Cost-effectiveness analysis comparing single-pill combination of perindopril/amlodipine/indapamide to the free equivalent combination in patients with hypertension from an Italian national health system perspective.

OBJECTIVE: To evaluate the cost-effectiveness of a single-pill combination (SPC) of perindopril/amlodipine/indapamide versus its free equivalent combination (FEC) in adults with hypertension in Italy. METHODS: A Markov model was developed to perform a cost-utility analysis with a lifetime horizon and an Italian healthcare payer's perspective. In the model, the additional effect of the SPC on blood pressure level compared with the FEC was translated into a decreased risk of cardiovascular events and CKD, which was modeled via Framingham risk algorithms. Difference in persistence rates of SPC and FEC were modeled via discontinuation rates. RESULTS: A perindopril/amlodipine/indapamide SPC is associated with lower cost and better health outcomes compared to its FEC. Over a lifetime horizon, it is associated with a 0.050 QALY gain and cost savings of €376, resulting from lower cardiovascular event rates. In the alternative scenario, where different approach for modeling impact of adherence was considered, incremental gain of 0.069 QALY and savings of €1,004 were observed. Results were robust to sensitivity and scenario analyses, indicating that use of this SPC is a cost-effective strategy. CONCLUSIONS: The findings indicate that a perindopril/amlodipine/indapamide SPC is a cost-saving treatment option for hypertension in Italy, compared to its FEC.

Combinação fixa de benazepril associado a anlodipino para adultos com hipertensão arterial sistêmica com controle inadequado da pressão arterial / Fixed combination of benazepril associated with amlodipine for adults with controlled systemic arterial hypertension inadequate blood pressure

INTRODUÇÃO: A hipertensão arterial sistêmica (HAS), uma doença crônica, é um grave problema de saúde pública, caracterizada por níveis elevados e persistentes da pressão sanguínea, medidos em geral como uma razão da pressão arterial sistólica e diastólica (respectivamente maior ou igual a 140 mmHg; e/ou maior ou igual a 90 mmHg). Esta é uma doença altamente prevalente em todo o mundo. No Brasil, os números podem variar de acordo com a metodologia utilizada. Reportou-se na Pesquisa Nacional de Saúde de 2013, cujos dados são obtidos por autorrelato, a prevalência de hipertensão em 21% dos pacientes, mas ao considerar a aferição da pressão arterial e uso de medicamentos, o percentual de adultos com pressão arterial ≥140/90 mmHg foi de 32%. Sabe-se que a falta de controle da pressão arterial pode elevar o risco de ocorrência de eventos cardiovasculares, como infarto agudo do miocárdio, insuficiência cardíaca, acidente vascular cerebral, doenças renais, entre outros. Isso consequentemente pode causar problemas crônicos que reduzem a qualidade de vida do indivíduo, e até mesmo o

Economic evaluation of olmesartan/amlodipine fixed-dose combination for hypertension treatment in China.

Objectives: To evaluate the cost-effectiveness of olmesartan/amlodipine fixed-dose combination vs olmesartan and amlodipine free combination, amlodipine single drug, and valsartan/amlodipine fixed-dose combination in the treatment of hypertensive patients from payer perspective in China.Methods: A Markov model was constructed, which included five health states of hypertensive patients who are aged 35-84 years at baseline and free of cardiovascular disease. Clinical data were obtained from a network meta-analysis. Epidemiology data, adverse events (AEs), cost, and utility data were obtained from the literature. The cost associated with AEs was estimated based on the cost of same symptoms of hypertensive patients in an electric medical record database. The model projected quality-adjusted life years (QALYs) gained, total costs per patient in a 20-year time horizon, and incremental cost-effectiveness ratios. Probability sensitivity analyses (PSA) and one-way sensitivity analyses were conducted for the main parameters to test the robustness of the model.Results: Compared to olmesartan and amlodipine free combination, amlodipine, and valsartan/amlodipine fixed-dose combination, treatment with olmesartan/amlodipine fixed-dose combination led to fewer CVD events and deaths; resulted in an incremental cost of ¥-5,439 ($-791.36), ¥6,530 ($950.09), and ¥-1,019 ($-148.26) and gained additional QALYs of 0.052, 0.094, and 0.037 per patient, respectively. Compared with olmesartan and amlodipine free combination and valsartan/amlodipine fixed-dose combination, olmesartan/amlodipine fixed-dose combination was dominant. Compared with amlodipine alone, the incremental cost-effectiveness ratios were below the WHO recommended cost-effectiveness threshold, indicating the olmesartan/amlodipine fixed-dose combination was a cost-effective option for hypertensive patients in China. The 10-years' time horizon scenario analysis showed similar results to the 20-years' time horizon. Probabilistic sensitivity analysis and one-way sensitivity analyses showed the robustness of the model results.Conclusions: Olmesartan/amlodipine fixed-dose combination confers better health outcomes and costs less compared with olmesartan and amlodipine free combination and valsartan/amlodipine fixed-dose combination, and is cost-effective compared to amlodipine for hypertension treatment in China.

