Apparent Treatment-resistant Hypertension Research Articles

Abstract 12444: Pulse Pressure and Cardiovascular and Renal Outcomes by Age in the Chronic Renal Insufficiency Cohort

Pulse pressure (PP) is associated with cardiovascular events and the progression of chronic kidney disease (CKD) to end stage kidney disease (ESKD). While PP is known to widen with age, it is less clear what other clinical factors affect PP and whether the risks associated with wide PP are the same across all ages. We used Cox proportional hazards models to investigate the association of PP with development of 1) atherosclerotic cardiovascular disease (ASCVD) events (congestive heart failure hospitalization, myocardial infarction, stroke and peripheral artery disease) or death and 2) 50% reduction in estimated glomerular filtration rate (eGFR) or ESKD in the Chronic Renal Insufficiency Cohort (CRIC) Study. In sensitivity analyses, we evaluated the association of time-updated PP with these outcomes, accounting for potential time-updated confounders using inverse probability of treatment weighting. We evaluated for effect modification by age (divided into tertiles), apparent treatment-resistant hypertension (HTN), baseline diabetes mellitus (DM) status, baseline CKD stage and baseline cardiovascular disease (CVD). Among 5,621 participants with CKD followed for ~5.4 years, mean PP was 57±19 mmHg, 1,396 (25%) had an ASCVD event, 1,186 (21%) died and 1,783 (32%) participants experienced the composite renal outcome. Every 10 mm Hg wider PP was associated with 6% higher risk of an ASCVD event or death (time-updated adjusted hazard ratio [HR]=1.06, 95% CI 1.04, 1.08) and 17% higher risk of the composite renal outcome (time-updated adjusted HR=1.17, 95% CI 1.16, 1.18). Wider PP was associated with a higher risk of ASCVD events or death among participants in the lowest age tertile (21-61 years; Figure 1A ), but a higher risk of the composite renal outcome in the oldest age tertile (71-79 years; Figure 1B ), suggesting PP may be associated with different pathophysiology across ages.

Dapagliflozin and Apparent Treatment-Resistant Hypertension in Heart Failure With Mildly Reduced or Preserved Ejection Fraction: The DELIVER Trial.

Apparent treatment-resistant hypertension (aTRH) is prevalent and associated with adverse outcomes in heart failure with mildly reduced or preserved ejection fraction. Less is known about the potential role of sodium-glucose co-transporter 2 inhibition in this high-risk population. In this post hoc analysis of the DELIVER trial (Dapagliflozin Evaluation to Improve the Lives of Patients with Preserved Ejection Fraction Heart Failure), we evaluated clinical profiles and treatment effects of dapagliflozin among participants with aTRH. DELIVER participants were categorized on the basis of baseline blood pressure (BP), with aTRH defined as BP ≥140/90 mm Hg (≥130/80 mm Hg if diabetes) despite treatment with 3 antihypertensive drugs including a diuretic. Nonresistant hypertension was defined as BP above threshold but not meeting aTRH criteria. Controlled BP was defined as BP under threshold. Incidence of the primary outcome (cardiovascular death or worsening heart failure event), key secondary outcomes, and safety events was assessed by baseline BP category. Among 6263 DELIVER participants, 3766 (60.1%) had controlled BP, 1779 (28.4%) had nonresistant hypertension, and 718 (11.5%) had aTRH at baseline. Participants with aTRH had more cardiometabolic comorbidities and tended to have higher left ventricular ejection fraction and worse kidney function. Rates of the primary outcome were 8.7 per 100 patient-years in those with controlled BP, 8.5 per 100 patient-years in the nonresistant hypertension group, and 9.5 per 100 patient-years in the aTRH group. Relative treatment benefits of dapagliflozin versus placebo on the primary outcome were consistent across BP categories (Pinteraction=0.114). Participants with aTRH exhibited the greatest absolute reduction in the rate of primary events with dapagliflozin (4.1 per 100 patient-years) compared with nonresistant hypertension (2.7 per 100 patient-years) and controlled BP (0.8 per 100 patient-years). Irrespective of assigned treatment, participants with aTRH experienced a higher rate of reported vascular events, including myocardial infarction and stroke, over study follow-up. Dapagliflozin modestly reduced systolic BP (by ≈1 to 3 mm Hg) without increasing risk of hypotension, hypovolemia, or other serious adverse events, irrespective of BP category, but did not improve the proportion of participants with aTRH attaining goal BP over time. aTRH was identified in >1 in 10 patients with heart failure and left ventricular ejection fraction >40% in DELIVER. Dapagliflozin consistently improved clinical outcomes and was well-tolerated, including among those with aTRH. URL: https://www.clinicaltrials.gov; Unique identifier: NCT03619213.

