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Drug Treatment of Hypertension in the Elderly
A Meta-Analysis
- Jorge T. Insua;
- Henry S. Sacks;
- Tai-Shing Lau;
- Joseph Lau;
- Dinah Reitman;
- Daniel Pagano; and
- Thomas C. Chalmers
- From the Mount Sinai School of Medicine, New York, New York and Harvard University School of Public Health and the New England Medical Center, Boston, Massachusetts. Requests for Reprints: Henry S. Sacks, MD, Clinical Trials Unit, Mount Sinai School of Medicine, Box 1042, New York, NY, 10029. Grant Support: In part by the Robert Wood Johnson, Jr. Charitable Trust and by grants HS 05936 and HS 077A2-01 from the Agency for Health Care Policy and Research of the United States Public Health Service.
Abstract
Purpose: A meta-analysis of the effect of antihypertensive drug treatment on mortality and morbidity in elderly patients.
Data sources: A literature search of published articles from January 1980 to February 1992.
Study selection: Randomized controlled trials of drug treatment of hypertension with end points for elderly patients reported separately.
Data extraction: Mortality or morbidity end points or both in patients older than 59 years were pooled by determination of typical odds ratio. A meta-regression was used to study heterogeneity.
Results: Nine major trials with 15 559 patients older than 59 years were identified. Death rates in the control group varied between 2.7% and 77.2%; stroke and coronary mortality increased with the severity-of-illness rank (P < 0.001). Overall, treated patients had an approximately 12% reduction in all-cause mortality (odds ratio, 0.88; 95% CI, 0.80 to 0.97; 953 events compared with 1069 events, P = 0.009). There was a 36% reduction in stroke mortality (odds ratio, 0.64; CI, 0.49 to 0.82; 94 events compared with 149 events, P < 0.001) and a 25% reduction in coronary heart disease mortality (odds ratio, 0.75; CI, 0.64 to 0.88; 263 events compared with 350 events, P < 0.001). Coronary morbidity was reduced 15% (odds ratio, 0.85; CI, 0.73 to 0.99; 325 events compared with 379 events, P = 0.036), and stroke morbidity was reduced 35% (odds ratio, 0.65; CI, 0.55 to 0.76; 247 events compared with 382 events, P < 0.001).
Conclusion: Overall, treatment of hypertension in elderly patients produces a significant benefit in total mortality and cardiovascular morbidity and mortality. However, this benefit may be reduced in the oldest age groups.
Estimates of hypertension in patients older than 65 years vary according to population factors and the cut-off value used [1]. Despite estimated prevalences of as high as 64% [2], conservative estimates are 20% for systolic-diastolic hypertension and 10% to 20% for isolated systolic hypertension [1, 3]. Hypertension increases the risk for cardiovascular death [4] and is one of the most modifiable risk factors [5]. Drug treatment has been shown to benefit the young, but the elderly have typically been under-represented in randomized, controlled trials [6, 7].
As people age, hypertension becomes less and less of a risk factor, presumably because those most susceptible have already died [8]. Indeed, blood pressure and mortality rates have been shown to vary inversely in very elderly men [8-10] and women [11, 12]. Because of the risk of drug interactions and side effects, questions about the risk–benefit of treatment in very old and frail patients have been raised [1, 8].
We did a meta-analysis to determine the effect of treatment on all-cause and cause-specific mortality, stroke, and coronary heart disease in the elderly. We also tried to evaluate the effects of disease severity and age of the trial populations on these end points to determine whether treatment should be applied to all elderly subgroups.
Methods
Data Sources
We identified randomized, controlled trials of antihypertensive drug treatment in the elderly through a MEDLINE search of articles published from January 1980 to February 1992. The following key words were used: hypertension, elderly or aged, and randomized, controlled trials. Additional studies were identified from pertinent review articles, a review of Current Contents (Clinical Medicine), and references of the retrieved articles.
Study Selection and Data Extraction
The following were the study selection criteria: 1) random assignment to treatment (control patients were not required to have received placebo); 2) hypertension defined as diastolic (>89 mm Hg), systolic (>159 mm Hg), or isolated systolic (>159 mm Hg systolic/<90 mm Hg diastolic) on at least one measurement; 3) interventions that included any antihypertensive drug treatments administered in any form (single, combined, or stepped); and 4) end points numerically identifiable at 5 years for elderly patients. Because some trials reported ages by decade (50 to 59 years, 60 to 69 years, and so forth), and some reported ages as younger or older than 65 years, we extracted data from any groups that included patients with a minimum age of 60 years.
