Filling the Gaps in Current Guidelines for the Management of Hypertension
Filling the Gaps in Current Guidelines for the Management of Hypertension
Guidelines for the management of hypertension invariably include sections where the evidence for or against treatment or for certain types of treatment in certain types of patients is inconclusive. The results of 3 clinical trials presented at the American College of Cardiology (ACC) 2008 meeting in Chicago address 3 of these areas of ambiguity or uncertainty and signal updates that will surely be made in future versions of the guidelines.
Since the modern age of diagnosing and treating high blood pressure (BP) began, exactly what the benefit would be to treating very elderly patients (≥ 80 years) with hypertension has been unclear, and very few mentions are made of this group in current hypertension guidelines. Epidemiologic evidence has suggested that elderly patients who are taking antihypertensive medication might be at higher risk for death. However, whether this risk exists and to what extent has remained elusive as randomized, controlled clinical trials have generally excluded very elderly individuals.
Initial data on the role of antihypertensive therapy in the very elderly emerged ~10 years ago from a meta-analysis of subjects aged ≥80 years who had been enrolled in trials. Findings from the meta-analysis suggested that antihypertensive treatment had a beneficial effect in reducing strokes, major cardiovascular events, and heart failure, although it did not show any benefit for cardiovascular death and was associated with a nonsignificant increase in all-cause death. Along with the results of the Swedish Trial in Old Patients with Hypertension 2 (STOP-Hypertension 2) trial, this meta-analysis was cited as evidence in support of the benefits of therapy in the ≥ 80 year age group in the current US national hypertension guidelines, the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7), published in 2003. Current European hypertension guidelines (2007) point out that:
"In subjects aged 80 years and over, evidence for benefits of antihypertensive treatment is as yet inconclusive. However, there is no reason for interrupting a successful and well-tolerated therapy when a patient reaches 80 years of age."
The World Health Organization/International Society of Hypertension (WHO/ISH) guidelines also point to the lack of clear evidence in very elderly patients.
The stage was thus set for a clinical trial to address this question, and it was in this context that the Hypertension in the Very Elderly Trial (HYVET), which has been called "the first morbidity/mortality trial to answer the questions of antihypertensive treatment in very elderly hypertensives," was inaugurated. The European guidelines mention the benefits of antihypertensive therapy on morbidity and mortality shown in the pilot trial for HYVET, and the 1999 WHO/ISH guidelines predicted that the main HYVET results would likely provide "reliable evidence about the benefits of blood pressure lowering therapy in this very high risk population."
Now the results of HYVET have been presented at the ACC08 meeting by trial coordinator Nigel S. Beckett, MB ChB (Imperial College London, UK) and published simultaneously in The New England Journal of Medicine. The results show that lowering BP in elderly patients can cut their total mortality by one fifth and their rate of cardiovascular events by one third. "These results will have important implications for the generation of future guidelines and mean that very elderly individuals with sustained systolic blood pressures [SBP] of 160 mm Hg or more should now be appropriately assessed and treated in accordance with the new findings," Dr. Beckett said. According to Prof. Bryan Williams, MD (University of Leicester, UK), a past president of the British Hypertension Society and advisor for the current United Kingdom and European hypertension guidelines, HYVET is "a landmark clinical trial that will change the practice of medicine across the world."
HYVET, sponsored by Imperial College London and supported by the British Heart Foundation and the Institut de Recherches Internationales Servier (Suresnes, France), was the largest randomized, controlled trial to assess the benefit-to-risk ratio of treating patients aged ≥ 80 years who have hypertension. The trial involved 3845 patients from Europe, China, Australasia, and Tunisia, with mean age at baseline of 83.6 years, about 61% female, and mean sitting BP of 173/90.8 mm Hg. Entry criteria included a SBP of 160-199 mmHg. Patients were otherwise generally healthy and living independently and not taking any other antihypertensive medications.
The active treatment regimen consisted of a diuretic, sustained release (SR) indapamide 1.5 mg, or matching placebo. The goal was a target BP of 150/80 mm Hg. To achieve this level, an angiotensin converting enzyme inhibitor (ACEI), perindopril at a dose of 2 mg increasing to 4 mg, or matching placebo once daily was added as required.
