Has ISH Established the Role of Antihypertensive Therapy in the Elderly?
Has ISH Established the Role of Antihypertensive Therapy in the Elderly?
Since the results of the Hypertension in the Very Elderly Trial (HYVET) were reported earlier this year, it has been apparent that antihypertensive treatment is effective, and can be used safely, in very elderly patients. Now more data are becoming available from HYVET substudies and other investigations that provide more information about the benefits of lowering blood pressure in patients aged 65 years and older. Some of these results were presented at Hypertension 2008, the joint congress of the European Society of Hypertension and the International Society of Hypertension (ISH), held in Berlin, Germany, June 14-19, 2008.
Before the results of HYVET became available, there was a lack of clinical trial evidence with regard to the safety and efficacy of lowering blood pressure with medication in elderly people. As a result, this population was consistently untreated or undertreated and remained at very high risk of stroke and cardiovascular disease, according to lead investigator Christopher J. Bulpitt, MD (Imperial College London, United Kingdom). HYVET was the first morbidity/mortality trial to address the question of whether antihypertensive treatment was safe and effective in very elderly hypertensive patients.
For the original trial a total of 3845 participants were recruited worldwide and observed for a median duration of 1.8 years. At 2 years, blood pressure was 15.0/6.1 mm Hg lower in the group that received active treatment group compared with the placebo group. The main results of the trial, which was sponsored by Imperial College London and supported by the British Heart Foundation and the Institut de Recherches Internationales Servier, were presented at the 2008 annual meeting of the American College of Cardiology and published simultaneously in The New England Journal of Medicine. They showed that in patients aged 80 years or older with systolic blood pressure (SBP) 160-199 mm Hg and diastolic blood pressure (DBP) < 110 mm Hg, antihypertensive treatment consisting of indapamide sustained-release (SR) 1.5 mg with or without perindopril 2 or 4 mg reduced fatal or nonfatal stroke, the primary endpoint of the study, by 39%. Although this reduction was not statistically significant, significant reductions associated with active treatment were seen in fatal stroke, death from any cause (total mortality), heart failure, and cardiovascular events. These results were widely hailed as confirming the validity of treatment of blood pressure in the very elderly, although a number of commentators also pointed out that the HYVET patients were a particularly healthy group for their age and living independently, unlike many very elderly individuals.
At the ISH conference in Berlin, a subgroup analysis of the HYVET results was presented by Nigel S. Beckett, MB ChB (Imperial College London). The cognitive substudy, known as HYVET-COG, found that the benefits of therapy on cognition were seen in both men and women, regardless of age, baseline blood pressure, or history of cardiovascular disease, and this was taken as providing additional evidence that blood pressure reduction may lower the risk of dementia in elderly patients.
In the main trial, active treatment was associated a 21% reduction in total mortality (95% confidence interval [CI] 4%-35%, P = .019) and a 32% reduction in cardiovascular events (cardiovascular mortality, nonfatal myocardial infarction [MI], nonfatal stroke, and nonfatal heart failure) (95% CI 18%-47%, P < .001). When these results were further analyzed, they revealed either statistically significant benefits or positive trends associated with blood pressure reductions across all predefined subgroups. Most important, similar reductions in total mortality were seen across sex, age, previous cardiovascular disease, and initial SBP ( Table 1 ). As noted by Dr. Beckett, HYVET was one of only a few studies of antihypertensive treatment to show a mortality benefit with blood pressure reduction.
There were also no differences in reduction of cardiovascular events across the same subgroups ( Table 2 ).
These results lend further support for blood pressure-lowering treatment of all very elderly hypertensives, Dr. Beckett said.
The HYVET-COG substudy, presented by Ruth Peters, PhD (Imperial College London), examined whether active treatment reduced the incidence of dementia (vascular dementia and Alzheimer's disease) and cognitive decline in the trial, as previously suggested by the results of some previous studies, such as the Systolic Hypertension in Europe (Syst-Eur) trial. Although no significant cognitive benefit was seen with the antihypertensive treatment in HYVET-COG, Dr. Peters said that the modest reduction seen in incident dementia cases was of clinical significance. Following the presentation in Berlin, the results of HYVET-COG were published in The Lancet Neurology.
