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Background and Aims: Whether bedtime versus morning administration of antihypertensive therapy is beneficial on outcomes is controversial. We evaluated the risk of total and cardiovascular mortality in a very large observational cohort of treated hypertensive patients, according to the timing of their usual treatment administration (morning versus evening)., Methods: Vital status and cause of death were obtained from death certificates of 28 406 treated hypertensive patients (mean age 62 years, 53% male individuals), enrolled in the Spanish Ambulatory Blood Pressure Monitoring (ABPM) Registry between 2004 and 2014. Among the 28 406 patients, most (86%) received their medication exclusively in the morning; whilst 13% were treated exclusively in the evening or at bedtime. Follow-up was for a median of 9.7 years and 4345 deaths occurred, of which 1478 were cardiovascular deaths., Results: Using Cox-models adjusted for clinical confounders and 24-h SBP, and compared with patients treated in the morning (reference group), all-cause mortality [hazard ratio 1.01; 95% CI 0.93-1.09) and cardiovascular mortality (hazard ratio 1.04; 95% CI 0.91-1.19) was not significantly different in those receiving evening medication dosing. The results were consistent in all the subgroups of patients analysed., Conclusion: In this very large observational study, morning versus bedtime dosing of antihypertensive medication made no difference to the subsequent risk of all-cause or cardiovascular mortality. These findings are in accordance with results from a recent randomized controlled trial and do not support the hypothesis of a specific beneficial effect of night-time antihypertensive treatment dosing on risk of all-cause or cardiovascular death., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background: The Global SYMPLICITY Registry DEFINE (Denervation Findings in Real World) investigates radiofrequency renal denervation (RDN) in a broad range of patients with hypertension. We evaluated whether the number or type of antihypertensive medications were associated with increased long-term blood pressure (BP) reductions and cardiovascular outcomes following radiofrequency RDN., Methods: Patients underwent radiofrequency RDN and were categorized by baseline number (0-3 and ≥4) and different combinations of medication classes. BP changes were compared between groups through 36 months. Individual and composite major adverse cardiovascular events were analyzed., Results: Of 2746 evaluable patients, 18% were prescribed 0 to 3 and 82% prescribed ≥4 classes. At 36 months, office systolic BP significantly decreased ( P <0.0001) by -19.0±28.3 and -16.2±28.6 mm Hg in the 0 to 3 and ≥4 class groups, respectively. Twenty-four-hour mean systolic BP significantly decreased ( P <0.0001) by -10.7±19.7 and -8.9±20.5 mm Hg, respectively. BP reduction was similar between the medication subgroups. Antihypertensive medication classes decreased from 4.6±1.4 to 4.3±1.5 ( P <0.0001). Most decreased (31%) or had no changes (47%) to the number of medications, while 22% increased. The number of baseline antihypertensive medication classes was inversely related to the change in prescribed classes at 36 months ( P <0.001). Cardiovascular event rates were generally low. More patients in the ≥4 compared with 0 to 3 medication classes had myocardial infarction at 36 months (2.8% versus 0.3%; P =0.009)., Conclusions: Radiofrequency RDN reduced BP safely through 36 months, independent of the number and type of baseline antihypertensive medication classes. More patients decreased than increased their number of medications. Radiofrequency RDN is a safe and effective adjunctive therapy regardless of antihypertensive medication regimen., Registration: URL: https://www., Clinicaltrials: gov; Unique identifier: NCT01534299., Competing Interests: Disclosures F. Mahfoud is supported by Deutsche Gesellschaft für Kardiologie, Deutsche Forschungsgemeinschaft (SFB TRR219), and Deutsche Herzstiftung and has received scientific support and speaker honoraria from Ablative Solutions, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Inari, Medtronic, Merck, ReCor Medical, Servier, and Terumo. G. Mancia has received speaker’s fees from Servier, Sanofi, Medtronic, Menarini, Merck, and Recordati. R.E. Schmieder has received speaker and consulting honoraria from Medtronic, Recor, and Ablative Solutions. Research grants have been given to his institution from Medtronic, Recor, and Ablative Solutions. K. Narkiewicz has received speaker and consulting honoraria from Berlin-Chemie/Menarini, Egis, Idorsia, Gedeon Richter, Krka, Medtronic, Novo Nordisk, Polpharma, Recordati, Sandoz, and Servier. M. Schlaich is supported by the National Health and Medical Research Council Senior Research Fellowship and has received consulting fees or travel and research support from Medtronic, Abbott, Novartis, Servier, Pfizer, and Boehringer Ingelheim. F. Ribichini reports consulting fees and research support from Abbott Vascular, Boston Scientific, Edwards Lifescience, Medtronic, and Volcano-Philips. J. Weil reports support from Medtronic, Recor Medical, Novartis, and AstraZeneca. K. Almerri is a member of the Advisory Committee in the Gulf Cooperation Council and has received speaker and proctor honoraria from Medtronic. F. Sharif has received speaker and consulting fees and research support from Medtronic. L. Lauder receives speaker honoraria from Medtronic and ReCor Medical. M. Wanten and M. Fahy are employees of Medtronic. M. Böhm is supported by the Deutsche Forschungsgemeinschaft (German Research Foundation; TTR 219, project number 322900939) and reports personal fees from Abbott, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Cytokinetics, Medtronic, Novartis, ReCor Medical, Servier, and Vifor during the conduct of the study. The other authors report no conflicts.