In July 2007, HYVET was stopped early on the recommendation of the independent trial data-monitoring and ethics committee. This was based on the results from the second planned interim analysis, which showed a significant reduction in the primary endpoint, fatal and nonfatal strokes, and total mortality. Median follow-up was 1.8 years. At 2 years, mean BP was 15.0/6.1 mmHg lower in the active-treatment group than in the placebo group. At 2 years, target BP had been reached by 48% of patients on active treatment compared with 19.9% of patients in the placebo group (P < .001).
Intention-to-treat analysis showed that active treatment was associated with a 30% reduction in the rate of fatal or nonfatal stroke ( Table 1 ). Although this reduction was nonsignificant, treatment resulted in significant reductions of 39% in the rate of death from stroke, 21% in the rate of death from any cause, 23% in the rate of death from cardiovascular causes, 64% in the rate of fatal or nonfatal heart failure, and 34% in cardiovascular events (defined as death from cardiovascular causes or stroke, myocardial infarction [MI], or heart failure). Benefit, especially in terms of stroke and heart failure, was seen with active treatment within the first year, Dr. Beckett noted. The reduction in stroke was not surprising, but the significant reduction in total mortality was, he said later, because this has never been shown before in patients aged ≥ 80 years.
All except 23 patients were included in a per-protocol analysis, which showed a significant reduction of 34% in all stroke as well as in other endpoints ( Table 2 ).
In patients who were followed for ≥ 2 years, no significant differences in changes from baseline were seen between the 2 groups in potassium, uric acid, glucose, or creatinine. Fewer serious adverse events were reported in the active-treatment group compared with the placebo group (358 vs 448, respectively; P = .001), and among these events, only 2 and 3 events, respectively, were considered to have been possibly related to the treatment.
Putting these results in perspective, Dr. Beckett noted that the patient population in HYVET was healthier overall than people of the same age in the general population. Therefore, although the number needed to treat over 2 years was 94 to prevent 1 stroke and 40 to prevent 1 death, this may be an overestimate, given the low rate of stroke, he suggested. He noted that further research is required to determine whether lowering SBP to < 150 mm Hg will have further benefit.
The ACC-designated commentator, C. Venakata Ram, MD (University of Texas Southwestern Medical Center, Dallas), welcomed the results, suggesting that newer guidelines should consider a special category for very old patients with appropriate definitions of BP goals. He also pointed to the reassuring absence of a "J-curve" phenomenon in the trial (ie, the theory that lowering diastolic BP [DBP] to a target < 90 mm Hg may no longer be of benefit or may even increase risk of events).
In an editorial in The New England Journal of Medicine, John B. Kostis, MD (Robert Wood Johnson Medical School, University of Medicine and Dentistry of New Jersey, New Brunswick) said that HYVET puts the question of the usefulness of treating hypertension in very aged patients to rest and provides important guidance to physicians and writers of guidelines. The findings of HYVET are consistent with those of previous trials and indicate an overall significant benefit of the treatment of hypertension in the very old, he believes. He cautioned, however, that:
In applying the findings of this trial, we should keep in mind that the patients in HYVET were healthier than normal for their age. Aging affects people to various degrees, depending on inherited characteristics, lifestyle, and disease. Like all clinical trials, those involving old persons with hypertension must also involve individualized treatment that takes into account the factors that are associated with aging as well as individual preference.
At a press conference, Prof. Williams declared that HYVET "removes uncertainty about the benefits of treating blood pressure in the very elderly and will clarify and change international guidelines." The HYVET results "confirm that the treatment of blood pressure is one of the most important medical interventions for the very elderly," he said.
Several substudies of HYVET are underway, including one designed to investigate whether the trial antihypertensive treatment will reduce the fracture rate in these very elderly subjects with hypertension. Thiazide diuretics have been shown to reduce urinary calcium, and several randomized trials have suggested that the use of a thiazide diuretic may preserve bone mineral density. Another substudy, HYVET-COG, will look at whether treatment of hypertension affected the incidence of dementia and decline in cognitive function in HYVET patients. Previous studies have suggested a link between hypertension and the development of dementia, but results have been inconclusive. Other HYVET substudies are investigating quality of life, arterial compliance, and ambulatory BP.
