Measures to improve angiotensin receptor blocker prescribing efficiency in the UK: findings and implications.

BACKGROUND: Generic losartan provides an opportunity to enhance angiotensin receptor blocker (ARB) prescribing efficiency, with all ARBs essentially being similar. Initially, there was limited activity in NHS Bury (UK). This changed in March 2011 with therapeutic switching and other measures encouraging the prescribing of losartan following generics to enhance its utilization versus patented ARBs. AIM: This study aims to assess the impact of multiple measures on losartan utilization, its price and total ARB expenditure. METHODS: An interrupted time series analysis was performed. Utilization was measured as prescription items dispensed, typically 28 days. RESULTS: No immediate change in losartan utilization was observed following generics. This changed after the multiple initiatives with losartan accounting for 65% of all single ARB items dispensed by the study end. ARB expenditure was 59% below prestudy levels by the study end, which was helped by a 92% reduction in expenditure per item for losartan. Annual net savings from the program were estimated at just under GB£290,000, which is over eight-times the cost of implementation. CONCLUSION: Multiple measures can enhance prescribing efficiency. Health authorities cannot rely on a 'spillover' effect from other classes in order to affect changes in physician prescribing habits.

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.

Design and development of ethosomal transdermal drug delivery system of valsartan with preclinical assessment in Wistar albino rats.

Valsartan (VLT) is a highly selective and orally active antihypertensive drug. However, its oral administration is associated with drawbacks like low bioavailability. The objective of this study was to design and develop a transdermal delivery system for VLT using ethosomal carriers to investigate their enhanced transdermal delivery potential. VLT ethosomes were prepared by cold method. VLT ethosomes were characterized by scanning electron microscopy. The prepared ethanolic liposomes were characterized to be spherical having low polydispersity of nano-size range with good entrapment efficiency. ETC5 ethosomal suspension with 4% of phospholipon 90H and 40% of ethanol was found to have highest entrapment efficiency, i.e. 80.230 ± 0.8748%. The permeation study of ethosomes was evaluated by ex vivo diffusion study through rat abdominal skin using Franz's diffusion cells and ETC5 ethosomal suspension was found to have highest permeation with flux of 92.819 ± 1.539 µg/cm²/h, when compared to the permeation profiles of drug solutions either in water or in a water-ethanol mixture. Transdermal application of ethosomal VLT on Wistar rats showed better and prolonged antihypertensive activity in comparison to orally administered VLT suspension by virtue of transdermal permeation through Wistar rat skin. Histopathological study of skin applied with ETC5 showed intercellular permeation across skin by dissolving intercellular lipids in epidermis without causing any rigorous changes in the skin cellular structure. In conclusion, ethosomes enabled the transdermal permeation of VLT, which amply proves its superiority over oral administration for antihypertensive treatment.

Influence of lifting prescribing restrictions for losartan on subsequent sartan utilization patterns in Austria: implications for other countries.

INTRODUCTION: Prescribing restrictions for angiotensin receptor blockers (ARBs) limited their utilization in Austria. Recently, generic losartan became available with its prescribing restrictions lifted while still in place for patented ARBs. OBJECTIVES: The main aim of this study is to assess the impact of the lifting of the prescribing restriction on utilization of losartan in ambulatory care versus other single ARBs, expenditure per defined daily dose (DDD) of losartan as well as total ARB expenditure and utilization of ARB combinations. Finally, to suggest potential measures that could be introduced to further enhance ARB-prescribing efficiency. METHODOLOGY: A quasi-experimental study of the utilization of different ARBs alone or in fixed dose combinations using a segmented time series. Utilization measured in DDDs, defined as 'the average maintenance dose of a drug when used in its major indication in adults'. Costs measured as total expenditure for different ARBs as well as their expenditure/DDD. RESULTS: Losartan utilization increased significantly following the withdrawal of prescribing restrictions (p > 0.001). Utilization of single-sourced ARBs also increased , but the growth rate was appreciably reduced once restrictions were lifted for losartan (p > 0.01). As a result, total expenditure of single ARBs increased but at an appreciably lower rate than utilization, helped by total expenditure/DDD for losartan declining by 78% over the study period. There was continuing appreciable utilization of fixed-dose combinations. CONCLUSION: Lifting of prescribing restrictions for losartan significantly enhanced its utilization, increasing ARB-prescribing efficiency, providing direction to other European authorities. Additional reforms are being considered to further switch utilization away from single-sourced ARBs to additionally improve prescribing efficiency as more multiple sourced ARBs become available.

