A Retrospective Observational Real-Word Analysis of the Adherence, Healthcare Resource Consumption and Costs in Patients Treated with Bisoprolol/Perindopril as Single-Pill or Free Combination.

INTRODUCTION: The present real-world analysis aims to compare the drug utilization, hospitalizations and direct healthcare costs related to the use of single-pill combination (SPC) or free-equivalent combination (FEC) of perindopril and bisoprolol (PER/BIS) in a large Italian population. METHODS: This observational retrospective analysis was based on administrative databases covering approximately 7 million subjects across Italy. All adult subjects receiving PER/BIS as SPC or FEC between January 2017-June 2020 were included. Subjects were followed for 1 year after the first prescription of PER/BIS as FEC (± 1 month) or SPC. Before comparing the SPC and FEC cohorts, propensity score matching (PSM) was applied to balance the baseline characteristics. Drug utilization was investigated as adherence (defined by the proportion of days covered, PDC) and persistence (evaluated by Kaplan-Meier curves). Hospitalizations and mean annual direct healthcare costs (due to drug prescriptions, hospitalizations and use of outpatient services) were analyzed during follow-up. RESULTS: The original cohort included 11,440 and 6521 patients taking the SPC and FEC PER/BIS combination, respectively. After PSM, two balanced SPC and FEC cohorts of 4688 patients were obtained (mean age 70 years, approximately 50% male, 24% in secondary prevention). The proportion of adherent patients (PDC ≥ 80%) was higher for those on SPC (45.5%) than those on FEC (38.6%), p < 0.001. The PER/BIS combination was discontinued by 35.8% of patients in the SPC cohort and 41.7% in the FEC cohort (p < 0.001). The SPC cohort had fewer cardiovascular (CV) hospitalizations (5.3%) than the free-combination cohort (7.4%), p < 0.001. Mean annual total healthcare costs were lower in the SPC (1999€) than in the FEC (2359€) cohort (p < 0.001). CONCLUSION: In a real-world setting, patients treated with PER/BIS SPC showed higher adherence, lower risk of drug discontinuation, reduced risk of CV hospitalization, and lower healthcare costs than those on FEC of the same drugs.

Patients with cardiovascular conditions often need to take many pills. This may result in patients not taking their pills as prescribed (i.e., low adherence) and compromise the potential benefits derived from prescription of cardiovascular protective drugs. Simplifying treatment by combining drugs into a single pill can improve adherence and, consequently, patient outcomes. In this analysis using data from real clinical practice, we explored whether using a single pill of perindopril and bisoprolol is associated with higher levels of adherence, lower proportion of patients with hospitalizations and lower economic costs than using the same drugs prescribed as free-equivalent combination in a large sample of the Italian population of approximately 7 million people. We identified two groups of patients taking single pill or free-equivalent combination of perindopril and bisoprolol (4688 patients in each cohort). Over 1-year follow-up, patients taking single pill were more likely to be adherent and were less likely to stop taking their treatment. They also had fewer cardiovascular hospitalizations with shorter hospital admission and had lower healthcare direct costs. In conclusion, simplifying treatment by combining perindopril and bisoprolol in a single pill instead of two may have a positive effect on adherence, outcomes and healthcare costs already after 1 year.

A real-world analysis of outcomes and healthcare costs of patients on perindopril/indapamide/amlodipine single-pill vs. multiple-pill combination in Italy.

