The challenge of blood pressure–lowering treatment in the very elderly

Robert H. FAGARD,MD, PhD
KU Leuven University – Leuven, BELGIUM

The challenge of blood pressure–lowering treatment in the very elderly

by R. H. Fagard, Belgium

Hypertension is prevalent in and remains an important risk factor in the elderly and very elderly. Randomized controlled outcome trials have shown the benefit of antihypertensive treatment in patients with systolic- diastolic hypertension and in patients with isolated systolic hypertension, aged 60 years and over. More recently, a benefit has also been shown in octogenarians with hypertension. The results of a meta-analysis of 1670 patients 80 years and over, who were included in trials in the elderly, suggested a benefit of treatment for cardiovascular events, stroke and heart failure, but not for mortality in these very old patients. The properly designed HYVET (HYpertension in the Very Elderly Trial) randomly assigned 3845 patients who were 80 years of age or older to receive either the diuretic indapamide or matching placebo. The ACE inhibitor perindopril, ormatching placebo, was added if necessary to achieve the target blood pressure of 150/80mmHg. Active treatment was associated with a 30% reduction in the rate of stroke (P=0.06), a 21% reduction in the rate of death from any cause (P=0.02), and a 64% reduction in the rate of heart failure P<0.001). In the HYVET-COG substudy (HYpertension in the Very Elderly Trial–COGnitive function), incident dementia tended to be 14% lower in the active treatment group; when combined with the results from other placebo-controlled trials of antihypertensive treatment, the combined risk reduction became significant (13%, P=0.045). In the fracture substudy, Cox proportional hazards regression analysis, with adjustment for baseline characteristics, indicated that incident fracture risk was 42% (P=0.05) lower in the active treatment group. Based on HYVET results, recent guidelines for the management of hypertension recommend that antihypertensive treatment should be extended to hypertensive patients aged 80 years or above.

Medicographia. 2012;34:57-62 (see French abstract on page 62)

Epidemiological studies show that blood pressure increases with age. Whereas systolic blood pressure continues to rise with age, diastolic blood pressure plateaus in the sixth decade of life and may even decrease thereafter. This results in a wider pulse pressure at higher age, mainly attributed to structural alterations of the arterial wall with aging, leading to increased stiffness of the aorta and elastic arteries due to loss of elasticity; in addition, atherosclerosis may contribute to the process. Therefore, hypertension is common in the elderly, with a large prevalence of isolated systolic hypertension,1 and high blood pressure remains an important cardiovascular risk factor in the elderly and very elderly,2 respectively defined as aged ≥60 years and aged ≥80 years.

Blood pressure as a risk factor at older age

The Prospective Studies Collaboration2 analyzed the age-specific relevance of usual blood pressure to vascular mortality in a meta-analysis of individual data for one million healthy adults from 61 prospective studies. The study showed that systolic and diastolic blood pressure are strongly and directly related to stroke mortality, mortality from ischemic heart disease, and other vascular mortality, and that this was the case in each decade of age, including in the elderly and very elderly. For example, age-specific hazard ratios for stroke mortality, associated with a 20 mm Hg lower usual systolic blood pressure, amounted to 0.43 (95% confidence interval [CI], 0.41-0.45) at ages 60-69 years, 0.50 (0.48-0.52) at ages 70-79 years, and 0.67 (0.63-0.71) at ages 80-89 years. Controlling for blood cholesterol, diabetes, weight, alcohol consumption, and smoking at baseline did not materially alter the estimated hazard ratios. Results were similar in men and women and were also observed for ischemic heart disease mortality and other vascular mortality. However, these observational data do not necessarily mean that lowering blood pressure by use of antihypertensive drugs would improve prognosis in these patients.