Amlodipine alters hemorheological parameters: Increased efficacy at the cost of edema?

BACKGROUND: Despite several decades of use of calcium channel blockers, the side effect of edema persists as a class effect, and its mechanism is unresolved. Amlodipine has effects on hemorheology (HR), and its hemodilutory property may partly contribute to its antihypertensive action. This aspect is not well studied, and the literature is sparse in this regard. OBJECTIVE: This experiment was planned to determine effect of a single-dose administration of amlodipine on HR parameters in normal human volunteers. METHODS AND RESULTS: Amlodipine (5 mg) or S (-) amlodipine (2.5 mg) was administered to 27 normal human volunteers. Whole-blood viscosity (WBV) at different shear rates, plasma viscosity (PV), red cell rigidity (RCR), red cell aggregation (RCA), hematocrit (Hct), plasma hemoglobin, along with plasma drug concentration were determined at time intervals, t = 0, 4, 8, 12, and 24 h. Statistically significant reductions were observed at tmax = 4 h in WBV at shear rates of 0.512 s-1 (p < 0.005), WBV at shear rates of 5.26 s-1 (p < 0.01), PV (p < 0.05), and Hct (p < 0.01). At t = 8 h, as drug concentration reduced, some of the changes persisted and later slowly decreased with the decreasing drug concentration till t = 24 h. Red blood cell-related parameters such as RCA and RCR remained unaltered. WBV values at all shear rates, when corrected for Hct = 0.45, did not show deviation from their original values at any time. CONCLUSIONS: Amlodipine causes a reduction in Hct and blood viscosity, along with hemodilution. These effects persist as long as the drug remains in plasma. Edema resulting from chronic dosing may be explained by the aforementioned effects. It is possible that antihypertensive action of the drug may be due to a combination of vasodilatation and an improvement in the HR properties.

Fixed-dose vs free-dose combinations for the management of hypertension-An analysis of 81 958 patients.

Fixed-dose combinations (FDC) have been developed to reduce the pill burden for hypertensive patients. Data on fixed-dose or free-dose (freeDC) ramipril/amlodipine (R/A) or candesartan/amlodipine (C/A) combination treatment initiation were assessed. 71 463 patients were prescribed R/A and 10 495 C/A. For both R/A and C/A, FDC patients were younger (both P < .001) and less comorbid. Prior MI (OR: 0.61 and 0.60), prior stroke (OR: 0.68 and 0.70) and CHD (OR: 0.68 and 0.64) were negatively associated with FDC use, whereas hyperlipidemia was positively associated (OR: 1.26 and 1.19). Use of antihypertensive comedication (OR: 0.78; OR: 0.55) and treatment discontinuation within 12 months (HR: 0.65 and 0.82) were less likely in FDC patients, who also showed superior adherence (mean MPR; both P < .001). Cost of the combination was higher for FDCs (both P < .001). FDCs improve persistence and adherence, although they are more commonly prescribed in patients with less cardiovascular disease.

Cost-benefit analysis of the polypill in the primary prevention of myocardial infarction and stroke.

