Published online before print April 7, 2008, doi: 10.1161/HYPERTENSIONAHA.108.189141
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(Hypertension. 2008;51:1403.)
© 2008 American Heart Association, Inc.
AHA Scientific Statement |
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
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Abstract |
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Top
Abstract
IntroductionResistant 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.
Key Words: AHA Scientific Statements • hypertension • blood pressure
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Introduction |
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Resistant hypertension is defined as blood pressure that remains 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.
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Prevalence |
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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 resistant 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 monitored, 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 participants 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 percentage, 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. Combined use of any 2 of the following classes of medications was discouraged: thiazide-type diuretics, angiotensin-converting enzyme (ACE) inhibitors, calcium channel blockers, and 
adrenergic receptor antagonists. Such combinations account for a substantial proportion of current clinical practice.
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Prognosis |
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The prognosis of patients with resistant hypertension compared 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 commonly 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 unknown. 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 successful treatment of resistant hypertension is unknown.
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Patient Characteristics |
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Blood pressure remains uncontrolled most often because of persistent elevations in systolic blood pressure. Among Framingham 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 participants (
60 years) but was <40% in older subjects (>75 years). Prospectively, ALLHAT demonstrated a similar difficulty 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 participants 60 years of age.2 The next strongest predictors of lack of systolic blood pressure control were the presence of 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 increased risk of never reaching goal blood pressure.7
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In ALLHAT, older age, higher baseline systolic blood pressure, LVH, and obesity all predicted treatment resistance as defined by needing 2 or more antihypertensive medications.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 southeastern 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 incidence of diabetes and CKD, the prevalence of resistant hypertension can be anticipated to increase.
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Genetics/Pharmacogenetics |
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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 evaluations of patients with resistant hypertension, investigators in Finland screened 347 patients with resistant hypertension for mutations of the β 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 β 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 difference in activity compared with ENaC wild-type, arguing against clinically meaningful effects for these mutations. The CYP3A5 enzyme (11β-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.
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Pseudoresistance |
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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 measurement 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 antihypertensive 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 regimens 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-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 ambulatory monitoring.19–21
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Lifestyle Factors |
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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
Dietary Salt
Excessive dietary sodium intake contributes to the development of resistant hypertension both through directly increasing blood pressure and by blunting the blood pressure–lowering effect of most classes of antihypertensive agents.25–27 These effects tend to be more pronounced in typical salt-sensitive patients, including the elderly, African Americans, and, in particular, patients with CKD.28 Although excessive dietary sodium is fairly widespread, it has been specifically documented as being common in patients with resistant hypertension. In an analysis of patients referred to a university hypertension center for resistant hypertension, average dietary salt ingestion based on 24-hour urinary sodium excretion exceeded 10 g a day.23
Alcohol
Heavy alcohol intake is associated with both an increased risk of hypertension, as well as treatment-resistant hypertension. In a cross-sectional analysis of Chinese adults ingesting 30 drinks a week, the risk of having various forms of hypertension increased from 12% to 14%.29 In a Finnish hypertension clinic, heavy drinkers, as suggested by increases in liver transaminase levels, were much less likely to have their blood pressure controlled during a 2-year follow-up compared with patients with normal transaminase levels.30 Prospectively, cessation of heavy alcohol ingestion by a small group of patients reduced 24-hour ambulatory systolic blood pressure by 7.2 mm Hg and diastolic blood pressure by 6.6 mm Hg while dropping the prevalence of hypertension from 42% to 12%.31
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Drug-Related Causes |
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Several classes of pharmacological agents can increase blood pressure and contribute to treatment resistance (Table 2). The effects of these agents, however, can be highly individualized, with most persons manifesting little or no effect, while other individuals may experience severe elevations in blood pressure.
