to determine whether the response to treatment differed on the basis of gender.when compared with the placebo group, those receiving active therapy (in a combined analysis) exhibited a 25% (95% CI 0.03, 0.42; P = 0.04) reduction in stroke, a 19% (95% CI -0.02, 0.36; P = 0.08) reduction in coronary events and a 3% (95% CI -0.14, 0.18; P = not available) reduction in all cause mortality. Following adjustment for baseline characteristics, the diuretic group had significantly reduced risks of stroke (RR 0.31; 95% CI 0.03, 0.51; P = 0.04), coronary events (RR 0.44; 95% CI 0.21, 0.60; P = ) and all cardiovascular events (RR 0.35; 95% CI 0.17, 0.49; P = ). However, those receiving the b-adrenoceptor antagonist, atenolol, showed no reduction in these endpoints [22]. Meanwhile in Europe a similar trial to SHEP, the Systolic Hypertension in Europe (Syst-Eur) trial, was established. This enrolled nearly 5000 older men and women ( 60, mean age: 70.2 ) again with grade 2 isolated systolic hypertension (average sitting systolic blood pressure mmhg, diastolic blood pressure <95 mmhg). A double-blind, placebo-controlled trial, Syst- Eur utilized a long acting dihydropyridine calcium antagonist, nitrendipine, as initial therapy (with enalapril and hydrochlorthiazide available as additional agents, if required). At cessation of follow up, the difference in systolic and diastolic blood pressures between the placebo group and those actively treated was 10.7 mmhg (95% CI 8.8, 12.5) and 4 7 mmhg (95% CI 3 7, 5 6) respectively. As with SHEP, the combined primary endpoint for Syst-Eur was fatal and non-fatal stroke. This occurred in 77 patients on placebo and 47 on active therapy (RR 0.42; 95% CI 0.60, 0.17; P < 0.003) and based on this interim analysis, the study was terminated prematurely. In addition to the significant reduction in stroke risk, a favourable reduction in all cause cardiac endpoints (fatal and non-fatal heart failure, fatal and non-fatal myocardial infarction, and sudden death) was observed (P = 0.03) [23]. In contrast to the adverse effect data from SHEP, which demonstrated increased self-reporting of impaired memory/concentration, the Syst-Eur trialists ran a substudy which reported that antihypertensive treatment for older adults experiencing isolated systolic hypertension, was associated with a lower incidence of dementia [24]. This sub-study demonstrated a 50% reduction in dementia rates from 7.7/1000 patient to 3.7/1000 patient, when using an intention to treat analysis [24]. Although the relative risk reduction was 50%, the absolute risk was low with only 19 cases of dementia prevented per 5000 patient of active treatment,a fact which has led many critics to argue that the data should be interpreted with caution [24, 25]. Moreover, whilst the authors attributed the observed effect to the use of dihydropyridine calcium antagonists, whether this is truly a drug/class specific effect is unclear [26, 27]. HYVET Given the lack of data for the treatment of hypertension amongst octogenarians, the HYpertension in the Very Elderly Trial (HYVET) was commissioned in An initial open label pilot recruited 1283 patients over the age of 80 from 10 different European countries. Subjects with a sustained blood pressure of / mmhg (based on an average of four readings) were allocated to one of three treatment arms, a diuretic based regimen, an angiotensin converting enzyme inhibitor based regimen or no active treatment. Active treatment was associated with a reduction in cerebrovascular events with a relative hazard rate (RHR) of 0.47 (95% CI 0.24, 0.93). However, there was a non-significant rise in all cause (RHR 1.23; 95% CI 0.75, 2.01) and stroke related mortality (RHR 0.57; 95% CI 0.25, 1.32), such that for each stroke prevented, there was the potential for one excess death [28]. In contrast, the HYVET study was a double-blind placebo-controlled trial performed in 195 centres in 13 countries. All patients had a sustained systolic blood pressure of mmhg, off treatment, during a 2 month run in period. Whilst the initial protocol also required a mean seated diastolic blood pressure of 90 to 109 mmhg, a protocol amendment 3 into the trial, relaxed this to <110 mmhg, thus allowing for the inclusion of those with isolated systolic hypertension. Subjects were either assigned to the non-thiazide, sulphonamide diuretic, indapamide (sustained release, 1.5 mg) or a placebo. If