Hypertension becomes more common with increasing age. As we gradually move towards having a higher proportion of elderly people in the population, greater numbers of octogenarians are being treated for hypertension. In this article we describe the main features of hypertension in the elderly and describe some of the particular issues that affect elderly patients. We also discuss the results of hypertension treatment trials in elderly patients and discuss treatment strategies and challenges associated with the management of hypertension in octogenarians.
Hypertension in the Elderly
According to data from the Health Survey for England 2006, 65–70% of women ≥80 years of age have hypertension and of these only around 20–30% have adequate blood pressure control.1 Systolic blood pressure gradually increases from early adulthood to old age while diastolic blood pressure increases until around 50 years of age, then plateaus before decreasing again (see Figure 1).2,3 This results in widening of the pulse pressure in later life. These changes are the result of stiffening of the arteries due to a combination of functional and structural changes that occur gradually over the years. Therefore, isolated systolic hypertension is very common in octogenarians. High systolic blood pressure readings are associated with worse outcomes.4 Similarly, various measures of arterial stiffness, including pulse pressure and pulse wave velocity, have been linked to adverse outcomes in different patient groups.5–9 Hypertension in the elderly is commonly associated with other co-morbidities and target organ damage has often already occurred.
Hypertension Treatment Trials in Octogenarians and Older
Historically, many hypertension treatment trials have excluded very elderly patients. Therefore, until recently we had very little data on the benefits of treating hypertension in octogenarians, except from sub-group analyses of trials that included a proportion of very elderly patients. That position changed with the publication of a keynote trial targeted towards answering the question of whether we should treat hypertension in patients ≥80 years of age.
The Hypertension in the Very Elderly Trial
The Hypertension in the Very Elderly Trial (HYVET) specifically set out to answer the question of whether treating high blood pressure in the very elderly was of benefit.10 In HYVET, a randomised, double-blind, placebo-controlled trial, 3,845 patients ≥80 years of age with systolic blood pressure consistently ≥160mmHg were randomised to treatment with indapamide slow-release (SR) 1.5mg or placebo. Perindopril 2 or 4mg daily or matching placebo was added as necessary, aiming for a target blood pressure of 150/80mmHg. The patients were then followed up for a median of 1.8 years for events, the primary end-point being fatal or non-fatal stroke. The mean age of patients in the study was 83.6 years.
HYVET showed that it was beneficial to treat high blood pressure with this regime in the very elderly. In the active treatment group, there was a 30% reduction in the primary end-point of fatal or non-fatal stroke (95% confidence interval [CI] –1 to 51; p=0.06) compared with the placebo group. In addition, there was a 39% reduction in death from stroke (95% CI 1–62; p=0.05), a 21% reduction in all-cause mortality (95% CI 4–35; p=0.02), a 23% reduction in cardiovascular mortality (95% CI -1 to 40; p=0.06) and a 64% reduction in heart failure (95% CI 42–78; p<0.001). This was the first large, randomised trial of hypertension treatment in the elderly and has been pivotal in guiding our practice.
Another important finding of HYVET was that there were fewer serious adverse events reported in the active treatment group than in the placebo group (358 versus 448 events; p=0.001). Prior to HYVET, there was often resistance among physicians to treating hypertension in the very elderly due to the belief that these patients might suffer more adverse effects of treatment than younger patients, changing the risk–benefit balance. However, these data from HYVET are reassuring in that serious cardiovascular outcomes can be reduced dramatically with antihypertensive therapy in the very elderly without increasing the risk of serious adverse events.
The International Verapamil Slow-release Trandolapril Study Sub-study
The International VErapamil SR-Trandolapril Study (INVEST) investigated the effects of antihypertensive treatment based on verapamil SR or atenolol in 22,576 patients with stable coronary artery disease and hypertension who were ≥50 years of age.11 A secondary analysis of the study that grouped patients by 10-year increments of age found J-shaped relationships between on-treatment systolic and diastolic blood pressures and the risk of the primary end-point (first occurrence of all-cause death, non-fatal myocardial infarction or non-fatal stroke) in all age groups.
There were 2,180 patients ≥80 years of age and, compared with the other age bands, these most elderly patients had the highest on-treatment systolic pressure hazard nadir (140mmHg) and the lowest diastolic pressure hazard nadir (70mmHg).12 Therefore, while HYVET found that treating hypertension in the very elderly was beneficial, our target treatment blood pressures may need to be adjusted slightly for very elderly patients, at least in those with co-existing coronary artery disease, to achieve maximum benefit.
