Treatment Of Resistant Hypertension Research Articles

Animal model evaluation of a novel renal denervation system for future laparoscopic treatment of resistant hypertension.

PurposeAlthough percutaneous catheter-based ablation of renal sympathetic nerve fibers has been used in the treatment of patients with resistant hypertension, a recent phase III study did not confirm its efficacy. In this study, we developed a novel laparoscopic renal denervation system and evaluated its safety and initial feasibility using an animal model.Materials and MethodsA novel surgical instrument that uses a smart algorithm with temperature-monitoring feedback was developed. We used 4 male pigs (6 weeks old, weighing approximately 45 kg each) to evaluate the safety and efficacy of the laparoscopic renal denervation system. We performed immunohistochemical staining analysis after renal denervation using various tip temperatures and over various durations through an open approach.ResultsWhen the temperature of the outer wall of the renal artery was maintained at 90℃ for 180 seconds, the artery was completely denervated without damaging its inner layer, as evaluated using Masson's trichrome staining. When the temperature ranged from 70℃ to 90℃ and the duration ranged from 90 to 420 seconds, partial or complete denervation without significant vessel injury was confirmed with anti- growth-associated protein 43 and anti-S100 staining.ConclusionsThis animal study confirmed the safety and feasibility of the novel laparoscopic renal denervation system. A safe and effective protocol was developed with ablation at a constant tissue temperature of 70℃ to 90℃ within 180 seconds. However, further developments are necessary before its clinical use.

Hypertensive Urgency and Emergency in Alcohol Withdrawal: A Literature Review.

To help clinicians recognize that hypertension, hypertensive urgency, and hypertensive emergency can arise in patients detoxifying from alcohol. Diagnostic and treatment implications are reviewed to help clinicians manage blood pressure in these situations. PubMed was searched with no restrictions on publication date or study type in June 2019 using the terms (alcohol withdrawal) AND hypertension. Of 531 studies retrieved, all were reviewed, and articles older than 20 years were excluded. Of the remaining 158 articles, all were reviewed by full-text reading, and 17 were selected based on relevance. Seven UpToDate articles and 2 older papers were also included for relevance. Various other searches were also performed; however, no relevant hits resulted when the following terms were entered: (hypertensive urgency/emergency) AND alcohol withdrawal OR detoxification; (hypertensive urgency/emergency) AND (alcohol withdrawal OR detoxification) AND treatment-resistant hypertension. Hypertension is typically self-limited in alcohol withdrawal syndrome; however, treatment is important to prevent hypertensive urgency or emergency. There is a paucity of data on how best to manage hypertension in patients withdrawing from alcohol, with treatment often individualized. Patients with underlying treatment-resistant hypertension may have more difficult-to-control blood pressure, especially in the first 24 hours of withdrawal. Multiple medications may be used to treat hypertension in the setting of alcohol withdrawal, with selection based on side effect profile and the patient's other comorbidities. In patients for whom there is concern for hypertensive urgency versus emergency, full medical evaluation is indicated to identify any potential end-organ damage.

Efficacy of Electrical Baroreflex Activation Is Independent of Peripheral Chemoreceptor Modulation.

Arterial baroreflex activation through electrical carotid sinus stimulation has been developed for the treatment of resistant hypertension. Previous studies suggested that the peripheral chemoreflex is tonically active in hypertensive patients and may inhibit baroreflex responses. We hypothesized that peripheral chemoreflex activation attenuates baroreflex efficacy evoked by electrical carotid sinus stimulation. We screened 35 patients with an implanted electrical carotid sinus stimulator. Of those, 11 patients with consistent acute depressor response were selected (7 men/4 women, age: 67±8 years, body mass index: 31.6±5.2 kg/m2, 6±2 antihypertensive drug classes). We assessed responses to electrical baroreflex stimulation during normoxia, isocapnic hypoxia (SpO2: 79.0±1.5%), and hyperoxia (40% end-tidal O2 fraction) by measuring heart rate, blood pressure, ventilation, oxygen saturation, end-tidal CO2 and O2 fractions, and muscle sympathetic nerve activity. During normoxia, baroreflex activation reduced systolic blood pressure from 164±27 to 151±25 mm Hg (mean±SD, P<0.001), heart rate from 64±13 to 61±13 bpm (P=0.002), and muscle sympathetic nerve activity from 42±12 to 36±12 bursts/min (P=0.004). Hypoxia increased systolic blood pressure 8±12 mm Hg (P=0.057), heart rate 10±6 bpm (P<0.001), muscle sympathetic nerve activity 7±7 bursts/min (P=0.031), and ventilation 10±7 L/min (P=0.002). However, responses to electrical carotid sinus stimulation did not differ between hypoxic and hyperoxic conditions: systolic blood pressure: -15±7 versus -14±8 mm Hg (P=0.938), heart rate: -2±3 versus -2±2 bpm (P=0.701), and muscle sympathetic nerve activity: -6±4 versus -4±3 bursts/min (P=0.531). We conclude that moderate peripheral chemoreflex activation does not attenuate acute responses to electrical baroreflex activation therapy in patients with resistant hypertension. These patients provided insight into human baroreflex-chemoreflex interactions that could not be gained otherwise.