Even though it has been more than a decade since renal denervation (RDN) was first used to treat hypertension and an intense effort on researching this therapy has been made, it is still not clear how RDN fits into the antihypertensive arsenal. There is no question that RDN lowers blood pressure (BP), it does so to an extent at best corresponding to one antihypertensive drug. The procedure has an excellent safety record. However, it remains clinically impossible to predict whose BP responds to RDN and whose does not. Long-term efficacy data on BP reduction are still unconvincing despite the recent results in the SPYRAL HTN-ON MED trial; experimental studies indicate that reinnervation is occurring after RDN. Although BP is an acceptable surrogate endpoint, there is complete lack of outcome data with RDN. Clear indications for RDN are lacking although patients with resistant hypertension, those with documented increase in activity of the sympathetic system and perhaps those who desire to take fewest medication may be considered., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Background and Aim: Blood pressure variability (BPV) is recognized as a prognostic contributor in hypertension. We aimed to assess differences in short-term BPV in treated hypertensive patients depending on the number, classes, combinations and individual compounds of the antihypertensive treatment., Methods: We selected 38 188 treated patients from the Spanish Ambulatory BP Monitoring (ABPM) Registry. SBP and DBP standard deviations (SD) from 24-h, daytime and night-time, weighted SD (WSD), and average real variability (ARV) were calculated through ABPM. They were compared (after adjustment for clinical confounders and BP) depending on the number of antihypertensive drugs, antihypertensive drug classes and compounds (in 13 765 patients on monotherapy), or combinations (in 12 716 patients treated with two drugs and 7888 treated with three drugs)., Results: Systolic and diastolic BPV significantly increased in patients treated with multiple drugs with respect to monotherapy. Among drug classes, calcium channel blockers, especially amlodipine, and diuretics were associated with lower systolic BPV, including daytime and night-time SD, WSD and ARV, compared with beta blockers, angiotensin-converting enzyme inhibitors and angiotensin receptor blockers. Likewise, in patients treated with two-drug and three-drug combinations, those which included a calcium channel blocker showed lower BPV in comparison to those without such drug class., Conclusion: Treatment with calcium channel blockers, especially amlodipine, and with diuretics is associated with slight, but significant lower values of short-term BPV in comparison to other major drug classes, both in monotherapy and in combination. These results could be helpful when considering BPV reduction as an additional treatment target., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Resistant hypertension (RH) is a concept that currently goes beyond the classical definition of blood pressure ≥140/90 mmHg in subjects receiving three or more drugs of different classes at maximally tolerated doses. Here, we review the clinical relevance of RH and the different types of RH-associated phenotypes, namely refractory hypertension, controlled resistant hypertension, and masked uncontrolled hypertension. We also discuss current drug strategies and future treatments for these high-risk phenotypes., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2019. For permissions, please email: journals.permissions@oup.com.)

Patients with coronary heart disease (CHD) can be particularly susceptible to the adverse effects of excessive blood pressure (BP) lowering by antihypertensive treatment. The identification of hypotension is thus especially important. This study estimated the prevalence of hypotension among CHD-treated hypertensive patients undergoing ambulatory blood pressure monitoring (ABPM) in routine clinical practice. We performed a cross-sectional study with 2892 CHD-treated hypertensive patients from the Spanish ABPM Registry. Based on previous studies, hypotension was defined as systolic/diastolic BP < 120 and/or 70 mmHg according to office measurements, <115 and/or 65 mmHg according to daytime ABPM, <100 and/or 50 mmHg according to nighttime ABPM, and <110 and/or 60 mmHg according to 24 h ABPM. The participants' mean age was 67.1 years (69.8% men). A total of 19.6% of the patients had office hypotension, 26.5% had daytime hypotension, 9.0% had nighttime hypotension, and 16.1% had 24-hr ABPM hypotension. Low diastolic BP values were responsible for most cases of hypotension. Fifty-eight percent of the cases of hypotension detected by daytime ABPM did not correspond to hypotension according to office BP. The variables independently associated with daytime ambulatory systolic/diastolic hypotension and diastolic hypotension (the latter being the most frequent type of ambulatory hypotension) were age, female sex, and the number of antihypertensive medications. In conclusion, in a large ABPM registry, one out of every four CHD-treated hypertensive patients was potentially at risk because of hypotension according to daytime ABPM, and more than half of them were not identified if office BP was relied on alone. We suggest that ABPM should be performed in these patients.

: The issue of a potential danger of antihypertensive drugs related to cancer susceptibility is currently generating a major debate in the scientific community, concerns in the public and emphasized interest from the media. The present article is a thorough review of what is known on the various classes of antihypertensive drugs concerning the risk of developing different neoplasms and about the suggested pathophysiological mechanisms, whenever available. The main limitations of evidence derived from studies currently available in this setting are also discussed, high-lightening the need for newly developed approaches to generate more accurate recommendations and informed advice for physicians.

Since the association of microalbuminuria (MAU) with cardiovascular (CV) risk was described, a huge number of reports have emerged. MAU is a specific integrated marker of CV risk and targets organ damage in patients with hypertension, chronic kidney disease (CKD), and diabetes and its recognition is important for identifying patients at a high or very high global CV risk. The gold standard for diagnosis is albumin measured in 24-hour urine collection (normal values of less than 30 mg/day, MAU of 30 to 300 mg/day, macroalbuminuria of more than 300 mg/day) or, more practically, the determination of urinary albumin-to-creatinine ratio in a urine morning sample (30 to 300 mg/g). MAU screening is mandatory in individuals at risk of developing or presenting elevated global CV risk. Evidence has shown that intensive treatment could turn MAU into normoalbuminuria. Intensive treatment with the administration of an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker, in combination with other anti-hypertensive drugs and drugs covering other aspects of CV risk, such as mineralocorticoid receptor antagonists, new anti-diabetic drugs, and statins, can diminish the risk accompanying albuminuria in hypertensive patients with or without CKD and diabetes., Competing Interests: No competing interests were disclosed.No competing interests were disclosed.Competing interests: Peter Rossing has received honoraria to his institution from services for AstraZeneca, Bayer, Boehringer Ingelheim, Novo Nordisk, MSD, and Eli Lilly., (Copyright: © 2019 Márquez DF et al.)

United States and European guidelines have recommended new treatment goals for office blood pressure (BP). We examined 9784 hypertensives of the Spanish Ambulatory BP Monitoring (ABPM) registry with office BP treated to the prior goal (<140/90 mm Hg); and evaluated the frequency and all-cause mortality of 4 BP strata depending on whether or not they attained more conservative or new office BP goal (130-139/80-89 and <130/80 mm Hg, respectively) and whether or not BP was controlled according to ABPM criteria in the European and US guidelines (24-hour ambulatory BP <130/80 and <125/75 mm Hg, respectively). Whether achieving or not the new office BP goal, the total-mortality risk during a 5-year follow-up was only significantly higher than the reference (normal office BP and ABPM) when 24-hour ambulatory BP was above goal (hazard ratio from multivariable Cox models was in the range of 2.4-2.9; P<0.001). The frequency of patients achieving the new office BP goal was 34.4%, and the frequencies of those not achieving the ABPM goal were 31.6% and 53.7% using the 130/80 or the 125/75 ABPM goal, respectively. Mean office systolic BP was 129 mm Hg for patients not achieving the ABPM goal. In hypertensive patients controlled under prior office BP goal, the frequency of those achieving new office BP goal <130/80 was high, suggesting this goal can be attained. In addition, patients had a higher mortality risk only when ABPM was above goal despite having mean office systolic BP under control, a condition that was also common.

