Treating Prehypertension
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《新英格兰医药杂志》
To the Editor: The study by Julius et al. of the efficacy of candesartan for prehypertension (April 20 issue)1 demonstrates what seemed obvious: if patients with prehypertension receive hypotensive drugs, arterial hypertension will develop in fewer of them because they are already being treated. This prediction was borne out in the study, but as compared with placebo, candesartan did not reduce cardiovascular events during the study period.
The question is, does the administration of a hypotensive drug at a fixed dose reduce the cardiovascular morbidity and mortality in patients with prehypertension, as compared with the use of nonpharmacologic treatment and the addition of hypotensive drugs only when arterial hypertension develops? In the first approach, we would be treating 100 percent of the patients with prehypertension, whereas in the second approach, we would be initiating treatment in about 40 percent of such patients within the first two years, according to the data of Julius et al. In other words, in the first approach, we would overtreat 60 percent of those with prehypertension, with the corresponding unnecessary costs. This outcome would be acceptable only if future studies find a reduced cardiovascular risk associated with drug treatment of patients with prehypertension.
Daniel G. Grassi, M.D.
Hospital Universitario Austral
1635 Pilar, Argentina
dgrassi@cas.austral.edu.ar
References
Julius S, Nesbitt SD, Egan BM, et al. Feasibility of treating prehypertension with an angiotensin-receptor blocker. N Engl J Med 2006;354:1685-1697.
To the Editor: Julius et al. propose active treatment with candesartan (an angiotensin-receptor blocker) in patients with prehypertension, despite the apparent absence of other concomitant cardiovascular risk factors, citing the lack of evidence of the long-term efficacy of lifestyle approaches. We should not forget, however, that the increasing incidence of hypertension and cardiovascular diseases is directly related to changes in lifestyle and eating patterns. Lowering the threshold for the initiation of pharmacologic therapy would have a tremendous economic effect on public health care systems and would probably not solve the problem if the trend toward obesity and a sedentary lifestyle continues to rise, requiring a further lowering of the threshold.
The Dietary Approaches to Stop Hypertension trial1 established that dietary changes may not only lower blood pressure but also may have other beneficial effects. There are few long-term studies of dietary interventions,2 probably because of the lack of commercial interest, but this does not necessarily imply an absence of efficacy. An effort should be made to implement programs that could engage people to adopt healthful lifestyles for the long term. Until then, we may just prescribe tablets.
Yaiza Lopez-Plasencia, M.D.
Raul Amela-Peris, M.D.
Hospital Universitario Insular
35016 Las Palmas de Gran Carneria, Spain
yloppla@gobiernodecanarias.org
Yaiza Garcia-Delgado, Ph.D.
Hospital General de Lanzarote
3550 Las Palmas, Spain
References
Appel LJ, Moore TJ, Obarzanek E, et al. A clinical trial of the effects of dietary patterns on blood pressure. N Engl J Med 1997;336:1117-1124.
Miura K, Nakagawa H. Can dietary changes reduce blood pressure in the long term? Curr Opin Nephrol Hypertens 2005;14:253-257.
To the Editor: Julius et al. report that over 60 percent of patients with prehypertension in the placebo group received a diagnosis of hypertension during follow-up. We are concerned that this percentage is overestimated. If we consider a hypothetical patient with three consecutive screening blood-pressure values of 140/88 mm Hg, 142/85 mm Hg, and 132/91 mm Hg, this patient would fulfill the inclusion criteria for prehypertension (mean blood pressure, 138/88 mm Hg). If this patient were randomly assigned to the placebo group and had the same three blood-pressure values during follow-up (as would be expected without therapy to lower blood pressure), the patient would be classified as having hypertension according to the study end-point criteria.
Thus, a part of the high conversion rate from prehypertension to hypertension may be explained by the definitions used by the Trial of Preventing Hypertension (TROPHY) study investigators and not by disease progression. There is considerable interindividual variability in blood-pressure measurements obtained in a physician's office.1 Since the variability in home blood-pressure measurement is lower,2 this method may give more precise information about the real rate of progression of blood pressure in the study population. Could the authors provide more details about the use of home measurements of blood pressure?
David Conen, M.D.
Benedict Martina, M.D.
University Hospital Basel
CH-4031 Basel, Switzerland
conend@uhbs.ch
References
Mansoor GA, McCabe EJ, White WB. Long-term reproducibility of ambulatory blood pressure. J Hypertens 1994;12:703-708.
Baguet JP, Mallion JM. Self-monitoring of blood pressure should be used in clinical trials. Blood Press Monit 2002;7:55-59.