Severity of Hypertension Mediates the Association of Hyperuricemia With Stroke in the REGARDS Case Cohort Study.

Previous studies do not widely support hyperuricemia as a risk factor for stroke and other cardiovascular diseases. We assessed the relationship between hyperuricemia and ischemic stroke (≈900 cases) using a large data set from the REGARDS study (Reasons for Geographic and Racial Differences in Stroke). We employed a case-cohort design (incident stroke cases and randomly selected cohort participants) and weighted Cox-proportional hazard models to estimate the association of serum urate level ≥6.8 mg/dL (ie, hyperuricemia) and 6.0 to <6.8 mg/dL versus <6.0 mg/dL (reference) with incident stroke. Analyses were stratified by race, gender, and age. Mediation of cardiovascular disease comorbidities on the serum urate-stroke association was tested. Hyperuricemia was associated with stroke (hazard ratio, 1.40 [95% CI, 1.10-1.78]) after adjustment for demographic variables and systolic and diastolic blood pressure. This association was substantially attenuated (hazard ratio, 1.17 [95% CI, 0.90-1.51]) by additional covariate adjustment. In particular, apparent treatment-resistant hypertension (systolic blood pressure ≥140 mm Hg or diastolic blood pressure ≥90 mm Hg on 3 antihypertensive medications or use of ≥4 antihypertensive medications) and the count of antihypertensive medication classes significantly reduced the effect of hyperuricemia on ischemic stroke. Specifically, apparent treatment-resistant hypertension and number of antihypertensive, respectively, mediate 45% and 43% of the association. There was no effect modification in the association between hyperuricemia and stroke by age, race, or gender. We conclude that hyperuricemia may be a risk factor for stroke. The substantial attenuation of this association by apparent treatment-resistant hypertension and number of antihypertensive suggests that severe hypertension may be a mediator.

Clinical characteristics, antihypertensive medication use and blood pressure control among patients with treatment-resistant hypertension: the Survey of PatIents with treatment ResIstant hyperTension study.

We evaluated the characteristics of patients with treatment-resistant hypertension (TRH) and the prevalence of TRH in a large multicountry sample of specialist tertiary centres. The Survey of PatIents with treatment ResIstant hyperTension (SPIRIT) study was a retrospective review of medical records of patients seen at tertiary centres located in Western Europe, Eastern Europe, North America, South America, Australia and Asia. Data on demographics, medical history and medication use were extracted from medical records. Prevalence and incidence of TRH were based upon estimated catchment populations. On thousand, five hundred and fifty-five patients from 76 centres were included, mostly from centres that specialize in hypertension (55%), cardiology (11%) or nephrology (19%). Mean age was 64, 60% were men, 62% were Caucasian, 36% had chronic kidney disease, 41% had diabetes, 12% were smokers and 31% had a previous cardiovascular event. Daytime and night-time ambulatory blood pressure (BP) was the most frequently used measurement for diagnosis (82%). Ninety-five percent of patients were prescribed diuretics, 93% an inhibitor of the renin-angiotensin system, 86% a calcium channel blocker, 74% a beta-blocker and 36% an aldosterone antagonist. The overall estimated mean incidence of TRH was 5.8 per 100 000 per year (ranging between 2.3 and 14.0 across regions) and the corresponding estimated mean prevalence of TRH was 23.9 per 100 000 (ranging between 7.6 and 90.5 across regions). Observed variation likely reflects real differences in patient characteristics and physician management practices across regions and specialities but may also reflect differences in patient selection and errors in estimation of catchment population across participating centres.