THU607 Improving Screening For Primary Aldosteronism Among People With Apparent Treatment Resistant Hypertension

Abstract Disclosure: K. Zekarias: None. K. Tessier: None. J. Kohlenberg: None. Introduction: The screening rate for primary aldosteronism (PA) is low among people with resistant hypertension. People with PA experience significantly more cardiovascular complications than those with primary hypertension and an equivalent degree of blood pressure control1. Therefore, identification of people with PA for early-directed therapy is crucial. Objective: We aimed to improve the screening rate for PA among people with apparent treatment resistant hypertension (aTRH), defined as blood pressure >140/90 despite the concurrent use of three antihypertensive drug classes or any person with hypertension on >4 antihypertensive medications. Methods: Using an electronic medical record (EMR) best practice alert (BPA), we implemented a quality improvement (QI) program from 9/17/2022-3/16/2023. We included adults ≥18 years of age with aTRH, who were identified using ICD codes, the last three blood pressure measurements and the antihypertensive medication list. During office visits with nephrologists, cardiologists, endocrinologists, family medicine physicians, and internists, a BPA notified providers if the person with aTRH had not been previously screened for PA with plasma aldosterone and plasma renin activity. The alert defined aTRH, suggested that screening be performed regardless of active medications, and contained an order set for plasma aldosterone, plasma renin activity, and plasma potassium. Furthermore, the BPA suggested referral to an endocrinologist if the patient fulfilled criteria for positive case detection for PA, defined as plasma renin activity < 1 ng/mL/hour and plasma aldosterone concentration (PAC) > 10 ng/dL or the plasma aldosterone to renin ratio (ARR) > 30 with PAC > 10. We compared the PA screening rate after the implementation of the BPA to the PA screening rate over the 1 year prior to the BPA implementation (9/16/2021-9/16/2022). Results: Plasma aldosterone lab orders were placed for 3.4% (179/5,261) of people with aTRH post-BPA implementation compared to 1.9% (211/10,944) pre-BPA implementation (p<0.01). Positive case detection for PA occurred in 25% (38/152) of people screened post -BPA implementation compared to 27% (47/173) pre-BPA implementation (p=0.66). People with aTRH who were younger (p<0.01) were more likely to be screened for PA pre-BPA implementation and this did not change post-implementation. Conclusion: Implementation of a QI program employing a BPA with an embedded order set in the EMR improved the screening rate for PA among adults with aTRH. Reference 1. Monticone S, D'Ascenzo F, Moretti C, Williams TA, Veglio F, Gaita F, Mulatero P. Cardiovascular events and target organ damage in primary aldosteronism compared with essential hypertension: a systematic review and meta-analysis. Lancet Diabetes Endocrinol. 2018 Jan; 6 (1):41-50. Presentation: Thursday, June 15, 2023

Characteristics and Predictors of Apparent Treatment-Resistant Hypertension in Real-World Populations Using Electronic Health Record-Based Data.

Apparent treatment-resistant hypertension (aTRH) is defined as uncontrolled blood pressure (BP) despite using ≥3 antihypertensive classes or controlled BP while using ≥4 antihypertensive classes. Patients with aTRH have a higher risk for adverse cardiovascular outcomes compared with patients with controlled hypertension (HTN). Although there have been prior reports on the prevalence, characteristics, and predictors of aTRH, these have been broadly derived from smaller datasets, randomized controlled trials, or closed healthcare systems. We extracted patients with HTN defined by ICD-9 and ICD-10 codes during 1/1/2015-12/31/2018, from 2 large electronic health record databases: the OneFlorida Data Trust (n = 223,384) and Research Action for Health Network (REACHnet) (n = 175,229). We applied our previously validated aTRH and stable controlled HTN computable phenotype algorithms and performed univariate and multivariate analyses to identify the prevalence, characteristics, and predictors of aTRH in these populations. The prevalence of aTRH among patients with HTN in OneFlorida (16.7%) and REACHnet (11.3%) was similar to prior reports. Both populations had a significantly higher proportion of Black patients with aTRH compared with those with stable controlled HTN. aTRH in both populations shared similar significant predictors, including Black race, diabetes, heart failure, chronic kidney disease, cardiomegaly, and higher body mass index. In both populations, aTRH was significantly associated with similar comorbidities, when compared with stable controlled HTN. In 2 large, diverse real-world populations, we observed similar comorbidities and predictors of aTRH as prior studies. In the future, these results may be used to improve healthcare professionals' understanding of aTRH predictors and associated comorbidities.

