Comparison of knowledge, attitude and practices among apparent treatment resistant hypertensive patients and non-apparent treatment resistant hypertensive patients in a tertiary care center

Apparent treatment resistant hypertension (aTRH) is characterized as uncontrolled hypertension (HTN) with the use of 3 or more antihypertensive medication classes or controlled HTN while treated with 4 or more antihypertensive medication classes. Few data are available on the association of aTRH with cardiovascular disease outcomes in comparison to more easily controlled HTN. We evaluated the risk for stroke, coronary heart disease (CHD) and all-cause mortality among 2,043 participants with aTRH and 9,519 participants with controlled HTN (systolic blood pressure < 140 mm Hg and diastolic blood pressure < 90 mm Hg) treated with < 4 antihypertensive medication classes from the population-based REasons for Geographic And Racial Differences in Stroke (REGARDS) study. aTRH was further categorized as controlled aTRH (≥ 4 antihypertensive medication classes and controlled HTN) and uncontrolled aTRH (≥ 3 antihypertensive medication classes and uncontrolled HTN). Participants with and without aTRH, respectively, were 68±9 and 66±9 years of age, 60.5% (1236 0f 2043) and 46.8% (4455 of 9519) black, and 49.2% (1005 of 2043) and 40.8% (3884 of 9519) male. After adjusting for demographic, clinical and comorbid factors, the hazard ratio (HR) for stroke, CHD, and all-cause mortality associated with aTRH (vs. controlled HTN and < 4 medication classes) was 1.29 (95% CI 0.96-1.73), 1.90 (95% CI 1.40-2.58), and 1.36 (95% CI 1.20-1.55), respectively. Compared to those with controlled hypertension, the multivariable-adjusted HR for stroke, CHD and all-cause mortality was increased for those with uncontrolled aTRH but not those with controlled aTRH (Table 1). Compared to those with controlled aTRH, uncontrolled aTRH was associated with CHD (HR 2.33; 95% CI: 1.21 [[Unable to Display Character: –]] 4.48) but not stroke (HR 1.05; 95% CI: 0.61 [[Unable to Display Character: –]] 1.81) or all-cause mortality (HR 1.15; 95% CI: 0.91 [[Unable to Display Character: –]] 1.45). We conclude achieving blood pressure control within aTRH is paramount to decrease risk for events similarly to other patients with more easily controlled HTN. Table 1. Hazard ratios for stroke, coronary heart disease, and all-cause mortality associated with apparent treatment resistant hypertension (aTRH). *< 4 antihypertensive medication classes Models are adjusted for age, race, gender, and geographic region of residence, waist circumference, smoking status, physical activity, alcohol consumption, C - reactive protein, statin use, Morisky score for medication adherence, total cholesterol, HDL-cholesterol, and hypertension duration, estimated glomerular filtration rate < 60 ml/min/1.73m 2 , albuminuria, and diabetes. Hazard ratios for stroke were also adjusted for history of coronary heart disease. Hazard ratios for coronary heart disease were also adjusted for history of stroke. Hazard ratios for all-cause mortality were also adjusted for history of coronary heart disease and stroke.

Treatment resistant hypertension (TRH) is defined as uncontrolled hypertension (HTN) despite the use of ≥3 antihypertensive medication classes or controlled HTN while treated with ≥4 antihypertensive medication classes. Risk factors for TRH include increasing age, diminished kidney function, higher body mass index, diabetes, and African American (AA) race. Importantly, previous studies suggest a genetic role in TRH, although the genetics of TRH are largely understudied. With 2203 treatment resistant cases and 2354 treatment responsive controls (36% AA) from the Genetics of Hypertension Associated Treatment Study (GenHAT), we assessed the association of 78 candidate gene polymorphisms with TRH status using logistic regression. After stratifying by race and adjusting for potential confounders, there were 2 genetic variants in the AGT gene (rs699, rs5051) statistically significantly associated with TRH among white participants. The Met allele of rs699 and the G allele of rs5051 were positively associated with TRH: OR = 1.27 (1.12–1.44), P = 0.0001, and OR = 1.36 (1.20–1.53), P < 0.0001, respectively. There was no similar association among AA participants (race interaction P = 0.0004 for rs699 and P = 0.0001 for rs5051). This research contributes to our understanding of the genetic basis of TRH, and further genetic studies of TRH may help reach the goal of better clinical outcomes for hypertensive patients.

