rdiology 32 (2016) 603e606

Canadian Journal of Ca

Viewpoint

Resistant and Refractory Hypertension: AntihypertensiveTreatment Resistance vs Treatment Failure

Mohammed Siddiqui, MD, Tanja Dudenbostel, MD, and David A. Calhoun, MDVascular Biology and Hypertension Program, University of Alabama at Birmingham, Birmingham, Alabama, USA

ABSTRACTResistant or difficult to treat hypertension is defined as high bloodpressure that remains uncontrolled with 3 or more different antihy-pertensive medications, including a diuretic. Recent definitions alsoinclude controlled blood pressure with use of 4 or more medications asalso being resistant to treatment. Recently, refractory hypertension, anextreme phenotype of antihypertensive treatment failure has beendefined as hypertension uncontrolled with use of 5 or more antihy-pertensive agents, including a long-acting thiazide diuretic and amineralocorticoid receptor antagonist. Patients with resistant vs re-fractory hypertension share similar characteristics and comorbidities,including obesity, African American race, female sex, diabetes, coro-nary heart disease, chronic kidney disease, and obstructive sleep ap-

Received for publication January 20, 2015. Accepted June 15, 2015.

Corresponding author: Dr David A. Calhoun, 430 BMR2, 15303rd Ave S, Birmingham, Alabama 35242, USA. Tel.: þ1-205-934-9281;fax: þ1-205-934-1302.

E-mail: dcalhoun@uab.eduSee page 605 for disclosure information.

http://dx.doi.org/10.1016/j.cjca.2015.06.0330828-282X/� 2016 Canadian Cardiovascular Society. Published by Elsevier Inc. A

R�ESUM�EL’hypertension r�esistante ou difficile à traiter se d�efinit comme unehypertension non maîtris�ee malgr�e un traitement par 3 agents anti-hypertenseurs ou plus, dont un diur�etique. Une d�efinition plus r�ecenteinclut �egalement dans cette cat�egorie une hypertension maîtris�ee àl’aide de 4 agents antihypertenseurs ou plus. R�ecemment, l’hy-pertension r�efractaire au traitement, un type extrême d’hypertensionr�esistante au traitement, a �et�e d�efinie comme une hypertension nonmaîtris�ee malgr�e l’administration de 5 agents antihypertenseurs ouplus, dont un diur�etique thiazidique à action prolong�ee et un antago-niste des r�ecepteurs min�eralocorticoïdes. Les patients atteints d’hy-pertension r�esistante et ceux atteints d’hypertension r�efractaire autraitement ont plusieurs caract�eristiques en commun et souffrent de

The terms, “resistant” and “refractory” hypertension havehistorically been used interchangeably to refer to patients withdifficult to treat hypertension, that is, hypertension resistant topharmacologic intervention.1,2 Most commonly, resistant orrefractory hypertension has been defined as high blood pres-sure with 3 or more medications needed to control, includinga diuretic.3 Recently, however, the term, refractory hyper-tension has been applied to an extreme phenotype of anti-hypertensive treatment failure.4 In this context, the definitionof refractory hypertension has been evolving, but has beenlargely based on failure to achieve blood pressure goal with useof 5 or more antihypertensive medications, including a long-acting thiazide diuretic. Recent considerations by investigatorswho evaluated this subgroup of patients have suggesteddefining the phenotype as hypertension uncontrolled (>140/90 mm Hg) with use of 5 or more different classes of anti-hypertensive agents, including a long-acting thiazide diureticand a mineralocorticoid receptor antagonist.4,5

In this viewpoint we discuss the emerging data on thisnovel phenotype of antihypertensive treatment failure andhow it compares and contrasts with resistant hypertension in

terms of definition, prevalence, patient characteristics, riskfactors, comorbidities, and possible underlying etiologies.

Definition

Resistant hypertension

Resistant hypertension is defined as high blood pressurethat remains uncontrolled (>140/90 mm Hg) despite the useof effective doses of 3 or more different classes of antihyper-tensive agents, including a diuretic. The first American HeartAssociation Scientific Statement on resistant hypertensionincluded patients whose blood pressure was controlled (<140/90 mm Hg) with 4 or more medications within the categoryof resistant hypertension.3

Refractory hypertension

The term, refractory hypertension has been recently usedto refer to an extreme phenotype of antihypertensive treat-ment failure. The first application of the term in this contextwas in a retrospective analysis of the phenotype from in-vestigators at the University of Alabama at Birmingham.4 Inthat report, refractory hypertension was defined uncontrolledblood pressure with use of 5 or more different antihyperten-sive classes, including a diuretic.

