Definition, Prevalence, and Patient Characteristics

In the 2017 AHA/ACC Hypertension Guidelines, resistant hypertension (RH) is defined as hypertension (HTN) that remains uncontrolled with three antihypertensives (including one diuretic), or blood pressure (BP) that is controlled on four medications.¹ The estimated prevalence of RH among treated hypertensives is approximately 13%.² RH is associated with older age, black race, left ventricular hypertrophy, chronic kidney disease, obesity and diabetes.^3,4 In contrast to resistant hypertension, HTN is called "refractory" when it remains uncontrolled on five or more antihypertensives of different classes including a diuretic and a mineralocorticoid receptor antagonist.⁵ This brief review will focus on the assessment and management of individuals with RH, though many of the recommendations outlined below are appropriate for patients with non-resistant hypertension and refractory hypertension.

Given the consistent associations between elevated BP and cardiovascular disease (CVD) and mortality, it is no surprise that patients with RH are at higher risk for CVD events than patients with non-resistant hypertension or white coat hypertension.^6,7 Thus, identification of individuals with RH is critical as they may benefit from closer monitoring to ensure adequate control of BP and other CVD risk factors so that their risks for adverse outcomes can be attenuated as much as possible. Further, patients with RH have a higher prevalence of "secondary" causes of HTN than hypertensive patients without RH. Identification of secondary causes is important because the underlying pathology may contribute to mortality and CVD risk independent of elevated BP, and correction of the secondary cause will often lead to improvements in BP and resolution of HTN in some.

Initial Blood Pressure Evaluation and Evaluation for Pseudo-resistant Hypertension

First, it's critical to establish the diagnosis of RH, as elevated blood pressure in the clinic does not necessarily define RH. Pseudo-resistant hypertension is an elevated office BP that is not due to antihypertensive medication treatment failure. Pseudo-resistance can be caused by erroneous BP measurements, white coathypertension, or medication nonadherence.

It is important to follow current recommendations for accurate BP measurement. Have the patient sit still for 5 minutes with the back supported, feet on the ground, and upper extremity supported before the initial BP measurement. Ensure that a correctly-sized cuff is used, otherwise significant under- or over-estimation of brachial BP can occur.¹ Multiple measurements (typically 2-3) can be averaged to increase the accuracy of the BP assessment. The average BP on two or more occasions should be used to estimate usual BP. On the first visit to clinic, measure BP in both arms and use the BP value in the higher of the two arms. BP readings that are different by more than 10mmHg should prompt an evaluation for vascular abnormalities, some of which could be causes for secondary HTN. Although accurate BP assessment can be time-consuming in clinical practice, it is vital to obtain as accurate an assessment of BP as possible, certainly before a diagnosis of RH is made.

When white coat or masked HTN is suspected, an ambulatory BP monitor can help. One study found that more than 37% of those with a diagnosis of RH had normal BPs on ambulatory monitoring. Similarly, individuals with correctly calibrated BP cuffs can measure their BP at home to assist in the assessment of their usual BP.

Medication nonadherence is the most common cause of uncontrolled HTN. This can be difficult to assess and improve in some patients. Although rates of nonadherence appear to be lower in RH than in the general population with HTN, steps should be taken to maximize patient adherence through simplification of treatment regimens, education, and behavioral strategies.^8,9

Lifestyle Factors and Medications

Evaluation of patients with HTN and RH should involve a detailed assessment of body mass index, lifestyle behaviors, and medication history. Obesity and physical inactivity contribute to elevated BP. Dietary factors, especially alcohol intake, high dietary sodium, and low dietary fiber lead to increased BP and make prevalent BP more difficult to control. Similarly, use of illicit drugs and excessive use of caffeine can lead to increases in BP as well.

Several widely-used medications, including nonsteroidal anti-inflammatory drugs, acetaminophen, sympathomimetic agents (e.g. decongestants), some herbal supplements, and oral contraceptives raise BP or blunt the response to antihypertensives and discontinuation in the setting of persistent uncontrolled HTN should be strongly considered.¹² Furthermore, less commonly administered medications like corticosteroids, certain immunosuppressants, and monoamine oxidase inhibitors (MAOIs) can raise BP in some patients. Decisions about the optimal dose or alternative treatment regimens for these patients should be considered on an individual basis.