Apparent treatment-resistant hypertension (aTRH) is defined as uncontrolled hypertension despite the use of ≥3 antihypertensive medication classes or controlled hypertension while treated with ≥4 antihypertensive medication classes. Although a high prevalence of aTRH has been reported, few data are available on its association with cardiovascular and renal outcomes. We analyzed data on 14 684 Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) participants to determine the association between aTRH (n=1870) with coronary heart disease, stroke, all-cause mortality, heart failure, peripheral artery disease, and end-stage renal disease. We defined aTRH as blood pressure not at goal (systolic/diastolic blood pressure ≥140/90 mm Hg) while taking ≥3 classes of antihypertensive medication or taking ≥4 classes of antihypertensive medication with blood pressure at goal during the year 2 ALLHAT study visit (1996-2000). Use of a diuretic was not required to meet the definition of aTRH. Follow-up occurred through 2002. The multivariable adjusted hazard ratios (95% confidence intervals) comparing participants with versus without aTRH were as follows: coronary heart disease (1.44 [1.18-1.76]), stroke (1.57 [1.18-2.08]), all-cause mortality (1.30 [1.11-1.52]), heart failure (1.88 [1.52-2.34]), peripheral artery disease (1.23 [0.85-1.79]), and end-stage renal disease (1.95 [1.11-3.41]). aTRH was also associated with the pooled outcomes of combined coronary heart disease (hazard ratio, 1.47; 95% confidence interval, 1.26-1.71) and combined cardiovascular disease (hazard ratio, 1.46; 95% confidence interval, 1.29-1.64). These results demonstrate that aTRH increases the risk for cardiovascular disease and end-stage renal disease. Studies are needed to identify approaches to prevent aTRH and reduce risk for adverse outcomes among individuals with aTRH.

Refractory Hypertension and Kidney Failure: Focusing on the Social Determinants of Health.

Apparent treatment-resistant hypertension and risk for stroke, coronary heart disease, and all-cause mortality

Apparent Treatment-resistant Hypertension Among Individuals with History of Stroke or Transient Ischemic Attack

BACKGROUND AND AIMS High blood pressure (BP) is an essential contributor to the risk of cardiovascular disease (CVD) and death. Hence, diagnosing and treating patients with high BP is paramount if the number of cardiovascular related death should be reduced. High nocturnal BP and blunting of normal nocturnal BP decrease have stronger correlation to the risk of CVD than high day time BP. Lowering nocturnal BP is assumed to reduce the risk of CVD. Patients with treatment resistant hypertension (TRH) represent a subgroup of hypertensive patients characterized by lack of BP control despite antihypertensive treatment. These patients are at particular risk of CVD and target organ damage. Patients with TRH are more likely to experience BP increase as a response to sodium loading than other individuals. Lifestyle modification is an important treatment angle in hypertensive patients. It is, in particular, central to reduce sodium intake, as high sodium intake increases the risk of TRH. Thus, in this study we aimed to analyse if self-performed dietary sodium restriction could be implemented in patients with TRH. Moreover, we aimed to analyse the effect of this attempted restriction on nocturnal BP and 24 h BP, on plasma levels of BNP and nitric oxide, and on body water content. METHOD Patients with TRH from 20 to 70 years with normal renal function were invited for participation in this cross-over interventional study. Patients were screened with 24 h ambulatory BP monitoring initiated after observed intake of usual antihypertensive medication, and they were included if 24 h systolic BP/diastolic BP ≥ 130/80 mmHg. Study participation included two periods of 14 days; a standard period with usual diet and an interventional period with instructed dietary sodium restriction and handed-out sodium-reduced bread. For both periods, all antihypertensive medication was dosed and handed out and ingested in the morning. At the end of each period, patients were examined with 24 h BP monitoring, 24 h urine collection (sodium excretion), blood samples (nitric oxide and BNP) and bioimpedance measurement (body water content). RESULTS Baseline characteristics of the fifteen included patients are shown in Table 1. Eleven of the patients were male. Patients had been treated for hypertension for a mean of 12.5 (7) years and excreted a mean of 11.2 grams of salt at baseline [192 (86) mmol sodium]. All patients but one reduced sodium excretion at follow up. Table 2 shows the effect of sodium restriction on BP, nitric oxide, BNP and body water content. Sodium excretion was reduced to 91 mmol/24 h, which equals 5.3 g of salt. BP (24 h, day and nocturnal) decreased significantly as well as body water content and plasma levels of BNP. These changes were, however, not correlated. Plasma levels of nitric oxide increased, but it was not related to the changes in BP. Nocturnal fraction of 24 h sodium excretion increased after sodium restriction; however, this was not correlated to changes in nocturnal BP. Renal function and urinary potassium excretion both remained unchanged. Four patients experienced side effects; three reported newly onset dizziness at follow-up; two of them had 24 h BP reduction &amp;gt; 10 mmHg systolic. One patient had increased creatinine and potassium at follow-up. CONCLUSION In a population of 15 treatment resistant hypertensive patients, we demonstrated that self-performed dietary sodium restriction could be implemented. Urinary sodium excretion was reduced significantly to 5.3 g/24 h. Nocturnal BP was reduced significantly; dipping status was, however, unchanged. Increased plasma levels of nitric oxide may be evidence of improved endothelial function. Hence, by the local vasodilating effect, NO may be one of the involved mechanisms in BP decrease following a sodium restriction. Reduced extracellular water content and BNP may be other explainable effects of BP reduction after inducing sodium restriction.