To the Editor: Julius and coworkers demonstrate that hypertension can be prevented or delayed in persons with high-normal blood pressure (also known as prehypertension). With increasing age, irreversible vascular changes due to hypertrophy or atherosclerosis might diminish the long-term response to temporary antihypertensive treatment.1,2 The subgroup analysis in the TROPHY study suggests, however, that there is no difference in the incidence of new-onset hypertension between younger and older persons. However, this analysis does not exclude the possibility that there may be a substantial difference between patients who have a response to treatment and those who do not have a response. Was there any age-related difference in terms of absolute blood-pressure reduction?
We notice a large difference between the rate of progression to hypertension of 63.0 percent in the placebo group in the TROPHY study and the 37.3 percent rate of progression from prehypertension to frank hypertension reported in the Framingham Study after four years of follow-up.3 We wonder whether the differences might be explained by the recruitment strategy used in the TROPHY study.
Marcus Baumann, M.D.
Cardiovascular Research Institute Maastricht
6200 MD Maastricht, the Netherlands
m.baumann@farmaco.unimaas.nl
Bert-Jan van den Born, M.D.
Academic Medical Centre
1100 DD Amsterdam, the Netherlands
References
Levy D, Garrison RJ, Savage DD, Kannel WB, Castelli WP. Prognostic implications of echocardiographically determined left ventricular mass in the Framingham Heart Study. N Engl J Med 1990;322:1561-1566.
Stokes J III, Kannel WB, Wolf PA, Cupples LA, D'Agostino RB. The relative importance of selected risk factors for various manifestations of cardiovascular disease among men and women from 35 to 64 years old: 30 years of follow-up in the Framingham Study. Circulation 1987;75:V65-V73.
Vasan RS, Larson MG, Leip EP, Kannel WB Levy D. Assessment of frequency of progression to hypertension in non-hypertensive participants in the Framingham Heart Study: a cohort study. Lancet 2001;358:1682-1686.
The authors reply: The results of the TROPHY study might appear obvious to Grassi, but when we designed the study it was unclear whether patients with prehypertension would have hypotensive side effects or whether near-normal blood pressures would be resistant to treatment. It was not a forgone conclusion that active treatment would suppress hypertension two years after the discontinuation of pills. By showing the feasibility of treatment, we hope to open the door to further studies. In the Discussion section, like Grassi, we recommended "a study of clinical outcomes with pharmacologic intervention in prehypertension."
Lopez-Plasencia and colleagues are right: lifestyle modification has benefits beyond blood-pressure lowering. Unfortunately, appeals to patients to do the right thing frequently fail. In the Framingham Study,1 only 8 percent of patients with prehypertension substantially decreased their weight. Worldwide and in the United States, populations are becoming heavier, and the incidence of hypertension certainly has not decreased. Against this background, it is appropriate to investigate pharmacologic treatment. The cost argument might not be valid. Early pharmacologic intervention could increase a person's productive years and reduce or at least significantly delay the costly burden of cardiovascular and renal disease.
We would respond to Conen and Martina by pointing out that because of the continuous distribution of blood pressures in the population, all definitions of hypertension are arbitrary. The average mean blood pressure of the hypothetical patient in their letter is 104.8 mm Hg, as compared with a mean blood pressure of 101.2 mm Hg in the placebo group on entry into the TROPHY study. The consequences of hypertension correlate positively with the prevailing blood pressure, and a difference of 3.6 mm Hg in the mean pressure might not be inconsequential. The home blood-pressure reading was taken at baseline and once a year thereafter. Home measurements were not obtained at the time of the end-point analysis.
As Baumann and van den Born suggest, the incidence rates of hypertension in our trial reflect our recruitment strategy. To select high-risk subjects, we stipulated that the additive average of three readings per session on three consecutive clinic visits must be in the high-normal range. Our conclusions apply only to subjects with similar selection criteria. In a reanalysis of subjects 40 years of age or younger, the adjusted odds ratio for hypertension at the end of the study among younger subjects was 0.78 (P=0.46), as compared with 0.64 among older subjects (P=0.006). Data from this small subgroup (18.6 percent) may generate hypotheses for larger trials. Do people who cross the border to prehypertension earlier have more extensive vascular damage? Would prolonged treatment periods or the use of lower blood-pressure targets yield better results?
Stevo Julius, M.D., Sc.D.
University of Michigan
Ann Arbor, MI 48106
sjulius@umich.edu
Shawna D. Nesbitt, M.D.
University of Texas Southwestern Medical Center at Dallas
Dallas, TX 75390
Brent M. Egan, M.D.
