Comparison of Dual Therapies for Lowering Blood Pressure in Black Africans.

BACKGROUND: The prevalence of hypertension among black African patients is high, and these patients usually need two or more medications for blood-pressure control. However, the most effective two-drug combination that is currently available for blood-pressure control in these patients has not been established. METHODS: In this randomized, single-blind, three-group trial conducted in six countries in sub-Saharan Africa, we randomly assigned 728 black patients with uncontrolled hypertension (≥140/90 mm Hg while the patient was not being treated or was taking only one antihypertensive drug) to receive a daily regimen of 5 mg of amlodipine plus 12.5 mg of hydrochlorothiazide, 5 mg of amlodipine plus 4 mg of perindopril, or 4 mg of perindopril plus 12.5 mg of hydrochlorothiazide for 2 months. Doses were then doubled (10 and 25 mg, 10 and 8 mg, and 8 and 25 mg, respectively) for an additional 4 months. The primary end point was the change in the 24-hour ambulatory systolic blood pressure between baseline and 6 months. RESULTS: The mean age of the patients was 51 years, and 63% were women. Among the 621 patients who underwent 24-hour blood-pressure monitoring at baseline and at 6 months, those receiving amlodipine plus hydrochlorothiazide and those receiving amlodipine plus perindopril had a lower 24-hour ambulatory systolic blood pressure than those receiving perindopril plus hydrochlorothiazide (between-group difference in the change from baseline, -3.14 mm Hg; 95% confidence interval [CI], -5.90 to -0.38; P = 0.03; and -3.00 mm Hg; 95% CI, -5.8 to -0.20; P = 0.04, respectively). The difference between the group receiving amlodipine plus hydrochlorothiazide and the group receiving amlodipine plus perindopril was -0.14 mm Hg (95% CI, -2.90 to 2.61; P=0.92). Similar differential effects on office and ambulatory diastolic blood pressures, along with blood-pressure control and response rates, were apparent among the three groups. CONCLUSIONS: These findings suggest that in black patients in sub-Saharan Africa, amlodipine plus either hydrochlorothiazide or perindopril was more effective than perindopril plus hydrochlorothiazide at lowering blood pressure at 6 months. (Funded by GlaxoSmithKline Africa Noncommunicable Disease Open Lab; CREOLE ClinicalTrials.gov number, NCT02742467.).

Importance of fixed-dose combinations in cardiovascular prevention: the possibility of treating two diagnoses with a single pill.

In the care of a cardiovascular risk patient there is certainly a more frequent situation in which we try to influence several risk factors at the same time. Treatment of a single self-occurring risk factor is rather an exception. In most cases, we need to intervene with more risk factors, often involving combination therapy, which can achieve the desired goals more quickly and reliably. However, with the number of tablets taken by the patient, the patients willingness to take long-term and correct use decreases, which has a significant impact on the effectiveness of therapy and the development of individual cardiovascular risk. In an effort to control all risk factors for cardiovascular disease, there is a growing need to extend the availability of fixed drug formulations to suit the patients ease of use and suitably formulated with varying dose grades to meet the needs of our attending physicians. With regard to the fact that early intervention of risk factors brings greater benefits than deferred, we are looking for appropriate ways to manage it. The current intervention of arterial hypertension and dyslipidemia with safe and proven drugs seems to be one of the ways to further improve the results of the prevention of cardiovascular diseases. The new fixed combination of atorvastatin with perindopril, which is entering the Czech market right now, appears to be in many ways an ideal “tablet for cardiovascular prevention”.

Role of renin-angiotensin system antagonists in the prevention of bevacizumab- and sunitinib-mediated cardiac dysfunction.