OBJECTIVES: This analysis compared adherence, cardiovascular (CV) events and all-cause mortality incidence, and healthcare costs among hypertensive patients treated with perindopril (PER)/indapamide (IND)/amlodipine (AML) in single-pill combination (SPC) vs. multiple-pill combination, in a real-world setting in Italy. METHODS: In this observational retrospective analysis of Italian administrative databases, adult patients treated with PER/IND/AML between 2010 and 2020 were divided into two cohorts: single-pill vs. multiple-pill. Patient data were available for at least one year before and after index date. Propensity score matching (PSM) was applied to reduce selection bias. Adherence was defined as proportion of days covered: non-adherence, <40%; partial adherence, 40-79%, and adherence ≥80%. Mortality incidence and CV events as single, or composite, endpoints were evaluated after first year of follow-up. Healthcare cost analyses were performed from the perspective of the Italian National Health Service. RESULTS: Following PSM, the single-pill cohort included 12 150 patients, and the multiple-pill cohort, 6105. The SPC cohort had a significantly higher percentage of adherent patients vs. the multiple-pill cohort (59.9% vs. 26.9%, P  < 0.001). Following the first year of follow-up, incidence of all-cause mortality, and combined endpoint of all-cause mortality and CV events were lower in the SPC cohort compared with multiple-pill cohort. Average annual direct healthcare costs were lower in the single-pill cohort (€2970) vs. multiple-pill cohort (€3642); cost of all drugs and all-cause hospitalizations were major contributors. CONCLUSION: The SPC of PER/IND/AML, compared with multiple-pill combination, is associated with higher adherence to medication, lower incidence of CV events and mortality, and reduced healthcare costs.

Comparing Cardiovascular Outcomes and Costs of Perindopril-, Enalapril- or Losartan-Based Antihypertensive Regimens in South Africa: Real-World Medical Claims Database Analysis.

INTRODUCTION: Differences in class or molecule-specific effects between renin-angiotensin-aldosterone system (RAAS) inhibitors have not been conclusively demonstrated. This study used South African data to assess clinical and cost outcomes of antihypertensive therapy with the three most common RAAS inhibitors: perindopril, losartan and enalapril. METHODS: Using a large, South African private health insurance claims database, we identified patients with a hypertension diagnosis in January 2015 receiving standard doses of perindopril, enalapril or losartan, alone or in combination with other agents. From claims over the subsequent 5 years, we calculated the risk-adjusted rate of the composite primary outcome of myocardial infarction, ischaemic heart disease, heart failure or stroke; rate of all-cause mortality; and costs per life per month (PLPM), with adjustments based on demographic characteristics, healthcare plan and comorbidity. RESULTS: Overall, 32,857 individuals received perindopril, 16,693 losartan and 13,939 enalapril. Perindopril-based regimens were associated with a significantly lower primary outcome rate (205 per 1000 patients over 5 years) versus losartan (221; P < 0.0001) or enalapril (223; P < 0.0001). The risk-adjusted all-cause mortality rate was lower with perindopril than enalapril (100 vs. 139 deaths per 1000 patients over 5 years; P = 0.007), but not losartan (100 vs. 94; P = 0.650). Mean (95% confidence interval) overall risk-adjusted cost PLPM was Rands (ZAR) 1342 (87-8973) for perindopril, ZAR 1466 (104-9365) for losartan (P = 0.0044) and ZAR 1540 (77-10,546) for enalapril (P = 0.0003). CONCLUSION: In South African individuals with private health insurance, a perindopril-based antihypertensive regimen provided better clinical and cost outcomes compared with other regimens.

Chromatographic Techniques for Assessment of Bisoprolol Fumarate and Perindopril Arginine in Solid Formulations under Various Stress Conditions and Application to Six Sigma, Content Uniformity, and Comparative Dissolution Approaches.