Background and Aim: Treatment-resistant hypertension (TRH) is associated with particular clinical features, nonadherence, and suboptimal treatment. We assessed possible associations of antihypertensive drug classes, specific agents inside each class, and types of combinations, with the presence of non-TRH vs. TRH, and with controlled vs. uncontrolled TRH., Methods: Comparisons were done in 14 264 patients treated with three drugs (non-TRH: 2988; TRH: 11 276) and in 6974 treated with at least four drugs (controlled TRH: 1383; uncontrolled TRH: 5591). Associations were adjusted for age, sex, and previous cardiovascular event., Results: In both groups of patients treated with three or with at least four drugs, aldosterone antagonists among drug classes [adjusted odds ratio (OR): 1.82 and 1.41, respectively], and ramipril (OR: 1.28 and 1.30), olmesartan (OR: 1.31 and 1.37), and amlodipine (OR: 1.11 and 1.41) inside each class were significantly associated with blood pressure control (non-TRH or controlled TRH). In patients treated with three drugs, non-TRH was also associated with the use of chlorthalidone (OR: 1.50) and bisoprolol (OR: 1.19), whereas in patients treated with at least four drugs, controlled TRH was significantly associated with the triple combination of a renin-angiotensin system blocker, a calcium channel blocker, and a diuretic (OR: 1.17)., Conclusion: The use of aldosterone antagonists is associated with blood pressure control in patients treated with three or more drugs. Similar results are observed with specific agents inside each class, being ramipril, olmesartan, chlorthalidone, amlodipine, and bisoprolol those exhibiting significant results. An increased use of these drugs might probably reduce the burden of TRH.

Introduction: Hypertension and diabetes are two of the most important modifiable risk factors for cardiovascular and renal disease. The majority of patients with diabetes also have high blood pressure (BP) and the presence of hypertension in these patients dramatically increases cardiovascular and renal risk. Areas covered: This article will discuss chemical therapies for hypertension in patients with diabetes, based on currently available evidence on the effects of antihypertensive treatment on metabolic profile and renal endpoints that are the factors mostly influencing drug choice. Expert opinion: Several lines of evidence suggest that angiotensin-converting-enzyme-inhibitors (ACEIs), angiotensin-receptor-blockers (ARBs) and calcium-channel-blockers (CCBs) have beneficial or neutral effects on carbohydrate metabolism, whereas old β-blockers and thiazide diuretics have not. Renal outcome trials clearly suggest that in proteinuric diabetic CKD ACEIs and ARBs reduce the rate of disease progression. Thus, an ACEI or an ARB, if tolerated, should be the first choice in diabetic individuals, followed by CCBs, vasodilating β-blockers and diuretics, depending on the individual patient characteristics. Recent studies suggest that the novel antidiabetic class of sodium-glucose co-transporter 2 inhibitors may offer a small reduction in BP together with important decrease in incidence of cardiovascular and renal events in patients with type 2 diabetes.

Introduction: Voltage-gated Ca 2+ channels are the primary route of Ca 2+ entry in vascular smooth muscle cells, playing a key role in the regulation of arterial tone and blood pressure. Since the 60´s, L-type Ca 2+ channel blockers (CCBs) have been widely used for the treatment of hypertension. Areas covered: T-type Ca 2+ channels regulate vascular tone in small-resistance vessels and aldosterone secretion, and N-type channels expressed in sympathetic nerve terminals regulate the release of neurotransmitters. We performed a literature search in MEDLINE, PubMed and ClinicalTrials.gov to identify eligible studies published between January 2001 and March 2016 and reviewed the antihypertensive and renoprotective effects of four CCBs with different pharmacological profiles: azelnidipine (L-type), cilnidipine (L-/N-type) and benidipine and efonidipine (L-/T-type CCBs). Despite similar blood pressure lowering effects, L/N- and L/T-type CCBs, compared with L-type CCBs, decreased intraglomerular pressure, improved renal hemodynamics and provided a greater decrease in proteinuria even in patients already treated with renin-angiotensin-aldosterone inhibitors. Expert opinion: Dual L/N- and L/T-type CCBs may exhibit therapeutic advantages over L-type blockers in hypertensive patients with chronic kidney disease. Because clinical trials supporting these advantages present important biases, further large-scale, long-term comparative trials are needed to confirm that these differences translate into improved clinical outcomes.

We aimed to determine the prevalence of hypotension and factors associated with the presence of this condition in treated hypertensive patients undergoing ambulatory blood pressure monitoring (ABPM). Data were taken from the Spanish ABPM Registry. Office blood pressure (BP) and ABPM were determined using validated devices under standardized conditions. Based on previous studies, hypotension was defined as office systolic/diastolic BP <110 and/or 70 mm Hg, daytime ABPM <105 and/or 65 mm Hg, nighttime ABPM <90 and/or 50 mm Hg, and 24-hour ABPM <100 and/or 60 mm Hg. Multivariable logistic regression was performed to determine the variables associated with the presence of hypotension. A total of 70,997 hypertensive patients on treatment (mean age 61.8 years, 52.5% men) were included in the study. The prevalence of hypotension was 8.2% with office BP, 12.2% with daytime ABPM, 3.9% with nighttime ABPM, and 6.8% with 24-hour ABPM. Low diastolic BP values were responsible for the majority of cases of hypotension. Some 68% of the hypotension cases detected by daytime ABPM did not correspond to hypotension according to office BP. The variables independently and consistently associated with higher likelihood of office, daytime, and 24 hour-based hypotension were age, female gender, history of ischemic heart disease, and body mass index <30 kg/m(2) (P < .05). In conclusion, in this large cohort of patients in usual daily practice, one in eight treated hypertensive patients are at risk of hypotension according to daytime BP. Two-thirds of them are not adequately identified with office BP. ABPM could be especially helpful for identifying ambulatory hypotension, in particular in patients who are older, women, or with previous ischemic heart disease where antihypertensive treatment should be especially individualized and cautious., (Copyright © 2016 American Society of Hypertension. Published by Elsevier Inc. All rights reserved.)