The primary prevention of cardiovascular disease is a public health priority. To assess the costs and benefits of a Polypill Prevention Programme using a daily 4-component polypill from age 50 in the UK, we determined the life years gained without a first myocardial infarction (MI) or stroke, together with the total service cost (or saving) and the net cost (or saving) per year of life gained without a first MI or stroke. This was estimated on the basis of a 50 % uptake and a previously published 83 % treatment adherence. The total years of life gained without a first MI or stroke in a mature programme is 990,000 each year in the UK. If the cost of the Polypill Prevention Programme were £1 per person per day, the total cost would be £4.76 bn and, given the savings (at 2014 prices) of £2.65 bn arising from the disease prevented, there would be a net cost of £2.11 bn representing a net cost per year of life gained without a first MI or stroke of £2120. The results are robust to sensitivity analyses. A national Polypill Prevention Programme would have a substantial effect in preventing MIs and strokes and be cost-effective.

Comparison of amlodipine/valsartan/hydrochlorothiazide single pill combination and free combination: adherence, persistence, healthcare utilization and costs.

OBJECTIVES: To determine whether amlodipine/valsartan/hydrochlorothiazide single pill combination (SPC) is associated with improved persistence, adherence and reduced healthcare utilization and costs compared to the corresponding free combination (FC). METHODS: Adult (≥18 years) patients covered by commercial and Medicare Supplemental insurance in the Truven MarketScan database with hypertension (HTN) diagnosis between October 2009 and December 2011 were included. At least two filled prescriptions for the SPC cohort or two periods of minimum 15 days of concurrent use of amlodipine, valsartan and hydrochlorothiazide (HCT) for the FC cohort were required. Cohorts were propensity score matched (PSM) to balance on important confounders. Outcomes included: 1) adherence (proportion of days covered [PDC] and medication possession ratio [MPR]); 2) persistence (treatment gap >30 days); 3) all-cause and HTN-specific healthcare utilization and costs at 12 months. RESULTS: After cohort matching with PSM, patients taking SPC (N = 9221) exhibited better outcomes than FC (N = 1884): higher mean adherence (85.7% vs. 77.0%), mean PDC (73.8% vs. 60.6%) and persistence (46.8% vs. 23.6%) (all p < 0.0001). Patients taking SPC were associated with higher odds of persistence (OR: 3.51; 95% CI: 3.08-4.02), MPR ≥80% (OR: 2.72; 95% CI: 2.40-3.08) and PDC ≥80% (OR: 2.88; 95% CI: 2.55-3.26). After PSM, the SPC cohort exhibited statistically significantly lower mean number of resource utilization events compared to FC. Patients in the SPC cohort also had a statistically significantly (p < 0.05) lower percentage of patients with ≥1 all-cause hospitalization (15.0% vs. 18.2%), ≥1 all-cause emergency room (ER) visits (25.7 vs. 31.4%), and ≥1 ER HTN-specific visits (9.7% vs. 14.1%). The costs incurred by SPC cohort patients were 2.8% to 41.7% numerically lower than the FC cohort, statistically significant for all-cause ER costs ($430.6 vs. $549.5, p < 0.05). CONCLUSIONS: Real-world data indicate an association of the amlodipine/valsartan/HCT SPC with improved adherence and persistence vs. FC with no difference in overall healthcare or hypertension specific costs between the cohorts.

Economic evaluation of single-pill combination of indapamide and amlodipine in the treatment of arterial hypertension in the Polish setting.

BACKGROUND: Arterial hypertension is a common disorder that affects around 9 million adults in Poland. Single-pill combinations (SPCs) for the treatment of arterial hypertension have significant advantages over the free combinations, resulting in lower risk of cardiovascular events and lower consumption of medical resources. The current ESC/ESH 2013 guidelines for the first time recommend treatment with a combination of thiazide-like diuretic with calcium channel blocker. Currently, no such combination is reimbursed from public funds in Poland. AIM: To assess the economic value of treatment with SPC of indapamide and amlodipine (Tertens-AM®) for hypertensive patients compared with free combination therapy (FC), in the Polish setting. METHODS: As there are currently no published data directly estimating the additional effect of using indapamide + amlo-dipine SPC vs. FC, two extreme approaches are presented: with difference in effectiveness due to improved adherence to the treatment estimated from published studies on other molecules used in hypertension such as SPCs and FCs - the base-case approach (1); and assuming no difference of effectiveness or adherence between SPC and FC of indapamide and amlodipine - the conservative approach (2). Modelling was carried out based on the Markov process in lifetime horizon. In the base-case approach, with the difference in effectiveness between SPC and FC, it was assumed that the differences in compliance translate into the differences in systolic blood pressure. Patients' characteristics were correlated with the risk of events associated with cardiovascular disease, based on the prediction algorithms from the Framingham Heart Study. Costs were considered from a National Health Fund (NHF) perspective and NHF and patient's perspective, and therefore direct medical costs were only included. RESULTS: The treatment with SPC of indapamide and amlodipine in place of FC resulted in 7.6 additional days of life in full health and longer overall patient survival by 2.9 days. The replacement of FC with SPC would result in national savings from both NHF perspective and NHF and patient's perspective, irrespective of the assumption of the difference in adherence between SPC and FC. The savings would amount to 1.602-3.954 million PLN and 16.498-19.186 million PLN from NHF perspective and NHF and patient's perspective, respectively. CONCLUSIONS: The treatment with SPC of indapamide and amlodipine for hypertensive patients was found to be dominant over FC or at least less expensive than treatment with FC when the difference in effectiveness was neglected. The replacement of FC with SPC would result in savings from both NHF perspective and NHF and patient's perspective.