BACKGROUND: Antihypertensives bisoprolol fumarate (BIS) and perindopril arginine (PER) were simultaneously determined in their pure, bulk, and combined tablet dosage form. OBJECTIVE: This study develops a novel, reproducible, and accurate Reversed phase high-performance liquid chromatography (RP-HPLC) and Reversed phase ultra-performance liquid chromatography (RP-UPLC) with photodiode array detection techniques, which were then applied to in vitro dissolution studies. METHODS: The first RP-HPLC method relied on isocratic elution using a mobile phase of methanol-0.05 M phosphate buffer pH 2.6 (1 + 1, by volume), and separation was performed using a Thermo Hypersil C8 column (150 mm × 4.6 mm, 5 µm). Ion-pair UPLC was the second method. An acceptable resolution was achieved using an RP-C18 chromatographic column, Agilent Eclipse (100 × 2.1 mm, 1.7 µm), with a mobile phase containing 0.005 M sodium 1-heptane sulfonate-triethylamine (64 + 1 + 35, by volume), adjusted with phosphoric acid to a pH of 2.0. RP-HPLC used a 1.0 mL/min flow rate, while UPLC used 0.5 mL/min, and the two methods used detection at 210 nm. RESULTS: Calibration curves of BIS and PER were linear for RP-HPLC and RP-UPLC methods at 0.5-15 and 0.5-40 µg/mL, respectively. BIS and PER had RP-UPLC LODs of 0.22 and 0.10 µg/mL, respectively, and LOQs of 0.68 and 0.31 µg/mL, respectively. As a result, the approach has been effectively applied to in vitro dissolution testing for drugs in generic and reference products, showing that the two products are comparable. The Six Sigma approach was implemented to compare the recommended and United States Pharmacopeia (USP) procedures, which both exhibited process capability index (Cpk) >1.33. A content uniformity test demonstrated that the drugs in their dosage form met the acceptance limit (85-115%). The degradation products were reliably distinguished from pure drugs for a range of retention times. CONCLUSION: In their commercial drug product, the proposed method could be used in QC laboratories for concurrent testing, content uniformity, and in vitro dissolution investigations of BIS and PER. The methods were successfully validated per International Council for Harmonisation (ICH) guidelines. HIGHLIGHTS: This study is innovative since it is the first to establish and validate specific and reproducible UPLC and HPLC methods for the concurrent quantitation of the studied drugs in their binary mixture and application to lean Six Sigma, content uniformity, and comparative dissolution approaches.

Cardiopulmonary exercise test-based assessment of the effects of sacubitril/valsartan on the blood pressure response to exercise in patients with acute myocardial infarction during hospitalization.

OBJECTIVE: To investigate the effects of sacubitril/valsartan (S/V) on cardiopulmonary function and blood pressure response to exercise during hospitalization in patients with acute myocardial infarction (AMI) based on the cardiopulmonary exercise test (CPET). METHODS: A total of 265 AMI patients were treated with either perindopril or S/V within 24 hours of admission. CPET was completed for all patients before discharge. There were 182 cases in the perindopril group and 83 cases in the S/V group. RESULTS: The proportion of exercise oscillatory ventilation (EOV) was higher in the S/V group than in the perindopril group (10.8% vs 1.6%, X2 = 11.148, P = .001). The resting heart rate (HR), resting diastolic blood pressure (DBP), and warm-up DBP were lower in the S/V group than in the perindopril group (P < .05). The resting systolic blood pressure (SBP) was 9.0 mmHg lower (115.7 ± 17.5 vs 106.7 ± 15.0, P < .001), the SBP during warm-up was 9.5 mmHg lower (124.8 ± 23.7 vs 115.3 ± 22.5,P = .002), the SBP at the anaerobic threshold (AT) was 10.5 mmHg lower (135.3 ± 24.8 vs 127.1 ± 25.1,P = .021),the SBP at max watts was 11.5 mmHg lower (148.9 ± 26.4 vs 137.4 ± 26.4,P = .001), and the SBP during one-minute recovery was 12.3 mmHg lower (146.5 ± 27.1 vs 134.2 ± 24.4, P = .001)in the S/V group than in the perindopril group. The S/V group had a higher oxygen ventilation equivalent and carbon dioxide ventilation equivalent (VE/VCO2) at AT and a lower oxygen uptake-work rate relationship during max watts (P < .05). The differences in the oxygen pulse, stroke volume, peak oxygen uptake (VO2 peak), and VE/VCO2 slope were not statistically significant between the two groups. CONCLUSION: Treatment with S/V was able to reduce the exercise blood pressure in patients with AMI during hospitalization, but did not significantly improve the VO2 peak, VE/VCO2 slope, or exercise tolerance.

Acute Increases in Serum Creatinine After Starting Angiotensin-Converting Enzyme Inhibitor-Based Therapy and Effects of its Continuation on Major Clinical Outcomes in Type 2 Diabetes Mellitus.

