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Cited by 1,153Blood Pressure and Hypertension StudiesHormonal Regulation and HypertensionSodium Intake and Health

The DOI matches its Crossref record; 420 of the 420 references it cites were found in a registry or an index; none of the 411 sources its claims cite is checked for support yet.

Resistant Hypertension: Detection, Evaluation, and Management: A Scientific Statement From the American Heart Association

Open access
Carey, Robert M., Calhoun, David A., Bakris, George L., Brook, Robert D., Daugherty, Stacie L., Dennison-Himmelfarb, Cheryl R., Egan, Brent M., Flack, John M., Gidding, Samuel S., Judd, Eric, Lackland, Daniel T., Laffer, Cheryl L., Newton-Cheh, Christopher, Smith, Steven M., Taler, Sandra J., Textor, Stephen C., Turan, Tanya N., White, William B., on behalf of the American Heart Association Professional/Public Education and Publications Committee of the Council on Hypertension; Council on Cardiovascular and Stroke Nursing; Council on Clinical Cardiology; Council on Genomic and Precision Medicine; Council on Peripheral Vascular Disease; Council on Quality of Care and Outcomes Research; and Stroke Council·2018·Hypertension
DOI 10.1161/hyp.0000000000000084PMC PMC6530990
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Abstract

Resistant hypertension (RH) is defined as above-goal elevated blood pressure (BP) in a patient despite the concurrent use of 3 antihypertensive drug classes, commonly including a long-acting calcium channel blocker, a blocker of the renin-angiotensin system (angiotensin-converting enzyme inhibitor or angiotensin receptor blocker), and a diuretic. The antihypertensive drugs should be administered at maximum or maximally tolerated daily doses. RH also includes patients whose BP achieves target values on ≥4 antihypertensive medications. The diagnosis of RH requires assurance of antihypertensive medication adherence and exclusion of the “white-coat effect” (office BP above goal but out-of-office BP at or below target). The importance of RH is underscored by the associated risk of adverse outcomes compared with non-RH. This article is an updated American Heart Association scientific statement on the detection, evaluation, and management of RH. Once antihypertensive medication adherence is confirmed and out-of-office BP recordings exclude a white-coat effect, evaluation includes identification of contributing lifestyle issues, detection of drugs interfering with antihypertensive medication effectiveness, screening for secondary hypertension, and assessment of target organ damage. Management of RH includes maximization of lifestyle interventions, use of long-acting thiazide-like diuretics (chlorthalidone or indapamide), addition of a mineralocorticoid receptor antagonist (spironolactone or eplerenone), and, if BP remains elevated, stepwise addition of antihypertensive drugs with complementary mechanisms of action to lower BP. If BP remains uncontrolled, referral to a hypertension specialist is advised.

Overview

AI snapshot

Written from the paper’s full text.

TL;DR

This AHA scientific statement updates the definition, evaluation, and management of resistant hypertension, emphasizing confirmed medication adherence and out-of-office BP to exclude pseudoresistance. It recommends lifestyle optimization, long-acting thiazide-like diuretics, mineralocorticoid receptor antagonists, and stepwise add-on therapy, while highlighting major evidence gaps.

Key findings

  • RH is defined as above-goal BP despite concurrent use of 3 antihypertensive classes at maximum or maximally tolerated doses, commonly a long-acting CCB, a renin-angiotensin system blocker, and a diuretic; it also includes patients controlled on ≥4 medications. Diagnosis requires confirming adherence and excluding the white-coat effect.
  • Apparent treatment-resistant hypertension (aTRH) occurs in ≈12%–15% of population-based and 15%–18% of clinic-based treated hypertensive adults, and in 34%–39% of clinical trial populations.
  • RH is associated with worse outcomes: in >200,000 patients with incident hypertension, RH conferred 47% higher risk of death, MI, heart failure, stroke, or CKD over median 3.8 years; in >400,000 patients, RH was linked to 32% increased end-stage renal disease, 24% increased ischemic heart events, 46% increased heart failure, 14% increased stroke, and 6% increased death.
  • Management includes maximizing lifestyle interventions, using long-acting thiazide-like diuretics (chlorthalidone or indapamide), adding a mineralocorticoid receptor antagonist (spironolactone or eplerenone), and stepwise addition of complementary antihypertensives; switching from hydrochlorothiazide to the same daily dose of chlorthalidone yields an additional SBP reduction of 7–8 mm Hg, and primary aldosteronism prevalence is ≈20% in confirmed RH.