Although anticancer systemic therapy agents clearly lead to improved survival in patients with cancer, these can come at the cost of serious complications including cardiotoxicity. Two types of targeted systemic therapies currently in use for colorectal cancer (CRC) and renal cell cancer (RCC), respectively, include the vascular endothelial growth factor inhibitor bevacizumab (BVZ) and the tyrosine kinase inhibitor sunitinib (SNT). Despite the beneficial effects of BVZ and SNT in improving clinical outcomes in the settings of CRC and RCC, there is an increased risk of cardiac dysfunction. The aim of the present study was to determine whether prophylactic administration of renin-angiotensin system (RAS) inhibitors would attenuate the cardiotoxic side effects of BVZ or SNT in a chronic in vivo murine model. A total of 194 wild-type C57Bl/6 male mice received: 1) 0.9% saline, 2) BVZ (10 mg·kg-1·wk-1), or 3) SNT (40 mg·kg-1·day-1) for 4 wk. Within each arm, mice received daily prophylactic treatment with hydralazine (0.05 mg/ml), aliskiren (50 mg/kg), perindopril (4 mg/kg), or valsartan (2 mg/kg). Although hydralazine effectively lowered blood pressure in BVZ- or SNT-treated mice, it did not prevent left ventricular systolic dysfunction. Prophylactic administration of aliskiren, perindopril, or valsartan prevented adverse cardiovascular remodeling in mice treated with either BVZ or SNT. The addition of RAS antagonists also downregulated expression of phosphorylated p38 and Bcl-2-like 19-kDa interacting protein 3 in SNT-treated mice. In our chronic in vivo murine model, RAS antagonists partially attenuated the development of BVZ- or SNT-mediated cardiac dysfunction. Future clinical studies are warranted to investigate the cardioprotective effects of prophylactic treatment with RAS inhibitors in the settings of CRC and RCC. NEW & NOTEWORTHY In the evolving field of cardio-oncology, bevacizumab and sunitinib improve clinical outcomes in the settings of metastatic colorectal cancer and renal cell cancer, respectively. These anticancer drugs, however, are associated with an increased risk of cardiotoxicity. The prophylactic administration of renin-angiotensin system antagonists is partially cardioprotective against bevacizumab- and sunitinib-mediated cardiac dysfunction.

Response of 1,5-anhydroglucitol level to intensive glucose- and blood-pressure lowering interventions, and its associations with clinical outcomes in the ADVANCE trial.

AIMS: To evaluate 1,5-anhydroglucitol (1,5-AG) according to clinical outcomes and assess the effects of glucose- and blood pressure-lowering interventions on change in 1,5-AG levels in people with type 2 diabetes. METHODS: We measured 1,5-AG in 6826 stored samples at baseline and in a random subsample of 684 participants at the 1-year follow-up visit in the ADVANCE trial. We examined baseline 1,5-AG [< 39.7, 39.7-66.2, ≥ 66.2 µmol/L (<6, 6-10, ≥10 µg/mL)] and microvascular and macrovascular events and mortality using Cox regression models during 5 years of follow-up. Using an intention-to-treat approach, we examined 1-year change in 1,5-AG (mean and percent) in response to the glucose- and blood pressure-lowering interventions in the subsample. RESULTS: Low 1,5-AG level [<39.7 µmol/L vs ≥ 66.2 µmol/L (<6 µg/mL vs ≥10 µg/mL)] was associated with microvascular events (hazard ratio 1.28, 95% confidence interval 1.03-1.60) after adjustment for risk factors and baseline glycated haemoglobin (HbA1c); however, the associations for macrovascular events and mortality were not independent of HbA1c. The glucose-lowering intervention was associated with a significant 1-year increase in 1,5-AG (vs standard control) of 6.69 µmol/L (SE 2.52) [1.01 µg/mL (SE 0.38)], corresponding to an 8.26% (SE 0.10%) increase from baseline. We also observed an increase in 1,5-AG of similar magnitude in response to the blood pressure intervention independent of the glucose-lowering effect. CONCLUSIONS: Our results suggest that 1,5-AG is a marker of risk in adults with type 2 diabetes, but only for microvascular events independently of HbA1c. We found that 1,5-AG was improved (increased) in response to an intensive glucose-lowering intervention, although the independent effect of the blood pressure-lowering intervention on 1,5-AG suggests potential non-glycaemic influences.

Thiolation of arabinoxylan and its application in the fabrication of pH-sensitive thiolated arabinoxylan grafted acrylic acid copolymer.

Current research work was conducted to synthesize Thiol modified arabinoxylan and its application in fabrication of hydrogel. Thioglycolic acid was esterified with arabinoxylan to prepare Thiolatedarabinoxylan. Appearance of peak at 2533.34 cm-1 in FTIR and thiol content showed successful thiolation. The pH-dependent Thiolatedarabinoxylan/acrylic acid (TAX/AA) hydrogels of perindopril erbumine were prepared via free-radical co-polymerization. Perindopril erbumine (PE) was employed as model drug. Different batches with different feed ratio of TAX, AA, and MBA were prepared and their influence on swelling, solvent penetration, and consequent drug release was investigated. Swelling coefficients increased with increase in pH. TAX/AA hydrogels were characterized by Fourier-transform infrared spectroscopy (FT-IR), Thermal Analysis (TA), X-Ray diffraction (XRD), and scanning electron microscope (SEM). Dissolution studies were performed at pH 1.2 and 7.4 in which drug release showed direct correlation with TAX and AA ratio. In vivo studies showed that Cmax of TAX-co-AA based hydrogel was 81.57 ± 0.35 ng/ml which was maintained for a longer time after its administration. All the results of in vivo studies were significant and TAX-co-AA based hydrogel enhances the bioavailability of perindopril erbumine.

