Resistant hypertension is defined as blood pressure. Resistant or Difficult-to-Treat Hypertension. R e v i e w P a p e r.

Transcription

1 R e v i e w P a p e r Resistant or Difficult-to-Treat Hypertension David A. Calhoun, MD Resistant hypertension, defined as uncontrolled hypertension on three medications, is becoming an increasingly common problem. In most cases, blood pressure remains elevated because of persistently high systolic blood pressure levels. Common characteristics of patients with resistant hypertension include older age, obesity, excessive dietary salt ingestion, and presence of sleep apnea. The evaluation of patients with resistant hypertension is focused on identifying contributing and secondary causes of hypertension. Treatment should include both lifestyle changes (weight loss, exercise, dietary salt restriction) and the use of effective multidrug regimens, including a diuretic. Recent data indicate that aldosterone antagonists may be effective when added to existing antihypertensive regimens even in the absence of primary aldosteronism. (J Clin Hypertens. 2006;8: ) 2006 Le Jacq Ltd. Resistant hypertension is defined as blood pressure (BP) that remains uncontrolled at levels >140/90 mm Hg in spite of use of three antihypertensive agents. Ideally, one of the agents should be a diuretic and all of the agents should be prescribed at doses that provide optimal benefit. Resistant hypertension is defined to identify patients at high risk of having reversible causes of hypertension From the Vascular Biology and Hypertension Program, Center for Sleep/Wake Disorders, University of Alabama at Birmingham, Birmingham, AL Address for correspondance: David A. Calhoun, MD, 430 BMR2, rd Avenue South, Birmingham, AL dcalhoun@uab.edu Manuscript received September 15, 2005; revised December 15, 2005; accepted January 4, ID: 4747 and, therefore, may benefit from special diagnostic and therapeutic considerations. Historically, resistant hypertension has been defined as BP that is uncontrolled on three or more medications, the implication being that if the BP is finally controlled, regardless of the number of medications required, then true resistance is not present. If a patient s BP is controlled, but the use of four or more medications is required, he or she may still have a reversible form of hypertension and should be considered to have resistant hypertension. PREVALENCE The prevalence of resistant hypertension is unknown; however, cross-sectional and outcome studies suggest that it is fairly common. In the recent National Health and Nutrition Examination Survey (NHANES) 1 only 53% of participants being treated for hypertension were controlled to <140/90 mm Hg. In Germany, BP control among treated overweight and obese patients was <20%. 2 In a similar analysis of diabetic patients in the United States, only 23% of African-American and 31% of Caucasian patients were controlled to <130/80 mm Hg in spite of being prescribed an average of 2.7 and 2.2 antihypertensive medications, respectively. 3 Hypertension outcome studies may provide the best estimate of the prevalence of resistant hypertension as medications are generally provided at no charge, adherence is monitored, and titration is dictated per protocol if the BP remains elevated. In this regard, the Antihypertensive and Lipid- Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) 4 may be the most relevant, given its size and the ethnic diversity of enrolled subjects. In ALLHAT, after 5 years of follow-up, 34% of subjects remained uncontrolled on an average of two medications, 23% of subjects were on three or more medications, and approximately 8% of subjects were prescribed four or more medications. VOL. 8 NO. 3 MARCH 2006 THE JOURNAL OF CLINICAL HYPERTENSION 181

