| | Resistant Hypertension: Core Curriculum 2008 published online 15 August 2008. Introduction  A patient with difficult-to-control hypertension commonly is referred to a nephrologist for evaluation and therapy. Resistant hypertension is defined as blood pressure that remains under suboptimal control despite the adherent use of 3 full-dose antihypertensive medications, inclusive of a diuretic. Classic teaching dictates that initial subspecialty referral and assessment must demand a careful history, physical examination, and laboratory investigation to exclude secondary causes of hypertension, including renovascular disease, chronic kidney disease, and endocrinopathies (Table 1). Nonetheless, these causes are identified in as little as 10% of resistant hypertension referrals. A greater prevalence of secondary causes is noted with increasing age or coexistent atherosclerosis. An earlier Core Curriculum on Hypertension by David Warnock and Stephen Textor outlines secondary hypertension causes.  | Coarctation of the aorta | | | Glucocorticoid-excess diseases | | |  Cushing syndrome | | | Mineralocorticoid-excess diseases | | | Hyperaldosteronism | | | Pheochromatocytoma | | | Renal parenchymal disease | | | Renal vascular disease | | | Sleep apnea | | | Thyroid disorders | | | | |
Suboptimal therapy is the most common cause of resistant hypertension. Suboptimal therapy may be defined as failure to use rational pharmacological combinations, attend to comorbid conditions, properly intervene for excess extracellular volume, or some combination of these. Furthermore, evaluation may be confounded by inaccurate blood pressure measurement, pseudohypertension, white coat effect, medical nonadherence, and concomitant ingestion of interfering or antagonizing substances. An intriguing line of investigation is emerging with regard to the importance of obesity, sleep apnea, and hyperaldosteronism in patients with resistant hypertension. An interrelated pathophysiological process of these disorders has been postulated. Careful assessment for these conditions may expose additional avenues for successful treatment of patients with resistant hypertension. Therapy for patients with resistant hypertension involves lifestyle modification, effective treatment of comorbid conditions, and rational pharmacological combinations. Individual lifestyle interventions have a small impact in isolation, but are useful in aggregate. A rational medication approach emphasizes appropriate drug class combinations at optimal doses, particular attention to adequate diuretic use, and a potential role for mineralocorticoid blockade. Additional Reading 1.Moser M, Setaro JF: Clinical practice. Resistant or difficult-to-control hypertension. N Engl J Med 355:385-392, 2006 2.Warnock DG, Textor SC: Hypertension. Am J Kidney Dis 44:369-375, 2004 3.Anderson GH Jr, Blakeman N, Streeten DH: The effect of age on prevalence of secondary forms of hypertension in 4429 consecutively referred patients. J Hypertens 12:609-615, 1994 4.Berlowitz DR, Ash AS, Hickey EC, et al: Inadequate management of blood pressure in a hypertensive population. N Engl J Med 339:1957-1963, 1998 5.Garg JP, Elliott WJ, Folker A, et al: Resistant hypertension revisited: A comparison of two university-based cohorts. Am J Hypertens 18:619-626, 2005 6.Goodfriend TL, Calhoun DA: Resistant hypertension, obesity, sleep apnea, and aldosterone: Theory and therapy. Hypertension 43:518-524, 2004 7.Chobanian AV, Bakris GL, Black HR, et al: The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: The JNC 7 report. JAMA 289:2560-2572, 2003 I.Accurate blood pressure assessment: techniqueA.Variables affecting clinic blood pressure measurement1.Arm positiona.Midcuff, upper arm, right atrium level 2.Cuff sizea.Largest error when cuff too small relative to arm circumference (falsely increased readings) b.Bladder length should be at least 80% and width at least 40% of arm circumference 3.Sphygmomanometer type and maintenancea.Mercury remains gold standard, although aneroid now more common; this requires periodic calibration b.Oscillometric automated monitors require no transducer and are less susceptible to external noisei.Less reliable in patients with stiff arteries ii.Require periodic validation 4.Frequency of readings 5.Patient factorsa.Anxiety; white coat effect b.Recent food, exercise, nicotine, caffeine