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Hypertension, Secondary and Resistant
George H. Maxted, MD
image BASICS
Uncontrolled hypertension (HTN) comprises the following entities (see “Alert” below):
  • Resistant HTN: defined as blood pressure that remains above goal in spite of the concurrent use of three antihypertensive agents of different classes. Ideally, one of the three agents should be a diuretic, and all agents should be prescribed at optimal dose amounts (1,2,3)[C].
  • Secondary HTN: elevated BP that results from an identifiable underlying mechanism (1,2,3)
  • Both the recent Eighth Joint National Committee (JNC 8) and AHA/ACC/CDC guidelines recommend a goal BP of <140/90 mm Hg, although JNC 8 allows for a goal of <150/90 mm Hg for patients older than age 60 years (4,5)[C].
Geriatric Considerations
  • Onset of HTN in adults >60 years of age is a strong indicator of secondary HTN.
  • In patients >80 years of age, consider a higher target systolic blood pressure (SBP) of ≥150 mm Hg. Be cautious to avoid excessive diastolic lowering.
  • Elderly may be particularly responsive to diuretics and dihydropyridine calcium channel blockers.
  • Systolic HTN is particularly problematic in the elderly.
  • Secondary causes more common in the elderly include sleep apnea, renal disease, renal artery stenosis, and primary aldosteronism.
  • Inaccurate measurement of BP
    • Cuff too small
    • Patient not at rest; sitting quietly for 5 minutes
  • Poor adherence: In primary care settings, this has been estimated to occur in 40-60% of patients with HTN.
  • White coat effect: prevalence 20-40%. Do not make clinical decisions about HTN based solely on measurement in the clinic setting. Home BP monitoring and/or ambulatory BP monitoring is more reliable.
  • Inadequate treatment
  • Predominant age: In general, HTN has its onset between ages 30 and 50 years. Patients with resistant HTN are more likely to experience the combined outcomes of death, myocardial infarction, congestive heart failure (CHF), stroke, or chronic kidney disease.
  • Depending on etiology, age of onset can vary. Age of onset <20 or >50 years increases likelihood of a secondary cause for HTN.
  • The strongest predictors for resistant HTN are age (>75 years), presence of left ventricular hypertrophy (LVH), obesity (body mass index [BMI] >30), and high baseline systolic BP. Other predictors include chronic kidney disease, diabetes, living in the southeastern United States, African American race (especially women), and excessive salt intake.
  • Prevalence of resistant HTN is unknown. NHANES analysis indicates only 53% of adults are controlled to a BP of <140/90 mm Hg.
  • Secondary HTN occurs in about 5-10% of adults with chronic HTN.
  • Obstructive sleep apnea (OSA): one study diagnosed OSA in 83% of treatment-resistant hypertensives.
  • Primary hyperaldosteronism (17-22% of resistant HTN cases)
  • Chronic renal disease (2-5% of hypertensives)
  • Renovascular disease (0.2-0.7%, up to 35% of elderly, 20% of patients undergoing cardiac catheterization)
  • Cushing syndrome (0.1-0.6%)
  • Pheochromocytoma (0.04-0.1% of hypertensives)
  • Other rare causes: hyperthyroidism, hyperparathyroidism, aortic coarctation, intracranial tumor
  • Drug-related causes
    • Medications, especially NSAIDs (may also blunt effectiveness of ACE inhibitors), decongestants, stimulants (e.g., amphetamines, attention deficient hyperactivity disorder [ADHD] medications), anorectic agents (e.g., modafinil, ephedra, guarana, ma huang, bitter orange), erythropoietin, natural licorice (in some chewing tobacco), yohimbine, glucocorticoids
    • Oral contraceptives: unclear association; mainly epidemiologic and with higher estrogen pills
    • Cocaine, amphetamines, other illicit drugs; drug and alcohol withdrawal syndromes
  • Lifestyle factors: Obesity and dietary salt may negate the beneficial effect of diuretics. Excessive alcohol may cause or exacerbate HTN. Physical inactivity also contributes.
A recent large cohort study revealed that those with resistant HTN (16.2%) were more likely to be male, Caucasian, older, and diabetic. They were also more likely to be taking &bgr;-blockers, calcium channel blockers, and &agr;-adrenergic blockers compared with other drug classes. Factors predictive of resistant or secondary HTN: female sex, African American race, obesity, diabetes, worsening of control in previously stable hypertensive patient, onset in patients age <20 years or >50 years, lack of family history of HTN, significant target end-organ damage, stage 2 HTN (systolic BP >160 mm Hg or diastolic BP >100 mm Hg), renal disease, and alcohol or drug use (3)[A]
The prevention of resistant and secondary HTN is thought to be the same as for primary or essential HTN: Adopting a Dietary Approaches to Stop Hypertension (DASH) diet, a low-sodium diet, weight loss in obese patients, exercise, limitation of alcohol intake, and smoking cessation may all be of benefit. Relaxation techniques may be of help, but data are limited.