This post hoc analysis from the Sevikar Compared to the Combination of Perindopril Plus Amlodipine on Central Arterial Blood Pressure in Patients With Moderate-to-Severe Hypertension (SEVITENSION) study assessed the efficacy and tolerability of olmesartan (OLM) and amlodipine (AML) in reducing central systolic blood pressure (CSBP) compared with perindopril (PER) plus AML in hypertensive patients with type 2 diabetes. Patients were randomized to OLM/AML 40/10 mg or PER/AML 8/10 mg for 24 weeks. The primary efficacy endpoint was the absolute change in CSBP from baseline to week 24, which was greater with OLM/AML (-13.72±1.14 mm Hg) compared with PER/AML (-10.21±1.11 mm Hg). The between-group difference was -3.51±1.60 mm Hg (95% confidence interval, -6.66 to -0.36 mm Hg) and was within the noninferiority margin (2 mm Hg) as well as the superiority margin (0 mm Hg). In addition, OLM/AML was associated with a higher proportion of patients achieving blood pressure normalization. In hypertensive patients with diabetes, the fixed-dose combination of OLM/AML was superior to PER/AML in reducing CSBP, as well as other secondary endpoints., (© 2015 Wiley Periodicals, Inc.)

Background: Hypertension is a multi-factorial disease of increasing prevalence and a major risk factor for cardiovascular mortality even in the presence of adequate treatment. Progression of cardiovascular disease (CVD) occurs frequently during chronic renin-angiotensin-system (RAS) suppression, and albuminuria is a marker of CV risk. High prevalence of albuminuria in treated hypertensive patients has been demonstrated, but there are no available markers able to predict evolution. The aim of this study was the identification of novel indicators of albuminuria progression measurable in urine of diabetic and non-diabetic patients., Methods: 1143 hypertensive patients under chronic treatment were followed for a minimum period of 3 years. Among them, 105 diabetic and non-diabetic patients were selected and classified in three groups according to albuminuria development during follow-up: (a) patients with persistent normoalbuminuria; (b) patients developing de novo albuminuria; (c) patients with maintained albuminuria. Differential urine analysis was performed by 2D gel electrophoresis (2D-DIGE) and further confirmed by liquid chromatography-mass spectrometry. Non-parametric statistical tests were applied., Results: CD59 glycoprotein and alpha-1 antitrypsin (AAT) resulted already altered in patients developing albuminuria de novo, with a similar response in those with maintained albuminuria. A prospective study in a sub-group of normoalbuminuric patients who were clinically followed up for at least 1 year from urine sampling, revealed CD59 and AAT proteins significantly varied in the urine collected from normoalbuminurics who will negatively progress, serving as predictors of future albuminuria development., Conclusions: CD59 and AAT proteins are significantly altered in hypertensive patients developing albuminuria. Interestingly, CD59 and AAT are able to predict, in normoalbuminuric individuals, who will develop albuminuria in the future, being potential predictors of vascular damage and CV risk. These findings contribute to early identify patients at risk of developing albuminuria even when this classical predictor is still in the normal range, constituting a novel strategy towards a prompt and more efficient therapeutic intervention with better outcome.

There is scarce information regarding ambulatory blood pressure (BP) achieved in daily practice with a wide range of antihypertensive drug combinations. We looked for differences in office and ambulatory BP among major drug combinations of two and three antihypertensive agents from a different drugs class. A total of 17187 patients treated with six types of two-drug combinations and 9724 treated with six types of three-drug combinations from the Spanish ABPM Registry were analyzed. We compared achieved office and ambulatory BP, as well as office (< 140/90 mmHg) and ambulatory (24-hour BP < 130/80; day BP < 135/85, and night BP < 120/70 mmHg) BP control among groups. The combination of renin-angiotensin system (RAS) blockers with diuretics and the triple combination of RAS blockers with diuretics and calcium channel blockers (CCB) were associated with lower values of 24-hour, daytime and nighttime BP, as well as more pronounced nocturnal BP dip. Compared with such combinations (reference), other double combinations had lower rates of ambulatory BP control. Moreover, triple combinations containing alpha blockers also had lower rates of ambulatory BP control. We conclude that even with similar office BP control, differences exist among antihypertensive two-drug and three-drug combinations with respect to ambulatory BP control achieved during treatment, with RAS blockers/diuretics and RAS blockers/CCBs/diuretics obtaining better control rates. This can help physicians choose among drug combinations in order to obtain further ambulatory BP reductions.

The authors investigated the differences in office and ambulatory blood pressure (BP) among major antihypertensive drug classes and among frequently used drugs in each class in 22,617 patients treated with monotherapy from the Spanish ABPM Registry. Using thiazides as the reference group, patients treated with calcium channel blockers have significantly (P<.01) elevated ambulatory BP and less ambulatory control after adjusting for confounders. Inside each class, no significant differences were observed among thiazides or angiotensin receptor blockers. Atenolol and bisoprolol among β-blockers, amlodipine among calcium channel blockers, and lisinopril and enalapril among angiotensin-converting enzyme inhibitors exhibited lower ambulatory BP and better control than other agents. Differences exist among antihypertensive drug classes and among different compounds in each class with respect to ambulatory BP control. This can help physicians choose among drug classes and among compounds in each class if BP reduction is the main objective of treatment., (© 2015 Wiley Periodicals, Inc.)

Neprilysin is a neutral endopeptidase and its inhibition increases bioavailability of natriuretic peptides, bradykinin, and substance P, resulting in natriuretic, vasodilatatory, and anti-proliferative effects. In concert, these effects are prone to produce a powerful ventricular unloading and antihypertensive response. LCZ696 (Valsartan/sacubitril) is a first-in-class angiotensin II-receptor neprilysin inhibitor. LCZ696 is a novel drug not only for the treatment of heart failure but it is also likely to be a useful antihypertensive drug and may have a preferential effect on systolic pressure. This review discusses (i) the mechanism of action, pharmacokinetics, and pharmacodynamics of this novel drug, (ii) the efficacy, safety, and tolerability of LCZ696 in treatment of hypertension from the available trials, (iii) evidence from other contemporary trials on combined Neprilysin inhibitors, (iv) future trials and areas of research to identify hypertensive patient populations that would most benefit from LCZ696., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2015. For permissions please email: journals.permissions@oup.com.)