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.

Assessment of long-term effects of irbesartan on heart failure with preserved ejection fraction as measured by the minnesota living with heart failure questionnaire in the irbesartan in heart failure with preserved systolic function (I-PRESERVE) trial.

BACKGROUND: The Minnesota Living with Heart Failure Questionnaire (MLHFQ) was used in a large, multinational, randomized, placebo-controlled trial to measure adverse effects of heart failure with preserved ejection fraction (HF-PEF) on patients' lives and the effects of irbesartan. METHODS AND RESULTS: Patients with symptomatic HF-PEF were randomly assigned to irbesartan (up to 300 mg daily) or placebo. The MLHFQ was administered at baseline (n=3605), month 6 (n=3137), month 14 (n=2904), and the end of study (median, 56 months, n=2205). Baseline MLHFQ scores of 43±21 indicated that HF-PEF had a substantial adverse effects. Estimated retest reliability was 0.80. Baseline MLHFQ scores were associated with other measures of the severity of heart failure including symptoms, signs of congestion, cardiac structure, and time to hospitalizations or deaths attributed to heart failure. Slight improvement in shortness of breath or fatigue was associated with significant improvement in MLHFQ scores (-5.9 and -5.0, P<0.0001). Compared with placebo, further improvement in MLHFQ scores was not observed with irbesartan after 6 months (mean adjusted difference, 0.4; 95% confidence interval, -0.8 to 1.7), 14 months (0.5; 95% confidence interval, -0.9 to 1.8), or the end of study (2.0; 95% confidence interval, -4.1 to 0.01). CONCLUSIONS: The MLHFQ scores are a reliable, valid, and sensitive measure of the adverse impact of HF-PEF on patients' lives. Irbesartan did not substantially improve MLHFQ scores during a long period of follow-up. Clinical Trial Registration- URL: http://www.clinicaltrials.gov. Unique identifier: NCT00095238.

Days alive and out of hospital and the patient journey in patients with heart failure: Insights from the candesartan in heart failure: assessment of reduction in mortality and morbidity (CHARM) program.

BACKGROUND: Conventional composite outcomes in heart failure (HF) trials, for example, time to cardiovascular death or first HF hospitalization, have recognized limitations. We propose an alternative outcome, days alive and out of hospital (DAOH), which incorporates mortality and all hospitalizations into a single measure. A refinement, the patient journey, also uses functional status (New York Heart Association [NYHA] class) measured during follow-up. The CHARM program is used to illustrate the methodology. METHODS: CHARM randomized 7,599 patients with symptomatic HF to placebo or candesartan, with median follow-up of 38 months. We related DAOH and percent DAOH (ie, percentage of time spent alive and out of hospital) to treatment using linear regression adjusting for follow-up time. RESULTS: Mean increase in DAOH for patients on candesartan versus placebo was 24.1 days (95% CI 9.8-38.3 days, P < .001). The corresponding mean increase in percent DAOH was 2.0% (95% CI 0.8%-3.1%, P < .001). These findings were dominated by reduced mortality (23 days) but enhanced by reduced time in hospital (1 day). Percent time spent in hospital because of HF was reduced by 0.10% (95% CI 0.04%-0.14%, P < .001). The patient journey analysis showed that patients in the candesartan group spent more follow-up time in NYHA classes I and II and less in NYHA class IV. CONCLUSIONS: Days alive and out of hospital, especially percent DAOH, provide a valuable tool for summarizing the overall absolute treatment effect on mortality and morbidity. In future HF trials, percent DAOH can provide a useful alternative perspective on the effects of treatment.

