Hypertension Treatment: Results from Clinical Trials

There is now no question that a significant reduction in cardiovascular and cerebrovascular morbidity and mortality results from treatment to reduce blood pressure in older hypertensive patients. Several randomized clinical trials of antihypertensive therapy in older populations have provided compelling evidence that treatment is effective in reducing cardiovascular (e.g., chronic congestive heart failure) and cerebrovascular (e.g., stroke) morbidity and mortality. A meta-analysis of outcome trials in systolic hypertension demonstrated that treatment was associated with significant reductions in overall mortality, cardiovascular events, and stroke.

The treatment effect was largest in men, in those over the age of 70 years, and in those who had larger pulse pressures. Similarly, another meta-analysis of nine treatment trials confirmed that treatment of hypertension in the older population is associated with significant benefits: the treatment group had significant reductions in all-cause mortality [odds ratio, 0.88; 95% confidence interval (CI), 0.80-0.97], stroke mortality (0.64; CI, 0.49-0.82), and morbidity (0.65; CI, 0.55-0.76), as well as cardiac mortality (0.75; CI, 0.64-0.88) and morbidity (0.85; 0.73-0.99). Based in part on these data, an analysis of the effectiveness of antihypertensive therapy utilizing data derived from the NHANES I survey suggested that the number needed to treat (assuming a 12 mmHg reduction in SBP for 10 years) to prevent cardiovascular events and deaths or all-cause mortality decreased as a function of the initial blood pressure reading and of increasing risk strata (derived from JNC-VI definitions); the prevention of 1 all-cause death required that 81 patients in the lowest risk grouping be treated compared to 9 patients in the highest risk group.

In addition to the demonstrated efficacy of antihypertensive therapy with respect to cardiovascular and stroke outcomes, it is worth noting that there may be other benefits. An analysis of data from the SHEP study identified that the relative risk of developing congestive heart failure among the treatment group was approximately one-half that of the control group. Other studies have focused on a possible relationship between hypertension and the risk of developing cognitive impairment. Results from a vascular dementia project designed as part of the Syst-Eur trial suggest that the rate of the development of dementia was significantly lower (approximately one-half) in the active treatment compared with the control group. It should be noted, however, that the dementia incidence was small (7.7 and 3.8 cases per 1000 patient-years in control and treated groups, respectively), and this observation has not yet been replicated.

Although the results from these randomized clinical trials have provided convincing support for the beneficial effects of treatment of hypertension in older patients, there nevertheless are several unanswered questions. The majority of these trials focused on those with simple hypertension and, for example, excluded those with significant comorbidities such as diabetes or a history of prior stroke or heart disease. The extent to which these results are applicable to frail older patients with multi-ple coexisting diseases is not known.

Another issue is whether these beneficial results extend to the old-old, individuals over the age of 85 years. One report has identified an inverse association between blood pressure and mortality in a group of individuals over the age of 85 years. This study reported the entry blood pressure measurements (separately grouped by systolic and diastolic) and 5-year survival rates of a group of 561 individuals over the age of 85 years who resided in the community, as well as in nursing homes and hospitals, in Tampere, Finland.

The lowest survival rate was in the lowest systolic and lowest diastolic groups. Because 80% of individuals in these groups resided in either hospital or nursing home settings, it is not certain whether other confounding disease-related factors might have accounted for their decreased survival. However, a subsequent report whose study population was restricted to community-dwelling elderly aged 84 to 88 years demonstrated increased mortality in those with either very low or very high blood pressure. Another report utilizing data obtained from the Established Populations for Epidemiological Studies of the Elderly (EPESE) determined the mortality risk associated with blood pressure in community-dwelling older people. This study found an increasing risk of death with increasing systolic blood pressure in men and women between age 65 and 84 years, but in men above the age of 85 years, an inverse relationship between systolic blood pressure and mortality risk was observed.





Very limited numbers of subjects over the age of 80 years have been included in the controlled clinical trials of hypertension treatment. Results from the European Working Party on High Blood Pressure in the Elderly (EWPHE) Trial suggested that no significant benefits of drug treatment occurred in those 80 years and older (group size, n = 155). A similar trend for a reduction in treatment benefit with age was noted in the meta-analysis of the nine studies already cited (including the EWPHE); however, this difference was not statistically significant. For isolated systolic hypertension, comparable treatment benefits were observed in the 649 subjects 80 years and older who were enrolled in the SHEP study. Finally, a meta-analysis of data from subjects older than 80 years enrolled in randomized controlled studies suggests that significant reductions in the development of stroke (34%), cardiovascular events (24%), and congestive heart failure (42%) occurred in the treatment compared to the control group. However, in this analysis a slight, although statistically nonsignificant, 6% increase in all-cause mortality was identified in the treatment group. Ultimately, results from the Hypertension in the Very Elderly trial should help to resolve this matter.

Another still unanswered question is a concern that reduction in blood pressure below a certain level may be associated with increased rather than decreased mortality, or a J-shaped curve. This relationship has been most often identified between the level of diastolic blood pressure and cardiovascular mortality. The knowledge that blood flow to the myocardium occurs primarily during diastole provides a potential physiologic mechanism to account for a relationship between low diastolic blood pressure and cardiovascular mortality.

The J-shaped curve has been raised as a concern in some treatment studies in which reduction in cerebrovascular but not cardiovascular mortality has been identified. Results from several longitudinal studies have identified an increased risk for stroke and overall mortality in individuals in the lowest systolic and, particularly, diastolic blood pressure levels. The relationship between the diastolic blood pressure achieved in subjects enrolled in the Systolic Hypertension in the Elderly Program with respect to their relative risk for developing cardiovascular disease has been shown to be inverse; namely, the relative risk increased as diastolic blood pressure decreased below 70 mmHg.

Thus, until additional prospective data are available to provide guidance in this therapeutic dilemma, it is prudent to use caution in lowering blood pressure in older individuals with hypertension. Excessive reductions in blood pressure (e.g., diastolic levels below 70 mmHg) and the development of treatment-induced postural hypotension should be avoided.

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