Prognostic Importance of Resistant Hypertension in Patients With Type 2 Diabetes: The Rio de Janeiro Type 2 Diabetes Cohort Study.

To evaluate the prognostic importance of resistant hypertension (RHT) for the development of complications in a cohort of individuals with type 2 diabetes. A total of 646 patients had the diagnosis of apparent treatment-resistant hypertension (aRHT) based on mean office blood pressure (BP) levels during the 1st year of follow-up. They were reclassified as white-coat/controlled or true/uncontrolled RHT according to 24-h ambulatory BP monitoring (ABPM), using the traditional BP cutoffs and the new 2017 American College of Cardiology (ACC)/American Heart Association (AHA) criteria. Multivariate Cox analyses examined the associations between RHT diagnoses and the occurrence of microvascular and cardiovascular complications and all-cause and cardiovascular mortality. During a median follow-up of 10 years, 177 patients had a cardiovascular event (145 major ones); 222 patients died (101 from cardiovascular diseases); 200 had a renal event; 156 had a retinopathy event; and 174 patients had a neuropathy event. In relation to non-RHT individuals, aRHT (present in 44.6% and 50% by the traditional and new criteria, respectively) predicted all cardiovascular and mortality outcomes, with hazard ratios (HRs) between 1.64 and 2.16, but none of the microvascular outcomes. True RHT increased the HRs (from 1.81 to 2.25) and additionally predicted renal outcomes. White-coat/controlled RHT implied an increased risk (HRs 1.33-1.86) that was intermediate between non-RHT and true RHT individuals. Classifications using the traditional and the new ACC/AHA criteria were equivalent. In patients with type 2 diabetes, the presence of aRHT implied an increased risk of cardiovascular and mortality outcomes, and classification based on ABPM predicted renal outcomes and improved cardiovascular/mortality risk stratification.

Obstructive Sleep Apnea and Systemic Hypertension: Gut Dysbiosis as the Mediator?

Obstructive sleep apnea (OSA) and systemic hypertension (SH) are common and interrelated diseases. It is estimated that approximately 75% of treatment-resistant hypertension cases have an underlying OSA. Exploration of the gut microbiome is a new advance in medicine that has been linked to many comorbid illnesses, including SH and OSA. Here, we will review the literature in SH and gut dysbiosis, OSA and gut dysbiosis, and whether gut dysbiosis is common in both conditions. We reviewed the National Center for Biotechnology Information database, including PubMed and PubMed Central. We identified a total of 230 articles. The literature search was conducted using the phrase "obstructive sleep apnea and gut dysbiosis." Only original research articles were included. This yielded a total of 12 articles. Most of the research conducted in this field was on animal models, and almost all trials confirmed that intermittent hypoxia models resulted in gut dysbiosis. Gut dysbiosis, however, can cause a state of low-grade inflammation through damage to the gut wall barrier resulting in "leaky gut." Neuroinflammation is a hallmark of the pathophysiology of OSA-induced SH. Gut dysbiosis seems to be an important factor in the pathophysiology of OSA-induced hypertension. Reversing gut dysbiosis at an early stage through prebiotics and probiotics and fecal microbiota transplantation combined with positive airway pressure therapy may open new horizons of treatment to prevent SH. More studies are needed in humans to elicit the effect of positive airway pressure therapy on gut dysbiosis.

Implications of Guideline Updates for the Management of Apparent Treatment Resistant Hypertension in the United States (A NCDR Research to Practice [R2P] Project)

The 2018 resistant hypertension scientific statement offers new treatment recommendations. To determine the implications of these changes, we sought to ascertain the prevalence of apparent treatment resistant hypertension (aTRH) and the therapies used to treat it in an US national ambulatory cardiovascular registry before these recent developments. Using the PINNACLE Registry from 2013 to 2014, we identified all patients receiving treatment for hypertension and then determined the proportion with aTRH as those who met the following criteria over ≥2 consecutive visits: (1) 3 blood pressure medication classes including a diuretic and blood pressure >140/90, OR (2) ≥4 blood pressure medications. Among those with aTRH, we examined past use of therapies now recommended in guidelines including: (1) first-line therapy with an angiotensin-converting enzyme inhibitor or angiotensin-II receptor blocker, calcium channel blocker and a thiazide diuretic, (2) use of chlorthalidone, and (3) use of a mineralocorticoid receptor antagonist (MRA) for those requiring a 4th medication. Of 84,624 patients on treatment for hypertension, 11,147 (13.1%) met criteria for prevalent aTRH. Among these patients: (1) Of those on 3 antihypertensive agents (n = 1,255), 315 (25%) were on the first-line regimen now recommended in guidelines, (2) 520 (6.7%) of the 7,930 patients on thiazides were using chlorthalidone, and (3) 3061 (27%) were using a MRA; another 4,523 (40.6%) were eligible for its addition. In conclusion, our findings of low historic use of therapies now recommended in guidelines suggest opportunities to improve care among patients with aTRH.

