Phenotype Of Antihypertensive Treatment Failure Research Articles

Refractory Hypertension: a Narrative Systematic Review with Emphasis on Prognosis.

To perform a narrative systematic review on refractory hypertension (RfHT) with particular emphasis on prognosis. There were 37 articles on RfHT, 13 non-systematic reviews, and 24 original studies. RfHT, a recently described extreme phenotype of anti-hypertensive treatment failure, shall be defined as uncontrolled out-of-office blood pressure (BP) levels despite the use of at least 5 anti-hypertensive drugs, including a long-acting diuretic and a mineraloreceptor antagonist. Its prevalence ranges from 0.5 to 4.3% of general treated hypertensives and between 3.6 and 51.4% of patients with resistant hypertension (RHT). RfHT is associated with younger age, African ancestry, obesity, hypertension-mediated organ damage and clinical cardiovascular diseases, and with some comorbidities, such as diabetes and obstructive sleep apnea. Its physiopathological mechanisms probably involve sympathetic overactivity and not volume overload. Patients with RfHT have a worse prognosis than non-refractory RHT individuals, with higher risks of adverse cardiovascular and renal outcomes and of mortality. RfHT represents a rare but true extreme phenotype of anti-hypertensive treatment failure distinct from RHT and with a significantly worse prognosis. Identifying such individuals is important to tailor specific interventions.

Reserpine Substantially Lowers Blood Pressure in Patients With Refractory Hypertension: A Proof-of-Concept Study

Refractory hypertension (RfHTN), a phenotype of antihypertensive treatment failure, is defined as uncontrolled automated office blood pressure (AOBP) ≥130/80 mm Hg and awake ambulatory blood pressure (ABP) ≥130/80 mm Hg on ≥5 antihypertensive medications, including chlorthalidone and a mineralocorticoid receptor antagonist. Previous studies suggest that RfHTN is attributable to heightened sympathetic tone. The current study tested whether reserpine, a potent sympatholytic agent, lowers blood pressure (BP) in patients with RfHTN. Twenty-one out of 45 consecutive patients with suspected RfHTN were determined to be fully adherent with their antihypertensive regimen. Seven patients agreed to participate in the current clinical trial with reserpine and 6 patients completed the study. Other sympatholytic medications, such as clonidine or guanfacine, were tapered and discontinued before starting reserpine. Reserpine 0.1 mg daily was administered in an open-label fashion for 4 weeks. All patients were evaluated by AOBP and 24-hour ABP at baseline and after 4 weeks of treatment. Reserpine lowered mean systolic and diastolic AOBP by 29.3 ± 22.2 and 22.0 ± 15.8 mm Hg, respectively. Mean 24-hour systolic and diastolic ABPs were reduced by 21.8 ± 13.4 and 15.3 ± 9.6 mm Hg, mean awake systolic and diastolic ABPs by 23.8 ± 11.8 and 17.8 ± 9.2 mm Hg, and mean asleep systolic and diastolic ABPs by 21.5 ± 11.4 and 13.7 ± 6.4 mm Hg, respectively. Reserpine, a potent sympatholytic agent, lowers BP in patients whose BP remained uncontrolled on maximal antihypertensive therapy, lending support to the hypothesis that excess sympathetic output contributes importantly to the development of RfHTN.

RESERPINE SUBSTANTIALLY LOWERS BLOOD PRESSURE IN PATIENTS WITH REFRACTORY HYPERTENSION, A PHENOTYPE OF ANTIHYPERTENSIVE TREATMENT FAILURE

Refractory hypertension (RfHTN), a phenotype of antihypertensive treatment failure, is defined as uncontrolled automated office BP [AOBP] ≥ 130/80 mmHg & 24-hr ambulatory BP [ABP] ≥ 125/75 mmHg on ≥5 antihypertensive medications, including chlorthalidone & a mineralocorticoid receptor

Clinical Implications

Clinical Implications

Antihypertensive Medication Adherence and Confirmation of True Refractory Hypertension.

