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难治性高血压指南

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难治性高血压指南 ISSN: 1524-4563 Copyright © 2008 American Heart Association. All rights reserved. Print ISSN: 0194-911X. Online 72514 Hypertension is published by the American Heart Association. 7272 Greenville Avenue, Dallas, TX DOI: 10.1161/HYPERTENSIONAHA.108.189141 2008;5...
难治性高血压指南
ISSN: 1524-4563 Copyright © 2008 American Heart Association. All rights reserved. Print ISSN: 0194-911X. Online 72514 Hypertension is published by the American Heart Association. 7272 Greenville Avenue, Dallas, TX DOI: 10.1161/HYPERTENSIONAHA.108.189141 2008;51;1403-1419; originally published online Apr 7, 2008; Hypertension Keith Ferdinand, Thomas D. Giles, Bonita Falkner and Robert M. Carey Sica,Robert D. Toto, Anthony White, William C. Cushman, William White, Domenic David A. Calhoun, Daniel Jones, Stephen Textor, David C. Goff, Timothy P. Murphy, Committee of the Council for High Blood Pressure Research Statement From the American Heart Association Professional Education Resistant Hypertension: Diagnosis, Evaluation, and Treatment: A Scientific http://hyper.ahajournals.org/cgi/content/full/51/6/1403 located on the World Wide Web at: The online version of this article, along with updated information and services, is http://www.lww.com/reprints Reprints: Information about reprints can be found online at journalpermissions@lww.com 410-528-8550. E-mail: Fax:Kluwer Health, 351 West Camden Street, Baltimore, MD 21202-2436. Phone: 410-528-4050. Permissions: Permissions & Rights Desk, Lippincott Williams & Wilkins, a division of Wolters http://hyper.ahajournals.org/subscriptions/ Subscriptions: Information about subscribing to Hypertension is online at by on April 16, 2010 hyper.ahajournals.orgDownloaded from Resistant Hypertension: Diagnosis, Evaluation, and Treatment A Scientific Statement From the American Heart Association Professional Education Committee of the Council for High Blood Pressure Research David A. Calhoun, MD, FAHA, Chair; Daniel Jones, MD, FAHA; Stephen Textor, MD, FAHA; David C. Goff, MD, FAHA; Timothy P. Murphy, MD, FAHA; Robert D. Toto, MD, FAHA; Anthony White, PhD; William C. Cushman, MD, FAHA; William White, MD; Domenic Sica, MD, FAHA; Keith Ferdinand, MD; Thomas D. Giles, MD; Bonita Falkner, MD, FAHA; Robert M. Carey, MD, MACP, FAHA Abstract—Resistant hypertension is a common clinical problem faced by both primary care clinicians and specialists. While the exact prevalence of resistant hypertension is unknown, clinical trials suggest that it is not rare, involving perhaps 20% to 30% of study participants. As older age and obesity are 2 of the strongest risk factors for uncontrolled hypertension, the incidence of resistant hypertension will likely increase as the population becomes more elderly and heavier. The prognosis of resistant hypertension is unknown, but cardiovascular risk is undoubtedly increased as patients often have a history of long-standing, severe hypertension complicated by multiple other cardiovascular risk factors such as obesity, sleep apnea, diabetes, and chronic kidney disease. The diagnosis of resistant hypertension requires use of good blood pressure technique to confirm persistently elevated blood pressure levels. Pseudoresistance, including lack of blood pressure control secondary to poor medication adherence or white coat hypertension, must be excluded. Resistant hypertension is almost always multifactorial in etiology. Successful treatment requires identification and reversal of lifestyle factors contributing to treatment resistance; diagnosis and appropriate treatment of secondary causes of hypertension; and use of effective multidrug regimens. As a subgroup, patients with resistant hypertension have not been widely studied. Observational assessments have allowed for identification of demographic and lifestyle characteristics associated with resistant hypertension, and the role of secondary causes of hypertension in promoting treatment resistance is well documented; however, identification of broader mechanisms of treatment resistance is lacking. In particular, attempts to elucidate potential genetic causes of resistant hypertension have been limited. Recommendations for the pharmacological treatment of resistant hypertension remain largely empiric due to the lack of systematic assessments of 3 or 4 drug combinations. Studies of resistant hypertension are limited by the high cardiovascular risk of patients within this subgroup, which generally precludes safe withdrawal of medications; the presence of multiple disease processes (eg, sleep apnea, diabetes, chronic kidney disease, atherosclerotic disease) and their associated medical therapies, which confound interpretation of study results; and the difficulty in enrolling large numbers of study participants. Expanding our understanding of the causes of resistant hypertension and thereby potentially allowing for more effective prevention and/or treatment will be essential to improve the long-term clinical management of this disorder. (Hypertension. 