Few data exist on whether healthy lifestyle factors are associated with better prognosis among individuals with apparent treatment-resistant hypertension, a high-risk phenotype of hypertension. The purpose of this study was to assess the association of healthy lifestyle factors with cardiovascular events, all-cause mortality, and cardiovascular mortality among individuals with apparent treatment-resistant hypertension. We studied participants (n=2043) from the population-based Reasons for Geographic and Racial Differences in Stroke (REGARDS) study with apparent treatment-resistant hypertension (blood pressure ≥140/90 mm Hg despite the use of 3 antihypertensive medication classes or the use of ≥4 classes of antihypertensive medication regardless of blood pressure control). Six healthy lifestyle factors adapted from guidelines for the management of hypertension (normal waist circumference, physical activity ≥4 times/week, nonsmoking, moderate alcohol consumption, high Dietary Approaches to Stop Hypertension diet score, and low sodium-to-potassium intake ratio) were examined. A greater number of healthy lifestyle factors were associated with lower risk for cardiovascular events (n=360) during a mean follow-up of 4.5 years. Multivariable-adjusted hazard ratios [HR (95% confidence interval)] for cardiovascular events comparing individuals with 2, 3, and 4 to 6 versus 0 to 1 healthy lifestyle factors were 0.91 (0.68-1.21), 0.80 (0.57-1.14), and 0.63 (0.41-0.95), respectively (P-trend=0.020). Physical activity and nonsmoking were individual healthy lifestyle factors significantly associated with lower risk for cardiovascular events. Similar associations were observed between healthy lifestyle factors and risk for all-cause and cardiovascular mortality. In conclusion, healthy lifestyle factors, particularly physical activity and nonsmoking, are associated with a lower risk for cardiovascular events and mortality among individuals with apparent treatment-resistant hypertension.