  • Ensure that the BP is measured correctly. The patient should be sitting quietly with back supported for 5 minutes before measurement. Proper cuff size: bladder encircling at least 80% of the arm. Support arm at heart level. Minimum of two readings at least 1 minute apart. Check BP in both arms. Also check standing BP for orthostasis.
  • Attention to findings related to possible etiologies: renovascular HTN: systolic/diastolic abdominal bruit. Pheochromocytoma: diaphoresis, tachycardia. Cushing syndrome: hirsutism, moon facies, dorsal hump, purple striae, truncal obesity. Thyroid disease: enlarged thyroid, tremor, exophthalmos, tachycardia. Coarctation of the aorta: upper limb HTN with decreased or delayed femoral pulses
  • Funduscopic exam
  • ECG performed as part of the initial workup; LVH is an important marker of resistant HTN.
  • Sleep study if history and physical indicate. The Epworth Sleepiness Scale is recommended.
  • Home-based polysomnography has been shown to be accurate in screening for OSA. Overnight oximetry is not helpful.
Initial Tests (lab, imaging)
Initial limited diagnostic testing should include urinalysis, CBC, potassium, sodium, glucose, creatinine, lipids, thyroid-stimulating hormone (TSH), and calcium. 50% of patients with hyperaldosteronism may have normal potassium levels.
  • Imaging tests listed are necessary only if history, physical, or lab data indicate.
  • Abdominal US: if renal disease is suspected
  • MR angiography (MRA) of renal vasculature: Preferred test for renovascular HTN. Sensitive but low specificity. Conventional angiography or CT angiography second line after MRA to look at distal renal artery. Renal arteriography remains the gold standard for renovascular disease.
  • Adrenal “incidentaloma” frequently arises in this era of multiple CT studies. If present in the setting of resistant HTN, consider hyperaldosterone or hyperadrenalcorticoid states.
Follow-Up Tests & Special Considerations
Further testing for primary aldosteronism (PA) may be considered.
  • Empiric treatment with an aldosterone inhibitor may be preferable and more clinically relevant: Spironolactone or eplerenone. Amiloride may be more effective in African Americans.
  • Plasma aldosterone-to-renin ratio (ARR) is the preferred lab test, but the test is difficult to perform and interpret properly. Consult your reference lab and interpret results with caution.
    • Further testing for pheochromocytoma: plasma
    • Other tests to consider for resistant or secondary HTN: 24-hour urine for free cortisol, calcium, parathyroid hormone (PTH), overnight 1-mg dexamethasone suppression test, urine toxicology screen

Diagnostic Procedures/Other
Consider 24-hour ambulatory BP monitoring, especially if white coat effect is suspected. Home BP monitor results predict mortality, stroke, and other target organ damage better than office BP. Optimal protocol involves two paired measurements: morning and evening (four measurements) over 4 to 7 days.
  • Oscillometric, electronic, upper arm, fully automatic device with memory; average multiple readings over several days
  • See http://www.dableducational.org/ for validated monitors.
  • Treatment modality depends on etiology of HTN. Please see each etiology listed for information on proper treatment.
  • Emphasize Adherence to JNC 8 and/or AHA/ACC guidelines, with emphasis on lifestyle modification. (4,5)[C]
    • Obese patients, African Americans, and elderly may be particularly responsive to diuretics.
    • Tolerance to diuretics may occur: long-term adaptation to thiazides or the “braking effect.” Consider increasing the dose of thiazide or adding an aldosterone inhibitor.
  • Treatment specific to certain secondary etiologies
    • Primary aldosteronism: aldosterone receptor antagonist: spironolactone or eplerenone
    • Cushing syndrome: aldosterone receptor antagonist
    • OSA: continuous positive airway pressure (CPAP) ± oxygen, surgery, weight loss.
      • Mandibular advancement devices may be equally effective in some patients.
    • Nocturnal hypoxia: oxygen supplementation
  • Earlier studies had suggested benefit from renal sympathetic denervation, but a recent sham study, SYMPLICITY HTN-3, was not supportive (6)[B].
  • Follow treatment guidelines and algorithms by JNC8 and AHA/ACC/CDC, understanding the differences between them (4,5)[C].
  • Aldosterone antagonists may offer significant benefit (7,8)[B].