Haemoglobin glycation index and risk for diabetes-related complications in the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) trial.

AIMS/HYPOTHESIS: Previous studies have suggested that the haemoglobin glycation index (HGI) can be used as a predictor of diabetes-related complications in individuals with type 1 and type 2 diabetes. We investigated whether HGI was a predictor of adverse outcomes of intensive glucose lowering and of diabetes-related complications in general, using data from the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) trial. METHODS: We studied participants in the ADVANCE trial with data available for baseline HbA1c and fasting plasma glucose (FPG) (n = 11,083). HGI is the difference between observed HbA1c and HbA1c predicted from a simple linear regression of HbA1c on FPG. Using Cox regression, we investigated the association between HGI, both categorised and continuous, and adverse outcomes, considering treatment allocation (intensive or standard glucose control) and compared prediction of HGI and HbA1c. RESULTS: Intensive glucose control lowered mortality risk in individuals with high HGI only (HR 0.74 [95% CI 0.61, 0.91]; p = 0.003), while there was no difference in the effect of intensive treatment on mortality in those with high HbA1c. Irrespective of treatment allocation, every SD increase in HGI was associated with a significant risk increase of 14-17% for macrovascular and microvascular disease and mortality. However, when adjusted for identical covariates, HbA1c was a stronger predictor of these outcomes than HGI. CONCLUSIONS/INTERPRETATION: HGI predicts risk for complications in ADVANCE participants, irrespective of treatment allocation, but no better than HbA1c. Individuals with high HGI have a lower risk for mortality when on intensive treatment. Given the discordant results and uncertain relevance beyond HbA1c, clinical use of HGI in type 2 diabetes cannot currently be recommended.

Chronotherapy for hypertension in obstructive sleep apnoea (CHOSA): a randomised, double-blind, placebo-controlled crossover trial.

BACKGROUND: Obstructive sleep apnoea (OSA) is an important cause of secondary hypertension. Nocturnal hypertension is particularly prevalent in OSA and is a strong predictor of cardiovascular mortality. Studies in patients with essential hypertension have suggested that nocturnal administration of antihypertensives improves nocturnal blood pressure (BP) without elevating daytime BP. We evaluated the efficacy of this technique in patients with OSA with stage I/II hypertension, both before and after the addition of CPAP. METHODS: In this double-blind randomised placebo-controlled crossover trial, patients with moderate-to-severe OSA and hypertension received 6 weeks each of evening or morning perindopril with opposing time-matched placebo. CPAP therapy was subsequently added for 8 weeks in addition to either morning or evening perindopril. The primary outcome was sleep systolic BP (SBP) using 24-hour BP monitoring, analysed using linear mixed models. RESULTS: Between March 2011 and January 2015, 85 patients were randomised, 79 completed both dosing times, 78 completed the CPAP phase. Sleep SBP reduced significantly from baseline with both evening (-6.9 mm Hg) and morning (-8.0 mm Hg) dosing, but there was no difference between dosing times (difference: 1.1 mm Hg, 95% CI -0.3 to 2.5). However, wake SBP reduced more with morning (-9.8 mm Hg) than evening (-8.0 mm Hg) dosing (difference: 1.8 mm Hg, 95% CI 1.1 to 2.5). Addition of CPAP to either evening or morning dosing further reduced sleep SBP, but by a similar amount (evening: -3.2 mm Hg, 95% CI -5.1 to -1.3; morning: -3.3 mm Hg, 95% CI -5.2 to 1.5). CONCLUSIONS: Our findings support combining OSA treatment with morning administration of antihypertensives. Unlike in essential hypertension, our results do not support evening administration of antihypertensives, at least with perindopril. Further research is required before this strategy can be widely adopted into hypertension guidelines and clinical practice. TRIAL REGISTRATION NUMBER: ACTRN12611000216910, Results.

The Treatment Effect of an ACE-Inhibitor Based Regimen with Perindopril in Relation to Beta-Blocker use in 29,463 Patients with Vascular Disease: a Combined Analysis of Individual Data of ADVANCE, EUROPA and PROGRESS Trials.