Discontinuation of angiotensin-converting enzyme (ACE) inhibitor is recommended if patients experience ≥30% acute increase in serum creatinine after starting this therapy. However, the long-term effects of its continuation or discontinuation on major clinical outcomes after increases in serum creatinine are unclear. In the ADVANCE trial (Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation), 11 140 diabetes mellitus patients were randomly assigned to perindopril-indapamide or placebo after a 6-week active run-in period. The current study included 11 066 participants with 2 serum creatinine measurements recorded before and during the active run-in period (3 weeks apart). Acute increase in creatinine was determined using these 2 measurements and classified into 4 groups: increases in serum creatinine of <10%, 10% to 19%, 20% to 29%, and ≥30%. The primary study outcome was the composite of major macrovascular events, new or worsening nephropathy, and all-cause mortality. An acute increase in serum creatinine was associated with an elevated risk of the primary outcome ( P for trend <0.001). The hazard ratios were 1.11 (95% CI, 0.97-1.28) for those with an increase of 10% to 19%, 1.34 (1.07-1.66) for 20% to 29%, and 1.44 (1.15-1.81) for ≥30%, compared with <10%. However, there was no evidence of heterogeneity in the benefit of randomized treatment effects on the outcome across subgroups defined by acute serum creatinine increase ( P for heterogeneity=0.94). Acute increases in serum creatinine after starting perindopril-indapamide were associated with greater risks of subsequent major clinical outcomes. However, the continuation of angiotensin-converting enzyme inhibitor-based therapy reduced the long-term risk of major clinical outcomes, irrespective of acute increase in creatinine. Clinical Trial Registration- URL: http://www.clinicaltrials.gov . Unique identifier: NCT00145925.

[Assessment of Efficacy of Combined Pharmacotherapy With Fixed Perindopril/Amlodipine Combination in Patients With Combined Cardiovascular Pathology in Outpatient Practice].

AIM: to study effects of using fixed perindopril/amlodipine combination in complex treatment of patients with combined cardiac pathology in active observation mode, in comparison with other angiotensin converting enzyme (ACE inhibitors) or angiotensin II receptor antagonists (ARA), including free combination with calcium channel blockers (CCB) in conditions of routine outpatient practice. MATERIALS AND METHODS: The design of the study included two stages: I - monitoring effectiveness of pharmacotherapy performed in routine outpatient practice (duration of 2 months), II - "active treatment (management)" - changing the pharmacotherapy scheme in patients who did not reach the target level of "office" blood pressure (BP), monitoring patients for 6 months and carrying out, if necessary, dose correction of the newly appointed treatment regimen. The study included 50 patients aged 45-65 years with combined cardiovascular pathology: II-III degree arterial hypertension, I-III functional class (FC) stable angina pectoris, I-III FC chronic cardiac failure. RESULTS: Number of patients who reached target level of office BP by the end of active observation was 41 (p.

A new LC-MS/MS bioanalytical method for perindopril and perindoprilat in human plasma and milk.

A first of its kind, simple, rapid, and sensitive liquid chromatography mass spectrometry (LC-MS/MS) method was developed and validated for quantification of perindopril and perindoprilat in both human plasma and breast milk. The analytes and internal standards (phenazone and acetyl salicylic acid) were extracted from biological matrices by protein precipitation. A Phenomenex® C-18 column was used to provide an appropriate chromatographic separation of the analytes, followed by detection with tandem mass spectrometry. Gradient chromatographic and mass spectrometric detection conditions with mobile phases (A: 5% methanol + 0.1% formic acid in water v/v, and B: 95% methanol + 0.1% formic acid in water v/v) were developed to achieve a LOQ of 0.5 ng/mL in both human plasma and milk. The method was suitable of evaluating clinical samples. The mass transition was followed as m/z 369.10/172.00 for perindopril, m/z 339.00/168.10 for perindoprilat, m/z 188.90/55.95 for phenazone, and m/z 179.04/137.02 for acetyl salicylic acid. The developed method was optimized and validated with a linear range of 0.1-200 ng/mL (r 2 = better than 0.99 for both perindopril and perindoprilat). The precision and accuracy values were within 15% CV. The overall recovery of the analytes was 80-110%. The method has good specificity and repeatability. Stability studies were conducted in both human plasma and bovine milk for up to 3 months, at the storage conditions of 25, 4, and -80 °C.

