First-line Therapy For Hypertension Research Articles

Targeting Hypertension: A Review on Pathophysiological Factors and Treatment Strategies.

Hypertension is one of the primary causes of cardiovascular diseases and death, with a higher prevalence in low- and middle-income countries. The pathophysiology of hypertension remains complex, with 2% to 5% of patients having underlying renal or adrenal disorders. The rest are referred to as essential hypertension, with derangements in various physiological mechanisms potentially contributing to the development of essential hypertension. Hypertension elevates the risk of cardiovascular disease (CVD) events (coronary heart disease, heart failure, and stroke) and mortality. First-line therapy for hypertension is lifestyle change, which includes weight loss, a balanced diet that includes low salt and high potassium intake, physical exercise, and limitation or elimination of alcohol use. Blood pressure-lowering effects of individual lifestyle components are partially additive, enhancing the efficacy of pharmaceutical treatment. The choice to begin antihypertensive medication should be based on the level of blood pressure and the existence of a high atherosclerotic CVD risk. First-line hypertension treatment includes a thiazide or thiazide-like diuretic, an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker, and a calcium channel blocker. Addressing hypertension will require continued efforts to improve access to diagnosis, treatment, and lifestyle interventions.

ME-2: MR BLOCKERS AS THE POSSIBLE FIRST-LINE THERAPY IN HYPERTENSION

Among 43 million hypertensive patients in Japan, blood pressure levels are controlled below 140/90mmHg in only a quarter of these patients. This fact may be due to poor adherence and inadequate lifestyles as well as “clinical inertia” (“diagnostic inertia” and “treatment inertia”) of health care providers. Primary aldosteronism (PA) is the most common endocrine hypertension and often associated with resistant hypertension. Five to 10% of all people in hypertension and 20% of resistant hypertension is PA. Most importantly, PA presents with higher prevalence of cardiovascular diseases than essential hypertensive patients whose blood pressure levels are controlled to the similar levels. For the case-detection testing, high plasma aldosterone (PAC) to plasma renin activity (PRA) ratio is useful based on the clinical practice guideline of many countries. However, screening of PA is rarely done between 0.7% to 4.2% of hypertensive patients in daily clinical practice. This situation is a sad state of affairs (“diagnostic inertia”), and the screening of PA should be done at least once in all hypertensive patients. For treatment of PA, administration of a mineralocorticoid receptor blocker (MRB) is recommended in patients with bilateral PA as well as ones who do not willing to undergo surgery. It is therefore crucial to administer a MRB as a first-line therapy, although it is not included in the “first-line antihypertensives”. In addition, since the PA screening test is done quantitatively, it may be insufficient to evaluate just “non-PA” when the ratio is lower than the cut-off values. It may be rather crucial to consider the pathogenesis as “borderline aldosteronism” or “mineralocorticoid receptor (MR)-associated hypertension” when the ratio is suboptimal, because a MR antagonist would be a better choice to control hypertension under such circumstances. In diabetes mellitus and chronic kidney disease, MR may be directly overactivated by varied molecular mechanisms. In addition, under the treatment with angiotensin receptor blocker (ARB) or angiotensin converting enzyme inhibitor (ACEi) in patients with diabetes and chronic kidney disease, PAC is suppressed firstly, but re-elevated sometimes over baseline levels (“aldosterone breakthrough”). We therefore presume that combination treatment of a MRB with first-line antihypertensives (ARB/ACEi and calcium channel blocker) may resolve “treatment inertia” of hypertension. Considering the resolution of both “diagnostic and treatment inertia” for hypertension, it is conceivable that MRB should be included in the first-line therapy for hypertension.