intake; modest impact B.Pseudohypertension1.Poor arterial compliance caused by advanced atherosclerosis or vascular calcification 2.Osler's maneuver as clinical signa.Palpable brachial or radial artery distal to fully inflated cuff b.Poor reproducibility 3.Intra-arterial monitoring as gold standard, but not often practical C.White coat effect1.Pressor response associated with blood pressure measured in physician's office 2.Evidence of end-organ damage is often used to discriminate true hypertension from white coat effecta.Left ventricular hypertrophy b.Microalbuminuria c.Retinal changes 3.Not completely benign?a.Hypertension and Ambulatory Recording Venetia Study (HARVEST)i.Left ventricular mass index and wall thickness greatest in patients with true hypertension, but these indexes in patients with white coat hypertension exceed those in patients with normotension ii.Microalbuminuria observed only in patients with true hypertension b.Discrimination of white coat from true resistant hypertensioni.Home monitoring; average of 3 consecutive readings once or twice daily used in investigative studies ii.Twenty-four–hour ambulatory blood pressure monitoring (ABPM) D.Blood pressure monitoring in resistant hypertension assessment1.Importance of repeated measuresa.Optimal frequency uncertain 2.Exclusion of white coat hypertension requires home monitoring or ABPM 3.Better cardiovascular risk prediction achieved with ABPMa.Night-time variationi.Nondipping as predictor of adverse cardiovascular events b.Relevance of load (percentage of abnormal values/total) 4.Adjunct assessment to therapy response 5.Cost-benefit advantage of 24-hour ABPM versus home monitoring or office/clinic monitoring is uncertain Additional Reading 1.Pickering TG, Hall JE, Appel LJ, et al: Recommendations for blood pressure measurement in humans and experimental animals: Part 1: Blood pressure measurement in humans: A statement for professionals from the Subcommittee of Professional and Public Education of the American Heart Association Council on High Blood Pressure Research. Circulation 111:697-716, 2005 2.Messerli FH, Ventura HO, Amodeo C: Osler's maneuver and pseudohypertension. N Engl J Med 312:1548-1551, 1985 3.Palatini P, Mormino P, Santonastaso M, et al: Target-organ damage in stage I hypertensive subjects with white coat and sustained hypertension: Results from the HARVEST study. Hypertension 31:57-63, 1998 4.Hansen TW, Jeppesen J, Rasmussen S, et al: Ambulatory blood pressure and mortality: A population-based study. Hypertension 45:499-504, 2005 5.Muxfeldt ES, Bloch KV, Nogueira AR, et al: Twenty-four hour ambulatory blood pressure monitoring pattern of resistant hypertension. Blood Press Monit 8:181-185, 2003 6.Clement DL, De Buyzere ML, De Bacquer DA, et al: Prognostic value of ambulatory blood-pressure recordings in patients with treated hypertension. N Engl J Med 348:2407-2415, 2003 7.Tatasciore A, Renda G, Zimarino M, et al: Awake systolic blood pressure variability correlates with target-organ damage in hypertensive subjects. Hypertension 50:325-332, 2007 8.Viazzi F, Leoncini G, Ratto E, et al: Microalbuminuria, blood pressure load, and systemic vascular permeability in primary hypertension. Am J Hypertens 19:1183-1189, 2006 9.Staessen JA, Den HE, Celis H, et al: Antihypertensive treatment based on blood pressure measurement at home or in the physician's office: A randomized controlled trial. JAMA 291:955-964, 2004 10.Pickering TG, Shimbo D, Haas D: Ambulatory blood-pressure monitoring. N Engl J Med 354:2368-2374, 2006 II.Ingestions/antagonizing substancesA.Magnitude of effect not rigorously studied B.Salt1.Increased sensitivity; diets greater than 100 mmol/da.Most consistent correlations with increased age, obesity, African American race, chronic kidney disease b.Induction of salt sensitivity by dietary potassium deficiency in African Americans c.Possible association with indolent tubulointerstitial renal injury 2.Utility of 24-hour urine sodium to estimate salt intake 3.Reduction to target intake impacts on systolic blood pressure from 2 to 8 mm Hg D.Moderate to severe alcohol use (>2 drinks/d) E.Other ingestions1.Caffeine, nicotine, licorice Additional Reading 1.Weinberger MH: Salt sensitivity of blood pressure in humans. Hypertension 27:481-490, 1996 2.Elliott P, Stamler J, Nichols R, et al: Intersalt revisited: Further analyses