William B. Applegate, MD
In developed countries, systolic blood pressure (SBP) generally increases throughout the average life span, whereas diastolic blood pressure (DBP) tends to rise until about age 50 (on average) and then levels off.1 However, newly diagnosed hypertension in persons over age 65 primarily is isolated systolic hypertension (ISH) rather than systolic/diastolic hypertension. In older persons, either form of hypertension is characterized by high peripheral vascular resistance and low plasma volume. Cardiac output and renal blood flow vary in older patients with high blood pressure, but they tend to be lower in those with long-term hypertension.1(Slide 22)
Results from Clinical Trials
Despite concerns that diuretics may increase coronary risk, this study's diuretic-based regimen produced an impressive and significant 25% reduction in combined fatal and nonfatal coronary heart disease events (Table 1), with a 5-year absolute benefit of 16 such events prevented per 1000 participants.2 In addition, there was a 13% reduction in total mortality in the treatment group, which did not reach statistical significance.(Slide 23) Subgroup analyses showed a benefit from treatment in all age, race, and gender subgroups, including persons over age 80 at entry and in those with or without baseline electrocardiogram abnormalities. The percentage reduction in stroke and cardiovascular disease was as great for participants with a baseline SBP of 160 to 170 mm Hg as it was for participants with a higher baseline SBP. This finding suggests that 160 mm Hg SBP is a fairly high cutoff for treating ISH, and future trends may indicate treatment of older persons with a DBP < 90 mm Hg and a SBP of 140 to 160 mm Hg. Finally, the magnitude of the benefit from treatment seen in this trial is actually greater than that seen in trials treating combined systolic and diastolic hypertension. As a result of the SHEP trial, it is no longer tenable for clinicians to focus exclusively on DBP when treating elderly patients with hypertension. Rather, treatment goals should target both SBP and DBP.
Swedish Trial in Old Persons with Hypertension (STOP-H). This study was conducted to assess the impact of antihypertensive treatment in persons aged 70 to 84 years.3 Participants were eligible if their SBP was between 180 and 230 mm Hg and DBP was less than or equal to 90 mm Hg, or if DBP was between 105 and 120 mm Hg regardless of SBP. A total of 1,627 participants were randomized in a multicenter, double-blind trial to atenolol 50 mg/d, hydrochlorothiazide 25 mg/d plus amiloride 2.5 mg/d, metoprolol 100 mg/d, pindolol 5 mg/d, or placebo. If supine SBP was >160 mm Hg or DBP was >95 mm Hg after at least 2 months of therapy or at any point thereafter, the diuretic was added to any of the beta blocker arms or vice versa. Study duration was 65 months, with an average time per participant of 25 months. Compared with placebo, the combined active treatment groups experienced a significant 40% reduction in total cardiovascular morbidity and mortality and a significant 47% reduction in total fatal and nonfatal strokes (Table 2). The treatment groups also experienced a significant 43% reduction in total mortality. There was a 13% reduction in fatal and nonfatal myocardial infarction (MI) and a 50% reduction in fatal MI plus sudden death,(Slide 24) neither of which reached statistical significance. Results have not been presented for the individual treatment arms, but it is unlikely that the study had sufficient power to detect significant differences. These results appear to demonstrate a benefit of treating high blood pressure in patients up to 84 years of age.