Individual Data Analysis of Antihypertensive Drug Intervention Trials Subgroup Meta-analysis
In 1999, Gueyffier et al., on behalf of the Individual Data Analysis of Antihypertensive Drug Intervention Trials (INDANA) group, published a meta-analysis of subgroups of patients ≥80 years of age within randomised controlled trials of antihypertensive treatment versus placebo, no treatment or lower-dose treatments.13 The primary outcome was fatal and non-fatal stroke, and secondary outcomes included all-cause mortality, cardiovascular mortality, fatal and non-fatal major coronary and cerebrovascular events and congestive heart failure. Data were included on 1,670 participants, 76% of whom were female, within seven antihypertensive treatment trials. The trials were the European Working Party on High Blood Pressure in the Elderly (EWPHE) trial,14 the Coope and Warrender trial,15 the Systolic Hypertension in the Elderly Program Pilot (SHEP-P),16 the Systolic Hypertension in the Elderly Program (SHEP),17 the Swedish Trial in Old Patients with Hypertension (STOP),18 the Cardiovascular Study in the Elderly (CASTEL) trial19 and the Systolic Hypertension in Europe (Syst-Eur) trial.20
Overall, active treatment reduced the risk of the primary end-point of fatal and non-fatal stroke by 34% (risk ratio [RR] 0.66, 95% CI 0.48–0.92; p=0.014). Of the secondary outcome measures, the only significant reductions with active treatment were in major cardiovascular events (RR 0.78; p=0.01) and heart failure (RR 0.61; p=0.01), while there was a non-significant trend towards increased total mortality (RR 1.08; p=0.30).
The trials included in this meta-analysis had not been specifically designed to answer the question of whether antihypertensive treatment in those ≥80 years of age was beneficial. Also, there were only small numbers of events and the authors concluded that the positive results from their meta-analysis were “not robust,” as additional data from one properly designed trial with no treatment effect would be enough to make the positive results non-significant.
At that time, the authors also concluded that a reduction in disabling stroke events might be balanced by a small increase in mortality in the minds of patients. However, as described above, HYVET, which was a properly designed prospective randomised controlled trial, later found that antihypertensive treatment in the very elderly reduced mortality in addition to reducing stroke events.
Choice of Antihypertensive Therapy in Octogenarians and Older
The joint British Hypertension Society and National Institute for Health and Clinical Excellence guidelines for hypertension treatment suggest that first-line therapy in older patients should be either a calcium channel blocker or a thiazide diuretic.21,22 In practice, many elderly patients will require treatment with more than one antihypertensive agent to reduce their systolic blood pressure to the usual target of ≤140mmHg.
A recent meta-analysis of randomised trials of antihypertensive therapy looked at the effects of different antihypertensive treatment regimens on major cardiovascular events in older and younger adults.23 The analysis included 31 trials with 190,606 participants. Participants were divided into older (≥65 years of age) and younger (<65 years of age) groups. The primary outcome measure was total major cardiovascular events, which included stroke (non-fatal stroke or death from cerebrovascular disease), coronary heart disease (non-fatal myocardial infarction or death from coronary heart disease including sudden death) and heart failure (causing death or resulting in hospital admission). Secondary outcome measures included stroke, coronary heart disease, heart failure, cardiovascular death and total mortality. Several comparisons were made based on the most commonly prescribed groups of antihypertensive drugs and the relationship between age and treatment effect. The authors concluded that blood pressure reduction produced similar benefits in older patients to those seen in younger patients and that there was no strong evidence that protection against major vascular events with different drug classes varied substantially with age. However, they added that there was a paucity of data for patients over 80 years of age (and for those under 50 years of age).
Therefore, while treatment guidelines may be helpful in some cases, the initial choice of antihypertensive drug therapy in the elderly may not be as important as previously thought in terms of providing cardiovascular protection. Issues around tolerability and side effects remain important considerations in guiding treatment choice in octogenarians.
Other Factors to Consider in the Management of Hypertension in Octogenarians
Other factors that are important when deciding how to manage hypertension in the elderly include drug intolerance and side effects, polypharmacy and multiple co-morbidities, resistance to treatment and the white coat effect.
Drug Intolerances and Side Effects
The elderly are more prone to certain medication side effects and adverse events that may lead to drug intolerance or toxicity. However, as mentioned above, in HYVET the incidence of serious adverse events in patients ≥80 years of age was actually lower in the active treatment group than in the placebo group. Some of the problems that are more common in elderly patients receiving antihypertensive therapy include postural hypotension and post-prandial hypotension. Sometimes this may lead to falls or syncope with further resulting co-morbidity and injuries. There is generally a reduction in the sensitivity of baroreflexes with increasing age at least through most of adulthood,24,25 although there is less evidence of continuing changes in octogenarians.26 Impaired baroreflex sensitivity can result in inadequate compensation for changes in posture and this can be exacerbated by certain antihypertensive drugs, such as vasodilators and beta blockers, which inhibit the compensatory heart rate response to changes to upright posture. Depletion of circulating volume due to diuretic therapy may also be an important factor in increasing the risk of syncope in the elderly.