of 24 hour sodium excretion and blood pressure within and across populations. Intersalt Cooperative Research Group. BMJ 312:1249-1253, 1996 3.Morgan T, Anderson A: The effect of nonsteroidal anti-inflammatory drugs on blood pressure in patients treated with different antihypertensive drugs. J Clin Hypertens (Greenwich) 5:53-57, 2003 4.Johnson AG, Nguyen TV, Day RO: Do nonsteroidal anti-inflammatory drugs affect blood pressure? A meta-analysis. Ann Intern Med 121:289-300, 1994 5.Johnson RJ, Herrera-Acosta J, Schreiner GF, Rodriguez-Iturbe B: Subtle acquired renal injury as a mechanism of salt-sensitive hypertension. N Engl J Med 346:913-923, 2002 6.Salerno SM, Jackson JL, Berbano EP: Effect of pseudoephedrine on blood pressure and heart rate: A meta-analysis. Arch Intern Med 165:1686-1694, 2005 7.Salerno SM, Jackson JL, Berbano EP: The impact of oral phenylpropanolamine on blood pressure: A meta-analysis and review of the literature. J Hum Hypertens 19:643-652, 2005 8.Sowers JR, White WB, Pitt B, et al: The effects of cyclooxygenase-2 inhibitors and nonsteroidal anti-inflammatory therapy on 24-hour blood pressure in patients with hypertension, osteoarthritis, and type 2 diabetes mellitus. Arch Intern Med 165:161-168, 2005 9.Carter BL, Lund BC, Hayase N, et al: A longitudinal analysis of antihypertensive drug interactions in a Medicaid population. Am J Hypertens 17:421-427, 2004 10.Zhu X, Wu S, Dahut WL, Parikh CR: Risks of proteinuria and hypertension with bevacizumab, an antibody against vascular endothelial growth factor: Systematic review and meta-analysis. Am J Kidney Dis 49:186-193, 2007 III.NonadherenceA.Causes and frequency1.Side effectsa.Most common with central α agonists, direct arterial vasodilaters, β-blockers, diuretics b.Studies of long-term follow-up with monotherapy of patients with essential hypertension show best adherence with angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) 2.Perceived lack of efficacy 3.Complex regimensa.Inclusion of short half-life, frequently dosed medications b.Increased nonadherence with greater number of medications or pillsi.Anecdotal; not systematically studied c.Inclusion of medications with greater side-effect incidence B.Assessment1.Patient interview; historical elements that corroborate medication usea.Fatigue (β-blockers, α1-antagonists, central α-agonists) b.Edema (calcium channel blockers, minoxidil) c.Dry mouth (central α-agonists) 2.Physician judgmenta.Sensitivity of physician estimate of compliance as low as 10% in some studies 3.Pill countsa.Easily manipulated by patients; not formally studied 4.Prescription renewal confirmation 5.Electronic monitoring systems; predominantly a research toola.Improved blood pressure control in two-thirds of patients during 2-month observation in 1 cohort 6.In-hospital direct observation in selected circumstances C.Intervention1.Conflicting results regarding the actual impact of adherence on outcomes in patients with resistant hypertensiona.One prospective case-control study of electronic monitoring in patients with resistant hypertension versus those with responsive hypertension failed to show a difference in adherence (>80% both groups) 2.Comprehensive pharmacy care programs show promisea.Standardized education, regular pharmacist follow-up, and controlled medication dispense mechanisms shown to improve blood pressure in an elderly cohort Additional Reading 1.Burnier M, Santschi V, Favrat B, et al: Monitoring compliance in resistant hypertension: An important step in patient management. J Hypertens Suppl 21:S37-S42, 2003 2.Wuerzner K, Hassler C, Burnier M: Difficult blood pressure control: Watch out for non-compliance! Nephrol Dial Transplant 18:1969-1973, 2003 3.Burnier M, Schneider MP, Chiolero A, et al: Electronic compliance monitoring in resistant hypertension: The basis for rational therapeutic decisions. J Hypertens 19:335-341, 2001 4.Nuesch R, Schroeder K, Dieterle T, et al: Relation between insufficient response to antihypertensive treatment and poor compliance with treatment: A prospective case-control study. BMJ 323:142-146, 2001 5.Lee JK, Grace KA, Taylor AJ: Effect of a pharmacy care program on medication adherence and persistence, blood pressure, and low-density lipoprotein cholesterol: A randomized controlled trial. JAMA 296:2563-2571, 2006 IV.Comorbid conditions influencing blood pressure