Medical Research Council (MRC) Trial. This randomized, single-blind trial involved 4,396 patients age 65 to 74 years with mean SBP of 160 to 209 mm Hg and mean DBP <115 mm Hg.4 Basically, this was a trial evaluating the impact of treating persons with predominant systolic hypertension, because the baseline SBP/DBP in all three treatment groups (diuretic, beta-blocker, placebo) averaged 193/91 mm Hg. Also, after the first 3 months, the placebo group had an average DBP of < 90 mm Hg. The mean age was 70.3 years, less than that for SHEP (71.6 years) or STOP-H (75.6 years). Participants were randomized to atenolol 50 mg/d, hydrochlorothiazide 25 or 50 mg/d plus amiloride 2.5 or 5 mg/d, or placebo. Mean follow-up was 5.8 years. If blood pressure was not controlled with the initial regimen (no blood pressure response after 12 weeks or target pressure not achieved after 6 months), then the diuretic regimen could be added to the beta blocker and vice versa. Both treatments reduced blood pressure significantly more than did placebo. Compared with the placebo group, actively treated subjects (diuretic and beta blocker groups) had a 25% reduction in stroke (P = 0.04), a 19% reduction in coronary events (P = 0.08), and a 17% reduction in all cardiovascular events (P = 0.03). There was no difference between active treatment and placebo in terms of all-cause mortality. After adjustment for baseline characteristics, the diuretic group had a significant 31% reduction in stroke (P = 0.04), a 44% reduction in coronary events (P = 0.0009), and a 35% reduction in all cardiovascular events (P = 0.0005) compared with placebo (Table 3). The beta blocker group did not have a significant reduction in any of these endpoints.(Slide 25)
One possible reason for the poor results in the MRC beta-blocker group was the higher rate of withdrawals for both intolerable side effects (333 patients) and failure to control blood pressure (12 patients) compared with the diuretic group (160 patients and 1 patient, respectively). The cumulative percentages of participants who stopped taking their randomized treatment, including those withdrawn from therapy but continuing on follow-up, as well as those withdrawn and lost to follow-up, were 48% for the diuretic group, 63% for the beta-blocker group, and 53% for the placebo group. The overall rate of participants lost over a 5.5-year follow-up was a surprisingly high 25%.4
Although there were approximately 1,700 participants with ISH, their data have not been reported separately. However, the authors stated that the favorable trend in reduction of cardiovascular events was similar to that of the overall cohort. This study confirms the SHEP conclusions that low-dose diuretic therapy is relatively well tolerated and will lower the rate of both stroke and coronary heart disease in older persons with hypertension.4
Factors Affecting Choice of Antihypertensive Therapy
As shown in Table 4, the presence of concomitant conditions can have a dramatic influence on the choice of antihypertensive therapy in the older patient. Although the number of older persons with concomitant conditions in randomized clinical trials is low, the prevalence of comorbid conditions in older patients with high blood pressure in clinical practice may well exceed 50%. Also, although some studies have shown remarkably similar side-effect profiles across major antihypertensive drug classes (particularly at low doses), others have found substantial differences.5 Therefore, it is incumbent upon the physician to consider each patient individually.
Differential Effects of Antihypertensive Agents
Diuretics. The diuretics have proven to be highly efficacious in lowering elevated SBP and are thus particularly useful in patients with predominant elevations of SBP.1-4 On the other hand, the diuretic-induced perturbations of lipid and glucose homeostasis make these drugs less ideal in older people with noninsulin-dependent diabetes mellitus or abnormal serum lipoproteins.(Slide 27)
Beta blockers. As a class, the beta blockers are less appealing for the elderly, because they generally increase peripheral resistance rather than reduce it. Older persons generally have a higher level of peripheral vascular resistance than younger persons, and so use of a drug that causes vasodilatation rather than vasoconstriction would seem to be a logical choice in elderly hypertensives. In addition, the use of beta blockers can be questioned on the basis of the MRC trial findings, in which atenolol was shown to be no better than placebo in reducing cardiovascular events.4 As pointed out by Bertel et al, beta blockers tend to be more effective in hypertensive patients with relatively high renin levels, but elderly patients with high blood pressure tend to have relatively low renin levels.7(Slide 27)
Calcium channel blockers. The calcium channel blockers are perhaps most appealing on a hemodynamic and pathophysiologic level as agents to manage high blood pressure in older persons. Calcium channel blockers dilate the coronary and peripheral arterial beds, are not dependent on the renin-angiotensin axis for their action, and probably increase renal blood flow. A randomized controlled trial by Applegate and colleagues comparing a calcium channel blocker, an angiotensin converting enzyme (ACE) inhibitor, and a beta blocker in the treatment of high blood pressure in older women demonstrated that the calcium channel blocker was more effective in blood pressure reduction and had a better side-effect profile.5
The subclasses of calcium channel blockers have very different hemodynamic profiles. The dihydropyridine calcium antagonists, represented by nifedipine, tend to act more through peripheral vasodilatation but have little, if any, effect in terms of slowing heart rate. On the other hand, the other two classes of calcium antagonists, represented primarily by verapamil and diltiazem, both lower heart rate and induce coronary and peripheral arterial vasodilatation. Although all three subclasses have negative inotropic effects on the heart, particular care must be used with verapamil.