Association of hypertension severity and control with risk of incident atrial fibrillation: The REasons for Geographic And Racial Differences in Stroke (REGARDS) study.

The association of hypertension (HTN) severity and control with the risk of incident atrial fibrillation (AF) is unclear. Increased HTN severity and poorer blood pressure control would be associated with an increased risk of incident AF. This analysis included 9485 participants (mean age 63 ± 8 years; 56% women; 35% Black). Participants were stratified into six mutually exclusive groups at baseline-normotension (n = 1629), prehypertension (n = 704), controlled HTN (n = 2224), uncontrolled HTN (n = 4123), controlled apparent treatment-resistant hypertension (aTRH) (n = 88), and uncontrolled aTRH (n = 717). Incident AF was ascertained at the follow-up visit, defined by either electrocardiogram or self-reported medical history of a physician diagnosis. Multivariable logistic regression analyses adjusted for demographic and clinical variables. Over an average of 9.3 years later, 868 incident AF cases were detected. Compared to those with normotension, incident AF risk was highest for those with aTRH (controlled aTRH: odds ratio (OR) 2.95; 95% confidence interval (CI) 1.60, 5.43, & uncontrolled aTRH: OR 2.47; 95% CI 1.76, 3.48). The increase in AF risk was smaller for those on no more than three antihypertensive agents regardless of their blood pressure control (controlled OR 1.72; 95% CI 1.30, 2.29 and uncontrolled OR 1.56; 95% CI 1.14, 2.13). The risk of developing AF is increased in all individuals with HTN. Risk is highest in those aTRH regardless of blood pressure control. A more aggressive approach that focuses on lifestyle and pharmacologic measures to either prevent HTN or better control HTN during earlier stages may be particularly beneficial in reducing related AF risk.

Apparently Resistant Hypertension in Polish Hemodialyzed Population: Prevalence and Risk Factors.

The aim of this study was to assess the prevalence, characteristics, and determinants of apparent treatment-resistant hypertension (aTRH) in an unselected large population of patients with end-stage kidney disease (ESKD) treated with hemodialysis (HD) throughout the country. A database of 5879 patients (mean age 65.2 ± 14.2 years, 60% of males receiving hemodialysis) was obtained from the biggest provider of hemodialysis in the country. Hypertension and aTRH were defined using pre- or/and post-dialysis BP values. Patients with and without aTRH (non-aTRH) were compared. Using pre- and post-dialysis criteria, hypertension was diagnosed in 90.7% and 89.1% of subjects, respectively. According to pre- and post-dialysis blood pressure criteria, aTRH incidences were 40.9% and 38.4%, respectively. The hypertensive patients with aTRH versus non-aTRH were younger, had a higher rate of cardiovascular disease, lower dialysis vintage, shorter time on dialysis, higher eKt/V, higher ultrafiltration, higher pre- and post-dialysis BP and HR, and higher use of antihypertensive drugs. Factors that increase the risk of aTRH according to both pre- and post-dialysis BP criteria were age-OR 0.99 [0.98-0.99] and 0.99 [0.98-0.99], the history of CVD 1.26 [1.08-1.46] and 1.30 [1.12-1.51], and diabetes 1.26 [1.08-1.47] and 1.28 [1.09-1.49], adjusted OR with 95% CI. In the real-life world, as much as 40% of HD patients may have aTRH. In ESKD HD patients, aTRH seems to be multifactorial, influenced by patient-related rather than dialysis-related factors. Various definitions of aTRH preclude easy comparisons between studies.

Association of uncontrolled blood pressure in apparent treatment-resistant hypertension with increased risk of major adverse cardiovascular events plus.

Patients with apparent treatment-resistant hypertension (aTRH) are at increased risk of end-organ damage and cardiovascular events. Little is known about the effects of blood pressure (BP) control in this population. Using a national claims database integrated with electronic medical records, the authors evaluated the relationships between uncontrolled BP (UBP; ≥130/80mmHg) or controlled BP (CBP; <130/80mmHg) and risk of major adverse cardiovascular events plus (MACE+; stroke, myocardial infarction, heart failure requiring hospitalization) and end-stage renal disease (ESRD) in adult patients with aTRH (taking ≥3 antihypertensive medication classes concurrently within 30 days between January 1, 2015 and June 30, 2021). MACE+ components were also evaluated separately. Multivariable regression models were used to adjust for baseline differences in demographic and clinical characteristics, and sensitivity analyses using CBP<140/90mmHg were conducted. Patients with UBP (n=22333) were younger and had fewer comorbidities at baseline than those with CBP (n=11427). In the primary analysis, which adjusted for these baseline differences, UBP versus CBP patients were at an 8% increased risk of MACE+ (driven by a 31% increased risk of stroke) and a 53% increased risk of ESRD after 2.7 years of follow-up. Greater MACE+ (22%) and ESRD (98%) risk increases with UBP versus CBP were seen in the sensitivity analysis. These real-world data showed an association between suboptimal BP control in patients with aTRH and higher incidence of MACE+ and ESRD linked with UBP despite the use of multidrug regimens. Thus, there remains a need for improved aTRH management.

