Indapamide Sustained Release Research Articles

Abstract P340: Efficacy and safety of a novel single-pill combination (SPC) of allisartan isoproxil and sustained-release indapamide for uncontrolled hypertension by allisartan isoproxil monotherapy: a multicenter, randomized, double-blind, parallel-group phase III study

Introduction: SAL0108 by Shenzhen Salubris Pharmaceuticals Co., Ltd is a novel SPC containing 240mg of allisartan isoproxil (AI) and 1.5 mg of sustained-release (SR) indapamide. AI is a novel angiotensin receptor blocke available in China for over ten years and has the same active compound EXP3174 with losartan, while indapamide SR is a long-standing thiazide-type diuretic. Hypothesis: We assessed the hypothesis that SAL0108 is more effective than AI monotherapy. Methods: Patients with uncontrolled HTN after AI monotherapy for a minimum duration of 4 weeks were enrolled and randomized 2:1 to receive SAL0108 or continue AI treatment for a 12-week duration (double-blinded phase). Subsequently, all participants receive SAL0108 treatment until week 52 (extended period). The primary endpoint was the change in mean seated systolic blood pressure (msSBP) from baseline to week 12, assessed utilizing a treatment policy estimand within the full analysis set. Results: A total of 366 patients were enrolled, with 243 randomized to SAL0108 cohort and 123 to AI cohort. The mean age was 58.7 years, with 50.3% of patients being female. Baseline characteristics were comparable between the two cohorts. After 12 weeks of treatment, the mean change in msSBP from baseline was -15.48±17.96 mmHg in SAL0108 cohort, and -10.19±17.93 mmHg in AI cohort. SAL0108 demonstrated a significantly greater reduction in msSBP compared to AI, showing a mean difference of -5.29 mmHg (95% CI: -9.24 to -1.33; P=0.009). The achievement of msSBP/diastolic blood pressure of < 130/80 mmHg at week 12 was observed in 15.3% and 6.3% of patients in SAL0108 and AI cohorts, respectively (proportion difference 8.9%; P=0.016). Throughout the double-blinded phase, adverse events were observed in 56.8% of patients in SAL0108 cohort (most commonly being hyperuricemia, hyperlipidemia and COVID-19 infection) and 45.5% in AI cohort. Serious adverse events (SAEs) occurred in 1.7% and 4.1% of patients receiving SAL0108 and AI, respectively, and were deemed unrelated to the study drugs. Hypokalemia was infrequent, noted in 4.1% of SAL0108 recipients and 1.6% of AI recipients. During extended period, SAEs were observed in 3.9% of patients and were unrelated to SAL0108. No deaths related to the study drugs were reported. Conclusions: In conclusion, SAL0108 exhibits better efficacy in reducing blood pressure compared to AI monotherapy. The results also highlight the favorable safety profile of SAL0108 for long-term HTN management.

Pharmacokinetics and Drug-Drug Interaction of Allisartan Isoproxil and Indapamide Sustained-Release Formulation.

Allisartan isoproxil (AI) is an angiotensin II type 1 receptor blocker and be converted into the active substance EXP3174 in vivo. We evaluated the drug-drug interactions of AI and an indapamide sustained-release (Ind SR) preparation, as well as the pharmacokinetic characteristics and safety of AI and Ind SR in healthy subjects. The trial was set up in 6 sequences and 3 cycles, and each cycle contained a 7-day washout period. Subjects received 3 different trial drugs (A, AI; B, Ind SR; C, AI+Ind SR) during 3 different cycles. Twenty-four subjects were enrolled in the clinical trial. Of these, 22 completed the study, 2 subjects dropped out due to adverse events (AEs). For subjects given AI alone or combined with Ind SR, the pharmacogenetic parameters Cmax and the geometric mean ratio of steady state (combined/single) of EXP3174 was 130%. The geometric mean ratio of area under the concentration-time curve over the dosing interval at steady state (combined/single use) was 144.5%. Therefore, the combination of Ind SR had an impact on the pharmacokinetics of AI. Then, the results indicated that the AI combination had no effect on the pharmacokinetics of Ind SR. Serious AEs did not occur. The AEs in this clinical trial were the same as those for AI and Ind SR. Combined administration resulted in 2 cases (2 subjects) of Grade 3 hypotension and 1 case of Grade 3 hypotension with AI alone. Considering that this trial included healthy volunteers, the risk of hypotension was expected to be manageable.