Influence of demand-side measures to enhance renin-angiotensin prescribing efficiency in Europe: implications for the future.

UNLABELLED: European countries strive to enhance prescribing efficiency. This includes renin-angiotensin drugs following the availability of generic angiotensin-converting enzyme inhibitors (ACEIs). AIMS: To compare angiotensin receptor blocker utilization and expenditure patterns in Austria and Croatia following prescribing restrictions, as well as with other European countries introducing different supply- and demand-side measures. Lastly, to appraise the impact of generic losartan in Croatia on utilization of patented angiotensin receptor blockers. METHOD: Observational retrospective study principally between 2001 and 2007, using defined daily doses and €/1000 inhabitants/year. Demand-side measures were based on the four 'E's - education, engineering, economics and enforcement. RESULTS: Greater intensity of follow-up of prescribing restrictions in Croatia enhanced utilization of ACEIs versus Austria. There was high utilization of ACEIs in Scotland following intensive demand-side measures, similar to Austria and Croatia. Demand-side measures in Spain (Catalonia) and Sweden also appeared to moderate angiotensin receptor blockers utilization. The combination of measures helped stabilize expenditure on renin-angiotensin drugs when adjusted for population sizes despite appreciable increases in volumes. The only exception was Portugal, with less intensive measures. CONCLUSION: Multiple and intensive demand-side measures enhanced prescribing efficiency. The more intense follow-up of ARB prescribing restrictions in Croatia had a greater influence on subsequent utilization patterns than Austria. Both findings confirm earlier studies. Reforms also favorably enhanced the prescribing of generic losartan once available.

Valsartan plus hydrochlorothiazide: a review of its use since its introduction.

INTRODUCTION: This review focuses on the role of the fixed-dose combination (FDC) drug valsartan/hydrochlorothiazide (HCTZ) in the treatment of hypertension. Effective blood pressure control often is not achieved with monotherapy and, instead, requires combinations of drugs with different mechanisms of action to produce additive or synergistic effects. AREAS COVERED: FDC valsartan/HCTZ enhances not only efficacy for blood pressure control but also provides beneficial effects on target organs beyond that expected from arterial pressure reduction alone. Data describe key clinical trial experiences with the FDC, with particular attention to efficacy and tolerability. Literature searches of these various topics were conducted in January 2011. There is evidence of potential benefits with this combination associated with left ventricular hypertrophy, left ventricular dysfunction and renal disease. The FDC is an effective treatment for patients with hypertension and is superior to monotherapy than either drug alone. EXPERT OPINION: In addition to the benefits of each drug, valsartan/HCTZ's metabolic interactions reduce some of the negative effects of both compounds. With its increased simplicity, minimal side-effect profile and efficacy without a significant cost penalty, valsartan/HCTZ represents an excellent choice for antihypertensive therapy.

Choice of angiotensin receptor blocker in moderate hypertension. A UK-based cost-benefit comparison of olmesartan- and candesartan-based regimens.