Combinatorial Approach of Polymeric Patches and Solid Microneedles for Improved Transdermal Delivery of Valsartan: A Proof-of-Concept Study

Valsartan (VALS) is a first-line therapy for hypertension that belong to the Angiotensin II Receptor Blockers class. VALS is currently administered orally, but it is associated with its low bioavailability. The transdermal route can be an alternative to overcome this problem. However, this route has low permeation caused by the presence of stratum corneum on the skin. The use of permeation enhancers is needed. This study aims to determine the effect of PEG 400 concentration on physical characteristics and release of VALS from transdermal patch preparations and determine the effect of solid microneedles on VALS permeation. The transdermal patch formula was made using HPMC as a base and PEG 400 as a permeation enhancer with various concentrations. The patches were evaluated for their physical appearance, weight uniformity, thickness, moisture content, folding endurance, drug content, in vitro drug release, in vitro drug permeation, and ex vivo permeation test. The results showed that all formulations showed good characteristics for transdermal administration, and the use of PEG 400 could increase the permeation of VALS. Importantly, when combined with solid microneedles, the permeation of VALS was significantly improved. To conclude, the combination of VALS patch transdermal and MNs can increase the amount of VALS permeated.

MH-76, a Novel Non-Quinazoline α1-Adrenoceptor Antagonist, but Not Prazosin Reduces Inflammation and Improves Insulin Signaling in Adipose Tissue of Fructose-Fed Rats

Background: Quinazoline α1-adrenoceptors antagonists have been shown to exert moderately favorable effects on the metabolic profile in hypertensive patients. However, based on AntiHypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) results, they are no longer recommended as a first line therapy of hypertension. Recent studies have shown that quinazoline-based α1-adrenoceptors antagonists (prazosin, doxazosin) induce the apoptosis and necrosis, which may be responsible for ALLHAT outcomes; however, these effects were proven to be independent of α1-adrenoceptor blockade and were associated with the presence of quinazoline moiety. MH-76 (1-[3-(2,6-dimethylphenoxy)propyl]-4-(2-methoxyphenyl)piperazine hydrochloride)) is a non-quinazoline α1-adrenoceptor antagonist which, in fructose-fed rats, exerted antihypertensive effect, and, contrary to prazosin, reduced insulin resistance and abdominal adiposity. In this study we aimed to further investigate and compare the effects of MH-76 and prazosin on inflammation in adipose tissue of fructose-fed rats. Methods: Abdominal adipose tissue was collected from four groups of fructose-fed rats (Control, Fructose, Fructose + MH-76 and Fructose + Prazosin) and subjected to biochemical, histopathological and immunohistochemical studies. Moreover, selected tissue distribution studies were performed. Results: Treatment with MH-76 but not with prazosin improved endothelial integrity, reduced adipose tissue inflammation and infiltration by immune cells, resulting in lowering leptin, MCP-1, IL-6, TNF-α and PAI-1 levels. In adipose tissue from Fructose + MH-76 animals, a higher amount of eosinophils accompanied with higher IL-4 concentration was observed. Treatment with MH-76 but not with prazosin markedly reduced phosphorylation of IRS-1 at Ser307. Conclusion: MH-76 may improve insulin signaling in adipose tissue by reducing the pro-inflammatory cytokine production and inhibiting the inflammatory cells recruitment. In contrast, in adipose tissue from animals treated with prazosin, the inflammatory effect was clearly enhanced.

630 Longer Sleep Duration Reduces the Odds of Hypertension in Children Referred to Nephrology for Elevated Blood Pressure