Difficult Hypertension Clinic Utilizing a Nurse Specialist: A Cost-Efficient Model for the Modern Era?

In the modern era in New Zealand, there has been a lack of specialist hypertension clinics where family practitioners might refer patients with difficult-to-treat or resistant hypertension. A new specialist referral hypertension clinic was established in 2009 at North Shore Hospital, Auckland, employing a model of care where much of the follow-up work is done by a nurse specialist. The authors review data from the first 1000 patients discharged from the clinic. Mean (treated) blood pressure improved by -26/12 mm Hg over an average of three visits, two thirds of which were to nurse specialist clinics. The authors propose this as a cost-efficient model that could easily be duplicated in other centers.

Pharmacokinetic drug-drug interaction assessment between LCZ696, an angiotensin receptor neprilysin inhibitor, and hydrochlorothiazide, amlodipine, or carvedilol.

LCZ696 is a first-in-class angiotensin receptor neprilysin inhibitor in development for treatments of hypertension and heart failure indications. In 3 separate studies, pharmacokinetic drug-drug interactions (DDIs) potential was assessed when LCZ696 was coadministered with hydrochlorothiazide (HCTZ), amlodipine, or carvedilol. The studies used a open-label, single-sequence, 3-period, crossover design in healthy subjects. Blood samples were collected to determine the pharmacokinetic parameters of LCZ696 analytes (AHU377, LBQ657, and valsartan), HCTZ, amlodipine, or carvedilol (R[+]- and S[-]-carvedilol) for statistical analysis. When coadministered LCZ696 with HCTZ, the 90% CIs of the geometric mean ratios of AUCtau,ss of HCTZ and that of LBQ657 were within a 0.80-1.25 interval, whereas HCTZ Cmax,ss decreased by 26%, LBQ657 Cmax,ss increased by 19%, and the AUCtau,ss and Cmax,ss of valsartan increased by 14% and 16%, respectively. Pharmacokinetics of amlodipine, R(+)- and S(-)-carvedilol, or LBQ657 were not altered after coadministration of LCZ696 with amlodipine or carvedilol. Coadministration of LCZ696 400 mg once daily (qd) with HCTZ 25 mg qd, amlodipine 10 mg qd, or carvedilol 25 mg twice a day (bid) had no clinically relevant pharmacokinetic drug-drug interactions. LCZ696, HCTZ, amlodipine, and carvedilol were safe and well tolerated when given alone or concomitantly in the investigated studies.

Blood pressure control and satisfaction of hypertensive patients following a switch to combined drugs of an angiotensin receptor blocker and a calcium channel blocker in clinical practice of nephrology.

BACKGROUND: Combination drugs containing an angiotensin receptor blocker and a calcium channel blocker have been widely commercialized in recent years, and their advantages, such as improvements in adherence, and reductions in medication costs, have been greatly emphasized. However, the actual situations and the impact of switching to combination drugs in clinical practice of nephrology are not fully understood. METHODS: This study was conducted in outpatients of nephrology who received antihypertensive medicines, and who switched to combination drugs. Changes in the potency of the antihypertensive drugs, and blood pressure were examined retrospectively before and after changing treatments. In addition, the study also involved patients' questionnaire, which examined changes in blood pressure at home, the presence or absence of missed doses, the impact on medication-related expenses, and the level of patients' satisfaction with regard to combination drugs. RESULTS: Survey results from 90 participants revealed that changing to combination drugs resulted in a reduction of missed doses, a decrease in blood pressure measured in an outpatient setting, and a reduction in medication-related expenses in total patients, non-chronic kidney disease (CKD) patients, and CKD patients. CONCLUSION: Our study shows that switching to combination antihypertensive drugs resulted in an improvement in adherence and a reduction in medication-related expenses, and revealed that patient satisfaction was high. Combination drugs for hypertensive patients may be beneficial in both medical and economical viewpoints.