Nonadherence Is Common in Patients With Apparent Resistant Hypertension: A Systematic Review and Meta-analysis.

The prevalence of medication nonadherence in the setting of resistant hypertension (RH) varies from 5% to 80% in the published literature. The aim of this systematic review was to establish the overall prevalence of nonadherence and evaluate the effect of the method of assessment on this estimate. MEDLINE, EMBASE, Cochrane, CINAHL, and Web of Science (database inception to November 2020) were searched for relevant articles. We included studies including adults with a diagnosis of RH, with some measure of adherence. Details about the method of adherence assessment were independently extracted by 2 reviewers. Pooled analysis was performed using the random effects model and heterogeneity was explored with metaregression and subgroup analyses. The main outcome measured was the pooled prevalence of nonadherence and the prevalence using direct and indirect methods of assessment. Forty-two studies comprising 71,353 patients were included. The pooled prevalence of nonadherence was 37% (95% confidence interval [CI] 27%-47%) and lower for indirect methods (20%, 95% CI 11%-35%), than for direct methods (46%, 95% CI 40%-52%). The study-level metaregression suggested younger age and recent publication year as potential factors contributing to the heterogeneity. Indirect methods (pill counts or questionnaires) are insufficient for diagnosis of nonadherence, and report less than half the rates as direct methods (direct observed therapy or urine assays). The overall prevalence of nonadherence in apparent treatment RH is extremely high and necessitates a thorough evaluation of nonadherence in this setting.

A flexible symbolic regression method for constructing interpretable clinical prediction models

Machine learning (ML) models trained for triggering clinical decision support (CDS) are typically either accurate or interpretable but not both. Scaling CDS to the panoply of clinical use cases while mitigating risks to patients will require many ML models be intuitively interpretable for clinicians. To this end, we adapted a symbolic regression method, coined the feature engineering automation tool (FEAT), to train concise and accurate models from high-dimensional electronic health record (EHR) data. We first present an in-depth application of FEAT to classify hypertension, hypertension with unexplained hypokalemia, and apparent treatment-resistant hypertension (aTRH) using EHR data for 1200 subjects receiving longitudinal care in a large healthcare system. FEAT models trained to predict phenotypes adjudicated by chart review had equivalent or higher discriminative performance (p < 0.001) and were at least three times smaller (p < 1 × 10−6) than other potentially interpretable models. For aTRH, FEAT generated a six-feature, highly discriminative (positive predictive value = 0.70, sensitivity = 0.62), and clinically intuitive model. To assess the generalizability of the approach, we tested FEAT on 25 benchmark clinical phenotyping tasks using the MIMIC-III critical care database. Under comparable dimensionality constraints, FEAT’s models exhibited higher area under the receiver-operating curve scores than penalized linear models across tasks (p < 6 × 10−6). In summary, FEAT can train EHR prediction models that are both intuitively interpretable and accurate, which should facilitate safe and effective scaling of ML-triggered CDS to the panoply of potential clinical use cases and healthcare practices.

Pharmacoepidemiologic study of association between apparent treatment resistant hypertension, cardiovascular disease and interaction effect by sex and age

