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Long-term phase 3 study of esaxerenone as mono or combination therapy with other antihypertensive drugs in patients with essential hypertension.
Rakugi, H, Ito, S, Itoh, H, Okuda, Y, Yamakawa, S
Hypertension research : official journal of the Japanese Society of Hypertension. 2019;(12):1932-1941
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Abstract
This study investigated the long-term antihypertensive effects of esaxerenone, a novel nonsteroidal mineralocorticoid receptor blocker, alone or in combination with a calcium channel blocker (CCB) or a renin-angiotensin system (RAS) inhibitor, in Japanese patients with essential hypertension. Patients were treated with esaxerenone starting at 2.5 mg/day increasing to 5 mg/day if required to achieve blood pressure (BP) targets as a monotherapy or with a CCB or RAS inhibitor. After the first 12 weeks of treatment, an additional antihypertensive agent could be added if required to achieve the target BP; the total treatment period was 28 or 52 weeks. The primary endpoint was a change from baseline in sitting BP. Of the 368 enrolled patients, 245 received monotherapy, and 59 and 64, respectively, took a CCB or RAS inhibitor concurrently. Mean changes from baseline in sitting systolic/diastolic BP (95% confidence intervals) at weeks 12, 28 and 52 were -16.1 (-17.3, -14.9)/-7.7 (-8.4, -6.9), -18.9 (-20.2, -17.7)/-9.9 (-10.7, -9.2), and -23.1 (-25.0, -21.1)/-12.5 (-13.6, -11.3) mmHg, respectively (all P < 0.0001 vs baseline). Similar BP reductions at these weeks were observed between all patient subgroups stratified by age, and the observed decreases in 24-h ambulatory BP were consistent with the efficacy observed in sitting BP. Esaxerenone was also well-tolerated with a rate of hyperkalemia at 5.4% (serum potassium ≥5.5 mEq/L), indicating a good safety profile for treatment over the long-term or in combination with a CCB or RAS inhibitor. In conclusion, esaxerenone may be a promising treatment option for patients with hypertension.
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A data-zone scoring system to assess the generalizability of clinical trial results to individual patients.
Laffin, LJ, Besser, SA, Alenghat, FJ
European journal of preventive cardiology. 2019;(6):569-575
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Abstract
INTRODUCTION Evaluating the applicability of a clinical trial to a specific patient is difficult. A novel framework, the Trial Score, was created to quantify the generalizability of a trial's result based on participants' baseline characteristics and not on the trial's inclusion and exclusion criteria. METHODS For each Systolic Blood Pressure Intervention Trial (SPRINT) participant, the Euclidean distance in six-dimensional space from the theoretical "average" participant was calculated to produce an individual Trial Score that incorporates multiple distinct continuous-variable baseline characteristics. We prospectively defined the "data-rich," "data-limited," and "data-free" zones as Trial Scores < 90th percentile, the 90th-97.5th percentile, and >97.5th percentile, respectively. Trial Scores were then calculated for National Health and Nutrition Examination Survey participants to map data zones of the general population. Individual participant data from the Action to Control Cardiovascular Risk in Diabetes blood pressure trial (ACCORD-BP) was used to test if participants further from the average SPRINT participant behave differently than the overall SPRINT results. RESULTS The National Health and Nutrition Examination Survey cohort and the ACCORD-BP trial demonstrate large percentages of participants in SPRINT's data-free and data-limited zones. Time-to-event rates seen with intensive and standard blood pressure control in SPRINT were the same as ACCORD-BP participants within SPRINT's data-rich zone (hazard ratio 0.97, p = 0.84 and hazard ratio 0.95, p = 0.70). However, these rates were significantly different than those of ACCORD-BP participants outside SPRINT's data-rich zone (hazard ratio 0.64, p < 0.01 and hazard ratio 0.77, p < 0.01). CONCLUSIONS ACCORD-BP participants with SPRINT Trial Scores in the 90th percentile or below have similar event rates to SPRINT participants in both the intensive and standard blood pressure groups. Quantifying the difference between an individual patient and the average clinical trial participant holds promise as a tool to more precisely determine applicability of a specific trial to individual patients.
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Pharmacokinetic Interaction Among Telmisartan, Amlodipine, and Hydrochlorothiazide After a Single Oral Administration in Healthy Male Subjects.