2 CHARACTERISTICS Resistant hypertension is most often a consequence of uncontrolled systolic BP. In a cross-sectional analysis from the Framingham Heart Study, 5 only 49% of treated subjects were at a systolic BP goal of <140 mm Hg, while 90% were at the diastolic goal of <90 mm Hg. At the end of the study in ALLHAT, 33% of subjects had systolic BP levels above goal while diastolic BP was uncontrolled in only 8%. 4 Older age and higher systolic BP are strong negative predictors of achieving BP control in both the Framingham Heart Study and ALLHAT. 4,6 In addition, in ALLHAT, obesity, diabetes, elevated serum creatinine, and living in the Southeastern United States were associated with lower control rates. Black race and female gender also predicted a lower likelihood of achieving BP control in ALLHAT; BP control was worst in black women (59%) and best in white men (70%). ADHERENCE Nonadherence to prescribed medications is a common cause of uncontrolled BP, which, however, is distinct from treatment resistance. For a threedrug regimen to have failed, medications had to have been taken correctly. Long-term adherence to antihypertensive therapies is poor, with as many as 50% of patients not refilling prescriptions after 4.5 years of follow-up. 7 Multiple pills, complex dosing, frequent medication changes, and expensive regimens worsen adherence. Ultimately, knowing the degree of adherence is dependent on the patient s self-report; therefore, establishing and maintaining good clinician-patient rapport is essential to recognizing and overcoming treatment barriers. WHITE COAT EFFECTS White coat effects (elevated clinic but normal or substantially lower out-of-clinic BP levels) are probably as common in patients with resistant hypertension as in subjects with more easily controlled hypertension, with a prevalence of between 20% 30%. 8,9 As described in other hypertensive cohorts, subjects with resistant hypertension but a prominent white coat effect are at lower cardiovascular risk than subjects with resistant hypertension confirmed by ambulatory monitoring. 10 White coat resistant hypertension should be suspected in patients with elevated clinic pressures but substantially lower out-of-clinic BP measurements, symptoms of overtreatment, or an absence of target organ damage in the setting of severe hypertension. If suspected, ambulatory BP monitoring should be done. If a prominent white coat effect is confirmed, out-of-clinic BP measurements should be used to guide therapy. OBESITY Obesity is associated with increasing severity of hypertension, use of an increasing number of antihypertensive medications, and an increased likelihood of never achieving goal BP. 2,5 On a population basis, the probability of lack of BP control in obese patients is about 50% higher than hypertensive patients who are at normal weight. 5 Accordingly, obesity is very common among patients with resistant hypertension. The mechanisms of obesity-related hypertension are not fully elucidated, but include increased sodium and fluid retention, greater sympathetic activation, and increased stimulation of the renin-angiotensin-aldosterone system. Benefit of weight reduction has not been specifically evaluated in subjects with resistant hypertension, but benefit is consistent in general hypertensive cohorts. In a recent review of long-term weight loss trials, a 10-kg weight loss was associated with a 6.0-mm Hg reduction in systolic BP and a 4.6-mm Hg reduction in diastolic BP. 11 DIETARY SALT High dietary salt ingestion blunts the benefit of most classes of antihypertensive agents. Studies of dietary salt restriction in hypertensive subjects demonstrate a reduction in systolic BP of 5 8 mm Hg and a reduction in diastolic BP of 3 6 mm Hg. 12 In patients who are more likely to be salt-sensitive, including the elderly, African Americans and, in particular, patients with chronic kidney disease, the effects of high dietary salt ingestion on BP are likely to be accentuated. Dietary salt restriction has not been specifically evaluated in subjects with resistant hypertension, but benefit has been demonstrated in subjects whose BP was uncontrolled with an angiotensin-converting enzyme (ACE) inhibitor alone or in combination with a diuretic. 13,14 Dietary salt restriction should be recommended to all subjects with resistant hypertension, ideally to <6 g/d of NaCl (approximately 100 meq of sodium). EXOGENOUS SUBSTANCES Pharmacologic agents that commonly worsen BP control include nonanalgesic narcotics, stimulants, glucocorticoids, sympathomemitics, cyclosporine, and erythropoietin (Table I). These agents are likely to have only a modest, if any, effect on BP in most persons. In certain individuals, however, the effect can be pronounced, causing severe elevations in BP and/or contributing to significant treatment resistance. 182 THE JOURNAL OF CLINICAL HYPERTENSION VOL. 8 NO. 3 MARCH 2006