2008;51:1403-1419.) Key Words: AHA Scientific Statements � hypertension � blood pressure The American Heart Association makes every effort to avoid any actual or potential conflicts of interest that may arise as a result of an outside relationship or a personal, professional, or business interest of a member of the writing panel. Specifically, all members of the writing group are required to complete and submit a Disclosure Questionnaire showing all such relationships that might be perceived as real or potential conflicts of interest. This statement was approved by the American Heart Association Science Advisory and Coordinating Committee on January 3, 2008. A single reprint is available by calling 800-242-8721 (US only) or by writing the American Heart Association, Public Information, 7272 Greenville Ave, Dallas, TX 75231-4596. Ask for reprint No. 71-0439. A copy of the statement is also available at http://www.americanheart.org/presenter.jhtml?identifier�3003999 by selecting either the “topic list” link or the “chronological list” link. To purchase additional reprints, call 843-216-2533 or e-mail kelle.ramsay@wolterskluwer.com. This statement has been copublished in Circulation. Expert peer review of AHA Scientific Statements is conducted at the AHA National Center. For more on AHA statements and guidelines development, visit http://www.americanheart.org/presenter.jhtml?identifier�3023366. Permissions: Multiple copies, modification, alteration, enhancement, and/or distribution of this document are not permitted without the express permission of the American Heart Association. Instructions for obtaining permission are located at http://www.americanheart.org/presenter.jhtml? identifier�4431. A link to the “Permission Request Form” appears on the right side of the page. © 2008 American Heart Association, Inc. Hypertension is available at http://hyper.ahajournals.org DOI: 10.1161/HYPERTENSIONAHA.108.189141 1403 AHA Scientific Statement by on April 16, 2010 hyper.ahajournals.orgDownloaded from Resistant hypertension is defined as blood pressure thatremains above goal in spite of the concurrent use of 3 antihypertensive agents of different classes. Ideally, one of the 3 agents should be a diuretic and all agents should be prescribed at optimal dose amounts. Although arbitrary in regard to the number of medications required, resistant hypertension is thus defined in order to identify patients who are at high risk of having reversible causes of hypertension and/or patients who, because of persistently high blood pressure levels, may benefit from special diagnostic and therapeutic considerations. As defined, resistant hypertension includes patients whose blood pressure is controlled with use of more than 3 medications. That is, patients whose blood pressure is controlled but require 4 or more medications to do so should be considered resistant to treatment. Prevalence The prevalence of resistant hypertension is unknown. Cross- sectional studies and hypertension outcome studies suggest, however, that it is not uncommon. In a recent analysis of National Health and Nutrition Examination Survey (NHANES) participants being treated for hypertension, only 53% were controlled to �140/90 mm Hg.1 In a cross- sectional analysis of Framingham Heart Study participants, only 48% of treated participants were controlled to �140/ 90 mm Hg and less than 40% of elderly participants (�75 years of age) were at a goal blood pressure.2 Among higher- risk populations and, in particular, with application of the lower goal blood pressures recommended in the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) for patients with diabetes mellitus or chronic kidney disease (CKD), the proportion of uncontrolled patients is even higher. Of NHANES participants with chronic kidney disease, only 37% were controlled to �130/80 mm Hg3 and only 25% of participants with diabetes were controlled to �130/85 mm Hg.1 Uncontrolled hypertension is not synonymous with resis- tant hypertension. The former includes patients who lack blood pressure control secondary to poor adherence and/or an inadequate treatment regimen, as well as those with true treatment resistance. To accurately determine the prevalence of resistant hypertension, a forced titration study of a large, diverse hypertensive cohort would be required. Such a study has not been done, but recent hypertension outcome studies offer an alternative as medications in these studies were usually provided at no charge, adherence was closely moni- tored, and titration of medications was dictated per protocol. In this regard, the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) may be the most relevant as it included a large number of ethnically diverse participants (�33 000): 47% female, 35% African American, 19% Hispanic, and 36% with diabetes.4 In ALLHAT, after approximately 5 years of follow-up, 34% of participants remained uncontrolled on an average of 2 medications.5 At the study’s