A limited number of studies have been conducted to test the magnitudes of the association between apparent treatment resistant hypertension (aTRH) and risk of cardiovascular disease (CVD). To investigate the association between aTRH and risk of CVD and examine whether sex and age modify this association. We applied an observational analysis study design using data from the United States Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). ALLHAT recruited participants (n = 25516) from 625 primary care settings throughout the United States, Canada, Puerto Rico, and United States Virgin Islands, aged 55 and older with hypertension and at least one additional risk factor for heart disease. aTRH was assessed from the year 2 visit. CVD event was defined as one of the following from the year 2 follow-up visit: Fatal or non-fatal myocardial infarction, coronary revascularization, angina, stroke, heart failure, or peripheral artery disease. Cox proportional hazards regression was used to examine the effect of aTRH on CVD risk. Potential modifications of sex and age on this association were examined on the multiplicative scale by interaction term and additive scale by joint effects and relative excess risk for interaction. Of the total study participants (n = 25516), 5030 experienced a CVD event during a mean of 4.7 years follow-up. aTRH was associated with a 30% increase in risk of CVD compared to non-aTRH [hazards ratio (HR) = 1.3, 95%CI: 1.19-1.42]. Sex and age modified this relationship on both multiplicative and additive scales independently. Stratified by sex, aTRH was associated with a 64% increase in risk of CVD (HR = 1.64, 95%CI: 1.43-1.88) in women, and a 13% increase in risk of CVD (HR = 1.13, 95%CI: 1.01-1.27) in men. Stratified by age, aTRH had a stronger impact on the risk of CVD in participants aged < 65 (HR = 1.53, 95%CI: 1.32-1.77) than it did in those aged ≥ 65 (HR = 1.18, 95%CI: 1.05-1.32). Significant two-way interactions of sex and aTRH, and age and aTRH on risk of CVD were observed (P < 0.05). The observed joint effect of aTRH and ages ≥ 65 years (HR = 1.85, 95%CI: 1.22-2.48) in males was less than what was expected for both additive and multiplicative models (HR = 4.10, 95%CI: 3.63-4.57 and 4.88, 95%CI: 3.66-6.31), although three-way interaction of sex, age, and aTRH on the risk of CVD and coronary heart disease did not reach a statistical significance (P > 0.05). aTRH was significantly associated with an increased risk of CVD and this association was modified by both sex and age. Further studies are warranted to test these mechanisms.

Hypertension severity, apparent treatment resistant hypertension and hyperuricemia in the REasons for Geographic And Racial Differences in Stroke (REGARDS) study.

Prior studies have identified an association between hypertension and hyperuricemia; however, there has been limited research on the association between hypertension severity and hyperuricemia. We studied 997 Black and white adults with serum urate data from the reasons for geographic and racial differences in stroke (REGARDS) study. Hypertension was defined as SBP ≥ 140 mmHg or DBP ≥ 90 mmHg or self-reported use of antihypertensive medication. Apparent treatment-resistant hypertension (aTRH) was defined as a SBP ≥ 140 mmHg or DBP ≥ 90 mmHg with concurrent use of three classes of antihypertensive medications, or taking four or more classes of antihypertensive medication regardless of BP level. Controlled BP was defined as SBP <140 mmHg and DBP <90 mmHg. Overall 5.9% of participants had aTRH and 36.6% had hyperuricemia, defined as serum urate >7.0 mg/dl for men and >6.0 mg/dl for women. After full multivariable adjustment, the odds ratio (OR) for hyperuricemia associated with hypertension was 1.60 [95% confidence interval (95% CI): 1.06-2.40]. Compared to participants not taking antihypertensive medication, the ORs for hyperuricemia for participants taking one, two and three classes of antihypertensive medication without aTRH were 1.98 (95% CI: 1.23-3.20), 2.08 (95% CI: 1.25-3.43), 4.31 (95% CI: 2.07-8.97), respectively, and 3.96 (95% CI: 1.75-8.96) for aTRH. Compared to participants without hypertension, the odds ratios for hyperuricemia were 1.67 (95% CI: 1.08-2.58) and 1.46 (95% CI: 0.88-2.44) among those with hypertension with and without controlled BP, respectively. Diuretic use was associated with a higher odds of hyperuricemia. This study suggests that individuals taking more classes of antihypertensive medication may benefit from monitoring for hyperuricemia.

Apparent treatment resistant hypertension. The drug could be culprit

Treatment of hypertension to goal should be the goal if its morbi-mortality consequences are to be curtailed. Notwithstanding, this ideal however, sub-optimal control plagues clinical practice largely due to non-adherence, adverse side-effects, and outright intolerance. When there is apparent treatment failure, the tendency is to consider these. If adjudged to be resistant or refractory to treatment, device therapy is contemplated notwithstanding cost implications and its invasive nature. Little attention is paid to the phenomenon of paradoxical hypertension, wherein in the presence of certain antihypertensives, blood pressure actually rises rather than falls. How much of this that occurs in clinical practice is not exactly known, but continuing to add new drug classes or increase doses in such situations will increase cost and possibility of side effects without optimal control. Target organ damages would persist with worse outcomes. The evolving area of pharmacogenomics is showing that for some genetic reasons, certain individuals would respond to certain drugs and not others. This may manifest in the occasional instances of paradoxical rise in blood pressure with the introduction of certain blood pressure drug classes. The authors encountered a few such cases and considered them of interest to other clinicians who manage difficult to treat hypertension. When hypertension treatment is sub-optimal especially rising with new drug introduction, it may be worth switching drugs just in case a paradoxical response to a drug class is responsible for non-response.