INTRODUCTION: In everyday practice, angiotensin converting enzyme inhibitors and beta-blockers are cornerstone treatments in patients with (cardio-)vascular disease. Clear data that evaluate the effects of the combination of these agents on morbidity and mortality are lacking. METHODS: In this retrospective pooled analysis of three large perindopril outcome trials (ADVANCE, EUROPA, PROGRESS), clinical outcomes were evaluated in 29,463 patients with vascular disease. Multivariate Cox regression analyses were performed in patients randomized to a perindopril-based regimen or placebo (treatment effect), and data were stratified according to background beta-blocker treatment. The primary endpoint was a composite of cardiovascular mortality, non-fatal myocardial infarction, and stroke. RESULTS: The cumulative incidence of the primary endpoint over mean follow-up of 4.0 years (Sd 1.0) was significantly lower in the beta-blocker/perindopril group (9.6%; 545/5700 patients) as compared to beta-blocker/placebo (11.8%; 676/5718 patients) (p < 0.01). Adding perindopril to existing beta-blocker treatment reduced the relative risk of the primary endpoint by 20% (hazard ratio (HR) 0.80; 95% confidence interval (CI) 0.71-0.90), non-fatal myocardial infarction by 23% (HR 0.77; 95% CI 0.65-0.91), and all-cause mortality by 22% (HR 0.78; 95% CI 0.68-0.88) as compared to placebo. Significant treatment benefit was not observed for stroke (HR 0.93; 95% CI 0.75-1.15). Significance was maintained for the primary endpoint and cardiovascular endpoints when data were further stratified by baseline hypertension. However, the mortality benefit was only observed in patients with hypertension with background beta-blocker use. CONCLUSIONS: These data suggest that the beneficial cardioprotective effects of perindopril treatment are additive to the background beta-blockers use.

[Lipertance® The ASCOT single-pill combination has finally arrived]. / Le médicament du mois : Lipertance® Atorvastatine - Perindopril - Amlodipine La combinaison fixe d'ASCOT est finalement arrivée.

The fixed association of atorvastatin, perindopril and amlodipine was recently launched by the firm SERVIER under the name of Lipertance®. It is the first fixed association of a statin, an ACE inhibitor and a calcium blocker present on the Belgian market to handle the risk factors that are hypertension and dyslipidemia which can be used both in primary and secondary cardiovascular prevention. The interests of such a triple combined therapy are many in terms of morbimortality reduction, as observed in ASCOT trial. Besides these results, the association of these three agents gives probably a synergic effect, which would be more effective to protect both heart and vessels. Moreover, a fixed association will improve treatment compliance and adherence, which are generally quite poor in the management of cardiovascular risk factors. Lipertance® is available with three different doses : 20/5/5 mg, 20/10/5 mg and 40/10/10 mg, respectively for atorvastatin, perindopril and amlodipine. Contraindications and side effects are the same as each component of this association and are well known.

L'association fixe d'atorvastatine, de perindopril et d'amlodipine a été récemment commercialisée par la firme Servier sous le nom de Lipertance®. Il s'agit de la première association statine/ inhibiteur de l'enzyme de conversion/inhibiteur calcique, présente sur le marché belge pour traiter les facteurs de risque que sont l'hypertension artérielle et la dyslipidémie, tant en prévention primaire que secondaire. Les intérêts d'une telle triple thérapie sont nombreux en termes de réduction de morbi-mortalité, notamment cardiovasculaire, comme on a pu l'observer dans l'étude ASCOT. Par ailleurs, associer ces trois molécules entraîne probablement des effets synergiques protecteurs tant sur le plan cardiaque que vasculaire. Outre les effets propres à chaque molécule qui sont bien connus, l'association en monoprise permet d'améliorer l'adhérence thérapeutique qui fait souvent défaut dans la prise en charge des facteurs de risque cardiovasculaire. Lipertance® est proposé en différents dosages, à savoir 20/5/5 mg, 20/10/5 mg et 40/10/10 mg, respectivement, pour l'atorvastatine, le perindopril et l'amlodipine. Les contre-indications de cette association sont les mêmes que celles de chaque molécule et il en va de même pour son profil de tolérance.

[One year persistence of free and fixed dose combinations of perindopril/amlodipine]. / A perindopril/amlodipin szabad és fix kombinációk egyéves terápiahusége.