A recent case-control study,8 along with a metaanalysis and a prospective cohort study,9 have raised the issue that the use of short-acting dihydropyridine calcium antagonists may result in somewhat higher rates of MI in hypertensive patients compared with the use of beta blockers. It is of particular concern that a prospective cohort study by Pahor and colleagues has implicated short-acting nifedipine in doubling the risk ratio for MI all-cause mortality in elderly hypertensive patients.10
Although these findings are not conclusive and large randomized trials are under way to evaluate this issue in a more definitive manner, clinicians may be advised to avoid short-acting dihydropyridines, when possible, in older hypertensive patients.(Slide 26) A possible biologic mechanism may help to explain these study findings. It is well known that short-acting dihydropyridines cause fluctuations in heart rate and cate-cholamine levels, which could increase myocardial oxygen demand.1 Because older persons in particular have a high prevalence of asymptomatic coronary atherosclerosis, they could be most vulnerable to the putative proischemic effect of the dihydropyridines.10
On the other hand, verapamil and diltiazem have been less implicated (although not uniformly so) in the recent calcium channel blocker controversies. It may be that calcium channel blockers that control heart rate as well as produce peripheral arterial dilatation provide the optimum balance in terms of lowering blood pressure without causing proischemic effects on the myocardium.(Slide 28)
ACE inhibitors. In general, the ACE inhibitors have been shown to be effective in lowering blood pressure in older adults and to have a relatively beneficial side-effect profile. However, ACE inhibitors do not appear to be particularly effective in older African-Americans. Materson et al found the ACE inhibitor captopril to be less effective than several other antihypertensive agents in lowering blood pressure in older persons.12 Among older blacks, captopril was the least effective of the six antihypertensive agents studied, and diltiazem and hydrochloro-thiazide proved the most effective. Older whites responded best to atenolol and diltiazem, with captopril ranking third.(Slide 28)
Adrenergic inhibitors. Adrenergic inhibitors (eg, methyldopa) may be useful in some hypertensive patients. However, they have been found to have a high frequency of side effects, particularly dizziness and depression, which would be problematic in certain older persons.
Drugs of choice. Given the uncertainties about using beta blockers, the dihydropyridine calcium channel blockers, and the ACE inhibitors in older persons with high blood pressure, diuretics currently appear to be the drugs of first choice for monotherapy for uncomplicated hypertension. For more complicated hypertension, one of the nondihydropyridine calcium channel blockers may be the drug of first choice.
Quality of Life
Applegate and colleagues conducted a randomized controlled trial of the effects of enalapril, diltiazem, and atenolol on blood pressure control and quality of life in 242 women with predominantly diastolic hypertension.5 All three drugs had substantial antihypertensive efficacy, although the greatest lowering of DBP was seen with diltiazem. More treatment failures associated with side effects were found in the atenolol and enalapril groups (Table 5). General well-being seemed to improve more in patients receiving diltiazem than in patients receiving the other two drug regimens, but there were no significant differences in any of the quality-of-life variables.(Slide 29)
These two studies again illustrate the problems that are sometimes hidden within averages. Although both the DVA trial and the study by Applegate and colleagues found significant increases in significant side effects of some drugs compared with others, the significant side effects occurred in only a minority of patients. Therefore, when various treatment groups were compared with regard to average quality-of-life measures, no differential effect was seen for any of the treatment groups, despite some significant differences in side effects.
Compliance Issues
A host of reports show that the interaction between physician and patient is a key issue in maintaining long-term adherence to drug therapy. A study conducted at the University of Tennessee on compliance in elderly patients living in community settings indicate that, at times, compliance with taking prescription medication and knowledge of its purpose can be relatively high.16 These observations reinforce findings of previous studies that older patients comply at least as well as younger persons with chronic-disease medication regimens. However, the same study showed that whereas understanding of the purpose of a medication may have been good, knowledge of its side effects was actually quite poor. Because antihypertensive medications often have subtle side effects in individual elderly patients, physicians need to educate their older patients about side effects and evaluate each patient individually to tailor the most effective long-term regimen for that particular patient.17(Slide 30)
References
[Introduction | Pharmacology | Cardiovascular Risk
Information/Questions | Table of Contents ]
[Introduction | Pharmacology | Cardiovascular Risk
Information/Questions | Table of Contents ]