Pharmacotherapy for Prehypertension — Mission Accomplished?
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《新英格兰医药杂志》
Prehypertension, defined as the blood-pressure range of 120 to 139 mm Hg systolic or 80 to 89 mm Hg diastolic, is present in about 70 million Americans.1,2 The condition heralds arterial hypertension and thus may be considered a starting point in the cardiovascular disease continuum. Because of its high prevalence and long-term complications, prehypertension has been estimated to decrease the average life expectancy by as much as five years.3,4,5 Unfortunately, current preventive strategies, although admirable from both individual and societal perspectives, are weak.
In this issue of the Journal, the investigators of the Trial of Preventing Hypertension (TROPHY) present data from a study of pharmacologic intervention for the prevention of hypertension.6 In their report, Julius and colleagues propose that inhibition of the renin–angiotensin system in persons with prehypertension may interfere with a self-accelerating process leading to hypertension and, ultimately, target-organ damage. Indeed, in young rats with spontaneous hypertension, in a model of essential hypertension, angiotensin-converting–enzyme inhibitors delayed the onset of hypertension far beyond the active treatment period.7
In the TROPHY study, 772 participants with blood pressures in the range of 130 to 139 mm Hg systolic or 85 to 89 mm Hg diastolic, or both — that is, in the upper half of the spectrum defined as prehypertensive — were treated for two years with either the angiotensin-receptor blocker candesartan or placebo (the first phase of the study).6 The two groups then received placebo for an additional two years (second phase). The end point, stage 1 hypertension, was reached in most cases when a single blood pressure reading at a clinic visit was higher than 159/99 mm Hg or when readings on three clinic visits, averaged, were higher than 139 mm Hg systolic or 89 mm Hg diastolic.
Two years after active treatment had been stopped, hypertension was observed less frequently among participants in the candesartan group than among those in the placebo group. Specifically, transient treatment with an angiotensin-receptor blocker was subsequently related to a significant absolute difference of 9.8 percent between the two groups and a relative risk reduction of 15.6 percent for the development of hypertension at the end of the four-year study. Moreover, there were slightly lower blood-pressure readings and fewer participants receiving antihypertensive medication among those formerly in the candesartan group. The authors conclude that administering an angiotensin-receptor blocker for two years postponed the manifestation of stage 1 arterial hypertension for a prolonged period.6
A number of scientific implications may be inferred from these results. Chiefly, medical treatment of prehypertension does not simply mask the subsequent development of overt hypertension. Rather, important effects can be observed, even if treatment with an angiotensin-receptor blocker is followed by a long period of placebo "washout." Thus, these investigators successfully tested the hypothesis that prehypertensive levels of blood pressure and the intimately involved renin–angiotensin system, together or separately, are key players in a vicious circle that ultimately leads to new-onset hypertension.
However, some of the study data should be interpreted with caution. In epidemiologic studies, by definition, the need for medical treatment with antihypertensive agents such as candesartan would fulfill the criteria for arterial hypertension. In this study, candesartan treatment was omitted from the list of criteria defining the end point of hypertension. Had it not been omitted, the average number of months in which participants took antihypertensive drugs would actually have been higher in the candesartan group.
Even more crucial to the interpretation of the data is the fact that the end point, stage 1 hypertension, was reached in most participants according to the criterion of three clinic blood-pressure measurements averaged. Inevitably, the profound decrease in blood pressure induced by active treatment with candesartan masked, rather than prevented, this end point during the first phase of the study. In addition, active treatment might also have affected the length of time until this end point was reached during the following placebo period. On the one hand, in years 1 and 2, the likelihood of having blood-pressure readings close to 140/90 mm Hg was greater in the placebo group than in the candesartan group, as was the likelihood of starting months 25 to 48 with one or two readings from the previous two-year period that were above the borderline blood-pressure cutoff point. For such persons in the placebo group, only a single additional reading above 140 mm Hg systolic or 90 mm Hg diastolic would have qualified them for the end point. On the other hand, relatively low readings in those receiving candesartan during months 1 through 24 decreased the average blood pressure during that period as well as the average when months 25, 27, and beyond are added to the equation.