1418Adverse effects of spironolactone in long-term treatment of resistant arterial hypertension

Abstract Background Spironolactone is recommended as a fourth line antihypertensive drug by current hypertension guidelines. This drug had relatively few adverse effects in short term clinical trials, but data about their occurrence during long-term treatment of resistant hypertension are scarce. Purpose To evaluate the occurrence and type of adverse effects of spironolactone during long-term treatment and their possible clinical and laboratory predictors. Methods We prospectively followed 274 patients with resistant arterial hypertension who started treatment with spironolactone between September 2007 and December 2016. The duration of spironolactone use, its dose, the incidence of adverse events, blood pressure, and laboratory findings were recorded at baseline and during the last clinical examination. Results Patients were followed for an average of 35 (± 29) months, the mean dose of spironolactone was 27.5 mg/day. Adverse effects occurred in 72 patients (26.3%) and in 61 (84.7%) lead to discontinuation of spironolactone. The most common adverse reactions were gynaecomastia (30.6%), hyperkalaemia (30.6%) and symptomatic hypotension (26.4%). The mean duration of spironolactone treatment before their occurrence was 25 (± 27) months. According to the Kaplan-Meier curve, the median for the incidence of adverse events would be 97 months (91.5–102.5 months), i.e. 50% of patients could be treated with no adverse events for more than 8 years. Adverse events were more common in the elderly (hazard ratio – HR 1.38, P=0.007), patients with higher baseline serum creatinine (HR 1.12, P=0.035) and patients taking angiotensin receptor blockers (HR 1.65, P=0.040). Kaplan-Meier estimate – adverse events Conclusion During long-term treatment of resistant hypertension with spironolactone, more than a quarter of patients experience adverse reactions that usually require discontinuation of spironolactone. Acknowledgement/Funding Supported by the grants of Palacký University in Olomouc Nr. IGA_LF_2016_038 and IGA_LF_2017_029.

The Current Status of Devices for the Treatment of Resistant Hypertension.

Arterial hypertension is associated with increased cardiovascular morbidity and mortality. Although blood pressure-lowering therapies significantly reduce the risk of major cardiovascular events, blood pressure control remains unsatisfactorily low. Several device-based antihypertensive therapies have been investigated in patients with treatment-resistant hypertension and in patients unable or unwilling to adhere to antihypertensive medication. As the field of device-based therapies is subject to constant change, this review aims at providing an up-to-date overview of different device-based approaches for the treatment of hypertension. These approaches target the sympathetic nervous system (renal denervation, baroreflex amplification therapy, baroreflex activation therapy, and carotid body ablation) or alter mechanical arterial properties by creating an iliac arteriovenous fistula. Notably, the use of all of these treatment options is not recommended for the routine treatment of hypertension by current guidelines but should be investigated in the context of controlled clinical studies.

Interpreting stimulated plasma renin and aldosterone to select physiologically individualized therapy for resistant hypertension: importance of the class of stimulating drugs.