Moon, SJ, Jeon, JY, Yu, KS, Kim, MG
Clinical therapeutics. 2019;(11):2273-2282
Abstract
PURPOSE Hypertension is a major risk factor for cardiovascular diseases, necessitating hypertension control. Antihypertensive drugs are more potent when administered in combinations of 2 or 3 different classes of drugs. One such therapy includes a combination of an angiotensin receptor blocker, a calcium channel blocker, and a diuretic. The objective of this study was to evaluate the pharmacokinetic interaction among telmisartan, amlodipine, and hydrochlorothiazide. METHODS A randomized, open-label, 3-period, 6-sequence, 3-treatment, single-dose crossover study was conducted in healthy male subjects. Subjects were randomly assigned to 1 of 6 sequences and one of the following treatments was administered in each period: treatment A, co-administration of one tablet of telmisartan 80 mg and one tablet of amlodipine 10 mg; treatment B, one tablet of hydrochlorothiazide 25 mg alone; and treatment C, co-administration of all 3 investigational products. Serial blood samples were collected up to 144 hours postdose. Plasma drug concentrations were measured by using LC/MS-MS. Pharmacokinetic parameters, including Cmax and AUC0-last, were determined by using noncompartmental analysis. The geometric least squares mean ratios and associated 90% CIs of log-transformed Cmax and AUC0-last for separate administration or co-administration were calculated to evaluate pharmacokinetic interactions. FINDINGS Twenty-seven subjects completed the study. The geometric least squares mean ratios and 90% CIs of Cmax and AUC0-last were 1.02 (0.85-1.21) and 1.04 (0.97-1.13) for telmisartan; 1.00 (0.95-1.04) and 0.95 (0.91-0.99) for amlodipine; and 0.88 (0.82-0.96) and 0.86 (0.82-0.90) for hydrochlorothiazide, respectively. No serious adverse events were recorded, and all reported adverse events were of mild intensity. IMPLICATIONS The pharmacokinetic parameters of telmisartan, amlodipine, and hydrochlorothiazide when administered separately or co-administered were compared, and all the parameters met the criteria for pharmacokinetic equivalence. Combination therapy of these 3 drugs had no significant impact on the pharmacokinetic parameters of each drug. (ClinicalTrials.gov Identifier: NCT03889145).
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Human monocyte transcriptional profiling identifies IL-18 receptor accessory protein and lactoferrin as novel immune targets in hypertension.
Alexander, MR, Norlander, AE, Elijovich, F, Atreya, RV, Gaye, A, Gnecco, JS, Laffer, CL, Galindo, CL, Madhur, MS
British journal of pharmacology. 2019;(12):2015-2027
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Abstract
BACKGROUND AND PURPOSE Monocytes play a critical role in hypertension. The purpose of our study was to use an unbiased approach to determine whether hypertensive individuals on conventional therapy exhibit an altered monocyte gene expression profile and to perform validation studies of selected genes to identify novel therapeutic targets for hypertension. EXPERIMENTAL APPROACH Next generation RNA sequencing identified differentially expressed genes in a small discovery cohort of normotensive and hypertensive individuals. Several of these genes were further investigated for association with hypertension in multiple validation cohorts using qRT-PCR, regression analysis, phenome-wide association study and case-control analysis of a missense polymorphism. KEY RESULTS We identified 60 genes that were significantly differentially expressed in hypertensive monocytes, many of which are related to IL-1β. Uni- and multivariate regression analyses of the expression of these genes with mean arterial pressure (MAP) revealed four genes that significantly correlated with MAP in normotensive and/or hypertensive individuals. Of these, lactoferrin (LTF), peptidoglycan recognition protein 1 and IL-18 receptor accessory protein (IL18RAP) remained significantly elevated in peripheral monocytes of hypertensive individuals in a separate validation cohort. Interestingly, IL18RAP expression associated with MAP in a cohort of African Americans. Furthermore, homozygosity for a missense single nucleotide polymorphism in LTF that decreases antimicrobial function and increases protein levels (rs1126478) was over-represented in patients with hypertension relative to controls (odds ratio 1.16). CONCLUSIONS AND IMPLICATIONS These data demonstrate that monocytes exhibit enhanced pro-inflammatory gene expression in hypertensive individuals and identify IL18RAP and LTF as potential novel mediators of human hypertension. LINKED ARTICLES This article is part of a themed section on Immune Targets in Hypertension. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.12/issuetoc.
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Hypertension and incident cardiovascular events following ibrutinib initiation.
Dickerson, T, Wiczer, T, Waller, A, Philippon, J, Porter, K, Haddad, D, Guha, A, Rogers, KA, Bhat, S, Byrd, JC, et al
Blood. 2019;(22):1919-1928
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Abstract
Ibrutinib is associated with dramatic efficacy against B-cell malignancies. Yet, it has been linked with potentially limiting cardiotoxicity, including emerging reports of profound hypertension (HTN). The long-term incidence, severity, and impact of HTN development with ibrutinib are unknown. Therefore, in 562 consecutive patients treated with ibrutinib for B-cell malignancies from 2009 through 2016, we assessed the new/incident or worsened HTN (systolic blood pressure [BP] cutoff, 130 mm Hg). Observed incident HTN rates were compared with Framingham-heart-predicted incident HTN rates. We also evaluated the relationship of HTN to the development of other major adverse cardiovascular events (MACEs), including arrhythmia, myocardial infarction, stroke, heart failure, and cardiovascular death. Further, we assessed the effects of different antihypertensive classes on ibrutinib-related HTN. Overall, 78.3% of ibrutinib users developed new or worsened HTN over a median of 30 months. New HTN developed in 71.6% of ibrutinib users, with a time to 50% cumulative incidence of 4.2 months. Among those without preceding HTN, 17.7% developed high-grade HTN (BP >160/100 mm Hg). In multivariate regression, new or worsened HTN was associated with increased MACEs (hazard ratio [HR], 2.17; 95% confidence interval [CI], 1.08-4.38). No single antihypertensive class was associated with prevention or control of ibrutinib-related HTN. However, antihypertensive initiation was associated with a lower risk of a MACE (HR, 0.40; 95% CI, 0.24-0.66). Collectively, these data suggest that ibrutinib is associated with a substantial increase in the incidence and severity of HTN, and that HTN development carries a higher risk of subsequent cardiotoxic events.