Treatment of Hypertension: Is There a Place for Personalization of the Approach in Modern Recommendations?

The important result of the revision of the European and Russian guidelines for the management of arterial hypertension was a conclusion about the need to use a double combination of antihypertensive drugs as the first stage of antihypertensive therapy. The review presents benefits of combined antihypertensive therapy, confirmed by the results of randomized clinical trials and meta-analysis. There are literature data suggesting one of the first line reasonable combinations is the combination of angiotensin converting enzyme inhibitors (ACEI) and thiazide-like diuretic. The article discusses the benefits of single-pill combinations before free ones, such as increase in patient adherence to long-term treatment, reduction in the cost of the drug and the number of tablets. As an example, a highly effective single-pill combination of one of the most used ACEI, lisinopril and indapamide sustained release, is considered, which has protective activity, vasodilator properties and metabolic neutrality. The article presents the data of the PIFAGOR IV study that indapamide is the most widely used diuretic in Russia, which is characterized by high antihypertensive efficacy, good tolerance, cardioprotective, nephroprotective and osteoprotective properties. The results of large-scale studies, which show the ability of lisinopril to retain target blood pressure level, antiproteinuric and cardioprotective activity, are also presented. This single-pill combination has a long additive effect, contributing to reliable daily monitoring of blood pressure. The authors expressed the opinion that the prescription of highly effective single-pill combinations will contribute to organ protection and reduce the risk of cardiovascular complications development.

The association between blood pressure control and well-being in primary care practice: An observational study

Objective: The objective of this study was to assess the effect of indapamide sustained release (SR) 1.5 mg in the treatment of hypertensive patients, untreated or uncontrolled on monotherapy with different antihypertensive agents, on blood pressure (BP) reduction and well-being. Patients and Methods: In a prospective multicenter study from 32 cities across India, 1545 patients between 40 and 70 years of age with untreated or uncontrolled hypertension (BP >140/90 mmHg) received indapamide SR 1.5 mg once daily as monotherapy, or in addition to the existing treatment for 90 days. The Nottingham general health questionnaire was used to assess the changes in well-being. Results: In 1545 hypertensive patients, with a mean (standard deviation) age of 56.86 years, 64.1% being men. Of those recruited, 29% were treatment naive and 71% were receiving different antihypertensive medications. In terms of a sense of well-being, a lack of energy was reported in 56.6%, emotional problems in 61.6%, and disturbed sleep in 58.1% of the patients. On an intention to treat basis, 842 patients (54.5%; 95% confidence interval, 52.0–57.0) achieved BP control. The patients who achieved BP control (compared to those who did not) felt more energetic by 6.3% (8.2–4.3, P< 0.0001), emotionally better by 5% (6.3–3.6, P< 0.0001), and had improved sleep by 5.6% (7.4–4.1, P< 0.001). Conclusion: In hypertensive patients, untreated or uncontrolled on monotherapy with any of the major drug classes, the addition of indapamide SR 1.5 mg is effective in reducing BP and in improving their well-being.

Effectiveness and safety of indapamide sustained-release in the treatment of post partial hypertension