Methods

  • Design: An updated American Heart Association scientific statement/consensus document, not primary research; it synthesizes evidence since the 2008 AHA RH statement.
  • Data or sample: No original study sample; it draws on population-, clinic-, and trial-based reports, prior guidelines, and cited literature, with tables and figures.
  • Main analysis: Narrative expert synthesis and recommendations for detection, evaluation, and management; no systematic review, meta-analysis, or formal primary data analysis is described.

Limitations

  • Stated: Knowledge gaps include the need for true RH prevalence accounting for inaccurate BP measurement, white-coat effect, and nonadherence; unclear pathophysiology; limited genetics/pharmacogenetics; uncertain optimal BP target and sodium intake; and investigational device therapy.
  • Stated: Evidence specific to improving adherence in RH is sparse; diet intervention trials in RH are absent; and no trials of alternative approaches in RH have been performed.
  • Evident from the text: As a scientific statement, recommendations rely on expert consensus and indirect evidence, with many cited RH studies being observational, small, or lacking rigorous randomized confirmation.

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Integrity signals

Registry

Crossref · 10.1161/hyp.0000000000000084

Cites

420 of 420 references verified0 citation errors · 0 not checkable

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Verification

Claims the paper makes

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Show all 165 claims

  • It may state two separate claims as one. 72
  • Probably not a substantial claim. 14
82 of 82

  • The paper relies on this without support.

    A large proportion of hypertensive adults fail to achieve recommended blood pressure targets on 3 antihypertensive medications or require at least 4 medications to achieve their targets despite conscientious clinical management.

    “Even with steady improvement during the past 30 years in hypertension awareness, treatment, and control rates, a large proportion of hypertensive adults, despite conscientious clinical management, still fail to achieve their recommended blood pressure (BP) treatment targets on 3 antihypertensive medications or require ≥4 medications to achieve their targets.”

  • The paper relies on this without support.

    Patients with resistant hypertension are more likely to have medication adverse effects, more likely to have a secondary cause of hypertension, and may benefit from special diagnostic or therapeutic approaches.

    “Moreover, they are more likely to have medication adverse effects, more likely to have a secondary cause of hypertension compared with hypertensive patients without drug resistance, and may benefit from special diagnostic or therapeutic approaches to control their BP.”

  • The paper relies on this without support.

    Medication adherence is an important determinant of hypertension control.

    “Medication adherence is an important determinant of hypertension control.”

  • The paper relies on this without support.

    Pharmacy databases for medication possession and refills provide a valid measure of adherence.

    “Pharmacy databases for medication possession and refills provide a valid measure of adherence.”

  • The paper relies on this without support.

    Measurement of pharmacodynamic parameters may have limited specificity.

    “Measurement of pharmacodynamic parameters (eg, heart rate for β-blockers, lack of rise of plasma renin activity [PRA] for renin-angiotensin inhibitors, N-acetyl-seryl-aspartyl-lysyl-proline measurements for ACE inhibitors) may have limited specificity.”

  • The paper relies on this without support.

    Witnessed medication taking followed by monitoring of effect on blood pressure has been effective in identifying suspected nonadherence in trials of novel treatment modalities.

    “Witnessed medication taking followed by monitoring of effect on BP has been effective in identifying suspected nonadherence in trials of novel treatment modalities, although this approach has not been widely used in general practice.”

  • The paper relies on this without support.

    Medication Event Monitoring System monitoring has superior sensitivity compared with other methods.

    “Medication Event Monitoring System monitoring of the date and time that a medication bottle is opened and closed has superior sensitivity compared with other methods, although ingestion of the medication is not confirmed.”

  • The paper relies on this without support.

    Urine or blood measurement of drug or metabolites with mass spectroscopy reliably determines whether a drug is present or absent.