  • Central-acting agents (e.g., clonidine) are effective at reducing BP, but outcome data are lacking.
First Line
See “Hypertension.”
Admission Criteria/Initial Stabilization
Hospitalization may be necessary for hypertensive urgency or emergency general measures.
Encourage aerobic activity of 30 min/day, depending on patient condition.
  • Reduced salt may lower BP.
  • Recommend the Mediterranean diet or DASH.
Home BP monitoring is recommended.
1. Calhoun DA, Jones D, Textor S, et al. 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. Hypertension. 2008;51(6):1403-1419.
2. Sarafidis PA, Bakris GL. Resistant hypertension: an overview of evaluation and treatment. J Am Coll Cardiol. 2008;52(22):1749-1757.
3. Daugherty SL, Powers JD, Magid DJ, et al. Incidence and prognosis of resistant hypertension in hypertensive patients. Circulation. 2012;125(13): 1635-1642.
4. James PA, Oparil S, Carter BL, et al. 2014 evidence-based guideline for the management of high blood pressure in adults: report from the panel members appointed to the Eighth Joint National Committee (JNC 8). JAMA. 2014;311(5):507-520.
5. Go AS, Bauman MA, Coleman King SM, et al. An effective approach to high blood pressure control: a science advisory from the American Heart Association, the American College of Cardiology, and the Centers for Disease Control and Prevention. Hypertension. 2014;63(4):878-885.
6. Bhatt DL, Kandzari DE, O'Neill WW, et al. A controlled trial of renal denervation for resistant hypertension. N Engl J Med. 2014;370(15):1393-1401.
7. Calhoun DA. Low-dose aldosterone blockade as a new treatment paradigm for controlling resistant hypertension. J Clin Hypertens (Greenwich). 2007;9(1 Suppl 1):19-24.
8. Gaddam KK, Nishizaka MK, Pratt-Ubunama MN, et al. Characterization of resistant hypertension: association between resistant hypertension, aldosterone, and persistent intravascular volume expansion. Arch Intern Med. 2008;168(11):1159-1164.
9. Cooper CJ, Murphy TP, Cutlip DE, et al. Stenting and medical therapy for atherosclerotic renal-artery stenosis. N Engl J Med. 2014;370(1):13-22.
Additional Reading
  • Agarwal R, Bills JE, Hecht TJ, et al. Role of home blood pressure monitoring in overcoming therapeutic inertia and improving hypertension control: a systematic review and meta-analysis. Hypertension. 2011;57(1):29-38.
  • Aronow WS, Fleg JL, Pepine CJ, et al. ACCF/AHA 2011 expert consensus document on hypertension in the elderly: a report of the American College of Cardiology Foundation Task Force on Clinical Expert Consensus documents developed in collaboration with the American Academy of Neurology, American Geriatrics Society, American Society for Preventive Cardiology, American Society of Hypertension, American Society of Nephrology, Association of Black Cardiologists, and European Society of Hypertension. J Am Coll Cardiol. 2011;57(20):2037-2114.
  • Basner RC. Cardiovascular morbidity and obstructive sleep apnea. N Engl J Med. 2014;370(24): 2339-2341.
  • Ernst ME, Moser M. Use of diuretics in patients with hypertension. N Engl J Med. 2009;361(22): 2153-2164.
  • Johansson JK, Niiranen TJ, Puukka PJ, et al. Optimal schedule for home blood pressure monitoring based on a clinical approach. J Hypertens. 2010;28(2):259-264.
  • Powers BJ, Olsen MK, Smith VA, et al. Measuring blood pressure for decision making and quality reporting: where and how many measures? Ann Intern Med. 2011;154(12):781-788.
  • Rimoldi SF, Scherrer U, Messerli FH. Secondary arterial hypertension: when, who, and how to screen? Eur Heart J. 2014;35(19):1245-1254.
See Also
Aldosteronism, Primary; Coarctation of the Aorta; Cushing Disease and Cushing Syndrome; Hyperparathyroidism; Hypertension, Essential; Hyperthyroidism; Pheochromocytoma
  • I15.9 Secondary hypertension, unspecified
  • I15.8 Other secondary hypertension
  • I15.0 Renovascular hypertension
Clinical Pearls
  • Onset of HTN in adults >60 years of age is a strong indicator of secondary HTN.
  • Common causes of resistant HTN: obstructive sleep apnea, excessive salt intake, medication nonadherence
  • Common secondary causes include sleep apnea, renal disease, renal artery stenosis, and primary aldosteronism.
  • Home BP monitoring predicts outcomes better than office monitoring of BP.