[Postregistration study of comparative assessment efficacy of the use of fixed combination of nebivolol and amlodipine for the treatment of patients with moderate and high degree of arterial hypertension].

AIM: of the study was to assess efficacy of the use of fixed combination of nebivolol and amlodipine in patients with moderate and high degree of arterial hypertension (AH). MATERIAL AND METHODS: Patients with diagnosis of primary AH (n=124) were divided into 2 groups by random sample method. Patients of group 1 (n=62) received of fixed combination of nebivolol and amlodipine, while those of group 2 (n=62) received free combination of nebivolol and amlodipine. Study drugs were administered both as initial therapy and replacement of preceding treatment. Duration of observation was 3 months with visits after first 2 weeks and in 1, 2, and 3 months after enrollment. RESULTS: Starting from 2nd week visit of fixed combination of nebivolol and amlodipine treated patients had significantly lower levels of systolic and diastolic AP. Already after 2 weeks of combined two-component therapy 60% of group 1 and 52% of group 2 patients achieved target AP. Target AP was achieved by the end of month 1 by 86 and 71%, of month 2 - by 93 and 78% of patients in groups 1 and 2, respectively. In 3 months almost all patients had target AP, but in 1.6% of group 1 and 2.3% of group 2 patients this level was achieved after addition of a thiazide diuretic. Patients receiving of fixed combination of nebivolol and amlodipine achieved noromosyslolia more quickly compared with patients who received free combination of nebivolol and amlodipine. CONCLUSION: Combined therapy with fixed combination of nebivolol and amlodipine appears to be one of effective approaches to treatment of patients with moderate and high degree AH.

Impact of antihypertensive combination and monotreatments on blood pressure variability: assessment by old and new indices. Data from a large ambulatory blood pressure monitoring database.

OBJECTIVES: High 24-h ambulatory blood pressure (ABP) variability is associated with poor cardiovascular outcomes. We analysed a large ABP monitoring database containing data from hypertensive patients treated with telmisartan/amlodipine combination or various monotherapies with the aim of quantifying the 24-h distribution of blood pressure (BP) reduction by treatment through the smoothness index and of developing and testing a new treatment-on-variability index (TOVI) to quantify the effects of treatment on both mean BP and BP variability. METHODS: ABP data were pooled from 10 studies (N = 4294) with a median follow-up of 60 days. Smoothness index was calculated by dividing the mean of treatment-induced hourly BP reductions by its SD. TOVI was calculated as the ratio of the mean of hourly BP reductions to weighted 24-h BP SD (weighted mean of daytime and night-time SDs) under treatment. RESULTS: The SBP/DBP smoothness index and TOVI values of telmisartan/amlodipine combination were significantly (P < 0.0001) higher (smoothness index: 1.81/1.51; TOVI: 2.71/2.13) compared with telmisartan 80  mg (smoothness index: 1.12/0.90; TOVI: 1.55/1.23), amlodipine 10  mg (smoothness index: 1.33/1.09; TOVI: 2.09/1.58), valsartan 160  mg (smoothness index: 1.01/0.81; TOVI: 1.35/1.07), ramipril 10  mg (smoothness index: 0.83/0.63; TOVI: 1.11/0.87) and placebo (smoothness index: 0.23/0.18; TOVI: 0.34/0.30), indicating a smoother 24-h BP reduction profile (higher smoothness index) as well as the achievement of significantly lower and smoother BP levels over 24  h (higher TOVI) with the combination. CONCLUSION: As compared with various monotherapies, the telmisartan/amlodipine combination was associated with a smoother BP reduction over 24  h and with a more favourable balance between mean 24-h BP reduction and the degree of BP variability on treatment, reflecting both its effectiveness in lowering BP levels and its longer duration of action. The agreement between smoothness index and TOVI demonstrates that they are similarly effective in the differentiation of antihypertensive treatments, although providing conceptually different information, the clinical relevance of which needs to be tested by ad-hoc outcome studies.