In the treatment of resistant hypertension, physiologically individualized therapy based on phenotyping with plasma renin activity (PRA) and plasma aldosterone significantly improves blood pressure control. Patients with a low-renin/low aldosterone (Liddle) phenotype respond best to amiloride, while those with low-renin/high aldosterone respond best to aldosterone antagonists, and those with high renin/high aldosterone (renal phenotype) respond best to angiotensin receptor blockers (ARB). However, it is important to measure PRA in a stimulated condition to distinguish between low levels due to high salt intake, licorice or nonsteroidal inflammatory drugs and low levels due to suppression by excess aldosterone secretion or renal tubular genetic variants causing retention of salt and water (Liddle phenotype). In the past, both diuretics and angiotensin converting inhibitors (ACEi) have been used for this purpose, and it has been assumed that these classes of drugs are equivalent. In this study of 2896 patients with hypertension, we evaluated that assumption. We found important differences among diuretics alone, ACEi/ARB alone, and ACEi/ARB + diuretics, which all stimulated PRA. However, ACEi/ARB lowers plasma aldosterone, and beta blockers lower PRA. Among patients with systolic pressure ≥ 180 mmHg ± diastolic pressure ≥ 100 mmHg stimulated only by diuretics, the phenotypes were 25% Liddle, 38% IA, 8.7% renal, and 28.3% mixed. In choosing physiologically individualized therapy based on PRA and aldosterone, it is important to consider the classes of stimulating drugs. Phenotypes are best distinguished by taking into account the aldosterone/PRA ratio in addition to the levels of PRA and aldosterone.

Copeptin Levels in Patients With Treatment-Resistant Hypertension Before and 6 Months After Renal Denervation.

Copeptin, the C-terminal peptide of provasopressin, is released from the neurohypophysis and reflects the activity of the hormone arginine vasopressin in patients with hypertension. Elevated copeptin levels are associated with increased cardiovascular and all-cause mortality. The aim of this study is to compare copeptin levels in patients with treatment-resistant hypertension (TRH) before and 6 months after renal denervation (RDN). Copeptin was measured in 34 patients with TRH and 30 patients with primary hypertension stage 1 or 2 (HT). In addition, copeptin levels were measured in patients with TRH at 6-month follow-up visit after RDN. RDN was performed by an experienced interventionalist applying at least 4 ablations longitudinally and rotationally within the lengths of each renal artery to cover a full 4-quadrant ablation. In patients with TRH 24-hour ambulatory blood pressure (BP) decreased from 154 ± 15/87 ± 12 mm Hg to 146 ± 13/83 ± 7.9 mm Hg after RDN (systolic: P = 0.001, diastolic: P = 0.034). There was no significant change in copeptin levels in these 34 patients with TRH before vs. 6 months after RDN (median 8.4 [interquartile range 3.6-14] vs. 8.5 [4.5-13] pmol/l, P = 0.334). Patients with TRH had higher copeptin levels (P = 0.024) than patients with HT (24-hour ambulatory BP: 142 ± 11/91 ± 8.3 mm Hg, copeptin: 4.2 [2.8-6.3] pmol/l). Patients with TRH showed 2-fold higher copeptin levels than patients with HT. RDN did not lead to any change of copeptin levels in patients with TRH 6 months after procedure despite significant fall in BP. NCT01318395, NCT01687725.

Renal denervation for the treatment of resistant hypertension in Spain. The Flex-Spyral Registry.

Renal denervation is a percutaneous intervention for the treatment of resistant hypertension. Randomized studies have shown contradictory results on its efficacy. We present the results of a renal denervation registry for the treatment of resistant hypertension in real-life patients in Spain. Multicenter registry of consecutive patients with resistant hypertension treated with renal denervation in Spain between 2009 and 2018. We included 125 patients (mean age, 56 years; 41% female; mean onset of hypertension 14±9 years previously). Office systolic and diastolic blood pressure and ambulatory blood pressure monitoring decreased 6 months after the intervention (166±20/95±16 to 149±22/87±16 mmHg and 151±14/89±12 to 143±15/84±11, both P <.0001). At 12 months, the blood pressure reduction was maintained and the number of antihypertensive drugs decreased from 4.9±1.2 to 4.4±1.5 (P=.0001). There were no significant procedure-related complications. The response rate to denervation at 1 year was 80%, but there were wide differences between centers. In patients with resistant hypertension, treatment with renal denervation was related to a decrease in office blood pressure and, more importantly, in ambulatory blood pressure monitoring, with a significant reduction in pharmacological treatment.

Genome-Wide Association Study of Apparent Treatment-Resistant Hypertension in the CHARGE Consortium: The CHARGE Pharmacogenetics Working Group.

