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1.  Blood Pressure Effects of High-Dose Amlodipine-Benazepril Combination in Black and White Hypertensive Patients Not Controlled on Monotherapy 
Drugs in R&d  2012;12(2):57-64.
Background
Black hypertensive patients are more resistant to angiotensin-converting enzyme (ACE) inhibitor monotherapy than White patients. This resistance can be overcome with the combination of ACE inhibitors with diuretics or calcium-channel blockers (CCBs).
Objectives
The objective of this clinical investigation was to evaluate the antihypertensive effectiveness of monotherapy with the ACE inhibitor benazepril or the CCB amlodipine and their combination in Black and White hypertensive patients in two separate studies.
Methods
This was a post hoc analysis of data from two separate studies, pooled because of their similarities, to increase the sample size. Outpatient Black and White hypertensive patients were selected for these studies. In study H2303, 201 patients of both sexes and races, whose mean seated diastolic blood pressure (MSDBP) was ≥95 mmHg after 4 weeks of single-blind treatment with benazepril 40mg/day, were randomized into two groups. Group 1 received benazepril 40mg/day and group 2 received amlodipine/benazepril 5/40mg/day, which was uptitrated to amlodipine/benazepril 10/40 mg/day at week 4 of the study. In study H2304, 812 similar patients, whose MSDBP was ≥95 mmHg after 4 weeks of single-blind treatment with amlodipine 10 mg/day, were randomized into three groups. Group 1 received amlodipine/benazepril 10/20 mg/day, uptitrated to amlodipine/benazepril 10/40 mg/day after 2 weeks. Group 2 received amlodipine/benazepril 10/20 mg/day. Group 3 received amlodipine 10 mg/day. All three groups were followed up for 6 additional weeks.
Results
This report presents the results of post hoc analysis of pooled data from two separate but similar studies. Combination therapy resulted in greater lowering of MSDBP and mean seated systolic blood pressure (MSSBP) than monotherapy with either benazepril or amlodipine (p< 0.001). With respect to combination therapy, the combination of amlodipine/benazepril 10/20 mg/day resulted in greater blood pressure (BP) reductions in White patients than in Black patients (p<0.004). In contrast, the combination of amlodipine/benazepril 10/40 mg/day resulted in similar BP reductions in both Black and White hypertensive patients. There were no serious clinical or metabolic side effects noted, with the exception of pedal edema, which was more common with amlodipine monotherapy.
Conclusion
This study showed that combination therapy with amlodipine/benazepril is more effective in BP lowering than monotherapy with the component drugs. Black hypertensive patients are responsive to the combination of amlodipine/benazepril; however, they require higher dose combinations for BP reductions similar to those achieved in White hypertensive patients.
doi:10.2165/11633430-000000000-00000
PMCID: PMC3586097  PMID: 22571394
2.  Blood Pressure Effects of High-Dose Amlodipine-Benazepril Combination in Black and White Hypertensive Patients Not Controlled on Monotherapy 
Drugs in R&D  2012;12(2):57-64.
Background
Black hypertensive patients are more resistant to angiotensin-converting enzyme (ACE) inhibitor monotherapy than White patients. This resistance can be overcome with the combination of ACE inhibitors with diuretics or calcium-channel blockers (CCBs).
Objectives
The objective of this clinical investigation was to evaluate the antihypertensive effectiveness of monotherapy with the ACE inhibitor benazepril or the CCB amlodipine and their combination in Black and White hypertensive patients in two separate studies.
Methods
This was a post hoc analysis of data from two separate studies, pooled because of their similarities, to increase the sample size. Outpatient Black and White hypertensive patients were selected for these studies. In study H2303, 201 patients of both sexes and races, whose mean seated diastolic blood pressure (MSDBP) was ≥95 mmHg after 4 weeks of single-blind treatment with benazepril 40mg/day, were randomized into two groups. Group 1 received benazepril 40mg/day and group 2 received amlodipine/benazepril 5/40mg/day, which was uptitrated to amlodipine/benazepril 10/40 mg/day at week 4 of the study. In study H2304, 812 similar patients, whose MSDBP was ≥95 mmHg after 4 weeks of single-blind treatment with amlodipine 10 mg/day, were randomized into three groups. Group 1 received amlodipine/benazepril 10/20 mg/day, uptitrated to amlodipine/benazepril 10/40 mg/day after 2 weeks. Group 2 received amlodipine/benazepril 10/20 mg/day. Group 3 received amlodipine 10 mg/day. All three groups were followed up for 6 additional weeks.
Results
This report presents the results of post hoc analysis of pooled data from two separate but similar studies. Combination therapy resulted in greater lowering of MSDBP and mean seated systolic blood pressure (MSSBP) than monotherapy with either benazepril or amlodipine (p< 0.001). With respect to combination therapy, the combination of amlodipine/benazepril 10/20 mg/day resulted in greater blood pressure (BP) reductions in White patients than in Black patients (p<0.004). In contrast, the combination of amlodipine/benazepril 10/40 mg/day resulted in similar BP reductions in both Black and White hypertensive patients. There were no serious clinical or metabolic side effects noted, with the exception of pedal edema, which was more common with amlodipine monotherapy.
Conclusion
This study showed that combination therapy with amlodipine/benazepril is more effective in BP lowering than monotherapy with the component drugs. Black hypertensive patients are responsive to the combination of amlodipine/benazepril; however, they require higher dose combinations for BP reductions similar to those achieved in White hypertensive patients.
doi:10.2165/11633430-000000000-00000
PMCID: PMC3586097  PMID: 22571394
3.  The combination of amlodipine/valsartan 5/160 mg produces less peripheral oedema than amlodipine 10 mg in hypertensive patients not adequately controlled with amlodipine 5 mg 
Aims:
To demonstrate the benefit of the combination amlodipine/valsartan 5/160 mg over amlodipine 10 mg, in producing a lower incidence of peripheral oedema for a comparable mean sitting systolic blood pressure (MSSBP) reduction.
Methods:
After a 4-week amlodipine 5 mg run-in phase, inadequately controlled hypertension patients (aged ≥ 55 years, MSSBP ≥ 130 and ≤ 160 mmHg) were randomised to receive amlodipine/valsartan 5/160 mg or amlodipine 10 mg for 8 weeks, followed by amlodipine/valsartan 5/160 mg for 4 weeks for all patients. Primary variables were MSSBP change from baseline to week 8 and incidence of peripheral oedema reported as an AE. Resolution of peripheral oedema was assessed 4 weeks after switching patients from amlodipine 10 mg to amlodipine/ valsartan 5/160 mg.
Results:
At week 8, MSSBP showed greater reduction with amlodipine/valsartan 5/160 mg than amlodipine 10 mg (least square mean: −8.01 vs.−5.95 mmHg, p<0.001 for non-inferiority and p=0.002 for superiority). Systolic control, overall BP control and systolic response rate at week 8 were significantly higher with combination than amlodipine 10 mg (34 vs. 26%; 57 vs. 50%; 36.57 vs. 27.77%, respectively). Incidence of peripheral oedema was significantly lower with the combination than amlodipine 10 mg (6.6 vs. 31.1%, p<0.001). Peripheral oedema resolved in 56% patients who switched from amlodipine 10 mg to the combination, without the loss of effect on BP reduction.