Ambulatory blood pressure monitoring (ABPM) accurately classifies blood pressure (BP) status but its impact on the prevalence and control of hypertension is little known. The authors conducted a cross-sectional study in 2012 among 1047 individuals 60 years and older from the follow-up of a population cohort in Spain. Three casual BP measurements and 24-hour ABPM were performed under standardized conditions. Approximately 68.8% patients were hypertensive based on casual BP (≥140/90 mm Hg or current BP medication use) and 62.1% based on 24-hour ABPM (≥130/80 mm Hg or current BP medication use) (P=.009). The proportion of patients with treatment-eligible hypertension who met BP goals increased from 37.4% based on the casual BP target to 54.1% based on the 24-hour BP target (absolute difference, 16.7%; P<.01). These results were consistent across alternative BP thresholds. Therefore, compared with casual BP, 24-hour ABPM led to a reduction in the proportion of older patients recommended for hypertension treatment and a substantial increase in the proportion of those with hypertension control., (© 2015 Wiley Periodicals, Inc.)

Background: The use of antihypertensive medication and hypertension control has significantly increased during recent decades in some developed countries, but the impact of improved drug treatment on blood pressure (BP) control in the population is unknown., Methods and Results: Data were taken from 2 surveys representative of the population aged ≥ 60 years in Spain conducted with the same methodology in 2000 to 2001 and in 2008 to 2010. BP was measured 6×. The first BP reading was discarded, and the average of the remaining 3 to 5 BP readings was taken for analysis. Hypertension prevalence was 68.7% in 2000 to 2001 and 66.0% in 2008 to 2010. Between both time periods there was an improvement in hypertension awareness (63.6%-67.7%), drug treatment among those aware (84.5%-87.5%), and BP control among treated hypertensives (30.3%-42.9%). Overall, BP control among all hypertensives increased from 16.3% to 25.4%. After adjustment for age, sex, education, hypertension duration, smoking, alcohol consumption, body mass index, sedentary behavior, diabetes mellitus, cardiovascular disease, and visits to the physician through logistic regression, ≈ 7% of the improvement in BP control among all hypertensives was explained by higher hypertension awareness, and 36.2% was explained by a higher treatment rate. Among the treated hypertensives, 22.6% of the progress in BP control was because of the increase in the number of BP medications used in each patient., Conclusions: BP control among the older hypertensive population in Spain has improved from 2000 to 2001 to 2008 to 2010 because of a higher treatment rate and more intense antihypertensive drug treatment., (© 2015 American Heart Association, Inc.)

The European Society of Hypertension (ESH)/European Society of Cardiology (ESC) 2013 guidelines for the management of arterial hypertension included simplified blood pressure (BP) targets across patient groups, more balanced discussion on monotherapy vs. combination therapy, as well as reconfirmation of the importance of out-of-office BP measurements. In light of these updates, we wished to review some issues raised and take a fresh look at the role of calcium channel blocker (CCB) therapy; an established antihypertensive class that appears to be a favorable choice in many patients. Relaxed BP targets for high-risk hypertensive patients in the 2013 ESH/ESC guidelines were driven by a lack of commanding evidence for an aggressive approach. However, substantial evidence demonstrates cardiovascular benefits from more intensive BP lowering across patient groups. Individualized treatment of high-risk patients may be prudent until more solid evidence is available. Individual patient profiles and preferences and evidence for preferential therapy benefits should be considered when deciding upon the optimal antihypertensive regimen. CCBs appear to be a positive choice for monotherapy, and in combination with other agent classes, and may provide specific benefits beyond BP lowering. Ambulatory and home BP monitoring have an increasing role in defining the diagnosis and prognosis of hypertension (especially non-sustained); however, their value for comprehensive diagnosis and appropriate treatment selection should be more widely acknowledged. In conclusion, further evidence may be required on BP targets in high-risk patients, and optimal treatment selection based upon individual patient profiles and comprehensive diagnosis using out-of-office BP measurements may improve patient management.

Introduction: Diuretics enhance the renal excretion of Na(+) and water due to a direct action at different tubular sites of the nephron where solute re-absorption occurs., Areas Covered: This paper focuses on the mechanism of action, pharmacodynamics, antihypertensive effects, adverse effects, interactions and contraindications of loop diuretics and potassium-sparing agents (including mineralocorticoid receptor antagonists (MRAs) and epithelial Na(+) channel blockers)., Expert Opinion: Loop diuretics are less effective than thiazide diuretics in lowering blood pressure, so that their major use is in edematous patients with congestive heart failure (HF), cirrhosis with ascites and nephritic edema. MRAs represent a major advance in the treatment of resistant hypertension, primary and secondary hyperaldosteronism and in patients with systolic HF to reduce the risks of hospitalization and of premature death. Potassium-sparing diuretics when coadministered with diuretics (thiazides and loop diuretics) working at more proximal nephron locations reduce the risk of hypokalemia and hypomagnesemia and the risk of cardiac arrhythmias. At the end of the article, the basis for the combination of diuretics with other antihypertensive drugs to achieve blood pressure targets is presented.

Introduction: Thiazides and thiazide-like diuretics inhibit the electroneutral Na(+)-Cl(-) cotransporter located on the apical membrane of the early segment of the distal convoluted tubule. They have been widely prescribed over 60 years in the treatment of hypertension and various edematous states., Areas Covered: Thiazide diuretics reduce blood pressure (BP), although the mechanisms by which they chronically lower BP remain unknown. These drugs present a flat dose-response curve that explains why when prescribed at high doses their use was associated with a wide range of adverse effects, particularly electrolyte changes and metabolic abnormalities that can be minimized at the low doses actually prescribed. This article reviews the clinical pharmacology of thiazide diuretics to provide an insight into the mechanisms involved in their antihypertensive and adverse effects, the determinants of drug response and the possible differences in their pharmacodynamic and pharmacokinetic properties in an attempt to improve their clinical use in the treatment of arterial hypertension., Expert Opinion: At low doses, thiazide diuretics remain as an effective and safe therapeutic alternative in the treatment of hypertension. Additionally, their ability to increase the efficacy of nearly all other classes of antihypertensives makes them a highly versatile therapeutic intervention in the treatment of hypertension.