INTRODUCTION: Selection of antihypertensive therapy hinges on an appropriate combination of efficacy, tolerability and compatibility with co-morbidities. Within a given class of antihypertensives, the choice of agent is often driven by cost, with the cheapest appropriate agent being chosen. Amongst the angiotensin receptor blockers (ARBs), this choice will often be losartan, as it is available in generic form. However, as the blood pressure lowering efficacy of losartan is modest, some patients will require an alternative ARB. In the UK this choice is often candesartan, although the agent with greatest BP lowering efficacy is olmesartan. The objective of this study was to use a cost-benefit model to compare the costs associated with target achievement using each of these two agents, in order to guide optimum use of prescribing budgets. METHOD: A probabilistic cost-benefit model was constructed for a cohort of patients with moderate hypertension, based on a standardised titration and maintenance algorithm using either olmesartan or candesartan, combined with thiazide and calcium channel blocker where required. Direct treatment costs were recorded, along with the proportion of patients achieving pre-defined treatment targets at each treatment level. Results were expressed as mean treatment cost per patient reaching target. RESULTS: Based on the current QoF target of 150 mmHg systolic, 94.3% of patients on the olmesartan-based regimen reached target of 150 mmHg, compared with 89.0% of those on the candesartan-based regimen. 86% of olmesartan patients reached target on <3 drugs, compared with 74% of candesartan patients. The mean 12-month cost per patient reaching target was £171.36 for olmesartan versus £189.91 for candesartan. Ongoing annual maintenance costs for patients at target were £169.97 and £182.64, respectively. Similar results were obtained when considering alternative treatment targets LIMITATIONS: The study only compared two ARBs - candesartan and olmesartan and the results relate to prescribing costs only and do not include other healthcare costs. Additionally, the chosen outcome was blood pressure target achievement, rather than clinical endpoints. Given the stated objectives of the model, we do not believe these issues will have introduced bias in the direction of either comparator CONCLUSION: Although olmesartan has an apparently higher acquisition cost than candesartan, its superior BP lowering efficacy means that the overall cost per patient treated to target is actually lower. This result could have significant implications for making savings within primary care prescribing budgets in the UK.

Primary care physicians' adoption of new drugs is not associated with their clinical interests: a pharmacoepidemiologic study.

OBJECTIVES. Increasing drug expenditures call for better understanding of the reasons behind individual general practitioners' (GPs') prescribing decisions. The aim was to analyse associations between GPs' clinical interests and their preference for new drugs. DESIGN. Historical cohort study using population-based prescription data and data collected by postal questionnaire. SETTING AND SUBJECTS. A total of 68 single-handed GPs in the County of Funen, Denmark. Main outcome measures. GPs' preferences for two new (2004) drug groups (selective cyclo-oxygenase-2 inhibitors and angiotensin-II antagonists) were analysed. The preference was defined as the percentage of patients receiving a new drug among first-time users of either the new drug or an older alternative. The GPs' preference proportion was modelled using linear regression analysis. Data from a questionnaire on GPs' interest in corresponding clinical areas (musculoskeletal diseases and hypertension, respectively), continuing medical education (CME) activities, and previous employment were the independent variables. RESULTS. The adjusted mean difference in preference for new drugs between GPs with high and low interest in each of the two clinical areas was 0.4% (95% CI -2.0% to 2.8%), and -2.2% (-15.0% to 10.7%), respectively. Only current CME activities in the area of hypertension were significantly associated with GPs' preference for new drugs (adjusted mean difference 17.9% (95% CI 5.8% to 30.0%). CONCLUSION. No clear association between GPs' self-rated clinical interest and their prescribing of new drugs was found.

[Fixed drug combinations in hypertension: a budget impact analysis for the Spanish Health System on the marketing of a fixed combination of olmesartan/amlodipine]. / Las combinaciones fijas en hipertensión: análisis de impacto presupuestario para el Sistema Nacional de Salud Español de la comercialización de la combinación fija de olmesartan/amlodipino.