[Evaluation of the pharmacoeconomic efficacy of prestance in the treatment of hypertensive patients on the basis of the results of the POTENTIAL program]. / Otsenka farmakoekonomicheskoi effektivnosti preparata prestans pri lechenii bol'nykh arterial'noi gipertoniei na osnove rezul'tatov programmy POTENTsIAL.

AIM: To pharmacoeconomically estimate the use of a fixed-dose combination of perindopril and amlodipine in the treatment of hypertensive patients. MATERIAL AND METHODS: A pharmacoeconomic study was conducted on the basis of the Russian postmarketing observational open program POTENTIAL, which included the estimation of direct and indirect costs associated with the addition of a fixed-dose combination of perindopril and amlodipine to conventional therapy for hypertension in patients who had not achieved adequate blood pressure (BP) control. Cost-difference, cost-effectiveness, and budget-impact analyses were carried out. RESULTS: The addition of prestance to conventional therapy for hypertension can reduce total costs by 5.-5.8 times, direct costs required to achieve 1% of patients with adequate BP control by 20.5-42.1 times, and direct costs to improve a patient's status by one visual analogue scale score by 1.03-2.11 times. Within a 5-year horizon, the administration of prestance can decrease the cost of therapy for high BP and related strokes by 1.39-1.46 times. CONCLUSION: Due its high efficacy, prestance (amlodipine + perindopril) is a pharmacoeconomically preferred alternative only to the conventional therapy for hypertension even if the least costly generics are used, in both the short and medium term.

An evaluation of the effect of an angiotensin-converting enzyme inhibitor on the growth rate of small abdominal aortic aneurysms: a randomised placebo-controlled trial (AARDVARK).

BACKGROUND: Although data are inconsistent, angiotensin-converting enzyme inhibitors (ACE-Is) have been associated with a reduced incidence of abdominal aortic aneurysm (AAA) rupture in analysis of administrative databases. OBJECTIVES: (1) To investigate whether or not the ACE-I perindopril (Coversyl arginine, Servier) reduces small AAA growth rate and (2) to evaluate blood pressure (BP)-independent effects of perindopril on small AAA growth and to compare the repeatability of measurement of internal and external aneurysm diameters. DESIGN: A three-arm, multicentre, single-blind, randomised placebo-controlled trial. SETTING: Fourteen hospitals in England. PARTICIPANTS: Men or women aged ≥ 55 years with an AAA of 3.0-5.4 cm in diameter by internal or external measurement according to ultrasonography and who met the trial eligibility criteria. INTERVENTIONS: Patients were randomised to receive 10 mg of perindopril arginine daily, 5 mg of the calcium channel blocker amlodipine daily or placebo daily. MAIN OUTCOME MEASURES: The primary outcome was AAA diameter growth using external measurements in the longitudinal plane, which in-trial studies suggested was the preferred measure. Secondary outcome measures included AAA rupture, AAA repair, modelling of the time taken for the AAA to reach the threshold for intervention (5.5 cm) or referral for surgery, tolerance of study medication (measured by compliance, adverse events and quality of life) and a comparison of the repeatability of measures of internal and external AAA diameter. Patients were followed up every 3-6 months over 2 years. RESULTS: In total, 227 patients were recruited and randomised into the three groups, which were generally well matched at baseline. Multilevel modelling was used to determine the maximum likelihood estimates for AAA diameter growth. No significant differences in the estimates of annual growth were apparent [1.68 (standard error 0.02) mm, 1.77 (0.02) mm and 1.81 (0.02) mm in the placebo, perindopril and amlodipine groups, respectively]. Similarly, no significant differences in the slopes of modelled growth over time were apparent between perindopril and placebo (p = 0.78) or between perindopril and amlodipine (p = 0.89). The results were essentially unaffected by adjustment for potential confounders. Compliance, measured by pill counts, was good throughout (> 80% at all visit time points). There were no significant in-trial safety concerns. Six patients withdrew because of adverse events attributed to the study medications (n = 2 perindopril, n = 4 amlodipine). No patients ruptured their AAA and 27 underwent elective surgery during the trial (n = 9 placebo, n = 10 perindopril, n = 8 amlodipine). CONCLUSIONS: We were unable to demonstrate a significant impact of perindopril compared with placebo or amlodipine on small AAA growth over a 2-year period. Furthermore, there were no differences in the times to reach a diameter of 5.5 cm or undergo surgery among the three groups. Perindopril and amlodipine were well tolerated by this population. External AAA measurements were found to be more repeatable than internal measurements. The observed AAA growth measurement variability was greater than that expected pre trial. This, combined with slower than expected mean growth rates, resulted in our having limited power to detect small differences between growth rates and hence this adds uncertainty to the interpretation of the results. Several further analyses are planned including a multivariate analysis of determinants of AAA growth, an evaluation of the possible differential effect of perindopril on fast AAA growth and an investigation into the roles of central BP and BP variability on AAA growth. TRIAL REGISTRATION: Current Controlled Trials ISRCTN51383267. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 20, No. 59. See the NIHR Journals Library website for further project information. The NIHR Biomedical Research Centre based at Imperial College NHS Trust supported the trial. Servier provided perindopril at no charge.