BackgroundUncontrolled hypertension is a major cardiovascular risk factor. We examined uncontrolled hypertension and differences in treatment regimens between a high-risk country, Russia, and low-risk Norway to gain better understanding of the underlying factors.MethodsPopulation-based survey data on 40–69 year olds with hypertension defined as taking antihypertensives and/or having high blood pressure (140+/90+ mmHg) were obtained from Know Your Heart Study (KYH, N = 2284), Russian Federation (2015–2018) and seventh wave of The Tromsø Study (Tromsø 7, N = 5939), Norway (2015–2016). Uncontrolled hypertension was studied in the subset taking antihypertensives (KYH: N = 1584; Tromsø 7: 2792)and defined as having high blood pressure (140+/90+ mmHg). Apparent treatment resistant hypertension (aTRH) was defined as individuals with uncontrolled hypertension on 3+ OR controlled on 4+ antihypertensive classes in the same subset.ResultsAmong all those with hypertension regardless of treatment status, control of blood pressure was achieved in 22% of men (KYH and Tromsø 7), while among women it was 33% in Tromsø 7 and 43% in KYH. When the analysis was limited to those on treatment for hypertension, the percentage uncontrolled was higher in KYH (47.8%, CI 95 44.6–50.9%) than Tromsø 7 (38.2, 36.1–40.5%). The corresponding figures for aTRH were 9.8% (8.2–11.7%) and 5.7% (4.8–6.8%).Antihypertensive monotherapies were more common than combinations and used by 58% in Tromsø 7 and 44% in KYH. In both KYH and Tromsø 7, untreated hypertension was higher in men, those with no GP visit in the past year and problem drinkers. In both studies, aTRH was associated with older age, CVD history, obesity, and diabetes. In Tromsø 7, also male gender and any drinking. In KYH, also chronic kidney disease.ConclusionThere is considerable scope for promoting combination therapies in line with European treatment guidelines in both study populations. The factors associated with untreated hypertension overlap with known correlates of treatment non-adherence and health check non-attendance. In contrast, aTRH was characterised by obesity and underlying comorbidities potentially complicating treatment.

Objective: Apparent treatment-resistant hypertension (ATRH) is highly prevalent in chronic kidney disease (CKD) and is a risk factor for rapid progression of CKD. Soluble klotho is an extracellular domain of klotho released into the circulation. Although soluble klotho is known to be a risk factor for hypertension, the association between soluble klotho and ATRH is unknown. The aim of this study is to evaluate the association of soluble klotho with ATRH in CKD. Design and method: In this cross-sectional study, we analyzed 1,737 predialysis CKD patients enrolled in the prospective Korean Cohort Study for Outcome in Patients With Chronic Kidney Disease (KNOW-CKD). Apparent treatment-resistant hypertension was defined as systolic blood pressure &gt; = 140 mm Hg or diastolic blood pressure &gt; = 90 mm Hg with concurrent use of three antihypertensive medication classes or use of four or more antihypertensive medication classes regardless of blood pressure level. Serum klotho levels were measured using an enzyme-linked immunosorbent assay. Participants were divided into quartiles. Results: Among study subjects, 303 patients (17.4%) had ATRH. Prevalence of ATRH were 21.9%, 18.9%, 18.2% and 10.8% for the 1st to 4th quartiles of soluble klotho, respectively (p for trend &lt; 0.001). The adjusted OR [95% CI] of 1st to 3th quartile of soluble klotho in reference to 4th quartile were 2.01 (1.32–3.06), 1.59 (1.04–2.42) and 1.69 (1.11–2.57). Conclusions: Soluble klotho level was inversely associated with the presence of ATRH in Korean predialysis CKD patients. This relationship was independent of various cardiovascular risk factors.

A New Era of Renal Denervation Trials for Patients With Hypertension?

Treatment resistant hypertension and the incidence of cardiovascular disease and end-stage renal disease: results from the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT)

Apparent treatment-resistant hypertension is defined as systolic/diastolic BP ≥ 140/90 mmHg with concurrent use of three or more antihypertensive medication classes or use of four or more antihypertensive medication classes regardless of BP level. The prevalence of apparent treatment-resistant hypertension among Reasons for Geographic and Racial Differences in Stroke study participants treated for hypertension (n=10,700) was determined by level of estimated GFR and albumin-to-creatinine ratio, and correlates of apparent treatment-resistant hypertension among those participants with CKD were evaluated. CKD was defined as an albumin-to-creatinine ratio ≥ 30 mg/g or estimated GFR<60 ml/min per 1.73 m(2). The prevalence of apparent treatment-resistant hypertension was 15.8%, 24.9%, and 33.4% for those participants with estimated GFR ≥ 60, 45-59, and <45 ml/min per 1.73 m(2), respectively, and 12.1%, 20.8%, 27.7%, and 48.3% for albumin-to-creatinine ratio<10, 10-29, 30-299, and ≥ 300 mg/g, respectively. The multivariable-adjusted prevalence ratios (95% confidence intervals) for apparent treatment-resistant hypertension were 1.25 (1.11 to 1.41) and 1.20 (1.04 to 1.37) for estimated GFR levels of 45-59 and <45 ml/min per 1.73 m(2), respectively, versus ≥ 60 ml/min per 1.73 m(2) and 1.54 (1.39 to 1.71), 1.76 (1.57 to 1.97), and 2.44 (2.12 to 2.81) for albumin-to-creatinine ratio levels of 10-29, 30-299, and ≥ 300 mg/g, respectively, versus albumin-to-creatinine ratio<10 mg/g. After multivariable adjustment, men, black race, larger waist circumference, diabetes, history of myocardial infarction or stroke, statin use, and lower estimated GFR and higher albumin-to-creatinine ratio levels were associated with apparent treatment-resistant hypertension among individuals with CKD. This study highlights the high prevalence of apparent treatment-resistant hypertension among individuals with CKD.