Conclusion:
In non-responders to amlodipine 5 mg, treatment with amlodipine/valsartan 5/160 mg induced significantly less peripheral oedema than amlodipine 10 mg for similar BP reduction. Peripheral oedema resolved in > 50% patients switching from amlodipine 10 mg to the combination.
doi:10.1111/j.1742-1241.2008.01977.x
PMCID: PMC2705817  PMID: 19196360
4.  Amlodipine Fatality in an Infant with Postmortem Blood Levels 
Journal of Medical Toxicology  2012;8(2):179-182.
Introduction
Amlodipine is a dihydropyridine calcium channel blocker used in the treatment of hypertension and angina pectoris. Toxic effects reported from amlodipine include hypotension, reflex tachycardia, metabolic acidosis, and pulmonary edema. We report a rare fatality in an infant after ingestion of amlodipine with benazepril, with postmortem blood concentrations.
Case report
An 11-month-old, 10.88-kg boy ingested 10 to 45 mg amlodipine with 40 to 180 mg benazepril. No action was taken initially because the parents believed only one or two capsules had been ingested. A later count revealed a maximum of nine capsules missing. The child was observed at home and vomited once with possible capsule fragments. Forty-five minutes post-ingestion, the child was noted to be suddenly unresponsive and was brought the local emergency department by a private vehicle. Upon arrival (90 min post-ingestion), the child was unresponsive with the following vital signs HR 133 bpm, BP 67/42 mmHg, respiratory rate 40/min, and temperature 97.5°F. Pertinent abnormal laboratory values were HCO3 13 mmol/l and glucose 302 mg/dl. The child was placed on oxygen via a non-rebreather mask and was intubated 45 min post-arrival. The patient became progressively bradycardic, and 55 min after arrival, the patient was in asystole with no palpable blood pressure. Resuscitation measures included chest compressions, epinephrine atropine, sodium bicarbonate, and calcium gluconate. Rescue insulin therapy was begun with 4 units IVP followed by 10 units per hour. Resuscitation efforts persisted for 1 h without success. An autopsy revealed pulmonary edema and no gross or microscopic evidence of natural disease. Stomach contents revealed food matter with small white fragments. Analysis of postmortem heart blood showed amlodipine 1,300 ng/ml (therapeutic <20 ng/ml). Benazepril levels were not available.
Discussion
We believe this is the first reported fatality in an infant from amlodipine. While benazepril may have contributed, ACE inhibitors have not been previously associated with rapid cardiovascular collapse.
Conclusion
Small doses of amlodipine (0.9 to 4.1 mg/kg) may produce rapid and fatal cardiovascular collapse in an infant.
doi:10.1007/s13181-011-0207-x
PMCID: PMC3550251  PMID: 22271567
Amlodipine; Postmortem; Infant; Overdose
5.  Tolerability and effectiveness of (S)-amlodipine compared with racemic amlodipine in hypertension: A systematic review and meta-analysis 
Background: Amlodipine is a calcium channel blocker prescribed for the management of angina and hypertension. As a racemic mixture, amlodipine contains (R)- and (S)-amlodipine isomers, but only (S)-amlodipine as the active moiety possesses therapeutic activity. Based on pharmacologic research, it remains uncertain if (S)-amlodipine alone has similar efficacy and fewer associated adverse events (AEs) compared with the racemic mixtures.
Objective: The aim of this systematic review and meta-analysis was to determine the effectiveness and tolerability of (S)-amlodipine compared with that of racemic amlodipine.
Methods: A systematic literature search was performed using MEDLINE (1966–2009), EMBASE (1966–2009), the Cochrane Central Register of Controlled Trials (issue 3, 2009), the Chinese Biomedical Database (1978–2009), and the China National Knowledge Internet (1980–2009). All randomized controlled trials (RCTs) comparing (S)-amlodipine 2.5 mg and racemic amlodipine 5.0 mg in the treatment of hypertension were included in the review. The outcome measures to be collected were cardiovascular events, systolic blood pressure (SBP), diastolic BP (DBP), and AEs. Quality assessments of clinical trials were conducted using a modified Jadad Scale, with trials being rated as low quality (score 0–3) or high quality (score 4–7). Meta-analysis of the included studies was performed using RevMan software.
Results: Of the 229 references identified, 214 were excluded after screening the titles, abstracts, or full texts. Fifteen RCTs were included, of which 13 were in Chinese and 2 in English. Based on the Jadad Scale score, 3 of the RCTs were classified as high quality (score 5 or 6) and the remaining 12 as low quality (score 1–3). None of the trials evaluated cardiovascular events beyond 40 weeks. Meta-analysis of the 15 trials indicated that (S)-amlodipine was not significantly different from racemic amlodipine in the effect on BP. When only high-quality studies were included, after 4 weeks' treatment, the weighted mean difference (WMD) of SBP and DBP decrease (1 study) was −2.84 (95% CI, −6.42 to 0.74) with (S)-amlodipine and −1.71 (95% CI, −3.48 to 0.06) with racemic amlodipine. After 8 weeks' treatment, the WMD of SBP and DBP decrease (2 studies) was −1.13 (95% CI, −5.29 to 3.03) and −1.34 (95% CI, −2.67 to −0.01), respectively. The risk difference (RD) for the number of patients who experienced AEs with (S)-amlodipine and racemic amlodipine was found to be −0.04 (95% CI, −0.06 to −0.02). When all the trials were included, (S)-amlodipine treatment was associated with significantly less edema than racemic amlodipine (RD, −0.02; 95% CI, −0.03 to 0.00); however, when only high-quality studies (2 studies) were included, no difference was found between the 2 groups (RD, 0.01; 95% CI, −0.02 to 0.03). One high-quality study found significant differences in increases in aspartate and alanine aminotransferase activities in the 2 groups (RD, 0.08; 95% CI, 0.01 to 0.05). No significant differences between the 2 groups were found in the incidence of headache (RD, 0.00; 95% CI, −0.02 to 0.01) or flushing (RD, −0.01; 95% CI, −0.02 to 0.00).
Conclusions: The majority of the clinical trials comparing (S)-amlodipine and racemic amlodipine treatment were low quality (12/15 [80%]). According to the limited evidence, there were no significant differences between (S)-amlodipine 2.5 mg and racemic amlodipine 5.0 mg in controlling BP. When all the trials were considered, (S)-amlodipine treatment was associated with significantly less edema than racemic amlodipine; however, when only high-quality trials were included, no significant difference was found. More long-term, high-quality RCTs with cardiovascular events as the primary outcome are needed to compare the safety and efficacy of (S)-amlodipine and racemic amlodipine.
doi:10.1016/j.curtheres.2010.02.005
PMCID: PMC3967363  PMID: 24683248
(S)-amlodipine; hypertension; systematic review
6.  Valsartan addition to amlodipine is more effective than losartan addition in hypertensive patients inadequately controlled by amlodipine 
Introduction:
This study evaluated the effects on blood pressure (BP) of valsartan 160 mg or losartan 100 mg addition to amlodipine 5 mg in hypertensive patients.
Methods:
221 patients with inadequately controlled BP (DBP ≥ 90 mmHg) after 4 weeks of treatment with amlodipine 5 mg were randomized to receive losartan/amlodipine combination therapy or valsartan/amlodipine combination therapy for 4 weeks in a cross-over study design. At the end of the wash-out period and of each treatment period, clinic and ambulatory BP measurements were recorded.