In other words, the candesartan-related reduction in blood pressure may have slowed the buildup of an average blood pressure to above 140/90 mm Hg during the second phase (years 3 and 4), when all study patients received placebo, and thus artifactually delayed the end point. Moreover, the proportion of participants in the placebo group who were started on antihypertensive medication during years 1 and 2 and the proportion of those in the candesartan group who were started on antihypertensive medication during years 3 and 4 (when the candesartan group was assigned to placebo) was almost identical (40.4 percent and 39.6 percent, respectively). All these points, taken together, suggest that because of the study design the difference between the two groups with respect to true prevention of hypertension may have been overestimated.
What are the clinical implications of all these findings? Ultimately, it is important to learn whether any target-organ damage can be prevented by drug treatment of persons with prehypertension. In this respect, current guidelines have moved the focus from the treatment of individual risk factors toward the treatment of persons with high global risk.1 This shift implies that prehypertension should be explored in conjunction with other risk factors or manifestations of vascular disease. Most people with prehypertension have at least one additional risk factor.8 The Atherosclerosis Risk in Communities (ARIC) study recently showed that complications associated with prehypertension are largely affected by many of these cofactors, including obesity.9 In the future, it will be important to ask whether particular demographic characteristics (age, sex, and race or ethnic group) and risk factors enhance the benefit of pharmacologic treatment in people who have prehypertension but are otherwise healthy. With respect to patients with prehypertension who have diabetes mellitus and chronic kidney disease, the data are already fairly clear.1 In fact, current guidelines recommend medical treatment of such patients if a trial of lifestyle modification fails to reduce blood pressure below 130/80 mm Hg.1 Moreover, antihypertensive treatment in patients with blood pressure in the prehypertensive range and coexisting vascular conditions may improve organ protection.10
Another important finding in the present study and other studies is the high rate of progression from prehypertension to hypertension.3,6 Thus, a reason for medical treatment of prehypertension — aside from preventing end-organ damage — may be to change the natural course of the condition. However, in this study, irrespective of the treatment group, more than 50 percent of the relatively young persons with prehypertension ended up having newly diagnosed hypertension. Thus, even a two-year course of preventive medication in combination with lifestyle interventions, as used by these investigators, fell short of entirely blocking the progression from prehypertension to the hypertensive stage.
Currently, recommendations for the management of prehypertension propose a healthful diet including sodium restriction, enhanced physical activity, weight loss, and moderation of alcohol intake.11 Such lifestyle interventions modulate more than a single risk factor. Moreover, such programs may directly address the mechanisms augmenting the epidemic growth of obesity, diabetes, and prehypertension and hypertension in Western societies.12 Is further improvement possible through pharmacotherapy? It is more convenient than the other interventions, to be sure. However, for the time being, too many questions remain open. Foremost, we need to understand the price in terms of patient safety and, possibly, prohibitive financial costs of what would approach population-wide drug treatment. Moreover, if there is a future for drug treatment of prehypertension, we need to learn who should be treated, for how many years, and with which drug and at what dose. For now, a healthy lifestyle is the foundation for all therapies in persons with prehypertension. This is still true even after the lessons of the TROPHY study. Ultimately, another battle must be won — that of successful control of blood pressure in millions of patients who have established hypertension.
Supported by grants from the Bundesministerium für Bildung und Forschung (BMBF-NGFN2 and Kompetenznetz Herzinsuffizienz) and the Deutsche Forschungsgemeinschaft (Schu672/14-1).
Dr. Schunkert reports having received lecture fees and consulting fees from MSD, Novartis, and Sanofi-Aventis and lecture fees from Pfizer and AstraZeneca. No other potential conflict of interest relevant to this article was reported.