    “Urine or blood measurement of drug or metabolites with mass spectroscopy reliably determines whether a drug is present or absent but does not determine whether it was taken regularly or at a therapeutic level.”

  • The paper relies on this without support.

    There is no gold standard for measuring adherence.

    “There is no gold standard for measuring adherence.”

  • The paper relies on this without support.

    Indirect methods such as pill count, self-report, and prescription refill data are simple, inexpensive, and widely used, but can easily be manipulated to overestimate adherence.

    “Indirect methods such as pill count, self-report, and prescription refill data are simple, inexpensive, and widely used. However, they can easily be manipulated to overestimate adherence.”

  • The paper relies on this without support.

    A direct method such as urine or blood measurement of drug or metabolites is considered more robust but is relatively expensive, is of limited availability, and does not perfectly reflect level of adherence.

    “A direct method such as urine or blood measurement of drug or metabolites is considered more robust but is relatively expensive, is of limited availability, and does not perfectly reflect level of adherence.”

  • The paper relies on this without support.

    All methods for measuring adherence have limitations.

    “All methods have limitations, and ideally, accurate assessment of adherence should involve a combination of approaches.”

  • The paper relies on this without support.

    Factors contributing to poor adherence are myriad and multilevel.

    “Factors contributing to poor adherence are myriad and multilevel.”

  • The paper relies on this without support.

    Evidence specific to improving adherence in the resistant hypertension population is sparse.

    “Evidence specific to improving adherence in the RH population is sparse.”

  • The paper relies on this without support.

    No single intervention is uniquely effective, and a sustained approach using multiple strategies is likely to be most effective.

    “No single intervention is uniquely effective, and a sustained approach using multiple strategies, including health system solutions and those that target the individual patient’s barriers to adherence, is likely to be most effective.”

  • The paper relies on this without support.

    Cuff size, body and arm positions, and measurement environment affect the accuracy of blood pressure measurement.

    “However, cuff size, body and arm positions, and measurement environment are common features of auscultatory and oscillometric methods that affect the accuracy of BP measurement.”

  • The paper relies on this without support.

    Cuff-measured blood pressure may differ from intra-arterial pressure.

    “Cuff-measured BP may differ from intra-arterial pressure.”

  • The paper relies on this without support.

    Severe arterial stiffness or medial calcification of the brachial artery may result in inaccurate detection of Korotkoff sounds with auscultatory blood pressure measurement.

    “Severe arterial stiffness or medial calcification of the brachial artery may result in an inaccurate detection of Korotkoff sounds when BP is measured with the auscultatory method.”

  • The paper relies on this without support.

    The degree to which arterial stiffness or brachial artery calcification affects blood pressure measurement with oscillometric devices is suspected to be less pronounced.

    “The degree to which arterial stiffness or brachial artery calcification affects BP measurement with oscillometric devices has not been established but is suspected to be less pronounced.”

  • The paper relies on this without support.

    Short duration of hypertension and absence of diabetes mellitus or chronic kidney disease are associated with pseudoresistance from a white-coat effect.

    “Short duration of hypertension and the absence of diabetes mellitus or CKD are also associated with pseudoresistance from a white-coat effect.”

  • The paper relies on this without support.

    The white-coat effect can be easily identified by 24-hour ambulatory blood pressure monitoring.

    “The white-coat effect can be easily identified by 24-hour ABPM.”

  • The paper relies on this without support.

    Blood pressure measurement by automated office blood pressure attenuates the white-coat effect.

    “BP measurement by automated office BP attenuates the white-coat effect.”

  • The paper relies on this without support.

    Individuals may alter their blood pressure logs or underreport high or low blood pressure values.

    “However, it is important to consider that individuals may alter their BP logs or underreport high or low BP values.”

  • The paper relies on this without support.

    Suboptimal antihypertensive therapy accounts for a large subset of patients not achieving blood pressure targets.

    “Suboptimal antihypertensive therapy accounts for a large subset of patients not achieving BP targets (Figure 1).140”

  • The paper relies on this without support.

    Relatively large interindividual variations exist in salt sensitivity of blood pressure.