required, investigators were able to add perindopril (2 mg or 4 mg) or a matching placebo to reach the target systolic blood pressure of <150 mmhg and the target diastolic blood pressure of <80 mmhg [29]. After the second interim analysis, the trial was stopped early. Active treatment decreased BP when compared with placebo (-15 mmhg/-6 mmhg) and this was associated with a non-significant reduction in the primary outcome measure, stroke (unadjusted hazard ratio 0.70; 95% CI 0.49, 1.01; P = 0.06). Cardiovascular morbidity and mortality were also non-significantly reduced (unadjusted hazard ratio 0.77; 95% CI 0.60, 1.01; P = 0.06), whilst a statistically significant reduction in congestive cardiac failure was observed (unadjusted hazard ratio 0.36; 95% CI 0.22, 0.58; P < 0.001). However, integral to the decision to stop early was an unexpected significant reduction in the incidence of all-cause mortality (unadjusted hazard ratio 0.79; 95% CI 0.65, 0.95; P = 0.02), with active treatment being well tolerated (see Adverse effects) [29]. These results provide definitive evidence that antihypertensive therapy in those with sustained hypertension, over the age of 80 (mean participant age Br J Clin Pharmacol / 75:1 / 39

5 O. Mukhtar & S. H. D. Jackson 83 ), is associated with benefit, prolonging life as opposed to increasing mortality. Whilst the reduction in fatal strokes in HYVET was greater than that observed in previous studies performed using younger subjects, the relative risk reduction in total mortality was consistent with the 95% CIs observed in other studies of hypertension in older adults, namely the Swedish Trial in Older Patients with Hypertension, the Systolic Hypertension in the Elderly Program and the Systolic Hypertension in Europe trial [21, 23, 30]. Nonetheless, the limitations of such a trial should not be overlooked. HYVET was reliant on patients from Eastern Europe and China, with potentially different pathophysiological mechanisms responsible for the mediation of hypertension in these populations as opposed to those from Western Europe [31]. It also focused on subjects in relatively good physical and mental condition, in common with many other clinical trials in older people, in an effort to limit drop-outs, rendering the trial population less representative of the real life setting [32]. Furthermore, the majority of patients included in the trial had systolic/ diastolic hypertension (67.5%) as opposed to isolated systolic hypertension (32.5%), suggesting that the benefits observed may be a function of a particular sub-type of hypertension [29]. In addition to this, the early evidence of mortality benefit resulted in a relatively short duration of follow up (median 1.8 ) [29]. Thus, it remains unclear whether such benefits persist or diminish over a longer time course. Post HYVET In 2010, a secondary analysis of the 2003 INternational VErapamil SR-Trandolapril STudy (INVEST) was published, focusing on the relationship between blood pressure and adverse outcomes in older adults. The clinically stable patients with both hypertension and coronary artery disease were stratified by age in 10 year increments ( 80, 70 80, 60 70, <60 ). Patients were then randomized to either a calcium antagonist (verapamil SR) or non-calcium antagonist (atenolol) based treatment strategy (with the option for additional trandolapril, with or without hydrochlorothiazide, when necessary to achieve blood pressure goals). BP targets were defined as having been achieved when a mean of two sitting clinic blood pressures were <140/90 mmhg (or <135/85 mmhg when diabetes mellitus or renal impairment were present) [33]. At baseline, increasing age was associated with higher systolic blood pressure, lower diastolic blood pressure and wider pulse pressure (P < 0.001). As expected, treatment was associated with a reduction in all three of these measures and those over the age of 80 experienced primary outcome measures most frequently (first occurrence of all-cause death, non-fatal myocardial infarction or non-fatal stroke). The adjusted hazard ratio for these outcomes demonstrated a J-shaped relationship with both systolic and diastolic blood pressures amongst all age Hazard ratio (adjusted) Diastolic Figure 2 groups (Figure 2), regardless of treatment strategy. With advancing age the hazard ratio nadir increased from a systolic blood pressure of 110 mmhg for patients under 60 of age, to 