3 Non-narcotic analgesics, in particular, nonsteroidal anti-inflammatory agents, including acetaminophen, increase the risk of developing hypertension. 15,16 Nonsteroidal anti-inflammatory agents have also been shown to blunt the antihypertensive effect of therapies including ACE inhibitors, angiotensin receptor blockers (ARBs), and β blockers The pressor effects of nonsteroidal anti-inflammatory agents are likely due, at least in part, to inhibition of renal prostaglandins and subsequent sodium and fluid retention. In relatively unusual cases, the associated increase in BP can be severe and may be accompanied by development of peripheral edema and acute renal insufficiency. Risk of such adverse effects is highest in the elderly and/or in patients with underlying renal disease. Selective cyclooxygenase-2 inhibitors can also worsen BP control, but perhaps to a somewhat lesser extent than nonselective compounds. 20 ALCOHOL Ingestion of large amounts of alcohol is associated with an increased risk of developing high BP and having BP that is resistant to treatment. In a crosssectional analysis of Chinese men who consumed >30 drinks a week, it was shown that the likelihood of having high BP was more than double. 21 In French men, excessive alcohol ingestion predicts an increased incidence of hypertension and lack of BP control in spite of treatment. 22,23 Cessation of heavy alcohol ingestion has been demonstrated to reduce 24-hour systolic and diastolic BP by 7.2 and 6.6 mm Hg, respectively, and to reduce the percentage of subjects with hypertension from 42% to 12%. 24 The mechanism by which excessive alcohol ingestion worsens BP control is unknown. It may be a direct effect of alcohol on BP levels and/or an indirect effect through worsening of medication adherence. To facilitate better BP control, moderation of alcohol intake ( 2 drinks per day) should be encouraged in patients with difficult-to-treat hypertension. SECONDARY HYPERTENSION The prevalence of secondary causes of hypertension is increased in patients with resistant hypertension compared with patients with more easily treated hypertension. The most common secondary causes of hypertension are obstructive sleep apnea, chronic kidney disease, hyperaldosteronism, and renal artery stenosis (Table II). The occurrence of these disorders increase with age in large part due to an increasing frequency of sleep apnea, kidney disease, and renal artery stenosis. Table I. Exogenous Substances That May Interfere With Blood Pressure Control Dietary salt Non-narcotic analgesics (nonsteroidal anti-inflammatory agents including selective cyclooxygenase-2 inhibitors and acetaminophen) Alcohol Stimulants (methylphenidate, dexmethylphenidate, dextroamphetamine, amphetamine, methamphetamine) Sympathomimetic agents (decongestants, diet pills, cocaine, caffeine) Anabolic steroids Oral contraceptives Cyclosporine Erythropoietin Tricyclic antidepressants Licorice Table II. Secondary Causes of Hypertension That May Contribute to Treatment Resistance COMMON RARE Obstructive sleep apnea Pheochromcytoma Renal parenchymal disease Coarctation of the aorta Hyperaldosteronism Cushing disease Renal artery stenosis Hypercalcemia Central nervous system tumors Acromegaly Carcinoid syndrome OBSTRUCTIVE SLEEP APNEA Sleep apnea significantly increases the risk of having hypertension and, if the patient is normotensive, is strongly associated with the development of hypertension. 25,26 Sleep apnea also increases the likelihood of having resistant hypertension. In cross-sectional analyses of hypertensive patients referred for a sleep study, the worse the sleep apnea the more likely the BP remained elevated in spite of treatment. 27 In a prospective evaluation of subjects with drug-resistant hypertension, 83% of subjects with drug-resistant hypertension were found to have sleep apnea (apnea/hypopnea index 10 events per hour), including almost all of the men (96%) and a majority of the women (65%). 28 Treatment of sleep apnea with continuous positive airway pressure likely benefits BP control, although assessments have reported varying results. In a recent evaluation, 9 weeks of continuous positive airway pressure use reduced both nighttime and daytime systolic and diastolic BPs by about 10 mm Hg. 29 Other continuous positive airway pressure intervention studies, however, have not demonstrated such a large benefit. In a small study of VOL. 8 NO. 3 MARCH 2006 THE JOURNAL OF CLINICAL HYPERTENSION 183