controlA.Obesity1.High prevalence in resistant hypertension 2.Association with insulin-resistance, obstructive sleep apnea (OSA), hyperaldosteronism 3.Consistent benefit of weight reduction on blood pressure control B.OSA1.Association with hypertension suggested in population-based studiesa.An independent variable even after accounting for body mass index, sex, age, alcohol, cigarettes, ethnicity 2.Mechanismsa.Increased muscle sympathetic nerve activity (MSNA) in OSAi.Not observed in obese patients who do not have OSA b.Association of OSA with increased plasma aldosterone concentration (PAC) 3.High prevalence reported in resistant hypertension 4.OSA therapy impactc.Reduced MSNA and improvement in blood pressure shown when effective nocturnal continuous positive airway pressure deliveredii.Greatest benefit in most severe cases C.Hyperaldosteronism1.Classically listed as “secondary” cause of hypertension, particularly in context of discrete adenoma (low incidence) 2.May be more prevalent in cases of resistant hypertension than previously appreciated; as high as 20% in some reportsa.PAC/plasma renin activity (PRA) ratio as a screeni.High PAC absolute (>15 mg/dL) and high PAC/PRA (>20 to 30) consistent with diagnosis ii.Interference of ACE inhibitors, ARBs, and mineralocorticoid blockade with interpretation b.Often normokalemic c.Prevalence may be overestimated by selection bias 3.Linked to obesity and OSAd.Evidence that oxidized fatty acid derivatives common in obesity may stimulate aldosterone secretion e.PAC increased in patients with OSA 4.Benefit of mineralocorticoid blockade in patients with resistant hypertension D.Diabetes mellitus1.Association of insulin resistance with hypertension 2.Interaction with salt sensitivity E.Metabolic syndrome Additional Reading 1.Bramlage P, Pittrow D, Wittchen HU, et al: Hypertension in overweight and obese primary care patients is highly prevalent and poorly controlled. Am J Hypertens 17:904-910, 2004 2.Wolk R, Shamsuzzaman AS, Somers VK: Obesity, sleep apnea, and hypertension. Hypertension 42:1067-1074, 2003 3.Peppard PE, Young T, Palta M, et al: Prospective study of the association between sleep-disordered breathing and hypertension. N Engl J Med 342:1378-1384, 2000 4.Nieto FJ, Young TB, Lind BK, et al: Association of sleep-disordered breathing, sleep apnea, and hypertension in a large community-based study. Sleep Heart Health Study. JAMA 283:1829-1836, 2000 5.Pratt-Ubunama MN, Nishizaka MK, Boedefeld RL, et al: Plasma aldosterone is related to severity of obstructive sleep apnea in subjects with resistant hypertension. Chest 131:453-459, 2007 6.Logan AG, Perlikowski SM, Mente A, et al: High prevalence of unrecognized sleep apnoea in drug-resistant hypertension. J Hypertens 19:2271-2277, 2001 7.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 107:68-73, 2003 8.Calhoun DA, Nishizaka MK, Zaman MA, et al: Hyperaldosteronism among black and white subjects with resistant hypertension. Hypertension 40:892-896, 2002 9.Gallay BJ, Ahmad S, Xu L, et al: Screening for primary aldosteronism without discontinuing hypertensive medications: Plasma aldosterone-renin ratio. Am J Kidney Dis 37:699-705, 2001 10.Suzuki M, Kimura Y, Tsushima M, et al: Association of insulin resistance with salt sensitivity and nocturnal fall of blood pressure. Hypertension 35:864-868, 2000 V.TreatmentA.Attention to extracellular volume status1.Techniques to assess plasma volume have shown that occult volume expansion is underappreciated in patients with hypertensiona.Isotopic albumin labeling labor intensive, not practical for routine use b.Thoracic bioimpedence technique derives stroke volume from low voltage current applied through skin electrodes that detect thoracic fluid volume during systolei.Stroke volume, heart rate, blood pressure used to calculate systemic vascular resistance and cardiac output ii.Impedence cardiography emerging as potential noninvasive tool to guide therapy; remains expensive iii.Direct comparison of hypertension specialist clinical assessment with bioimpedence method showed physician tendency to underestimate need for diuretic therapy in patients with resistant hypertension 2.Emphasis on dietary salt restriction 3.Consideration of mineralocorticoid blockade as primary or adjunct diuretic therapy in patients with resistant hypertensiona.Relative risk of hyperkalemia with concurrent use