Combination Of Perindopril Research Articles

Enhancing the Practicality along with Greenness Sustainability of a High Throughput HPLC-MS/MS Bioanalytical Method for the Simultaneous Determination of Amlodipine, Perindopril, and Its Active Metabolite Perindoprilat in Human Plasma: Application to a Pharmacokinetic Study

Numerous studies have demonstrated the benefits of amlodipine and perindopril combination therapy in decreasing blood pressure and improving outcomes for high-risk patients. In order to assess the pharmacokinetics of the 2 drugs along with perindoprilat; the active metabolite of perindopril, a simultaneous LC-MS/MS quantification method of amlodipine (AML), perindopril (PER) and perindoprilat (LAT) in human plasma has been developed and validated using amlodipine D4, perindopril D4 and perindoprilat D4 as internal standards (ISs), respectively. A simple and fast protein precipitation method was used to analyze the three analytes from K3EDTA human plasma. The chromatographic separation included the use of a mixture of methanol and acetonitrile (80:20, v/v) and 0.2% aqueous formic acid (60:40, v/v) as a mobile phase pumped onto a Zorbax® SB-AQ C18 column. Detection was carried out using a tandem mass spectrometer (MS/MS) in multiple reactions monitoring (MRM) mode. This method exhibited great sensitivity (LLOQ of 0.2 ng/mL for AML and PER and 0.4 ng/mL for LAT), linearity, accuracy (ranging from 97.64% to 110.28%), precision (ranging from 2.54% to 7.60%), and stability. The method showed good linearity over the range of (0.2-10 ng/mL) for AML, (0.2-160 ng/mL) for PER and (0.4-80 ng/mL) for LAT. The average extraction recoveries of AML, PER and LAT samples were between 81.92 % and 85.07%. Total elution time was as low as 3 min only. In addition, to ensure the practicality of the developed method, BAGI tool was applied, and the current method has achieved the highest score among the compared methods. Moreover, the sustainability of the proposed method was evaluated using AGREE tool and RGB 12 paradigm showing remarkable sustainability. The developed method is fast, accurate, sensitive, reproducible, ecofriendly, sustainable and suitable for the determination of the concentration of the cited analytes in human plasma. Moreover, it was applied for the bioequivalence study of a generic product to the innovator.

Real-world analysis exploring the association between anti-hypertensive therapy with perindopril-based single-pill combinations (SPC) and cardiovascular outcomes and all-cause mortality in Italy

Abstract Background/Introduction A combination of blood pressure (BP)-lowering medications is recommended by guidelines as an effective strategy to obtain rapid and optimal BP control in hypertensive patients. However, the prescription of multiple BP-lowering medications increases the pill burden, potentially reducing medication adherence. Guidelines also recommend using single pill combinations(SPCs) containing ≥2 anti-hypertensive medications as a practical approach to simplify treatment schedules and possibly improve adherence. Yet, real-world evidence on the association between SPC or free combination of BP-lowering medications and hyperthensive patient outcome remains limited. Purpose We compared the association of SPC versus free-pill combination(free) on cardiovascular outcomes and all-cause mortality in hypertensive patients treated with perindopril(PER)-based therapies in real clinical practice in Italy. Methods A retrospective analysis was conducted using administrative databases covering 6.7 million health-assisted Italian residents. Among adults with hospitalization discharge diagnosis or exemption code for hypertension between 2010 and 2021, the study included patients prescribed with a combination of PER with amlodipine(AML) and/or indapamide(IND), either as SPC or free or mixed (SPC plus separate pill) combinations. Results The analysis included 24,476 hypertensive subjects receiving a PER-based therapy, 22,663 (93%) of them using SPC, 1458 (6%) free and 355 (1.4%) mixed. The last cohort was not included in the analysis due to the small sample size (N=355). The patients in the free cohort were significantly older than those in the SPC cohort (69.5±12.3 vs. 64.3±12.2 years, p<0.001), showed a higher number of pre-existing comorbidities (0.5±0.8 vs. 0.4±0.7, p<0.001), and received a larger number of different medications (pill burden: 1.2±1.7 vs. 0.7±1.3, p<0.001). To minimize selection bias, the groups were balanced with propensity score and inverse probability weighting (IPW), adjusting for baseline covariates, including comorbidity profile and pill burden. The IPW-adjusted Kaplan-Meier plots and Cox’s proportional hazard model (Table 1) revealed that, compared with SPC users, patients on free regimens had a significantly increased risk of all-cause mortality (36%, p<0.001), all cardiovascular events (45%, p<0.001), ischemic heart disease (29%, p<0.05), cerebrovascular events (84%, p<0.001), and occurrence of the composite outcome cardiovascular events/all-cause mortality (40%, p<0.001). Conclusions This real-world data from a large Italian administrative dataset suggested that PER-based anti-hypertensive therapy with SPC results in significant clinical benefits in terms of lowered risk of cardiovascular/cerebrovascular events and all-cause mortality. Reducing pill burden and simplifying therapeutic schedules is of crucial importance to maximize the potential benefits derived from the prescription of anti-hypertensive treatment.

