Large therapeutic studies in elderly patients with hypertension

(2002) 16 (Suppl 1), S38 S43 2002 Nature Publishing Group All rights reserved 0950-9240/02 $25.00 www.nature.com/jhh Large therapeutic studies in elderly patients with hypertension Centro Clinico Profesional Caracas, San Bernardino, Caracas, Venezuela Hypertension, including isolated systolic hypertension, is one of the major risk factors for stroke and coronary heart disease in elderly subjects, and is a common antecedent of heart failure, because it increases the risk either directly through increased after-load or indirectly as a risk factor for acute myocardial infarction. The proportion of people aged 65 and above is increasing. It is well documented that hypertension treatment in elderly patients reduces cardiovascular morbidity and mortality more than could be expected from the results of trials in middle-aged subjects. Most of the trials on old and new antihypertensive drugs have yielded similar results. Nevertheless, evidence in subjects above 80 years of age is still limited. Hypertension (systolic-diastolic) and isolated systolic hypertension should be treated in elderly patients, starting with low doses of medication, particularly diuretics alone or in combination with betablockers or angiotensin-converting enzime inhibitors. Isolated systolic hypertension could also be treated with a long-acting calcium antagonist starting with low doses. The large therapeutic studies, because of the limitations imposed upon conclusions by the selection and exclusion criteria, by the statistical techniques that established the trial designs and by other study-related constraints, cannot be applied to all elderly patients seen in daily practice. Specifically patients may differ in age, severity of illness, presence of morbidity and a myriad of other clinical nuances. Non-pharmacological measures such as lifestyle modifications (losing weight, limiting alcohol intake, reducing sodium intake and exercise), should be instituted or improved if they existed, to maximise the benefit and minimise the risk inherent in pharmacological treatment. A medical approach may reconcile the results of these large therapeutic studies with real life quality of life and patients preferences in order to improve treatment compliance. (2002) 16 (Suppl 1), S38 S43. DOI: 10.1038/sj/jhh/1001340 Keywords: elderly; hypertension; large studies Introduction The proportion of people aged over 65 years is increasing. Comorbid conditions and physiological alteration in the elderly 1 should be considered before treatment in order to decide on pharmacotherapy. Hypertension is one of the major risk factors of stroke and heart disease and is also a common antecedent of congestive heart failure (CHF), renal failure, chronic occlusive peripheral vascular disease, and aortic aneurysm. 2 The prevalence of isolated systolic hypertension (ISH) defined as systolic blood pressure (SBP) 160 mm Hg and diastolic blood pressure (DBP) 90 mm Hg, rises curvilinearly with age, and it has been pathogenically linked with an age-related decrease in the elasticity of the large arteries. ISH is also considered a frequent antecedent of heart failure. 3 5 Clinical trials in hypertension (Table 1) HEP Study 6 This was a non-double-blind, randomised, controlled trial, carried out in 884 patients aged 60 to Correspondence: Dra. Maritza Orozco Valero. Centrol Clinico Profesional Caracas, piso 3 consultorio 300. Av. Panteón con Alameda; San Bernardino. Caracas, Venezuela 79 years. The antihypertensive agents were atenolol titrated from 50 to 100 mg, bendrofluazide 5 mg alone or in combination with atenolol 50 mg, or when 100 mg of atenolol was not tolerated. If atenolol-diuretic combination failed in decreasing BP, 500 mg of methyldopa was added at night time, if it was not effective, nifedipine SR 20 mg b.i.d. was indicated in addition. Average study duration was 4.4 years. The reduction in BP was 18 mm Hg SBP, 11 mm Hg DBP. In the