I am indebted to Renate Domeier for expert secretarial assistance.
Source Information
From the Medizinische Klinik, University of Lübeck, Lübeck, Germany.
This article was published at www.nejm.org on March 14, 2006.
References
Chobanian AV, Bakris GL, Black HR, et al. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report. JAMA 2003;289:2560-2572.
Qureshi AI, Suri MF, Kirmani JF, Divani AA. Prevalence and trends of prehypertension and hypertension in United States: National Health and Nutrition Examination Surveys 1976 to 2000. Med Sci Monit 2005;11:CR403-CR409.
Vasan RS, Larson MG, Leip EP, et al. Impact of high-normal blood pressure on the risk of cardiovascular disease. N Engl J Med 2001;345:1291-1297.
Franco OH, Peeters A, Bonneux L, de Laet C. Blood pressure in adulthood and life expectancy with cardiovascular disease in men and women: life course analysis. Hypertension 2005;46:280-286.
Russell LB, Valiyeva E, Carson JL. Effects of prehypertension on admissions and deaths: a simulation. Arch Intern Med 2004;164:2119-2124.
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.
Harrap SB, Van der Merwe WM, Griffin SA, Macpherson F, Lever AF. Brief angiotensin converting enzyme inhibitor treatment in young spontaneously hypertensive rats reduces blood pressure long-term. Hypertension 1990;16:603-614.
Liszka HA, Mainous AG III, King DE, Everett CJ, Egan BM. Prehypertension and cardiovascular morbidity. Ann Fam Med 2005;3:294-299.
Kshirsagar AV, Carpenter M, Bang H, Wyatt SB, Colindres RE. Blood pressure usually considered normal is associated with an elevated risk of cardiovascular disease. Am J Med 2006;119:133-141.
Nissen SE, Tuzcu EM, Libby P, et al. Effect of antihypertensive agents on cardiovascular events in patients with coronary disease and normal blood pressure: the CAMELOT study: a randomized controlled trial. JAMA 2004;292:2217-2225.
Svetkey LP. Management of prehypertension. Hypertension 2005;45:1056-1061.
Tuomilehto J, Lindstr?m J, Eriksson JG, et al. Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance. N Engl J Med 2001;344:1343-1350.(Heribert Schunkert, M.D.)
In this issue of the Journal, the investigators of the Trial of Preventing Hypertension (TROPHY) present data from a study of pharmacologic intervention for the prevention of hypertension.6 In their report, Julius and colleagues propose that inhibition of the renin–angiotensin system in persons with prehypertension may interfere with a self-accelerating process leading to hypertension and, ultimately, target-organ damage. Indeed, in young rats with spontaneous hypertension, in a model of essential hypertension, angiotensin-converting–enzyme inhibitors delayed the onset of hypertension far beyond the active treatment period.7
In the TROPHY study, 772 participants with blood pressures in the range of 130 to 139 mm Hg systolic or 85 to 89 mm Hg diastolic, or both — that is, in the upper half of the spectrum defined as prehypertensive — were treated for two years with either the angiotensin-receptor blocker candesartan or placebo (the first phase of the study).6 The two groups then received placebo for an additional two years (second phase). The end point, stage 1 hypertension, was reached in most cases when a single blood pressure reading at a clinic visit was higher than 159/99 mm Hg or when readings on three clinic visits, averaged, were higher than 139 mm Hg systolic or 89 mm Hg diastolic.