Based on the literature that showed superiority of chlor-thalidone over hydrocholorothiazide (HCTZ) and specific

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nea. Patients with refractory vs resistant hypertension tend to beyounger and are more likely to have been diagnosed with congestiveheart failure. Refractory hypertension might also differ from resistanthypertension in terms of underlying cause. Preliminary evidence sug-gests that refractory hypertension is more likely to be neurogenic inetiology (ie, heightened sympathetic tone), vs a volume-dependenthypertension that is more characteristic of resistant hypertension ingeneral.

comorbidit�es semblables, notamment : ob�esit�e, ascendance afro-am�ericaine, sexe f�eminin, diabète, coronaropathie, n�ephropathiechronique et apn�ee du sommeil obstructive. Les patients atteintsd’hypertension r�efractaire au traitement tendent toutefois à être plusjeunes et sont plus susceptibles d’avoir reçu un diagnostic d’insuffi-sance cardiaque congestive que ceux atteints d’hypertensionr�esistante. De plus, la cause sous-jacente de l’hypertension r�efractaireau traitement peut diff�erer de celle de l’hypertension r�esistante. Eneffet, des donn�ees pr�eliminaires semblent indiquer que l’hypertensionr�efractaire au traitement serait plutôt de nature neurog�enique (c.-à-d.une augmentation du tonus sympathique), tandis qu’une hypervol�emieserait en g�en�eral à l’origine de l’hypertension r�esistante.

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benefit of spironolactone6-9 for treatment of resistant hyper-tension, 5 drug combinations that include these 2 agents,likely represent maximal antihypertensive treatment. Accord-ingly, the working definition of refractory hypertension hasevolved to be increased blood pressure levels (>140/90 mmHg) despite the use of optimal doses of 5 or more differentclasses of antihypertensive agents, including chlorthalidoneand a mineralocorticoid receptor antagonist (Fig. 1).

Prevalence

Resistant hypertension

A number of observational studies have characterized pa-tients with resistant hypertension from a variety of differentcohorts. Multiple studies indicate that the prevalence ofresistant hypertension is approximately 10%-15% of treatedhypertensive patients. For example, in a cross-sectional anal-ysis of > 470,000 individuals, 60,327 had resistant hyper-tension.10 This represented 12.8% of all hypertensiveindividuals and 15.3% of those taking antihypertensivemedications.

Refractory hypertension

Two studies have been published on refractory hyperten-sion based on a definition that distinguishes it from resistant

Figure 1. Hypertension classification based on blood pressure controland number of antihypertensive medications (No of Med).

hypertension. The first was a retrospective analysis of patientsreferred to the University of Alabama at Birmingham forevaluation and treatment of resistant hypertension.4 Of the304 patients referred for resistant hypertension and who hadadequate follow-up (a minimum of 3 clinic visits), 29 (10%)never achieved blood pressure control despite maximal anti-hypertensive therapy of 6 different classes of antihypertensiveagents, including chlorthalidone and spironolactone.

The second published study of refractory hypertension wasa cross-sectional evaluation of participants in the Reasons forGeographic and Racial Differences in Stroke (REGARDS)study, a large (n ¼ 30,239), community-based cohort study.5

In this analysis, refractory hypertension was defined as un-controlled clinic blood pressure (>140/90 mm Hg) despiteuse of 5 or more different antihypertensive classes of agents.The prevalence of refractory hypertension was 3.6% of pa-tients with resistant hypertension (uncontrolled blood pres-sure with 3 or more medications or controlled blood pressurewith 4 or more) and 0.5% of all hypertensive participantsincluded in the cohort.

Patient Characteristics and AssociatedComorbidities

Resistant hypertension

Compared with individuals with nonresistant hyperten-sion, that is, controlled blood pressure (<140/90 mm Hg)with 1 or 2 medications, individuals with resistant hyperten-sion were older, obese, and more likely African American andfemale,11 and also had a greater prevalence of comorbidconditions, including diabetes, ischemic heart disease, cere-brovascular disease, and chronic kidney disease (CKD).