treatment group, the rate of fatal and non-fatal stroke decreased 58%, the fatal stroke decreased 30% compared with the control group. Total mortality and myocardial infarction (MI) were unaffected by treatment. About a quarter of the patients were unable to tolerate beta-blocker (BB) because of side effects, ie general fatigue, muscular weakness, and breathlessness on exertion. EWPHE 7 A double-blind, randomised, placebo-controlled trial, which included 840 patients aged 60 70 years, who were randomised either to active treatment (hydrochlorothiazide (HCTZ) 25 mg plus triamterene 50 mg) or to a matching placebo. The active treatment could be increased to double, when BP remained high and after one more month methyl-

Large therapeutic studies in elderly patients with hypertension Table 1 Randomised parallel studies on antihypertensive therapy in the elderly S39 Study Objectives Patients Design Treatment (daily Mean Results doses in mg) followup No. Age Principal inclusion and exclusion (years) criteria HEP (6) (1) Stroke, MI, 884 60 79 Were excluded Controlled Atenolol 50 or 100+ 4.4 Treatment total mortality following Bendrofluazide 5+ decrease: fatal (2) Side effects, conditions: atrial methyldopa 500+ and total strokes morbidity fibrilation, A V SR Nifedipine 40 Total mortality heart block, HF, and MI were bronchial asthma, unaffected by SBP 280 mm Hg; DBP 120 mm Hg treatment BB was less tolerated EWPHE Cardiovascular, 840 60 70 Age: 60 years or Double-blind HCTZ and 4.7 Active treatment: (7) cardiac and more. placebo- triamterene Decrease cardiac cerebrovascular SBP: 160 239 controlled 25/50 50/100+ and CV mortality mortality mm Hg; DBP: 90 methyldopa Non-significant 110 mm Hg. 250 200 decrease in HF, history of Placebo cerebrovascular stroke, malig- mortality nancy, diabetes Diuretic decrease mellitus requiring glucose tolerance insulin treatment, were excluded and increase uric acid and creatinine MRC (8) Diuretic or BB 4396 65 74 Mean SBP: 160 Single-blind Atenolol 50 100 5.8 Diuretic decrease: reduces: stroke, 209 mm Hg; DBP: placebo- HCTZ and stroke mainly in CHD and death 115 mm Hg. controlled Amiloride non-smokers, CV Patients with 25/2.5 50/5 events, coronary suspected Placebo events secondary BB: not showed hypertension, significant heart failure, reduction in history of MI or these end points stroke, diabetics, were excluded. STOP Stroke, MI, CV, 1627 70 84 SBP: 180 230 Double-blind Atenolol 2.1 Active treatment Hyper- mortality and mm Hg with DBP placebo- 50 + Diuretic decrease: MI, tension total mortality at least 90 mm Hg controlled HCTZ and stroke, CV (9) or DBP: 105 120 Amiloride morbidity and mm Hg 25/2.5 + BB total mortality irrespective of Metoprolol Majority needed SBP. Previous (12 100 + Diuretic combined months) history of Pindolol 5 + Diuretic treatment MI, stroke, treated Placebo angina pectoris were excluded. STOP 2 Comparing 6614 70 84 SBP: 180 mm Hg Probe (1) Conventional 4 6 Both therapies (10) effect of DBP: 105 mm Hg Atenolol were similar in conventional 50 + Diuretic prevention of therapy with Metoprolol cardiovascular the new 100 + Diuretic mortality or therapy on Pindolol 5 + Diuretic major events cardiovascular HCTZ and amiloride mortality and morbidity 25/2.5 + BB (2) New Enalapril 10 + HCTZ: 12.5 25 Lisinopril 10 + HCTZ: 12.5 25 Felodipine 2.5 + BB Isradipine 2.5 + BB Continued

Large therapeutic studies in elderly patients with hypertension S40 Table 1 Continued Study Objectives Patients Design Treatment (daily Mean Results doses in mg) followup No. Age Principal inclusion and exclusion (years) criteria STONE Effectivity of 1632 60 79 SBP: 160 mm Hg; Single-blind SR Nifedipine 20 2.6 SR Nifedipine (11) SR Nifedipine DBP: 96 mm Hg. placebo- 60 + captopril decrease stroke, Patients with controlled 20 50 or DHCTZ CV events, severe secondary 25 or + both arrthythmias, and hypertension, Placebo total CV mortality severe arrhythmia, CHF, angina pectoris, diabetes, MI were excluded SHEP (1) Effect