A review of the efficacy and tolerability of combination amlodipine/valsartan in non-white patients with hypertension.

This article discusses racial/ethnic disparities in hypertension, with particular focus on non-white populations including blacks, Hispanics/Latinos, and Asians. Hypertension and its related morbidity and mortality affect a disproportionate number of black patients compared with white patients. Blacks, Hispanics/Latinos, and Asians have poor rates of hypertension awareness, treatment, and control. Given the high prevalence of comorbidities (e.g., obesity, diabetes, and metabolic syndrome) in these populations, renin-angiotensin-aldosterone system blockers are a good choice for foundation therapy. This review also discusses the importance of adherence and persistence with antihypertensive medication, which remain suboptimal in these non-white populations. Evidence suggests improvement with the use of single-pill combination therapy. Lastly, clinical trial data on the antihypertensive efficacy and safety of the combination of a dihydropyridine calcium channel blocker and an angiotensin receptor blocker, a widely utilized combination, in non-white populations are presented. PubMed was searched using the title/abstract key words (amlodipine AND valsartan AND [hypertension OR hypertensive] AND [black(s) OR African American(s) OR Hispanic(s) OR Latino(s) OR Mexican(s) OR Asian(s)]). In total, eight studies in patients with stage 1 or 2 hypertension were identified (n = 1,111 black, n = 389 Hispanic/Latino, and n = 3,094 Asian). Results showed that treatment with the combination of amlodipine plus valsartan is a reasonable choice for initial therapy or in patients who fail to respond to monotherapy. These drug classes have complementary mechanisms of action and, when used concomitantly, the magnitude of blood pressure lowering in these non-white populations is generally comparable with that seen in non-Hispanic white patients.

Antihypertensive response to combination of olmesartan and amlodipine does not depend on method and time of drug administration.

Fixed combinations of antihypertensive drugs have the potentiality to improve blood pressure (BP) control. However, when pharmacokinetic parameters of the two drugs are different, both method and time of administration of the two drugs may modify the antihypertensive response. In an open-label, single-blind, randomized study we compared antihypertensive effect of four administration schemes of a combination therapy of olmesartan and amlodipine in the same group of hypertensive patients, using ambulatory blood pressure monitoring (ABPM). The olmesartan + amlodipine combination has demonstrated to provide a good control of BP, with systolic and diastolic BP constantly below 130 and 85 mmHg over the 24 h. The simultaneous or separate administration of the 2 drugs fully overlapped, suggesting that the fixed combination and the separate administration induce a similar and sustained BP control.

Pill burden in hypertensive patients treated with single-pill combination therapy--an observational study.

INTRODUCTION: Hypertension is a condition which in many cases is treated with more than one drug. Additionally, patients with hypertension often suffer from other concomitant diseases, such as diabetes mellitus or dyslipidemia, which adds to the number of pills that patients need to take (pill burden). The aim of this study was to investigate the impact of this pill burden on patients with hypertension in clinical practice in Germany. METHODS: This prospective, open-label, observational study enrolled adult patients for whom their physician considered treatment with a single-pill combination of amlodipine, valsartan, and hydrochlorothiazide as indicated. At the start of the observation period, physicians and patients filled in a respective questionnaire. RESULTS: The questionnaires of 7,101 patients and 905 physicians were analyzed. The survey among the patients showed that the majority of patients felt burdened by the high number of pills to be taken. This was also seen as a potential reason for medication errors. Approximately half of the patients would be willing to make an out-of-pocket payment for reducing the number of pills to half. The results of the physician questionnaire indicate that the physicians were well aware of the set of problems that is generally associated with the high pill burden and that there is a clear willingness to use combination products in order to reduce the pill burden. CONCLUSION: A high number of pills is considered a burden by the patients. This burden increases with the number of pills taken per day.

I-ADD study: assessment of efficacy and safety profile of irbesartan/amlodipine fixed-dose combination therapy compared with irbesartan monotherapy in hypertensive patients uncontrolled with irbesartan 150 mg monotherapy: a multicenter, phase III, prospective, randomized, open-label with blinded-end point evaluation study.