Apparent treatment-resistant hypertension associated lifetime cardiovascular risk in a longitudinal national registry.

Apparent treatment-resistant hypertension (aRH), wherein blood pressure elevation requires treatment with multiple medications, is associated with adverse cardiovascular events over the short-term. We sought to evaluate the degree of excess risk associated with aRH across the lifespan. We identified all individuals with hypertension who were prescribed at least one anti-hypertensive medication from the FinnGen Study, a cohort of randomly selected individuals across Finland. We then identified the maximum number of concurrently prescribed anti-hypertensive medication classes prior to age 55 and classified those co-prescribed ≥4 anti-hypertensive medication classes as aRH. Using multivariable adjusted Cox proportional hazards models, we assessed the association of aRH well as the number of co-prescribed anti-hypertensive classes with cardiorenal outcomes across the lifespan. Among 48 721 hypertensive individuals, 5715 (11.7%) met the aRH criteria. Compared to those prescribed only one anti-hypertensive medication class, the lifetime risk of renal failure increased with the addition of each additional medication class, beginning with the second, while the risk of heart failure and ischaemic stroke increased after addition of the third drug class. Similarly, those with aRH suffered increased risk of renal failure (hazard ratio 2.30, 95% CI 2.00-2.65), intracranial haemorrhage (1.50, 1.08-2.05), heart failure (1.40, 1.24-1.63) cardiac death (1.79, 1.45-2.21), and all-cause death (1.76, 1.52-2.04). Among individuals with hypertension, aRH that develops prior to mid-life is associated with substantially elevated cardiorenal disease risk across the lifespan.

Abstract 27: Genetic Risk of Blood Pressure on Antihypertensive Efficacy and Apparent Treatment Resistant Hypertension in Participants of the Genetics of Hypertension Associated Treatments (GenHAT) Study

Background: Polygenic risk scores (PRS) have shown promise in complementing existing clinical risk factors and improving early diagnosis of cardiovascular disease. Recently, several studies have developed PRS for blood pressure traits; however, few have examined to what extent these PRS predict antihypertensive (AHT) efficacy. Hypothesis: We hypothesize that applying a systolic blood pressure (SBP) PRS developed and trained in multi-ancestral observational studies will predict response to chlorthalidone (CHL), as well as non-response to AHT treatment (apparent treatment resistant hypertension, aTRH), among African Americans (AA). Methods: We applied an optimized multi-ancestry PRS generated in a pooled Trans-Omics for Precision Medicine (TOPMed) cohort of &gt;21,000 adults for SBP (PRS SBP ) to 4,297 AA Genetics of Hypertension Associated Treatment (GenHAT) participants randomized to CHL as part of the Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) with genome wide association study data. We then used linear regression to test the association of PRS SBP quintiles with CHL response (6 month BP - baseline BP) adjusting for age, sex, genetic ancestry, and baseline SBP. For the analysis of aTRH, cases were defined as individuals (a) treated with 3 different AHT classes, with average BP ≥140/90 mmHg at year 3 follow-up or (b) ≥4 AHT classes regardless of BP (cases, n=286). Treated controls were defined as individuals with BP &lt;140/90 mmHg and on trial drug monotherapy at year 3 (n=2,391). Logistic regression models adjusting for age, sex, and genetic ancestry were used to calculate the odds ratio for aTRH comparing the highest and lowest quintile (Q5 and Q1, respectively). Results: The PRS SBP was associated with reduced SBP response in Q5 (-5.01 [-6.15, -3.87] mmHg) versus Q1 (-8.24 [-9.39, -7.09] mmHg) and Q2 (-7.25 [-8.39, -6.11] mmHg). In regard to aTRH, Q5 was nominally associated with higher odds of aTRH compared to Q1 (1.48 [1.00, 2.20]). Conclusions: We found that a general SBP PRS was associated with BP response in AAs from GenHAT. On average, a greater SBP reduction was found in participants at low genetic risk (Q1 or Q2) compared to the high risk (Q5) taking the same AHT. Similarly, when compared to participants in the bottom 20% of the distribution, those in the top 20% had increased odds of aTRH. Additional work using the PRS SBP in other ancestral populations, as well as developing novel AHT class treatment response PRS, is warranted and in progress to determine whether we can identify individuals who would benefit the most from specific AHT classes.