Background. Hypertensive disorders in pregnancy have been recognized as an important risk factor for atherosclerotic CVD in women. Therefore, lifestyle modifications, regular blood pressure control, and control of metabolic factors are recommended after delivery, to avoid complications in subsequent pregnancies and to reduce maternal cardiovascular risk in the future. There are no uniform recommendations for the treatment of post partial hypertension (HT) yet.Methods. In a case-control, open-label 1-year study, 54 post-partum hypertensive women (aged 22-38 years; body mass index 26.7±3.8 kg/m2; 18 with previous pre-eclampsia, 18 pre-existing HT, 18 pre-existing HT plus superimposed pre-eclampsia) were studied. Nursing mothers (n=27) received adjusted-dose methyldopa (Egis) 500-2000 mg daily, 27 non-feeding women received indapamide SR (Servier) 1.5 mg daily. No significant differences observed between two groups at baseline.Results. After comprehensive follow-up, clinical blood pressure was not found to differ substantially between indapamide and methyldopa groups (124.8±3.2/83.2±2.1 mmHg vs 125.3±3.8/81.5±2.9 mmHg respectively; p =NS), but indapamide significantly better improved diurnal BP patterns. No maternal adverse effects were registered in both groups, except for sleepiness and bad mood in 18.5% of methyldopa patients. There was a significant difference in weight reduction, in favour of indapamide (-11.3 kg vs -2.7 kg; p =0.032), as well as in decrease of microalbuminuria (-189.2 mg/24 h vs -51.4 mg/24 h; p

No evidence that frailty modifies the positive impact of antihypertensive treatment in very elderly people: an investigation of the impact of frailty upon treatment effect in the HYpertension in the Very Elderly Trial (HYVET) study, a double-blind, placebo-controlled study of antihypertensives in people with hypertension aged 80 and over.

BackgroundTreatment for hypertension with antihypertensive medication has been shown to reduce stroke, cardiovascular events, and mortality in older adults, but there is concern that such treatment may not be appropriate in frailer older adults. To investigate whether there is an interaction between effect of treatment for hypertension and frailty in older adults, we calculated the frailty index (FI) for all available participants from the HYpertension in the Very Elderly Trial (HYVET) study, a double-blind, placebo-controlled study of antihypertensives in people with hypertension aged 80 and over, and obtained frailty adjusted estimates of the effect of treatment with antihypertensive medication on risk of stroke, cardiovascular events, and mortality.MethodsParticipants in HYVET were randomised 1:1 to active treatment with indapamide sustained release 1.5 mg ± perindopril 2 to 4 mg or to matching placebo. Data relating to blood pressure, comorbidities, cognitive function, depression, and quality of life were collected at entry into the study and at subsequent follow-up visits. The FI was calculated at entry, based on 60 potential deficits. The distribution of FI was similar to that seen in population studies of adults aged 80 years and above (median FI, 0.17; IQR, 0.11–0.24). Cox regression was used to assess the impact of FI at entry to the study on subsequent risk of stroke, total mortality, and cardiovascular events. Models were stratified by region of recruitment and adjusted for sex and age at entry. Extending these models to include a term for a possible interaction between treatment for hypertension and FI provided a formula for the treatment effect as a function of FI. For all three models, the point estimates of the hazard ratios for the treatment effect decreased as FI increased, although to varying degrees and with varying certainty.ResultsWe found no evidence of an interaction between effect of treatment for hypertension and frailty as measured by the FI. Both the frailer and the fitter older adults with hypertension appeared to gain from treatment.ConclusionsFurther work to examine whether antihypertensive treatment modifies frailty as measured by the FI should be explored.Trial registrationClinicalTrials.gov NCT00122811 (July 2005)Electronic supplementary materialThe online version of this article (doi:10.1186/s12916-015-0328-1) contains supplementary material, which is available to authorized users.

Triple combination therapy in hypertension: the antihypertensive efficacy of treatment with perindopril, amlodipine, and indapamide SR.