A higher adherence to perindopril-based anti-hypertensive therapy is associated with a reduced risk of cardiovascular outcomes and all-cause mortality in real clinical practice in Italy

Abstract Background Therapeutic management of hypertension is a landmark of cardiovascular (CV) risk prevention. Combined therapies with at least 2 anti-hypertensive agents are required in many patients in whom monotherapy and lifestyle interventions failed in blood pressure control. It is well-known that poor medication adherence remains a major barrier to achieving the therapeutic targets for all CV drugs, including anti-hypertensives. Purpose We evaluated the relationship between adherence to perindopril (PER)-based therapeutic regimen prescribed as single-pill combination (SPC) or free-pill and CV outcomes and all-cause mortality in a large Italian population. Methods A retrospective analysis was performed using administrative databases corresponding to around 6.7 million health-assisted residents. Hypertensive adults were first identified through hospitalization discharge diagnosis or exemption codes for hypertension between 2010 and 2021. Patients prescribed PER-based therapies were screened for all combinations of PER with amlodipine (AML) and/or indapamide (IND) (all formulations, single-pill or free-pill). Time of the first prescription of a PER-based regimen during the inclusion period was considered the index-date. The analysis included all hypertensive subjects prescribed a PER-based therapy, having available data at least 12 months before and 24 months after the index-date, respectively. Since the analysis was focused on the possible associations between adherence level and CV outcomes and all-cause mortality, adherence was assessed during the first year of follow-up on alive patients and outcomes were assessed during the second year. Adherence was assessed using the proportion of days covered (PDC) approach on 1-year follow-up, and considering a PDC<80% as poor-to-moderate adherence, and PDC ≥80% as good adherence. The Cox’s proportional hazard model was applied to estimate Hazard Ratio (HR) adjusting for baseline covariates, including comorbidity profile and pill burden. Results The included cohort (N=24,476) was divided into sub-groups according to adherence in poor-to-moderate (N=6,781) and good adherent patients (N=17,695) with a mean age of 64.8±13.3 and 64.6±11.9 years old, respectively. The Cox’s proportional hazard model showed that good adherence was associated with a relative risk reduction of 23% in all-cause mortality (Table 1A), 21% in all CV events (Table 1B), 17% in ischemic heart disease (Table 1C), 33% in cerebrovascular events (Table 1E), and 22% in the composite outcome of CV events/all-cause mortality (Table 1G). Conclusions The present analysis provided evidence from the Italian real clinical practice that good adherence to PER-based anti-hypertensive therapy results in significantly lower cardiovascular risk and all-cause mortality. These data further emphasize the importance of promoting cost-effective measures to increase medication adherence in patients on anti-hypertensive treatment.

Pooled analysis of the three trials of the TRIUMF series: efficacy of a triple fixed combination of antihypertensive drugs in the practice of physicians of different specialties in Ukraine

Study objectives – to compare the data obtained in the TRIUMF (antihyperTensive theRapy in UkraIne – BP optiMization in Focus) trials, in particular, TRIUMF-1, TRIUMF-2, TRIUMF-3, to determine possible patterns and significant factors affecting BP control in patients taking 2 or more antihypertensive drugs and switching to the original single pill combination (SPC) of perindopril arginine/indapamide/amlodipine.Materials and Methods. For the pooled analysis, data on 5960 patients obtained from the three trials of the TRIUMF series were selected. All the studies were multicenter prospective trials conducted at different times in Ukraine with the involvement of general practitioners (TR-1), cardiologists (TR-2), and family practitioners (TR-3). According to the inclusion criteria, patients over 18 years of age with hypertension and a history of taking 2 or 3 antihypertensive drugs for at least 1 month whose BP remained above 140/90 mm Hg could be included in the study. The drug of choice for further therapy was Triplixam (Servier, France) – a single pill combination (SPC) of perindopril arginine, amlodipine and indapamide. Each patient was observed for 3 months. Patients visited physicians in 1–2 weeks, 2 months after the start of the study and the corresponding therapy adjustment. The adherence rate was assessed before and after 2 months. The use of beta-blockers (BBs) in the treatment of the cohort of patients with hypertension was analyzed separately. The final analysis included a comparison of the data obtained in the TRIUMF trial series.Results and Discussion. The use of a SPC of perindopril arginine/indapamide/amlodipine allowed to achieve the target BP levels (140/90 or less) after 2 months of therapy in 84 % of patients with a history of taking a combination therapy (2 drugs – 65 %, 3 drugs – 35 %). One of the important criteria for choosing the dose of a triple SPC is the baseline BP values. The higher the degree of hypertension, the higher the dose prescribed by physicians. The minimum dose of the SPC of perindopril arginine, indapamide and amlodipine (5/1.25/5 mg) was prescribed for stage 1 hypertension in 62 %, stage 2 hypertension in 38 %, and stage 3 hypertension in 15 % of patients; the maximum dose (10/2.5/10 mg) was prescribed for stage 1 hypertension in 9 %, stage 2 hypertension in 15 %, and stage 3 hypertension in 43 % of patients included in the study (p<0.05). Therapy with the triple SPC of perindopril arginine, indapamide and amlodipine was well tolerated: adverse events were observed in 0.63 % (TR-1), 1 % (TR-3) and 1.86 % (TR-2) of cases, which was largely due to the previous use of two (65 %) or three (35 %) antihypertensive drugs comprising the SPC by the study patients. Beta-blockers (n=2012) were prescribed due to the presence of a comorbidity (coronary heart disease, angina pectoris – 33.5 %, heart failure – 28.3 %) rather than due to lowered BP. The combination of perindopril arginine/indapamide/amlodipine with BB was well tolerated and 83.9 % of patients achieved BP ≤ 140/90 mm Hg, while 9.36 % achieved ≤ 130/80 mm Hg after 2 months of treatment. There was a significant improvement in the adherence to treatment (TR-2, TR-3) in the majority of patients (75 and 70 %), due to high antihypertensive efficacy, convenience of pill’s administration (one pill instead of three) and good tolerability of the original SPC.Conclusions. Regular medical supervision (cardiologists, family practitioners, general practitioners), high antihypertensive efficacy of the SPC (84 % of patients reached the target BP levels after 2 months of therapy ), convenience of pill’s administration (one pill instead of three), high adherence to treatment confirmed in TR-2 and TR-3 in most patients, and good tolerability of the original SPC of perindopril arginine, indapamide and amlodipine led to a significant improvement in the effectiveness of treatment of patients with hypertension.