Abstract 59: Social Determinants of Health and Incident Apparent Treatment Resistant Hypertension in a National Cohort of Black and White US Adults

Background: Identifying social determinants of health (SDOH) associated with incident apparent treatment resistant hypertension (aTRH) may guide interventions to reduce the incidence of aTRH and its associated cardiovascular disease risk. Methods: We analyzed data from 2,769 White and 2,254 Black US adults from the REasons for Geographic and Racial Differences in Stroke study taking antihypertensive medication with controlled blood pressure (BP) at baseline to estimate the association of SDOH with incident aTRH. SDOH were guided by the Healthy People 2030 domains of education, economic stability, social context, neighborhood environment and healthcare access. Incident aTRH was defined as systolic BP ≥140 mm Hg or diastolic BP ≥90 mm Hg, systolic BP ≥130 mm Hg or diastolic BP ≥80 mm Hg for those with diabetes or chronic kidney disease, while taking ≥3 classes of antihypertensive medication or taking ≥4 classes of antihypertensive medication regardless of BP level, at a follow-up visit. Results: Over a median 9.5 years of follow-up, 16.1% of White versus 23.7% of Black adults developed aTRH. After age and sex adjustment, the SDOH associated with incident aTRH (hazard ratio; 95% CI) included having less than a high school education (1.51; 1.22 - 1.87), being a high school graduate (1.30; 1.10 - 1.53), and attending some college (1.29; 1.10 - 1.52) versus college graduate; annual household income &lt;$20,000 (1.83; 1.46 - 2.30), $20,000 to &lt;$35,000 (1.53; 1.23 - 1.90) and $35,000 to &lt;$75,000 (1.24; 1.00 - 1.53) versus ≥$75,000; having no one to care for you if ill (1.29; 1.08 - 1.55); living in a disadvantaged neighborhood in quartiles 1 (1.72; 1.42 - 2.08) and 2 (1.48; 1.22 - 1.80) versus 4, or a high poverty zip code (1.26; 1.09 - 1.47); not having health insurance (1.36; 1.06 - 1.74) and residing in a state with low public health infrastructure (1.17; 1.02 - 1.33). Results stratified by race are presented in the Table. Conclusion: SDOH were associated with transitioning from controlled BP to incident aTRH among White and Black adults.

PS-BPC11-4: LOW SOLUBLE KLOTHO IS ASSOCIATED WITH RESISTANT HYPERTENSION IN CKD: FROM THE KNOW-CKD STUDY

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 genome-wide association study identifies a novel association between SDC3 and apparent treatment-resistant hypertension

BackgroundCompared with patients who require fewer antihypertensive agents, those with apparent treatment-resistant hypertension (aTRH) are at increased risk for cardiovascular and all-cause mortality, independent of blood pressure control. However, the etiopathogenesis of aTRH is still poorly elucidated.MethodsWe performed a genome-wide association study (GWAS) in first cohort including 586 aTRHs and 871 healthy controls. Next, expression quantitative trait locus (eQTL) analysis was used to identify genes that are regulated by single nucleotide polymorphisms (SNPs) derived from the GWAS. Then, we verified the genes obtained from the eQTL analysis in the validation cohort including 65 aTRHs, 96 hypertensives, and 100 healthy controls through gene expression profiling analysis and real-time quantitative polymerase chain reaction (RT-qPCR) assay.ResultsThe GWAS in first cohort revealed four suggestive loci (1p35, 4q13.2-21.1, 5q22-23.2, and 15q11.1-q12) represented by 23 SNPs. The 23 significant SNPs were in or near LAPTM5, SDC3, UGT2A1, FTMT, and NIPA1. eQTL analysis uncovered 14 SNPs in 1p35 locus all had same regulation directions for SDC3 and LAPTM5. The disease susceptible alleles of SNPs in 1p35 locus were associated with lower gene expression for SDC3 and higher gene expression for LAPTM5. The disease susceptible alleles of SNPs in 4q13.2-21.1 were associated with higher gene expression for UGT2B4. GTEx database did not show any statistically significant eQTLs between the SNPs in 5q22-23.2 and 15q11.1-q12 loci and their influenced genes. Then, gene expression profiling analysis in the validation cohort confirmed lower expression of SDC3 in aTRH but no significant differences on LAPTM5 and UGT2B4, when compared with controls and hypertensives, respectively. RT-qPCR assay further verified the lower expression of SDC3 in aTRH.ConclusionsOur study identified a novel association of SDC3 with aTRH, which contributes to the elucidation of its etiopathogenesis and provides a promising therapeutic target.