Efficacy and Safety Assessment of Hypertension Management with Coveram (Perindopril/Amlodipine Fixed Combination) in Patients with Previous Angiotensin Receptor Blocker (ARB) Treatment: Arabian Gulf STRONG Study.

OBJECTIVE: We evaluated the safety and efficacy of hypertension management with Coveram (perindopril/amlodipine combination) in patients with uncontrolled blood pressure (BP). All patients were on previous angiotensin receptor blocker (ARB) treatment. METHODS: This was a 3 country, multi-centre (7 cities), open-label, observational study in the Arabian Gulf. Patients (≥18 years) were recruited between October 2012 and November 2013 and followed-up for 3 months after enrolment. Outcomes included changes in BP from baseline and BP goal attainment rates as per Joint National Committee- 8 (<140/90 mmHg for diabetics and those <60 years of age and <150/90 mmHg for those ≥60 years of age without diabetes). Medication tolerance was also assessed from both patient and physician perspectives. RESULTS: Hypertensive patients (n=760; mean age: 51±10 years; 67% were males) were included. A total of 178 patients (23%) were lost to follow-up. The perindopril/amlodipine combination was associated with an overall reduction in systolic BP (SBP) (31 mmHg; p<0.001) and diastolic BP (DBP) (18 mmHg; p<0.001) from baseline. An overall BP control rate was achieved in 87% (n=507) of the participants. There were significant incremental BP reductions with dose up-titration, especially SBP (p<0.001). Those with high SBP (>180 mmHg) at baseline were associated with a mean reduction of 59 mmHg (p<0.001). The perindopril/amlodipine combination had excellent tolerance levels over the study period from both patient and physician perspectives (at 99% and 98%, respectively; p<0.001). CONCLUSIONS: The perindopril/amlodipine combination is an effective and well tolerated anti-hypertensive option in patients on previous ARB treatment.

Individualized Angiotensin-Converting Enzyme (ACE)-Inhibitor Therapy in Stable Coronary Artery Disease Based on Clinical and Pharmacogenetic Determinants: The PERindopril GENEtic (PERGENE) Risk Model.