OBJECTIVE: To carry out a budget impact analysis (BIA) of olmesartan/amlodipine (20/5, 40/5 and 40/10mg) marketed as a fixed combination (FC) in its approved indication for the National Health System (NHS). DESIG: We developed a decision tree model in order to estimate usual hypertension treatment algorithm in Spanish clinical practice. SETTINGS: The BIA has been developed from the perspective of the NHS for a period of 3 years (years 2010-2012). PARTICIPANTS: Spanish hypertensive population ≥ 35 years old. INTERVENTIONS: Introduction into the market of a fixed combination (FC) olmesartan/amlodipine in Spain. PRIMARY MEASURES: Expected costs to be assumed by the Spanish NHS (RRP-VAT) for hypertensive population able to be treated with the FC versus currently assumed costs by the NHS with free combination olmesartan and amlodipine. RESULTS: Estimated pharmaceutical costs in hypertensive population treated with olmesartan and amlodipine (2 pills) would be €25.2M (1(st) year), €26.4M (2011), €27.6M (2012), with a total 3-year period of €79.2M. According to patient tree model, the population able to be treated with FC would be 71,283 patients (2010), with a growth rate of 4.8% in the successive years, which supposes an annual cost of €21.2M (2010), €21.8M (2011) and €22.4M (2012), with a total 3-year period of €65.4M. The BIA shows savings of €13.8M in a total 3-year period. CONCLUSION: The BIA of FC olmesartan/amlodipine could generate net savings of €13.8M for the NHS in the period ranging from years 2010 to 2012.

Management of chronic heart failure guided by individual N-terminal pro-B-type natriuretic peptide targets: results of the PRIMA (Can PRo-brain-natriuretic peptide guided therapy of chronic heart failure IMprove heart fAilure morbidity and mortality?) study.

OBJECTIVES: The purpose of this study was to assess whether management of heart failure (HF) guided by an individualized N-terminal pro-B-type natriuretic peptide (NT-proBNP) target would lead to improved outcome compared with HF management guided by clinical assessment alone. BACKGROUND: Natriuretic peptides may be attractive biomarkers to guide management of heart failure (HF) and help select patients in need of more aggressive therapy. The PRIMA (Can PRo-brain-natriuretic peptide guided therapy of chronic heart failure IMprove heart fAilure morbidity and mortality?) study is, to our knowledge, the first large, prospective randomized study to address whether management of HF guided by an individualized target NT-proBNP level improves outcome. METHODS: A total of 345 patients hospitalized for decompensated, symptomatic HF with elevated NT-proBNP levels at admission were included. After discharge, patients were randomized to either clinically-guided outpatient management (n = 171), or management guided by an individually set NT-proBNP (n = 174) defined by the lowest level at discharge or 2 weeks thereafter. The primary end point was defined as number of days alive outside the hospital after index admission. RESULTS: HF management guided by this individualized NT-proBNP target increased the use of HF medication (p = 0.006), and 64% of HF-related events were preceded by an increase in NT-proBNP. Nevertheless, HF management guided by this individualized NT-proBNP target did not significantly improve the primary end point (685 vs. 664 days, p = 0.49), nor did it significantly improve any of the secondary end points. In the NT-proBNP-guided group mortality was lower, as 46 patients died (26.5%) versus 57 (33.3%) in the clinically-guided group, but this was not statistically significant (p = 0.206). CONCLUSIONS: Serial NT-proBNP measurement and targeting to an individual NT-proBNP value did result in advanced detection of HF-related events and importantly influenced HF-therapy, but failed to provide significant clinical improvement in terms of mortality and morbidity. (Effect of NT-proBNP Guided Treatment of Chronic Heart Failure [PRIMA]; NCT00149422).

Pharmacokinetics and bioequivalence evaluation of two losartan potassium 50-mg tablets: A single-dose, randomized-sequence, open-label, two-way crossover study in healthy Chinese male volunteers.