Abstract Introduction Lifestyle modification is often prescribed as first line-therapy for hypertension in childhood. We aimed to determine if there was an association between sleep duration and hypertension in children referred for evaluation to Nephrology for elevated blood pressure (BP). We hypothesized that, longer sleep duration would be associated with a reduced likelihood of a hypertension diagnosis. Methods Medical record data were retrospectively extracted from patients referred to the Children’s Hospital of Philadelphia’s pediatric nephrology clinic for the evaluation of elevated BP, without a prior hypertension diagnosis. Ambulatory blood pressure monitoring (ABPM) data collected between December 2015 to December 2018 were extracted. Hypertension was defined by ABPM according to American Heart Association recommendations for pediatric ABPM and we evaluated BP indexed to sex and height. Sleep duration was calculated as the difference between self-reported time of sleep onset and offset. Regression models were adjusted for age, sex, race, body mass index, and weeknight status. Results Our sample included 249 patients, with a mean age of 14.5 (SD: 3.1) years. Of these, 29% were obese and 42% met criteria for hypertension. Mean sleep duration was 9.3 (SD: 1.6) hours per night and duration was shorter with increasing age in years (β=-0.11, 95% CI: -0.18, -0.05) and on week vs. weekend nights (β=-0.62, 95% CI: -1.05, -0.24). Each additional hour of sleep was associated with lower daytime systolic BP Index Z-score (β=-0.12, 95% CI: -0.20, -0.05), lower daytime diastolic BP Index Z-score (β=-0.11, 95% CI: -0.19, -0.03) and 19% reduced odds of daytime hypertension (OR=0.81, 95% CI: 0.67, 0.98). Each additional hour of earlier timing of sleep onset was associated with lower daytime systolic BP Index Z-score (β=-0.10, 95% CI: -0.19, -0.01), lower daytime diastolic BP Index Z-score (β=-0.16, 95% CI -0.25, -0.06) and 16% reduced odds of daytime hypertension (OR=0.84, 95% CI: 0.68, 1.05). Conclusion In children referred for the evaluation of elevated BP, longer sleep duration and earlier sleep onset were associated with a reduced likelihood of being diagnosed with hypertension. Targeting improvements in sleep should be further investigated as part of first line therapy to treat pediatric hypertension. Support (if any) NIH/NHLBI K01HL123612

Chlorthalidone or Hydrochlorothiazide for Treatment of Hypertension

Chlorthalidone or Hydrochlorothiazide for Treatment of Hypertension

A Validated RP-HPLC Stability Method for the Estimation of Chlorthalidone and Its Process-Related Impurities in an API and Tablet Formulation.

Low-dose thiazide and thiazide-like diuretics are widely used as first-line therapy for hypertension. Chlorthalidone, a monosulfamyl diuretic, is frequently prescribed in cases of hypertension and congestive heart failure. In this research paper, an improved reverse-phase HPLC method was developed for the simultaneous identification and quantitation of pharmacopoeia-listed and in-house process- and degradation-related impurities of chlorthalidone in bulk drug and formulations. Chromatographic separation was carried out on a C8 column (250 × 4.6 mm; ‘5 μm particle size) at a flow rate of 1.4 mL/min with a 220 nm detection wavelength. Mobile phase A consisted of buffer solution (diammonium hydrogen orthophosphate (10 mM, pH 5.5)) and methanol at a 65 : 35 ratio (v/v), and mobile phase B consisted of buffer solution and methanol at a 50 : 50 ratio (v/v). The API and formulation were subjected to stress conditions such as acid, alkali, oxidation, thermal, and photolytic conditions. Validation studies for the in-house process impurities were performed for specificity, limit of detection (LOD), limit of quantitation (LOQ), linearity, precision, accuracy, and robustness. Thus, an improved RP-HPLC method capable of good separation of all known and unknown impurities with acceptable resolution and tailing factor was developed.

Antihypertensive Therapy in Patients Receiving Maintenance Hemodialysis: A Narrative Review of the Available Clinical-Trial Evidence.

Blood pressure (BP)-lowering with the use of antihypertensive drugs appears to protect the cardiovascular (CV) system in hemodialysis patients. However, the optimal treatment algorithm of hypertension remains elusive; extrapolation of clinical-trial evidence from the general population may not be optimal. For this narrative review, we searched the Medline/PubMed database (inception to August 01, 2019) to identify randomized clinical trials evaluating the efficacy of antihypertensive drugs on CV outcomes and mortality in patients on hemodialysis. Randomized trials with angiotensin-converting-enzyme-inhibitors (ACEIs) or angiotensinreceptor- blockers (ARBs) failed to provide consistent cardioprotection. β-blockers may provide a more consistent CV benefit. Although some early clinical trials have shown that mineralocorticoid-receptorantagonists (MRAs) reduce CV mortality, the associated risk of hyperkalemia raises important safety concerns on the use of MRAs as add-on therapy. Our first-line therapy of hypertension in hemodialysis is the assessment and management of dry-weight and optimization of dialysis prescription. Based on the available clinical-trial evidence, we prescribe atenolol 3 times/week after dialysis as the first-line pharmacological option of hypertension to our patients without specific indications for other agents. Long-acting dihydropyridines and ACEIs/ARBs are our second-line and third-line choices, respectively. We avoid using MRAs and await results from ongoing trials testing their safety and efficacy. In patients receiving maintenance hemodialysis, randomized trials are clearly warranted in order to define BP targets and the comparative effectiveness of different antihypertensive drugs.