BACKGROUND: Patients with stable coronary artery disease (CAD) constitute a heterogeneous group in which the treatment benefits by angiotensin-converting enzyme (ACE)-inhibitor therapy vary between individuals. Our objective was to integrate clinical and pharmacogenetic determinants in an ultimate combined risk prediction model. METHODS AND RESULTS: Clinical, genetic, and outcomes data were used from 8726 stable CAD patients participating in the EUROPA/PERGENE trial of perindopril versus placebo. Multivariable analysis of phenotype data resulted in a clinical risk score (range, 0-21 points). Three single-nucleotide polymorphisms (rs275651 and rs5182 in the angiotensin-II type I-receptor gene and rs12050217 in the bradykinin type I-receptor gene) were used to construct a pharmacogenetic risk score (PGXscore; range, 0-6 points). Seven hundred eighty-five patients (9.0%) experienced the primary endpoint of cardiovascular mortality, nonfatal myocardial infarction or resuscitated cardiac arrest, during 4.2 years of follow-up. Absolute risk reductions ranged from 1.2% to 7.5% in the 73.5% of patients with PGXscore of 0 to 2. As a consequence, estimated annual numbers needed to treat ranged from as low as 29 (clinical risk score ≥10 and PGXscore of 0) to 521 (clinical risk score ≤6 and PGXscore of 2). Furthermore, our data suggest that long-term perindopril prescription in patients with a PGXscore of 0 to 2 is cost-effective. CONCLUSIONS: Both baseline clinical phenotype, as well as genotype determine the efficacy of widely prescribed ACE inhibition in stable CAD. Integration of clinical and pharmacogenetic determinants in a combined risk prediction model demonstrated a very wide range of gradients of absolute treatment benefit.

The advantages of combination therapy on hypertension: development of immediate release perindopril-indapamide tablet and assessment of bioequivalence studies.

Hypertension has a major associated risk for organ damage and mortality, which is further heightened in patients with prior cardiovascular events, comorbid diabetes mellitus, microalbuminuria and renal impairment. Convers Plus tablet including perindopril erbumine (PE), which is an angiotensin converting enzyme (ACE) inhibitor, and indapamide, which is diuretic, was designed as a combined tablet to succes in the treatment of hypertension. Physico-pharmaceutical properties and characterization studies were evaluated in vitro conditions. Later on in vivo study was planned as a cross-designed, randomized, open-labeled, single-dose, single-center study via peroral route in 24 healthy male subjects. In this study, bioequivalence with primary pharmacokinetical target parameters reference (Bipreterax 4/1.25 mg Tablet-S.A.Servier Benelux N.V.) and test (Convers Plus 4/1.25 mg Tablet-ARGESAN Pharmaceutical Company) tablets have been found bioequivalent. The results of pharmacokinetic parameters for perindopril, perindoprilat and indapamide were found as Cmax = 23.179 µg/mL, tmax = 0.729 h, t1/2 = 1.429 h; AUC0-t = 26.998 µgs/mL, AUC0-inf = 27.117 µgs/mL; Cmax = 1.834 µg/mL, tmax = 8.792 h, t1/2 = 40.699 h; AUC0-t = 54.828 µgs/mL, AUC0-inf = 77.113 µgs/mL; Cmax = 18.994 µg/mL, tmax = 3.417 h, t1/2 = 16.626 h and AUC0-t = 385.829 µgs/mL, AUC0-inf = 410.728 µgs/mL respectively. In conclusion, physico-pharmaceutical properties and results of clinical trials show that Convers Plus tablets have been found as bioequivalent for perindopril, perindoprilat and indapamide in terms of AUC and Cmax, in 90% confidence limits.

Prediction of 10-year vascular risk in patients with diabetes: the AD-ON risk score.