Refractory hypertension (RfHTN) is a phenotype of antihypertensive treatment failure defined as uncontrolled BP despite the use of effective doses of ≥5 antihypertensive medications including a long-acting thiazide-like diuretic (chlorthalidone) and a mineralocorticoid receptor antagonist. The degree of medication nonadherence is unknown among patients with RfHTN. In this prospective evaluation, 54 patients with apparent RfHTN were recruited from the University of Alabama at Birmingham Hypertension Clinic after having uncontrolled BP at 3 or more clinic visits. All patients' BP was evaluated by automated office BP and 24-hour ambulatory BP monitoring (n=49). Antihypertensive medication adherence was determined by measuring 24-hour urine specimens for antihypertensive medications and their metabolites by high-performance liquid chromatography-tandem mass spectrometry (n=45). Of the 45 patients who completed 24-hour ambulatory BP monitoring, 40 (88.9%) had confirmed RfHTN based on an elevated automated office BP (≥130/80 mm Hg), mean 24-hour ABP (≥125/75 mm Hg), and mean awake (day-time) ABP (≥130/80 mm Hg). Out of the 40 fully evaluated patients with RfHTN, 16 (40.0%) were fully adherent with all prescribed medications. Eighteen (45.0%) patients were partially adherent and 6 (15.0%) had none of the prescribed agents detected in their urine. Of 18 patients who were partially adherent, 5 (12.5%) were adherent with at least 5 medications, including chlorthalidone and the mineralocorticoid receptor antagonist, consistent with true RfHTN. Of patients identified as having apparent RfHTN, 52.5% were adherent with at least 5 antihypertensive medications, including chlorthalidone and a mineralocorticoid receptor antagonist, confirming true RfTHN. These findings validate RfHTN as a rare, but true phenotype of antihypertensive treatment failure.

HIGH PREVALENCE OF INFLAMMATORY DISORDERS IN PATIENTS WITH REFRACTORY HYPERTENSION

Objective: Refractory hypertension (RfHTN) is a phenotype of antihypertensive treatment failure defined as uncontrolled BP (> = 135/85 mmHg) despite the use of five or more different antihypertensive agents, including a long-acting thiazide-like diuretic (chlorthalidone) and a mineralocorticoid receptor antagonist (spironolactone or eplerenone). Experimental and clinical studies link the development of hypertension to inflammation and various inflammatory disorders play an important role in development of hypertension. The prevalence of inflammatory disorders such as systemic lupus erythematosus (SLE) and sarcoidosis in patients with RfHTN has not been previously determined. Design and method: In this prospective evaluation, 40 patients with confirmed RfHTN were recruited from the Hypertension Clinic after having uncontrolled BP at three or more clinic visits. All patients were evaluated by automated office BP (AOBP) with the BpTRU device, ambulatory BP monitoring (ABPM), and by 24-hr urine collection to detect antihypertensive medication adherence by high-performance liquid chromatography-tandem mass spectrometry. Out of 36 patients who underwent ABPM monitoring, 32 patients had RfHTN as confirmed by AOBP and by ABPM. Of these, 9 patients were fully adherent on medications. Twenty-five patients with controlled resistant hypertension (RHTN) by AOBP, ABPM with total medication adherence served as the comparative group. Results: 56% of patients with RfHTN had sarcoidosis and/or SLE. In comparison, the prevalence of the two disorders in patients with controlled RHTN was only 16% (p = 0.034). In addition, C-reactive protein was significantly higher in rfhtn compared to controlled RHTN (19.8 ± 3.2 vs 3.2 ± 1.2 mg/L; p = 0.042). Conclusions: Patients with confirmed RfHTN have a higher prevalence sarcoidosis and/or SLE compared to non-refractory controls, suggesting a possible role autoimmune or inflammatory disorders in the development of RfHTN.