Results:
166 patients completed the study. Both combination treatments induced a greater ambulatory BP reduction than did monotherapy. However, the further mean reductions in BP versus monotherapy were significantly greater with the valsartan/amlodipine combination (SBP/DBP: −7.9 ± 3.4/−6.5 ± 2.6 mmHg for 24-hour, −8.0 ± 3.4/−6.6 ± 2.7 mmHg for daytime; −7.7 ± 3.3/−6.4 ± 2.7 mmHg for nighttime) than with the losartan/amlodipine combination (SBP/DBP: −5.5 ± 2.8/−4.2 ± 2.1 mmHg for 24-hour, −5.7 ± 2.9/−4.4 ± 2.2 mmHg for daytime; −4.8 ± 2.8/−3.7 ± 2.2 mmHg for nighttime; P < 0.01 vs valsartan/amlodipine). The incidence of adverse events with valsartan/amlodipine (8%) and losartan/amlodipine (9%) was lower than that observed with amlodipine monotherapy (17%; P < 0.05 vs combinations).
Conclusion:
Valsartan 160 mg plus amlodipine 5 mg produced greater BP reductions than losartan 100 mg plus amlodipine 5 mg.
PMCID: PMC2835558  PMID: 20234783
angiotensin receptor blocker; ambulatory blood pressure monitoring; valsartan; losartan; amlodipine; combination therapy
7.  Bioavailability study of fixed-dose tablet versus capsule formulation of amlodipine plus benazepril: A randomized, single-dose, two-sequence, two-period, open-label, crossover study in healthy volunteers 
Background:
In the treatment of hypertension, combination therapy is important10 because antihypertensive monotherapy is effective in only 40% of patients worldwide. Amlodipine is a dihydropyridine calcium channel blocker with a slow onset and long duration of action. Benazepril hydrochloride is a prodrug hydrolyzed by esterase to the active metabolite benazeprilat, an angiotensin-converting enzyme inhibitor. In 1995, the US Food and Drug Administration approved the use of a capsule formulation of combination amlodipine-benazepril for hypertension.
Objective:
The aim of this study was to compare the bioavailability and tolerability10 of the capsule formulation with those of a tablet formulation of combination amlodipine-benazepril in healthy volunteers.
Methods:
This single-dose, 2-sequence, 2-period, open-label, crossover10 study recruited healthy, adult, male volunteers with normotension. Subjects were randomly assigned to 1 of 2 treatment sequences: a single-dose tablet containing amlodipine 5 mg plus benazepril 10 mg, followed by a single-dose capsule containing the same dose of each drug (AB), or vice versa (BA). The treatment period for each drug consisted of dosing and pharmacokinetic analysis on day 1, followed by pharmacokinetic analysis on days 2 to 7. Treatment periods were separated by a 4-week washout period. For pharmacokinetic analysis, serial blood samples were obtained before dosing and at 20, 40, 60, 80, and 100 minutes and 2, 3, 4, 5, 6, 7, 8, 10, 12, 24, 36, 60, 84, 108, 132, and 156 hours after dosing. Tolerability was assessed using subject interview and spontaneous reporting.
Results:
Twelve healthy, male, Taiwanese subjects (mean [SD] age, 23.510 [1.7] years) participated in the study. No statistically significant differences inbioavailability were found between the 2 formulations based on the pharmacokinetic measurements of amlodipine and benazeprilat. The rate and extent of absorption of the tablets were found to be comparable to those of the capsules (90% CI, between 80% and 125%). The mean (SD) relative bioavailabilities, as represented by AUC0−∞, of amlodipine and benazeprilat for tablets versus capsules were 1.060 (0.170) versus 0.949 (0.197), respectively. The mean plasma concentration-time profiles of amlodipine and benazeprilat were graphically similar. No adverse effects were observed with either formulation.
Conclusions:
The results of this bioavailability comparison study in this 10 population of healthy, male, Taiwanese volunteers suggest that the tablet and capsule formulations of combination amlodipine-benazepril are bioequivalent. Both formulations were well tolerated.
doi:10.1016/j.curtheres.2005.04.005
PMCID: PMC3964558  PMID: 24672114
bioequivalence; bioavailability; pharmacokinetics; amlodipinebesylate; benazepril hydrochloride; fixed-dose combination
8.  Efficacy and tolerability of a switch to fixed-dose combination therapy with amlodipine besylate/benazepril hydrochloride after monotherapy with amlodipine besylate: Data from the African-American subpopulation of a practice-based, open-label study (the LOGIC study)☆ 
Background: The LOGIC (LOtrel: Gauging Improved Control) study assessed the efficacy and tolerability of switching from amlodipine besylate monotherapy to fixed-dose combination therapy with amlodipine besylate/benazepril hydrochloride (HCI) in patients who were experiencing uncontrolled blood pressure (BP) or edema with monotherapy.
Objective: This article reports the efficacy and tolerability of amlodipine besylate/benazepril HCI combination therapy in the predefined African-American population of the LOGIC study.
Methods: This multicenter (1518 centers across the United States), practice-based, open-label, clinical trial enrolled patients with mild to moderate essential hypertension. Patients in group 1 had uncontrolled BP (sitting diastolic BP [DBP] ≥90 mm Hg and ≤110 mm Hg) during treatment with amlodipine besylate monotherapy 5 or 10 mg/d, and those in group 2 had controlled BP (sitting DBP ⩽90 mm Hg), but also had experienced edema during amlodipine besylate monotherapy. Participants were instructed to discontinue amlodipine besylate and were given amlodipine besylate/benazepril HCl 5/10 mg/d or 5/20 mg/d for 4 weeks. For group 1, the primary efficacy outcome was the change in mean sitting DBP (MSDBP) from baseline to week 4; a secondary efficacy outcome was the change in mean sitting systolic BP (MSSBP) from baseline to week 4. The primary efficacy outcome for group 2 was the percentage of patients whose edema improved with the switch to combination therapy. The secondary efficacy variables in group 2 were the changes in MSDBP and MSSBP from baseline to week 4. Patients in groups 1 and 2 were questioned about any adverse events that may have occurred since the previous visit. At both study visits, medications were reviewed, and the level of edema was assessed.
Results: A total of 2055 African-American patients were enrolled in the study. At study end, African-American patients in group 1 (n = 1422 assessable patients) experienced significant reductions in MSSBP (13.9 mm Hg) and MSDBP (10.4 mm Hg) from those achieved during amlodipine besylate monotherapy (both P < 0.001). In group 2 (n = 266 assessable patients), 81% of African-American patients reported improvement in edema, and BP remained well controlled.
Conclusions: In this study of an African-American subpopulation of patients with mild to moderate essential hypertension who had uncontrolled BP while receiving amlodipine besylate monotherapy, switching from amlodipine besylate monotherapy to fixed-dose amlodipine besylate/benazepril HCl combination therapy reduced BP to a greater extent than with amlodipine besylate alone, and reduced the incidence of edema in patients who were edematous but who had controlled BP. Fixed-dose combination therapy with amlodipine besylate/benazepril HCI has the potential to improve BP control, leading to improved clinical outcomes and enhanced treatment compliance.
doi:10.1016/S0011-393X(04)90028-8
PMCID: PMC4052965  PMID: 24936113
African-American patients; amlodipine besylate; benazepril HCI; combination therapy; edema; hypertension
9.  Efficacy of fixed-dose amlodipine and losartan combination compared with amlodipine monotherapy in stage 2 hypertension: a randomized, double blind, multicenter study 
BMC Research Notes  2011;4:461.