This study aimed to investigate the characteristics of out-of-office blood pressure (BP) measurements in patients with apparent treatment-resistant hypertension (aRH) enrolled from 15 tertiary care centers in South Korea. aRH was defined as having uncontrolled office BP ≥ 130/80 mmHg despite receiving three classes of antihypertensive medication or any level of BP despite receiving ≥4 classes of antihypertensive medication. Patients with complete data for office BP, 24-h ambulatory BP monitoring (ABPM), and home BP measurements at baseline were included. BP control status between ABPM and home BP measurements was compared. Out of 1457 patients, 823 meeting the enrollment criteria were included (mean age: 59.9 ± 13.6 years; 57.5% male patients). Among them, 7.2% had controlled BP, 8.7% had whitecoat uncontrolled hypertension, 15.1% had masked uncontrolled hypertension, and 69% had sustained hypertension, as measured through baseline ABPM. Additionally, 43% of patients with controlled BP based on home BP measurement had nocturnal hypertension. Relying solely on home BP measurement may result in misclassifying 70% of patients as having either controlled BP or whitecoat uncontrolled BP. This study reaffirms the circadian pattern of resistant hypertension, characterized by a higher prevalence of non-dipping and rising patterns, even in patients with BP controlled based on ABPM. Considering the persistent difference between home BP measurement and ABPM, even at a lower home BP threshold, integrating both measurements into the management of aRH is advisable.

Hypertension requiring treatment with multiple antihypertensive medications is common among individuals with chronic kidney disease (CKD). Small clinic-based studies have reported a high prevalence of treatment resistant hypertension (TRH) among patients with CKD. However, the prevalence of TRH has not been estimated for people with CKD in population-based studies. We hypothesized that lower estimated glomerular filtration rate (eGFR) and higher albumin-to-creatinine ratio (ACR) would be associated with a higher prevalence of TRH. We determined the prevalence of TRH among REasons for Geographic And Racial Differences in Stroke (REGARDS) study participants (n=30,239) by eGFR and ACR and evaluated clinical and demographic correlates of TRH in those with CKD. Blood pressure was measured twice, pill bottles were inspected, and serum creatinine and an ACR were measured during an in-home study visit. TRH was defined as systolic/diastolic blood pressure ≥140/90 mmHg with concurrent use of ≥3 antihypertensive medication classes or use of ≥4 antihypertensive medication classes. CKD was defined as an ACR ≥30 mg/g or a CKD-EPI equation-derived eGFR &lt;60 ml/min/1.73m 2 . The mean age of the 11,285 REGARDS participants treated for hypertension was 66.0 (SD=9.0) years, 56.9% were women and 48.8% were black. The prevalence of TRH was 14.5%, 23.5%, and 31.2% for those with an eGFR ≥60, 45-59, and &lt;45 mL/min/1.73m 2 , respectively. The prevalence of TRH was 11.3%, 18.8%, 25.5%, and 44.5% for ACR &lt;10, 10-29, 30-299, and ≥300 mg/g, respectively. A graded association between lower eGFR and higher ACR with TRH remained present after multivariable adjustment (Table 1). Also, after multivariable adjustment, black race, a larger waist circumference, diabetes, and history of myocardial infarction and stroke were associated with TRH among individuals with CKD. In conclusion, individuals with CKD have a high prevalence of TRH. Strategies are needed to improve blood pressure control in this population and reduce cardiovascular disease risk.