Resistant and refractory arterial hypertension: similarities and differences, new approaches to diagnosis and treatment

Refractory hypertension is a novel phenotype of antihypertensive treatment failure. The terms "refractory hypertension" and "resistant hypertension" were considered interchangeable for a long time and related to difficult-to-treat hypertension. Recently, the term "refractory hypertension" refers to a very small group of patients who do not really reach the target blood pressure for maximum antihypertensive therapy. In this review we discuss similarities and contrasts definition, prevalence, patient characteristics, risk factors, and possible underlying etiologies of refractory and resistant hypertension.

Abstract P209: Antihypertensive Medication Non-Adherence is Common in Patients With Suspected Refractory Hypertension

Introduction: Refractory hypertension is a phenotype of antihypertensive treatment failure defined as uncontrolled BP (> 135/85 mmHg) despite the use of five or more different antihypertensive agents, including long-acting thiazide like diuretic (chlorthalidone) and mineralocorticoid receptor antagonist (Spironolactone or Eplerenone). Recently white coat effect has been shown to be uncommon in patients with refractory hypertension. However, the degree of medication non-adherence, an important cause of apparent refractory hypertension, is unknown. Methods: In this prospective evaluation, 37 refractory hypertensive patients were recruited from the University of Alabama at Birmingham Hypertension Clinic after having uncontrolled BP at three or more clinic visits. All patients were evaluated by automated office BP (AOBP) with the BpTRU device, ambulatory BP monitoring (ABPM), and 24-hr urine collection to detect antihypertensive medication adherence by high-performance liquid chromatography-tandem mass spectrometry. Out of 34 patients who underwent ABPM monitoring, 30 (88%) patients were refractory hypertensive by AOBP and by ABPM. Of these, 27 patients had 24-hr urine collection for detection of prescribed antihypertensive medications or their metabolites. Results: Out of 27 patients, 11 (40.7%) patients had complete adherence with five or more antihypertensive medications, indicating true refractory hypertension. Ten (37.0%) patients were partially adherent, and 6 (22.2%) patients had total non-adherence to their antihypertensive medications. Conclusion: Of patients identified as having apparent refractory hypertension, 40% were adherent with at least 5 of their prescribed antihypertensive agents, confirming true refractory hypertension. The remaining 60% were partially or fully non-adherent. These results indicate that non-adherence is common in patients suspected of having refractory hypertension.

Refractory Hypertension Is not Attributable to Intravascular Fluid Retention as Determined by Intracardiac Volumes.

Refractory hypertension (RfHTN) is an extreme phenotype of antihypertensive treatment failure defined as lack of blood pressure control with ≥5 medications, including a long-acting thiazide and a mineralocorticoid receptor antagonist. RfHTN is a subgroup of resistant hypertension (RHTN), which is defined as blood pressure >135/85 mm Hg with ≥3 antihypertensive medications, including a diuretic. RHTN is generally attributed to persistent intravascular fluid retention. It is unknown whether alternative mechanisms are operative in RfHTN. Our objective was to determine whether RfHTN is characterized by persistent fluid retention, indexed by greater intracardiac volumes determined by cardiac magnetic resonance when compared with controlled RHTN patients. Consecutive patients evaluated in our institution with RfHTN and controlled RHTN were prospectively enrolled. Exclusion criteria included advanced chronic kidney disease and masked or white coat hypertension. All enrolled patients underwent biochemical testing and cardiac magnetic resonance. The RfHTN group (n=24) was younger (mean age, 51.7±8.9 versus 60.6±11.5 years; P=0.003) and had a greater proportion of women (75.0% versus 43%; P=0.02) compared with the controlled RHTN group (n=30). RfHTN patients had a greater left ventricular mass index (88.3±35.0 versus 54.6±12.5 g/m2; P<0.001), posterior wall thickness (10.1±3.1 versus 7.7±1.5 mm; P=0.001), and septal wall thickness (14.5±3.8 versus 10.0±2.2 mm; P<0.001). There was no difference in B-type natriuretic peptide levels and left atrial or ventricular volumes. Diastolic dysfunction was noted in RfHTN. Our findings demonstrate greater left ventricular hypertrophy without chamber enlargement in RfHTN, suggesting that antihypertensive treatment failure is not attributable to intravascular volume retention.