4 subjects with resistant hypertension, 2 months of continuous positive airway pressure use was associated with a reduction in nighttime and daytime systolic BP of 14.4 and 9.3 mm Hg, respectively. 30 CHRONIC KIDNEY DISEASE Poorly controlled hypertension is both a common cause and consequence of chronic renal insufficiency. Chronic kidney disease is generally associated with sodium and fluid retention, and patients are prone to treatment resistance secondary to volume expansion. All patients with resistant or difficultto-control hypertension should have their renal function assessed by determination of glomerular filtration rate or creatinine clearance because the serum creatinine can be misleading, particularly in the elderly. Dietary salt restriction is particularly important in the setting of chronic kidney disease. ACE inhibitors or ARBs should be preferentially used in an attempt to preserve renal function and loop diuretics may be necessary to effectively reduce intravascular volume and facilitate BP control. HYPERALDOSTERONISM Recent reports suggest that primary aldosteronism may be more common than previously believed, particularly in patients with resistant hypertension. In three separate reports, the prevalence of primary aldosteronism was found to be approximately 20% in subjects with difficult-to-treat hypertension. In an analysis of 88 consecutive subjects with resistant hypertension, investigators at the University of Alabama at Birmingham reported that 20% of subjects had primary aldosteronism based on inappropriate urinary excretion of aldosterone in spite of high dietary salt ingestion. 31 This high frequency of primary aldosteronism in subjects with resistant hypertension is consistent with observations from investigators in Seattle, WA, and Oslo, Norway, who reported prevalence rates of 17% and 23%, respectively. 32,33 The cause of current high rates of aldosterone excess are unknown. Obesity is associated with generalized stimulation of the renin-angiotensinaldosterone system. In addition, aldosterone excess has been linked to symptoms of sleep apnea, suggesting a possible cause and effect. 34 RENAL ARTERY STENOSIS Renal artery stenosis is present in about 20% of select patients evaluated at the time of coronary angiography, although it is unknown what percentage of those lesions contribute to the development of renovascular hypertension. 35,36 Renal artery stenosis is undoubtedly even more common in patients with resistant hypertension, but the overall prevalence is also unknown. Noninvasive screening for renal artery stenosis can be challenging. In published series, the sensitivity and specificity of the various imaging modalities such as duplex Doppler and magnetic resonance angiography are generally high, but real-world predictive values likely vary depending on institutional experience. In patients in whom there is a high level of suspicion, equivocal or even negative test results may warrant repeat testing with a different imaging modality. Approximately 10% of obstructive renal artery lesions are secondary to fibromuscular dysplasia, which typically occur in women younger than 50 years of age. Such lesions respond well to angioplasty although restenosis may occur in up to 20% of cases. 37 The remaining 90% of renal artery lesions are atherosclerotic, which should be suspected in patients with known atherosclerotic disease, declining renal function, or a history of flash pulmonary edema. In contrast to fibromuscular dysplasia, the preferred method of treatment of atherosclerotic lesions is controversial. Little or no BP benefit may occur with angioplasty and stenting, such that superiority over intensive medical therapy has not been established. Demonstration of long-term benefit is also lacking in patients with resistant hypertension, but given the antecedent failure of medical therapy, a recommendation in favor of angioplasty seems appropriate. EVALUATION Evaluation of patients