Only a handful of genetic discovery efforts in apparent treatment-resistant hypertension (aTRH) have been described. We conducted a case-control genome-wide association study of aTRH among persons treated for hypertension, using data from 10 cohorts of European ancestry (EA) and 5 cohorts of African ancestry (AA). Cases were treated with 3 different antihypertensive medication classes and had blood pressure (BP) above goal (systolic BP ≥ 140 mm Hg and/or diastolic BP ≥ 90 mm Hg) or 4 or more medication classes regardless of BP control (nEA = 931, nAA = 228). Both a normotensive control group and a treatment-responsive control group were considered in separate analyses. Normotensive controls were untreated (nEA = 14,210, nAA = 2,480) and had systolic BP/diastolic BP < 140/90 mm Hg. Treatment-responsive controls (nEA = 5,266, nAA = 1,817) had BP at goal (<140/90 mm Hg), while treated with one antihypertensive medication class. Individual cohorts used logistic regression with adjustment for age, sex, study site, and principal components for ancestry to examine the association of single-nucleotide polymorphisms with case-control status. Inverse variance-weighted fixed-effects meta-analyses were carried out using METAL. The known hypertension locus, CASZ1, was a top finding among EAs (P = 1.1 × 10-8) and in the race-combined analysis (P = 1.5 × 10-9) using the normotensive control group (rs12046278, odds ratio = 0.71 (95% confidence interval: 0.6-0.8)). Single-nucleotide polymorphisms in this locus were robustly replicated in the Million Veterans Program (MVP) study in consideration of a treatment-responsive control group. There were no statistically significant findings for the discovery analyses including treatment-responsive controls. This genomic discovery effort for aTRH identified CASZ1 as an aTRH risk locus.

Patiromer versus placebo to enable spironolactone use in patients with resistant hypertension and chronic kidney disease (AMBER): a phase 2, randomised, double-blind, placebo-controlled trial

Spironolactone is effective at reducing blood pressure in patients with uncontrolled resistant hypertension. However, the use of spironolactone in patients with chronic kidney disease can be restricted by hyperkalaemia. We evaluated use of the potassium binder patiromer to allow more persistent use of spironolactone in patients with chronic kidney disease and resistant hypertension. In this phase 2 multicentre, randomised, double-blind, placebo-controlled study, we enrolled participants aged 18 years and older with chronic kidney disease (estimated glomerular filtration rate 25 to ≤45 mL/min per 1·73 m2) and uncontrolled resistant hypertension from 62 outpatient centres in ten countries (Bulgaria, Croatia, Georgia, Hungary, Ukraine, France, Germany, South Africa, the UK, and the USA). Patients meeting all eligibility criteria at the final screening visit were stratified by local serum potassium measurement (4·3 to <4·7 mmol/L vs 4·7 to 5·1 mmol/L) and history of diabetes. Participants were randomly assigned (1:1) with an interactive web response system to receive either placebo or patiromer (8·4 g once daily), in addition to open-label spironolactone (starting at 25 mg once daily) and their baseline blood pressure medications. Participants, the study team that administered treatments and measured blood pressure, and the investigators were masked to assigned treatment groups. Dose titrations were permitted after 1 week (patiromer) and 3 weeks (spironolactone). The primary endpoint was the between-group difference at week 12 in the proportion of patients on spironolactone. Efficacy endpoints and safety were assessed in all randomised patients (intention to treat). The study was registered with Clinicaltrials.gov, NCT03071263. Between Feb 13, 2017, and Aug 20, 2018, we screened 574 patients. 295 (51%) of 574 patients met all inclusion criteria and were randomly assigned to spironolactone in addition to double-blind treatment with either placebo (n=148) or patiromer (n=147). At week 12, 98 (66%) of 148 patients in the placebo group and 126 (86%) of 147 patients in the patiromer group remained on spironolactone (between-group difference 19·5%, 95% CI 10·0-29·0; p<0·0001). Adverse events were mostly mild or moderate in severity and occurred in 79 (53%) of 148 patients in the placebo group and 82 (56%) of 147 patients in the patiromer group. In patients with resistant hypertension and chronic kidney disease, patiromer enabled more patients to continue treatment with spironolactone with less hyperkalaemia. Persistent spironolactone enablement in this population of patients has clinical relevance for the treatment of resistant hypertension. Relypsa, a Vifor Pharma Group Company.

New Molecules for Treating Resistant Hypertension: a Clinical Perspective.