AIMS: To formulate a combined cardiovascular risk score in diabetes that could be useful both to physicians and healthcare funders. METHODS: Data were derived from the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation Observational (ADVANCE-ON) study, a randomized controlled trial (mean duration 5 years) with a post-randomization follow-up (mean 4.9 years), that included 11 140 high-risk patients with diabetes. The outcome analysed was the occurrence of either fatal or non-fatal macrovascular or renal disease. A Cox regression model was used to determine weightings in the risk score. The resultant score was recalibrated to each of three major global regions, as covered by the ADVANCE-ON study. RESULTS: Over a median of 9.9 years, 1145 patients experienced at least one component of the combined outcome event. The resultant score, the AD-ON risk score, incorporated 13 demographic or clinical variables. Its discrimination was modest [c-statistic = 0.668 (95% confidence interval 0.651, 0.685)] but its calibration was excellent (predicted and observed risks coincided well, within disparate global regions). In terms of the integrated discrimination improvement index, its performance was marginally superior, over a 10-year risk horizon, to existing risk scores in clinical use, from a restricted version of the same data, for macrovascular and renal disease separately. CONCLUSIONS: The AD-ON risk score has advantages over the existing vascular risk scores in diabetes that used data from the original ADVANCE trial, which treat macrovascular and renal diseases separately. These advantages include its simplicity of use and global application.

Development and validation of a cardiovascular risk assessment model in patients with established coronary artery disease.

Appropriate risk stratification of patients with established, stable coronary artery disease could contribute to the prevention of recurrent cardiovascular events. The purpose of the present study was to develop and validate risk prediction models for various cardiovascular end points in the EURopean trial On reduction of cardiac events with Perindopril in stable coronary Artery disease (EUROPA) database, consisting of 12,218 patients with established coronary artery disease, with a median follow-up of 4.1 years. Cox proportional hazards models were used for model development. The end points examined were cardiovascular mortality, noncardiovascular mortality, nonfatal myocardial infarction, coronary artery bypass grafting, percutaneous coronary intervention, resuscitated cardiac arrest, and combinations of these end points. The performance measures included Nagelkerke's R², time-dependent area under the receiver operating characteristic curves, and calibration plots. Backward selection resulted in a prediction model for cardiovascular mortality (464 events) containing age, current smoking, diabetes mellitus, total cholesterol, body mass index, previous myocardial infarction, history of congestive heart failure, peripheral vessel disease, previous revascularization, and previous stroke. The model performance was adequate for this end point, with a Nagelkerke R² of 12%, and an area under the receiver operating characteristic curve of 0.73. However, the performance of models constructed for nonfatal and combined end points was considerably worse, with an area under the receiver operating characteristic curve of about 0.6. In conclusion, in patients with established coronary artery disease, the risk of cardiovascular mortality during longer term follow-up can be adequately predicted using the clinical characteristics available at baseline. However, the prediction of nonfatal outcomes, both separately and combined with fatal outcomes, poses major challenges for clinicians and model developers.

[Effect of different doses of perindopril on myocardial energy expenditure in patients with heart failure following myocardial infarction].

OBJECTIVE: To investigate the changes of myocardial energy expenditure in patients with heart failure following myocardial infarction after treatment with different doses of perindopril. METHODS: Sixty-three patients with heart failure after myocardial infarction were treated with perindopril for 12 months at the doses of 4 mg (group N) and 8 mg (group H). Doppler imaging was used to measure the structural and systolic functional parameters before and after the treatment, and the circumferential end-systolic wall stress (cESS) and myocardial energy expenditure (MEE) were calculated. The biochemical indicators including serum creatinine and plasma NT-proBNP were detected before and after the treatment. RESULTS: The two groups had similar measurements before treatment. After 12 months of perindopril treatment, the patients in group N showed higher LA, LV, RA, RV, LVIDs, AD, cESS, lgNT-proBNP, and MEE with lower LVFS and LVEF than those in group H. Compared to those before treatment, LVFS and LVEF were increased and LA, LV, RA, RV, AD, LVIDs, LVMI, lgNT-proBNP and MEEm lowered after the 12-month treatment in group H. Significant changes were also found in the measured parameters except for PWTs, LVET, LVSV and LVFS in group N after the treatment. Bivariate analysis showed a significant positive correlation between MEE and lgNT-proBNP (r=0.513, P<0.01). CONCLUSION: A 12-month treatment with perindopril can suppress myocardial remodeling, improve left ventricular systolic function, and lower NT-proBNP and myocardial energy expenditure in patients with heart failure after myocardial infarction, and a higher dose can produce better results.