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Given their widespread use, nonnarcotic analgesics, including nonsteroidal antiinflammatory agents (NSAIDs), aspirin, and acetaminophen, are probably the most common offending agents in terms of worsening blood pressure control.32,33 NSAIDs, in particular, are associated with modest but predictable increases in blood pressure. Meta-analyses of the effects of NSAIDs have indicated average increases in mean arterial pressure of approximately 5.0 mm Hg.34 Additional studies indicate that NSAIDs can blunt the blood pressure–lowering effect of several antihypertensive medication classes, including diuretics, ACE inhibitors, angiotensin receptor blockers (ARBs), and β-blockers.35,36 Similar effects have been described with the selective cyclooxygenase-2 (COX-2) inhibitors.37,38
Although NSAIDs have an overall modest effect on blood pressure levels, in susceptible individuals significant fluid retention, increases in blood pressure, and/or acute kidney disease may occur. These effects presumably occur secondary to inhibition of renal prostaglandin production, especially prostaglandin E2 and prostaglandin I2, with subsequent sodium and fluid retention. Elderly patients, diabetics, and patients with CKD are at increased risk of manifesting these adverse effects.
Other medication classes that may worsen blood pressure control include sympathomimetic compounds such as decongestants and certain diet pills, amphetamine-like stimulants, modafinil39, and oral contraceptives. Glucocorticoids, such as prednisone, induce sodium and fluid retention and can result in significant increases in blood pressure. Corticosteroids with the greatest mineralocorticoid effect (eg, cortisone, hydrocortisone) produce the greatest amount of fluid retention, but even agents without mineralocorticoid activity (eg, dexamethasone, triamcinolone, betamethasone) produce some fluid retention. Herbal preparations containing ephedra (or ma huang) have been associated with worsening blood pressure.40,41 Licorice, a common ingredient in oral tobacco products, can raise blood pressure by suppressing the metabolism of cortisol, resulting in increased stimulation of the mineralocorticoid receptor.42,43 In anemic patients with CKD, erythropoietic agents may increase blood pressure in both normotensive and hypertensive patients.
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Secondary Causes |
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Secondary causes of hypertension are common in patients with resistant hypertension, although the overall prevalence is unknown (Table 3). The likelihood of a readily definable secondary cause of hypertension is greater in older patients because of a greater prevalence of sleep apnea, renal parenchymal disease, renal artery stenosis, and possibly primary aldosteronism.44–46 Uncommon secondary causes of hypertension include pheochromocytoma, Cushing’s syndrome, hyperparathyroidism, aortic coarctation, and intracranial tumors.
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Obstructive Sleep Apnea
Untreated obstructive sleep apnea is strongly associated with hypertension and in normotensive persons predicts development of hypertension.47,48 Sleep apnea is particularly common in patients with resistant hypertension. In an evaluation of 41 consecutive patients (24 men, 17 women) with treatment-resistant hypertension, 83% were diagnosed with unsuspected sleep apnea based on an apnea-hypopnea index 10 events/h.49 There was a significant gender difference, with sleep apnea being both more common and more severe in the men compared with women patients. Cross-sectional studies indicate that the more severe the sleep apnea, the less likely blood pressure is controlled despite the use of an increasing number of medications.50,51
The mechanisms by which sleep apnea contributes to the development of hypertension have not been fully elucidated. A well-described effect is that the intermittent hypoxemia, and/or increased upper airway resistance associated with sleep apnea, induces a sustained increase in sympathetic nervous system (SNS) activity.52,53 Increases in SNS output would be expected to raise blood pressure through increases in cardiac output and peripheral resistance as well as by increased fluid retention. In addition, sleep apnea has been associated with increases in reactive oxygen species with concomitant reductions in nitric oxide bioavailability.54,55
Primary Aldosteronism
Recent studies indicate that primary aldosteronism is a much more common cause of hypertension than had been demonstrated historically. In an evaluation of more than 600 patients with hypertension, the prevalence of primary hyperaldosteronism was found to be 6.1%.56 In this study, the prevalence of primary aldosteronism varied according to the underlying severity of hypertension, with a prevalence of 13% among patients with severe hypertension (>180/110 mm Hg). Importantly from a clinical standpoint, in this study and others documenting a high prevalence of primary aldosteronism, serum potassium levels were rarely low in patients confirmed to have primary aldosteronism, suggesting that hypokalemia is a late manifestation of the disorder preceded by the development of hypertension.56–58
Primary aldosteronism is common in patients with resistant hypertension with a prevalence of approximately 20%. In an evaluation of patients referred to a hypertension specialty clinic, investigators at the University of Alabama at Birmingham found that 18 of 88, or 20%, consecutively evaluated patients with resistant hypertension were diagnosed with primary aldosteronism based on a suppressed renin activity and a high 24-hour urinary aldosterone excretion in the course of a high dietary sodium intake.59 The prevalence of primary aldosteronism was similar in African-American and white patients. In a study conducted in Seattle, Washington, primary aldosteronism was diagnosed in 17% of patients with resistant hypertension.60 Similarly, investigators in Oslo, Norway, have reported confirming primary aldosteronism in 23% of patients with resistant hypertension.61
As in the general hypertensive population, the stimulus for the aldosterone excess in patients with resistant hypertension has not been identified. Generalized activation of the renin-angiotensin-aldosterone system has been described with obesity, while other studies suggest that adipocytes may release secretagogues that stimulate aldosterone release independent of angiotensin-II.62–64 In addition, preliminary results relate aldosterone excess to sleep apnea in patients with resistant hypertension.65 Although cause-and-effect has not been confirmed, these studies suggest that the increased occurrence of primary aldosteronism may be linked to the increasing incidence of obesity.