Although the blood pressure (BP) of many patients can be controlled using standard combinations, treatment of hypertension frequently represents a clinical challenge to the primary care physician. This article will review best practices for managing patients with easy- and difficult-to-treat hypertension, including preferred antihypertensive combinations, optimizing adherence and persistence, recognizing white-coat hypertension, and intensifying therapy for treatment-resistant patients. Each physician must decide based on his or her own level of experience at what point a patient becomes too challenging and would benefit from referral to a hypertension specialist for more intensive management and to complete the exclusion of secondary forms of arterial hypertension. With intensive pharmacotherapy, many patients with difficult-to-treat hypertension can achieve BP control. If it fails, interventional strategies (e.g., renal denervation) are a valid option to get BP controlled., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Despite the high prevalence of hypertension and documented benefits of blood pressure (BP) control, >40% of patients with hypertension are not controlled. A majority of uncontrolled hypertensive patients receive two or more antihypertensive drugs. The current review examined the relationship between antihypertensive combination drug therapy, achievement of goal BP, and cardiovascular (CV) outcomes. Articles were selected from a PubMed search using a prespecified search strategy. Randomized, controlled clinical trials of adult human subjects published in English between January 1991 and January 2013 were included. From 2319 identified articles, 28 met inclusion criteria and contained a total of 226,877 subjects. There were seven placebo-controlled studies and 21 treatment comparator and combination therapy studies. The studies included in this review reported a positive association between the degree of BP lowering, number of medications, and CV outcomes. As combination therapy became available, it was increasingly utilized in clinical trials and enabled an increased proportion of patients to achieve a prespecified BP target. Adverse events with monotherapy and combination therapy were as anticipated for the specific classes of antihypertensive therapy. Although many patients reach BP goal, combination antihypertensive therapy is often needed to reach BP goal. Effective BP lowering has been shown to result in improvements in CV outcomes., (Copyright © 2014 American Society of Hypertension. Published by Elsevier Inc. All rights reserved.)

The renin-angiotensin aldosterone system (RAAS) is central to the pathogenesis of cardiovascular disease. RAAS inhibition can reduce blood pressure, prevent target organ damage in hypertension and diabetes, and improve outcomes in patients with heart failure and/or myocardial infarction. This review presents the history of RAAS inhibition including a summary of key heart failure, myocardial infarction, hypertension and atrial fibrillation trials. Recent developments in RAAS inhibition are discussed including implementation and optimization of current drug therapies. Finally, ongoing clinical trials, opportunities for future trials and issues related to the barriers and approvability of novel RAAS inhibitors are highlighted., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Hypertension is a modifiable risk factor for cardiovascular disease. Lowering blood pressure (BP) reduces cardiovascular risk; yet despite the availability of numerous antihypertensives, the proportion of patients achieving BP control remains low. Treatment guidelines are based on evidence from clinical trials, however this evidence may not be representative of real-world treatment effectiveness. Many studies evaluating antihypertensives continue to rely on office BP measurements that provide a less realistic evaluation of hypertension status than ambulatory measures. New studies are needed with greater consideration on evaluating efficacy for translation into clinical effectiveness. In addition, novel therapies for reducing BP and with a greater capacity to improve BP control are still required. This article discusses some of the challenges of hypertension management and reviews strategies and treatment advances that may pave the way to more effective BP control.

This review discusses the rationale for earlier use of single-pill combinations (SPCs) of antihypertensive drugs, with a focus on telmisartan/amlodipine (T/A) and telmisartan/hydrochlorothiazide (T/H) SPCs. Compared with the respective monotherapies, the once-daily T/A and T/H SPCs have been shown to result in significantly higher blood pressure (BP) reductions, BP goal rates, and response rates in patients at all stages of hypertension. As expected, BP reductions are highest with the highest dose (T80/A10 and T80/H25) SPCs. Subgroup analyses of the telmisartan trials have reported the efficacy of both SPCs to be consistent, regardless of the patients' age, race, and coexisting diabetes, obesity, or renal impairment. In patients with mild-to-moderate hypertension, the T/A combination provides superior 24-hour BP-lowering efficacy compared with either treatment administered as monotherapy. Similarly, the T/H SPC treatment provides superior 24-hour BP-lowering efficacy, especially in the last 6 hours relative to other renin-angiotensin system inhibitor-based SPCs. The T/A SPC is associated with a lower incidence of edema than amlodipine monotherapy, and the T/H SPC with a lower incidence of hypokalemia than hydrochlorothiazide monotherapy. Existing evidence supports the use of the T/A SPC for the treatment of hypertensive patients with prediabetes, diabetes, or metabolic syndrome, due to the metabolic neutrality of both component drugs, and the use of the T/H SPC for those patients with edema or in need of volume reduction.

Background: About half of the global burden of cardiovascular disease has been attributed to high blood pressure (BP). Worldwide, 7·6 million premature deaths (about 13·5% of the global total), 54% of strokes, and 47% of cases of ischemic heart disease were caused by high BP in 2001., Methods and Results: All guidelines agree that pharmacological treatment of patients with hypertension should be initiated as soon as BP rises >140/90 mmHg. Available data support the reduction of BP to values to <140/90 mmHg, but do not favor a reduction to <130/80 mmHg in patients with diabetes or a history of cardiovascular disease because of the absence of evidence obtained in prospective studies., Conclusions: This review updates the controversies and challenges involved in the treatment of patients with established arterial hypertension, such as the progression of high-normal BP to overt hypertension, the choice of appropriate threshold and goal BP levels, the adequate number of drugs to be used since the early stages of hypertension, and which type of combination therapy offers most advantages to the patient., (© 2012 The Authors. European Journal of Clinical Investigation © 2012 Stichting European Society for Clinical Investigation Journal Foundation.)