Managing hypertension in patients with heart failure: an ongoing quandary.

Hypertension (HTN) is one of the strongest risk factors for heart failure and is prevalent in up to 91% of patients with newly diagnosed heart failure. This article offers a practical approach to HTN in patients with heart failure. To date, no randomized trials comparing specific antihypertensive regimens have been conducted in the heart failure population. Management of heart failure with reduced ejection fraction patients with elevated blood pressure (BP) should include guideline-directed medical therapy [angiotensin-converting-enzyme inhibitors (ACEis), aldosterone receptor blockers, AT1 neprilysin-inhibitors, beta blockers and aldosterone blockers] titrated to maximal tolerated doses regardless of BP. Despite the lack of survival benefit current available data suggest the use of ACEis, aldosterone receptor blockers as first-line therapy for HTN in patients with heart failure with preserved ejection fraction. Management of HTN in heart failure patients should be based on left ventricular function. Recent findings suggest that AT1 neprilysin-inhibitors offer better BP control when compared with ACEi, or aldosterone receptor blockers and therefore should be used as first-line therapy in hypertensive patients with heart failure with reduced ejection fraction. Their role as antihypertensive agents in heart failure with preserved ejection fraction seems promising but remains under investigation.

Thiazide-associated hyponatremia attenuates the fracture-protective effect of thiazide: A population-based study.

BackgroundThiazide, a first-line therapy for hypertension, lowers blood pressure, increases bone mineral density, and reduces the risk of fractures. However, hyponatremia, an adverse effect of thiazide, is associated with increased risk of osteoporosis and fractures. It is currently unclear whether thiazide-associated hyponatremia (TAH) outweighs the protective effects of thiazide.MethodsUsing data from Taiwan’s National Health Insurance Research Database, we identified patients who were prescribed thiazide between 1998 and 2010. Those diagnosed with hyponatremia within three years after initiation of thiazide were selected for the TAH group. Thiazide users without hyponatremia were selected for the control group. The association between TAH and fracture risk was further evaluated using multivariable Cox regression models adjusted for comorbidities and medications. Subjects were followed up from the index date until the appearance of a fracture, death, or the end of a 3-year period.ResultsA total of 1212 patients were included in the TAH group, matched with 4848 patients in the control group. The incidence rate of fracture was higher in the TAH group than in the control group (31.4 versus 20.6 per 1000 person-years). TAH was associated with a higher risk of total fractures (adjusted hazard ratio [aHR]: 1.47, 95% confidence interval [CI] = 1.15–1.88), vertebra fractures (aHR: 1.84, 95% CI = 1.12–3.01), and hip fractures (aHR: 1.66, 95% CI = 1.12–2.46) after controlling for comorbidities and other medications.ConclusionsThiazide users with hyponatremia have a higher risk of fracture than thiazide users without hyponatremia. The fracture-protective effect of thiazide is attenuated by TAH.

Clinical efficacy of African traditional medicines in hypertension: A randomized controlled trial with Combretum micranthum and Hibiscus sabdariffa.