Clinical Effectiveness of the Fixed‐Dose vs Free‐Dose Triple Combinations in Patients with Uncontrolled Arterial Hypertension

Background: The purpose of our study was a comparative assessment of the antihypertensive effectiveness of 2 triple combination antihypertensive therapy (AHT) regimens in a free-dose and fixed-dose combination of perindopril, indapamide, and amlodipine in hypertensive patients with high cardiovascular risk and a poor response to the 2-drug combinations in the clinic practice. Methods and Results: Our study included 143 patients (79 men and 88 women) with arterial hypertension (AH) Grades 1-3 (ESC/ESH, 2018) and high cardiovascular risk who did not achieve the target blood pressure (TBP) on dual combination AHT. The mean age of patients was 55.76±9.35 years; the average duration of AH was 10.69±6.61 years. All patients underwent the examinations according to the 2018 ESC/ESH Guidelines for the management of arterial hypertension. Patients included in the study were divided into 2 groups using the envelope method: Group 1 (n=84) received a fixed-dose, triple combination of perindopril, indapamide, and amlodipine; Group 2 (n=83) received a free-dose combination of these drugs. In both groups, treatment began after discontinuation of previous therapy, with a low dose of a triple combination of antihypertensive drugs (perindopril [5 mg/day], indapamide [1.25 mg/day], amlodipine [5 mg/day]) in the form of a fixed or free combination. The initial doses of perindopril/indapamide/amlodipine in both groups were not statistically different: 6.9±2.4/1.74±0.6/7.1±2.4mg/day in Group 1 and 6.9±2.7/1.95±0.6/7.1±2.5 mg/day in Group 2. After 4 weeks of therapy, if necessary, the doses of drugs were increased, starting with perindopril; the next adjustment of drug doses was carried out after 12 weeks of therapy. The final treatment results were determined after 24 weeks of AHT. Target blood pressure (TBP) of <140/90 mmHg was reached by 94.4% of patients in Group 1 and 83.3% in Group 2 (χ²=7.471, Р=0,006); TBP of <130/80 mmHg was reached by 70% of patients in Group 1 and 42% in Group 2 (χ²=11.61, Р=0,0001). A significant improvement in the diurnal BP profile was also revealed during treatment. According to ABPM data, both groups achieved TBP in terms of the average 24-h and average daytime systolic blood pressure (SBP) and diastolic blood pressure (DBP). Regarding average nighttime SBP and DBP and normalization of average nighttime diastolic blood pressure variability, target values were achieved only in Group 1(P=0.028). In both groups, 24-week triple-combination therapy led to a significant decrease in central SBP, central DBP, and pulse wave velocity (PWV). At the same time, the positive dynamics of central SBP were more pronounced in Group 1 than in Group 2 (Table 4), and PWV in Group 1 reached standard values. Conclusion: The results of our study showed that in the treatment of uncontrolled hypertension on previous therapy in AH patients with high cardiovascular risk, a single-pill triple combination of the ACEI perindopril, the CCB amlodipine, and the thiazide-like diuretic indapamide contributed to the effective daily blood pressure control, the improvement of diurnal blood pressure profile, and a positive effect on central blood pressure and PWV, thereby having a positive impact on the prognosis and quality of life of AH patients with high cardiovascular risk.

WEIGHT LOSS IN HYPERTENSIVE PATIENTS WITH OBESITY UNDER THE INFLUENCE OF LIRAGULTIDE IS ASSOCIATED WITH A REDUCTION IN INSULIN RESISTANCE AND INCREASED EFFECTIVENESS OF THERAPY

Objective: One of the most important areas of treatment for patients with arterial hypertension (AH) with abdominal obesity (AO) is reduction of body weight (BW), which can be achieved using the glucagon-like peptide-1 (GLP-1) receptor agonist liraglutide. Objective: to study the relationship between the degree of weight loss under the influence of liraglutide and the effectiveness of antihypertensive and lipid-lowering therapy in hypertensive patients with AO. Design and method: 42 patients with AH of 2-3 degrees and AO of I-II degrees (24 men) aged from 46 to 60 years were examined using standard methods. Insulin resistance (IR) was determined by HOMA-IR. All patients received three-component antihypertensive therapy (a fixed combination of perindopril, indapamide and amlodipine) and, due to elevated low-density lipoprotein-cholesterol (LDL-C), atorvastatin in optimal doses. Liraglutide was administered as daily subcutaneous injections at a daily dose of 0.6 mg, with a gradual weekly dose increase of 0.6 mg to reach 3.0 mg/day. The duration of observation was 16 weeks. Results: After 16 weeks of treatment with liraglutide, 30 patients (71%) (the first subgroup) experienced a decrease in BW of 5% or more compared to baseline. At the same time, in 13 patients (29%) (second subgroup) BW decreased by less than 5% compared to the initial level or did not decrease. In the first subgroup of patients, a significant decrease in IR was detected from (5.06 ± 1.14) to (2.40 ± 1.22), p<0.05), whereas in the second subgroup the IR indicator did not change significantly. Among patients of the first subgroup, a significantly higher frequency of achieving target levels of “office” blood pressure (in 100% of patients) and target levels of LDL-C (in 73% of patients) was found in comparison with patients of the second subgroup (in 69% of patients, p<0.05) and in 39% of patients, p<0.05), respectively). Conclusions: A pronounced decrease in BW in hypertensive patients with AO under the influence of liraglutide is associated with a significant decrease in IR and also with a significant increase in the effectiveness of both antihypertensive and lipid-lowering therapy.