We used for our analyses the protocol definitions of morbidity end points in the primary studies that were not uniform for either coronary events or strokes. Transient ischemic attacks were excluded. In some instances, subtypes of strokes were combined. In one case, the number of deaths at 5 years had to be approximated from the mortality rate [13]. One trial [14] provided only morbidity end points. Data were extracted by two readers who were blinded to treatment assignment, and the final result was reached by consensus.
Analysis and Data Synthesis
Included trials were graded blindly by two readers according to a previously described quality-grading system [15] that assigns a score between 0 and 1 using more than 30 elements of study design, randomization, blinding, statistical analysis, and reporting.
The outcomes were mortality and other events in the treatment and control groups using intention-to-treat analysis [16]. We used the Yusuf-Peto method [17, 18] to obtain a combined estimate of the odds ratio under the assumption of homogeneity of the odds ratio across the strata; it provided a test of significance of the combined odds ratio. There is also a test of the homogeneity of effect (that is, that any difference between the study results can be attributed to random variation). Other methods used included the DerSimonian and Laird random-effects model [19], the Robins, Greenland, and Breslow model [20], the Mantel-Haenszel model [21], and the pooled relative risk model [22]. Because no major differences in results were found, results are presented only for the Yusuf-Peto method. We used approximate chi-square tests for statistical heterogeneity [18]. All P values are two-sided.
We considered blood pressure reduction an intermediate effect [16] rather than the primary end point of interest. We defined blood pressure reduction as the mean systolic or diastolic value of treated patients minus the mean of the controls at 5 years of follow-up.
We ranked the primary study populations according to severity of illness (from 1 to 7, with 1 being the least ill) using two main available criteria: the health care setting from which the patients were recruited and the amount of end-organ damage at study entry. We assumed that patients in long-term care facilities were the most severely ill, followed by those in acute care hospitals and then by those in primary care, and that patients recruited from their communities were the least ill. An approximation of baseline end-organ damage was provided by simple addition of cardiovascular disease markers at trial entry and by the severity of the exclusion criteria. Trials with less strict inclusion criteria usually had more end-organ damage burden and vice-versa. One trial could not be ranked because of the lack of end-organ damage description [23-25] and another because of the lack of mortality data [14].
Further analysis of the trial populations according to ranking was done by using 5-year incidence rates of various end points. Analysis for trend according to ranking was done using weighted regression [26].
The ranking obtained was entered as an effect modifier measure into a “meta-regression” [16] in which each trial was a unit of analysis. The dependent variables for the meta-regression were log odds ratio and log relative risk. Statistical methods for the effect of severity-of-illness ranking on outcome are provided in the Appendix.
Results
Trial Characteristics
We identified 31 trials but excluded 22 for the following reasons: Four gave no age criteria [27-30]; 11 did not give results separately for elderly patients [31-41]; 2 included only patients with previous strokes [42, 43]; 1 used multiple interventions [44]; 3 used historical controls [45-47]; and 1 had fewer than 5 years of follow-up [48]. The 9 identified studies that fulfilled the inclusion criteria are shown in Tables 1 and 2 [1, 3, 14, 23-25,44-74], but only 7 could be ranked according to severity of illness. These 9 studies included multiple publications that were perused to abstract the required data.
The 15 559 patients older than 59 years studied in the trials (7750 treated patients and 7809 controls) had an average follow-up of 4.13 years, which yields more than 64 000 patient-years of follow-up. The trials had a mean quality score of 0.67 (range, 0.39 to 0.91), which is higher than that of trials of mild hypertension we reviewed in a previous study [75].
Some trials did not provide systolic blood pressure reduction [50, 62, 73], and another [13] provided only blood pressure at 6 months of follow-up (Tables 1 and 2). The average diastolic and systolic blood pressure reduction at 5 years was 8.72 mm Hg and 17.13 mm Hg, respectively.
All trials included stepped care (defined as sequential use of one or more drugs) except for one [13] that used only methyldopa. All of the stepped-care regimens included treatment with diuretic agents, and five of them [25, 62, 65, 72, 74] included β-blockers. In three trials, no placebo was used in the control group [13, 65, 73].