of ACE inhibitors, ARBs, β-blockers, direct renin inhibitors, or impaired kidney function B.Nonpharmacological interventions1.Not studied in specific context of resistant hypertension; studies in primary prevention and standard hypertensive care presumed to be applicable 2.Weight reductiona.Potentially the greatest impact as an isolated variable b.Systolic blood pressure reduction 5 to 20 mm Hg/10 kg weight loss 3.Salt restriction to less than 100 mEq (<2.4 g)/da.3 to 6 mm Hg/100 mmol reduction in sodium intake 4.Diet; possible impact of Dietary Approaches to Stop Hypertension (DASH)a.8 to 14 mm Hg reduction in systolic blood pressure 5.Aerobic exercise; 30 min/da.4 to 9 mm Hg reduction in systolic blood pressure 6.Limit alcohol use to fewer than 2 drinks/da.2 to 4 mm Hg reduction in systolic blood pressure 7.Smoking cessation C.Pharmacological therapies1.Suboptimal medical regimen may be most common cause of resistant hypertensiona.Accounted for 43% of causes in 1 tertiary care clinic study 2.Complementary class effect interventions for easily controlled hypertension outlined in Joint National Commission 7 Report and previous Hypertension Core Curriculuma.Common initial regimens typically include some combination of angiotensin-interfering agents (ACE inhibitors or ARBs), β-blockers, calcium channel blockers, and diuretics b.Regimens tailored, when appropriate, to comorbid condition indications for diabetes, coronary artery disease, congestive heart failure, chronic kidney disease, and cerebrovascular disease c.Necessity of appropriate dosing 3.Additional considerations in resistant hypertension; not systematically investigateda.Intensification of diuretics, including a combination with mineralocorticoid antagonismi.Half-life longer and antihypertensive efficacy enhanced with thiazides ii.If loop diuretics used, necessity for increased frequency or selection of longer acting agents (eg, torsemide) b.Combined renin-angiotensin system interruptioni.ACE inhibitor plus ARB ii.Mineralocorticoid blockade iii.Utility of direct renin inhibitors? iv.Risk of hyperkalemia and acute kidney injury c.α1-Antagonists d.Dual calcium channel blockade (dihydropyridine plus nondihydropyridine) e.Direct vasodilators: hydralazine or minoxidili.Need for concurrent β-blocker and diuretic D.Caution regarding unfavorable or antagonistic drug combinations1.β-Blockers and verapamil or diltiazem 2.Direct vasodilators with insufficient β-blockade and diuretic 3.Lack of additive effect of calcium channel blockers with diuretics Additional Reading 1.Graves JW, Bloomfield RL, Buckalew VM Jr: Plasma volume in resistant hypertension: Guide to pathophysiology and therapy. Am J Med Sci 298:361-365, 1989 2.Taler SJ, Textor SC, Augustine JE: Resistant hypertension: Comparing hemodynamic management to specialist care. Hypertension 39:982-988, 2002 3.Chapman N, Dobson J, Wilson S, et al: Effect of spironolactone on blood pressure in subjects with resistant hypertension. Hypertension 49:839-845, 2007 4.Nishizaka MK, Zaman MA, Calhoun DA: Efficacy of low-dose spironolactone in subjects with resistant hypertension. Am J Hypertens 16:925-930, 2003 5.Whelton PK, Appel LJ, Espeland MA, et al: Sodium reduction and weight loss in the treatment of hypertension in older persons: A randomized controlled trial of nonpharmacologic interventions in the elderly (TONE). TONE Collaborative Research Group. JAMA 279:839-846, 1998 6.He J, Whelton PK, Appel LJ, et al: Long-term effects of weight loss and dietary sodium reduction on incidence of hypertension. Hypertension 35:544-549, 2000 7.Sacks FM, Svetkey LP, Vollmer WM, et al: Effects on blood pressure of reduced dietary sodium and the Dietary Approaches to Stop Hypertension (DASH) diet. DASH-Sodium Collaborative Research Group. N Engl J Med 344:3-10, 2001 8.Whelton SP, Chin A, Xin X, et al: Effect of aerobic exercise on blood pressure: A meta-analysis of randomized, controlled trials. Ann Intern Med 136:493-503, 2002 9.Xin X, He J, Frontini MG, et al: Effects of alcohol reduction on blood pressure: A meta-analysis of randomized controlled trials. Hypertension 38:1112-1117, 2001 Acknowledgements Support: None. Financial Disclosure: None.  Address correspondence to Mark G. Parker, MD, Division of Nephrology, Maine Medical Center, 22 Bramhall St, Portland, ME 04102
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