BACKGROUND: Hypertension guidelines recommend the use of 2 agents with synergistic action when >1 agent is needed to achieve blood pressure goals. Newer antihypertensive treatment combinations include fixed-dose combinations of an angiotensin receptor blocker and a calcium channel blocker. OBJECTIVE: The I-ADD study aimed to demonstrate whether the antihypertensive efficacy of fixed-dose combination irbesartan 300 mg/amlodipine 5 mg (I300/A5) was superior to that of irbesartan (I300) monotherapy in lowering home systolic blood pressure after 10 weeks' treatment. METHODS: The I-ADD study was a 10-week, multicenter, Phase III, prospective, randomized, parallel-group, open-label with blinded-end point study. The main inclusion criterion was essential uncontrolled hypertension (systolic blood pressure ≥145 mm Hg at office after at least 4 weeks of irbesartan 150 mg [I150] monotherapy administered once daily). Patients continued to receive I150 for 7 to 10 days and were randomized to either monotherapy with I150 for 5 weeks then I300 for the next 5 weeks, or to a fixed-dose combination therapy (I150/A5, then I300/A5). Safety profile was assessed by recording adverse events reported by patients or observed by the investigator. RESULTS: Following enrollment, 325 patients were randomized to treatment, and 320 (mean [SD] age, 56.7 [11.4] years; 41% male) were included in the intention-to-treat analysis: 155 patients treated with I150/A5 then I300/A5, and 165 patients treated with I150 then I300. At randomization, mean home systolic blood pressure was similar in both groups: 152.7 (11.8) mm Hg in the I150/A5 group and 150.4 (10.1) mm Hg in the I150 group. At week 10, the adjusted mean difference in home systolic blood pressure between groups was -8.8 (1.1) mm Hg (P < 0.001). The percentage of controlled patients (mean home blood pressure <135 and 85 mm Hg) was nearly 2-fold higher in the I300/A5 group versus the I300 group (P < 0.001). Treatment-emergent adverse events were experienced by 10.5% of I300/A5-treated patients and 6.6% of I300-treated patients during the second 5-week period. Three serious adverse events were reported; 2 with monotherapy (1 with I150 and 1 with I300) and 1 with fixed-dose combination I300/A5. All patients affected by serious adverse events made a full recovery. CONCLUSIONS: These 10-week data from this patient population suggest a greater antihypertensive efficacy of the fixed-dose combination I300/A5 over I300 alone in lowering systolic blood pressure. Both treatments were well tolerated throughout the study. ClinicalTrials.gov identifier: NCT00957554.

I-COMBINE study: assessment of efficacy and safety profile of irbesartan/amlodipine fixed-dose combination therapy compared with amlodipine monotherapy in hypertensive patients uncontrolled with amlodipine 5 mg monotherapy: a multicenter, phase III, prospective, randomized, open-label with blinded-end point evaluation study.

BACKGROUND: Hypertension guidelines recommend the use of 2 agents with synergistic action when >1 agent is needed to achieve blood pressure goals. Newer antihypertensive treatment combinations include fixed-dose combinations of an angiotensin receptor blocker and a calcium channel blocker. OBJECTIVE: The I-COMBINE study aimed to determine whether the antihypertensive efficacy of the fixed-dose combination irbesartan 150 mg/amlodipine 5 mg (I150/A5) was superior to that of amlodipine 5 mg (A5) monotherapy in lowering home systolic blood pressure (HSBP) after 5 weeks' treatment. METHODS: The I-COMBINE study was a 10-week, multicenter, Phase III, prospective, randomized, parallel-group, open-label with blinded-endpoint study. The main inclusion criterion was essential uncontrolled hypertension (SBP ≥145 mm Hg at office, after at least 4 weeks of A5 monotherapy administered once daily). Patients continued to receive A5 for 7 to 10 days and were randomized to either monotherapy with A5 for 5 weeks then amlodipine 10 mg (A10) for the next 5 weeks or to a fixed-dose combination therapy (I150/A5 then I150/A10). Safety profile was assessed by recording adverse events reported by patients or observed by the investigator. RESULTS: Following enrollment, 290 patients were randomized to treatment, and 287 (mean [SD] age, 57.3 [11.2] years; 48% male) were included in the intention-to-treat analysis: 144 patients treated with I150/A5 then I150/A10, and 143 patients treated with A5 then A10. At randomization, mean HSBP was similar in both groups: 148.5 (10.3) mm Hg in the I150/A5 group and 149.2 (9.7) mm Hg in the A5 group. At week 5, the adjusted mean difference in HSBP between groups was -6.2 (1.0) mm Hg (P < 0.001). The proportion of controlled patients (mean home blood pressure <135 and 85 mm Hg) was significantly higher in the I150/A5 group than in the A5 group (P < 0.001). Treatment-emergent adverse events were experienced by 13.8% of I150/A5-treated patients and 11.9% of A5-treated patients during the first 5-week period, and by 15.8% of I150/A10-treated patients and 17.0% of A10-treated patients during the second 5-week period. Two serious adverse events were reported with the fixed-dose combination; both patients recovered. CONCLUSIONS: Data from this adult population with essential hypertension suggest greater efficacy with the fixed-dose combination I150/A5 over A5 monotherapy in lowering SBP after 5 weeks. Both treatment regimens were well tolerated throughout the study. ClinicalTrials.gov identifier: NCT00956644.