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Treatment and Prevention of Hypertensive Disorders During Pregnancy.
Leavitt, K, Običan, S, Yankowitz, J
Clinics in perinatology. 2019;(2):173-185
Abstract
This article reviews the pharmacology of the most commonly used antihypertensive medications during pregnancy; their mechanism of action; and the effects on the mother, the fetus, and lactation. Each class of antihypertensive pharmacologic agents have specific mechanisms of action by which they exert their antihypertensive effect. β-Adrenoreceptor antagonists block these receptors in the peripheral circulation. Calcium channel blockers result in arterial vasodilation. α-Agonists inhibit vasoconstriction. Methyldopa is a centrally acting adrenoreceptor antagonist. Vasodilators have a direct effect on vascular smooth muscle. Diuretics decrease intravascular volume. Medications acting on the angiotensin pathway are avoided during pregnancy because of fetotoxic effects.
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How Low Do We Go (in the Post-SPRINT Era)?
Burgner, A, Lewis, JB
Advances in chronic kidney disease. 2019;(2):110-116
Abstract
Hypertension is frequently both a cause and complication of CKD. The optimal blood pressure target in CKD has been of hot debate over the decades with little data to inform the goals. Here, we review the data from the Systolic Blood Pressure Intervention Trial (SPRINT), Modification of Diet in Renal Disease (MDRD), African American Study of Kidney Disease and Hypertension (AASK), Ramipril Efficacy in Nephropathy-2 (REIN-2), and Action to Control Cardiovascular Risk in Diabetes (ACCORD) trials to use the available evidence to better inform what blood pressure goal should be recommended in patients with CKD and to answer the question "How low should we go?".
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Hypertension in childhood obesity.
Wühl, E
Acta paediatrica (Oslo, Norway : 1992). 2019;(1):37-43
Abstract
AIM: The prevalence of childhood hypertension is rising in parallel with global increases in the prevalence of overweight and obesity. We looked at key papers and documents covering three decades. METHODS This mini review examined a wide range of material published in English, with the main focus on 1993-2018, including clinical trials, meta-analyses, guidelines and data produced by the World Health Organization and the World Obesity Federation. RESULTS The literature showed that body weight and blood pressure are closely correlated and obesity-related hypertension contributes further to the clustering of cardiovascular risk factors in obesity. Because the duration of hypertension affects the risk of end-organ damage, timely diagnosis and initiation of treatment are important. First-line interventions should aim for blood pressure control and weight reduction. However, lifestyle modifications are often not successful with regard to attaining and maintaining long-term blood pressure and weight control, despite a multidisciplinary approach. Antihypertensive treatment is recommended for all hypertensive children with failure of nonpharmacological treatment, diabetes, secondary hypertension, stage 2 hypertension or target organ damage. CONCLUSION We found that obesity-related hypertension was associated with a significantly increased cardiovascular morbidity and mortality, and early diagnosis and treatment for blood pressure control and weight reduction is essential.
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Hypertension Treatment in Diabetes: Focus on Heart Failure Prevention.
Bensimhon, HF, Cavender, MA
Heart failure clinics. 2019;(4):551-563
Abstract
Diabetes is strongly associated with development of cardiovascular disease and poor cardiovascular outcomes. Management of hypertension reduces cardiovascular outcomes among patients with diabetes. Many studies have examined the benefits of various classes of antihypertensives among patients with diabetes. Based on these, the American Diabetes Association has advised that all patients (particularly those with microalbuminuria) be treated first with an angiotensin-converting enzyme inhibitor or an aldosterone receptor blocker followed by a calcium channel blocker or diuretic. Recently, sodium glucose transporter 2 inhibitors have been identified for their benefit in blood pressure control and cardiovascular risk reduction in patients with diabetes.
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Hypertension and Arrhythmias.
Afzal, MR, Savona, S, Mohamed, O, Mohamed-Osman, A, Kalbfleisch, SJ
Heart failure clinics. 2019;(4):543-550
Abstract
Hypertension is the most common cardiovascular risk factor and underlies heart failure, coronary artery disease, stroke, and chronic kidney disease. Hypertensive heart disease can manifest as cardiac arrhythmias. Supraventricular and ventricular arrhythmias may occur in the hypertensive patients. Atrial fibrillation and hypertension contribute to an increased risk of stroke. Some antihypertensive drugs predispose to electrolyte abnormalities, which may result in atrial and ventricular arrhythmias. A multipronged strategy involving appropriate screening, aggressive lifestyle modifications, and optimal pharmacotherapy can result in improved blood pressure control and prevent the onset or delay progression of heart failure, coronary artery disease, and cardiac arrhythmias.