Pheochromocytoma
Pheochromocytoma represents a small but important fraction of secondary causes of resistant hypertension. The prevalence of pheochromocytoma is 0.1% to 0.6% of hypertensives in a general ambulatory population.66,67 The exact prevalence of pheochromocytoma as a cause of resistant hypertension is unknown, but the literature is replete with case reports of malignant and difficult-to-control hypertension secondary to pheochromocytoma. Although the clinical presentation of pheochromocytoma is highly variable, approximately 95% of patients demonstrate hypertension and 50% have sustained hypertension.68 Furthermore, pheochromocytoma is characterized by increased blood pressure variability,69 which constitutes an additional independent risk factor beyond increased blood pressure itself for cardiovascular morbidity and mortality.70,71 The occurrence of a sustained increase and the degree of blood pressure variability are both related to the level of norepinephrine secretion by the tumor.72
Despite improved diagnostic techniques that can reduce the time to specific identification of pheochromocytoma in a hypertensive patient, there remains an average of 3 years between the initial symptoms and final diagnosis.73 Many cases of pheochromocytoma are missed altogether based on autopsy studies in which the tumors contributed to 55% of the deaths and were not suspected in 75% of cases.74
The diagnosis of pheochromocytoma should be entertained in a hypertensive patient with a combination of headaches, palpitations, and sweating, typically occurring in an episodic fashion, with a diagnostic specificity of 90%.75 The best screening test for pheochromocytoma is plasma free metanephrines (normetanephrine and metanephrine), which carries a 99% sensitivity and an 89% specificity.75
Cushing’s Syndrome
Hypertension is present in 70% to 90% of patients with Cushing’s syndrome.76 Although the main mechanism of hypertension in Cushing’s syndrome is overstimulation of the nonselective mineralocorticoid receptor by cortisol,77 other factors such as sleep apnea and the insulin resistance syndrome are major contributors to hypertension in this disease.78,79
Although the exact prevalence of resistant hypertension in patients with Cushing’s syndrome is unknown, one group found that 17% had severe hypertension.80 Furthermore, it is well documented that target organ damage in Cushing’s syndrome is more severe than in primary hypertension.81 The overall cardiovascular risk in Cushing’s syndrome is substantial because the disorder is associated with other major risk factors such as diabetes mellitus, the metabolic syndrome, sleep apnea, obesity, and dyslipidemia, in addition to hypertension.82
Because the pathogenesis of hypertension in Cushing’s syndrome involves activation of mineralocorticoid receptors, the usual antihypertensive agents employed in treating primary hypertension (renin-angiotensin system blockers, calcium channel antagonists, adrenergic blockers, diuretics) may not be effective in lowering blood pressure to goal.79 Surgical excision of an adrenocorticotropic hormone (ACTH)—or cortisol-producing tumor—effectively lowers blood pressure.79 The most effective antihypertensive pharmacological agent in Cushing’s syndrome is a mineralocorticoid receptor antagonist (spironolactone or eplerenone).79
Renal Parenchymal Disease
CKD is both a common cause and complication of poorly controlled hypertension.83,84 Recent studies reviewing 16 589 participants in the NHANES indicate that 3% of the population have increased serum creatinine above 1.6 mg/dL, corresponding to more than 5.6 million of the general population.85 Most of this population was receiving antihypertensive drug therapy (75%), but achievement of current goal levels (<130/85 mm Hg) was uncommon. In a recent cross-sectional analysis of patients with CKD being followed in nephrology clinics, less than 15% had their blood pressure controlled to <130/80 mm Hg despite of the use on average of 3 different antihypertensive agents.86 In ALLHAT, CKD as indicated by a serum creatinine of >1.5 mg/dL was a strong predictor of failure to achieve goal blood pressure.5 Treatment resistance in patients with CKD is undoubtedly related in large part to increased sodium and fluid retention and consequential intravascular volume expansion.