Background
The objective of this trial was to compare the blood-pressure lowering efficacy of amlodipine/losartan combination with amlodipine monotherapy after 6 weeks of treatment in Korean patients with stage 2 hypertension.
Results
In this multi-center, double-blind, randomized study, adult patients (n = 148) with stage 2 hypertension were randomized to amlodipine 5 mg/losartan 50 mg or amlodipine 5 mg. After 2 weeks, patients with systolic blood pressure (SBP) > 140 mmHg were titrated to amlodipine 10 mg/losartan 50 mg or amlodipine 10 mg. After 4 weeks of titration, hydrochlorothiazide 12.5 mg could be optionally added to both groups. The change from baseline in SBP was assessed after 6 weeks. The responder rate (defined as achieving SBP < 140 mmHg or DBP < 90 mmHg) was also assessed at 2, 6 and 8 weeks as secondary endpoints. Safety and tolerability were assessed through adverse event monitoring and laboratory testing. Baseline demographics and clinical characteristics were generally similar between treatment groups. Least-square mean reduction in SBP at 6 weeks (primary endpoint) was significantly greater in the combination group (36.5 mmHg vs. 31.6 mmHg; p = 0.0117). The responder rate in SBP (secondary endpoints) was significantly higher in the combination group at 2 weeks (52.1% vs. 33.3%; p = 0.0213) but not at 6 weeks (p = 0.0550) or 8 weeks (p = 0.0592). There was no significant difference between groups in the incidence of adverse events.
Conclusion
These results demonstrate that combination amlodipine/losartan therapy provides an effective and generally well-tolerated first line therapy for reducing blood pressure in stage 2 hypertensive patients.
Trial Registration
ClinicalTrials.gov: NCT01127217
doi:10.1186/1756-0500-4-461
PMCID: PMC3219858  PMID: 22035131
hypertension; amlodipine; losartan
10.  Effects of amlodipine and candesartan on arterial stiffness estimated by cardio-ankle vascular index in patients with essential hypertension: A 24-week study 
Background: Aortic stiffness assessed by brachio-ankle pulse wave velocity (baPWV) can be used to predict cardiovascular events. However, baPWV is dependent on blood pressure. Antihypertensive drugs have been reported to reduce baPWV; but it is difficult to determine if this effect is associated with lowered blood pressure or reduced arterial stiffness.
Objectives: The primary end point of this study was to assess whether antihypertensive drugs reduce arterial stiffness as estimated by cardio-ankle vascular index (CAVI). The secondary end point was to compare the effects of 2 widely used drugs, the calcium-channel blocker amlodipine and the angiotensin II receptor blocker candesartan, on arterial stiffness.
Methods: Between October 2005 and September 2006, consecutive Japanese outpatients with essential hypertension (EHT) (defined as using antihypertensive drugs at screening, systolic blood pressure [SBP] > 140 mm Hg, or diastolic BP [DBP] >90 mm Hg) were assigned to treatment for 24 weeks with either amlodipine (5–10 mg/d) or candesartan (8–12 mg/d). Arterial stiffness was evaluated with CAVI before and after 24 weeks of treatment. Relative change in arterial stiffness from baseline was also compared. The evaluator was blinded to treatment.
Results: Twenty patients (11 men, 9 women; mean [SD] age, 62 [10] years) were included in the study. There were no significant differences in clinical characteristics between the 2 groups. At baseline, mean (SD) CAVI was not significantly different in the amlodipine group compared with the candesartan group (8.93 [0.93] vs 8.46 [1.34], respectively). During the 24-week treatment period, mean SBP and DBP decreased significantly in both the amlodipine (14/10 mm Hg; P = 0.006 and P = 0.005) and the candesartan groups (13/11 mm Hg; P = 0.033 and P = 0.005). Amlodipine was associated with a significant change in CAVI from baseline (8.93 [0.93] vs 8.60 [1.50]; P = 0.017), whereas candesartan was not (8.46 [1.34] vs 8.81 [1.20]). The percentage change in CAVI was significantly different in the amlodipine group compared with the candesartan group (−7.14 [8.83] vs 5.85 [16.0], respectively; P = 0.038). After 24 weeks of treatment, the CAVI of the amlodipine group was still numerically larger than baseline CAVI of the candesartan group, although the difference was not statistically significant. Furthermore, there was no significant difference in absolute CAVI between the 2 groups after 24 weeks, but the relative change from baseline was significant in favor of amlodipine. Logistic regression analysis revealed that amlodipine improved CAVI independent of its antihypertensive effect.
Conclusion: These data suggest that amlodipine and candesartan had different effects on aortic stiffness estimated by CAVI, despite similar effects on brachial blood pressure after 24 weeks of treatment in these Japanese patients with EHT.
doi:10.1016/j.curtheres.2008.10.002
PMCID: PMC3969957  PMID: 24692816
arterial stiffness; amlodipne; candesartan; cardio-ankle vascular index
11.  Olmesartan/amlodipine: a review of its use in the management of hypertension 
Combination therapy is an effective strategy to increase antihypertensive efficacy in those patients with poor blood pressure (BP) control. In order to achieve BP targets, at least 75% of patients may require combination therapy, and European guidelines advocate this approach, particularly in those patients with a high cardiovascular risk. Evidence from large, randomized controlled trials, and the European hypertension treatment guidelines is supportive of the use of an angiotensin receptor blocker (ARB) with a calcium channel blocker (CCB). Fixed-dose combination formulations of olmesartan medoxomil, an ARB, and the CCB amlodipine are approved in several European countries for patients with essential hypertension. The olmesartan/amlodipine combination has demonstrated greater efficacy than its component monotherapies in reducing BP in patients with mild-to-severe hypertension. Significantly greater reductions in seated diastolic BP were observed between baseline and after eight weeks of treatment with olmesartan/amlodipine, compared with equivalent doses of olmesartan or amolodipine monotherapy (P < 0.001), in the factorial Combination of Olmesartan Medoxomil and Amlodipine Besylate in Controlling High Blood Pressure (COACH) trial. About 85% of the maximal BP reductions after the 8-week treatment period were already observed after two weeks. Uptitration as necessary, with or without hydrochlorothiazide, allowed the majority of patients to achieve BP control in a 44-week open-label extension treatment period to the COACH trial. The use of olmesartan/amlodipine allowed up to 54% of patients, with previously inadequate responses to amlodipine or olmesartan monotherapy, to achieve their BP goals. Data from post-registration studies using tight BP control and forced titration regimens have further demonstrated the high efficacy of olmesartan/amlodipine in achieving BP goal rates. Moreover, consistent reductions in BP were observed over the 24-hour dosing interval using ambulatory measurements. Olmesartan/amlodipine was generally well tolerated over the short- and long-term, with a lower frequency of peripheral edema with olmesartan/amlodipine 40/10 mg than with amlodipine 10 mg monotherapy.