INTRODUCTION: In management of hypertension patient adherence is one of the most important factors. In hypertension the cardiovascular risk reduction can be reached only by prolonged and effective pharmacotherapy. AIM: To evaluate the persistence of one-year treatment of free and fixed-dose combination of perindopril/amlodipine in hypertension. METHOD: Information from the National Health Insurance of Hungary prescriptions database on pharmacy claims between October 1, 2012 and September 30, 2013 was analysed. Authors identified patients who filled prescriptions for free and fixed-dose combination of perindopril/amlodipine, prescribed for the first time for hypertension. Patients have not received antihypertensive therapy with similar active substances during the one year before. Apparatus of survival analysis was used, where "survival" was the time to abandon the medication. As it was available to month precision, discrete time survival analysis was applied. RESULTS: 109,248 patients met the inclusion criteria. Combination antihypertensive therapy with perindopril/amlodipine was started with a free or a fixed-dose combination of these agents in 19,365 and 89,883 patients, respectively. One year persistence rate in patients taking perindopril/amlodipine as a free combination was 27.15%, whereas it was 46.89% in those on the fixed-dose combination. Mean duration of persistence was 177.6 days in patients on the perindopril/amlodipine free, whereas 245.7 days on fixed-dose combination. Actual rate of discontinuation was approximately twice higher with the treatment of free, compared with the use of the fixed-dose combination (hazard ratio =1.94 [95% CI: 1.91-1.98], p<0.001). Orv Hetil. 2017; 158(36): 1421-1425.

[COSYREL - an efficient fixed combination for treatment of hypertension, stable ISHD and heart failure]. / COSYREL - úcinná fixní kombinace pro lécbu hypertenze, stabilní ICHS a srdecního selhání.

Fixed combinations of two or three drugs are being frequently used in cardiovascular diseases. This approach markedly increases adherence of the patients to prolonged therapy and thus leads to better control of the diseases. Fixed combinations are often used in hypertension and coronary artery disease (CAD). Cosyrel is the first fixed combination of betablocker (bisoprolol fumarat) and ACE inhibitor (perindopril arginin) available in czech market. The advantage is availability in several concentrations (10 mg/10 mg, 10 mg/5 mg a 5 mg/10 mg a 5 mg/5 mg) , when first indicates bisoprolol dose and the second perindopril. This combination is indicated in arterial hypertension and/or in stable CAD (in patients after myocardial infarction or revascularisation) and/or in dosages 5 mg/5 mg and 5 mg/10 mg in patients with chronic heart failure with systolic dysfunction. This article aimed to evaluate briefly clinical characteristics of this fixed combination. Bisoprol and perindopril arginin have a lot of data indication their positive impact on CV risk and prognosis.Key words: bisoprolol - coronary artery disease - heart failure - hypertension - perindopril.

[Effect of a fixed-dose combination of perindopril arginine/amlodipine on the level and variability of blood pressure according to its office visit-to-visit measurements and self-measurements at home: A subanalysis of the PREVOSHODSTVO (SUPERIORITY) program]. / Vliianie fiksirovannoi kombinatsii perindoprila arginin/amlodipin na uroven' i variabel'nost' arterial'nogo davleniia po dannym izmereniia na prieme u vracha i samokontrolia: cubanaliz programmy PREVOSKhODSTVO.

AIM: To study the effect of a fixed-dose combination of perindopril arginine/amlodipine (prestans) on the goal levels and variability of blood pressure (BP) according to its office visit-to-visit measurements and self-measurement (OVVM and SM) in a subgroup of 483 people from the population of the Russian observational SUPERIORITY program, most cases of whom are given the combination replacing the previously ineffective mono- and combination antihypertensive therapy (AHT). SUBJECTS AND METHODS: The subanalysis included data on 483 patients (34% men) aged 57.9±10.8 years with uncontrolled hypertension, who were both untreated and treated with antihypertensive mono- or combination therapy using a free or fixed-dose combination of 2-3 antihypertensive drugs and in whom the physicians decided to use prestans to correct AHT. The follow-up period was 24 weeks. RESULTS: At the end of the investigation, the patients received prestans in the following doses: 5/5 mg (34% of the patients), 10/5 mg (39.5%), 5/10 mg (3.9%), and 10/10 mg (22%). In the analyzed patient group, the baseline BP was 160.8±8.8/92.6±7.4 mm Hg and dropped to 125.9±7.9/77.8±5.0 mm Hg at 24 weeks (p<0.001). According to SM, the morning BP significantly decreased from 147.0±13.3/85.6±7.2 to 127.5±8.3/78,9±5.6 mm Hg at 24 weeks (p<0.001). The evening BP readings showed the similar trends. Target BP was achieved in 93 and 78% of the patients, as shown by OVVM and SM, respectively. According to SCM, the day-to-day variability of BP significantly decreased from 5.1±3.2/3.4±2.3 Hg mm at Visit 2 to 2.7±2/0/2,3±1/5 mm Hg at Visit 5 (p<0.001). CONCLUSION: The use of the fixed-dose combination of perindopril arginine/amlodipine in hypertensive patients just at the beginning of treatment, by switching from insufficiently effective mono- or combination AHT to the fixed-dose combination of perindopril arginine/amlodipine, is an effective way to optimize AHT in clinical practice, which lowers the BP level and variability, as evidenced by both OVVM and SM.