of 4736 60 SBP: 160 and 219 Double-blind Chlorthalidon 4.5 Active treatment: (12) drug treatment mm Hg; DBP: 90 placebo- 12.5 25 or decrease: Total on the risk of mm Hg. Free of controlled placebo + stroke CV events, fatal and non- major illness: Atenolol 25 50 or total death fatal stroke cancer, alcoholic placebo Coronary events (2) CV and liver disease, renal Reserpina 0.05 were not coronary dysfunction (when BB was significantly morbidity and contraindicated) reduced mortality Low incidence of (3) All-cause side effects mortality No excess, (4) Quality of incidence of life depression or dementia Combination of drugs was often required Syst- Active 4695 60 SBP: 160 219 Double-blind Nitrendipine 2 Active treatment: Eur treatment mm Hg; DBP: 95 placebo- 10 40+ decreased: total (13) decrease. mm Hg. Free of: controlled Enalapril 5 20+ and non-fatal (1) fatal and CHF, dissecting HCTZ 12.5 25 stroke and CV non-fatal stroke aortic aneurysm, Placebo complications (2) CV dementia, severe (sudden death, complications CV or non-cv non-fatal cardiac disease end points. Fatal and non-fatal CV events) Syst- Drug treatment 1253 66.5 Sitting SBP: 160 Single-blind Nitrendipine 2 Active treatment: China could reduce 219 mm Hg. Free placebo- 10 40 + decrease: total (14) stroke and of: severe CV or controlled Captopril 12.5 50 and fatal stroke other CV non-cv disorders, or + and CV complication in creatinine HCTZ 12.5 50 or complications ISH 180 mol/l both (CV events; CV Placebo fatal and nonfatal end points, CV mortality. PROBE: This design has been termed a prospective, randomised, open, blinded end-point; DHCTZ: dihydrocholorothiazide; HCTZ: hydrochlorothiazide; BB: beta-blocker; SR: slow release; CV: cardiovascular; CHD: coronary heart disease; MI: myocardical infarction; CHF: congestive heart failure; HF: heart failure; ISH: isolated systolic hypertension; SBP: systolic blood pressure; DBP: diastolic blood pressure. dopa tablets titrated from 250 mg to 2 g (daily) could be added to the active treatment group, and placebo tablets to the placebo group. The mean follow-up was 4.7 years. The mean reduction on BP treatment groups was 20 mm Hg SBP/10 mm Hg DBP. Cardiac mortality was reduced by 38%, and cardiovascular (CV) mortality by 27%, compared with the placebo group. Non-significant decrease in cerebrovascular mortality was observed. Deaths from MI were significantly reduced by 60%. Others benefits identified were decreased in severe CHF and stroke. MRC Working Party 8 This study was a randomised, placebo-controlled and single-blind trial. This included 4396 patients

aged 65 74 years who were randomised to atenolol 50 to 100 mg, HCTZ 25 to 50 mg plus amiloride 2.5 to 5 mg daily or placebo. Mean follow-up was 5.8 years. Both treatments reduced BP below the level in the placebo group. The diuretic group reduced the risk of stroke by 31% mainly in non-smokers, all CV events by 35%, and coronary events by 44% compared with the placebo group. The BB group showed no significant reductions in these end points. Stop-Hypertension 9 This was a randomised, double-blind, placebo-controlled study, carried out in 1627 patients aged 70 84 years, followed up for an average 2.1 years. The active antihypertensive therapy was atenolol 50 mg, metoprolol 100 mg, pindolol 5 mg or HCTZ 25 mg plus amiloride 2.5 mg; and placebo. The diuretic was added to any of the BBs and vice versa. BP reduction was 19.5 mm Hg SBP/8.1 mm Hg DBP. Active treatment significantly reduced fatal and non-fatal stroke and MI, as well as in CV morbidity and total mortality. The majority required combined treatment. Stop-Hypertension 2 10 This was a probe design (a prospective, randomised, open, blinded end point) randomised trial that included 6614 patients aged 70 84 years with hypertension. The principal objective was to compare the effect of conventional (atenolol 50 mg, metoprolol 100 mg, pindolol 5 mg or HCTZ 25 mg plus amiloride 2.5 mg daily) antihypertensive drugs with newer