doi:10.2147/VHRM.S16852
PMCID: PMC3072742  PMID: 21490944
hypertension; combination therapy; BP control; BP goals; antihypertensive monotherapy; patients
12.  Uptitrating amlodipine significantly reduces blood pressure in diabetic patients with hypertension: a retrospective, pooled analysis 
Diabetic patients with hypertension are approximately twice as likely to develop cardiovascular disease as non-diabetic patients with hypertension. Given that hypertension affects ∼60% of patients with diabetes, effective blood pressure (BP) management is important in this high-risk population. This post-hoc analysis pooled data from six clinical studies to quantify additional BP efficacy achieved when titrating hypertensive diabetic patients from amlodipine 5 mg to 10 mg. Approximately half of the diabetic patients were male (44/98; 44.9%) with a mean (standard deviation [SD]) age of 60.6 (9.6) years and a baseline mean (standard error [SE]) systolic blood pressure/diastolic blood pressure (SBP/DBP) of 150.8 (1.30)/87.5 (0.94) mmHg while on amlodipine 5 mg (159.1 [1.40]/92.6 [0.94] mmHg prior to treatment). In comparison, 350/610 (57.4%) non-diabetic patients were male with a mean (SD) age of 58.7 (11.1) years and baseline mean (SE) SBP/DBP of 150.3 (0.62)/90.9 (0.41) mmHg while on amlodipine 5 mg (160.0 [0.67]/96.2 [0.45] mmHg prior to treatment). Increasing amlodipine from 5 mg to 10 mg lowered sitting SBP by −12.5 mmHg (95% confidence interval (CI): −15.5, −9.5; P<0.0001) and DBP by −6.0 mmHg (−7.4, −4.6; P<0.0001) in diabetic patients; and SBP by −12.4 mmHg (−13.5, −11.3; P<0.0001) and DBP by −7.3 mmHg (−8.0, −6.7; P<0.0001) in non-diabetic patients. In total, 12.0% (95% CI: 6.4, 20.0) of diabetic patients achieved their BP goal versus 46.4% (42.4, 50.4) of non-diabetic patients after titration to amlodipine 10 mg. Overall, 22.0% of diabetic patients experienced 31 adverse events (AEs) and 28.9% of non-diabetic patients experienced 282 AEs. Serious AEs were reported by one (1.0%) diabetic and five (0.8%) non-diabetic patients. In this analysis, increasing amlodipine from 5 mg to 10 mg produced a clinically significant reduction in the BP of diabetic hypertensive patients, similar to non-diabetic patients, highlighting the importance of optimizing amlodipine titration in this high-risk population.
doi:10.2147/VHRM.S64511
PMCID: PMC4240189  PMID: 25484592
hypertension; diabetes; calcium channel blockers; cardiovascular disease prevention; efficacy
13.  Valsartan Improves Endothelial Dysfunction in Hypertension: A Randomized, Double-Blind Study 
Cardiovascular Therapeutics  2009;27(3):151-158.
Endothelial dysfunction can predict cardiac outcomes in hypertension and reversing this abnormality has become an attractive therapeutic objective. We tested the hypothesis that blocking the angiotensin type 1 (AT1) receptor with valsartan in comparison with amlodipine would lead to an improvement in forearm resistance artery endothelial dysfunction. In total, 25 hypertensive subjects (mean age 60 years, SD 8) with a mean daytime ambulatory blood pressure (BP) of 154 (10)/97 (6) mmHg were randomized following a 3-week placebo run-in period to a double-blind, crossover trial of 16-week treatment periods with either valsartan or amlodipine, separated by a 3-week washout period. Intra-arterial infusions of acetylcholine (ACh) and NG-monomethyl-L-arginine (L-NMMA) were used to assess stimulated and basal endothelium-dependent nitric oxide (NO) release, respectively. Coinfusion of ACh and L-NMMA was employed to investigate the existence of an NO-independent vasodilatory pathway. Valsartan and amlodipine each lowered the clinical BP to the same extent (139 [7]/87 [6] and 139 [11]/89 [4] mmHg, respectively). The vasodilatory response to ACh was significantly increased with valsartan (maximal percentage change in forearm blood flow (max. ΔFBF%) 301 [47] vs. 185 [34], mean [SEM]; P < 0.05) as compared with placebo, but remained unchanged with amlodipine. Both valsartan and amlodipine similarly increased the vasoconstrictive response to L-NMMA (max. ΔFBF%–43 [5], −42 [5], respectively, vs. –26 [3] baseline; P < 0.001). The vasodilatory response after coinfusion of ACh and L-NMMA was significantly (P < 0.05) enhanced only with valsartan. Valsartan reserved peripheral endothelial dysfunction through both NO-dependent and -independent pathways, while for the same degree of BP control, amlodipine had only a partial effect on NO bioactivity.
doi:10.1111/j.1755-5922.2009.00085.x
PMCID: PMC2948429  PMID: 19604249
Amlodipine; Blood pressure; Endothelium; Nitric oxide; Valsartan
14.  Survival and echocardiographic data in dogs with congestive heart failure caused by mitral valve disease and treated by multiple drugs: A retrospective study of 21 cases 
The Canadian Veterinary Journal  2011;52(11):1219-1225.
This retrospective study reports the survival time [onset of congestive heart failure (CHF) to death from any cause] of 21 dogs with mitral regurgitation (MR) and CHF treated with a combination of furosemide, angiotensin-converting enzyme inhibitor (ACEI, benazepril, or enalapril), pimobendan, spironolactone, and amlodipine. Baseline echocardiographic data: end-systolic and end-diastolic volume indices (ESVI and EDVI), left atrium to aorta ratio (LA/Ao), and regurgitant fraction (RF) are reported. Median survival time (MST) was 430 d. Initial dosage of furosemide (P = 0.0081) and LA/Ao (P = 0.042) were negatively associated with survival. Baseline echocardiographic indices (mean ± standard deviation) were 40.24 ± 16.76 for ESVI, 161.48 ± 44.49 mL/m2 for EDVI, 2.11 ± 0.75 for LA/Ao, and 64.71 ± 16.85% for RF. Combining furosemide, ACEI, pimobendan, spironolactone, and amlodipine may result in long survival times in dogs with MR and CHF. Severity of MR at onset of CHF is at least moderate.
PMCID: PMC3196016  PMID: 22547843
15.  Combination Therapy with Olmesartan and Amlodipine in the Treatment of Hypertension  
Pharmaceuticals  2009;2(3):125-133.
Background: Combination therapy with antihypertensive agents utilises different mechanisms of action and may be responsible for a more effective decrease in blood pressure. Objective: To review the recently published trials on efficacy and safety of the combination therapy with olmesartan and amlodipine. Results: The double-blind American COACH (Combination of Olmesartan Medoxomil and Amlopdine Besylate in Controlling High Blood Pressure) study (2008) showed in 1,940 patients that after eight weeks of treatment the BP goals were most frequently achieved in the ‘combination therapy group’, with 56.3% (54.1–58.5%) and 54.0% (51.8–56.2%) of patients reaching adequate blood pressure of <140/90 mmHg with olmesartan/amlodipine 20/10 and 40/10 respectively. Combination therapy was generally well tolerated. The most common side effect was oedema [olmesartan 20 mg 9.9% (8.6–11.3%), amlodipine 10 mg 36.8% (34.7–39.0%), placebo 12.3% (10.9–13.8%)]. The frequency of oedema was lower in the groups combining amlodipine 10 mg with olmesartan 10 mg (26.5%, 24.5–28.5%), 20 mg (25.6%, 23.7–27.6%) or 40 mg (23.5%, 21.6–25.4%). In 2009 three double-blind controlled European studies including 500–1,000 patients each and performed independently of one another have confirmed the above study, and have demonstrated similar efficacy-safety effects from the combination of olmesartan medoxomil with amlodipine, particularly for patients not achieving adequate blood pressure control with olmesartan monotherapy. Conclusions: Combinations of olmesartan and amlodipine were significantly more effective at reducing blood pressure and realising guideline blood pressure goals in patients with mild to severe hypertension than monotherapy (with a placebo component). Combination therapy is well tolerated and is associated with a lower incidence of side effects, such as oedema, compared to monotherapy with high amlodipine dosages (10 mg).
doi:10.3390/ph2030125
PMCID: PMC3978537
olmesartan; amlodipine; combination therapy; hypertension
16.  T/L-type calcium channel blocker reduces the composite ranking of relative risk according to new KDIGO guidelines in patients with chronic kidney disease 
BMC Nephrology  2013;14:135.