[Efficiency of triple antihypertensive therapy in patients with uncontrolled hypertension and depressive disorders]. / Éffektivnost' trekhkomponentnoi antigipertenzivnoi terapii u patsientov s nekontroliruemoi arterial'noi gipertoniei i depressivnymi rasstroistvami.

AIM: To evaluate the efficiency of triple antihypertensive therapy in patients with uncontrolled hypertension and depressive disorders (DD). MATERIAL AND METHODS: 153 patients with uncontrolled hypertension were examined, of whom 82 patients were diagnosed with mild and moderate DD. A combination of perindopril 10 mg/day, indapamide SR 1.5 mg/day, and amlodipine at an initial dose of 5 mg/day was given to patients with hypertension and DD. After 4 weeks of treatment, if target blood pressure (BP) levels could not be achieved, the dose of amlodipine was increased up to 10 mg/day. General clinical examination and 24-hour BP monitoring (BPM) were performed in all the patients at baseline and in the patients with DD also after 24 weeks of therapy. The traditional measures of the diurnal BP profile, as well as the parameters characterizing arterial stiffness and central aortic pressure (CAP) were estimated. RESULTS: After 8 weeks of therapy, target BP levels were recorded in 63 (76.8%) patients. After 24 weeks of treatment, the hypertensive patients with DD showed significant positive changes in all the investigated 24-hour BPM parameters and normalization of the diurnal BP profile in 65.1% of cases. During the treatment, there were significant decreases in pulse wave velocity, brachial arterial and aortic augmentation indices, aortic systolic and diastolic pressures, and mean aortic BP and an increase in the velocity of the reflected wave. CONCLUSION: Triple therapy, including perindopril, indapamide SR, and amlodipine, contributed to the achievement of target BP levels in the majority of hypertensive patients with DD, with significant positive changes in all 24-hour BPM parameters, optimization of the diurnal BP profile in most patients, clinically significant improvement of the parameters that characterize arterial stiffness and CAP.

Efficacy and Safety of Fixed-Dose Perindopril Arginine/Amlodipine in Hypertensive Patients Not Adequately Controlled with Amlodipine 5 mg or Perindopril tert-Butylamine 4 mg Monotherapy.

OBJECTIVES: To assess the blood pressure-lowering efficacy and tolerability of perindopril/amlodipine fixed-dose combinations in Chinese patients with mild-to-moderate essential hypertension not adequately controlled with monotherapy alone. METHODS: In 2 separate double-blind studies, patients received a 4-week run-in monotherapy of amlodipine 5 mg or perindopril 4 mg, respectively. Those whose blood pressure was uncontrolled were then randomized to receive the fixed-dose combination of perindopril 5 mg/amlodipine 5 mg (Per/Amlo group) or remain on the monotherapy for 8 weeks. Patients who were uncontrolled at the week 8 (W8) visit were up-titrated for the Per/Amlo combination, or received additional treatment if on monotherapy, for a further 4 weeks. The main efficacy assessment was at 8 weeks. RESULTS: After 8 weeks, systolic blood pressure (SBP; primary criterion) was statistically significantly lower in the Per/Amlo group (vs. Amlo 5 mg, p = 0.0095; vs. Per 4 mg, p < 0.0001). Uncontrolled patients at W8 who received an up-titration of the Per/Amlo combination showed a further SBP reduction. These changes were mirrored by reassuring reductions in diastolic blood pressure. The fixed-dose combinations were well tolerated. CONCLUSIONS: Single-pill combinations of perindopril and amlodipine provide hypertensive patients with a convenient and effective method of reducing blood pressure.

Perindopril and ß-blocker for the prevention of cardiac events and mortality in stable coronary artery disease patients: A EUropean trial on Reduction Of cardiac events with Perindopril in stable coronary Artery disease (EUROPA) subanalysis.