Renal Artery Stenosis
Renovascular disease is a common finding in hypertensive patients undergoing cardiac catheterization, with more than 20% of patients having unilateral or bilateral stenoses (with a degree of obstruction 70%).87 Unknown, however, is the role of such lesions in causing hypertension. Studies of treatment-resistant hypertension commonly reveal a high prevalence of previously unrecognized renovascular disease, particularly in older patient groups.45,88 The former series suggested that 12.7% of patients 50 years of age referred to a hypertension center had a secondary cause of hypertension, the most common of which (35%) was renovascular disease. A large experience with both surgical and endovascular revascularization indicates that some patients with renovascular disease experience improved blood pressure control after correction of renal artery stenosis, although randomized clinical trials in general have not shown convincing benefit in regard to improvement in renal function or blood pressure control.89,90
More than 90% of renal artery stenoses are atherosclerotic in origin.91 The likelihood of atherosclerotic renal artery stenosis is increased in older patients; in smokers; in patients with known atherosclerotic disease, especially peripheral arterial disease; and in patients with unexplained renal insufficiency. Bilateral renal artery stenoses should be suspected in patients with a history of "flash" or episodic pulmonary edema, especially when echocardiography indicates preserved systolic heart function. Less than 10% of renal lesions are fibromuscular in etiology developing most commonly in women, <50 years of age.
Renal artery stenosis can be difficult to identify with any certainty using noninvasive studies. Duplex ultrasound, magnetic resonance angiography (MRA), renal scintigraphy, and computed tomography (CT) angiography have good test characteristics in published studies,92 but the true positive and negative predictive value will vary both with the populations at risk and the level of expertise at each institution. Negative imaging studies warrant additional examinations for patients in whom there is a high level of clinical suspicion and for whom renal revascularization is being seriously considered. MRA is highly sensitive for stenosis, but the specificity can be low, and minimal lesions are often characterized as moderate or high grade.93
Diabetes
Diabetes and hypertension are commonly associated, particularly in patients with difficult-to-control hypertension. In ALLHAT, diabetes predicted lack of blood pressure control during the course of the study.5 Clinical trials have indicated that in order to achieve the lower blood pressure goal recommended for patients with diabetes, an average range of 2.8 to 4.2 antihypertensive medications will be needed.94 The degree to which insulin resistance directly contributes to the development of hypertension versus simply being associated with hypertension because of common underlying causes has not been determined. Pathophysiologic effects attributed to insulin resistance that may contribute to worsening hypertension include increased sympathetic nervous activity, vascular smooth muscle cell proliferation, and increased sodium retention.
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Evaluation |
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The evaluation of patients with resistant hypertension should be directed toward confirming true treatment resistance; identification of causes contributing to treatment resistance, including secondary causes of hypertension; and documentation of target-organ damage (Figure). Accurate assessment of treatment adherence and use of good blood pressure measurement technique is required to exclude pseudoresistance. In most cases, treatment resistance is multifactorial in etiology with obesity, excessive dietary sodium intake, obstructive sleep apnea, and CKD being particularly common factors. Target-organ damage such as retinopathy, CKD, and LVH supports a diagnosis of poorly controlled hypertension and in the case of CKD will influence treatment in terms of classes of agents selected as well as establishing a blood pressure goal of <130/80 mm Hg.95
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Medical History
The medical history should document duration, severity, and progression of the hypertension; treatment adherence; response to prior medications, including adverse events; current medication use, including herbal and over-the-counter medications; and symptoms of possible secondary causes of hypertension. Daytime sleepiness, loud snoring, and witnessed apnea are suspicious for sleep apnea. A history of peripheral or coronary atherosclerotic disease increases the likelihood of renal artery stenosis. Labile hypertension, in association with palpitations and/or diaphoresis, suggests the possibility of pheochromocytoma.