White-Coat Effect Is Uncommon in Patients With Refractory Hypertension

Refractory hypertension is a recently described phenotype of antihypertensive treatment failure defined as uncontrolled blood pressure (BP) despite the use of ≥5 different antihypertensive agents, including chlorthalidone and spironolactone. Recent studies indicate that refractory hypertension is uncommon, with a prevalence of ≈5% to 10% of patients referred to a hypertension specialty clinic for uncontrolled hypertension. The prevalence of white-coat effect, that is, uncontrolled automated office BP ≥135/85 mm Hg and controlled out-of-office BP <135/85 mm Hg, by awake ambulatory BP monitor in hypertensive patients overall is ≈30% to 40%. The prevalence of white-coat effect among patients with refractory hypertension has not been previously reported. In this prospective evaluation, consecutive patients referred to the University of Alabama at Birmingham Hypertension Clinic for uncontrolled hypertension were enrolled. Refractory hypertension was defined as uncontrolled automated office BP ≥135/85 mm Hg with the use of ≥5 antihypertensive agents, including chlorthalidone and spironolactone. Automated office BP measurements were based on 6 serial readings, done automatically with the use of a BpTRU device unobserved in the clinic. Out-of-office BP measurements were done by 24-hour ambulatory BP monitor. Thirty-four patients were diagnosed with refractory hypertension, of whom 31 had adequate ambulatory BP monitor readings. White-coat effect was present in only 2 patients, or 6.5% of the 31 patients with refractory hypertension, suggesting that white-coat effect is largely absent in patients with refractory hypertension. These findings suggest that white-coat effect is not a common cause of apparent lack of BP control in patients failing maximal antihypertensive treatment.

1059 POLYSOMNOGRAPHIC CHARACTERISTICS OF PATIENTS WITH REFRACTORY HYPERTENSION COMPARED TO CONTROLLED RESISTANT HYPERTENSION

Refractory hypertension (rHTN), a unique phenotype of antihypertensive treatment failure, is defined as the persistence of uncontrolled high blood pressure (>140/90 mmHg) despite treatment with 5 or more antihypertensive agents. Controlled resistant hypertension (crHTN) is defined as controlled blood pressure requiring 3 or more medications from different classes, including a diuretic. We have previously reported that patients with rHTN exhibit heightened sympathetic tone when compared with those with crHTN. Therefore, this study sought to investigate sleep as a potential mediating mechanism underlying rHTN. We hypothesized that patients with rHTN would have more severe obstructive sleep apnea (OSA) than patients with crHTN as a contributing factor to their heightened sympathetic tone. Consecutive patients (n=80) from the UAB Hypertension Clinic with either rHTN (n=29) or crHTN (n=51) were evaluated by overnight polysomnography. Multivariate analysis of variance was used to compare sleep characteristics between these two groups of patients. Compared with patients with crHTN, those with rHTN were younger (54.6 ± 9.9 versus 58.1 ± 11.6 years) and more likely to be black (75.9% versus 54.9%) and female (69.0% versus 37.3%). Patients with rHTN had more total sleep time (p=0.017) and more time spent in N2 sleep (p=0.002). There were no other significant differences in sleep architecture, number of awakenings, or time spent awake after sleep onset. Patients with rHTN had a higher sleeping heart rate (p=0.040). There were statistically non-significant trends for patients with rHTN to have a higher mean apnea hypopnea index (AHI), as well as for a larger percentage of these patients to have an AHI>5, although these trends were not statistically significant (p=0.367). These findings indicate that patients with rHTN do not exhibit worse OSA compared with patients with crHTN. Therefore, more severe OSA does not explain the heightened sympathetic tone observed in patients with rHTN. This study was supported by NIH grant R01 HL113004 and grant 15SFRN2390002 from the American Heart Association.

Refractory versus resistant hypertension.