BACKGROUND: ß-Blockers relieve angina/ischemia in stable coronary artery disease (CAD), and angiotensin-converting enzyme inhibitors prevent CAD outcomes. In EUROPA, the angiotensin-converting enzyme inhibitor perindopril reduced cardiovascular outcomes in low-risk stable CAD patients over 4.2 years. This post hoc analysis examined whether the addition of perindopril to ß-blocker in EUROPA had additional benefits on outcomes compared with standard therapy including ß-blocker. METHODS: EUROPA was a multicenter, double-blind, placebo-controlled, randomized trial in patients with documented stable CAD. Randomized EUROPA patients who received ß-blocker at baseline were identified, and the effect on cardiovascular outcomes of adding perindopril or placebo was analyzed. Endpoints were the same as those in EUROPA. RESULTS: At baseline, 62% (n = 7534 [3789 on perindopril and 3745 on placebo]) received ß-blocker. Treatment with perindopril/ß-blocker reduced the relative risk of the primary end point (cardiovascular death, nonfatal myocardial infarction, and resuscitated cardiac arrest) by 24% compared with placebo/ß-blocker (HR, 0.76; 95% CI, 0.64-0.91; P = .002). Addition of perindopril also reduced fatal or nonfatal myocardial infarction by 28% (HR, 0.72; 95% CI, 0.59-0.88; P = .001) and hospitalization for heart failure by 45% (HR, 0.55; 95% CI, 0.33-0.93; P = .025). Serious adverse drug reactions were rare in both groups, and cardiovascular death and hospitalizations occurred less often with perindopril/ß-blocker. CONCLUSIONS: The addition of perindopril to ß-blocker in stable CAD patients was safe and resulted in reductions in cardiovascular outcomes and mortality compared with standard therapy including ß-blocker.

Treatment of Hypertension: Favourable Effect of the Twice-Daily Compared to the Once-Daily (Evening) Administration of Perindopril and Losartan.

BACKGROUND/AIMS: Little is known about the effect of twice daily administration of same dose of ACE inhibitor and ARB on the diurnal/nocturnal blood pressure (BP) ratio. We aimed to assess the effect of two widely used long-acting drugs: perindopril and losartan in the treatment of hypertension comparing the once-daily (evening) vs. twice-daily (morning and evening) administration with the same daily doses. METHODS: Untreated primary hypertensive patients without complaints (a total of 164: 65 men, 99 women, 55.7 ± 13.7 years of age, 41-41 patients per treated groups) were selected with non-dipper phenomenon, estimated by diurnal index (DI) <10%. The effect of evening (8 mg perindopril or 100 mg losartan) vs morning and evening (4-4 mg perindopril or 50-50 mg losartan) administration was determined on a 14-day treatment by ABPM. RESULTS: The mean BP, the percent time elevation index, and the hyperbaric impact decreased in both drug groups. Significant difference was observed in the DI in the case of twice-daily administration vs once-daily evening dosing. CONCLUSIONS: The twice-daily administration with the same daily dose of perindopril or losartan seems to be more effective compared to the once daily evening administration in eliminating the non-dipper phenomenon. According to some authors the non-dipping phenomenon increases cardiovascular risk, while others are of the opinion that the association of non-dipping with cardiovascular events does not necessarily mean that selective treatment of non-dipping improves cardiovascular outcomes.

Single-pill combination therapy in the initial treatment of marked hypertension: a propensity-matched analysis.

BACKGROUND: Many drugs combinations are available and equally recommended for the initial treatment of patients with marked blood pressure (BP) elevation and high cardiovascular risk. HYPOTHESIS: To investigate safety and efficacy of such combination therapies. METHODS: Prospectively collected data were retrospectively reviewed, inclusion criteria were: initial single-pill combination therapy, availability of clinical and echocardiographic 6-month follow-up. Six treatment groups were identified: Enalapril 20 mg+ Hydrochlorothiazide 12.5 mg (E/H), E 20 mg + Lercanidipine 10 mg (E/L), Ramipril 2.5 mg+ H 12.5 mg (R/H), Perindopril 5 mg+ Amlodipine 5 mg (P/A), Olmesartan 40 mg+ H 12.5 mg (O/H) and Telmisartan 40 mg+ H 12.5 mg (T/H). To avoid selection bias a Propensity score (goodness of fit: c-statistic 0.78, p = 0.0001) was used to select comparable cohorts of patients (n = 142 each). RESULTS: After 4 weeks of treatment BP goal was achieved by 624/852 (73.2%) patients, and adverse events were registered in 24/852 (2.8%) patients. After 6 months, 562/624 (90.1%) patients maintained the BP goal. Six-month responder rate was significantly higher in the E/L (69.0%) and P/A (68.3%) groups (p = 0.05); especially among diabetics (52.0% and 51.0%, respectively; p = 0.003). Patients receiving E/L (-19.8 ± 3.2 mmHg) and P/A (-19.9 ± 4.6 mmHg) showed greater reductions of diastolic BP (p = 0.03); whereas reductions of systolic BP were similar between treatment groups (p = 0.46). Echocardiographic follow-up revealed greater left ventricular reverse remodeling among patients receiving ACE-inhibitors (E/L, R/H, E/H and P/A), but this trend did not reach statistical significance. CONCLUSIONS: Single-pill fixed-dose combination therapies are highly effective and safe in the study settings. Best clinical and echocardiographic outcomes were noted among patients receiving E/L, R/H and P/A.