completion, 27% of partici- pants were on 3 or more medications. Overall, 49% of ALLHAT participants were controlled on 1 or 2 medications, meaning that approximately 50% of participants would have needed 3 or more blood pressure medications. This percent- age, however, may underestimate the degree of treatment resistance relative to the general hypertensive population, as patients with a history of difficult-to-treat hypertension (needing more than 2 medications to achieve a blood pressure of �160/100 mm Hg) were precluded from enrolling in ALLHAT. Conversely, this percentage might overestimate the prevalence of resistant hypertension as a consequence of the restricted treatment regimens allowed in ALLHAT. Com- bined use of any 2 of the following classes of medications was discouraged: thiazide-type diuretics, angiotensin- converting enzyme (ACE) inhibitors, calcium channel block- ers, and � adrenergic receptor antagonists. Such combina- tions account for a substantial proportion of current clinical practice. Prognosis The prognosis of patients with resistant hypertension com- pared with patients with more easily controlled hypertension has not been specifically evaluated. Presumably, prognosis is impaired as such patients typically present with a long- standing history of poorly controlled hypertension and com- monly have associated cardiovascular risk factors such as diabetes, obstructive sleep apnea, left ventricular hypertrophy (LVH), and/or CKD. The degree to which cardiovascular risk is reduced with treatment of resistant hypertension is un- known. The benefits of successful treatment, however, are likely substantial as suggested by hypertension outcome studies in general and by the early Veterans Administration cooperative studies, which demonstrated a 96% reduction in cardiovascular events over 18 months with use of triple antihypertensive regimens compared with placebo in patients with severe hypertension (diastolic blood pressure 115 to 129 mm Hg).6 How much of this benefit occurs with success- ful treatment of resistant hypertension is unknown. Patient Characteristics Blood pressure remains uncontrolled most often because of persistent elevations in systolic blood pressure. Among Fra- mingham participants being treated for hypertension, 90% had achieved a diastolic blood pressure goal of �90 mm Hg, while only 49% were at a systolic blood pressure goal of �140 mm Hg.2 This disparity in systolic versus diastolic blood pressure control worsened with increasing age such that systolic control rates exceeded 60% for younger partic- ipants (�60 years) but was �40% in older subjects (�75 years). Prospectively, ALLHAT demonstrated a similar dif- ficulty in controlling systolic blood pressure in that only 67% of the participants had their systolic blood pressure lowered to �140 mm Hg, whereas 92% of participants achieved a goal diastolic blood pressure of �90 mm Hg.5 In an analysis of Framingham study data, the strongest predictor of lack of blood pressure control was older age, with participants �75 years being less than one fourth as likely to have systolic blood pressure controlled compared with par- ticipants �60 years of age.2 The next strongest predictors of lack of systolic blood pressure control were the presence of 1404 Hypertension June 2008 by on April 16, 2010 hyper.ahajournals.orgDownloaded from LVH and obesity (body mass index [BMI]�30 kg/m2) (Table 1). In terms of diastolic blood pressure control, the strongest negative predictor was obesity, with blood pressure being controlled about one third less often compared with lean participants (BMI �25 kg/m2). In a prospective analysis of Framingham participants, in addition to older age, higher baseline systolic blood pressure was associated with in- creased risk of never reaching goal blood pressure.7 In ALLHAT, older age, higher baseline systolic blood pressure, LVH, and obesity all predicted treatment resistance as defined by needing 2 or more antihypertensive medica- tions.5 Overall, the strongest predictor of treatment resistance was having CKD as defined by a serum creatinine of �1.5 mg/dL. Other predictors of the need for multiple medications included having diabetes mellitus and living in the southeast- ern United States. African-American participants had more treatment resistance, as did women, such that black women had the lowest control rate (59%) and non-black men the highest (70%). Although the exact prevalence is unknown, the above studies indicate that resistant hypertension is a common clinical problem. Further, with a progressively older and heavier population in association with an increasing inci- dence of diabetes and CKD, the prevalence of resistant hypertension can be anticipated to increase. Genetics/Pharmacogenetics As resistant hypertension represents an extreme phenotype, it seems reasonable to predict that genetic factors may play a greater role than in the general hypertensive population. However, genetic assessments of patients with resistant hypertension are limited. In one