The blood pressure (BP) of most patients on antihypertensive monotherapy or bitherapy remains uncontrolled. Our study evaluated the efficacy of triple therapy with perindopril, amlodipine, and indapamide sustained release (SR) in patients with uncontrolled hypertension on previous antihypertensive therapy. This 4-month, multicenter, prospective, observational, open-label study included patients switched from previous antihypertensive therapy to triple therapy with perindopril, amlodipine, and indapamide SR. The main outcome was change in office BP from baseline to 4 months, as well as changes in 24-h ambulatory BP monitoring (ABPM) parameters in a subgroup of patients. Age was 62.8 ± 11.3 years in 6,088 patients (55 % were male). Office BP at baseline was 158.1 ± 13.0/92.6 ± 8.8 mmHg. By 4 months, office BP decreased by 26.7 ± 13.3/12.9 ± 9.4 mmHg (p < 0.001). ABPM was performed in 62 patients. In these patients, 24-h systolic BP decreased (from 138.7 ± 12.5 to 125.5 ± 12.8 mmHg), as did 24-h diastolic BP (from 77.5 ± 11.4 to 70.4 ± 8.7 mmHg) (both p < 0.0001). Heart rate remained unchanged. In patients previously on renin-angiotensin-aldosterone system (RAAS) inhibitor/amlodipine, 24-h ambulatory systolic and diastolic BP decreased from 136.9 ± 12.8 to 125.4 ± 13.3 mmHg (p = 0.0003) and from 76.3 ± 12.6 to 70.2 ± 9.5 mmHg (p = 0.0005). In those previously on RAAS inhibitor/hydrochlorothiazide, 24-h ambulatory systolic and diastolic BP decreased from 137.8 ± 12.7 to 122.7 ± 15.4 mmHg (p = 0.0039) and from 73.6 ± 9.4 to 65.7 ± 7.3 mmHg (p = 0.002). Most (74 and 80 %, respectively) patients reached target ABPM values (<130/80 mmHg). A triple combination of perindopril, amlodipine, and indapamide SR controlled BP effectively in hypertensive patients uncontrolled by previous antihypertensive monotherapy or bitherapy, including RAAS inhibitor/amlodipine or RAAS inhibitor/hydrochlorothiazide combinations.

Correction: Blood Pressure Control with a Single-Pill Combination of Indapamide Sustained-Release and Amlodipine in Patients with Hypertension: The EFFICIENT Study

Correction: Blood Pressure Control with a Single-Pill Combination of Indapamide Sustained-Release and Amlodipine in Patients with Hypertension: The EFFICIENT Study

Blood Pressure Control with a Single-Pill Combination of Indapamide Sustained-Release and Amlodipine in Patients with Hypertension: The EFFICIENT Study

Objective Despite antihypertensive treatment, most hypertensive patients still have high blood pressure (BP), notably high systolic blood pressure (SBP). The EFFICIENT study examines the efficacy and acceptability of a single-pill combination of sustained-release (SR) indapamide, a thiazide-like diuretic, and amlodipine, a calcium channel blocker (CCB), in the management of hypertension.MethodsPatients who were previously uncontrolled on CCB monotherapy (BP≥140/90 mm Hg) or were previously untreated with grade 2 or 3 essential hypertension (BP≥160/100 mm Hg) received a single-pill combination tablet containing indapamide SR 1.5 mg and amlodipine 5 mg daily for 45 days, in this multicenter prospective phase 4 study. The primary outcome was mean change in BP from baseline; percentage of patients achieving BP control (BP<140/90 mm Hg) was a secondary endpoint. SBP reduction (ΔSBP) versus diastolic BP reduction (ΔDBP) was evaluated (ΔSBP/ΔDBP) from baseline to day 45. Safety and tolerability were also assessed.Results Mean baseline BP of 196 patients (mean age 52.3 years) was 160.2/97.9 mm Hg. After 45 days, mean SBP decreased by 28.5 mm Hg (95% CI, 26.4 to 30.6), while diastolic BP decreased by 15.6 mm Hg (95% CI, 14.5 to 16.7). BP control (<140/90 mm Hg) was achieved in 85% patients. ΔSBP/ΔDBP was 1.82 in the overall population. Few patients (n = 3 [2%]) reported side effects, and most (n = 194 [99%]) adhered to treatment.ConclusionIn patients who were previously uncontrolled on CCB monotherapy or untreated with grade 2 or 3 hypertension, single-pill combination indapamide SR/amlodipine reduced BP effectively—especially SBP— over 45 days, and was safe and well tolerated.Trial RegistrationClinical Trial Registry – India CTRI/2010/091/000114