Three trials [13, 51, 66] did not provide drop-out data. Between 10% [74] and 35% [65] of the treated groups in the remaining trials had premature termination of drug treatment. It was not possible to pool treatment side effects because they were recorded differently. In one trial [74], 44% of the patients in the control group received active drug treatment at 5 years of follow-up.
Meta-analysis
All-cause mortality was approximately 12% lower in the treated patients (odds ratio, 0.88; 95% CI, 0.80 to 0.97; 953 events compared with 1069 events). Treated patients had 36% fewer fatal strokes (odds ratio, 0.64; CI, 0.49 to 0.82; 94 events compared with 149 events). Fatal coronary events in the treated group were 25% lower (odds ratio, 0.75; CI, 0.64 to 0.88; 263 events compared with 350 events) (Figure 1). However, nonvascular deaths were 8% higher in the treated group (odds ratio, 1.08; CI, 0.94 to 1.25; 423 events compared with 396 events) (data not shown). Nonfatal strokes were 35% lower in the treated patients (odds ratio, 0.65; CI, 0.55 to 0.76; 247 events compared with 382 events), and coronary morbidity was 15% lower (odds ratio, 0.85; CI, 0.73 to 0.99; 325 events compared with 379 events) (Figure 2). When the clinical history definition of coronary events in the Hypertension Detection and Follow-up Program [76] was used, the observed reduction in coronary morbidity was 23% (odds ratio, 0.77; CI, 0.64 to 0.92). We observed no consistent pattern in a separate analysis of most end points in those trials with placebo control compared with those without.
Because the Systolic Hypertension in the Elderly Program (SHEP) trial [74] only considered systolic hypertension, and patients with isolated systolic hypertension may not be similar to those with diastolic hypertension, analyses were done that included and excluded the SHEP trial. The SHEP trial results were not consistently different from the results of the other trials in the direction and magnitude of effect (Figures 1 and 2).
However, the SHEP trial was not the only study that included patients with isolated systolic hypertension. In one trial, 23% of patients had diastolic blood pressures of less than 90 mm Hg [77]. Another trial included patients with diastolic blood pressures of 90 to 95 mm Hg [78]. In a third trial, almost half of the patients had diastolic pressures of less than 90 mm Hg [72].
The all-cause mortality rate in the controls increased significantly with severity-of-illness ranking (P < 0.001), as did stroke and coronary mortality (Figure 3). The benefit of treatment on mortality end points tended to decrease with increasing severity-of-illness rank, but this did not reach statistical significance (data not shown).
Increasing age tended to reduce (but not significantly) the benefit of treatment on total mortality (P = 0.08 to 0.27 depending on the method used). Multivariate analyses of confounding independent variables of all ranked trials were done with total mortality, odds ratios, and relative risks as dependent variables; none was statistically significant.
Discussion
Our analysis shows that, in general, treatment of hypertension in patients aged 60 years and older reduces total mortality and cardiovascular morbidity and mortality but also suggests that the benefit of treatment may be diminished in more severely ill or more elderly patients.
The analysis has several methodologic hazards that must be considered. It is of concern that many trials either did not include older patients or did not separate the results for these patients and therefore had to be excluded; nevertheless, data are available from more than 15 000 patients. Our analysis is subject to the general problems of meta-analyses [79, 80]. However, the trials were of relatively high quality, and we believe that the conclusions are reliable. In all included trials, treatments were randomly assigned. However, ascertainment of end points in the primary studies was different, and we were unable to generalize the findings to the oldest patients with diastolic hypertension because they are under-represented. Because of the strict exclusion criteria of the trials, it is also difficult to generalize the findings to the elderly patients with additional diseases who are commonly seen in clinical practice. The issue of the under-representation of women in randomized, controlled trials [81, 82] is not a problem here because 60% of the patients were women. The group primarily represents patients with mild to moderate hypertension and may underestimate treatment benefit in those with severe hypertension.
Our meta-analysis includes the results of a trial of purely isolated systolic hypertension (SHEP) [74]. However, some of the other trials also included patients with isolated systolic hypertension [25, 77, 78]. Thus, we are unable to determine whether isolated systolic hypertension should be treated differently. Epidemiologic data [1, 5, 83-86] that confirm the association of isolated systolic hypertension with cardiovascular morbidity and mortality support the assumption that similar physiopathology underlies both disorders [1, 87]. In fact, drug treatment decreased both systolic and diastolic blood pressure in all trials, including the SHEP trial (Table 2).