Background
Recently, the Kidney Disease: Improving Global Outcomes (KDIGO) group recommended that patients with chronic kidney disease (CKD) be assigned according to stage and composite relative risk on the basis of glomerular filtration rate (GFR) and albuminuria criteria. The aim of this post-hoc analysis was to investigate the effects of add-on therapy with calcium channel blockers (CCBs) on changes in the composite ranking of relative risk according to KDIGO guidelines. Benidipine, an L- and T-type CCB, and amlodipine, an L-type CCB to angiotensin II receptor blocker (ARB), were examined.
Methods
Patients with blood pressure (BP) > 130/80 mmHg, an estimated GFR (eGFR) of 30–90 mL/min/1.73 m2, and albuminuria > 30 mg/gCr, despite treatment with the maximum recommended dose of ARB, were randomly assigned to two groups. Each group received one of two treatments: 2 mg benidipine daily, increased to 8 mg daily (n = 52), or 2.5 mg amlodipine daily, increased to 10 mg daily (n = 52).
Results
After 6 months of treatment, a significant and comparable reduction in systolic and diastolic BP was observed in both groups. The eGFR was significantly decreased in the amlodipine group, but there was no significant change in the benidipine group. The decrease in albuminuria in the benidipine group was significantly lower than in the amlodipine group. The composite ranking of relative risk according to the new KDIGO guidelines was significantly improved in the benidipine group; however, no significant change was noted in the amlodipine group. Moreover, significantly fewer cases in the benidipine group than the amlodipine group showed a reduced risk category score.
Conclusion
The present post-hoc analysis showed that compared to amlodipine benidipine results in a greater reduction in albuminuria accompanied by an improved composite ranking of relative risk according to the KDIGO CKD severity classification.
Trial registration
Trial registration Number: UMIN000002644
doi:10.1186/1471-2369-14-135
PMCID: PMC3703301  PMID: 23815742
Benidipine; Calcium channel blocker; Kidney Disease: Improving Global Outcomes (KDIGO); T-type calcium channel
17.  Functional Vascular Study in Hypertensive Subjects with Type 2 Diabetes Using Losartan or Amlodipine 
Background
Antihypertensive drugs are used to control blood pressure (BP) and reduce macro- and microvascular complications in hypertensive patients with diabetes.
Objectives
The present study aimed to compare the functional vascular changes in hypertensive patients with type 2 diabetes mellitus after 6 weeks of treatment with amlodipine or losartan.
Methods
Patients with a previous diagnosis of hypertension and type 2 diabetes mellitus were randomly divided into 2 groups and evaluated after 6 weeks of treatment with amlodipine (5 mg/day) or losartan (100 mg/day). Patient evaluation included BP measurement, ambulatory BP monitoring, and assessment of vascular parameters using applanation tonometry, pulse wave velocity (PWV), and flow-mediated dilation (FMD) of the brachial artery.
Results
A total of 42 patients were evaluated (21 in each group), with a predominance of women (71%) in both groups. The mean age of the patients in both groups was similar (amlodipine group: 54.9 ± 4.5 years; losartan group: 54.0 ± 6.9 years), with no significant difference in the mean BP [amlodipine group: 145 ± 14 mmHg (systolic) and 84 ± 8 mmHg (diastolic); losartan group: 153 ± 19 mmHg (systolic) and 90 ± 9 mmHg (diastolic)]. The augmentation index (30% ± 9% and 36% ± 8%, p = 0.025) and augmentation pressure (16 ± 6 mmHg and 20 ± 8 mmHg, p = 0.045) were lower in the amlodipine group when compared with the losartan group. PWV and FMD were similar in both groups.
Conclusions
Hypertensive patients with type 2 diabetes mellitus treated with amlodipine exhibited an improved pattern of pulse wave reflection in comparison with those treated with losartan. However, the use of losartan may be associated with independent vascular reactivity to the pressor effect.
doi:10.5935/abc.20140089
PMCID: PMC4126761  PMID: 25014057
Hypertension / complications; Diabetes Mellitus, Type 2 / complications; Atherosclerosis; Endothelium / physiopathology; Losartan / therapeutic, use; Amlodipine / therapeutic, use
18.  Effect of amlodipine and lisinopril on microalbuminuria in patients with essential hypertension: A prospective study 
Indian Journal of Nephrology  2010;20(1):15-20.
Microalbuminuria can be present in 25–100% of patients with essential hypertension and is associated with increased incidence of cardiovascular events. Our goal was to evaluate the effect of a commonly used calcium channel blocker, amlodipine, and an angiotensin converting enzyme inhibitor, lisinopril on urinary albumin excretion in patients with mild to moderate essential hypertension. We screened 324 patients with essential hypertension for microalbuminuria and documented it in 120 patients. These 120 patients with microalbuminuria were randomly divided into two groups of 60 each, matched for age, sex, arterial pressure, creatinine clearance, and urinary albumin excretion so as to receive amlodipine or lisinopril. We prospectively measured their urinary albumin excretion and creatinine clearance prior to treatment and, four and eight weeks after treatment with amlodipine or lisinopril. Mean arterial pressure (mean ± SD) at baseline, after four weeks, and after eight weeks was 113.01 ± 4.38,104.93 ± 3.12, and 98.89 ± 1.75 mmHg (P < 0.0000); and 114.13 ± 7.11, 106.52 ± 3.50, and 100.89 ± 2.80 mmHg (P < 0.0000) in amlodipine and lisinopril groups, respectively. Urinary albumin excretion (mean ± SEM) at baseline, after four, and after eight weeks was 79.30 ± 3.74, 62.03 ± 3.61, and 52.02 ± 3.05 (P < 0.0000); and 73.96 ± 4.10, 72.39 ± 3.74, 66.12 ± 3.94 (P = 0.1742) in lisinopril and amlodipine groups, respectively. Lisinopril but not amlodipine, reduced the urinary albumin excretion significantly despite their similar antihypertensive efficacy. The clinical and prognostic significance of these observations need to be established.
doi:10.4103/0971-4065.62090
PMCID: PMC2878405  PMID: 20535265
Angiotensin converting enzyme inhibitors; calcium channel blockers; hypertension; microalbuminuria
19.  Moderate versus intensive treatment of hypertension with amlodipine/valsartan for patients uncontrolled on angiotensin receptor blocker monotherapy 
Journal of hypertension  2011;29(1):161-170.
Objectives
Many angiotensin receptor blocker (ARB) monotherapy patients need at least two agents to control blood pressure (BP). We investigated whether initiating intensive treatment with combination amlodipine/valsartan was superior to moderate treatment with amlodipine/valsartan in patients previously uncontrolled on ARB monotherapy.