with resistant hypertension should focus on identifying reversible causes of hypertension and documenting the degree of target organ deterioration. Adherence should be carefully reviewed. Potentially contributing factors should be screened for by history, physical examination, biochemical evaluation, and radiographic imaging as appropriate. In most cases, resistance to antihypertensive treatment will be multifactorial in etiology, with obesity, excessive salt ingestion, and use of interfering substances likely to be present. Secondary causes of hypertension, particularly sleep apnea and hyperaldosteronsim, are also common. Use of good BP measurement technique, including use of a correctly sized cuff and having the patient sit quietly for 3 to 5 minutes before measuring the BP, is essential to avoid falsely high BP readings. Supine and upright pressures should be measured at the initial visit and at follow-up to avoid orthostatic complications. Ambulatory BP monitoring is appropriate to screen for substantive 184 THE JOURNAL OF CLINICAL HYPERTENSION VOL. 8 NO. 3 MARCH 2006

5 white coat effects. All patients should be encouraged to keep a diary of out-of-office BP measurements to help guide therapy. In addition to measurement of a basic metabolic profile and plasma aldosterone and renin, a 24-hour urine collection is recommended to quantify sodium, creatinine, and protein excretion. Polysomnographic evaluation for sleep apnea is also recommended, particularly for men. TREATMENT Treatment of resistant hypertension will be most effective with identification and reversal of contributing factors. Beyond these specific interventions, treatment requires combined use of lifestyle changes and multidrug regimens. Nonpharmacologic therapies (weight loss, exercise, dietary salt restriction, moderation of alcohol intake) should be encouraged in all patients, as appropriate, and reinforced during follow-up. Barriers to medication adherence should be addressed and resolved, if possible. Pharmacologic therapy is based on use of effective multidrug regimens. A triple regimen of an ACE inhibitor or ARB, calcium channel blocker, and a thiazide diuretic is generally very effective and well tolerated. The combination can be prescribed as two pills with use of fixed-dose products or generically with use of three pills. Assessments of ineffective antihypertensive regimens have almost always indicated lack or underuse of diuretic therapy. 38,39 Most patients with resistant hypertension have inappropriate sodium and fluid retention such that effective diuretic therapy is essential for BP control. In most patients, long-acting thiazide diuretics should be used preferentially both because of efficacy and well documented outcome benefit. Loop diuretics may be necessary in patients with chronic kidney disease (creatinine clearance <60 ml/min) and should be used if also prescribing potent vasodilators such as hydralazine or minoxidil. Furosemide is relatively short-acting and requires at least twicedaily dosing for effective use. Alternatively, longeracting agents such as torsemide can be used. Recent clinical reports indicate that aldosterone antagonists provide significant additional BP reduction when used in patients with resistant hypertension. In an open-label evaluation of patients uncontrolled on an average of four medications, including an ACE inhibitor or ARB and a diuretic, spironolactone mg daily further reduced BP by 25±20/12±12 mm Hg at 6-month follow-up (Figure). 40 Interestingly, the degree of antihypertensive benefit was similar in subjects BP responses (mm Hg) Follow-up 6 Weeks 3 Months 6 Months Figure. Spironolactone-induced reduction in systolic (black bars) and diastolic blood pressure (white bars) at 6-week, 3-month, and 6-month follow-up in subjects with resistant hypertension. Reprinted with permission from Am J Hypertens. 2003;16: with and without primary aldosteronism and was not predicted by baseline plasma aldosterone or renin levels or by 24-hour urinary aldosterone excretion. Benefit was also similar in African- American and white subjects. In a similar experience, amiloride 2.5 mg daily added to multidrug regimens in patients with low-renin, resistant hypertension lowered BP by 31±21/15±11 mm Hg at 3-week follow-up. 33 Further reductions in BP were observed in a subset of the patients in whom the amiloride was titrated to 5 mg daily. In the above studies, spironolactone and amiloride were generally well tolerated. Spironolactone use did cause breast tenderness in about 10% of the male subjects. 