Refractory hypertension is a recently proposed phenotype of antihypertensive treatment failure. As such it represents an extreme subtype of resistant or difficult-to-treat hypertension. Resistant hypertension is relatively common with an estimated prevalence of 10-20% of treated hypertensive patients. It is typically defined as having an uncontrolled blood pressure on three or more antihypertensive medications, including a diuretic. Refractory hypertension is rare with a prevalence of approximately 5% of patients with uncontrolled resistant hypertension. It is defined as an uncontrolled blood pressure with the use of five or more antihypertensive medications, including a long-acting thiazide diuretic, such as chlorthalidone, and a mineralocorticoid receptor antagonist such as spironolactone. Persistent excess fluid retention is thought to commonly underlie development of resistant hypertension, recent studies suggest that refractory may be more likely attributable to heightened sympathetic output as opposed to inappropriate fluid retention. Treatment recommendations for resistant hypertension are generally based on intensification of diuretic therapy, especially with combined use of chlorthalidone and spironolactone. Although fuller elucidation is needed, such an approach may not be appropriate for refractory hypertension, which instead, may require effective sympathetic inhibition, either with medications or device-based approaches.

Resistant and Refractory Hypertension: Antihypertensive Treatment Resistance vs Treatment Failure

Resistant or difficult to treat hypertension is defined as high blood pressure that remains uncontrolled with 3 or more different antihypertensive medications, including a diuretic. Recent definitions also include controlled blood pressure with use of 4 or more medications as also being resistant to treatment. Recently, refractory hypertension, an extreme phenotype of antihypertensive treatment failure has been defined as hypertension uncontrolled with use of 5 or more antihypertensive agents, including a long-acting thiazide diuretic and a mineralocorticoid receptor antagonist. Patients with resistant vs refractory hypertension share similar characteristics and comorbidities, including obesity, African American race, female sex, diabetes, coronary heart disease, chronic kidney disease, and obstructive sleep apnea. Patients with refractory vs resistant hypertension tend to be younger and are more likely to have been diagnosed with congestive heart failure. Refractory hypertension might also differ from resistant hypertension in terms of underlying cause. Preliminary evidence suggests that refractory hypertension is more likely to be neurogenic in etiology (ie, heightened sympathetic tone), vs a volume-dependent hypertension that is more characteristic of resistant hypertension in general.

Refractory Hypertension

Refractory hypertension is an extreme phenotype of antihypertensive treatment failure. Participants in the REasons for Geographic And Racial Differences in Stroke (REGARDS) Study, a large (n=30 239), population-based cohort were evaluated to determine the prevalence of refractory hypertension and associated cardiovascular risk factors and comorbidities. Refractory hypertension was defined as uncontrolled blood pressure (systolic/diastolic, ≥140/90 mm Hg) on ≥5 antihypertensive drug classes. Participants with resistant hypertension (systolic/diastolic, ≥140/90 mm Hg on ≥3 or <140/90 mm Hg on ≥4 antihypertensive classes) and all participants treated for hypertension served as comparator groups. Of 14 809 REGARDS participants receiving antihypertensive treatment, 78 (0.5%) had refractory hypertension. The prevalence of refractory hypertension was 3.6% among participants with resistant hypertension (n=2144) and 41.7% among participants on ≥5 antihypertensive drug classes. Among all participants with hypertension, black race, male sex, living in the stroke belt or buckle, higher body mass index, lower heart rate, reduced estimated glomerular filtration rate, albuminuria, diabetes mellitus, and history of stroke and coronary heart disease were associated with refractory hypertension. Compared with resistant hypertension, prevalence ratios for refractory hypertension were increased for blacks (3.00; 95% confidence interval, 1.68-5.37) and those with albuminuria (2.22; 95% confidence interval, 1.40-3.52) and diabetes mellitus (2.09; 95% confidence interval, 1.32-3.31). The median 10-year Framingham risk for coronary heart disease and stroke was higher among participants with refractory hypertension when compared with those with either comparator group. These data indicate that although resistant hypertension is relatively common among treated patients with hypertension, true antihypertensive treatment failure is rare.