BACKGROUND: Losartan is a nonpeptide angiotensin II receptor antagonist used as an antihypertensive agent. The relative bioavailability of a newly developed tablet compared with an established branded formulation has not been reported in a Chinese population. OBJECTIVE: To meet the requirements for marketing a new generic product, the study was designed to compare the pharmacokinetic parameters and relative bioavailability of a new generic losartan potassium 50-mg tablet (test formulation) with a branded 50-mg tablet (reference formulation) in healthy Chinese male volunteers. METHODS: A single-dose, randomized-sequence, openlabel, 2-way crossover study was conducted in healthy Chinese male volunteers. Eligible participants were randomly assigned in a 1:1 ratio to receive a single 50-mg tablet of the test or reference formulation, followed by a 1-week washout period and then administration of the alternate formulation. The study drugs were administered after a 10-hour overnight fast. Plasma samples were collected over 36 hours. Tolerability was evaluated by recording adverse events (AEs) and monitoring vital signs, ECGs, and laboratory tests at baseline and at completion of the study. Plasma concentrations of losartan and its active metabolite (EXP3174) were analyzed by LC-MS/MS. Pharmacokinetic parameters, including C(max), AUC(0-36), and AUC(0-infinity), were calculated. If the 90% CIs for the log-transformed values of AUC were within 80% to 125%, and that of C(max) was within 70% to 143%, the 2 products would be considered bioequivalent according to the guidelines of the US Food and Drug Administration and the State Food and Drug Administration of China. RESULTS: Twenty-seven healthy Chinese male volunteers participated in this study (mean [SD] age, 24.5 [2.3] years [range, 20-29 years]; weight, 64.6 [4.0] kg [range, 60.0-75.0 kg]; height, 172.2 [4.8] cm [range, 165.0183.0 cm]; and body mass index, 21.8 [1.2] kg/m(2) [range, 20.0-25.0 kg/m(2)]). One volunteer (3.7%) experienced an AE (microscopic hematuria) after administration of the test formulation. This resolved spontaneously after 10 days and was considered by the investigator as mild; the relationship with the study drug was uncertain. No serious AEs were reported. Both formulations were associated with significant reductions in systolic and diastolic blood pressure and significant increases in heart rate compared with baseline values (all, P < 0.05). No period, formulation, or sequence effects were observed for any pharmacokinetic parameter, except for a significant subject effect. For parent losartan, the 90% CIs for the ratios (test/reference) of C(max), AUC(0-36), and AUCAUC(0-infinity) were 83.65% to 113.36%, 89.79% to 98.25%, and 90.95% to 99.55%, respectively. For the metabolite EXP3174, the 90% CIs for the ratios of C(max), AUC(0-36), and AUCAUC(0-infinity) were 93.49% to 103.61%, 96.79% to 104.09%, and 97.06% to 105.83%. Both C(max) and AUC met the predetermined criteria for assuming bioequivalence. The relative bioavailability of the test formulation to the reference formulation was 93.92% for losartan and 100.40% for EXP3174. CONCLUSIONS: In this small study in healthy Chinese male volunteers, a single 50-mg oral dose of a losartan potassium tablet (test formulation) met the regulatory criteria for assuming bioequivalence to the established reference formulation. Both formulations were well tolerated.

Telmisartan improves morphologic and functional changes in both left ventricular myocardium and carotid arterial wall in patients with hypertension: assessment by tissue Doppler imaging and carotid ultrasonography.

OBJECTIVE: The aim of the present study was to clarify the beneficial effects of telmisartan on the morphologic and functional changes in left ventricular (LV) myocardium and carotid arterial wall in patients with hypertension (HT) using tissue Doppler imaging and carotid ultrasonography. METHODS: Telmisartan (20-40 mg daily) was administered to 35 previously untreated patients with HT. Conventional and pulsed tissue Doppler echocardiography were performed after medication had been continued for 1-2 months with normal values for blood pressure (BP) (phase I) and for 12 months (phase II). Subclinical atherosclerosis also was determined by measuring the intima-media thickness (IMT) and stiffness ß of the left and right common carotid arteries using B- and M-mode ultrasonography. RESULTS: In the phase II, the LV mass index and isovolumic relaxation time were lower, the peak systolic and early diastolic mitral annular motion velocities were greater compared to the phase I. The stiffness ß and mean IMT were lower in the phase II than in the phase I. On multivariate regression analyses, age, BP, and LV diastolic variables emerged as stronger predictors of carotid arterial IMT and stiffness ß. CONCLUSIONS: The 1-year use of telmisartan improved LV hypertrophy, regional LV myocardial contraction and relaxation, and carotid atherosclerosis in patients with HT. Our results support cardio- and arterioprotective benefits from continuous long-term telmisartan monotherapy, and combined analysis of tissue Doppler imaging and carotid ultrasonography may be a useful tool for understanding ventriculoarterial coupling in patients with HT.