For this substudy, a subset of 3336 HYVET patients (mean age 83.5 years) were selected, 1687 from the active treatment group and 1649 on placebo; all underwent baseline and ≥ 1 annual follow-up assessment of cognitive function by the Mini-Mental State Examination (MMSE). Cognitive decline was diagnosed in patients who had MMSE scores that fell to < 24 points or by ≥3 points in 1 year, and diagnoses of incident dementia were confirmed by an expert committee on the basis of evidence from the Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV), computed tomography scans, and a modified ischemic score. The results were analyzed in 2 ways: to assess the impact of blood pressure lowering on cognitive decline (mean follow-up 2 years with 6680 patient years of follow-up) and to assess the impact of blood pressure lowering on diagnosed dementia (mean follow-up 2.2 years with 7400 patient years).
A total of 971 patients were diagnosed with cognitive decline, including 263 cases of dementia, 164 with Alzheimer's disease, and 15 with nonspecific dementia. Rates of incident dementia were 33 vs 38 per 1000 patient years in the active treatment vs placebo groups, respectively. There were no significant differences between active treatment and placebo on cognitive decline or dementia in unadjusted analyses or analyses adjusted for education, age, and geographic region, all of which found a significant effect on decline ( Table 3 ). Neither strokes nor antihypertensive treatment during or prior to the trial had any impact on the results. Results of analyses by subtype of dementia were also not significant.
Dr. Peters and colleagues conducted a meta-analysis in which the HYVET-COG data were added to those of 3 earlier placebo-controlled trials of antihypertensive agents that assessed incident dementia: the Syst-Eur trial; the Systolic Hypertension in the Elderly Program (SHEP); and the Protection Against Recurrent Stroke Study (PROGRESS) trial. (The Study on COgnition and Prognosis in the Elderly [SCOPE] trial was omitted because of the high rate of antihypertensive therapy use in the placebo group.) The results of the meta-analysis showed a significant reduction of 13% in relative risk (RR) of incident dementia (RR 0.87 [95% CI 0.76-1.00; P = .045]) ( Table 4 ).
Dr. Peters said that she believes that longer follow-up may be required to demonstrate a statistically significant impact on dementia. Like Syst-Eur, which continued to investigate incident dementia in an open-label phase after the end of the double-blind trial, the HYVET trial is continuing as an open-label study and cases of incident dementia will continue to be assessed, allowing evaluation after a longer follow-up. The failure to obtain a significant reduction in dementia could also be attributed to the choice of treatment, Dr. Peters and her colleagues suggested in The Lancet Neurology. They noted that in Syst-Eur, which reported the biggest effect of antihypertensive therapy on dementia to date, treatment was based on a calcium channel blocker (CCB), nitrendipine. Meantime, they concluded that, "The HYVET results provide some support for the treatment of very elderly people with hypertension to reduce incident dementia."
In a commentary published alongside the HYVET-COG results in The Lancet Neurology, Ingmar Skoog, MD, PhD (Sahlgrenska Academy at Göteburg University, Sweden), highlighted another important finding of HYVET-COG, namely that antihypertensive treatment did not increase the risk of dementia or cognitive decline. This contrasts with "the commonly held belief among many doctors that treatment of hypertension in the very elderly might have negative effects on brain function via a reduction in cerebral blood flow," Dr. Skoog said, pointing out that there is "no empirical support" for this "common misunderstanding."
Dr. Skoog suggested that the failure of trials such as HYVET to show a beneficial effect of antihypertensive drugs on the incidence of dementia to date could be due to several reasons. One was the length of follow-up in the trials, which might have been too short to detect any effect. For ethical reasons, because of the benefit of treatment on cardiovascular outcomes, it is unlikely that any long-term placebo-controlled studies will be conducted in future, Dr. Skoog noted. Other methodological factors to explain the lack of benefit could be that most of the trials involved participants who were mentally healthy at baseline, selective dropout in relation to dementia, and the difficulties in diagnosing dementia in large trials. Some HYVET participants had MMSE scores of < 23 points, suggesting that they already had dementia at baseline, Dr. Skoog added. He stressed the important of diagnosing cognitive impairment in elderly patients, because "low cognitive function might have implications for patient compliance." However, "most individuals with hypertension and dementia are not detected by the healthcare system," he warned.
Other substudies of HYVET are underway. One is investigating whether treatment with indapamide (1.5 mg sustained release) reduced the incidence of skeletal fractures, a secondary endpoint in the HYVET trial. (Thiazide diuretics have been shown to reduce urinary calcium and several randomized trials have suggested that use of a thiazide diuretic may preserve bone mineral density.) Another substudy is looking at quality of life and an ambulatory blood pressure monitoring substudy is examining whether active treatment has an effect on sustained hypertension, postural hypotension, and postprandial hypotension, over a 24-hour period.