    “However, relatively large interindividual variations exist in “salt sensitivity” of BP.”

  • The paper relies on this without support.

    The effects of pharmacologic agents that increase blood pressure are highly individualized, with the majority of individuals manifesting little or no effect and others demonstrating severe elevations in blood pressure levels.

    “However, the effects of these agents are found to be highly individualized, with the majority of individuals manifesting little or no effect and others demonstrating severe elevations in BP levels.”

  • The paper relies on this without support.

    Sympathetic amines increase blood pressure by activation of the sympathetic nervous system.

    “Sympathetic amines increase BP by activation of the sympathetic nervous system.”

  • The paper relies on this without support.

    Cyclosporine and tacrolimus increase blood pressure by inducing systemic and renal vasoconstriction and sodium retention.

    “Cyclosporine and tacrolimus increase BP by inducing systemic and renal vasoconstriction and sodium retention.”

  • The paper relies on this without support.

    Chronic kidney disease is both a cause and a complication of poorly controlled hypertension.

    “CKD is both a cause and a complication of poorly controlled hypertension.”

  • The paper relies on this without support.

    Reduced kidney function results in impaired salt excretion, overactivation of the renin-angiotensin-aldosterone system, increased sympathetic nervous system activity, and altered medication efficacy.

    “Reduced kidney function results in impaired salt excretion, overactivation of the renin-angiotensin-aldosterone system, increased sympathetic nervous system activity, and altered medication efficacy.”

  • The paper relies on this without support.

    Pheochromocytoma and paraganglioma are rare even in the hypertensive population, with a prevalence estimated at 0.01% to 0.2%.

    “The chromaffin cell tumors, pheochromocytoma (adrenal catecholamine producing, 90%) and paraganglioma (extra-adrenal, sympathetic/parasympathetic derived, 10%), are rare even in the hypertensive population, with a prevalence estimated at 0.01% to 0.2%.”

  • The paper relies on this without support.

    One-third of pheochromocytoma/paraganglioma cases are inherited.

    “Given the high morbidity and mortality of not treating these tumors, the usual 3-year delay in diagnosis, and the fact that one-third are inherited, it is essential to consider the diagnosis in anyone referred for RH.”

  • The paper relies on this without support.

    Hypertensive patients frequently have elevated levels of catecholamine metabolites, especially in the presence of obesity and OSA and with the use of certain drugs such as tricyclic antidepressants.

    “Hypertensive patients frequently have elevated levels of catecholamine metabolites, especially in the presence of obesity and OSA and with the use of certain drugs such as tricyclic antidepressants.”

  • The paper relies on this without support.

    True resistant hypertension usually has multiple causes, including excessive dietary salt intake, obesity, CKD, and OSA.

    “True RH usually has multiple causes, including excessive dietary salt intake, obesity, CKD, and OSA.”

  • The paper relies on this without support.

    The specificity for a high aldosterone-to-renin ratio is low as a result of the common occurrence of low-renin states (eg, volume expansion, dietary salt excess or sensitivity).

    “The specificity for a high ARR is low as a result of the common occurrence of low-renin states (eg, volume expansion, dietary salt excess or sensitivity).”

  • The paper relies on this without support.

    Hydrochlorothiazide does not induce a predictable natriuresis below a GFR of 45 mL⋅min−1⋅1.73 m−2, but chlorthalidone induces natriuresis down to an eGFR of 30 mL⋅min−1⋅1.73 m−2.

    “Hydrochlorothiazide does not induce a predictable natriuresis below an GFR of 45 mL⋅min−1⋅1.73 m−2, but chlorthalidone induces natriuresis down to an eGFR of 30 mL⋅min−1⋅1.73 m−2.”

  • The paper relies on this without support.

    Most cases of resistant hypertension are linked to either volume excess, especially in CKD, or high sympathetic tone.

    “Because most cases of RH are linked to either volume excess, especially in CKD, or high sympathetic tone, establishment of the pathogenesis will optimally facilitate the choice of the fourth drug.”

  • The paper relies on this without support.

    With prolonged use at higher doses, gynecomastia and erectile dysfunction in men and menstrual irregularities in women may limit the use of spironolactone.