Assessment of Adherence
Ultimately, adherence in a clinical setting can only be known by patient self-report. Patients should be specifically asked, in a nonjudgmental fashion, how successful they are in taking all of their prescribed doses, including discussion of adverse effects, out-of-pocket costs, and dosing inconvenience, all of which can limit adherence. Family members will often provide more objective assessments of a patient’s adherence, but such input should generally be solicited in the presence of the patient.
Blood Pressure Measurement
Use of good blood pressure measurement technique is essential to the accurate diagnosis of resistant hypertension, including having the patient sit quietly in a chair with his or her back supported for 5 minutes before taking the measurement; use of the correct cuff size with the air bladder encircling at least 80% of the arm (the adult large cuff for the majority of patients); and supporting the arm at heart level during the cuff measurement.11 A minimum of 2 readings should be taken at intervals of at least 1 minute and the average of those readings should be taken to represent the patient’s blood pressure. The blood pressure should be measured carefully in both arms and the arm with the higher pressures generally should be used to make future measurements. Supine and upright blood pressures should be measured during follow-up to detect orthostatic complications with treatment.
Physical Examination
A fundoscopic examination should document the presence and severity of retinopathy. The presence of carotid, abdominal, or femoral bruits increases the possibility that renal artery stenosis exists. Diminished femoral pulses and/or a discrepancy between arm and thigh blood pressures suggest aortic coarctation or significant aortoiliac disease. Cushing’s disease is suggested by abdominal striae, particularly if pigmented; moon facies; or prominent interscapular fat deposition.
Ambulatory Blood Pressure Monitoring
Documentation of a significant white-coat effect requires reliable assessment of out-of-office blood pressure values. This is accomplished most objectively with the use of 24-hour ambulatory blood pressure monitoring. Alternatively, work site measurements by trained health practitioners and/or out-of-office assessments with use of manual or automated blood pressure monitors can be relied on. In the case of patient self-assessments, use of good blood pressure technique with validation of the accuracy of readings is essential. Cuffs adequately sized for use with extremely obese patients are generally not available with ambulatory or home automated monitors. In such cases, use of wrist monitors may become necessary, but the accuracy of such units can prove variable.96,97
A significant white-coat effect should be suspected in patients with resistant hypertension in whom clinic blood pressure measurements are consistently higher than out-of-office measurements; in patients who repetitively show signs of overtreatment, particularly orthostatic symptoms; and in patients with chronically high office blood pressure values but an absence of target organ damage (LVH, retinopathy, CKD). In such cases, 24-hour ambulatory blood pressure monitoring is recommended. A mean ambulatory daytime blood pressure of >135/85 mm Hg is considered elevated.11 If a significant white-coat effect is confirmed, out-of-office measurements should be relied on to adjust treatment.98
Biochemical Evaluation
Biochemical evaluation of the treatment-resistant hypertensive should include a routine metabolic profile (sodium, potassium, chloride, bicarbonate, glucose, blood urea nitrogen, and creatinine); urinalysis; and a paired, morning plasma aldosterone and plasma renin or plasma renin activity to screen for primary aldosteronism. Even in the setting of ongoing antihypertensive treatment (excluding potassium-sparing diuretics, particularly aldosterone antagonists), the aldosterone/renin ratio is an effective screening test for primary aldosteronism, having a high negative predictive value.23,99 A high ratio, however, has a low specificity for primary aldosteronism, likely reflecting the common occurrence of low-renin hypertension in patients with resistant hypertension. The specificity of the ratio is improved if a minimum plasma renin activity of 0.5 ng/mL/h is used in its calculation and/or a plasma aldosterone level 15 ng/dL is required for the ratio to be considered high. A high ratio (generally 20 to 30 when plasma aldosterone is reported in nanograms per deciliter and plasma renin activity in nanograms per milliliter per hour) is suggestive of primary aldosteronism, but further evaluation is necessary to confirm the diagnosis.