Benefit of antihypertensive treatment in the elderly

_ Systolic-diastolic hypertension
As early as 1992, Thijs et al3 reported a meta-analysis of 6 randomized controlled outcome trials of antihypertensive drug treatment in patients with systolic-diastolic hypertension, aged 60 years and over.4-9 In trials including younger as well as older patients, only the subgroups above the age of 60 years were considered. The analysis included a total of 8420 elderly patients, of whom 4253 were in the control groups and 4169 in the intervention groups. The percentage of women ranged from 45% to 70% in these trials. The analysis was restricted to mortality. Whereas all-cause mortality tended to decrease by 9% (95% CI, -1 to 18), cardiovascular, cerebrovascular, and coronary mortality decreased significantly in the active treatment groups compared with the control groups, by 22% (10-32), 33% (9-50), and 26% (9-40), respectively. Furthermore, the significant overall decrease in cardiovascular, cerebrovascular, and coronary mortality was not caused by any particular study. There was no significant influence on noncardiovascular mortality (+11%; 95% CI, –6 to 31). Notably in these older trials, first-line treatment consisted of a diuretic or a β-blocker, with a variety of additional blood pressure—lowering drugs for better blood pressure control, such as reserpine, methyldopa, hydralazine, nifedipine, and clonidine. Blood pressure was lower in the intervention group than in the control group of these trials, by on average 5 to 22 mm Hg for systolic blood pressure and by 2 to 10 mm Hg for diastolic blood pressure. The authors of the meta-analysis3 concluded that pharmacological treatment of elderly patients with combined systolic and diastolic hypertension decreased cardiovascular mortality, whereas the incidence of fatal noncardiovascular end points was not significantly affected.

_ Isolated systolic hypertension
Isolated systolic hypertension is quite prevalent in subjects older than 60 years and is rare at younger ages. In 1999, Staessen et al10 published a meta-analysis of 3 placebo-controlled outcome trials on antihypertensive drug treatment of this disorder.11-13 Entry systolic blood pressure was at least 160 mm Hg in all trials, whereas the upper diastolic blood pressure was less than 90 mm Hg in SHEP (Systolic Hypertension in the Elderly Program),11 and less than 95 mm Hg in the Syst-Eur trial (Systolic Hypertension in Europe)12 and in the Syst-China trial (Systolic Hypertension in China).13 Average ages were 72, 70 and 67 years, respectively, and the percentage of males 43%, 33% and 64%. A total number of 11 825 patients were included in the meta-analysis. All-cause mortality was reduced by 17% (P<0.01) and cardiovascular mortality by 25% (P=0.005). All fatal and nonfatal cardiovascular events, strokes, and coronary events were reduced by 32% (P<0.001), 37% (P<0.001), and 25% (P<0.005), respectively. Active treatment, in SHEP, was started with the diuretic chlorthalidone, with the possible addition of atenolol or reserpine; in Syst-Eur and Syst China, active treatment commenced with the calcium channel blocker nitrendipine, with the possible addition of enalapril and/or hydrochlorothiazide. Mean net effects of active treatment on blood pressure ranged from 6.9 to 11.5 mm Hg for systolic blood pressure and from 2.3 to 4.1 mm Hg for diastolic blood pressure. The authors concluded that the pooled results of the 3 placebo-controlled trials in older patients with isolated systolic hypertension prove that antihypertensive treatment is beneficial if, on repeated measurements, systolic pressure is 160 mm Hg or higher.