Since the results of the Hypertension in the Very Elderly Trial (HYVET) were reported earlier this year, it has been apparent that antihypertensive treatment is effective, and can be used safely, in very elderly patients. Now more data are becoming available from HYVET substudies and other investigations that provide more information about the benefits of lowering blood pressure in patients aged 65 years and older. Some of these results were presented at Hypertension 2008, the joint congress of the European Society of Hypertension and the International Society of Hypertension (ISH), held in Berlin, Germany, June 14-19, 2008.
Before the results of HYVET became available, there was a lack of clinical trial evidence with regard to the safety and efficacy of lowering blood pressure with medication in elderly people. As a result, this population was consistently untreated or undertreated and remained at very high risk of stroke and cardiovascular disease, according to lead investigator Christopher J. Bulpitt, MD (Imperial College London, United Kingdom). HYVET was the first morbidity/mortality trial to address the question of whether antihypertensive treatment was safe and effective in very elderly hypertensive patients.
For the original trial a total of 3845 participants were recruited worldwide and observed for a median duration of 1.8 years. At 2 years, blood pressure was 15.0/6.1 mm Hg lower in the group that received active treatment group compared with the placebo group. The main results of the trial, which was sponsored by Imperial College London and supported by the British Heart Foundation and the Institut de Recherches Internationales Servier, were presented at the 2008 annual meeting of the American College of Cardiology and published simultaneously in The New England Journal of Medicine. They showed that in patients aged 80 years or older with systolic blood pressure (SBP) 160-199 mm Hg and diastolic blood pressure (DBP) < 110 mm Hg, antihypertensive treatment consisting of indapamide sustained-release (SR) 1.5 mg with or without perindopril 2 or 4 mg reduced fatal or nonfatal stroke, the primary endpoint of the study, by 39%. Although this reduction was not statistically significant, significant reductions associated with active treatment were seen in fatal stroke, death from any cause (total mortality), heart failure, and cardiovascular events. These results were widely hailed as confirming the validity of treatment of blood pressure in the very elderly, although a number of commentators also pointed out that the HYVET patients were a particularly healthy group for their age and living independently, unlike many very elderly individuals.
At the ISH conference in Berlin, a subgroup analysis of the HYVET results was presented by Nigel S. Beckett, MB ChB (Imperial College London). The cognitive substudy, known as HYVET-COG, found that the benefits of therapy on cognition were seen in both men and women, regardless of age, baseline blood pressure, or history of cardiovascular disease, and this was taken as providing additional evidence that blood pressure reduction may lower the risk of dementia in elderly patients.
In the main trial, active treatment was associated a 21% reduction in total mortality (95% confidence interval [CI] 4%-35%, P = .019) and a 32% reduction in cardiovascular events (cardiovascular mortality, nonfatal myocardial infarction [MI], nonfatal stroke, and nonfatal heart failure) (95% CI 18%-47%, P < .001). When these results were further analyzed, they revealed either statistically significant benefits or positive trends associated with blood pressure reductions across all predefined subgroups. Most important, similar reductions in total mortality were seen across sex, age, previous cardiovascular disease, and initial SBP ( Table 1 ). As noted by Dr. Beckett, HYVET was one of only a few studies of antihypertensive treatment to show a mortality benefit with blood pressure reduction.
There were also no differences in reduction of cardiovascular events across the same subgroups ( Table 2 ).
These results lend further support for blood pressure-lowering treatment of all very elderly hypertensives, Dr. Beckett said.
The HYVET-COG substudy, presented by Ruth Peters, PhD (Imperial College London), examined whether active treatment reduced the incidence of dementia (vascular dementia and Alzheimer's disease) and cognitive decline in the trial, as previously suggested by the results of some previous studies, such as the Systolic Hypertension in Europe (Syst-Eur) trial. Although no significant cognitive benefit was seen with the antihypertensive treatment in HYVET-COG, Dr. Peters said that the modest reduction seen in incident dementia cases was of clinical significance. Following the presentation in Berlin, the results of HYVET-COG were published in The Lancet Neurology.