A 24-hour urine collected during ingestion of the patient’s normal diet can be helpful in estimating dietary sodium and potassium intake, calculating creatinine clearance, and measuring aldosterone excretion. To do so from the same collection, however, requires that a nonsalt acid (eg, acetic acid) be used as the preservative for aldosterone. If a 24-hour urine is not used to calculate creatinine clearance, renal function can be calculated by any of a number of validated urine-free formulae. Measurement of 24-hour urinary metanephrines or plasma metanephrines is an effective screen for patients in whom pheochomocytoma is suspected.100
Noninvasive Imaging
Imaging for renal artery stenosis should be reserved for patients in whom there is an increased level of suspicion. This would include young patients, particularly women, whose presentation suggests the presence of fibromuscular dysplasia and older patients at increased risk of atherosclerotic disease. The preferred imaging modality will vary by institution, depending on the level of training and experience. For patients with CKD, modalities that do not involve iodinated contrast may be preferred over CT angiography. Diagnostic renal arteriograms in the absence of suspicious noninvasive imaging are not recommended. Likewise, due to poor specificity, abdominal CT imaging is not recommended to screen for adrenal adenomas in the absence of biochemical confirmation of hormonally active tumors (hyperaldosteronism, pheochromocytoma, Cushing’s syndrome).
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Treatment Recommendations |
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Resistant hypertension is almost always multifactorial in etiology. Treatment is predicated on identification and reversal of lifestyle factors contributing to treatment resistance; accurate diagnosis and appropriate treatment of secondary causes of hypertension; and use of effective multi-drug regimens (Figure). Lifestyle changes, including weight loss; regular exercise; ingestion of a high-fiber, low-fat, low-salt diet; and moderation of alcohol intake should be encouraged where appropriate. Potentially interfering substances should be withdrawn or down-titrated as clinically allowable. Obstructive sleep apnea should be treated if present.
Maximize Adherence
Treatment adherence worsens with the use of an increasing number of pills, with increasing complexity of the dosing regimen, and as out-of-pocket costs increase. Accordingly, prescribed regimens should be simplified as much as possible, including the use of a long-acting combination of products to reduce the number of prescribed pills and to allow for once-daily dosing. Adherence is also enhanced by more frequent clinic visits and by having patients record home blood pressure measurements.101,102 Although expensive and labor intensive, use of a multidisciplinary treatment approach including nurse case managers, pharmacists, and nutritionists can improve treatment results.103 Involving the patient by having him or her maintain a diary of home blood pressure values should improve follow-up and enhance medication adherence, while involvement of family members will likely enhance persistence with recommended lifestyle changes.
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Nonpharmacological Recommendations |
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Weight Loss
Weight loss, although not specifically evaluated in patients with resistant hypertension, has a clear benefit in terms of reducing blood pressure and often allows for reduction in the number of prescribed medications. A recent review of long-term weight loss studies indicated that a 10-kg weight loss is associated with an average 6.0-mm Hg reduction in systolic and a 4.6-mm Hg reduction in diastolic blood pressure.104 An earlier meta-analysis of randomized, controlled, weight loss trials found that the greatest benefit, at least for diastolic blood pressure reduction, was in patients already receiving antihypertensive therapy.105 While difficult to achieve and even more difficult to maintain, weight loss should be encouraged in any patient with resistant hypertension who is either overweight or obese.
Dietary Salt Restriction
The benefit of dietary salt reduction is well documented in general hypertensive patients with observed reductions in systolic and diastolic blood pressure of 5 to 10 and 2 to 6 mm Hg, respectively.106,107 African-American and elderly patients tend to show larger benefit.107 Dietary salt reduction has not been specifically evaluated in patients with resistant hypertension. However, in an evaluation of patients whose blood pressure was uncontrolled on a combination of an ACE inhibitor and hydrochlorothiazide, a reduced-salt diet lowered systolic and diastolic blood pressure at 1 month follow-up by 9 and 8 mm Hg, respectively.108 Accordingly, dietary salt restriction, ideally to less than 100 mEq of sodium/24-hour, should be recommended for all patients with resistant hypertension.