Methods
In this 12-week study, patients aged at least 18 years on ARB (other than valsartan) for at least 28 days (with treatment-naïve patients or those not controlled on agents other than an ARB treated with open-label olmesartan 20 or 40 mg, respectively, for 28 days) and with uncontrolled mean sitting systolic blood pressure (MSSBP; ≥150–<200 mmHg) were randomized to amlodipine/valsartan 5/320 mg (n = 369) or 5/160 mg (n = 359). At week 2, the dose was increased to 10/320 mg in the intensive arm. Hydrochlorothiazide 12.5 mg was added to both arms at week 4. Optional up-titration with hydrochlorothiazide 12.5 mg at week 8 was allowed if MSSBP was more than 140 mmHg.
Results
At baseline, mean office sitting BP was comparable in the intensive (163.9/95.5 mmHg) and moderate (163.3/95.0 mmHg) groups. Intensive treatment provided greater BP reductions versus moderate treatment (P<0.05) from week 4 (−23.0/−10.4 versus −19.2/−8.7 mmHg; primary endpoint) to week 12 (−29.0/−14.8 versus −25.3/−12.3 mmHg). Adverse events were reported by a similar percentage of patients in both groups (36.3% intensive, 37.6% moderate); peripheral edema was more common with intensive versus moderate treatment (8.7 versus 4.5%; P=0.025).
Conclusions
Initiating treatment with an intensive dose of amlodipine/valsartan provides significantly greater BP lowering versus moderate treatment in hypertensive patients unresponsive to ARB monotherapy. Both treatment regimens were generally well tolerated based on adverse event reports, but the lack of routine laboratory testing after screening limits conclusions on tolerability.
doi:10.1097/HJH.0b013e32834000a7
PMCID: PMC3682653  PMID: 21045734
amlodipine; blood pressure; efficacy; hydrochlorothiazide; hypertension; safety; valsartan
20.  Postmarketing surveillance study of benazepril in chinese patients with hypertension: An open-label, experimental, epidemiologic study 
Background
Benazepril hydrochloride is an angiotensin-converting enzyme inhibitor. Previous clinical trials show that antihypertensive treatment with benazepril provides effective blood pressure (BP) control and is generally well tolerated by patients with hypertension. However, the long-term antihypertensive effects and tolerability of benazepril remain to be established in Chinese patients with hypertension.
Objective
The aim of this study was to investigate the long-term efficacy and tolerability of benazepril in Chinese patients with essential hypertension.
Methods
This 36-month, community-based, open-label, postmarketing surveillance study was conducted in the Nanshi District (Shanghai, China). Chinese patients with essential hypertension were to receive 1 or more benazepril tablets PO QD in the morning for 36 months. Data for BP and pulse pressure (PP) were collected at baseline (month 0) and throughout the surveillance period. The rate of patients achieving BP targets (systolic BP [SBP]/diastolic BP [DBP], <140/<90 mm Hg) was determined, as was the rate of decrease in BP. Subanalyses by sex and age group also were conducted.
Results
A total of 1831 patients (1090 men, 741 women; mean [SD] age, 55.8 [10.1] years [range, 35–88 years]) entered the study. After the 36-month treatment period, 75.7% of patients receiving benazepril as prescribed (1289 patients) had achieved the SBP target, 87.4% achieved the DBP target, and 71.5% achieved both targets. After 36 months of treatment, the mean (SD) decreases in SBP, DBP, and PP were 15.1 (0.4) mm Hg, 11.0 (0.3) mm Hg, and 4.2 (0.4) mm Hg, respectively, among compliers. In general, the rate of BP decrease slowed over time. No serious adverse drug reactions (ADRs) were detected during the 36-month follow-up period. All ADRs except cough (19.9%) occurred at a relatively low incidence rate (<3.0%). The cumulative incidence of benazepril related cough was statistically significantly higher in women than in men (23.6% vs 18.8%, respectively; P = 0.007). Of the 1831 patients studied, 1360 patients (74.3%) persisted in taking benazepril and were considered optimally compliant at 36-month follow-up.
Conclusion
In this study of Chinese patients with hypertension, benazepril was associated with prolonged, stable efficacy in lowering BP and relatively low incidence of ADRs.
doi:10.1016/S0011-393X(04)80117-6
PMCID: PMC3964560  PMID: 24672086
21.  24-Hour ambulatory blood pressure control with triple-therapy amlodipine, valsartan and hydrochlorothiazide in patients with moderate to severe hypertension 
Journal of Human Hypertension  2011;25(10):615-622.
To determine the effectiveness and safety of once-daily combination therapy with amlodipine, valsartan and hydrochlorothiazide for reducing ambulatory blood pressure (ABP) in patients with moderate to severe hypertension, a multicenter, double-blind study was performed (N=2271) that included ABP monitoring in a 283-patient subset. After a single-blind, placebo run-in period, patients were randomized to receive amlodipine/valsartan/hydrochlorothiazide (10/320/25 mg), valsartan/hydrochlorothiazide (320/25 mg), amlodipine/valsartan (10/320 mg) or amlodipine/hydrochlorothiazide (10/25 mg) each morning for 8 weeks. Efficacy assessments included change from baseline in 24-h, daytime and night time mean ambulatory systolic BP (SBP) and diastolic BP (DBP). Statistically significant and clinically relevant reductions from baseline in all these parameters occurred in all treatment groups (P<0.0001, all comparisons versus baseline). At week 8, least squares mean reductions from baseline in 24-h, daytime and night time mean ambulatory SBP/DBP were 30.3/19.7, 31.2/20.5 and 28.0/17.8 mm Hg, respectively, with amlodipine/valsartan/hydrochlorothiazide; corresponding reductions with dual therapies ranged from 18.8–24.1/11.7–15.5, 19.0–25.1/12.0–16.0 and 18.3–22.6/11.1–14.3 mm Hg (P⩽0.01, all comparisons of triple versus dual therapy). Treatment with amlodipine/valsartan/hydrochlorothiazide maintained full 24-h effectiveness, including during the morning hours; all hourly mean ambulatory SBP and mean ambulatory DBP measurements were ⩽130/85 mm Hg at end point. Amlodipine/valsartan/hydrochlorothiazide combination therapy was well tolerated. Once-daily treatment with amlodipine/valsartan/hydrochlorothiazide (10/320/25 mg) reduces ABP to a significantly greater extent than component-based dual therapy and maintains its effectiveness over the entire 24-h dosing period.
doi:10.1038/jhh.2010.115
PMCID: PMC3175529  PMID: 21248785
triple therapy; amlodipine; valsartan; hydrochlorothiazide
22.  The Effect of Amlodipine and Sildenafil on the NT-ProBNP Level of Patients with COPD-Induced Pulmonary Hypertension  
Pulmonary hypertension (PH) is an important cause of heart failure in chronic obstructive pulmonary disease (COPD). The pro brain natriuretic peptide N-terminal (NT-proBNP) has been suggested as a noninvasive marker to evaluate ventricular function. However, there is no evidence to support the use of NT-proBNP in monitoring the benefits of vasodilators in COPD induced PH. Thus, we used NT-proBNP as a biomarker to evaluate the effect of oral vasodilators on cardiac function in COPD-induced PH.
Forty clinically-stable PH patients were enrolled with history of COPD, normal left ventricular ejection-fraction (LVEF), right ventricular systolic pressure (RVSP) > 45 mmHg and baseline blood NT-proBNP levels >100 pg/mL. Patients were randomized into two groups, one group received sildenafil and second group were given amlodipine for two weeks. NT-proBNP and systolic pulmonary arterial pressure (systolic PA-pressure) were measured at the beginning and the end of study.