of the few genetic evalua- tions of patients with resistant hypertension, investigators in Finland screened 347 patients with resistant hypertension for mutations of the � and � subunits of the epithelial sodium channel (ENaC).8 Mutations of these subunits can cause Liddle’s syndrome, a rare monogenic form of hypertension. Compared with normotensive controls, 2 � ENaC and � ENaC gene variants were significantly more prevalent in the patients with resistant hypertension. The presence of the gene variants was associated with increased urinary potassium excretion relative to plasma renin levels but was not related to baseline plasma aldosterone or plasma renin activity. In addition, when inserted into Xenopus oocytes, the most commonly used expression system for ENaC functional studies, the gene variants did not show a significant differ- ence in activity compared with ENaC wild-type, arguing against clinically meaningful effects for these mutations. The CYP3A5 enzyme (11�-hydroxysteroid dehydrogenase type 2) plays an important role in the metabolism of cortisol and corticosterone, particularly in the kidney. A particular CYP3A5 allele (CYP3A5*1) has been associated in African- American patients with higher systolic blood pressure levels in normotensive participants9 and hypertension more resistant to treatment.10 Although based on a very small number of patients, these results are provocative and support additional attempts to identify genotypes that may relate to treatment resistance. Identification of genetic influences on resistance to current therapies might also lead to development of new therapeutic targets. Pseudoresistance Poor Blood Pressure Technique Inaccurate measurement of blood pressure can result in the appearance of treatment resistance. Two of the most common mistakes—measuring the blood pressure before letting the patient sit quietly and use of too small a cuff—will result in falsely high blood pressure readings.11 Although the degree to which inaccurate measurement of blood pressure results in falsely labeling patients as having uncontrolled hypertension is unknown, assessments of office blood pressure measure- ment technique suggest that it is likely a common clinical problem.11 Poor Adherence Poor adherence to antihypertensive therapy is a major cause of lack of blood pressure control.12 Retrospective analyses indicate that approximately 40% of patients with newly diagnosed hypertension will discontinue their antihyperten- sive medications during the first year of treatment.13,14 During 5 to 10 years of follow-up, less than 40% of patients may persist with their prescribed antihypertensive treatment.13,15 While poor adherence is common at the primary care level, it may be less common among patients who are seen by specialists. In a retrospective analysis at a hypertension specialty clinic, it was estimated that poor adherence was a significant contributing factor to the lack of blood pressure control in only 16% of evaluated patients.16 Lack of blood pressure control is distinct from treatment resistance. For an antihypertensive regimen to have failed, it has to have been taken correctly. This distinction is clinically important as patients with poorly controlled hypertension secondary to lack of adherence need not be subjected to the evaluations and continued manipulations in treatment regi- mens that are undertaken for patients with true treatment resistance. White-Coat Effect Studies indicate that a significant white-coat effect (when clinic blood pressures are persistently elevated while out-of- Table 1. Patient Characteristics Associated With Resistant Hypertension Older age High baseline blood pressure Obesity Excessive dietary salt ingestion Chronic kidney disease Diabetes Left ventricular hypertrophy Black race Female sex Residence in southeastern United States Calhoun et al Resistant Hypertension 1405 by on April 16, 2010 hyper.ahajournals.orgDownloaded from office values are normal or significantly lower) is as common in patients with resistant hypertension as in the more general hypertensive population, with a prevalence in the range of 20% to 30%.17,18 Also, as with more general hypertensive patients, patients with resistant hypertension on the basis of a “white coat” phenomenon manifest less severe target organ damage and appear to be at less cardiovascular risk compared with those patients with persistent hypertension during am- bulatory monitoring.19–21 Lifestyle Factors Obesity Obesity is associated with more severe hypertension, a need for an increased number of antihypertensive medications, and an increased likelihood of never achieving blood pressure control.5,22 As a consequence, obesity is a common feature of patients with resistant hypertension.23 Mechanisms of obesity-induced hypertension are complex and not fully elucidated but include impaired sodium excretion, increased sympathetic nervous system activity, and activation of the renin-angiotensin-aldosterone system.24
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