    “With prolonged use at higher doses, gynecomastia and erectile dysfunction in men and menstrual irregularities in women may limit the use of spironolactone.”

  • The paper relies on this without support.

    Because of its shorter half-life compared with spironolactone, eplerenone should be administered twice daily for optimal effect.

    “Because of its shorter half-life compared with spironolactone, eplerenone should be administered twice daily for optimal effect.”

  • The paper relies on this without support.

    Except for rare monogenetic causes, the pathophysiology of primary hypertension appears to be governed by a multiplicity of genes, each contributing only weak effects.

    “Except for the rare monogenetic causes, the pathophysiology of primary hypertension appears to be governed by a multiplicity of genes, each contributing only weak effects.”

  • The paper relies on this without support.

    The current approach to blood pressure control in resistant hypertension, focused on adding or substituting drugs or drug classes based on pharmacological principles, is only partially successful in true resistant hypertension.

    “Currently, the approach to BP control in RH has focused on the addition or substitution of drugs or drug classes based on meaningful pharmacological principles that are only partially successful in true RH.”

  • The paper relies on this without support.

    Validation of true benefit for device-based sympatholytic treatments has not been confirmed in rigorous, double-blind comparisons with sham intervention.

    “Although previously approved and used in different countries worldwide, validation of true benefit has not been confirmed in rigorous, double-blind comparisons with sham intervention.”
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  1. Proteus Digital Health. U.S. FDA accepts first digital medicine new drug application for Otsuka and Proteus Digital Health. http://www.proteus.com/press-releases/u-s-fda-accepts-first-digital-medicine-new-drug-application-for-otsuka-and-proteus-digital-health/. September 10 2015. Accessed January 5 2016.
  2. 10.1016/j.jval.2013.03.1631 · DOI · Paper page
  3. 10.1007/s11900 · DOI

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Metadata

Authors
Carey, R. M., Calhoun, D. A., Bakris, G. L., Brook, R. D., Daugherty, S. L., Dennison-Himmelfarb, C. R., Egan, B. M., Flack, J. M., Gidding, S. S., Judd, E., Lackland, D. T., Laffer, C. L., Newton-Cheh, C., Smith, S. M., Taler, S. J., Textor, S. C., Turan, T. N., White, W. B., & on behalf of the American Heart Association Professional/Public Education and Publications Committee of the Council on Hypertension; Council on Cardiovascular and Stroke Nursing; Council on Clinical Cardiology; Council on Genomic and Precision Medicine; Council on Peripheral Vascular Disease; Council on Quality of Care and Outcomes Research; and Stroke Council
ORCID
Venue
Hypertension
Publisher
Ovid Technologies (Wolters Kluwer Health)
Published
2018-11
Volume
72
Issue
5
Pages
e53-e90
ISSN
  • 0194-911X (ISSN-L)
  • 1524-4563
DOI
10.1161/hyp.0000000000000084
PMC
PMC6530990
OpenAlex
W2896865390
Semantic Scholar
7bc2c45787107f8db70d5450bd091d6280e73dd3
Cited by
1,153
References
420
Citations by year
2026: 164 · 2025: 159 · 2024: 154 · 2023: 183 · 2022: 151 · 2021: 129 · 2020: 120 · 2019: 82 · 2018: 8
FWCI
64.03
Type
journal article
Language
en
Open access
Locations
  • Hypertension (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
National Institute of Diabetes and Digestive and Kidney Diseases (K23DK102660)
Topics
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Blood Pressure and Hypertension Studies
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Hormonal Regulation and Hypertension
  • Health Sciences › Nursing › Nutrition and Dietetics › Sodium Intake and Health
Keywords
resistant hypertension, blood pressure control, antihypertensive medication adherence, white coat effect, out-of-office blood pressure, secondary hypertension, target organ damage, thiazide-like diuretics, chlorthalidone, indapamide, mineralocorticoid receptor antagonists, spironolactone, eplerenone, renin-angiotensin system blockade, lifestyle modification
MeSH terms
American Heart Association, Antihypertensive Agents, Blood Pressure, Humans, Hypertension, United States, Disease Management

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