[Evaluation of pharmacotherapy with perindopril, lozartan potassium and its combination in elderly patients with chronic heart failure].

To assess the pharmacotherapy of elderly patients with chronic heart failure (CHF), by studying the effect of perindopril, lozartan potassium and their combination on the severity of clinical symptoms, hemodynamics, exercise capacity and heart morphofunctional parameters, 78 patients with chronic heart failure II-IV FC (for classification NYHA), complicating the course of coronary heart disease (CHD) with left ventricular ejection fraction ≤45 % were examined. Men were 42 (53,8 %), women - 36 (46,2 %), mean age 64,8±3,7 years. The study revealed that the background as long-term monotherapy with perindopril and lozartan potassium in patients with CHF complicating CHD, CHF FC decreased significantly and significantly increased left ventricular ejection fraction (p < 0,05). The combined treatment with perindopril and lozartan potassium showed no advantage over monotherapy with these agents. These patients showed a decrease in the frequency of angina attacks by 28,5 and 27 % respectively (p < 0,05) only after a long course of treatment with perindopril and the combination of perindopril and lozartan potassium.

Development and in vitro/in vivo evaluation of immediate release perindopril tablets.

Perindopril erbumine (PE) is a BCS (Biopharmaceutics Classification System) class 3 drug with high solubility and low permeability. It is an inhibitor of the enzyme that converts angiotensin I (Angiotensin Converting Enzyme, ACE) into angiotensin II as well as causing the degradation of the vasodilator bradykinin into an inactive heptapeptide. The aim of this study was to develop an alternative drug product by using a different salt of perindopril and to evaluate the bioequivalence between PE, not still licensed, and perindopril arginine (PA), licensed in many countries, and to prepare PE tablets by using direct compression method. Many different formulations were prepared, among which F3-coded formulation was only selected due to releasing of 98.03% active substance at 45th minute. Bioequivalence study was planned as a cross-designed, randomized, open-labeled, single-dose, single-center study and conducted in 24 male healthy volunteers via peroral route. The results of bioequivalence study were evaluated for Perindopril and Perindoprilat according to Cmax, tmax and AUC criteria. The geometric mean ratios (90% CI) of perindopril and perindoprilat followed test and reference drug were calculated for AUC0-t and Cmax, 105.946% (100.218-112.002%) and 110.437% (102.534-118.948%); 109.542% (98.364-121.992%) and 115.729% (101.031-132.565%), respectively. The 90% confidence intervals of them were found within the standard bioequivalence range (80-125%).

[Therapy of Arterial Hypertension in Patients With Chronic Heart Failure and Signs of Chronic Kidney Disease With Fixed Perindopril/Amlodipine Combination].

PURPOSE: to assess efficacy of a fixed combination of perindopril arginine and amlodipine besylate in the treatment of hypertensive patients with chronic heart failure (CHF) and signs of chronic kidney disease (CKD). MATERIAL AND METHODS: Persons with CKD (n = 53, age 64.5 ± 8.2 years) were selected from 118 patients with grade 2-3 essential hypertension with CHF. Presence of CKD was confirmed by elevated blood levels of cystatin C and lowered glomerular filtration rate (GFR). Used doses of fixed perindopril/amlodipine combination were 5/5, 5/10, 10/10 mg. Efficacy was assessed after 2 months of therapy on the basis of results of the examination which included clinical blood pressure (BP), BP monitoring, 6-min walk test. Blood levels of creatinine, urea, cystatin C and GFR were also measured. RESULTS: Target BP was achieved in 92.6% of patients. Clinical BP was significantly decreased. Daily average systolic BP decreased by 14.7%, diastolic BP--by 14.4%. Systolic and diastolic BP load also decreased. Clinical condition improved. Tolerance to physical work increased. Level of cystatin C significantly decreased while GFR increased. CONCLUSION: Fixed perindopril/amlodipine combination produced good therapeutic effect in hypertensive patients with CHF and CKD.