Medicinal plants are widely used as a first-line therapy for hypertension, often without comparative clinical data. A prospective, randomized controlled trial was conducted to assess efficacy of Combretum micranthum (kinkeliba) and Hibiscus sabdariffa (bissap), in the galenic form of capsules of plant powder, on blood pressure in adult patients with non-complicated hypertension ( > 140/90 mm Hg). One hundred and twenty five patients were randomly allocated into group 1 (kinkeliba leaves 190 mg × 2/day), or group 2 (bissap calyx 320 mg × 2/day), or group 3 (ramipril 5 mg /day) during four consecutive weeks. Blood and urinary samples were collected on day 0 and 28 while patients' blood pressure was measured weekly. In all three groups SBP and DBP decreased over 3 weeks of treatment (P < 0.001). For SBP, mean decrease was higher with ramipril (-16.7 ± 8.4 mm Hg) than with kinkeliba (-12.2 ± 6.6 mm Hg, P = 0.016) and bissap (-11.2 ± 3.3 mm Hg, P = 0.001). For DBP, mean decrease with ramipril (-6.7 ± 3.6 mm Hg) was more important than with kinkeliba (-5.0 ± 3.0 mm Hg, P = 0.011) but not statistically different to bissap group (-6.0 ± 4.7 mm Hg, P = 0.271). A significant natriuretic effect was observed in the kinkeliba and bissap groups but not in patients under ramipril treatment. At the end of the four weeks, 39% [95% CI: 25.7-54.3] of patients in the ramipril group, 37% [95% CI: 23.6-51.9] of patients in the kinkeliba group and 21% [95% CI: 11.7-35.9] of those taking bissap had normalized their BP.

Management of hypertension in 2017: targets and therapies.

Approximately one-fourth of the adult population is diagnosed with hypertension, which has been associated with increased cardiovascular morbidity and mortality including cardiovascular death, myocardial infarction, heart failure and stroke. Early detection and treatment is key and can lead to a significant reduction in cardiovascular morbidity and mortality. In this review, we discuss the management and treatment strategies in patients with hypertension in the current era. Blood pressure (BP) targets will be reviewed in accordance with the recent literature and current guidelines. There is a controversy about lower BP target in patients with coronary artery disease with some studies showing a J-curve relationship but a recent randomized trial (SPRINT) showing a benefit, albeit with controversy as to how BP was measured in the trial. Nevertheless, lower BP targets come with a price of needing more medication (thus impacting cost and compliance) and increases in medication-related adverse effects. There is a growing recognition that angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, calcium antagonists or thiazide diuretics can be used a first-line therapy for hypertension. Evidence also supports the use of combination drug therapy as opposed to monotherapy for more synergistic effect on lowering of BP, offsetting side effects and for improved adherence to a drug regimen. Overall, we aim to review BP targets and medical therapies for hypertension in the current era, recognizing varying clinical characteristics such as comorbidities and patient-risk profile.

Management of Hypertension in Older People

Systolic hypertension above > 160 mmHg is associated with cardiac, renal and cerebrovascular complications. In older people, treating hypertension offers cardiovascular benefits. Reduced salt intake and weight loss for obese older people improves blood pressure without any risk of adverse drug reactions. Blood pressure reduction is more important than the type of antihypertensive for cardiovascular risk reduction. The recommended drugs to start an older patient with isolated systolic hypertension are thiazides, calcium-channel blockers or angiotensin II receptor blocker. Studies were performed on relatively fit older patients, so benefits may not be generalisable to frail elderly. Alpha-blockers and beta-blockers are not recommended for first line therapy of hypertension but may be considered if there are other indications for their use.

A retrospective case-control study evaluating thiazide-induced hyponatraemia-related hospitalisation among older Singaporeans