Background: Patients with grade 2 or 3 hypertension may require high-dose combination therapy to achieve blood pressure (BP) targets in a timely manner., Objectives: This study compared the effectiveness and tolerability of a single-pill combination (SPC) of telmisartan/hydrochlorothiazide 80/25 mg (T80/H25) with T80 monotherapy., Methods: In a Phase IV, multinational, randomized, double-blind, double-dummy, active-controlled, parallel-group trial, 894 patients with mean seated trough cuff systolic BP [SBP] ≥160 mm Hg and diastolic BP [DBP] ≥100 mm Hg were randomly assigned in a 2:1 ratio to receive T40/H12.5 SPC or telmisartan 40 mg monotherapy for 1 week before the dose was uptitrated to T80/H25 SPC or T80, respectively, administered for 6 weeks. The primary efficacy measure was the change from baseline in mean seated cuff trough SBP. Adverse events (AEs) were recorded., Results: A total of 888 patients received treatment (294 and 594 patients in the T80/H25 and T80 groups, respectively) (mean age, 57.0 years; age ≥65 years, 25.7%; male, 53.8%; white, 68.0%); 61 patients prematurely discontinued. Mean baseline SBP/DBP values were 172.3/104.3 mm Hg (T80/H25) and 173.3/104.5 mm Hg (T80). After 7 weeks, SBP was changed by -37.0 and -28.5 mm Hg in the T80/H25 and T80 groups (P < 0.0001); DBP was changed by -18.6 and -15.4 mm Hg respectively (P < 0.0001). These differences were significant after 2 weeks at the higher dosage (P < 0.0001). BP target (SBP/DBP <140/<90 mm Hg) was achieved in 55.5% and 34.7% of patients in the T80/H25 and T80 groups (P < 0.0001). T80/H25 SPC and T80 had a similar frequency of overall AEs (16.0% vs 17.0%). The prevalences of treatment-related AEs with T80/H25 SPC and T80 were low (4.6% and 2.8%), as were the rates of AEs that led to discontinuation (1.0% and 2.8%)., Conclusions: In these patients with grade 2 or 3 hypertension, initial therapy with T80/H25 was associated with a significantly greater reduction in mean seated cuff trough SBP compared with T80 alone, as well as with improved hypertension goal attainment rates. Both treatments appeared to be well tolerated., (Copyright © 2012 Elsevier HS Journals, Inc. All rights reserved.)

Background and Aim: Clinical characteristics of resistant hypertensive patients in comparison to controlled patients have not been fully investigated in large cohorts. The aim of the study was to evaluate clinical differences, target organ damage and ambulatory blood pressure monitoring in resistant hypertensive patients and patients controlled on three or less drugs., Methods: In December 2010, from the Spanish Ambulatory Blood Pressure Monitoring Registry, we identified 14 461 patients fulfilling criteria of resistant hypertension and 13 436 hypertensive patients controlled on three or less drugs. Clinical characteristics were compared between these two groups., Results: Compared to controlled patients, those having resistant hypertension were older, more obese and had longer hypertension duration. They also had more frequently diabetes, dyslipidemia, reduced renal function, microalbuminuria, left-ventricular hypertrophy and previous history of cardiovascular events. In multivariate analyses, hypertension duration, obesity, abdominal obesity, left-ventricular hypertrophy, reduced estimated glomerular filtration rate, and microalbuminuria were independently associated with resistant hypertension. Resistant hypertensive patients had higher ambulatory blood pressures, but differences between office and ambulatory blood pressure (white-coat effect) were also more pronounced in this group, revealing a proportion of 40% of patients with normal 24-h blood pressure. On the contrary, values of 24-h blood pressure above 130 and/or 80 mmHg (masked hypertension) were present in 31% of apparently controlled patients., Conclusion: Resistant hypertension is associated with obesity, longer hypertension duration and kidney and cardiac damage. Ambulatory blood pressure monitoring reveals that white-coat hypertension is common among resistant hypertensive patients, as well as is masked hypertension among apparently controlled patients.

Background: We have previously demonstrated in the Randomized Olmesartan and Diabetes Microalbuminuria Prevention study that the angiotensin receptor blocker (ARB) olmesartan delays the onset of microalbuminuria in patients with type 2 diabetes. Now, we investigated the effect in the subpopulation with hypertension., Methods: Overall, 4020 patients with type 2 diabetes and hypertension at baseline (defined by a SBP/DBP ≥130/80 mmHg or use of antihypertensive medication) received either 40 mg olmesartan once daily or placebo for a median of 3.2 years in a randomized, double-blind, multicenter, controlled trial. Additional antihypertensive drugs (except angiotensin-converting enzyme inhibitors or ARBs) were used as needed to lower blood pressure (BP) to less than 130/80 mmHg., Results: The average BP was 126.3/74.7 and 129.5/76.6 mmHg, respectively (P < 0.001). Olmesartan delayed the time to onset of microalbuminuria by 25% (hazard ratio = 0.75; 95% confidence interval = 0.61-0.92, P = 0.007). Patients with a baseline SBP above the median of 136.7 mmHg and a SBP reduction above the median of 17.45 mmHg had a lower incidence of microalbuminuria than patients with a SBP reduction of less than 17.45 (8.1 vs. 11.2%, P < 0.0001). Independent from the baseline BP and the degree of BP reduction a 15-39% increase in the time to onset of microalbuminuria was detectable by olmesartan treatment. Cardiovascular events were comparable and occurred in 93 (4.6%) patients taking olmesartan and 86 (4.4%) taking placebo., Conclusion: Patients with a better BP reduction are less likely to develop microalbuminuria. Treatment with olmesartan delayed the onset of microalbuminuria independent of the baseline BP and the degree of BP reduction.