Two years after active treatment had been stopped, hypertension was observed less frequently among participants in the candesartan group than among those in the placebo group. Specifically, transient treatment with an angiotensin-receptor blocker was subsequently related to a significant absolute difference of 9.8 percent between the two groups and a relative risk reduction of 15.6 percent for the development of hypertension at the end of the four-year study. Moreover, there were slightly lower blood-pressure readings and fewer participants receiving antihypertensive medication among those formerly in the candesartan group. The authors conclude that administering an angiotensin-receptor blocker for two years postponed the manifestation of stage 1 arterial hypertension for a prolonged period.6
A number of scientific implications may be inferred from these results. Chiefly, medical treatment of prehypertension does not simply mask the subsequent development of overt hypertension. Rather, important effects can be observed, even if treatment with an angiotensin-receptor blocker is followed by a long period of placebo "washout." Thus, these investigators successfully tested the hypothesis that prehypertensive levels of blood pressure and the intimately involved renin–angiotensin system, together or separately, are key players in a vicious circle that ultimately leads to new-onset hypertension.
However, some of the study data should be interpreted with caution. In epidemiologic studies, by definition, the need for medical treatment with antihypertensive agents such as candesartan would fulfill the criteria for arterial hypertension. In this study, candesartan treatment was omitted from the list of criteria defining the end point of hypertension. Had it not been omitted, the average number of months in which participants took antihypertensive drugs would actually have been higher in the candesartan group.
Even more crucial to the interpretation of the data is the fact that the end point, stage 1 hypertension, was reached in most participants according to the criterion of three clinic blood-pressure measurements averaged. Inevitably, the profound decrease in blood pressure induced by active treatment with candesartan masked, rather than prevented, this end point during the first phase of the study. In addition, active treatment might also have affected the length of time until this end point was reached during the following placebo period. On the one hand, in years 1 and 2, the likelihood of having blood-pressure readings close to 140/90 mm Hg was greater in the placebo group than in the candesartan group, as was the likelihood of starting months 25 to 48 with one or two readings from the previous two-year period that were above the borderline blood-pressure cutoff point. For such persons in the placebo group, only a single additional reading above 140 mm Hg systolic or 90 mm Hg diastolic would have qualified them for the end point. On the other hand, relatively low readings in those receiving candesartan during months 1 through 24 decreased the average blood pressure during that period as well as the average when months 25, 27, and beyond are added to the equation.
In other words, the candesartan-related reduction in blood pressure may have slowed the buildup of an average blood pressure to above 140/90 mm Hg during the second phase (years 3 and 4), when all study patients received placebo, and thus artifactually delayed the end point. Moreover, the proportion of participants in the placebo group who were started on antihypertensive medication during years 1 and 2 and the proportion of those in the candesartan group who were started on antihypertensive medication during years 3 and 4 (when the candesartan group was assigned to placebo) was almost identical (40.4 percent and 39.6 percent, respectively). All these points, taken together, suggest that because of the study design the difference between the two groups with respect to true prevention of hypertension may have been overestimated.
What are the clinical implications of all these findings? Ultimately, it is important to learn whether any target-organ damage can be prevented by drug treatment of persons with prehypertension. In this respect, current guidelines have moved the focus from the treatment of individual risk factors toward the treatment of persons with high global risk.1 This shift implies that prehypertension should be explored in conjunction with other risk factors or manifestations of vascular disease. Most people with prehypertension have at least one additional risk factor.8 The Atherosclerosis Risk in Communities (ARIC) study recently showed that complications associated with prehypertension are largely affected by many of these cofactors, including obesity.9 In the future, it will be important to ask whether particular demographic characteristics (age, sex, and race or ethnic group) and risk factors enhance the benefit of pharmacologic treatment in people who have prehypertension but are otherwise healthy. With respect to patients with prehypertension who have diabetes mellitus and chronic kidney disease, the data are already fairly clear.1 In fact, current guidelines recommend medical treatment of such patients if a trial of lifestyle modification fails to reduce blood pressure below 130/80 mm Hg.1 Moreover, antihypertensive treatment in patients with blood pressure in the prehypertensive range and coexisting vascular conditions may improve organ protection.10
Another important finding in the present study and other studies is the high rate of progression from prehypertension to hypertension.3,6 Thus, a reason for medical treatment of prehypertension — aside from preventing end-organ damage — may be to change the natural course of the condition. However, in this study, irrespective of the treatment group, more than 50 percent of the relatively young persons with prehypertension ended up having newly diagnosed hypertension. Thus, even a two-year course of preventive medication in combination with lifestyle interventions, as used by these investigators, fell short of entirely blocking the progression from prehypertension to the hypertensive stage.