[Shortening of donepezil-induced QTc prolongation with a change in the interacting drug, after electrocardiograph monitoring by community pharmacists: a case report].

UNLABELLED: We used a mobile electrocardiograph to manage the adverse effects and interactions of drugs, especially QT-prolonging drugs, in a community pharmacy setting. We report the case of a patient in whom the risk of drug-induced torsades de pointes (TdP) was lowered, after monitoring by community pharmacists. CASE: An 80-year-old woman was under donepezil (5 mg/d) therapy for Alzheimer's disease and also taking other drugs that interact with donepezil, namely, benidipine (8 mg/d) and atorvastatin (10 mg/d). The patient was visited almost every month, and an electrocardiogram was usually obtained. QTc prolongation (avg. 470±9 ms) was observed in the first to third tests. Her doctor was informed about these results and the risk factors (advanced age, gender, and drugs interactions (benidipine and atorvastatin)) associated with TdP and asked to respond promptly since several cases of donepezil-induced TdP have been reported. As a result, benidipine was replaced with amlodipine, while the remaining drugs were continued. After the change, a significant decrease in QTc values were observed in the fourth to seventh tests (avg. 441±9 ms, p=0.010), thereby indicating a decrease in TdP risk. The Drug Interaction Probability Scale (object drug, donepezil; precipitant drug, benidipine) score was +6 (probable). Thus, QTc shortening was a result of differences in donepezil-benidipine and donepezil-amlodipine interactions.

Assessment on antihypertensive effect and safety of nifedipine controlled-release tablet administered at 80 mg/day in practical clinic.

In this study, the effect of nifedipine controlled-release tablets at a dose of 80 mg/day (NCR80) on blood pressure (BP) and safety was investigated. In essential hypertension (n = 50, >140/90 mm Hg) despite a combined therapy with antihypertensive agents, NCR80 was administered instead of the previous antihypertensive agents and changes in BP and pulse rate (PR), side effects, and changes in laboratory test values were examined for 24 months. Thirty-three patients switched to NCR80 as the initial dose from the previous antihypertensive agents (Initial), while 17 patients started treatment at NCR40 and increased to NCR80 after 1-3 months (Up-titration). In the Initial group, BP decreased significantly and this significant reduction continued for 24 months, but not in the case of PR. In the Up-titration group, BP decreased significantly during the treatment with NCR40, and further reduced in 1-2 month(s) after NCR80. This significant reduction continued for 12 months, but not in the case of PR. The mean change in BP after increasing NCR40 to NCR80 was -16/-6 mm Hg at 6 months. When patients who received NCR80 were stratified into three grades according to the baseline systolic blood pressure level (SBP) (≥180, 160-179, and 140-159 mm Hg), the mean change in BP at 1 month was -55, -27, and -16 mm Hg, respectively. None of the 50 patients treated with NCR80 experienced any side effects and no abnormal change was observed in their laboratory test values. These findings suggested that NCR80 demonstrated the ability to control BP appropriately depending on the severity with favorable safety.