Protective Impact of Combined Perindopril and Coenzyme Q10 Treatment Against Cerebral Ischemia/Reperfusion Injury in Male Rats

Background: Cerebral ischemia is reason of death and disability worldwide with 11.6\% of all death and 5.7\% of the total disability. Thrombosis and embolism of a major cerebral artery, mainly the middle cerebral artery, account for over 70\% of stroke cases. The other major type of stroke is cerebral hemorrhage either intracerebral or subarachnoid hemorrhage. The oxygen requirements of the nervous tissue are excessively high bringing the brain highly susceptible to ischemia. The subsequent reperfusion after brain ischemia can precipitate more brain injury. Objectives: Assess the neuroprotective effects of perindopril and coenzyme Q10 in combination, as well as to speculate on their mechanism. Method: A total of forty-nine adult male Sprauge-dawley rats weighing between 200 and 300 g were randomly assigned to 7 groups: sham (no Bilateral common carotid artery occlusion (BCCAO)), control group (BCCAO for 30 minutes followed by reperfusion for an hour), vehicle-1 group (rat were pretreatment with oral 1% carboxymethylcellulose for seven days followed by control group), vehicle-2 group (seven days of oral distilled water pretreatment then as control group), perindopril group (rat were pretreatment with perindopril for then as control group), coenzyme Q10 group (rat were pretreatment with coenzyme Q10 for seven days then as control group), and combination group (rat were pretreatment with perindopril plus coenzyme Q10 for seven days then as control group). The brain tissues were separated in order to measure the size of the brain infarction, assess the histology, and measure the levels of cerebral IL-6, IL-10, TNF-\(\alpha\), ICAM-1, NF-\(\kappa\)B p65, and total antioxidant capacity. Results: The brain levels of IL-6, IL-10, ICAM-1, TNF-\(\alpha\), NF-\(\kappa\)B p65, and the cerebral infarct size were substantially increased in control and vehicle in relation to sham groups, while the total anti-oxidant capacity was considerably reduced. Perindopril and coenzyme Q10 treatment alone and in combination resulted in marked elevation in IL-10 and the total antioxidant capacity, with significant decrement in IL-6, ICAM-1, TNF-\(\alpha\), and NF-\(\kappa\)B p65 in respect to vehicle and control group. There was severe histopathological ischemic damage in control and vehicle groups which was remarkedly decreased by perindopril and coenzyme Q10 treatment alone and in combination pretreatment. Conclusions: Due to their anti-inflammatory and anti-oxidative characteristics, perindopril and coenzyme Q10, either separately or in combination, exhibit neuroprotective benefits in male rats that have been treated to cerebral ischemia/reperfusion injury.

In the prevention of dementia, the focus should be on early and consistent treatment of hypertension.

The brain is among the target organs of hypertension. Patients with hypertension have a higher risk of developing stroke as well as experiencing a decline in cognitive functions and dementia. Changes in the white matter and atrophy of the grey matter of the brain induced by high blood pressure develop insidiously since the onset of hypertension, even in young individuals. The effect of high blood pressure on the vessel wall cumulates in time; therefore, hypertension in younger people implies an increased risk of dementia in older age. Hypertension in young age cannot be considered a benign condition. Hypertension in middle age increases the risk of dementia by 61 %. Consistent and early hypertension control can reverse the adverse development towards dementia and lack of self-sufficiency in the patient. Data comparing individual antihypertensive drugs in terms of preventing dementia are scarce. However, renin angiotensin system blockers have been found to protect against Alzheimer's disease more than other classes of antihypertensive drugs. To achieve rapid and effective hypertension control, a combination of antihypertensive drugs is usually required. Using a fixed-dose triple combination of perindopril, indapamide, and amlodipine, blood pressure targets of < 130/80 mm Hg can be achieved within three months in 93 % of patients.

Development and validation of high‐performance thin layer chromatographic method for simultaneous quantitation of novel combination perindopril erbumine and moxonidine hydrochloride

AbstractThe primary purpose of the present study was to develop and validate a high‐performance thin‐layer chromatography method for quantitatively determining an anti‐hypertensive agent, perindopril erbumine, and moxonidine hydrochloride in bulk and synthetic mixture. The densitometric procedure was performed on aluminum thin‐layer chromatography plates pre‐coated with silica gel 60F254, employing a combination of dichloromethane: toluene: methanol: ammonia (7:1:2:0.1 v/v/v/v) as the mobile phase. The thin‐layer chromatography scanner was operated in absorbance mode at a wavelength of 223 nm to evaluate densitograms. The linearity of the method was established in the range of 1000–5000 ng/band for perindopril erbumine and 40–200 ng/band for moxonidine hydrochloride; the correlation coefficient (r2) was 0.9993 and 0.9983, respectively. The values of a limit of detection (186.06 and 3.51 ng/band, respectively, for perindopril erbumine and moxonidine hydrochloride) and limit of quantification (620.23 and 11.73 ng/band, respectively, for perindopril erbumine and moxonidine hydrochloride) have demonstrated the sensitivity of the developed method. The reported process was precise in both intra‐day and inter‐day analysis; the percentage relative standard deviation of peak area was less than 2% and has an accuracy within 100 ± 2%. The developed method has the potential to quantify perindopril erbumine and moxonidine hydrochloride from its synthetic mixture without any interference from other components or in quality control laboratories.