40 Hyperkalemia, with or without accompanying acute renal insufficiency is uncommon, but may occur with use of aldosterone antagonists. Risk is increased in patients with chronic kidney disease, diabetics, elderly subjects, and subjects already receiving an ACE inhibitor or an ARB. Serum potassium levels and renal function must be monitored after initiating treatment and with subsequent titrations. Potassium supplementation should be discontinued (or substantially reduced if on large doses), and patients should be advised not to use salt substitutes that contain potassium. Eplerenone is a selective mineralocortiocid receptor antagonist with a lower affinity for progesterone and androgen receptors than spironolactone. As a consequence, it is better tolerated with a lower incidence of breast tenderness, gynecomastia, sexual dysfunction, and menstrual irregularities. 41,42 Eplerenone has not been specifically evaluated for treatment of resistant hypertension; however, in men or women who develop adverse effects with VOL. 8 NO. 3 MARCH 2006 THE JOURNAL OF CLINICAL HYPERTENSION 185

6 spironolactone, it is an obvious alternative. As with spironolactone, eplerenone use requires monitoring of serum potassium levels and renal function. Disclosures: This work was supported by National Heart, Lung, and Blood Institute grants HL and SCCOR P50HL Author disclosure: grant support (Novartis, AstraZeneca Pharmaceuticals LP); speaker honorarium (Merck & Co.); and consultant (Pfizer Inc.). REFERENCES 1 Hajjar I, Kotchen TA. Trends in prevalence, awareness, treatment, and control of hypertension in the United States, JAMA. 2003;290: Bramlage P, Pittrow D, Hans-Ulrich W, et al. Hypertension in overweight and obese primary care patients is highly prevalent and poorly controlled. Am J Hypertens. 2004;17: Riehle JF, Lackland DT, Okonofua EC, et al. Ethnic differences in the treatment and control of hypertension in patients with diabetes. J Clin Hypertens. 2005;7: Cushman WC, Ford CE, Cutler JA, et al. Success and predictors of blood pressure control in diverse North American settings: the Antihypertensive and Lipid-Lowering and Treatment to Prevent Heart Attack Trial (ALLHAT). J Clin Hypertens. 2002;4: Lloyd-Jones DM, Evans JC, Larson MG, et al. Differential control of systolic and diastolic blood pressure: factors associated with lack of blood pressure control in the community. Hypertension. 2000;36: Lloyd-Jones DM, Evans JC, Larson MG, et al. Treatment and control of hypertension in the community: a prospective analysis. Hypertension. 2002;40: Caro JJ, Speckman JL, Salas M. Effect of initial drug choice on persistence with antihypertensive therapy: the importance of actual practice data. CMAJ. 1999;160: Brown MA, Buddle ML. Martin. Is resistant hypertension really resistant? Am J Hypertens. 2001;14: Hermida RC, Ayala DE, Calvo C, et al. Effects of time of day of treatment on ambulatory blood pressure pattern of patients with resistant hypertension. Hypertension. 2005;46: Redon J, Campos C, Narciso ML, et al. Prognostic value of ambulatory blood pressure monitoring in refractory hypertension: a prospective study. Hypertension. 1998;31: Aucott L, Poobalan A, Smith WC, et al. Effects of weight loss in overweight/obese individuals and long-term hypertension outcomes: a systematic review. Hypertension. 2005;45: He JF, Markandu ND, MacGregor GA. Modest salt reduction lowers blood pressure in isolated systolic hypertension and combined hypertension. Hypertension. 2005;46: Wing LM, Arnolda LF, Harvey PJ, et al. Low-dose diuretic and/or dietary sodium restriction when blood pressure is resistant to ACE inhibitor. Blood Press. 1998;7: Singer DR, Markandu ND, Sugden AL, et al. Sodium restriction in hypertensive patients treated with a converting enzyme inhibitor and a thiazide. Hypertension. 1991;17: Dedier J, Stampfer MJ, Hankinson SE, et al. Nonnarcotic analgesic use and the risk of hypertension in US women. Hypertension. 