140 mmhg for the very old.however, the hazard ratio nadir relative to diastolic pressures was only marginally lower for those 80 (70 mmhg) when compared with their younger counterparts (75 mmhg) data which might yet inform a future debate about target blood pressure for older adults [33]. Adverse effects Systolic Blood pressure (mmhg) BP Nadirs SBP DBP Risk of adverse outcomes by age and blood pressure [33]. Reproduced with permission. <60 ( ); 60 <70 ( ); 70 <80 ( ); 80 ( ) Whilst landmark trials have progressively demonstrated the benefits of antihypertensive therapy amongst older adults, adverse effect data have not consistently or comprehensively been reported. The Veterans Administration Cooperative Study simply noted that 28 out of the 73 patients receiving active treatment required dose reductions because of low blood pressure levels... or because of side effects such as severe headache or weakness. This contrasted with 66 patients out of 70 who completed placebo based therapy [17]. However, the SHEP trialists provided a more detailed breakdown of troublesome or intolerable effects by treatment group. Active therapy (initially utilizing the diuretic chlorthalidone, with atenolol 25 mg or reserpine 0.05 mg available as adjuncts) was associated with intolerable adverse effects in 28.1% of patients whilst placebo was associated with an adverse effect rate of 20.8% (z-score 5.9). Falls were more frequently observed amongst those undergoing active treatment 40 / 75:1 / Br J Clin Pharmacol

6 Risk: benefit of treating high blood pressure in older adults Table 1 Landmark trials of anti-hypertensive therapy in older adults Trial publication year Number of subjects mean age () range () SBP/DBP (mmhg) per inclusion criteria Intervention Headline result Veteran s Association; 1967 [17] 143 males Mean age: 51 Range: Hypertension Detection and Follow-up Program (HDFP); 1979 [18] European Working Party on Hypertension in the Elderly (EWPHE); 1985 [20] Systolic Hypertension in the Elderly Program (SHEP); 1991 [21] Medical Research Council (MRC) trial of treatment of hypertension in older adults; 1992 [22] Systolic Hypertension in Europe (Syst-Eur); 1997 [23] HYpertension in the Very Elderly Trial (HYVET); 2008[28] males and females Mean age: 50.8 Range: males and females Mean age: 72 Range: males and females Mean age: 71.6 Range: males and females Mean age: 70.3 Range: males and females Mean age: 70.2 Range: males and females Mean age: 83.6 Range: NA/ Hydrochlorothiazide plus reserpine and hydralazine vs. placebo NA/>90 Stepped care (treatment in specialist centres, increased stepwise to achieve and maintain BP to or below set goals) vs. referred care (treatment via usual source) / mg hydrochlorothiazide and 50 mg triamterene (doubled as required) vs. placebo >160 / < mg chlorthalidone with atenolol 25 mg or reserpine 0.05 mg vs. placebo / <115 Hydrocholorothiazide plus amiloride vs. atenolol vs. placebo / <95 Nitrendipine enalapril hydrochlorthiazide vs. placebo Twenty-seven severe hypertension-related complications and four mortalities arising in the placebo arm vs. two complications and no deaths in the active group 17% reduction in 5 year all-cause mortality between the two arms in favour of stepped care (6.4 vs. 7.7 per 100; P < 0.01). Significant reduction (-38%; P = 0.036) in cardiac mortality and a non-significant decrease in cerebrovascular mortality (-32%; P = 0.16) associated with active therapy. 36% P = ) reduction in stroke (nonfatal or fatal) amongst those assigned active therapy. Diuretic use was associated with a significant reduction in stroke risk (RR 0.31; 95% CI 0.03, 0.51; P = 0.04), coronary events (RR 0.44; 95% CI 0.21, 0.60; P = ) and all cardiovascular events (RR 0.35; 95% CI 0.17, 0.49; P = ) when compared with placebo. However, atenolol showed no significant reduction in these endpoints when compared with placebo. 42% (P = 0.003) reduction in stroke (non-fatal or fatal) amongst those assigned active therapy / <110 Indapamide perindopril vs. placebo Significant reduction in all-cause mortality associated with active therapy (unadjusted hazard ratio 0.79; 95% CI 0.65, 0.95; P = 0.02). Br J Clin Pharmacol / 75:1 / 41