Effects of telmisartan and perindopril combination on hypertension and cardiovascular damage

Effects of telmisartan and perindopril combination on hypertension and cardiovascular damage

Potential of primary drug prevention of cardiotoxicity in the context of anticancer therapy

Aim. To search early signs of cardiotoxicity in patients receiving anticancer therapy and evaluate the effectiveness of cardioprotection with an angiotensin-converting enzyme inhibitor, beta-blocker and myocardial cytoprotector.Material and methods. The study included 98 patients with high and very high risk of cardiotoxicity according to the Mayo Clinic scale (USA). Cancer patients with hypertension were offered cardioprotective treatment with a fixed-dose combination of perindopril and bisoprolol, and patients with very high risk and concomitant coronary artery disease additionally trimetazidine.The patients were divided into 2 following groups: the experimental group (n=50), where patients were prescribed cardioprotective therapy, and the control group (n=48), which consisted of patients who refused or had contraindications to cardioprotection. All patients underwent an examination, including the collection of complaints and anamnesis, physical examination, electrocardiography and echocardiography with an assessment of left ventricular (LV) global longitudinal strain before chemotherapy and 1, 3, 6, 9 and 12 months after initiation of anticancer therapy.Results. In patients of the control group, by the end of the follow-up, the left atrial volume index and LV end-diastolic volume index significantly increased. In the main group, these indicators did not change significantly. In the control group, by the final visit, the LV ejection fraction significantly decreased in comparison with the initial value and the value in the first group. After 6, 9 and 12 months, there was a significant decrease in the LV global longitudinal strain in the control group, while in the main group this indicator remained within the normal range. The mortality rate in the control group was significantly higher (15% vs 2% in the experimental group). In the experimental group, cardiotoxic complications occurred in 28%, while in the control group — in 78% of patients.Conclusion. The study demonstrated the significant importance of cardiac monitoring and primary drug prevention of cardiotoxicity of anticancer therapy. A sig nificant deterioration in LV systolic function was shown in patients with a high and very high risk of cardiotoxicity who did not receive cardioprotective therapy, while its high efficiency was demonstrated in patients of the experimental group.

PS-C36-6: REAL-WORLD ANALYSIS OF ADHERENCE, OUTCOMES AND HEALTHCARE COSTS OF THE QUADRUPLE COMBINATION PERINDOPRIL, INDAPAMIDE, AMLODIPINE AND BISOPROLOL IN ITALY

Objective: this real-world analysis aimed to evaluate drug utilization, outcomes and direct healthcare costs in hypertensive patients treated with the combination of perindopril, indapamide, amlodipine and bisoprolol (PER/IND/AML/BIS) in Italy. Design and method: a retrospective analysis was performed using administrative databases covering approximately 7 million health-assisted Italian subjects. Adults prescribed with PER/IND/AML/BIS in free combination during 2018 were included. Index date corresponded to first prescription date of the four drugs (prescribed within 30 days). Follow-up was 1 year after index date; patients who died during this period were excluded. Drug utilization was evaluated as adherence (proportion of days covered (PDC): PDC < 40% non-adherence; PDC = 40–79% partial adherence; PDC> = 80% adherence); persistence/interruption (presence/absence of PER/IND/AML/BIS in last trimester of follow-up); add-on (new antihypertensive agent added to PER/IND/AML/BIS), switch (change of at least 1 among PER/IND/AML/BIS). Outcomes [i.e. incidence rate per 1,000-person/year of death and cardiovascular (CV) events] and mean annual direct healthcare costs (related to all-cause drugs, hospitalizations and outpatient services) covered by National Health Service, were evaluated. Results: A total of 5,677 patients (50.6% male, mean age 70 years) had a prescription of the antihypertensive drugs PER/IND/AML/BIS. 98.5% had a history of cardiovascular diseases and 35.2% had diabetes. During first year of follow-up, 44% of patients were adherent to PER/IND/AML/BIS, 24% partially adherent, 32% non-adherent. A higher proportion of adherent patients was found among those receiving PER/IND/AML/BIS in 2 pills compared to 3 pills (45.4% and 30.2%, p < 0.001). Among all patients, 682 (12%) received additional antihypertensive treatment to PER/IND/AML/BIS, while 761 (13%) had at least one switch. Switch of therapy was around 5-times more frequent among non-adherent patients (25.3% vs 5.1%, p < 0.001). 53% of patients were persistent to PER/IND/AML/BIS while 47% had an interruption. In adherent patients, a significant reduction of the incidence rate of death and CV events was found (62.7/1,000-person/year) compared to non-adherent and partially-adherent (88.1 and 76.8/1,000-person/year, respectively, p < 0.001). Mean total individual annual direct cost was higher for non-adherent (euro 2,456) compared to adherent (euro 2,071), with hospitalization costs almost 2-fold higher in non-adherent patients (euro 918 vs euro 456, p < 0.001). Conclusions: This analysis provides real-world evidence on sub-optimal adherence and persistence in patients treated concomitantly with four antihypertensive drugs in Italy. In non-adherent patients, higher incidence of CV events and higher healthcare costs were reported. Better adherence was observed when fewer pills were taken. Further strategies to improve treatment adherence, especially in poly-medicated patients, are needed.