Medical University of South Carolina
Charleston, SC 29425
References
Moore LL, Visioni AJ, Qureshi MM, Bradlee ML, Ellison RC, D'Agostino R. Weight loss in overweight adults and the long-term risk of hypertension: the Framingham study. Arch Intern Med 2005;165:1298-1303.
The question is, does the administration of a hypotensive drug at a fixed dose reduce the cardiovascular morbidity and mortality in patients with prehypertension, as compared with the use of nonpharmacologic treatment and the addition of hypotensive drugs only when arterial hypertension develops? In the first approach, we would be treating 100 percent of the patients with prehypertension, whereas in the second approach, we would be initiating treatment in about 40 percent of such patients within the first two years, according to the data of Julius et al. In other words, in the first approach, we would overtreat 60 percent of those with prehypertension, with the corresponding unnecessary costs. This outcome would be acceptable only if future studies find a reduced cardiovascular risk associated with drug treatment of patients with prehypertension.
Daniel G. Grassi, M.D.
Hospital Universitario Austral
1635 Pilar, Argentina
dgrassi@cas.austral.edu.ar
References
Julius S, Nesbitt SD, Egan BM, et al. Feasibility of treating prehypertension with an angiotensin-receptor blocker. N Engl J Med 2006;354:1685-1697.
To the Editor: Julius et al. propose active treatment with candesartan (an angiotensin-receptor blocker) in patients with prehypertension, despite the apparent absence of other concomitant cardiovascular risk factors, citing the lack of evidence of the long-term efficacy of lifestyle approaches. We should not forget, however, that the increasing incidence of hypertension and cardiovascular diseases is directly related to changes in lifestyle and eating patterns. Lowering the threshold for the initiation of pharmacologic therapy would have a tremendous economic effect on public health care systems and would probably not solve the problem if the trend toward obesity and a sedentary lifestyle continues to rise, requiring a further lowering of the threshold.
The Dietary Approaches to Stop Hypertension trial1 established that dietary changes may not only lower blood pressure but also may have other beneficial effects. There are few long-term studies of dietary interventions,2 probably because of the lack of commercial interest, but this does not necessarily imply an absence of efficacy. An effort should be made to implement programs that could engage people to adopt healthful lifestyles for the long term. Until then, we may just prescribe tablets.
Yaiza Lopez-Plasencia, M.D.
Raul Amela-Peris, M.D.
Hospital Universitario Insular
35016 Las Palmas de Gran Carneria, Spain
yloppla@gobiernodecanarias.org
Yaiza Garcia-Delgado, Ph.D.
Hospital General de Lanzarote
3550 Las Palmas, Spain
References
Appel LJ, Moore TJ, Obarzanek E, et al. A clinical trial of the effects of dietary patterns on blood pressure. N Engl J Med 1997;336:1117-1124.
Miura K, Nakagawa H. Can dietary changes reduce blood pressure in the long term? Curr Opin Nephrol Hypertens 2005;14:253-257.
To the Editor: Julius et al. report that over 60 percent of patients with prehypertension in the placebo group received a diagnosis of hypertension during follow-up. We are concerned that this percentage is overestimated. If we consider a hypothetical patient with three consecutive screening blood-pressure values of 140/88 mm Hg, 142/85 mm Hg, and 132/91 mm Hg, this patient would fulfill the inclusion criteria for prehypertension (mean blood pressure, 138/88 mm Hg). If this patient were randomly assigned to the placebo group and had the same three blood-pressure values during follow-up (as would be expected without therapy to lower blood pressure), the patient would be classified as having hypertension according to the study end-point criteria.
Thus, a part of the high conversion rate from prehypertension to hypertension may be explained by the definitions used by the Trial of Preventing Hypertension (TROPHY) study investigators and not by disease progression. There is considerable interindividual variability in blood-pressure measurements obtained in a physician's office.1 Since the variability in home blood-pressure measurement is lower,2 this method may give more precise information about the real rate of progression of blood pressure in the study population. Could the authors provide more details about the use of home measurements of blood pressure?
David Conen, M.D.
Benedict Martina, M.D.
University Hospital Basel
CH-4031 Basel, Switzerland
conend@uhbs.ch
References
Mansoor GA, McCabe EJ, White WB. Long-term reproducibility of ambulatory blood pressure. J Hypertens 1994;12:703-708.
Baguet JP, Mallion JM. Self-monitoring of blood pressure should be used in clinical trials. Blood Press Monit 2002;7:55-59.