To review the findings of trials evaluating pharmacological treatment approaches for hypertension in general, and resistant hypertension (RH) in particular, and propose future research and clinical directions. RH is defined as blood pressure (BP) that remains above target levels despite adherence to at least three antihypertensive medications, including a diuretic. Thus far, clinical trials of pharmacological approaches in RH have focused on older molecules, with spironolactone being demonstrated as the most efficacious fourth-line agent. However, the use of spironolactone in clinical practice is hampered by its side effect profile and the risk of hyperkalaemia in important RH subgroups, such as patients with moderate-severe chronic kidney disease (CKD). Clinical trials of new molecules targeting both well-established and more recently elucidated pathophysiologic mechanisms of hypertension offer a multitude of potential treatment avenues that warrant further evaluation in the context of RH. These include selective mineralocorticoid receptor antagonists (MRAs), aldosterone synthase inhibitors (ASIs), activators of the counterregulatory renin-angiotensin-system (RAS), vaccines, neprilysin inhibitors alone and in combined formulations, natriuretic peptide receptor agonists A (NPRA-A) agonists, vasoactive intestinal peptide (VIP) agonists, centrally acting aminopeptidase A (APA|) inhibitors, antimicrobial suppression of central sympathetic outflow (minocycline), dopamine β-hydroxylase (DβH) inhibitors and Na+/H+ Exchanger 3 (NHE3) inhibitors. There is a paucity of data from trials evaluating newer molecules for the treatment of RH. Emergent novel molecules for non-resistant forms of hypertension heighten the prospects of identifying new, effective and well-tolerated pharmacological approaches to RH. There is a glaring need to undertake RH-focused trials evaluating their efficacy and clinical applicability.

Resistant Hypertension: Questions and Contemporary Answers

The review presents the important problem of resistant hypertension. Its real prevalence is unknown. According to population studies and metaanalyzes of clinical studies, the prevalence of this most severe form of hypertension reaches 12-15% in the general population and 15-18% in clinical cohorts. Over the past decades, an increase in its frequency among patients with hypertension has been noted. Based on the results of large-scale studies, risk factors are detected that allow to assess the risk for the resistance to antihypertensive drugs. Adherence to ongoing antihypertensive therapy is crucial to addressing the issue of hypertension resistance; there are acceptable ways to evaluate it in clinical practice. The review discusses the most common mistakes in the choice of therapy, which can cause resistance to antihypertensive treatment, namely irrational drug combinations, insufficient dosage of the drug, and the use of non-prolonged forms of drugs. The latest recommendations for the diagnosis and treatment of hypertension, including its resistant form, are analyzed. The review contains a rationale based on the results of randomized clinical trials, the choice antihypertensive strategy in this variant of arterial hypertension. The importance of fixed combination antihypertensive drugs, as well as thiazine-like diuretics and amlodipine is stressed. The results of studies demonstrate the rational for the use of antimineralcorticoid drugs, namely spironolactone, for this category of patients. The authors offer an updated algorithm for the diagnosis and treatment of resistant hypertension, based on the sections of the latest clinical recommendations on this problem.

Abstract 106: The Association Between Overnight Rostral Fluid Shift and Sleep Disordered Breathing in Patients With Treatment Resistant Hypertension

Background: Sleep disordered breathing (SDB) is an important modifiable risk factor of treatment resistant hypertension (TRH). Overnight rostral fluid shift from lower extremities is associated with the severity of SDB in patients prone to fluid accumulation (e.g. TRH, heart failure, and end-stage renal disease). However, the association between overnight rostral fluid shift and SDB in Japanese patients with TRH remains unclear. Methods: All patients with TRH underwent polysomnography. Neck circumference (NC) and leg fluid volume (LFV) were measured by tape measure and bioelectrical impedance just before sleep and after waking up. Correlation between apnea-hypopnea index (AHI), overnight change of LFV (ΔLFV), and overnight change of NC (ΔNC) were assessed by regression analysis. Results: Total 11 patients were examined (7 men [63%], Age: 62.6±13.4 years, body mass index: 28.1±4.2 kg/m 2 ). Mean AHI, ΔLFV, and ΔNC were 30.5±24.1/h. -267.5±156.1 ml, and 0.4±0.5 cm, respectively. ΔLFV correlated significantly with ΔNC (r=-0.63; P=0.04). Besides, both ΔLFV and ΔNC were significantly associated AHI respectively (ΔLFV, r=-0.92; P&lt;0.01, ΔNC, r=0.67; P=0.02). In the stepwise regression analysis including estimated glomerular filtration rate, B-type natriuretic peptide along with ΔNC and ΔLFV, onlyΔLFV was the significant independent correlate with AHI, Conclusion: In Japanese patients with TRH, overnight rostral fluid shift contributes to the worsening of SDB, in association with the increase in NC.