Effectiveness and Safety of Fixed-dose Combination of Perindopril/Amlodipine/ Indapamide, and Telmisartan/Amlodipine/ Chlorthalidone in Grade 2 Hypertensive Patients at High Cardiovascular Risk: A Real-world Observational Study

Introduction: Fixed-dose combination containing triple antihypertensive agents (Angiotensin-Converting Enzyme Inhibitor (ACE-I)/Angiotensin Receptor Blocker (ARB), diuretic and Calcium Channel Blocker (CCB)) is recommended to achieve target Blood-Pressure (BP). However, none of the study has compared ACE-I based and ARB-based triple fixed dose combinations. Aim: To evaluate the effectiveness and safety of fixed-dose combination of Perindopril (Per)/Amlodipine (Aml)/Indapamide (Ind) and Telmisartan (Tel)/Aml/Chlorthalidone (Chl) in grade-2 hypertensive patients at high Cardiovascular (CV) risk. Materials and Methods: This retrospective, observational, single-centre study enrolled treatment-naïve grade-2 hypertensive patients who were at high CV risk and were treated with ACE-I based (Per/Aml/Ind; Per/Aml/Ind group) or ARB-based (Tel/Aml/Chl; Tel/Aml/Chl group) triple fixeddose combination for atleast one-month at the study centre. Office Blood Pressure (BP) at one-month follow-up was used as a parameter to measure treatment effectiveness. Safety was assessed based on the occurrence of Adverse Events (AEs). Results: A total of 69 patients (n=32 in Per/Aml/Ind group and n=37 in Tel/Aml/Chl group) were included. Office Systolic BP (SBP)/Diastolic BP (DBP) were 181.44±8.52/95.19±7.25 mmHg and 183.32±6.65/94.81±7.14 mmHg in patients belonging to Per/Aml/Ind and Tel/Aml/Chl groups, respectively. There was a significant reduction in office SBP/DBP at one-month follow-up (Per/Aml/Ind: 129.31±6.44/75.06±4.85 mmHg and Tel/Aml/Chl: 129.10±5.90/75.00±4.82 mmHg; p-value=0.0001). Between-group comparisons did not showed any significant difference in terms of reducing office BP. Both groups exhibited identical safety profile. Conclusion: The study demonstrated comparable treatment effectiveness and safety profile with triple fixed dose combinations containing Per/Aml/Ind and Tel/Aml/Chl in a real-world setting.

PS-R03-9: PERIODIC PARALYSIS AS A PRESENTATION OF PRIMARY HYPERALDOSTERONISM: A CASE REPORT

Objective: the typical clinical presentations of patients with primary aldosteronism (PA) include generalized weakness, fatigue, high blood pressure and potassium deficiency. However, onset of PA with periodic paralysis is rare. Design and method: herein, we present the case of a 40-year-old, Caucasian women (BMI 25,6 kg/m2) with severe resistance arterial hypertension (BP 200–190/110–120 mmHg while taking antihypertensive drugs: valsartan 320 mg/day, bisoprolol 5 mg, hydrochlorthiasid 12,5 mg, amlodipin 10 mg/day, spironolacton 25 mg/day) and muscle weakness. Over the last 2 years prior to presentation, she had multiple such episodes of generalized weakness and losing the ability to stand up, move limbs, wich typically lasted for few minutes to hours/days and resolved spontaneously. Her blood pressure was uncontroled despite taking antihypertensive drugs. She was hospitalized several times because of these conditions, but there is no data on potassium levels during that period. Due to misdiagnosis, she was operated on twice (discectomy C5-C6, C6-C7 and resection of the right internal carotid artery due to pathological tortuosity), but her condition did not improve. Results: At the presentation U waves were registered in the electrocardiography the laboratory examination revealed low plasma potassium level (3,05 mmol/l). Serum TSH, cortisol level were normal. Pasma aldosteron level was 38,6ng/dl (n. 4–31). CT abdomen: adenoma of left adrenal gland. Surgical adrenalectomy was performed. Pathological diagnosis was a bening cortical adenoma. Outcomes: Patient's serum potassium level became normalized after surgical removal of adrenal adenoma. Patient's blood pressue is controlled (130/80 mmHg) by taking a fixed combination perindopril 10 mg/indapamid 2,5 mg/amlodipin 10 mg daily and there is no muscle weakness. Conclusions: Patients with periodic acute muscles weakness and arterial hypertension should monitor electrolyte levels, especially potassium, and evaluate for primary hyperaldosteronism to avoid delayed diagnosis and treatment.

Clinical Utility of Short-Term Blood Pressure Measures to Inform Long-Term Blood Pressure Management.