Guidelines for the management of hypertension invariably include sections where the evidence for or against treatment or for certain types of treatment in certain types of patients is inconclusive. The results of 3 clinical trials presented at the American College of Cardiology (ACC) 2008 meeting in Chicago address 3 of these areas of ambiguity or uncertainty and signal updates that will surely be made in future versions of the guidelines.
HYVET: Support for Antihypertensive Treatment in Patients > 80 Years Old
Since the modern age of diagnosing and treating high blood pressure (BP) began, exactly what the benefit would be to treating very elderly patients (≥ 80 years) with hypertension has been unclear, and very few mentions are made of this group in current hypertension guidelines. Epidemiologic evidence has suggested that elderly patients who are taking antihypertensive medication might be at higher risk for death. However, whether this risk exists and to what extent has remained elusive as randomized, controlled clinical trials have generally excluded very elderly individuals.
Initial data on the role of antihypertensive therapy in the very elderly emerged ~10 years ago from a meta-analysis of subjects aged ≥80 years who had been enrolled in trials. Findings from the meta-analysis suggested that antihypertensive treatment had a beneficial effect in reducing strokes, major cardiovascular events, and heart failure, although it did not show any benefit for cardiovascular death and was associated with a nonsignificant increase in all-cause death. Along with the results of the Swedish Trial in Old Patients with Hypertension 2 (STOP-Hypertension 2) trial, this meta-analysis was cited as evidence in support of the benefits of therapy in the ≥ 80 year age group in the current US national hypertension guidelines, the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7), published in 2003. Current European hypertension guidelines (2007) point out that:
"In subjects aged 80 years and over, evidence for benefits of antihypertensive treatment is as yet inconclusive. However, there is no reason for interrupting a successful and well-tolerated therapy when a patient reaches 80 years of age."
The World Health Organization/International Society of Hypertension (WHO/ISH) guidelines also point to the lack of clear evidence in very elderly patients.
The stage was thus set for a clinical trial to address this question, and it was in this context that the Hypertension in the Very Elderly Trial (HYVET), which has been called "the first morbidity/mortality trial to answer the questions of antihypertensive treatment in very elderly hypertensives," was inaugurated. The European guidelines mention the benefits of antihypertensive therapy on morbidity and mortality shown in the pilot trial for HYVET, and the 1999 WHO/ISH guidelines predicted that the main HYVET results would likely provide "reliable evidence about the benefits of blood pressure lowering therapy in this very high risk population."
Now the results of HYVET have been presented at the ACC08 meeting by trial coordinator Nigel S. Beckett, MB ChB (Imperial College London, UK) and published simultaneously in The New England Journal of Medicine. The results show that lowering BP in elderly patients can cut their total mortality by one fifth and their rate of cardiovascular events by one third. "These results will have important implications for the generation of future guidelines and mean that very elderly individuals with sustained systolic blood pressures [SBP] of 160 mm Hg or more should now be appropriately assessed and treated in accordance with the new findings," Dr. Beckett said. According to Prof. Bryan Williams, MD (University of Leicester, UK), a past president of the British Hypertension Society and advisor for the current United Kingdom and European hypertension guidelines, HYVET is "a landmark clinical trial that will change the practice of medicine across the world."
HYVET Design and Early Termination
HYVET, sponsored by Imperial College London and supported by the British Heart Foundation and the Institut de Recherches Internationales Servier (Suresnes, France), was the largest randomized, controlled trial to assess the benefit-to-risk ratio of treating patients aged ≥ 80 years who have hypertension. The trial involved 3845 patients from Europe, China, Australasia, and Tunisia, with mean age at baseline of 83.6 years, about 61% female, and mean sitting BP of 173/90.8 mm Hg. Entry criteria included a SBP of 160-199 mmHg. Patients were otherwise generally healthy and living independently and not taking any other antihypertensive medications.
The active treatment regimen consisted of a diuretic, sustained release (SR) indapamide 1.5 mg, or matching placebo. The goal was a target BP of 150/80 mm Hg. To achieve this level, an angiotensin converting enzyme inhibitor (ACEI), perindopril at a dose of 2 mg increasing to 4 mg, or matching placebo once daily was added as required.