Introduction:Thiazide diuretics are recommended as first-line therapy for hypertension in older adults. However, thiazides are also associated with hyponatraemia-related hospitalisations in older patients. This study aims to determine the predictors of hospitalisation due to thiazides usage in older adults.Methods:This is a retrospective matched case-control study. Patients aged ⩾65 admitted due to adverse drug reactions based on International Classification of Diseases, Ninth Revision (ICD9) codes from the period of 1 June to 31 December 2011 in Singapore General Hospital were extracted. Patients with the ICD9 code E944.3 Saluretics causing adverse effects in therapeutic use and who experienced thiazide-induced hyponatraemia were identified. Controls were identified from a pool of patients from outpatient clinics who were prescribed thiazide during the study period. Each case was matched to four controls based on gender and race. Patients’ demographics, length of stay, and cost of hospital admission were obtained.Results:In total, 19 cases with thiazide-induced hyponatraemia were matched with 76 controls. Cases were older than control (78.8±6.1 vs. 75.6±7.0, p=0.052), with the majority being females (84.2%) and Chinese (94.7%). The mean length of stay was 4 (±3) days; the mean cost of stay was SGD 1118 (±898). Serum potassium levels and concurrent use of beta-blockers were identified as unadjusted possible predictors for hospitalisation due to thiazide-induced hyponatraemia.Conclusion:Potential predictors of hospitalisation due to thiazide-induced hyponatraemia include low potassium levels and concurrent use of beta-blockers. Identification of predictors is crucial to guide safe and effective prescribing of thiazides in older patients.

Inibidores da enzima de conversão da angiotensina ou antagonistas dos recetores da angiotensina: evidências na mortalidade e eventos cardiovasculares major em diabéticos hipertensos

Objective: Our aim was to assess the evidence for the effects of angiotensin converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARB) on mortality and major cardiovascular events in individuals with hypertension and diabetes. Data Sources: National Guideline Clearinghouse, Guidelines Finder, Canadian Medical Association Practice Guidelines, Cochrane Library, DARE, Bandolier, MEDLINE, Index of Portuguese Medical Journals and General Directorate of Health databases. Methods: The two authors independently performed a search of meta-analyzes (MA), systematic reviews (SR), randomized clinical trials (RCT) and clinical practice guidelines (CPG), published between 31/08/2009 and 31/08/2014 in Portuguese, Spanish, English and French languages. We used the MeSH terms: Diabetes Mellitus AND Hypertension AND Angiotensin-Converting Enzyme Inhibitors OR Angiotensin Receptor Antagonists. The strength of recommendation taxonomy scale was used for the allocation of levels of evidence (LE) and strength of recommendation (SR). Results: Of the 478 articles found, we included five MA and sixCPG in this report. A Cochrane MA showed that ACE inhibitors significantly decreased mortality from all causes (LE 1) and one MA concluded that this class of medications decreased the risk of myocardial infarction (LE 1). The use of ARB was shown to decrease the risk of stroke in one MA. Another MA showed no significant differences between the two classes of drugs. A recent MA found that ACE inhibitors significantly decreased all-cause mortality, cardiovascular mortality, myocardial infarction, and heart failure (LE 1). In the same MA, ARB decreased the risk of heart failure. Most guidelines recommend ACE inhibitors or ARBs as first line therapy for hypertension in diabetic patients. Conclusions: The effects of ACE inhibitors and ARB on mortality and cardiovascular events appear to be different. We found consistent evidence favoring the use of ACE inhibitors as a first option in preventing morbidity and mortality in this population (SR A).

Primary Aldosteronism: New Answers, New Questions.

There have been 2, and possibly 3, major questions for primary aldosteronism (PA) answered at least in principle over the past 5 years. The first is that of somatic mutations underlying the majority of aldosterone producing adenomas. The second is the extension of our knowledge of the genetics of familial hypertension, and the third the role of renal intercalated cells in sodium homeostasis. New questions for the next 5 years include a single accepted confirmatory/exclusion test; standardisation of assays and cut-offs; alternatives to universal adrenal venous sampling; reclassification of 'low renin hypertension'; recognition of the extent of 'occult' PA; inclusion of low-dose mineralocorticoid receptor antagonist in first-line therapy for hypertension; and finally, possible resolution of the aldosterone/inappropriate sodium status enigma at the heart of the cardiovascular damage in PA.

Effect of selective vagal nerve stimulation on blood pressure, heart rate and respiratory rate in rats under metoprolol medication.