Decisions about hypertension management are substantially influenced by blood pressure (BP) levels measured before and soon after starting BP lowering drugs. We aimed to assess the utility of short-term BP changes in individuals in terms of long-term treatment response. Post hoc analyses of 2 randomized trials with 4-to-6 weeks active run-in for all participants, followed by randomization to active BP lowering treatment (combination perindopril±indapamide) or placebo. We categorized individuals by degree of systolic BP (SBP) change during active run-in treatment and assessed associations with subsequent postrandomization placebo-corrected BP reduction, cardiovascular events, and tolerability. We included individuals with baseline BP ≥140/90 mm Hg from the PROGRESS trial (Perindopril Protection Against Recurrent Stroke Study; 4275 individuals with cerebrovascular disease) and ADVANCE trial (The Action in Diabetes and Vascular Disease: Preterax and Diamicron-MR Controlled Evaluation; 6610 individuals with diabetes). During the active run-in period, the proportion of participants with initial SBP changes in 4 categories (SBP increase, 0-9.9 mm Hg decrease, 10-19.9 mm Hg decrease, and ≥20 mm Hg decrease) were 17%, 27%, 28%, and 28% in PROGRESS and 21%, 22%, 24%, and 33% in ADVANCE. Randomization to active therapy achieved similar placebo-corrected long-term BP reductions across the 4 initial SBP change groups in both trials (P-values for heterogeneity >0.1). There was no significant difference in achieving BP <140/90 mm Hg at follow-up, major cardiovascular events, nor treatment tolerability according to the SBP change during active run-in period (all P-values >0.1). An individual's apparent BP change immediately after commencing therapy has limited clinical utility. Therefore, more emphasis should be given to use of evidence-based regimens and measures over the long-term to ensure sustained BP control. URL: https://www. gov; Unique identifier: NCT00145925.

Hypotensive effects of drug combinations in elderly and old patients with controlled arterial hypertension

Aim. To assess the frequency of arterial hypotension, orthostatic hypotension, low blood pressure (BP) and their clinical manifestations in the group of elderly and senile patients with a controlled course of arterial hypertension (AH), taking combinations of drugs based on an angiotensin-converting enzyme inhibitor (ACE inhibitor).Materials and methods. The study included 171 male and female residents of Krasnodar Territory with drug-controlled AH (blood pressure - BP less than 140/90 mm Hg in the background of previous antihypertensive therapy containing an ACE inhibitor perindopril), and with diseases of atherosclerotic genesis. All patients were questioned, tested for balance control, assessed for the risk of falls according to the Morse scale, hypotension in orthostasis was determined, measured office BP, carried out daily monitoring of BP with the determination of the time indices of hypotension and low BP.Results. Most often patients took a combination of ACE inhibitors with calcium channel blockers (CCB) (28.1% of cases), beta-blockers (BB) (27.1%) or diuretics (29.1%). Assessing the risk of falls on the Morse scale, there was a significantly lower level in patients who took the combination of perindopril with CCB compared with those who received perindopril with BB (15 versus 25 points respectively, p=0.039). Patients receiving perindopril and CCB lost balance in the “legs together” position in 19.3% and in the “tandem” or “semi-tandem” position of the feet in 29.8% of cases, that could be compared to the group taking perindopril and a diuretic (22% and 33.9%, respectively) and significantly lower than in the groups with perindopril and BB therapy (34.5% and 50.9%, respectively, p1=0.037, p2=0.043). The time index of low systolic and diastolic BP during therapy with perindopril and CCB was significantly lower than the corresponding indicator in the groups of patients treated with perindopril and BB (22% and 17% versus 27% and 21%, respectively, p1=0,009, p2=0,024), and the time index of low systolic BP for the combination of perindopril and diuretic is lower than for the combination of perindopril and BB (23% versus 27%, respectively, p=0.023).Conclusion. The data obtained on the frequency of arterial hypotension, orthostatic hypotension and low BP in the group of elderly and senile patients indicate the advisability of further studying the risks of drug hypotension in order to better personalize the treatment of AH.

Short-Term Changes in Serum Potassium and the Risk of Subsequent Vascular Events and Mortality: Results from a Randomized Controlled Trial of ACE Inhibitors.

Hyperkalemia after starting renin-angiotensin system inhibitors has been shown to be subsequently associated with a higher risk of cardiovascular and kidney outcomes. However, whether to continue or discontinue the drug after hyperkalemia remains unclear. Data came from the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) trial, which included a run-in period where all participants initiated angiotensin-converting enzyme inhibitor-based therapy (a fixed combination of perindopril and indapamide). The study population was taken as patients with type 2 diabetes with normokalemia (serum potassium of 3.5 to <5.0 mEq/L) at the start of run-in. Potassium was remeasured 3 weeks later when a total of 9694 participants were classified into hyperkalemia (≥5.0 mEq/L), normokalemia, and hypokalemia (<3.5 mEq/L) groups. After run-in, patients were randomized to continuation of the angiotensin-converting enzyme inhibitor-based therapy or placebo; major macrovascular, microvascular, and mortality outcomes were analyzed using Cox regression during the following 4.4 years (median). During active run-in, 556 (6%) participants experienced hyperkalemia. During follow-up, 1505 participants experienced the primary composite outcome of major macrovascular and microvascular events. Randomized treatment of angiotensin-converting enzyme inhibitor-based therapy significantly decreased the risk of the primary outcome (38.1 versus 42.0 per 1000 person-years; hazard ratio, 0.91; 95% confidence interval, 0.83 to 1.00; P=0.04) compared with placebo. The magnitude of effects did not differ across subgroups defined by short-term changes in serum potassium during run-in (P for heterogeneity =0.66). Similar consistent treatment effects were also observed for all-cause death, cardiovascular death, major coronary events, major cerebrovascular events, and new or worsening nephropathy (P for heterogeneity ≥0.27). Continuation of angiotensin-converting enzyme inhibitor-based therapy consistently decreased the subsequent risk of clinical outcomes, including cardiovascular and kidney outcomes and death, regardless of short-term changes in serum potassium. Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE), NCT00145925.