For this substudy, a subset of 3336 HYVET patients (mean age 83.5 years) were selected, 1687 from the active treatment group and 1649 on placebo; all underwent baseline and ≥ 1 annual follow-up assessment of cognitive function by the Mini-Mental State Examination (MMSE). Cognitive decline was diagnosed in patients who had MMSE scores that fell to < 24 points or by ≥3 points in 1 year, and diagnoses of incident dementia were confirmed by an expert committee on the basis of evidence from the Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV), computed tomography scans, and a modified ischemic score. The results were analyzed in 2 ways: to assess the impact of blood pressure lowering on cognitive decline (mean follow-up 2 years with 6680 patient years of follow-up) and to assess the impact of blood pressure lowering on diagnosed dementia (mean follow-up 2.2 years with 7400 patient years).
A total of 971 patients were diagnosed with cognitive decline, including 263 cases of dementia, 164 with Alzheimer's disease, and 15 with nonspecific dementia. Rates of incident dementia were 33 vs 38 per 1000 patient years in the active treatment vs placebo groups, respectively. There were no significant differences between active treatment and placebo on cognitive decline or dementia in unadjusted analyses or analyses adjusted for education, age, and geographic region, all of which found a significant effect on decline ( Table 3 ). Neither strokes nor antihypertensive treatment during or prior to the trial had any impact on the results. Results of analyses by subtype of dementia were also not significant.
Dr. Peters and colleagues conducted a meta-analysis in which the HYVET-COG data were added to those of 3 earlier placebo-controlled trials of antihypertensive agents that assessed incident dementia: the Syst-Eur trial; the Systolic Hypertension in the Elderly Program (SHEP); and the Protection Against Recurrent Stroke Study (PROGRESS) trial. (The Study on COgnition and Prognosis in the Elderly [SCOPE] trial was omitted because of the high rate of antihypertensive therapy use in the placebo group.) The results of the meta-analysis showed a significant reduction of 13% in relative risk (RR) of incident dementia (RR 0.87 [95% CI 0.76-1.00; P = .045]) ( Table 4 ).
Dr. Peters said that she believes that longer follow-up may be required to demonstrate a statistically significant impact on dementia. Like Syst-Eur, which continued to investigate incident dementia in an open-label phase after the end of the double-blind trial, the HYVET trial is continuing as an open-label study and cases of incident dementia will continue to be assessed, allowing evaluation after a longer follow-up. The failure to obtain a significant reduction in dementia could also be attributed to the choice of treatment, Dr. Peters and her colleagues suggested in The Lancet Neurology. They noted that in Syst-Eur, which reported the biggest effect of antihypertensive therapy on dementia to date, treatment was based on a calcium channel blocker (CCB), nitrendipine. Meantime, they concluded that, "The HYVET results provide some support for the treatment of very elderly people with hypertension to reduce incident dementia."
In a commentary published alongside the HYVET-COG results in The Lancet Neurology, Ingmar Skoog, MD, PhD (Sahlgrenska Academy at Göteburg University, Sweden), highlighted another important finding of HYVET-COG, namely that antihypertensive treatment did not increase the risk of dementia or cognitive decline. This contrasts with "the commonly held belief among many doctors that treatment of hypertension in the very elderly might have negative effects on brain function via a reduction in cerebral blood flow," Dr. Skoog said, pointing out that there is "no empirical support" for this "common misunderstanding."
Dr. Skoog suggested that the failure of trials such as HYVET to show a beneficial effect of antihypertensive drugs on the incidence of dementia to date could be due to several reasons. One was the length of follow-up in the trials, which might have been too short to detect any effect. For ethical reasons, because of the benefit of treatment on cardiovascular outcomes, it is unlikely that any long-term placebo-controlled studies will be conducted in future, Dr. Skoog noted. Other methodological factors to explain the lack of benefit could be that most of the trials involved participants who were mentally healthy at baseline, selective dropout in relation to dementia, and the difficulties in diagnosing dementia in large trials. Some HYVET participants had MMSE scores of < 23 points, suggesting that they already had dementia at baseline, Dr. Skoog added. He stressed the important of diagnosing cognitive impairment in elderly patients, because "low cognitive function might have implications for patient compliance." However, "most individuals with hypertension and dementia are not detected by the healthcare system," he warned.
Other substudies of HYVET are underway. One is investigating whether treatment with indapamide (1.5 mg sustained release) reduced the incidence of skeletal fractures, a secondary endpoint in the HYVET trial. (Thiazide diuretics have been shown to reduce urinary calcium and several randomized trials have suggested that use of a thiazide diuretic may preserve bone mineral density.) Another substudy is looking at quality of life and an ambulatory blood pressure monitoring substudy is examining whether active treatment has an effect on sustained hypertension, postural hypotension, and postprandial hypotension, over a 24-hour period.