7 O. Mukhtar & S. H. D. Jackson Table 2 Selected adverse effect data from the SHEP trial [21] Symptom Prevalence active treatment (%) Prevalence placebo (%) z value Faintness on standing Feelings of unsteadiness or imbalance Loss of consciousness/passing out Heart beating fast or skipping beats Heart beating unusually slowly Chest pain or heaviness Unusual tiredness Cold or numb hands Ankle swelling Trouble with memory/concentration Depression interfering with activities Problems in sleeping Problems in sexual function Falls Muscle weakness or cramping Excessive thirst Unusual joint pain Severe headaches Waking frequently at night to urinate (12.8% vs. 10.4%; z-score 4.9), as were cold/numb hands (13.6% vs. 9.8%; z-score 4.1) and problems with sexual function (4.8% vs. 3.2%; z-score 2.9), amongst others (Table 2). Of the 29 adverse effects recorded, only two occurred with increased frequency amongst those receiving placebo, namely severe headaches (z-score -1.1) and heart beating fast or skipping beats (z-score -1.4) [21]. As in the EWPHE trial, serum potassium concentrations were lower in the active treatment group than amongst those receiving placebo (serum potassium <3.2 mmol l -1 ; 3.9% vs. 0.8%; active vs. placebo; z-score 6.7); serum uric acid ( mmol l -1 ; 5.3% vs. 1.3%; active vs. placebo; z-score 7.5) and glucose ( 11.1 mmol l -1 ; 9.3% vs. 7.6%; active vs. placebo; z-score 2.0) concentrations were higher in the active treatment group [21, 34]. Moreover, in the EWHPE trial, greater numbers of treated patients stopped medication because of adverse effects compared with those receiving placebo (14 vs. 7), a finding replicated in the MRC study where 160 withdrawals occurred over 5 amongst those receiving diuretic therapy as a result of adverse effects, compared with 333 such withdrawals amongst those receiving atenolol and only 82 adverse effect related withdrawals associated with placebo therapy [22, 35]. This excess of adverse effects reported with antihypertensive therapy in the VA, SHEP, MRC and EWHPE trials contrasts with data from the HYVET working group [17, 21, 22, 34, 35]. In this instance it was found that the number of serious adverse events was 448 in the placebo group and 358 in the active treatment group (P = 0.001). Details relating to these adverse events were not published.[29] For patients who completed at least 2 of follow-up in the HYVET study, data relating to serum potassium, glucose, urea and creatinine were offered and indicated no significant difference between active and placebo treatment (P > 0.05) [29]. These differences in adverse affect data may, in part, be attributable to differing trial designs, therapeutic regimens, patient characteristics and data reporting mechanisms. Nonetheless, concern relating to greater adverse effects may lead to cautious prescribing for older adults experiencing hypertension [36]. In fact, the perceived adverse effects of antihypertensives were responsible for 10% of all non-adherence by patients in one study of older adults [37]. Such reticence on the part of both patient and prescriber is unsurprising given the data from the Honolulu Heart Program, as described earlier as excessive reductions in blood pressure resulting in orthostatic hypotension (a decrease in systolic blood pressure of 20 mmhg on standing) have consistently been associated with negative outcomes both in terms of QoL and mortality [16]. Conclusion The evidence for treating hypertension amongst older adults clearly suggests that the benefits outweigh the risks. However, our appreciation of the adverse effects associated with use of anti-hypertensive therapy in older 42 / 75:1 / Br J Clin Pharmacol

8 Risk: benefit of treating high blood pressure in older adults adults remains limited. Furthermore, when embarking on pharmacological treatment physicians should note that co-morbidities, especially those requiring drug treatment, may represent compelling indications or contraindications to particular antihypertensive agents. Given that the number of older adults continues to grow, further research should be undertaken in order to define appropriate treatment thresholds and targets, to compare the effectiveness of different therapeutic regimens in achieving such targets and to determine the relative efficacy of those regimens in preventing mortality and morbidity. Competing Interests There are no competing interests to declare. REFERENCES 1 Lawes CM, Vander Hoorn S, Law MR, Elliott P, MacMahon S, Rodgers A. Blood pressure and the global burden of disease Part 1: estimates of blood pressure levels. 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