Selective vagal nerve stimulation (sVNS) has been shown to reduce blood pressure without major side effects in rats. This technology might be the key to non-medical antihypertensive treatment in patients with therapy-resistant hypertension. β-blockers are the first-line therapy of hypertension and have in general a bradycardic effect. As VNS itself can also promote bradycardia, it was the aim of this study to investigate the influence of the β1-selective blocker Metoprolol on the effect of sVNS especially with respect to the heart rate. In 10 male Wistar rats, a polyimide multichannel-cuff electrode was placed around the vagal nerve bundle to selectively stimulate the aortic depressor nerve fibers. The stimulation parameters were adapted to the thresholds of individual animals and were in the following ranges: frequency 30-50 Hz, amplitude 0.3-1.8 mA and pulse width 0.3-1.3 ms. Blood pressure responses were detected with a microtip transducer in the carotid artery, and electrocardiography was recorded with s.c. chest electrodes. After IV administration of Metoprolol (2 mg kg(-1) body weight), the animals' mean arterial blood pressure (MAP) and heart rate (HR) decreased significantly. Although the selective electrical stimulation of the baroreceptive fibers reduced MAP and HR, both effects were significantly alleviated by Metoprolol. As a side effect, the rate of stimulation-induced apnea significantly increased after Metoprolol administration. sVNS can lower the MAP under Metoprolol without causing severe bradycardia.

Effects of thiazide-type and thiazide-like diuretics on cardiovascular events and mortality: systematic review and meta-analysis.

Thiazide diuretics are recommended as first-line therapy for hypertension and are among the most commonly prescribed drugs worldwide. According to their molecular structure, thiazide diuretics can be divided in thiazide-type (TT) and thiazide-like (TL) diuretics. TL diuretics have a longer elimination half-life compared with TT diuretics and have been shown to exert additional pharmacological effects, which may differently affect cardiovascular risk. In this meta-analysis, we compared the effects of TT and TL diuretics on cardiovascular events and mortality. Randomized, controlled studies in adult hypertensive patients that compared TT or TL diuretics with placebo or antihypertensive drugs and had ≥1 year follow-up were included. Primary outcome was cardiovascular events; secondary outcomes included coronary events, heart failure, cerebrovascular events, and all-cause mortality. Meta-regression analysis was used to identify confounders and correct for the achieved blood pressure reductions. Twenty-one studies with >480 000 patient-years were included. Outcomes were not affected by heterogeneity in age, sex, and ethnicity among included studies, whereas larger blood pressure reductions were significantly associated with increased risk reductions for all outcomes (P<0.001). Corrected for differences in office blood pressure reductions among trials, TL diuretics resulted in a 12% additional risk reduction for cardiovascular events (P=0.049) and a 21% additional risk reduction for heart failure (P=0.023) when compared with TT diuretics. The incidence of adverse events was comparable among TT, TL diuretics, and other antihypertensive therapy. Our data suggest that the best available evidence seems to favor TL diuretics as the drug of choice when thiazide treatment is considered for hypertension.

Hypertension Treatment for Patients with Advanced Chronic Kidney Disease.

Chronic kidney disease is common and frequently complicated with hypertension. As a major modifiable risk factor for cardiovascular disease in this high risk population, treatment of hypertension in chronic kidney disease is of paramount importance. We review the epidemiology and pathogenesis of hypertension in chronic kidney disease and then update the latest study results for treatment including salt restriction, invasive endovascular procedures, and pharmacologic therapy. Recent trials draw into question the efficacy of renal artery stenting or renal denervation for hypertension in chronic kidney disease, as well as renin-angiotensin-aldosterone system blockade as first line therapy of hypertension in end stage renal disease. Positive trial results reemphasize salt restriction and challenge the prevailing prejudice against the use of thiazide-like diuretics in advanced chronic kidney disease. Lastly, clinical practice guidelines are trending away from recommending tight blood pressure control in chronic kidney disease.

Beta-Blockers Lose Luster for Hypertension Therapy

Beta-Blockers Lose Luster for Hypertension Therapy