drugs (enalapril 10 mg, lisinopril 10 mg or felodipine 2.5 mg or isradipine 2 5 mg daily). Fatal stroke, fatal MI and other fatal CV disease were assessed. The mean follow-up was 4 6 years. In the conventional drugs group the decrease in BP from baseline to the last visit was 34.8 mm Hg SBP and 16.6 mm Hg DBP in conventional drugs group; 34.5/16.2 mm Hg in the angiotensin-converting enzyme inhibitors (ACEIs) group; and 34.5/17.5 mm Hg in the calcium antagonist group. All three therapies showed similar efficacy in prevention of CV mortality and major morbidity. The frequencies of MI and CHF were significantly lower in the patients treated with ACEIs than those receiving calcium antagonists. Stone 11 In this single-blind, randomised, placebo-controlled study, 1632 patients aged 60 79 years were recruited and alternatively allocated to either sustained-released (SR) nifedipine preparation or placebo after a 4-week placebo period, with a mean follow-up of 2.6 years. A titration of nifedipine dosage from 10 mg tablet twice a day to 60 mg once a Large therapeutic studies in elderly patients with hypertension day was carried out. If the desired BP levels were not reached 20 50 mg/day captopril or 25 mg/day dihydrochlorothiazide (DHCTZ) or both, were given until the BP goal had been attained. BP reduction with SR nifedipine was 21.65 ± 17.96 mm Hg SBP and 13.14 ± 9.84 mm Hg DBP. In the placebo group BP decreased 12.31 ± 16.56 mm Hg SBP and 7.59 ± 10.08 mm Hg DBP. The active treatment reduced severe clinical outcomes and total CV mortality significantly, it also decreased combined CV events by 62%; major CV events such as strokes, reduction and severe arrhythmia attained significance when considered separately. Clinical trials in ISH (SBP 160 DBP 95 mm Hg) (Table 1) SHEP 12 A randomised, double-blind, placebo-controlled study, carried out in 4736 patients with ISH, mean age 60 years, mean duration 4.5 years, as active treatment were administered: (a) chlorthalidone from 12.5 mg to 25 mg or placebo, (b) atenolol 25 50 mg or placebo, (c) when BB was contraindicated reserpina 0.05 mg was given. The average SBP of the active treatment group was lower during the trial by about 26 mm Hg and about 11 mm Hg lower than the placebo group. The average DBP of the active treatment group was about 3 to 4 mm Hg lower than the placebo group. Active treatment diuretic decreased the incidence of total stroke by 36%, all cardiovascular events by 32%, death rate from all causes by 13%, compared with placebo treatment, as well as significantly decreasing the fatal or nonfatal heart failure and MI. Syst-Eur 13 Trial design was a randomised, double-blind, placebo-controlled study; 4695 patients with ISH, aged 60 to 100 years were randomly assigned to either a placebo group or to an active group. Active treatment consisted of nitrendipine 10 40 mg, enalapril 5 20 mg, HCTZ 12.5 25 mg or both. Mean followup was 2 years. SBP and DBP decreased 23 mm Hg/7 mm Hg in active treatment compared with placebo, the differences were SBP 10.1 mm Hg and DBP 4.5 mm Hg. In the active treatment group total stroke was reduced to 42%, non-fatal stroke decreased by 44%, fatal and non-fatal CV end points decreased by 31%, non-fatal cardiac end points decreased by 33%, and sudden death 26%, compared with the placebo group. Syst China 14 This was a single-blind, placebo-controlled trial that recruited 1253 patients aged 60 years and over with a mean follow-up of 2 years. All patients were initially started on masked placebo. Alternate S41