Elderly people also have alterations in their pharmacokinetic handling of medications. For example, significant reductions are found in the excretion of some renally excreted compounds and their metabolites, associated with the decrease in glomerular filtration rate that occurs with increasing age. Hepatic metabolism of some drugs may also be impaired in the very elderly.
One approach that maximises the effectiveness of antihypertensive therapy while minimising side effects might be to give combination therapy, using each individual medication at a low dose. In a meta-analysis by Law et al., while the blood-pressure-lowering effects of different antihypertensive agents were additive, the incidence of adverse effects was less than additive when half-standard dose medications were used together, as most treatment-related symptoms are dose-related.27 In a further meta-analysis, combining antihypertensive drugs from two different classes was around five times more effective in lowering blood pressure than doubling the dose of a single agent.28
Polypharmacy and Multiple Co-morbidities
The elderly are the highest users of prescription medications, with many taking several different prescription medications concurrently and some taking as many as 20–30 different medications. While this might be expected due to the presence of multiple co-morbidities, and can be rationalised to a certain extent, it can lead to confusion with treatment regimes, non-adherence and an increased risk of adverse events due to drug interactions.29 In particular, it is important to avoid prescribing medications to treat the side effects of other medications, such as giving a diuretic to treat ankle oedema secondary to a calcium channel blocker. A better approach is to change the primary medication causing the side effect. On the other hand, it can be argued that with so many available risk-reducing therapies, avoiding polypharmacy in the elderly may deprive this age group of effective medications to reduce their risk of serious events.30 The multiple co-morbidities often present in octogenarians may also predispose them to drug toxicities and adverse events.
Resistance to Antihypertensive Treatment
Many factors contribute to resistance to antihypertensive treatment in the elderly. These include non-adherence to therapy, the white coat effect (see below), pseudohypertension (in which severe arterial stiffening makes blood pressure measurement and treatment difficult), drug interactions, secondary hypertension (particularly atherosclerotic renal artery stenosis) and lifestyle factors such as high salt intake. Indeed, a recent randomised cross-over study showed that restricting salt intake was a very effective way to lower blood pressure in patients with resistant hypertension. Compared with a high-sodium diet (250mmol/day), a low-sodium diet (50mmol/day) was associated with a 22.7mmHg lower systolic blood pressure and a 9.1mmHg lower diastolic blood pressure.31 Potassium-sparing diuretics such as spironolactone are increasingly being used to treat resistant hypertension and this appears to be safe32 and highly effective.33
White Coat Effect
The white coat effect refers to an increase in measured blood pressure occurring during visits to health professionals. It is usually, but not always, associated with a degree of chronic hypertension. The white coat effect adds complexity to decision-making in the management of hypertension, as blood pressure measurements made in the clinical setting are often greatly elevated above a patient’s usual blood pressure, and the effect may be more pronounced in the elderly.
In a recent study, 2,004 patients had office blood pressure measurements and 24-hour ambulatory blood pressure monitoring (ABPM) on the same day. The white coat effect in each patient was estimated as the difference between office and mean daytime ambulatory blood pressure. Regression analysis revealed that several factors were independent determinants of the magnitude of the white coat effect on systolic blood pressure. In order of importance, these independent determinants were office systolic blood pressure (beta 0.727; p<0.001), female gender (beta 0.166; p<0.001), daytime variability in systolic blood pressure (beta 0.128; p<0.001), age (beta 0.039; p=0.020) and smoking (beta 0.031; p=0.048). The same factors were found to be important in determining the diastolic white coat effect.34
The best way to detect white coat hypertension is using 24-hour ABPM. This typically shows a peak blood pressure at the beginning of the measurement period when the patient is still with the health professional fitting the monitor. Sometimes there is a second peak when the patient comes to return the monitor the following day just before it is removed. Therefore, ABPM may be a useful investigation in the early assessment of elderly patients with clinic blood pressure measurements suggestive of hypertension. In elderly patients, ABPM is a better predictor of cardiovascular outcome than clinic readings.35 Similarly, home blood pressure measurements are increasingly being used and are a better predictor of cardiovascular events than clinic readings.36
Conclusions
Until recently we had little evidence to show whether antihypertensive therapy in the very elderly was beneficial. However, the HYVET study results have shown that there is much to be gained from effective antihypertensive therapy in octogenarians. There are many challenges associated with treating octogenarians with hypertension, but with an understanding of the multiple factors that need to be considered, successful treatment can be given safely. There is no longer any excuse for inadequate treatment of the elderly with hypertension.