Mean NT-proBNP level in the first group was 1297 ± 912 pg/mL before therapy and 554 ± 5 pg/mL after two weeks drug therapy, respectively. Similarly, in second group NT-proBNP level was 1657 ± 989 pg/mL and 646 ± 5 pg/mL before and after treatment. Amlodipine or sildenafil significantly reduced NT-proBNP levels in COPD-induced PH patients (p < 0.05).
Our study shows that amlodipine and sildenafil have a similar effect on NT-proBNP levels. In both groups NT- proBNP levels were significantly reduced after treatment. Therefore, our findings support the potential benefits of treatment with vasodilators in COPD induced PH.
Pulmonary hypertension, Chronic obstructive pulmonary disease, NT-proBNP, Amlodipine, Sildenafil
PMCID: PMC3977066  PMID: 24711842
23.  Results of a 14-Week, Multicenter, Prospective, Randomized, Open-Label, Noninferiority Clinical Trial Comparing the Antihypertensive Effect and Edema Incidence of Lacidipine and Amlodipine in Older Korean Patients with Mild-to-Moderate Hypertension☆ 
Background
It has been shown that administration of lacidipine markedly reduces systolic blood pressure in elderly patients with hypertension without increasing the incidence of cardiovascular events and total mortality. But in Korea, there were no available data about the effectiveness and safety of lacidipine.
Objectives
The goal of our study was to compare the effect of lacidipine and amlodipine besylate on sitting systolic blood pressure (SBP) and edema regression time as primary parameters, and sitting diastolic blood pressure (DBP) and tolerability as a secondary parameter in patients with hypertension.
Method
This was a prospective, randomized, open-label, noninferiority study in which patients received 14 weeks of treatment with either lacidipine or amlodipine besylate. Patients aged 55 to 80 years having uncomplicated, mild-to-moderate essential hypertension (SBP 140 to <180 mm Hg or DBP ≥90 mm Hg) and receiving no antihypertensive medications during the 2 weeks before randomization were randomly assigned to receive lacidipine or amlodipine. The incidence of adverse events was also assessed.
Results
In total, 315 patients (154 men, mean age 67.6 years) were included in the intent-to-treat analysis and randomly assigned to receive lacidipine (n = 162) or amlodipine besylate (n = 153); 286 patients were included in the per-protocol analysis (n = 150 for lacidipine, n = 136 for amlodipine) (12 in the lacidipine group and 17 in the amlodipine group were excluded from the per-protocol analysis due to consent withdrawal or protocol violation). There were no differences in demographic profiles between the 2 groups. Mean (SD) SBP changes at 14 weeks were −18.9 (12.7) mm Hg in the lacidipine group and −20.6 (12.4) mm Hg in the amlodipine group (P >0.05). Because the 1-sided 95% CI for the difference in mean SBP changes between groups (−4.18 to 0.72) was within the pre-specified lower limit (−5 mm Hg), lacidipine was considered noninferior to amlodipine. There were no differences in mean edema regression time and in mean DBP changes. These results were consistent in the isolated systolic hypertension subgroup analysis. The overall incidence of clinical adverse events was comparable between the 2 groups (ie, 7.4% in the lacidipine group and 11.1% in the amlodipine group [P >0.05]). The most common adverse events were headache and facial flushing (5 out of 162 patients [3.1%] in the lacidipine group and 11 out of 153 patients [7.2%] in the amlodipine group].
Conclusions
Fourteen weeks of lacidipine treatment significantly reduced blood pressure in older Korean patients with mild-to-moderate hypertension. The efficacy of lacidipine was not inferior to that of amlodipine besylate and tolerability was comparable between the 2 treatment groups. ClinicalTrials.gov identifier: NCT00460915.
doi:10.1016/j.curtheres.2013.02.001
PMCID: PMC3862199  PMID: 24384734
amlodipine; blood pressure; hypertension; lacidipine
24.  Effects of combining azilsartan medoxomil with amlodipine in patients with stage 2 hypertension 
Blood Pressure Monitoring  2014;19(2):90-97.
Objective
The aim of the study was to measure the effects on blood pressure (BP) of the angiotensin receptor blocker azilsartan medoxomil, in 40 and 80 mg doses, combined with 5 mg of the calcium channel blocker amlodipine and to compare these effects with placebo plus amlodipine 5 mg.
Methods
This was a randomized, controlled, double-blind study of 6 weeks’ duration in 566 patients with stage 2 hypertension. The primary endpoint was 24-h systolic BP by ambulatory monitoring.
Results
The mean age of the participants was 58 years; men and women were equally represented, and baseline 24-h BP (153–154/93 mmHg) and clinic BP (165–166/94–95 mmHg) were similar across the three treatment groups. After 6 weeks, 24-h BP decreased by 25/15 mmHg in both the azilsartan medoxomil/amlodipine 40/5 and 80/5 mg groups. These reductions were each greater than the 14/8 mmHg decrease with placebo plus amlodipine 5 mg (P≤0.001 for both comparisons). All treatments were well tolerated, and adverse events did not increase with the azilsartan medoxomil doses. Edema or fluid retention was less common in both combination groups (2.6 and 2.7%) than with placebo plus amlodipine (7.6%).
Conclusion
Coadministration of azilsartan medoxomil with amlodipine was well tolerated and led to meaningful additional BP reductions compared with placebo plus amlodipine.
doi:10.1097/MBP.0000000000000027
PMCID: PMC3966914  PMID: 24445723
ambulatory blood pressure monitoring; amlodipine; angiotensin II receptor blockers; azilsartan medoxomil
25.  Adherence with single-pill amlodipine/atorvastatin vs a two-pill regimen 
While clinical trials demonstrate the benefits of blood pressure and cholesterol reduction, medication adherence in clinical practice is problematic. We hypothesized that a single-pill would be superior to a 2-pill regimen for achieving adherence. In this retrospective, cohort study based on pharmacy claims data, patients newly initiated on a calcium channel blocker (CCB) or statin simultaneously or within 30 days, regardless of sequence, were followed (N = 4703). Adherence was measured over 6 months as proportion of days covered (PDC). At baseline, mean age was 63.0 years, 51.6% were female, and mean number of other medications was 7.8. Overall, 16.9% of patients were on single-pill amlodipine/atorvastatin, 15.6% amlodipine + atorvastatin, 24.7% amlodipine + other statin, 13.9% other CCB + atorvastatin, 28.9% other CCB + other statin. Percentages of patients achieving adherence (PDC ≥ 80%) were: 67.7% amlodipine/atorvastatin; 49.9% amlodipine + atorvastatin; 40.4% amlodipine + other statin; 46.9% other CCB + atorvastatin; 37.4% other CCB +other statin. After adjusting for treatment selection and cohort differences, odds ratios for adherence with amlodipine/atorva-statin were 1.95 (95% confidence interval [CI], 1.80–2.13) vs amlodipine + atorvastatin, 3.10 (95% CI, 2.85–3.38) vs amlodipine + other statin, 2.06 (95% CI, 1.89–2.24) vs other CCB + atorvastatin, 2.85 (95% CI, 2.61–3.10) vs other CCB + other statin (all p <0.0001). Single-pill amlodipine/atorvastatin may provide clinical benefits through improving adherence, offering clinicians a practical solution for cardiovascular risk management.
PMCID: PMC2515427  PMID: 18827917
amlodipine besylate; atorvastatin calcium; adherence; persistence

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