Abstract P2067: Trends in Ambulatory and Home Blood Pressure Monitoring Use for Confirmation of Hypertension or Resistant Hypertension Among the Commercially-Insured in the U.S., 2008-2017

Objectives: Out-of-office BP measurement, including ambulatory and home BP monitoring (ABPM, HBPM, respectively) are considered the gold standard for hypertension and treatment-resistant hypertension (TRH) confirmation, but their real-world use is not well-studied. We examined recent trends in submitted claims for ABPM and HBPM among commercially-insured U.S. adults with suspected hypertension or TRH. Methods: Using Truven commercial claims data (2008–2017), we identified adults (age ≥18 years) with hypertension, and ≥1 antihypertensive medication fill. We evaluated CPT codes for claims submitted for ABPM and HBPM from 6 months before to 1 month after initial antihypertensive drug use (incident treated hypertension [ITH] cohort) or the first occurrence of overlapping use of ≥4 antihypertensive drugs (incident TRH cohort). We excluded persons without continuous enrollment during the 7-month observation period. Results: Overall, 3,378,645 patients with ITH and 335,200 with incident TRH met inclusion criteria. Of those with ITH, 13,063 (3.9 per 1,000 persons) had ≥1 ABPM or HBPM claim between 6 months prior to and 1 month after initiating treatment. The annual proportion of patients with ≥1 claim ranged from 1.6 to 3.0 per 1,000 for ABPM and 1.3 to 2.1 per 1,000 for HBPM. Among those with incident TRH, 1126 (3.4 per 1,000) had ≥1 ABPM or HBPM claim between 6 months prior to and 1 month after initiating a fourth agent. The annual proportion with ≥1 claim ranged from 1.2 to 2.0 per 1,000 persons for ABPM and 1.1 to 2.9 per 1,000 for HBPM. From 2008 to 2017, use of ABPM modestly increased in the ITH cohort and decreased in the TRH cohort; no time trends were observed with HBPM. Sensitivity analyses suggested that ABPM was used most often for diagnosis confirmation (especially in the ITH cohort), followed by treatment monitoring, whereas HBPM was distributed more evenly. Conclusion: Our findings suggest ABPM is used rarely for guiding treatment initiation decisions among those with incident hypertension or apparent TRH. Claim submissions for HBPM were similarly low, but a significant proportion of HBPM may occur without attempting reimbursement. Future research is needed to understand the factors responsible for low utilization, billing and coverage of these services.

Prevalence of refractory hypertension in the United States from 1999 to 2014.

Refractory hypertension has been defined as uncontrolled blood pressure (at or above 140/90 mmHg) when on five or more classes of antihypertensive medication, inclusive of a diuretic. Because unbiased estimates of the prevalence of refractory hypertension in the United States are lacking, we aim to provide such estimates using data from the National Health and Nutrition Examination Surveys (NHANES). Refractory hypertension was assessed across multiple NHANES cycles using the aforementioned definition. Eight cycles of NHANES surveys (1999-2014) representing 41 552 patients are the subject of this study. Prevalence of refractory hypertension across these surveys was estimated in the drug-treated hypertensive population after adjusting for the complex survey design and standardizing for age. Across all surveys, refractory hypertension prevalence was 0.6% [95% confidence interval (CI) (0.5, 0.7)] amongst drug-treated hypertensive adults; 6.2% [95% CI (5.1, 7.6)] of individuals with treatment-resistant hypertension actually had refractory hypertension. Although the prevalence of refractory hypertension ranged from 0.3% [95% CI (0.1, 1.0)] to 0.9% [95% CI (0.6, 1.2)] over the eight cycles considered, there was no significant trend in prevalence over time. Refractory hypertension prevalence amongst those prescribed five or more drugs was 34.5% [95% CI (27.9, 41.9)]. Refractory hypertension was associated with advancing age, lower household income, black race, and also chronic kidney disease, albuminuria, diabetes, prior stroke, and coronary heart disease. We provided the first nationally representative estimate of refractory hypertension prevalence in US adults.