Evaluation for End Organ Damage and Secondary Causes of Hypertension

Patients with RH should be evaluated for evidence of end organ damage with a basic metabolic panel to quantify renal function, an ECG or echocardiogram to detect left ventricular hypertrophy (LVH), and a fundoscopic exam to screen for hypertensive retinopathy.

The prevalence of secondary causes of HTN in RH is not established, but a treatable underlying cause exists for approximately 10% of cases of HTN.¹² Common causes of secondary HTN include renal parenchymal disease, renovascular disease, primary hyperaldosteronism, obstructive sleep apnea, and drug- or medication-induced cases as discussed above.¹ Less common to rare causes include pheochromocytoma, hypothyroidism, hyperthyroidism, Cushing syndrome, unrepaired aortic coarctation (often associated with bicuspid aortic valves), other mineralocorticoid excess syndromes, hyperparathyroidism, and acromegaly.¹

Secondary HTN should be considered in patients with abrupt onset or accelerating HTN, malignant HTN, excessive target organ damage for the level of BP, new diastolic HTN in patients > 65-years-old, RH, and HTN onset before 30 years of age. Furthermore, the presence of suggestive clinical indications, like low serum potassium, or exam findings, like abdominal bruits or unequal BPs between arms, should prompt evaluation for secondary causes.

If a patient's clinical presentation is suggestive of a secondary cause, they should undergo further evaluation for the causes outlined above. Primary aldosteronism should be evaluated with a plasma aldosterone/renin level, which requires withdrawal of aldosterone antagonists for at least 4 weeks and correction of potassium level. Patients with elevated creatinine or BUN levels warrant further evaluation for renal parenchymal disease with a renal ultrasound and urinalysis. Young females and patients with known atherosclerosis or abdominal bruits should be screened for renal vascular disease with a renal duplex Doppler ultrasound or abdominal magnetic resonance angiography (MRA) or CT. A history consisting of episodic palpitations, HTN, and/or headache should trigger evaluation for pheochromocytoma with 24-hour urinary metanephrines or plasma metanephrines. Screening for obstructive sleep apnea is indicated in patients with daytime somnolence, snoring, or witnessed apnea.^1,12 Screening tests suggestive of the presence of these causes should be referred to the appropriate specialists for further evaluation and treatment.

RH Treatment

The initial treatment for RH consists of aggressive lifestyle modification. Patients should be counseled on weight loss, increased physical activity, a diet plan (e.g. the Dietary Approaches to Stop Hypertension [DASH] diet), reduced overall sodium intake, and moderation of alcohol consumption. Increased dietary potassium intake may also reduce BP in patients without baseline hyperkalemia. Contributing medications or drugs should be discontinued. Often, changes to lifestyle are adequate to improve BP control and decrease the burden of antihypertensive medications needed. The large impact of these modifiable causes should be stressed to patients.

Careful attention should be paid to medication adherence. Often these patients require careful individualization of their mediation regimens to optimize BP control. Fixed-dose combination antihypertensives have shown to improve medication compliance.¹⁰ Other strategies include patient self-monitoring of BP, adherence feedback to the patient, motivational interviewing, and linking of adherence behaviors with daily habits.¹¹

In addition to a standard BP regimen, aldosterone antagonists are the preferred add-on agent for RH in patients without hyperkalemia or significant renal dysfunction. Spironolactone is dosed once daily but has higher rates of gynecomastia and erectile dysfunction, whereas eplerenone is typically more effective with fewer side effects but twice daily dosing.¹

If adequate BP control cannot be achieved through the strategies outlined above, consider referral to a hypertension specialist for further evaluation and consideration for enrollment in randomized controlled trials (RCTs) of novel therapies (e.g., renal sympathetic nerve ablation) or other therapies under investigation.

Summary

Resistant hypertension is common and portends a worse prognosis compared to individuals with hypertension controlled with fewer medications. The exclusion of pseudo resistant hypertension is an important first step, and screening for potentially reversible causes of hypertension is indicated in patients with suggestive clinical findings. Treatment of RH is centered around aggressive lifestyle modification, cessation of contributing medications, targeting of underlying causes, and the addition of a mineralocorticoid receptor antagonist. Referral to a specialist should be considered in individuals who screen positive for a secondary etiology of hypertension or whose BP remains uncontrolled despite these steps.