Abstract 13365: Real World Clinical Outcomes Associated With Controlled versus Uncontrolled Blood Pressure in Patients With Apparent Treatment Resistant Hypertension

AHA estimated 10.3 million US adults with apparent treatment resistant hypertension (aTRH) in 2018; limited data exist regarding clinical outcomes for these patients. This retrospective cohort study assessed risk of major adverse cardiac events (MACE: stroke, myocardial infarction, heart failure hospitalization) and end stage renal disease (ESRD) among aTRH patients, comparing those with controlled blood pressure (CBP; SBP/DBP &lt;130/80 mm Hg) vs uncontrolled blood pressure (UBP; ≥130/80 mm Hg), using linked IQVIA Ambulatory EMR- US and IQVIA PharMetrics® Plus claims data. Patients taking ≥3 antihypertensive (anti-HTN) classes within 30 days (index regimen) between 1/1/2015 and 6/30/2021, having ≥2 BP values post-index regimen (2 nd BP date = index date) with ≥12 months pre-index enrollment (baseline) were included. Unbalanced covariates were adjusted in the multivariable model. Cohorts consisted of 11,427 CBP and 22,333 UBP patients: mean (SD) age 62 (13) vs 60 (12) years, female (48% vs 46%), African-American (8% vs 12%), mean (SD) baseline SBP/DBP 118 (8)/70 (6) vs 141 (14)/82 (9) mm Hg, mean (SD) BMI 32 (8) vs 34 (10) kg/m 2 , respectively. The index regimen consisted of 3, 4, or ≥5 anti-HTN classes in 82% vs 79%, 15% vs 18%, and 2% vs 3% of CBP vs UBP patients, respectively (all p&lt;0.001). Frequently observed baseline comorbidities in CBP vs UBP patients included hyperlipidemia (79% vs 76%), mild to moderate diabetes (43% vs 42%), chronic pulmonary disease (31% vs 25%), and congestive heart failure (27% vs 16%). Mean (SD) follow-up time was 2.7 (2.1) years for both cohorts. Patients with UBP were at 8% and 53% increased risk of developing MACE and ESRD, respectively, MACE risk was mainly driven by a 31% increased risk of stroke (figure). Despite being treated with 3+ anti-HTN classes, 66% of aTRH patients had UBP and demonstrated increased risk of MACE and ESRD compared to CBP patients. Development of future innovative treatment approaches can add value in the management of aTRH.

Phosphate Homeostasis and Apparent Treatment Resistant Hypertension in CKD: The CRIC Study

Phosphate Homeostasis and Apparent Treatment Resistant Hypertension in CKD: The CRIC Study

Prevalence of Apparent Treatment-Resistant Hypertension in Chronic Kidney Disease in Two Large US Health Care Systems.

More intensive BP goals have been recommended for patients with CKD. We estimated the prevalence of apparent treatment-resistant hypertension among patients with CKD according to the 2017 American College of Cardiology/American Heart Association (ACC/AHA; BP goal <130/80 mm Hg) and 2021 Kidney Disease Improving Global Outcomes (KDIGO; systolic BP <120 mm Hg) guidelines in two US health care systems. We included adults with CKD (an eGFR <60 ml/min per 1.73 m2) and treated hypertension from Kaiser Permanente Southern California and the Veterans Health Administration. Using electronic health records, we identified apparent treatment-resistant hypertension on the basis of (1) BP above the goal while prescribed three or more classes of antihypertensive medications or (2) prescribed four or more classes of antihypertensive medications regardless of BP. In a sensitivity analysis, we required diuretic use to be classified as apparent treatment-resistant hypertension. We estimated the prevalence of apparent treatment-resistant hypertension per clinical guideline and by CKD stage. Among 44,543 Kaiser Permanente Southern California and 241,465 Veterans Health Administration patients with CKD and treated hypertension, the prevalence rates of apparent treatment-resistant hypertension were 39% (Kaiser Permanente Southern California) and 35% (Veterans Health Administration) per the 2017 ACC/AHA guideline and 48% (Kaiser Permanente Southern California) and 55% (Veterans Health Administration) per the 2021 KDIGO guideline. By requiring a diuretic as a criterion for apparent treatment-resistant hypertension, the prevalence rates of apparent treatment-resistant hypertension were lowered to 31% (Kaiser Permanente Southern California) and 23% (Veterans Health Administration) per the 2017 ACC/AHA guideline. The prevalence rates of apparent treatment-resistant hypertension were progressively higher at more advanced stages of CKD (34%/33%, 42%/36%, 52%/41%, and 60%/37% for Kaiser Permanente Southern California/Veterans Health Administration eGFR 45-59, 30-44, 15-29, and <15 ml/min per 1.73 m2, respectively) per the 2017 ACC/AHA guideline. Depending on the CKD stage, up to a half of patients with CKD met apparent treatment-resistant hypertension criteria.