Benefit of antihypertensive treatment in the very elderly

_ The INDANA meta-analysis
A number of the randomized controlled trials on the benefit of antihypertensive treatment in the elderly included patients aged 80 years and over. The INDANA (INdividual Data ANalysis of Antihypertensive drug intervention) working group took the initiative to meta-analyze the results in these octogenarians.14,15 The meta-analysis included data from 4 trials on diastolic hypertension6-8,16 and 2 on systolic hypertension.11,12 The very elderly subgroups represented about 15% of the participants in the various trials and involved 1670 subjects between 80 and 98 years of age (mean age, 83 years), of whom 76% were women. First-line treatment consisted of a diuretic, a β-blocker, or a calcium channel blocker in the included trials. As shown in Figure 1,15 all-cause and cardiovascular mortality were not significantly different between active treatment and control. However, there was a 22% (P=0.01) reduction in the incidence of major cardiovascular events, a 34% (P=0.01) reduction in fatal and nonfatal strokes, and a 39% (P<0.05) reduction in heart failure in the active treatment groups. There was only a nonsignificant tendency for a reduction in major coronary events (23% reduction). Overall, the results suggest a significant benefit of treatment in very old patients for cardiovascular events, stroke, and heart failure, but not for mortality. In the overall analysis, all-cause mortality tended to increase by 6% (P=0.30) on active treatment, but the increase amounted to 14% (P=0.05) in the double-blind trials,6,8,11,12 which was a reason for concern. The authors also noted that the apparent beneficial results were not robust, because of the relatively small number of subjects, and that confirmation would be needed through a properly designed trial in very old people aged 80 years or more.

Figure 1
Figure 1. Odds ratios (OR) and 95% confidence limits for the odds of fatal
events, and combined fatal and nonfatal events occurring among treated
patients to the odds of its occurring among controls, in very old hypertensive

_ The HYpertension in the Very Elderly Trial pilot study
Before embarking on the main HYpertension in the Very Elderly Trial (HYVET), the HYVET investigators performed a pilot study to test the trial administration, obtain a preliminary estimate of the rate of recruitment, test the techniques of measurement and recording, determine the safety of active treatment, and obtain a rough estimate of any treatment effects.17 In this multicenter international open trial, 1283 patients aged over 80 years and having sustained blood pressures of 160-219/90-109 mm Hg were allocated randomly to 1 of 3 treatments—a diuretic-based regimen, an ACE inhibitor regimen, or no treatment. The protocol permitted doses of the drug to be titrated and slow-release diltiazem to be added to active treatment. Target blood pressure was <150/ 80 mm Hg and mean follow-up was 13 months. In the combined actively treated groups, the reduction in the relative hazard rate (RHR) for stroke events was 0.47 (95% CI, 0.24-0.93; P=0.02). However, the estimate of total mortality supported the possibility of excess deaths with active treatment (RHR 1.23; 95% CI, 0.75-2.01; P=0.42). The preliminary results suggested that treatment of 1000 patients for one year may reduce stroke events by 19, but may be associated with 20 extra nonstroke deaths, and supported the need for the main HYVET trial.

_ The main HYVET trial
In the meantime, the results of the main HYVET have become available.18,19 In the trial, 3845 patients aged 80 or above, with sustained systolic blood pressures between 160 and 199 mm Hg, were randomly assigned to receive either the diuretic indapamide (sustained release, 1.5 mg) or matching placebo, to which the angiotensin-converting-enzyme (ACE) inhibitor perindopril (2 to 4 mg), or matching placebo, could be added if necessary to achieve the target blood pressure of 150/80 mm Hg. At the start of the trial, in the year 2000, the mean diastolic blood pressure had to be 90 to 109 mm Hg; but in 2003, a protocol amendment allowed the inclusion of patients with isolated systolic hypertension. At 2 years, 73.4% of actively treated patients were on combination treatment, and 85.2% of the patients were on placebo. Patient age averaged 83.6 years and the mean sitting blood pressure was 173.0/90.8 mm Hg at baseline. At 2 years, blood pressure was 15.0/6.1 mm Hg lower in the active treatment group than in the placebo group. The incidence of the primary end point, ie, fatal and nonfatal stroke, was reduced by 30% (95% CI, –1 to 51; P=0.06), and the rate of fatal stroke was reduced by 39% (95% CI, 1-62; P<0.05). Table I (page 60)19 summarizes the effects on other end points. The significant 21% reduction in the rate of all-cause mortality is remarkable in view of the concern raised by the pilot trial and the INDANA meta-analysis. In the meta-analysis, the significant reductions in stroke and heart failure were associated with a significant increase in mortality in the doubleblind trials, although not in the overall analysis. In HYVET, there were no significant differences between the groups with regard to changes in serum potassium, uric acid, glucose, and creatinine, and there were fewer serious adverse events inthe active treatment group than in the placebo group. It should be noted, however, that the patients in HYVET were generally healthier than those in the general population.