Currently, recommendations for the management of prehypertension propose a healthful diet including sodium restriction, enhanced physical activity, weight loss, and moderation of alcohol intake.11 Such lifestyle interventions modulate more than a single risk factor. Moreover, such programs may directly address the mechanisms augmenting the epidemic growth of obesity, diabetes, and prehypertension and hypertension in Western societies.12 Is further improvement possible through pharmacotherapy? It is more convenient than the other interventions, to be sure. However, for the time being, too many questions remain open. Foremost, we need to understand the price in terms of patient safety and, possibly, prohibitive financial costs of what would approach population-wide drug treatment. Moreover, if there is a future for drug treatment of prehypertension, we need to learn who should be treated, for how many years, and with which drug and at what dose. For now, a healthy lifestyle is the foundation for all therapies in persons with prehypertension. This is still true even after the lessons of the TROPHY study. Ultimately, another battle must be won — that of successful control of blood pressure in millions of patients who have established hypertension.
Supported by grants from the Bundesministerium für Bildung und Forschung (BMBF-NGFN2 and Kompetenznetz Herzinsuffizienz) and the Deutsche Forschungsgemeinschaft (Schu672/14-1).
Dr. Schunkert reports having received lecture fees and consulting fees from MSD, Novartis, and Sanofi-Aventis and lecture fees from Pfizer and AstraZeneca. No other potential conflict of interest relevant to this article was reported.
I am indebted to Renate Domeier for expert secretarial assistance.
Source Information
From the Medizinische Klinik, University of Lübeck, Lübeck, Germany.
This article was published at www.nejm.org on March 14, 2006.
References
Chobanian AV, Bakris GL, Black HR, et al. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report. JAMA 2003;289:2560-2572.
Qureshi AI, Suri MF, Kirmani JF, Divani AA. Prevalence and trends of prehypertension and hypertension in United States: National Health and Nutrition Examination Surveys 1976 to 2000. Med Sci Monit 2005;11:CR403-CR409.
Vasan RS, Larson MG, Leip EP, et al. Impact of high-normal blood pressure on the risk of cardiovascular disease. N Engl J Med 2001;345:1291-1297.
Franco OH, Peeters A, Bonneux L, de Laet C. Blood pressure in adulthood and life expectancy with cardiovascular disease in men and women: life course analysis. Hypertension 2005;46:280-286.
Russell LB, Valiyeva E, Carson JL. Effects of prehypertension on admissions and deaths: a simulation. Arch Intern Med 2004;164:2119-2124.
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.
Harrap SB, Van der Merwe WM, Griffin SA, Macpherson F, Lever AF. Brief angiotensin converting enzyme inhibitor treatment in young spontaneously hypertensive rats reduces blood pressure long-term. Hypertension 1990;16:603-614.
Liszka HA, Mainous AG III, King DE, Everett CJ, Egan BM. Prehypertension and cardiovascular morbidity. Ann Fam Med 2005;3:294-299.
Kshirsagar AV, Carpenter M, Bang H, Wyatt SB, Colindres RE. Blood pressure usually considered normal is associated with an elevated risk of cardiovascular disease. Am J Med 2006;119:133-141.
Nissen SE, Tuzcu EM, Libby P, et al. Effect of antihypertensive agents on cardiovascular events in patients with coronary disease and normal blood pressure: the CAMELOT study: a randomized controlled trial. JAMA 2004;292:2217-2225.
Svetkey LP. Management of prehypertension. Hypertension 2005;45:1056-1061.
Tuomilehto J, Lindstr?m J, Eriksson JG, et al. Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance. N Engl J Med 2001;344:1343-1350.(Heribert Schunkert, M.D.)