Our analysis is consistent with others that suggest that the treatment effect diminishes with age [64], particularly among those older than 80 years. The SHEP trial found no less effect in this group [74], perhaps because of self-selection [88], but an analysis of the Swedish data [25] suggested a lesser effect in the very old. Although it fulfills several of the guidelines for subgroup analysis [89], the possible differential effect of treatment on total mortality according to severity-of-illness ranking should only be considered a hypothesis-generating analysis.
As previously reported in prevention trials [90], we found a trend toward an increase in nonvascular deaths, probably because of competing mortality. Deaths from cancer increased in patients treated for hypertension [72]. The consistency of this finding across trials suggests a real phenomenon but should be studied further.
We found a significant 22% reduction (odds ratio, 0.78) in vascular deaths. Stroke reduction by our analysis is similar to previous estimates [76, 91, 92] (Figures 1 and 2). The rate of stroke increases with age [93] and is one of the major causes of severe disability [93-95] and dementia [96]. The reduction of the rate of such a severely disabling disease [97] is of great importance to the goal of increasing the quality and expectancy of life of elderly patients [98].
In contrast to previously published results [76, 84, 91, 92, 99], our analysis showed that treatment produced a significant decrease in coronary heart disease mortality in the elderly (odds ratio, 0.75) (Figure 1). This should be emphasized because coronary heart disease is the leading cause of death among the elderly.
We found that in the elderly [91, 92, 99], the rate of coronary heart disease is reduced less than that of stroke. Small trial sample size and silent ischemia have been offered as explanations of this resistance to benefit from drug treatment found in trials of persons of all ages with hypertension [100]. Our data seem to confirm both explanations. The sample size increase caused by the inclusion of new trials improved statistical power [101, 102]. The variation in end-organ damage at study entry (Table 1) and the increase in the coronary disease mortality of the controls with severity-of-illness ranking (Figure 3) suggest that coronary damage at study entry was uneven among trials. Hypertension is known to produce silent ischemia [100] and increase the rate of sudden death [103]. However, the hypothesis of a J-shaped curve relating coronary heart disease mortality to blood pressure levels [104-106] could not be tested by our data.
In conclusion, these results show that treating hypertension in the elderly yields the greatest benefits in relation to stroke and coronary heart disease. Importantly, total mortality and coronary heart disease mortality were found to be significantly reduced. These effect-size estimates suggest a considerable potential public health benefit of drug treatment.
The practitioner caring for most elderly patients and trying to reduce disability, particularly in ambulatory care settings, clearly should try to control systolic and diastolic hypertension. But in the oldest and most severely ill and frail patients, particularly those in long-term care settings, treatment may be less beneficial or even harmful. Further randomized, controlled trials of drug treatment of hypertension in frail older patients are needed before firm recommendations can be made for this group.
Addendum
Since this paper was submitted, two meta-analyses of the effect of treatment of hypertension in patients older than 60 years have been published [107, 108], both of which found statistically significant reductions in cardiovascular mortality and strokes and near-significant reductions in total mortality.
Appendix
We studied the effects of drug treatment of high blood pressure on total mortality in elderly persons, taking into account the severity of illness. This is done by weighted regression with the log relative risk {log[p(t)/p(c)]} as the dependent variable and the ranking of severity as the independent variable. Each log relative risk is weighted by its asymptotic variance, which can be obtained by the delta method [109]:
EQUATION OMITTED
where p(t) and p(c) are the death rates among the treatment group and control group, respectively, and n(t) and n(c) are the sample sizes for the treatment and control group, respectively. The trend exists if the slope coefficient obtained by weighted regression divided by its standard error (corrected as suggested by Greenland [16]) is significantly different from zero.
We also applied the method of weighted regression with the log odds ratio as the dependent variable and the ranking as the independent variable. The variance of the log odds ratio is given in Fleiss [110]. The trend exists if the slope obtained by weighted regression, in which the weight is given by the reciprocal of the variance, is significantly different from zero.
- Copyright ©2004 by the American College of Physicians
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