Initiatives to enhance renin-angiotensin prescribing efficiency in Austria: impact and implications for other countries.

AIM: To assess the utilization of renin-angiotensin drugs, including combinations, in Austria in practice given the limited availability of diuretics, as well as the impact of recent reforms and initiatives on the utilization and expenditure of angiotensin-converting enzyme inhibitors (ACEis) and angiotensin receptor blockers (ARBs), following prescribing restrictions on ARBs immediately after their introduction. METHODS: Utilization of dispensed prescriptions in ambulatory care was captured from 2001 to 2007 using defined daily doses as well as defined daily doses/1000 inhabitants/day for patients covered by the social health-insurance system. The data were provided by the internal data warehouse of Hauptverband der Osterreichischen Sozialversicherungsträger. Total costs in Euros were used for the analysis to facilitate comparisons with earlier studies. RESULTS: There was appreciable utilization of fixed-dose diuretic combinations at between 36 and 38% of all renin-angiotensin products, in line with expectations. The reduction in expenditure/defined daily dose for originator and generic ACEis and their combinations is, again, in line with expectations, mirroring earlier findings for proton pump inhibitors and statins. ARB utilization was just under 27% of all renin-angiotensin products. This is higher than the low utilization rates seen with atorvastatin following its prescribing restrictions, and may reflect the difficulties if restrictions are based on subjective criteria. ARB utilization rates were lower or similar to other countries, who have implemented a different range of demand-side reforms to limit their prescribing with the advent of generic ACEis. CONCLUSION: The results confirm the successful implementation of the latest pricing policies and demand-side measures for generics and originators in Austria. We believe the prescribing restrictions for ARBs reduced their utilization in practice and offer an alternative approach to other demand-side measures.

Changing patterns of secondary preventive medication among newly diagnosed coronary heart disease patients with diabetes in Finland: a register-based study.

AIMS: Information on medicine use among coronary heart disease (CHD) patients with diabetes in unselected patient populations is scarce. This study examines the use of medication to prevent new cardiac events among newly diagnosed CHD patients with diabetes comparing them to patients without diabetes and examines socioeconomic differences in medicine use in these patient groups. METHODS: Data on CHD patients (43,501 men and 31,125 women) with or without diabetes were individually linked from nationwide registers (covering both patients treated in ambulatory and in hospital inpatient care). Age-standardised rates for medication use were calculated and differences between patient groups examined using Poisson regression. RESULTS: beta-blocker use was high in all patient groups in 1997-2002, angiotensin-converting enzyme (ACE) inhibitor and angiotensin II antagonist use increased and remained higher among patients with diabetes. More than half of men and women with diabetes used ACE inhibitors and one out of five used angiotensin II antagonists in 2002. Lipid-lowering medication use increased, especially among women. In 1997-98 it was lower in lower socioeconomic groups; among men with diabetes the use remained lower than among others. CONCLUSIONS: beta-blocker use was constant and ACE inhibitor and angiotensin II antagonist use increased. Lipid-lowering medication use increased considerably after a health insurance reform in 2000, in which elevated reimbursement of drug costs (75%) was extended to include all CHD patients with hyperlipidaemia.Socioeconomic differences in medication use disappeared after the reform. However, lipid-lowering medication use remained at a lower level among men with diabetes, suggesting that their treatment did not follow guidelines.