2002;40: Forman JP, Stampfer MJ, Curhan GC. Non-narcotic analgesic dose and risk of incident hypertension in US women. Hypertension. 2005;46: Johnson AG, Nguyen TV, Day RO. Do nonsteroidal antiinflammatory drugs affect blood pressure? Ann Intern Med. 1994;121: Radack KL, Deck CC, Bloomfield SS. Ibuprofen interferes with the efficacy of antihypertensive drugs: a randomized, double-blind, placebo-controlled trial of ibuprofen compared with acetaminophen. Ann Intern Med. 1987;107: Conlin PR, Moore TJ, Swartz SL, et al. Effect of indomethacin on blood pressure lowering by captopril and losartan in hypertensive patients. Hypertension. 2000;36: White WB, Kent J, Taylor A, et al. Effects of celecoxib on ambulatory blood pressure in hypertensive patients on ACE inhibitors. Hypertension. 2002;39: Wildman RP, Gu D, Muntner P, et al. Alcohol intake and hypertension subtypes in Chinese men. J Hypertens. 2005;23: de Gaudemaris R, Lang T, Chatellier G, et al. Socioeconomic inequalities in hypertension: prevalence and care: the IHPAF study. Hypertension. 2002;39: Radi S, Lang T, Lauwers-Cancès V, et al. One-year hypertension incidence and its predictors in a working population: the IHPAF study. J Human Hypertens. 2004;18: Aguilera MT, de la Sierra A, Coca A, et al. Effect of alcohol abstinence on blood pressure: assessment by 24-hour ambulatory blood pressure monitoring. Hypertension. 1999;33: Nieto FJ, Young TB, Lind BK, et al., for the Sleep Heart Health Study. Association of sleep-disordered breathing, sleep apnea, and hypertension in a large community-based study. JAMA. 2000;283: Peppard PE, Young T, Palta M, et al. Prospective study of the association between sleep-disordered breathing and hypertension. N Engl J Med. 2000;342: Lavie P, Hoffstein V. Sleep apnea syndrome: a possible contributing factor to resistant hypertension. Sleep. 2001;24: Logan AG, Perlikowski SM, Mente A, et al. High prevalence of unrecognized sleep apnea in drug-resistant hypertension. J Hypertens. 2001;19: Becker HF, Jerrentrup A, Ploch T, et al. Effect of nasal continuous positive airway pressure treatment on blood pressure in patients with obstructive sleep apnea. Circulation. 2003;107: Logan AG, Tkacova R, Perlikowski SM, et al. Refractory hypertension and sleep apnoea: effect of CPAP on blood pressure and baroreflex. Eur Respir J. 2003;21: Calhoun DA, Nishizaka MK, Zaman MA, et al. High prevalence of primary aldosteronism among black and white subjects with resistant hypertension. Hypertension. 2002;40: Gallay BJ, Ahmad S, Xu L, et al. Screening for primary aldosteronism without discontinuing hypertensive medications: plasma aldosterone-renin ratio. Am J Kidney Dis. 2001;37: Eide IK, Torjesen PA, Drolsum A, et al. Low-renin status in therapy-resistant hypertension: a clue to efficient treatment. J Hypertens. 2004;22: Calhoun DA, Nishizaka MK, Zaman MA, et al. Aldosterone excretion among subjects with resistant hypertension and symptoms of sleep apnea. Chest. 2004;125: Harding MB, Smith LR, Himmelstein SI, et al. Renal artery stenosis: prevalence and associated risk factors in patients undergoing routine cardiac catherization. J Am Soc Nephrol. 1992;2: Rihal CS, Textor SC, Breen JF, et al. Incidental renal artery stenosis among a prospective cohort of hypertensive patients undergoing coronary angiography. Mayo Clin Proc. 2002;77: Birrer M, Do DD, Mahler F, et al. Treatment of renal artery fibromuscular dysplasia with ballon angioplasty: a prospective follow-up study. Eur J Vasc Endovasc Surg. 2002;23: Taler SJ, Textor SC, Augustine JE. Resistant hypertension: comparing hemodynamic management to specialist care. Hypertension. 2002;39: Garg JP, Elliott WJ, Folker A, et al., for the RUSH Hypertension Service. Resistant hypertension revisted: a comparison of 2 university-based cohorts. Am J Hypertens. 2005;18: Nishizaka MK, Zaman MA, Calhoun DA. Efficacy of lowdose spironolactone in subjects with resistant hypertension. Am J Hypertens. 2003;16: Weinberger MH, Roniker B, Krause SL, et al. Eplerenone, a selective aldosterone blocker, in mild-to-moderate hypertension. Am J Hypertens. 2002;15: Flack JM, Oparil S, Pratt JH, et al. Efficacy and tolerability of eplerenone and losartan in hypertensive black and white patients. J Am Coll Cardiol. 2003;41: THE JOURNAL OF CLINICAL HYPERTENSION VOL. 8 NO. 3 MARCH 2006