Antagonism of renin-angiotensin-aldosterone system is exerted through angiotensin-converting enzyme inhibitors, angiotensin receptor antagonists, renin inhibitors and mineralocorticoid receptor antagonists. These drugs have been successfully tested in numerous trials and in different clinical settings. The original indications of renin-angiotensin-aldosterone system blockers have progressively expanded from the advanced stages to the earlier stages of cardiorenal continuum. To optimize the degree of blockade of renin-angiotensin-aldosterone system, dose uptitrations of angiotensin-converting enzyme inhibitors and angiotensin receptor antagonists or the use of a dual blockade, initially identified with the combination of angiotensin-converting enzyme inhibitors and angiotensin receptor antagonists, have been proposed. The data from the Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial (ONTARGET) study do not support this specific dual blockade approach. However, the dual blockade of angiotensin-converting enzyme inhibitors/angiotensin receptor antagonists with direct renin inhibitors is currently under investigation while that based on an aldosterone blocker with any of the previous three drugs requires more evidence beyond heart failure. In this review, we revisited potential advantages of dual blockade of renin-angiotensin-aldosterone system in arterial hypertension and diabetes.

Elevated blood pressure (BP) is probably the most-important modifiable risk factor for cardiovascular disease (CVD). BP influences the development of CVD, even if levels of BP are well below the usual cut-off point that defines the presence of arterial hypertension. Adequate measurement of BP is the most-important requirement for the diagnosis and treatment of patients with suspected hypertension. The use of methodologies such as ambulatory and home BP monitoring have become powerful tools for defining the 'real' BP of patients, discarding the white-coat effect, and discovering masked hypertension. Early intervention with life-style changes and antihypertensive drugs is required to obtain the best outcome for the patient. In this sense, early use of combination antihypertensive drug therapy is recommended. The treatment of resistant hypertension-the type of elevated BP that is most difficult to control-has clearly improved over the past decade. Further studies are required to define how antihypertensive therapy should be used in the earliest stages of hypertension and for the treatment of patients with a mild-to-moderate increase in global cardiovascular risk.

The increasing burden on health care providers from chronic kidney disease (CKD) is due to the escalating prevalence of obesity, hypertension and type 2 diabetes. The gradual decline in kidney function in the presence of these risk factors is also associated with increased cardiovascular disease. Excess angiotensin II production by the renin-angiotensin system is responsible, at least in part, for development of hypertension and for damage in the kidneys and the cardiovascular system. Pharmacological targeting of the renin-angiotensin system not only reduces blood pressure, but may also provides more direct vascular protection. Angiotensin receptor blockers (ARBs) are better tolerated than angiotensin-converting enzyme inhibitors and, thus, may be a more practical therapeutic option. Clinical studies have demonstrated the efficacy of irbesartan, losartan, telmisartan and valsartan in the management of CKD. All ARBs tested to date have proved effective in improving at least some aspects of renal dysfunction. Few within-class comparative studies exist. Telmisartan provides superior reductions in proteinuria to losartan, however, even when blood pressures are equalized with concomitant antihypertensives. This superiority is probably linked to higher receptor affinity, longer plasma half-life and higher lipophilicity of telmisartan compared with other ARBs. The reduction of proteinuria with ARBs is also linked to improved cardiovascular outcomes. After a decade of research, there is now substantial evidence to show that the use of ARBs provides an efficacious treatment option for the prevention of renal disease progression in patients with hypertension and/or diabetes.

Background and Rationale: To date, few studies have investigated the effects of combined renin-angiotensin system blockade/calcium channel blockade on central aortic blood pressure. The Conduit Artery Function Evaluation (CAFE) sub-study of the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) investigated the effects of amlodipine/perindopril and atenolol/bendroflumethiazide on central aortic blood pressure (CABP). Similar brachial blood pressure levels were achieved; however, there was a significant difference, in favor of the amlodipine/perindopril combination, on the effects of CABP. No study has investigated the effects of a combination of an angiotensin receptor blocker/calcium channel blocker compared to those of a calcium channel blocker/angiotensin-converting enzyme inhibitor combination. To confirm and support previous findings, the SEVITENSION study will assess the effects on CABP of treatment with the high dose combination of perindopril plus amlodipine as used in ASCOT-CAFE compared with the high dose combination of olmesartan/amlodipine in patients with moderate-to-severe hypertension uncontrolled on amlodipine monotherapy., Objective: To demonstrate non-inferiority of fixed-dose olmesartan/amlodipine combination therapy compared with the combination of perindopril plus amlodipine on the mean change from baseline in central aortic systolic blood pressure., Design: A multicenter, double-blind, parallel-group, non-inferiority study comprising a 2-4-week open-label run-in period with amlodipine and a 24-week active treatment period. CABP will be measured by the SphygmoCor® Vx Pulse Wave Velocity System., Patients: 720 moderate-to-severe hypertensive patients aged ≥ 40 to ≤ 80 years and ≥ 3 additional risk factors will be enrolled., Interventions: Study treatment will comprise orally-administered combination of olmesartan/amlodipine (40/10mg) or perindopril (8 mg) plus amlodipine (10mg), and matching placebos. (EudraCT number: 2009-012966-30; ClinicalTrials.gov identifier: NCT01101009)., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Background: Eplerenone is claimed to be a more selective blocker of the mineralocorticoid receptor than spironolactone being associated with fewer antiandrogenic side-effects. We compared the efficacy, safety and tolerability of eplerenone versus spironolactone in patients with hypertension associated with primary aldosteronism., Methods: The study was multicentre, randomized, double-blind, active-controlled, and parallel group design. Following a single-blind, placebo run-in period, patients were randomized 1: 1 to a 16-week double-blind, treatment period of spironolactone (75-225 mg once daily) or eplerenone (100-300 mg once daily) using a titration-to-effect design. To be randomized, patients had to meet biochemical criteria for primary aldosteronism and have a seated DBP at least 90 mmHg and less than 120 mmHg and SBP less than 200 mmHg. The primary efficacy endpoint was the antihypertensive effect of eplerenone versus spironolactone to establish noninferiority of eplerenone in the mean change from baseline in seated DBP., Results: Changes from baseline in DBP were less on eplerenone (-5.6 ± 1.3 SE mmHg) than spironolactone (-12.5 ± 1.3 SE mmHg) [difference, -6.9 mmHg (-10.6, -3.3); P<0.001]. Although there were no significant differences between eplerenone and spironolactone in the overall incidence of adverse events, more patients randomized to spironolactone developed male gynaecomastia (21.2 versus 4.5%; P=0.033) and female mastodynia (21.1 versus 0.0%; P=0.026)., Conclusion: The antihypertensive effect of spironolactone was significantly greater than that of eplerenone in hypertension associated with primary aldosteronism., (© 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins)