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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.

Objective The current study was planned to formulate, characterize and evaluate the pharmacokinetics, and pharmacodynamics of a novel 'NanoFDC' comprising hydrochlorothiazide, candesartan (CNDT) and amlodipine. Methodology The candidate drugs were loaded in poly(DL-lactide-co-glycolide) by emulsion-diffusion-evaporation method. The formulations were evaluated for their size, morphology, drug loading and in-vitro release individually. Repeat dose pharmacokinetic and pharmacodynamic study of the nano-fixed dose combination (FDC) was done in dexamethasone-induced animal model. Results The entrapment efficiencies ranged from 44 ± 2.1, 32.2 ± 4 and 40.5 ± 2.6% for amlodipine, hydrochlorothiazide and CNDT, respectively. The nanoparticles ranged in size from 164 to 215 nm. In-vitro release profile of the nanoformulation showed unto 90% release by day 7 in simulated gastric fluid and simulated intestinal fluid, respectively. In pharmacokinetic analysis a sustained-release for 7 days was observed in nano-FDC group. Once weekly oral dosing of nano-FDC of amlodipine, CNDT and hydrochlorothiazide provided adequate antihypertensive effect which was not statistically different from daily dosing of free drugs in dexamethasone-induced animal model. Conclusion Once weekly oral dosing of nano-FDC of amlodipine, CNDT and hydrochlorothiazide provided adequate antihypertensive effect and was not statistically different from daily dosing of free drugs in dexamethasone-induced animal model. This study provides proof of concept of feasibility of once weekly dosing of a nano-FDC comprising three antihypertensive drugs, which can lead to significant improvement in patient adherence to therapy.

Supplemental Digital Content is available in the text, Objectives: The aim of this study was to identify associations between the smoothness index of central SBP (CSBP) and changes of ambulatory carotid femoral pulse wave velocity in response to 20-week treatments with losartan and amlodipine vs. losartan and hydrochlorthiazide combinations. Methods: For 142 (losartan and hydrochlorthiazide: 72, losartan and hydrochlorthiazide: 70) patients examined with ambulatory central blood pressure (BP) monitoring device, we calculated smoothness indices and trough-to-peak ratios of brachial SBP, CSBP, ambulatory pulse pressure amplification (APPA), ambulatory augmentation index at heart rate 75 beats per minute (AAIx75) and ambulatory carotid femoral pulse wave velocity (AcfPWV). Results: Mean age was 58.9 ± 12.3 years, and women accounted for 25.9%. Changes in office SBP/DBP were not different between groups (losartan and hydrochlorthiazide: −15.2 ± 15.0/−7.8 ± 8.0 vs. losartan and amlodipine: −14.9 ± 13.7/−9.2 ± 7.5 mmHg). Reduction of 24-h CSBP was not significantly different (losartan and hydrochlorthiazide: 6.4 ± 1.1 vs. losartan and amlodipine: 9.2 ± 1.1 mmHg, P = 0.074). Reduction in nocturnal AcfPWV was greater in the losartan and amlodipine group (losartan and hydrochlorthiazide: 0.09 ± 0.05 vs. losartan and amlodipine: 0.26 ± 0.05 m/s, P = 0.0216). Intraindividual SIs for CSBP were higher in the losartan and amlodipine group (0.40 ± 0.57 vs. 0.65 ± 0.74, P = 0.022). In multivariable regression analysis, smoothness index of CSBP was independently associated with the losartan and amlodipine group. In model additionally considering the changes in arterial stiffness, decrease in AcfPWV instead of the treatment group was independently associated with smoothness indices. In mediation analysis, smoothness index was fully mediated by reduction in night-time AcfPWV. Conclusion: Losartan and amlodipine combination was superior to the losartan and hydrochlorthiazide combination in terms of achieving higher smoothness index for CSBP after 20-week treatments. The effect of losartan and amlodipine on smoothness index was fully mediated by reduction of night-time AcfPWV.

The aim of this study was to identify associations between the smoothness index of central SBP (CSBP) and changes of ambulatory carotid femoral pulse wave velocity in response to 20-week treatments with losartan and amlodipine vs. losartan and hydrochlorthiazide combinations.For 142 (losartan and hydrochlorthiazide: 72, losartan and hydrochlorthiazide: 70) patients examined with ambulatory central blood pressure (BP) monitoring device, we calculated smoothness indices and trough-to-peak ratios of brachial SBP, CSBP, ambulatory pulse pressure amplification (APPA), ambulatory augmentation index at heart rate 75 beats per minute (AAIx75) and ambulatory carotid femoral pulse wave velocity (AcfPWV).Mean age was 58.9 ± 12.3 years, and women accounted for 25.9%. Changes in office SBP/DBP were not different between groups (losartan and hydrochlorthiazide: -15.2 ± 15.0/-7.8 ± 8.0 vs. losartan and amlodipine: -14.9 ± 13.7/-9.2 ± 7.5 mmHg). Reduction of 24-h CSBP was not significantly different (losartan and hydrochlorthiazide: 6.4 ± 1.1 vs. losartan and amlodipine: 9.2 ± 1.1 mmHg, P = 0.074). Reduction in nocturnal AcfPWV was greater in the losartan and amlodipine group (losartan and hydrochlorthiazide: 0.09 ± 0.05 vs. losartan and amlodipine: 0.26 ± 0.05 m/s, P = 0.0216). Intraindividual SIs for CSBP were higher in the losartan and amlodipine group (0.40 ± 0.57 vs. 0.65 ± 0.74, P = 0.022). In multivariable regression analysis, smoothness index of CSBP was independently associated with the losartan and amlodipine group. In model additionally considering the changes in arterial stiffness, decrease in AcfPWV instead of the treatment group was independently associated with smoothness indices. In mediation analysis, smoothness index was fully mediated by reduction in night-time AcfPWV.Losartan and amlodipine combination was superior to the losartan and hydrochlorthiazide combination in terms of achieving higher smoothness index for CSBP after 20-week treatments. The effect of losartan and amlodipine on smoothness index was fully mediated by reduction of night-time AcfPWV.

Objective Increased visit-to-visit blood pressure variability (vvBPV) has negative effects on multiple organ systems. Prior research has suggested that dihydropyridine calcium channel blockers (CCB) may reduce vvBPV, which we attempted to verify in a high-quality dataset with robust statistical methodology. Methods We performed a post hoc analysis of the SPRINT trial and included participants who were on a dihydropyridine CCB either 0 or 100% of follow-up study visits. The primary outcome was vvBPV, defined as residual standard deviation (rSD) of SBP from month 6 until study completion. We estimated the average treatment effect of the treated (ATET) after augmented inverse-probability-weighting (AIPW) matching. Results Of the 9361 participants enrolled in SPRINT, we included 5020, of whom 1959 were on a dihydropyridine CCB and 3061 were not; mean age was 67.4 ± 9.2 years, 34.5% were men, 65.9% were white, 49.4% were randomized to intensive blood pressure control, and the rSD was 10.1 ± 4.0 mmHg. Amlodipine represented greater than 95% of dihydropyridine CCB use. After AIPW matching of demographics and other antihypertensive medications, the ATET estimation for participants on a dihydropyridine CCB was an rSD that was 2.05 mmHg lower (95% CI -3.19 to -0.91). We did not find that other antihypertensive medications classes decreased vvBPV, and several increased it. Conclusion In the SPRINT trial, consistent use of a dihydropyridine CCB was associated with a 2 mmHg reduction in vvBPV. The implication of this hypothesis-generating finding in a high-quality dataset is that future trials to reduce vvBPV could consider using dihydropyridine CCBs.

Background: Blood pressure (BP) control is important in chronic kidney disease (CKD), but a reduction in brachial BP may not mirror changes in central aortic BP (cBP) during antihypertensive medication. We hypothesize that a fall in cBP is better reflected during enhanced vasodilation treatment (EVT) compared with reduced vasodilation treatment (RVT) because of different hemodynamic actions of these interventions.Methods: Eighty-one hypertensive CKD stage 3-4 patients (mean measured glomerular filtration rate 36 ml/min per 1.73 m2) were randomized to either EVT based on renin--angiotensin blockade and/or amlodipine or RVT based on nonvasodilating β-blockade (metoprolol). Before randomization and following 18 months of treatment, we performed 24-h ambulatory BP measurements (ABPM) and radial artery pulse wave analysis for estimation of cBP and augmentation index (AIx). Forearm resistance (Rrest) was determined by venous occlusion plethysmography and arterial stiffness by carotid--femoral pulse wave velocity (PWV). Matched healthy controls were studied once for comparison.Results: Compared with controls, CKD patients had elevated ABPM, cBP and PWV. Although ABPM remained unchanged from baseline to follow-up in both treatment groups, cBP decreased 4.7/2.9 mmHg (systolic/diastolic) during EVT and increased 5.1/1.5 mmHg during RVT (Δ=9.8/4.4 mmHg, P=0.02 for SBP, P = 0.05 for DBP). At follow-up, the difference between systolic cBP and 24-h ABPM (ΔBPsyst) was negatively associated with heart rate and positively associated with AIx and Rrest (all P < 0.01) but not PWV (P = 0.32).Conclusion: In CKD patients, EVT and RVT have opposite effects on cBP and the difference between cBP and ambulatory BP is larger for EVT than RVT.

Use of amlodipine for treatment of arterial hypertension and stable coronary artery disease (CAD) is sometimes limited by occurrence of peripheral edema and headache. We aimed to explore the true magnitude of this phenomenon by determining the rate and placebo-adjusted rate of these side effects.We performed a meta-analysis by including all randomized, placebo-controlled trials reporting edema and headache with amlodipine in patients with arterial hypertension and CAD. Placebo-adjusted rate (%) was determined as follows: (SE amlodipine % - SE placebo %)/SE amlodipine %.Data from 7226 patients of 22 trials were analyzed. Rate of edema was higher on amlodipine vs. placebo (16.6 vs. 6.2%, risk ratio: 2.9, 95% CI: 2.50-3.36, P 0.0001). The placebo-adjusted rate was 63%, indicating that 37% of edema cases were unrelated to amlodipine. Treatment with low/medium doses (2.5-5 mg) resulted in lower rates of edema (risk ratio: 2.01, 95% CI: 1.41-2.88, P = 0.0001) vs. high dose (10 mg) (risk ratio: 3.08, 95% CI 2.62-3.60, P 0.0001, Pforinteraction = 0.03). Incidence of headache was reduced using amlodipine vs. placebo (7.9 vs. 10.9%, risk ratio: 0.77, 95% CI: 0.65-0.90, P = 0.002) and was driven by use of low/medium doses (risk ratio: 0.52, 95% CI: 0.40-0.69, P 0.00001 vs. risk ratio: 0.92, 95%-CI: 0.74-1.15, P = 0.45, for high doses, Pforinteraction = 0.002).Although risks of peripheral edema are three-fold higher on amlodipine, up to one-third of edema cases on amlodipine might not be induced by amlodipine. Headache is reduced on amlodipine treatment, mainly driven by use of this drug at low/medium doses.

Introduction Hypertension control reduces cardiovascular and renal risks in type 2 diabetes. Sodium-glucose cotransporter-2 inhibitors prevent renal glucose reabsorption and decrease glucose plasma levels, blood pressure (BP) and weight reduction. Treatment of hypertension and sodium-glucose cotransporter-2 are able to improve arterial stiffness. Aims To evaluate, in patients with type 2 diabetes and hypertension, the effects of 6 months treatment with canagliflozin, or perindopril, an angiotensin converting enzyme inhibitor, on central BP and carotid-femoral pulse wave velocity (cfPWV). Methods Thirty type 2 diabetic patients with hypertension taking amlodipine, 10 mg daily, and metformin, 750-2000 mg daily, were randomized and a third medication was added: canagliflozin, 300 mg daily (n = 15, nine women, mean age: 63 ± 8 years), or perindopril, 10 mg daily (n = 15, five women, mean age 59 ± 4 years), for 6 months. Ambulatory BP monitoring was assessed at baseline and after 3 and 6 months of treatment, whereas cfPWV was measured before and after 6 months of treatment. Plasma fasting glucose, glycated hemoglobin, creatinine, plasma and urinary sodium and potassium were also measured. Results Both treatments significantly reduced BP and cfPWV. Only canagliflozin maintained the PWV action after adjusting for BP values and reduced glycemia, glycated hemoglobin and 24 h urinary sodium. Other security laboratory parameters, including gluthamic oxaloacetic transaminase, gluthamic piruvic transaminase; and bilirubin failed to show any change. Conclusion Canagliflozin reduced BP and improve arterial stiffness, independently of the BP effect. These two conditions could explain the cardiovascular protection observed with canagliflozin compared with perindopril.

Aim:Progression of chronic kidney disease (CKD) may be accelerated by tissue hypoxia due to impaired blood supply. This could be induced by small artery narrowing resulting in abnormally high intrarenal vascular resistance (RVR). We investigated whether a reduction in RVR achieved by adding vasodilating medical therapy (AVT) is superior to adding nonvasodilating medical therapy (AnonVT) regarding tissue oxygenation and preservation of kidney function.Methods:Eighty-three grade 3 and 4 CKD patients [estimated glomerular filtration rate (GFR) 34.6ml/min per 1.73m 2] were randomized to either AVT with amlodipine and/or renin angiotensin blockade or AnonVT with the nonvasodilating beta-blocker metoprolol. Investigations were performed at baseline and after 18 months of therapy. Systemic vasodilation was documented in the forearm vasculature using resting venous occlusion plethysmography. GFR was measured as 51Chrome-EDTA plasma clearance. Using MRI, renal artery blood flow was measured for calculation of RVR and for estimating renal oxygenation (R 2∗).Results:AVT and AnonVT achieved as planned similar blood pressure levels throughout the study. At follow-up, resistance had decreased by 7% (P2∗ values between AVT and AnonVT were observed, and the GFR decline was similar in the two groups (3.0 vs. 3.3ml/min per 1.73m 2).Conclusion:Long-term intensified vasodilation treatment reduced peripheral and RVR, but this was not associated with improvement of R 2∗ or protection against loss of kidney function in CKD patients.

β-blockers are no longer considered as first-line antihypertensive drugs due to their lower cardioprotection.Considering the differences in the pharmacological properties of β-blockers, the present work compared the effects of third-generation β-blockers - carvedilol and nebivolol - with a first-line agent - amlodipine - on hemodynamic parameters, including short-term blood pressure variability (BPV), and their ability to prevent target organ damage in spontaneously hypertensive rats (SHR). SHR rats were orally treated with carvedilol, nebivolol, atenolol, amlodipine or vehicle for 8 weeks. Wistar Kyoto rats treated with vehicle were used as normotensive group. Echocardiographic evaluation, BP, and short-term BPV measurements were performed. Left ventricle and thoracic aorta were removed for histological evaluations and to assess the expression of transforming growth factor β (TGF-β), tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6).Carvedilol, nebivolol or amlodipine induced a greater reduction of carotid BP, short-term BPV and echocardiography parameters than atenolol in SHR rats. Carvedilol, nebivolol and amlodipine were more effective than atenolol in the prevention of cardiac hypertrophy, and cardiac and aortic collagen deposit. Carvedilol and nebivolol, but not atenolol, reduced the expressions of fibrotic and inflammatory biomarkers - TGF-β, TNF-α and IL-6 - in SHR rats to a similar extent to that of amlodipine.Chronic treatment with carvedilol or nebivolol attenuates carotid BP and short-term BPV, and reduces target organ damage in SHR to a greater extent than atenolol. Our findings suggest that the lower cardiovascular protection of nonvasodilating β-blockers, as atenolol, in hypertension must not be translated to third-generation β-blockers.

Objectives Gout is a common complication of blood pressure management and a frequently cited cause of medication nonadherence. Little trial evidence exists to inform antihypertensive selection with regard to gout risk. Methods The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) was a randomized clinical trial on the effects of first-step hypertension therapy with amlodipine, chlorthalidone, or lisinopril on fatal coronary heart disease or nonfatal myocardial infarction (1994-2002). Trial participants were linked to CMS and VA gout claims (ICD9 274.XX). We determined the effect of drug assignment on gout with Cox regression models. We also determined the adjusted association of self-reported atenolol use (ascertained at the 1-month visit for indications other than hypertension) with gout. Results Claims were linked to 23 964 participants (mean age 69.8 ± 6.8 years, 45% women, 31% black). Atenolol use was reported by 928 participants at the 1-month visit. Over a mean follow-up of 4.9 years, we documented 597 gout claims. Amlodipine reduced the risk of gout by 37% (hazard ratio 0.63; 95% CI 0.51--0.78) compared with chlorthalidone and by 26% (hazard ratio 0.74; 95% CI 0.58--0.94) compared with lisinopril. Lisinopril nonsignificantly lowered gout risk compared with chlorthalidone (hazard ratio 0.85; 95% CI 0.70--1.03). Atenolol use was not associated with gout risk (adjusted hazard ratio 1.18; 95% CI 0.78--1.80). Gout risk reduction was primarily observed after 1 year of follow-up. Conclusion Amlodipine lowered long-term gout risk compared with lisinopril or chlorthalidone. This finding may be useful in cases where gout risk is a principal concern among patients being treated for hypertension.This trial is registered at clinicaltrials.gov, number: NCT00000542.

Objective During the Candesartan Antihypertensive Survival Evaluation in Japan (CASE-J) trial, patients with hypertension who received amlodipine had similar cardiovascular risks as those who received candesartan. We conducted a post-trial study, the Candesartan Antihypertensive Survival Evaluation in Japan 10-year follow-up (CASE-J 10). This study aimed to confirm the long-term cardiovascular effects of candesartan and amlodipine. Methods Case report forms were sent to CASE-J investigators who agreed to participate in the CASE-J 10. All the available information was retrospectively collected. The primary endpoint was a time-to-first event for a composite of cerebrovascular, cardiac, renal, and vascular events, and sudden death. Secondary endpoints included new-onset diabetes (NOD), cardiovascular mortality, and all-cause mortality. For each endpoint, treatment effect was compared on an intention-to-treat basis, according to previous randomization categories. Results A total of 1313 patients' data have been updated. The 10-year Kaplan-Meier rates of the primary endpoint were 14.7% for candesartan and 14.8% for amlodipine. After adjusting for baseline characteristics, the rates for the primary endpoint were similar between the two treatments (hazards ratioadj = 0.99, 95% CI 0.82-1.20). Candesartan had a lower Kaplan-Meier rate of NOD than amlodipine (8.3 vs. 11.1%), and when adjusted for clinical factors, candesartan remained an independent predictor for NOD prevention (hazard ratioadj = 0.71, 95% CI 0.52-0.98). Conclusion With more than 28 385 patient-years follow-up, we demonstrated that candesartan and amlodipine were comparable in reducing cardiovascular events in patients with high-risk hypertension. Additionally, our results may support candesartan's superiority in reducing NOD incidence compared with amlodipine even after the long-term follow-up.

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.

This 4-month, double-blind, randomized, controlled trial was designed to demonstrate the superiority of perindopril/indapamide/amlodipine single pill over perindopril/indapamide after 1 month and to determine further up-titration efficacy and safety in patients with mild-to-moderate hypertension. After a 1-month run-in period on perindopril/indapamide 5/1.25 mg, patients with SBP/DBP at least 150/95 mmHg and no diabetes or renal insufficiency received perindopril/indapamide/amlodipine 5/1.25/5 mg single pill or continued on the same treatment. At 1, 2, and 3 months, patients with uncontrolled blood pressure (SBP/DBP ≥ 140/90 mmHg) were gradually up-titrated with a higher dose of the triple therapy up to perindopril/indapamide/amlodipine 10/2.5/10 mg in both groups. Efficacy was assessed on office supine SBP (main criterion) and DBP, blood pressure control, and response rates. Treatment effect on ambulatory blood pressure monitoring (ABPM) and home blood pressure monitoring (HBPM) parameters was also assessed in two subpopulations of 276 and 263 patients, respectively. A total of 454 hypertensive patients (diabetes and renal insufficiency excluded) were randomized, 227 to each group (56% were men, mean age was 55 years, blood pressure 162.3/101.1 mmHg). After 1 month, superior SBP (−3.1 mmHg, P = 0.02) and DBP (−2.8 mmHg, P

The objective of this study is to evaluate the efficacy and safety of sacubitril/valsartan (LCZ696, an angiotensin receptor and neprilysin inhibitor) add-on to amlodipine compared with amlodipine monotherapy in Asian patients with systolic hypertension uncontrolled with amlodipine.Patients with mean clinic SBP at least 145 mmHg and less than 180 mmHg after a 4-week treatment with amlodipine 5 mg/day were randomized to receive LCZ696/amlodipine (200/5 mg/day) or amlodipine 5 mg/day for 8 weeks. The primary assessment was the superiority of LCZ696/amlodipine versus amlodipine in lowering 24-h ambulatory SBP from baseline to week 8. Secondary assessments included 24-h ambulatory DBP and pulse pressure (PP), daytime and night-time BP, clinic BP and PP, BP control/responder rate (140/90 mmHg or a reduction ≥20/10 mmHg from baseline), and safety.Of the 371 patients screened, 266 (71.7%) patients (mean age 55.4 years; 24-h SBP/DBP 139.0/86.1 mmHg at baseline) who did not respond to 4-week treatment with amlodipine 5 mg/day were randomized. At week 8, LCZ696/amlodipine provided greater reductions in 24-h SBP compared with amlodipine monotherapy from baseline (-13.9 versus -0.8 mmHg, P 0.001). All the secondary efficacy assessments were significantly (P 0.001) in favour of LCZ696/amlodipine, for instance, 24-h PP (-5.8 versus -0.6 mmHg). Overall, the incidence of adverse events was 20.0% with LCZ696/amlodipine and 21.3% with amlodipine.LCZ696/amlodipine showed significantly greater 24-h ambulatory BP and PP reductions compared with amlodipine monotherapy. Both treatments were generally well tolerated. Therefore, LCZ696/amlodipine combination could be an effective treatment for patients with systolic hypertension uncontrolled with amlodipine.

We compared the autonomic and hemodynamic cardiovascular effects of amlodipine and enalapril treatment associated with an aerobic physical training program on spontaneously hypertensive rats.Eighteen-week-old (n = 48) spontaneously hypertensive rats were assigned to one of two groups: sedentary (n = 24) and trained (n = 24) through a 10-week swimming training program. Each group was subdivided into three groups (n = 8): control (vehicle group), amlodipine (amlodipine group; 10 mg/kg per day) and enalapril (enalapril group; 10 mg/kg per day) (both for 10 weeks). We cannulated the femoral artery and vein of all animals for recording arterial pressure and injecting drugs, respectively. Autonomic assessment was performed by double blockade with propranolol and atropine, analysis of heart rate variability (HRV), systolic arterial pressure variability and baroflex sensitivity.Arterial pressure reduction was more prominent in the sedentary and trained enalapril groups. Amlodipine sedentary group presented important autonomic adjustments characterized by a predominance of vagal tone in cardiac autonomic balance, increased HRV associated with sympathetic autonomic modulation reduction and increased vagal autonomic modulation, and increased baroflex sensitivity. All findings were not potentialized by physical training. In turn, the enalapril trained group, but not its sedentary counterpart, also had vagal tone prevalence in cardiac autonomic balance, increased HRV, increased baroflex sensitivity and decreased low-frequency band in systolic arterial pressure variability.Amlodipine was more effective in promoting beneficial autonomic cardiovascular adaptations in sedentary animals. In contrast, enalapril achieved better autonomic results only when combined with aerobic physical training.

Background Amlodipine is a representative calcium channel blocker that is frequently prescribed for the treatment of hypertension. In this study, the possibility of drug-drug interactions between amlodipine and coadministered antibiotics (ampicillin) was investigated in rats; thus, changes in the metabolic activities of gut microflora and the consequent pharmacokinetic pattern of amlodipine following ampicillin treatment were characterized. Methods and results In human and rat fecalase incubation samples, amlodipine was metabolized to yield a major pyridine metabolite. The remaining amlodipine decreased and the formation of pyridine metabolite increased with incubation time, indicating the involvement of gut microbiota in the metabolism of amlodipine. Pharmacokinetic analyses showed that systemic exposure of amlodipine was significantly elevated in antibiotic-treated rats compared with controls. Conclusion These results showed that antibiotic intake might increase the bioavailability of amlodipine by suppressing gut microbial metabolic activities, which could be followed by changes in therapeutic potency. Therefore, coadministration of amlodipine with antibiotics requires caution and clinical monitoring.

Objective:To evaluate the effects of the combinations of Amlodipine/ Lisinopril (A/L) and Amlodipine/ Carvedilol (A/C) on levels of blood pressure (BP), hypertensive reaction under isometric exercise (IE), lipid and carbohydrate metabolism, quality of life (QoL) in patients (pts) with arterial hyper

Objective:to investigate effects of single-pill combination (SPC) of valsartan/amlodipine (V/A) on left ventricular (LV) and left atrial (LA) myocardial stiffness (MS) parameters and LV mass index (LVMI) in the middle-aged patients with stage II grade 1–2 essential arterial hypertension (EAH) withou

Objective:The aim of our study was to assess the influence of spironolactone added to a standard therapy of amlodipine/lisinopril on parameters of 24-hour blood pressure (BP) monitoring in patients with uncontrolled hypertension.Design and method:60 patients (28 men and 32 women, aged 50.8 ± 8.9) we

Objective:The aim of the study was to determine the impact on the variability of blood pressure of three hypotensive drugs: perindopril, nebivolol and amlodipine.Design and method:58 people with newly diagnosed, untreated arterial hypertension, in the average age of 41.2 ± 11.7 years were enrolled i

OBJECTIVE:: To evaluate perindopril 3.5mg/amlodipine 2.5mg once daily, a novel fixed-dose combination adapted for first-step treatment in patients with hypertension. This fixed dose had to be equivalent to amlodipine 5mg in terms of blood pressure efficacy, but with an expected better tolerability profile. We selected two drugs with complementary modes of action, with doses chosen so that each drug would contribute similarly to the overall blood pressure-lowering effect METHODS:: An international, randomized, double-blind, placebo-controlled study with six equal parallel treatment arms and an 8-week randomized treatment period, whose design, clinical significance and non-inferiority criteria were in accordance with European guidelines. RESULTS:: In all, 1581 patients with mild-to-moderate uncomplicated hypertension (mean age 51.7 years) were randomized and 94.7% completed the study. The combination was statistically and clinically superior to placebo (between-group differences: SBP: -7.22mmHg, DBP: -4.12mmHg, P

Objectives: An international double-blind, parallel-group, randomized controlled trial was performed to determine the efficacy and safety of a new first-line strategy in mild to moderate hypertension based on a single-pill combination of perindopril/amlodipine versus a validated stepped-care strategy (initiation with valsartan monotherapy, up-titrating to valsartan/amlodipine after 2 months). Methods: At inclusion, patients received perindopril/amlodipine 3.5/2.5 mg or valsartan 80 mg. At 1, 2, and 3 months, patients were up-titrated if they had uncontrolled hypertension (≥140/90 mmHg). The up-titration steps were: perindopril/amlodipine 7/5 mg, 14/10 mg, and 14/10 mg + indapamide sustained release 1.5 mg; or valsartan 160 mg, valsartan/amlodipine 160/5 mg, and 160/10 mg. The two groups were similar at baseline (55.5 years, 53% men, blood pressure 163.5/100.2 mmHg); 881 perindopril/amlodipine and 876 valsartan/amlodipine patients were analyzed for efficacy. Results: After 1 month, the rate of controlled hypertension was 33% with perindopril/amlodipine versus 27% with valsartan/amlodipine (estimate of difference, +6.1%; P = 0.005); this between-strategy difference remained significant at every visit (P < 0.05). After 3 months, blood pressure was 137.8 ± 12.4/83.3 ± 8.7 and 139.7 ± 13.3/84.8 ± 9.0 mmHg, respectively, with greater reductions from baseline with perindopril/amlodipine (primary endpoint -2.0/-1.5 mmHg; both P < 0.001). Similar results were observed at all other visits (all P ≤ 0.001). The safety of the two strategies was equivalent. CONCLUSIONS: The three-step strategy of initiation with single-pill perindopril/amlodipine produces greater reductions in blood pressure, and better and quicker rates of control of hypertension. This can be expected to be associated with benefits beyond blood pressure control, notably improved compliance and better cardioprotection.

Objective: To measure the placebo-controlled effects of combination therapy on hypotension, treatment discontinuation, and major renal outcomes, according to baseline blood pressure. Methods: We conducted an analysis of the action in diabetes and vascular disease: preterax and diamicron-MR controlled evaluation ADVANCE and perindopril protection against recurrent stroke study PROGRESS trials, including 14 684 participants allocated combination therapy or placebo. The mean age was 65 years, 61% were men, and 64% were receiving background blood pressure lowering (BPL) therapy. Participants were stratified into five subgroups by baseline SBP less than 120, 120-129, 130-139, 140-159, and at least 160 mmHg. Discontinuation of study treatment during the active run-in phase and postrandomization follow-up was assessed for hypotension/dizziness and other causes. Major renal outcomes (sustained doubling in creatinine or renal death) were also assessed. Results: Discontinuation during the 4-6-week active runin phase due to hypotension/dizziness ranged from 3.6% in those with SBP less than 120mmHg to 1.3% in those with SBP at least 160 mmHg. Median follow-up in the randomized phase was 5.6 years, and discontinuation for hypotension was higher with combination therapy compared with placebo in the less than 120mmHg group (4.7 vs. 1.2%). However, for each subgroup with baseline SBP 120-129, 130-139, and 140-159 mmHg, the absolute excess of discontinuation due to hypotension with combination therapy was 0.7%. Total discontinuations were only increased in the less than 120mmHg group (18.4 vs. 12.5%) and the 120-129-mmHg subgroup (17.6 vs. 14.2%). There were no clear differences across the SBP subgroups for the combined renal outcome (overall, 0.8 vs. 0.6%). Conclusion: Compared with those with baseline SBP 140-159 mmHg, side effects of dual combination BPL are essentially the same for people with SBP 130-139mmHg and only modestly increased among patients with SBP 120-129 mmHg. During long-term therapy, side effects sufficient to stop treatment that are treatment related (i.e. occur in excess of rates seen with placebo) occur at less than 0.5%/year in patients with baseline SBP 120-139 mmHg. These results have important implications in assessing the likely balance of benefits and side effects of BPL with combination therapy among those with SBP 120-139 mmHg.

We report the results of an echocardiographic substudy carried out in a trial comparing the effects of two different treatment strategies - mineralocorticoid receptor blockade (MRB) and dual renin-angiotensin system blockade (RASB) - in patients with resistant hypertension. Both strategies reduce left ventricular mass index (LVMI), but they have not been compared in patients with resistant hypertension.After 4-week treatment with 300 mg irbesartan + 12.5 mg hydrochorothiazide + 5 mg amlodipine, 86 patients with resistant hypertension were randomized to the add-on 25 mg spironolactone (MRB group, n = 46) or 5 mg ramipril (RASB group, n = 40) groups for 12 weeks. Treatment intensity was increased at week 4, 8 or 10 if home blood pressure (BP) was equal to or above 135/85 mmHg, by sequentially adding 20-40 mg furosemide and 5 mg amiloride (MRB group), or 10 mg ramipril and 5-10 mg bisoprolol (RASB group). Transthoracic echography was performed at baseline and week 12.Daytime ambulatory BP decreased by 19 ± 12/11 ± 8 mmHg in the MRB group and by 8 ± 13/7 ± 7 mmHg in the RASB group (P = 0.0003/0.03). LVMI decreased by 8.2 ± 18.9 g/m in the MRB group, whereas it increased by 1.8 ± 19.1 g/m in the RASB group (P = 0.03). The decreases in posterior wall thickness, left ventricular (LV) end-systolic diameter, E/e' ratio and left atrial area were significantly greater with MRB than with RASB. The difference between groups remained significant after adjustment for the decrease in ambulatory BP.In patients with resistant hypertension, MRB-based treatment decreased both BP and LVMI more efficiently than a strategy based on dual RASB.

OBJECTIVE Calcium channel blockers (CCBs) are used as antihypertensive agents and have a strong vasodilatory effect; however, the sympathetic activation mediated by baroreflex might cause adverse effects. A recently developed CCB, azelnidipine, decreases the heart rate (HR) while lowering blood pressure (BP), possibly by inhibiting sympathetic nerve activity in animal models. In this study, we evaluated whether azelnidipine inhibited sympathetic nerve activity, compared to amlodipine, in primary hypertensive patients. DESIGN AND METHODS We conducted a prospective, randomized, open-label, and crossover study of 14 patients. We measured the patients' BP, HR and baroreflex sensitivity, and directly recorded muscle sympathetic nerve activity (MSNA), via microneurography, after treatment with either CCB for 8 weeks. RESULTS Although systolic and diastolic BPs did not differ between the azelnidipine and amlodipine groups, the HR in the azelnidipine group significantly decreased compared with that in the amlodipine group. MSNA was significantly reduced in the azelnidipine compared with the amlodipine group (47.7 ± 14.9 vs. 61.5 ± 10.7 bursts per 100 beats, P

Objective:To investigate the effect of valsartan/amlodipine fixed-dose combination(Val/Aml FDC) monotherapy on short-term and long-term systolic blood pressure variability(SBPV).Design and method:980 consecutive hypertensives from 27 medical centers in China were enrolled to receive daily Val/Aml FD

Objective:Hypertension is worldwide spread and represents the leading cause of death. Diabetes rich epidemic levels in global population. Hypertension and diabetes are frequently present in the same patient and represents independent cardiovascular risk factors. Both hypertension and diabetes are as

Objective:To evaluate effectiveness of indapamide/ amlodipine single-pill combination (SPC) in patients older than 55 years with grade 1 or 2 arterial hypertension who did not achieve blood pressure (BP) targets on the previous therapy or who were not previously treated for hypertension.Design and m

Objective:to investigate arterial stiffness markers in the middle-aged naive patients with grade 1–2 essential arterial hypertension (EAH) and to compare effects of valsartan/amlodipine (V/A) and perindopril/indapamide (P/I) single-pill combinations (SPC) on these parameters.Design and method:Retros

Objective:Hypertension (HTN) is the leading risk factor for cardiovascular mortality globally. Numerous studies have compared safety and efficacy between antihypertensive classes, but in-class comparisons of angiotensin II receptor blockers (ARBs) in fixed-dose combinations (FDC) with a calcium chan

Objective Combination therapy with angiotensin receptor blockers (ARBs) and calcium channel blockers or diuretics is common for hypertensive patients. This study aimed to determine which combination is better for elderly hypertensive patients. Methods In this prospective, randomized, open-label trial, hypertensive outpatients aged at least 65 years who had not achieved their target blood pressure (BP) with standard ARB dosages were randomly assigned to receive either a fixed-dose combination of losartan (50 mg) and hydrochlorothiazide (12.5 mg) (ARB+D; n = 72) or a combination of amlodipine (5 mg) and the typical dosage of ARBs (ARB+C; n = 68) to evaluate the change in the BP, laboratory values and cognitive function. Results At 3 months, the SBP/DBP was found to have significantly decreased from 156/83 ± 15/11 mmHg to 139/76 ± 14/10 mmHg in the ARB+D group and 155/83 ± 11/10 mmHg to 132/72 ± 14/10 mmHg in the ARB+C group. The BP reduction efficacy was greater in the ARB+C group than in the ARB+D group. At 6 months, the SBP/DBP reached the same level in both groups. At 12 months, the urine albumin/creatinine ratio was significantly decreased from the geometric mean of 17.1 to 9.6 mg/g in the ARB+D group, whereas it was increased from 19.8 to 23.7 mg/g in the ARB+C group. Conversely, the estimated glomerular filtration rate tended to show a decrease in the ARB+D group. There was no significant difference in mini-mental state examination after 1 year. Conclusion ARB+amlodipine (5 mg) yielded a greater BP reduction, whereas ARB+HCTZ (12.5 mg) resulted in a greater reduction in the albuminuria, suggesting that each combination therapy is advantageous in a different manner for elderly hypertensive patients.

The main purpose in hypertension treatment is the reduction of cardiovascular disease burden. Among different first-line antihypertensive drug classes, angiotensin-receptor blockers are characterized by their both good effectiveness and tolerability. Furthermore, the interruption of the renin-angiotensin cascade is related with several benefits in target organ protection and cardiovascular prevention. Among different angiotensin-receptor blockers, olmesartan has been examined in several trial of organ protection, showing improvements in several disease markers, such as microinflammation, regression of both plaque volume and vascular hypertrophy, as well as microalbuminuria prevention. Olmesartan has been also widely examined in combination of either hydrochlorothiazide or amlodipine, as well as with both drugs in a single-pill triple combination, showing improvements in antihypertensive efficacy without significant effects on tolerability. This treatment strategy based on a drug with such characteristics and the availability of different types of combinations with other first-line drug classes may represent an effective way for achieving blood pressure control in a majority of hypertensive patients and this could also be related with a better cardiovascular disease prevention.

OBJECTIVES: Microalbuminuria is closely associated with an increased risk of renal and cardiovascular adverse outcomes. The present study tested the hypothesis that titration of telmisartan reduces urinary excretion of albumin more than does addition of amlodipine in patients treated with a standard dose of telmisartan combined with a low-dose diuretic for the same degree of blood pressure (BP) reduction. METHODS: Hypertensive patients with type 2 diabetes mellitus and microalbuminuria under treatment with a combination of a standard dose of telmisartan (40 mg/day) and trichlormethiazide (1 mg/day) were randomly assigned to receive either an increased dose of telmisartan (80 mg/day) combined with trichlormethiazide [increased dose angiotensin receptor blocker (ARB) group, n = 20] or a combination consisting of telmisartan (40 mg/day), trichlormethiazide, and amlodipine (5 mg/day) (triple combination group, n = 20) for 6 months. The primary endpoint was a reduction in urinary albumin levels. RESULTS: Although BP was reduced to a similar extent by the two regimens, patients receiving the increased dose ARB showed a higher reduction in urinary albumin (-37.4 ± 16.9%) than those on the triple combination regimen (-8.9 ± 23.7%; P < 0.0001). The reduction in urinary albumin was correlated with the drop in BP in the latter group, but not in the increased dose ARB group. CONCLUSION: Uptitration of telmisartan more effectively reduces urinary albumin than addition of amlodipine in hypertensive patients with diabetes treated with a combination of telmisartan and diuretic for the same degree of BP reduction.

OBJECTIVE The L/N-type calcium channel blocker (CCB) cilnidipine suppresses sympathetic nerve activity and has a superior renoprotective effect compared with L-type CCBs such as amlodipine. The cardioprotective action of cilnidipine has remained largely uncharacterized, however. We have now investigated the effects of cilnidipine, in comparison with amlodipine, on cardiac pathophysiology in rats with salt-sensitive hypertension. METHODS Dahl salt-sensitive rats fed a high-salt diet from 6 weeks of age were treated with vehicle (LVH group), amlodipine (3 mg/kg per day), or cilnidipine (3 mg/kg per day) from 7 to 11 weeks. RESULTS The salt-induced increase in SBP apparent in LVH rats was attenuated to a similar extent by treatment with amlodipine or cilnidipine. The two drugs also similarly inhibited the development of left ventricular (LV) hypertrophy. However, cilnidipine attenuated the increase in relative wall thickness as well as ameliorated LV perivascular and interstitial fibrosis and diastolic dysfunction to a greater extent than did amlodipine. In addition, cilnidipine treatment was associated with greater inhibition of cardiac oxidative stress, inflammation, and renin-angiotensin system (RAS) gene expression. The decrease in cardiac norepinephrine content apparent in LVH rats was similarly inhibited by both drugs. CONCLUSIONS Cilnidipine attenuated LV fibrosis and diastolic dysfunction as well as LV concentricity to a greater extent than did amlodipine in Dahl salt-sensitive rats. The superior cardioprotective action of cilnidipine is likely attributable, at least in part, to the greater antioxidant and anti-inflammatory effects associated with inhibition of cardiac RAS gene expression observed with this drug.