In July 2007, HYVET was stopped early on the recommendation of the independent trial data-monitoring and ethics committee. This was based on the results from the second planned interim analysis, which showed a significant reduction in the primary endpoint, fatal and nonfatal strokes, and total mortality. Median follow-up was 1.8 years. At 2 years, mean BP was 15.0/6.1 mmHg lower in the active-treatment group than in the placebo group. At 2 years, target BP had been reached by 48% of patients on active treatment compared with 19.9% of patients in the placebo group (P < .001).
Analysis of Results
Intention-to-treat analysis showed that active treatment was associated with a 30% reduction in the rate of fatal or nonfatal stroke ( Table 1 ). Although this reduction was nonsignificant, treatment resulted in significant reductions of 39% in the rate of death from stroke, 21% in the rate of death from any cause, 23% in the rate of death from cardiovascular causes, 64% in the rate of fatal or nonfatal heart failure, and 34% in cardiovascular events (defined as death from cardiovascular causes or stroke, myocardial infarction [MI], or heart failure). Benefit, especially in terms of stroke and heart failure, was seen with active treatment within the first year, Dr. Beckett noted. The reduction in stroke was not surprising, but the significant reduction in total mortality was, he said later, because this has never been shown before in patients aged ≥ 80 years.
All except 23 patients were included in a per-protocol analysis, which showed a significant reduction of 34% in all stroke as well as in other endpoints ( Table 2 ).
In patients who were followed for ≥ 2 years, no significant differences in changes from baseline were seen between the 2 groups in potassium, uric acid, glucose, or creatinine. Fewer serious adverse events were reported in the active-treatment group compared with the placebo group (358 vs 448, respectively; P = .001), and among these events, only 2 and 3 events, respectively, were considered to have been possibly related to the treatment.
Comments and Further Studies
Putting these results in perspective, Dr. Beckett noted that the patient population in HYVET was healthier overall than people of the same age in the general population. Therefore, although the number needed to treat over 2 years was 94 to prevent 1 stroke and 40 to prevent 1 death, this may be an overestimate, given the low rate of stroke, he suggested. He noted that further research is required to determine whether lowering SBP to < 150 mm Hg will have further benefit.
The ACC-designated commentator, C. Venakata Ram, MD (University of Texas Southwestern Medical Center, Dallas), welcomed the results, suggesting that newer guidelines should consider a special category for very old patients with appropriate definitions of BP goals. He also pointed to the reassuring absence of a "J-curve" phenomenon in the trial (ie, the theory that lowering diastolic BP [DBP] to a target < 90 mm Hg may no longer be of benefit or may even increase risk of events).
In an editorial in The New England Journal of Medicine, John B. Kostis, MD (Robert Wood Johnson Medical School, University of Medicine and Dentistry of New Jersey, New Brunswick) said that HYVET puts the question of the usefulness of treating hypertension in very aged patients to rest and provides important guidance to physicians and writers of guidelines. The findings of HYVET are consistent with those of previous trials and indicate an overall significant benefit of the treatment of hypertension in the very old, he believes. He cautioned, however, that:
In applying the findings of this trial, we should keep in mind that the patients in HYVET were healthier than normal for their age. Aging affects people to various degrees, depending on inherited characteristics, lifestyle, and disease. Like all clinical trials, those involving old persons with hypertension must also involve individualized treatment that takes into account the factors that are associated with aging as well as individual preference.
At a press conference, Prof. Williams declared that HYVET "removes uncertainty about the benefits of treating blood pressure in the very elderly and will clarify and change international guidelines." The HYVET results "confirm that the treatment of blood pressure is one of the most important medical interventions for the very elderly," he said.
Several substudies of HYVET are underway, including one designed to investigate whether the trial antihypertensive treatment will reduce the fracture rate in these very elderly subjects with hypertension. Thiazide diuretics have been shown to reduce urinary calcium, and several randomized trials have suggested that the use of a thiazide diuretic may preserve bone mineral density. Another substudy, HYVET-COG, will look at whether treatment of hypertension affected the incidence of dementia and decline in cognitive function in HYVET patients. Previous studies have suggested a link between hypertension and the development of dementia, but results have been inconclusive. Other HYVET substudies are investigating quality of life, arterial compliance, and ambulatory BP.