To the Editor: Julius and coworkers demonstrate that hypertension can be prevented or delayed in persons with high-normal blood pressure (also known as prehypertension). With increasing age, irreversible vascular changes due to hypertrophy or atherosclerosis might diminish the long-term response to temporary antihypertensive treatment.1,2 The subgroup analysis in the TROPHY study suggests, however, that there is no difference in the incidence of new-onset hypertension between younger and older persons. However, this analysis does not exclude the possibility that there may be a substantial difference between patients who have a response to treatment and those who do not have a response. Was there any age-related difference in terms of absolute blood-pressure reduction?
We notice a large difference between the rate of progression to hypertension of 63.0 percent in the placebo group in the TROPHY study and the 37.3 percent rate of progression from prehypertension to frank hypertension reported in the Framingham Study after four years of follow-up.3 We wonder whether the differences might be explained by the recruitment strategy used in the TROPHY study.
Marcus Baumann, M.D.
Cardiovascular Research Institute Maastricht
6200 MD Maastricht, the Netherlands
m.baumann@farmaco.unimaas.nl
Bert-Jan van den Born, M.D.
Academic Medical Centre
1100 DD Amsterdam, the Netherlands
References
Levy D, Garrison RJ, Savage DD, Kannel WB, Castelli WP. Prognostic implications of echocardiographically determined left ventricular mass in the Framingham Heart Study. N Engl J Med 1990;322:1561-1566.
Stokes J III, Kannel WB, Wolf PA, Cupples LA, D'Agostino RB. The relative importance of selected risk factors for various manifestations of cardiovascular disease among men and women from 35 to 64 years old: 30 years of follow-up in the Framingham Study. Circulation 1987;75:V65-V73.
Vasan RS, Larson MG, Leip EP, Kannel WB Levy D. Assessment of frequency of progression to hypertension in non-hypertensive participants in the Framingham Heart Study: a cohort study. Lancet 2001;358:1682-1686.
The authors reply: The results of the TROPHY study might appear obvious to Grassi, but when we designed the study it was unclear whether patients with prehypertension would have hypotensive side effects or whether near-normal blood pressures would be resistant to treatment. It was not a forgone conclusion that active treatment would suppress hypertension two years after the discontinuation of pills. By showing the feasibility of treatment, we hope to open the door to further studies. In the Discussion section, like Grassi, we recommended "a study of clinical outcomes with pharmacologic intervention in prehypertension."
Lopez-Plasencia and colleagues are right: lifestyle modification has benefits beyond blood-pressure lowering. Unfortunately, appeals to patients to do the right thing frequently fail. In the Framingham Study,1 only 8 percent of patients with prehypertension substantially decreased their weight. Worldwide and in the United States, populations are becoming heavier, and the incidence of hypertension certainly has not decreased. Against this background, it is appropriate to investigate pharmacologic treatment. The cost argument might not be valid. Early pharmacologic intervention could increase a person's productive years and reduce or at least significantly delay the costly burden of cardiovascular and renal disease.
We would respond to Conen and Martina by pointing out that because of the continuous distribution of blood pressures in the population, all definitions of hypertension are arbitrary. The average mean blood pressure of the hypothetical patient in their letter is 104.8 mm Hg, as compared with a mean blood pressure of 101.2 mm Hg in the placebo group on entry into the TROPHY study. The consequences of hypertension correlate positively with the prevailing blood pressure, and a difference of 3.6 mm Hg in the mean pressure might not be inconsequential. The home blood-pressure reading was taken at baseline and once a year thereafter. Home measurements were not obtained at the time of the end-point analysis.
As Baumann and van den Born suggest, the incidence rates of hypertension in our trial reflect our recruitment strategy. To select high-risk subjects, we stipulated that the additive average of three readings per session on three consecutive clinic visits must be in the high-normal range. Our conclusions apply only to subjects with similar selection criteria. In a reanalysis of subjects 40 years of age or younger, the adjusted odds ratio for hypertension at the end of the study among younger subjects was 0.78 (P=0.46), as compared with 0.64 among older subjects (P=0.006). Data from this small subgroup (18.6 percent) may generate hypotheses for larger trials. Do people who cross the border to prehypertension earlier have more extensive vascular damage? Would prolonged treatment periods or the use of lower blood-pressure targets yield better results?
Stevo Julius, M.D., Sc.D.
University of Michigan
Ann Arbor, MI 48106
sjulius@umich.edu
Shawna D. Nesbitt, M.D.
University of Texas Southwestern Medical Center at Dallas
Dallas, TX 75390
Brent M. Egan, M.D.
Medical University of South Carolina
Charleston, SC 29425
References
Moore LL, Visioni AJ, Qureshi MM, Bradlee ML, Ellison RC, D'Agostino R. Weight loss in overweight adults and the long-term risk of hypertension: the Framingham study. Arch Intern Med 2005;165:1298-1303.