Beware-of-triple-whammy

The term “triple whammy” refers to a drug interaction following the concurrent use of angiotensin-converting enzyme inhibitors or angiotensin-II receptor blockers, diuretics and non-steroidal anti-inflammatory drugs, the combination of which greatly increases the odds of acute kidney injury. Here, we report a case of a 66-year-old gentleman who was admitted into a tertiary care hospital for elective orthopaedic intervention. He had previously been prescribed sacubitril/valsartan and frusemide and had newly been started on celecoxib during hospitalisation. Upon the initiation of celecoxib, a mild increase in his serum creatinine was immediately observed, and this occurrence is believed to be due to the “triple whammy” combination. The combination of perindopril, frusemide and celecoxib continued to be overlooked throughout his hospitalisation. He was subsequently planned to be discharged with celecoxib on top of his existing chronic medications. However, upon discharge, the dispensing pharmacist took notice of the drug interaction and successfully intervened to withhold celecoxib.

THE VALUES AND THE DIFFERENCES OF THE SEROTONIN LEVELS IN SERUM AND BRAIN TISSUE IN AN INDUCED DIABETIC NEPHROPATHY WHITE LABORATORY RAT UNDER THE IMPACT OF PERINDOPRIL AND CANDESARTAN

Angiotensin II is the primary vasoactive hormone of the renin-angiotensin-aldosterone system (RAAS) and plays a role in the pathophysiology of hypertension, heart failure, renal failure and other cardiovascular disorders. RAAS is activated in diabetic nephropathy (DN) and leads to more renal damage. Angiotensin converting enzyme inhibitors (ACEis) and angiotensin receptor blockers suppress this (ARBs). A large body of evidence demonstrates that, in addition to its typical activity as a hormone, Ang II is a neuropeptide produced by the central nervous system (CNS) that acts as a regulator of neurotransmission and nerve cell excitability. Peripheral serotonin is an endocrine component that promotes energy storage efficiency. Serotonin also enters the bloodstream and interacts with multiple organs, priming the body for energy storage by promoting insulin secretion and de novo lipogenesis in the liver and white adipose tissue. However, the actions of serotonin extend beyond neuronal communication in the CNS and enteric nervous system (ENS) to peripheral tissues. Serotonin mediates numerous nonneuronal processes such as bladder function, respiratory drive, hemostasis, vascular tone, immune function, and intestinal inflammation . The goal of this study is to see how the ACE inhibitor perindopril and the ARB AT1 candesartan, taken singly and in combination (double blockade), affect serotonin levels in the serum and brain tissue of Wistar rats with DN caused by streptozotocin (STZ). The levels of serotonin in the serum and brain of four experimental groups of animals were measured using an enzyme-linked immunosorbent assay (ELISA): a control group with DN, a group with DN treated with perindopril, a group with DN treated with candesartan, and a DN group treated with a combination of perindopril and candesartan. Perindopril (6 mg/Kg/day), candesartan (5 mg/Kg/day), and dual therapy with perindopril (3 mg/Kg/day) and candesartan (2,5 mg/Kg/day) were given orally every day for eight weeks, beginning four weeks after STZ was given, whereas the control group received just water. The rats were slaughtered at the end of the therapy so that the serum and brain tissue could be used to test serotonin levels. The results showed that blocking the renin-angiotensin system (RAS) with perindopril, candesartan, or their combination considerably decreased serotonin levels in the serum but dramatically elevated serotonin levels in the brain tissue in all groups.

Readings of 24-hour ambulatory blood pressure monitoring (ABPM) in patients with stage II arterial hypertension (HTN) receiving planned antihypertensive therapy

The aim of the study:to analyze ABPM readings in patients with stage II HTN receiving antihypertensive therapy in order to plan a personalized algorithm for managing HTN patients at the stage of the outpatient care. Materials and methods. 60 patients with stage II HTN were examined. ABPM readings were assessed on the background of planned antihypertensive therapy (ARBs and diuretics) and after the adjustment of the therapy (perindopril and amlodipine).Results. The use of long period monitoring provides comprehensive information about the patterns of blood pressure changesthroughout the day. Patients with stage II HTN receiving planned antihypertensive therapy with ARBs and diuretics did not have targeted BP during the day and had a systolic HTN of stage I, while there was a statistically significant increase in BP variability during the day and in the readings indicating a hypertensive load of target organs in comparison with a group of patients receiving a combination of perindopril and amlodipine for 3 months. In addition, there was a statistically significant (ANOVA, p&lt;0.05) difference in the rate of morning BP rise, which can serve as a precursor for the development of cardiovascular events in the morning compared to the group of patients with theadjusted therapy. Among hypertensive patients receiving ARBs and diuretics a disturbed circadian rhythm predominated in the structure of the diurnal BP profilecompared with the patients who received combined therapy with perindopril and amlodipine. In addition, the proportion of night-peakers among patients taking ARBs and diuretics was 2 times higher than among patients whose therapywas adjusted 3 months ago.Conclusion. Thus, in the group of patients whose antihypertensive therapy was timely adjusted, there was an improvement in hemodynamics: due to the achievement of targeteddiurnal blood pressurereadings, a significant decrease in BP variability during the day and the rate of the morning rise in blood pressure, as well as the proportion of patients with a normal diurnal blood pressure profileincreased.