Refractory hypertension

In the retrospective analysis by Acelajado et al., of patientsreferred to a hypertension specialty clinic, 29 subjects iden-tified as having refractory hypertension were compared with275 subjects with controlled resistant hypertension.4 Subjectswith refractory hypertension tended to be younger and heaviercompared with subjects with controlled resistant hyperten-sion. In addition, the refractory subjects tended to be moreoften African American and female. With regard to comor-bidities, refractory hypertensive subjects were more likely tohave a history of congestive heart failure, stroke, and

Siddiqui et al. 605Resistant and Refractory Hypertension

obstructive sleep apnea. CKD and diabetes association was notstatistically significant between the 2 groups.

In the cross-sectional assessment of the REGARDS cohort,of the 14,809 participants being treated for hypertension, 78were identified as having refractory hypertension based on anuncontrolled blood pressure (>140/90 mm Hg) whilereceiving 5 or more antihypertensive medications, whichincluded in all cases, HCTZ.5 These 78 refractory subjectswere compared with all participants with treated hypertensionand all participants with resistant hypertension. In an unad-justed and adjusted comparison with all hypertensive partici-pants, African American race, male sex, and higher body massindex were associated with an increased prevalence ratio ofhaving refractory hypertension. In the adjusted comparison,African American race was the strongest predictor of havingrefractory hypertension, with a prevalence ratio of 4.88 (95%confidence interval, 2.79-8.72). Compared with resistanthypertension, African American race only was associated witha higher prevalence ratio, before and after multivariateadjustment. Increased age was not associated with higher riskof refractory hypertension, with the mean age of the partici-pants with refractory hypertension tending be less than that ofparticipants with resistant hypertension.

Comorbidities associated with refractory hypertensioncompared with all hypertensive participants in the REGARDScohort included reduced estimated glomerular filtration rate,albuminuria, diabetes, history of stroke, and known coronaryheart disease after multivariate adjustment.5 Of thesecomorbidities, the strongest predictor was albuminuria, withan adjusted prevalence ratio of 4.02 (95% confidence interval,2.53-6.41). Compared only with the participants with resis-tant hypertension, the comorbidities associated with refractoryhypertension were albuminuria and diabetes.

Possible Mechanisms of Resistant vsRefractory Hypertension

A large body of literature implicates persistent intravascularfluid retention as a common underlying cause of resistanthypertension, including studies that documented intravascularexpansion estimated according to thoracic fluid content.12

Causes of excess fluid retention are no doubt multifactorialbut include CKD, hyperaldosteronism,12,13 heightened so-dium sensitivity, and high dietary sodium intake.14

In contrast to resistant hypertension, refractory hyperten-sion might represent a different phenotype in terms of etiol-ogy in not being volume-dependent. The analysis byAcelajado et al. showed consistently higher resting heart ratesin the individuals with refractory hypertension compared withindividuals with controlled resistant hypertension, suggestinga more likely neurogenic etiology of antihypertensive failure.4

In contrast, failure of intensive diuretic therapy with chlor-thalidone and spironolactone to control blood pressure in therefractory patients argued against a volume-dependent causeof treatment failure.4

ConclusionsRefractory hypertension has been proposed as an extreme

phenotype of antihypertensive treatment failure. The defini-tion of refractory hypertension, although evolving, has most

recently been suggested as failure to control blood pressuredespite maximal antihypertensive effort based on use of atleast 5 different classes of antihypertensive agents, including iftolerated, chlorthalidone and spironolactone.

Refractory hypertension is uncommon, with an estimatedprevalence of 10% of patients referred to a hypertensionspecialty clinic for resistant hypertension and < 1% of treatedhypertensive participants in a community-based cohort.4,5

Like resistant hypertension, obesity, diabetes, CKD, andespecially African American race are associated with havingrefractory hypertension compared with patients with moreeasily controlled hypertension. Patients with refractory hy-pertension are at increased risk of having already had a car-diovascular complication, such as stroke and congestive heartfailure, compared with patients with resistant but controlledhypertension.

The mechanisms of refractory hypertension lack fullelucidation, but preliminary assessments, based mostly onfailure to control blood pressure with intensive diuretictreatment and consistently higher heart rates, suggest thatrefractory hypertension might be more neurogenic in etiology(ie, heightened sympathetic output), as opposed to beingvolume-dependent. Additional studies of sympathetic tone,including assessments of peripheral resistance, heart ratevariability, norepinephrine levels, and peripheral nerve trafficshould provide further insight into this possibility.

DisclosuresThe authors have no conflicts of interest to disclose.

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