References

1. Whelton PK, Carey RM, Aronow WS et al. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA Guideline for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults: Executive Summary: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol 2018;71:2199-269.
2. Achelrod D, Wenzel U, Frey S. Systematic review and meta-analysis of the prevalence of resistant hypertension in treated hypertensive populations. Am J Hypertens 2015;28:355-61.
3. 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 treatment to prevent heart attack trial (ALLHAT). J Clin Hypertens (Greenwich) 2002;4:393-404.
4. Lloyd-Jones DM, Evans JC, Larson MG, Levy D. Treatment and control of hypertension in the community: a prospective analysis. Hypertension 2002;40:640-6.
5. Calhoun DA, Booth JN, 3rd, Oparil S et al. Refractory hypertension: determination of prevalence, risk factors, and comorbidities in a large, population-based cohort. Hypertension 2014;63:451-8.
6. Salles GF, Cardoso CR, Muxfeldt ES. Prognostic influence of office and ambulatory blood pressures in resistant hypertension. Arch Intern Med 2008;168:2340-6.
7. Pierdomenico SD, Lapenna D, Bucci A et al. Cardiovascular outcome in treated hypertensive patients with responder, masked, false resistant, and true resistant hypertension. Am J Hypertens 2005;18:1422-8.
8. Daugherty SL, Powers JD, Magid DJ et al. Incidence and prognosis of resistant hypertension in hypertensive patients. Circulation 2012;125:1635-42.
9. Irvin MR, Shimbo D, Mann DM et al. Prevalence and correlates of low medication adherence in apparent treatment-resistant hypertension. J Clin Hypertens (Greenwich) 2012;14:694-700.
10. Gupta AK, Arshad S, Poulter NR. Compliance, safety, and effectiveness of fixed-dose combinations of antihypertensive agents: a meta-analysis. Hypertension 2010;55:399-407.
11. Conn VS, Ruppar TM, Chase JA, Enriquez M, Cooper PS. Interventions to Improve Medication Adherence in Hypertensive Patients: Systematic Review and Meta-analysis. Curr Hypertens Rep 2015;17:94-94.
12. 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;51:1403-19.

Clinical Topics: Anticoagulation Management, Cardiovascular Care Team, Congenital Heart Disease and Pediatric Cardiology, Diabetes and Cardiometabolic Disease, Dyslipidemia, Invasive Cardiovascular Angiography and Intervention, Noninvasive Imaging, Prevention, Valvular Heart Disease, Vascular Medicine, Congenital Heart Disease, CHD and Pediatrics and Imaging, CHD and Pediatrics and Interventions, CHD and Pediatrics and Prevention, CHD and Pediatrics and Quality Improvement, Lipid Metabolism, Novel Agents, Interventions and Imaging, Interventions and Structural Heart Disease, Interventions and Vascular Medicine, Angiography, Computed Tomography, Echocardiography/Ultrasound, Magnetic Resonance Imaging, Nuclear Imaging, Hypertension, Sleep Apnea

Keywords: Mineralocorticoid Receptor Antagonists, Antihypertensive Agents, White Coat Hypertension, Aldosterone, Metanephrine, Renin, Blood Pressure, Sympathomimetics, Nasal Decongestants, Monoamine Oxidase Inhibitors, Mineralocorticoids, Hypertensive Retinopathy, Body Mass Index, Risk Factors, Hypertrophy, Left Ventricular, Diuretics, Pheochromocytoma, Medication Adherence, Cushing Syndrome, Factor IX, Aortic Coarctation, Anti-Inflammatory Agents, Non-Steroidal, Contraceptives, Oral, Factor VIII, Immunosuppressive Agents, Magnetic Resonance Angiography, Blood Urea Nitrogen, Blood Pressure Monitoring, Ambulatory, Hypertension, Heart Valve Diseases, Hyperaldosteronism, Obesity, Diabetes Mellitus, Sleep Apnea, Obstructive, Renal Insufficiency, Chronic, Atherosclerosis, Life Style, Hyperthyroidism, Hypothyroidism, Treatment Failure, Hyperparathyroidism, Ultrasonography, Doppler, Electrocardiography, Tomography, X-Ray Computed

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