Table I
Table I. Main fatal and nonfatal end points
in the intention-to-treat analysis in HYVET
(HYpertension in the Very Elderly Trial).

After reference 19: Beckett et al; HYVET Study Group.
N Engl J Med. 2008;358:1887-1898. Copyright © 2008,
Massachusetts Medical Society.

In conclusion, HYVET provided unique evidence that antihypertensive treatment in the very elderly, based on sustained-release indapamide and the possible addition of perindopril, with the goal of achieving a target blood pressure of 150/80 mm Hg, is beneficial and safe, and is associated with reduced risks of death from stroke, death from any cause, and heart failure.Whether treatment of patients with grade 1 hypertension, and whether further reduction of blood pressure would be more beneficial still needs to be established. Finally, it would be premature to extrapolate the results from HYVET to patients in this age group who are frailer.

_ An updated meta-analysis
After the publication of the results of the HYVET trial, Bejan- Angoulvant et al20 noticed that results of randomized controlled trials on antihypertensive treatment in very old patients are consistent in showing reduced rates of stroke, heart failure, and cardiovascular events, but inconsistent with regard to the effect on total mortality. An updated meta-analysis including HYVET20 confirmed the beneficial effect on stroke, heart failure, and cardiovascular events, but the overall relative risk for total mortality was not significant (RHR, 1.06; 95% CI, 0.89- 1.25). It should be noted that there was significant heterogeneity for mortality between HYVET and the other trials, which could be due to methodological aspects, the study population, type and dose of antihypertensive treatment, and the achieved difference in blood pressure. The authors concluded that the heterogeneity could not be explained by the double- blind character of HYVET, differences in the follow-up duration between trials, the health condition of the various study populations, and the use of long-acting thiazide (like) diuretics as first-line therapy. However, exploratory meta-regression analysis suggested possible associations between an increase in total mortality and higher intensity of antihypertensive treatment. A similar association was observed between the increase in total mortality and the achieved systolic blood pressure reduction. The authors concluded that the most reasonable strategy in octogenarians is the one proposed by the HYVET trial, ie, a thiazide-like diuretic as first-line therapy and maximal antihypertensive therapy with two drugs in low doses.20

HYVET substudies

_ Incident dementia and cognitive function
Observational epidemiological studies have shown a positive association between hypertension and risk of incident dementia; however, the effects of antihypertensive therapy on cognitive function in controlled trials have been conflicting and meta-analyses of the trials have not provided clear evidence of whether antihypertensive treatment reduces dementia incidence. Participants in HYVET had no clinical diagnosis of dementia at baseline. In the HYVET-COG substudy (HYpertension in the Very Elderly Trial—COGnitive function),21 cognitive function was assessed at baseline and annually thereafter in all participants, using the Mini Mental State Examination (MMSE); cases of dementia were identified by various means during follow-up. There were 263 incident cases of dementia in the 3336 HYVET participants with at least one follow-up assessment, a prerequisite for inclusion in the substudy.21,22 The rates of incident dementia were 38 per 1000 patient-years in the placebo group and 33 per 1000 patient-years in the treatment group. There was no significant difference between treatment and placebo groups (RHR, 0.86; 95% CI, 0.67-1.09). However, when these data were combined in a meta-analysis withother placebo-controlled trials of antihypertensive treatment,11,23,24 the combined risk ratio favored treatment (RHR, 0.87; 95% CI, 0.76-1.00; P=0.045). The authors concluded that antihypertensive treatment in the very elderly patients included in HYVETdoes not statistically reduce incidenceofdementia.This negative finding might have been due to the short follow-up, owing to early termination of the trial, or to the modest effect of treatment. Nevertheless, the HYVET findings, when included in a meta-analysis with other trials, might support antihypertensive treatment to reduce incident dementia. Finally, the mean change in MMSE score in HYVET at 2 years was –1.1 points (standard deviation [SD]=3.9) in the placebo group versus 0.7 points (SD=4.0) in the active treatment group (P=0.08).