Moderation of Alcohol Intake
Whether by undoing negative physiological effects and/or improvements in medication adherence, cessation of heavy alcohol ingestion can significantly improve hypertension control. Daily intake of alcohol should be limited to no more than 2 drinks (1 ounce of ethanol) per day (eg, 24 ounces of beer, 10 ounces of wine, or 3 ounces of 80 proof liquor) for most men and 1 drink per day for women or lighter-weight persons.95
Increased Physical Activity
In a small group of African-American men with severe hypertension (untreated systolic 180 or diastolic blood pressure 110 mm Hg who received up to 3 antihypertensive agents to lower diastolic blood pressure by 10 mm Hg and/or to <95 mm Hg), 16 weeks of an aerobic exercise regimen (stationary cycling 3 times a week) lowered diastolic blood pressure by 5 mm Hg and systolic blood pressure by 7 mm Hg, although the latter change was not statistically significant.109 Reductions in diastolic blood pressure were maintained after 32 weeks of exercise, even with withdrawal of some antihypertensive medications. In a meta-analysis that included studies of both normotensive and hypertensive cohorts, regular aerobic exercise produced average reductions of 4 mm Hg in systolic and 3 mm Hg in diastolic blood pressure.110 Based on these observed benefits, patients should be encouraged to exercise for a minimum of 30 minutes on most days of the week.
Ingestion of a High-Fiber, Low-Fat Diet
Ingestion of a diet rich in fruits and vegetables; high in low-fat dairy products, potassium, magnesium, and calcium; and low in total saturated fats (ie, the Dietary Approaches to Stop Hypertension or DASH diet) reduced systolic and diastolic blood pressure by 11.4 and 5.5 mm Hg more, respectively, than the control diet in hypertensive patients.111 The benefit of such a diet has not been separately evaluated in patients with resistant hypertension, but some degree of blood pressure reduction seems likely.
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Treatment of Secondary Causes of Hypertension |
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When primary aldosteronism, pheochromocytoma, or Cushing’s disease is suspected or confirmed, treatment will be specific for that particular disorder. Effective management of these diseases may require referral to an appropriate specialist.
Treatment of Obstructive Sleep Apnea
Treatment of sleep apnea with continuous positive airway pressure (CPAP) likely improves blood pressure control, although the benefit in CPAP intervention trials has been variable. In a well-controlled evaluation that included both normotensive and mildly hypertensive subjects, 9 weeks of CPAP use (5.5 hours per night) lowered 24-hour mean ambulatory systolic and diastolic blood pressure by 10.3 and 9.5 mm Hg, respectively.112 In an uncontrolled evaluation of 11 patients with resistant hypertension, 2 months of CPAP use was associated with reductions in nighttime and daytime ambulatory systolic blood pressure of 14.4 and 9.3 mm Hg, respectively, and a 7.8 mm Hg reduction in nighttime diastolic blood pressure.113 CPAP use averaged 4.2 hours per night. The large blood pressure reductions observed in these 2 studies, however, need to be reconciled with other studies that have reported modest or no antihypertensive benefit with CPAP use.114,115 Review of randomized CPAP intervention trials suggests that CPAP use can be expected to lower blood pressure in hypertensive patients, with the largest benefit being seen in patients with severe sleep apnea and in patients already receiving antihypertensive treatment.116
Treatment of Renal Artery Stenosis
Angioplasty of fibromuscular lesions almost always benefits, and is often curative, of the associated hypertension and therefore is the recommended treatment of choice.117 Restenosis, however, may occur in excess of 20% of patients after 1 year. Whether endovascular revascularization is needed for most atherosclerotic lesions is controversial. In patients with either controlled blood pressure or resistant hypertension, the relative benefit of intensive medical therapy versus angioplasty with stenting has not been clearly established.118 Poorly controlled hypertension imparts a major level of cardiovascular risk, however, and endovascular angioplasty, with or without stenting, should be considered when drug therapy alone is unsuccessful. Valuable information on this topic should come from the Cardiovascular Outcomes in Renal Atherosclerotic Lesions (CORAL) trial, which is an ongoing NIH-funded study designed to determine more precisely whether percutaneous intervention with stenting plus medical therapy versus medical therapy alone improves long-term cardiovascular outcomes in patients with renal artery stenosis. Pending the results of the CORAL trial, available evidence does not support a relative advantage of either medical treatment versus revascularization procedures for treatment of renal stenosis.119 However, if the blood pressure remains poorly controlled in spite of optimal medical therapy, revascularization is recommended, recognizing that a significant blood pressure response is not assured.
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Pharmacological Treatment |
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