Cost effectiveness of angiotensin receptor blocker monotherapy in patients with hypertension in the Netherlands: a comparative analysis using clinical trial and drug utilization data.

BACKGROUND AND OBJECTIVE: Health gains and related cost savings achieved by optimizing treatment in hypertensive patients is highly important. The aim of this study was to evaluate the costs and cost effectiveness of treatment with angiotensin II receptor antagonists (angiotensin II receptor blockers [ARBs]) in patients with essential hypertension and to compare within-trial with real-life dosing of ARBs. METHODS: Cost effectiveness was estimated based on a published clinical trial comparing the BP-lowering effects of olmesartan, losartan, valsartan, and irbesartan. BP lowering after 8 weeks of treatment was entered into the Framingham risk functions to estimate cardiovascular complications after 1 and 5 years, using an international health economics model that was adapted to the Netherlands. Dutch costs (2006 values) and complications derived from the model were discounted at 4% and 1.5%, respectively, and cost effectiveness was expressed in net costs per cardiovascular complication averted. In a drug-utilization study, pharmacy dispensing records were used to evaluate differences between within-trial and daily-practice dosing and related costs for treatment in the Netherlands. RESULTS: After 8 weeks, the trial-based analysis showed that treatment with olmesartan versus losartan, valsartan, and irbesartan resulted in a significantly larger decrease in BP (11.5 vs 8.2, 7.9 and 9.9 mmHg [p < 0.05], respectively) and consequently more complications averted. Cost effectiveness for olmesartan, losartan, valsartan, and irbesartan was estimated at euro39,100, euro77,100, euro70,700, and euro50,900 per cardiovascular complication averted, respectively. The incremental cost-effectiveness analysis indicated the most favorable cost-effectiveness outcome for olmesartan, with lower costs and less cardiovascular complications for olmesartan compared with the other three ARBs. The drug-utilization analysis showed that the dosing followed within clinical trials was not found in daily practice. On average, losartan, valsartan, and irbesartan were administered at doses above those used in clinical trials, whereas olmesartan was dosed lower than in clinical trials, resulting in relatively lower costs. CONCLUSION: Based on the exact trial data, olmesartan was estimated to be the most favorable option of the four ARBs based on within-trial decreases in BP levels after 8 weeks and in terms of cost-effectiveness for this particular Dutch setting. However, for definite conclusions to be drawn, this hypothesis-generating study requires confirmation from further prospective studies comparing ARBs based on comparable BP control and including hard endpoints.

Use of multiattribute utility theory for formulary management in a health system.

PURPOSE: The application, utility, and flexibility of the multiattribute utility theory (MAUT) when used as a formulary decision methodology in a Korean medical center were evaluated. METHODS: A drug analysis model using MAUT consisting of 10 steps was designed for two drug classes of dihydropyridine calcium channel blockers (CCBs) and angiotensin II receptor blockers (ARBs). These two drug classes contain the most diverse agents among cardiovascular drugs on Samsung Medical Center's drug formulary. The attributes identified for inclusion in the drug analysis model were effectiveness, safety, patient convenience, and cost, with relative weights of 50%, 30%, 10%, and 10%, respectively. The factors were incorporated into the model to quantify the contribution of each attribute. For each factor, a utility scale of 0-100 was established, and the total utility score for each alternative was calculated. An attempt was made to make the model adaptable to changing health care and regulatory circumstances. RESULTS: The analysis revealed amlodipine besylate to be an alternative agent, with the highest total utility score among the dihydropyridine CCBs, while barnidipine hydrochloride had the lowest score. For ARBs, losartan potassium had the greatest total utility score, while olmesartan medoxomil had the lowest. CONCLUSION: A drug analysis model based on the MAUT was successfully developed and used in making formulary decisions for dihydropyridine CCBs and ARBs for a Korean health system. The model incorporates sufficient utility and flexibility of a drug's attributes and can be used as an alternative decision-making tool for formulary management in health systems.