In a subsequent paper, Peters et al25 modeled dynamics of cognition in relation to treatment of hypertension to see if treatment effects might be better discerned by a model that included baseline measures of cognition and consequent mortality. They observed that the probability of maintaining cognitive function, based on baseline function, was slightly higher in the actively treated group and that people treated with antihypertensives may maintain their cognitive health state for longer. However, the authors concluded that these findings need to be confirmed by additional studies.

_ Fracture risk
Fractures may have serious implications in an elderly individual. In view of the fact that thiazide diuretics and indapamide reduce urinary calcium and may increase bone mineral density, a fracture substudy was designed to investigate whether or not the HYVET antihypertensive treatment would reduce the fracture rate in very elderly hypertensive subjects. In the trial, considerable care was taken to ascertain any fractures and to identify risk factors for fracture.26,27 Incident fractures were validated and analyzed based on time to first fracture. Among 102 reported fractures, there were 90 validated first fractures, 38 in the active group and 52 in the placebo group. When the treatment groups were compared using a Cox proportional hazards regression model, the group receiving antihypertensive treatment tended to be favored, with a hazard ratio of 0.69 (95% CI, 0.46-1.05; P=0.086). Adjusting for the baseline factors that were indicated as potentially impacting on subsequent fracture (age, gender, and previous use of β-blockers) resulted in a hazard rate of 0.58 (95% CI, 0.33-1.00; P=0.0498). The authors concluded that despite the lowering of blood pressure, treatment with a thiazide-like diuretic and an ACE inhibitor does not increase, and may in fact decrease, fracture rate.

Impact of HYVET on hypertension guidelines

The 2007 ESH/ESC (European Society of Hypertension/European Society of Cardiology) guidelines28 regretted that, although there was overwhelming evidence of the benefits of pharmacological lowering of blood pressure in the elderly, this evidence was inconclusive for patients aged 80 years or above, in whom only a meta-analysis of a limited number of patients from various trials15 and the HYVET pilot study17 were available, suggesting beneficial effects for morbidity, but not for mortality. In the meantime, this gap has been filled with the publication of the HYVET results, which indicate that even in the very elderly stratum of the population, antihypertensive treatment is well tolerated and not only prevents cardiovascular morbid events, but also translates into prolongation of life. However, because hypertensive patients were generally in good physical and mental condition, with a low rate of cardiovascular disease, the extent to which the results can be extrapolated to more fragile octogenarians is uncertain. In addition, the premature interruption of the trial made its duration so short (1.8 years) as to leave unanswered the question of whether the benefit of antihypertensive treatment persists for several years. Finally, only a small fraction of the participants was more than 85 years old, which leaves open the question of whether the benefit extends to older ages.28

On the basis of the important evidence provided by HYVET, and within the context of its limitations, the reappraisal of the European hypertension guidelines published in 200929 recommended that antihypertensive treatment should be extended to hypertensive patients aged 80 years or above. An evidence-based general recommendation was given to prescribe antihypertensive treatment to octogenarians with systolic blood pressure above 160 mm Hg, with the target to lower it below 150 mm Hg. However, due to differences in the general health of very elderly patients, the decision to treat should be taken on an individual basis, and blood pressure lowering should be in any case gradual and carefully monitored. The optimal blood pressure goal for reducing cardiovascular events and mortality is not known.

More recently, the ACCF/AHA (American College of Cardiology Foundation/American Heart Association) 2011 Expert Consensus Document on Hypertension in the Elderly30 stated that the HYVET results provide clear evidence that blood pressure lowering by drugs is associated with definite cardiovascular benefits in patients aged 80 years or above, and that previous guidelines, which avoided firm recommendations on drug treatment in octogenarians because of questionable benefit, should be modified accordingly. _

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Keywords: antihypertensive treatment; dementia; elderly; fractures; hypertension; mortality; octogenarians; prognosis