S42 Large therapeutic studies in elderly patients with hypertension patients were assigned nitrendipine at 10 40 mg daily with the addition of captopril 12.5 50 mg daily or HCTZ 12.5 50 mg daily or both, if a BP fall was not obtained. Principal objectives were to investigate whether active treatment could reduce the incidence of stroke and other CV complications in older patients with ISH. After 2 years of follow-up, sitting systolic and diastolic BP in the active treatment group decreased 20 mm Hg SBP and 5 mm Hg DBP compared with placebo reduction which was 9.1 mm Hg and 3.2 mm Hg DBP. In the active treatment total stroke was reduced by 38% (from 20.8 to 13.0 end points per 1000 patients-years), all-causes of mortality by 39% (from 28.4 to 17.4 end points per 1000 patient-years), CV mortality 39% (from 15.2 to 9.4 end points per 1000 patient-years), stroke mortality by 58% (from 6.9 to 2.9 end points per 1000 patient-years) and all fatal and non-fatal CV end points by 37% (from 33.3 to 21.4 end points per 1000 patient-years). Discussion and conclusions The treatment trials of hypertension in the elderly shows the reduction of cardiovascular events by treating both hypertension and ISH. SHEP and Syst- Eur trials found a reduction in cardiac mortality in the elderly that was greater than expected from the results of trials in middle-aged subjects. The benefit risk comparison from active treatment needs to be determined in the very elderly (older than 80 years), the Hypertension in the Very Elderly Trial (HYVET) in part will study this issue. 15 In older persons SBP is a better predictor of CV, cerebrovascular, renal and total mortality events than is DBP. 16 Looking at the results of ISH in the elderly, drug treatment is justified in older patients whose SBP is 160 mm Hg or higher, in this case, treatment prevents stroke more effectively than coronary events. In ISH patients, low doses of diuretics (12.5 mg of HCTZ or chlorthalidona) or long-acting formulations of calcium antagonists should be given. The cardiovascular benefits of diuretics for elderly hypertensive patients is clear but not for those receiving beta-blockers. 17 Combinations containing low doses of diuretics, ie BB-diuretics, ACEIsdiuretics, are highly effective with less dosedependent adverse effects. 18,19 Non-pharmacological measures such as lifestyle modifications should be instituted or improved if they existed to maximise the benefits and minimise the risk inherent in pharmacological treatment. 19,20 Physiological changes such as: reduced myocardial contractility, renal function, total body water, baroreceptor responsiviness, and cognitive function, together with comorbidities (angina, atrial tachycardia or fibrilation, diabetes, essential tremor, heart failure, prostatism, renal insufficiency) in the elderly, must be taken into account in order to choose the adequate individual therapy. 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Prevention of stroke by antihypertensive drug treatment in older persons with isolated Systolic Hypertension: final results of the Systolic Hypertension in the Elderly Program (SHEP). JAMA 1991; 265: 3255 3264. 13 Staessen JA et al. Randomised double-blind comparison of placebo and active treatment for older patients with isolated systolic hypertension. Lancet 1997; 350: 757 764. 14 Lui L et al. For the Systolic Hypertension in China (Syst-China) Collaborative Group: comparison of active treatment and placebo in older Chinese patients with isolated systolic hypertension. J Hypertens 1998; 16: 1823 1829. 15 Beckett NS, Fletcher AE, Bulpitt CJ. The rationale for the HYpertension in the Very Elderly Trial (HYVET). Eur Heart J Supp 1999; (Suppl p): 13 16. 16 National High Blood Pressure Education Program Working Group. National High Blood Pressure Education Program Working Group Report on Hypertension in elderly. Hypertension 1994; 23: 275 285. 17 Messerli FH, Grossman E, Goldbourt U. 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18 Kaplan MN. Low dose combinations in the treatment of hypertension: theory and practice. J Hum Hypertens 1999; 13: 707 710. 19 The Sixth Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of Large therapeutic studies in elderly patients with hypertension High Blood Pressure. Arch Intern Med 1997; 157: 2413 2446. 20 Prisant LM, Moser M. Hypertension in the elderly. Can we improve results of therapy? Arch Intern Med 2000; 160: 283 289. S43