Increased pulse pressure linked to dementia

High blood pressure (BP) has been associated with increased risk of dementia. Concerns have been raised about lowering BP too far in the very elderly and thereby increasing risk. There is some evidence to suggest a potential 'J'-shaped relationship between DBP and risk of cognitive impairment. This was investigated using data from the HYpertension in the Very Elderly Trial (HYVET). HYVET was a double-blind, placebo-controlled trial of antihypertensives in patients aged at least 80 years with an untreated SBP of 160-199 mmHg. Active medication was indapamide sustained release 1.5 mg+/- perindopril 2-4 mg to reach goal pressure of less than 150/80 mmHg. Incident dementia was a secondary endpoint and was not significantly different between the two treatment groups. The relationship between pressure and incident dementia was assessed using Cox proportional hazards regression with BP entered as either a discrete (quartile analysis) or continuous predictor variable. Achieved BP was calculated as the mean of all pressures from the 9 month visit onwards. During a mean follow-up of 2.2 years 263 incident cases of dementia were diagnosed. After adjustment for various covariates, baseline DBP was inversely related to incident dementia (P=0.0064). Achieved DBP did not predict later dementia in the placebo group (P=0.43), but showed a U-shaped relationship in the active treatment group (P=0.0195). The relationship between incident dementia and DBP did however not differ significantly between the placebo and active treatment groups (P=0.38). SBP was not associated with incident dementia, at baseline (P=0.62) or during follow-up (placebo group P=0.13, active group P=0.36). Wider achieved pulse pressure (PP) was associated with increased risk of dementia in both treatment groups (placebo P=0.032, active P=0.0046). The same tendency was observed for baseline PP (P=0.095). Wider PP may possibly indicate an increased risk for dementia. Active treatment may act to change the shape of the relationship between DBP and dementia. Future studies need to focus on exploring the ideal goal pressure for this age group.

Does White Coat Hypertension Require Treatment Over Age 80?

White coat hypertension is considered to be a benign condition that does not require antihypertensive treatment. Ambulatory blood pressure (ABP) was measured in 284 participants in the Hypertension in the Very Elderly Trial (HYVET), a double-blind randomized trial of indapamide sustained release 1.5 mg±perindopril 2 to 4 mg versus matching placebo in hypertensive subjects (systolic blood pressure 160–199 mm Hg) aged &gt;80 years. ABP recordings (Diasys Integra II) were obtained in 112 participants at baseline and 186 after an average follow-up of 13 months. At baseline, clinic blood pressure (CBP) exceeded the morning ABP by 32/10 mm Hg. Fifty percent of participants fulfilled the established criteria for white coat hypertension. The highest ABP readings were in the morning (average 140/80 mm Hg), the average night-time pressure was low at 124/72 mm Hg, and the average 24-hour blood pressure was 133/77 mm Hg. During follow-up, the systolic/diastolic blood pressure placebo-active differences averaged 6/5 mm Hg for morning ABP, 8/5 mm Hg for 24-hour ABP, and 13/5 mm Hg for CBP. The lowering of blood pressure over 24 hours supports the reduction in blood pressure with indapamide sustained release±perindopril as the explanation for the reduction in total mortality and cardiovascular events observed in the main HYVET study. Because we estimate that 50% had white coat hypertension in the main study, this condition may benefit from treatment in the very elderly.

Solid-state compatibility screening of excipients suitable for development of indapamide sustained release solid-dosage formulation

Differential scanning calorimetry and Fourier transform infrared spectroscopy were applied as screening analytical methods to assess the solid-state compatibility of indapamide (4-chloro-N-(2-methyl-2,3-dihydroindol-1-yl)-3-sulfamoyl-benzamide) with several polymers aimed for development of 24 h sustained release solid-dosage formulation. After the initial research phase which was directed towards selection of suitable polymer matrices, based on their solid-state compatibility with the studied pharmaceutical active ingredient, the second phase of evaluation was intended for compatibility selection of other excipients required to complete a sustained release formulation. The preformulation studies have shown that polyvinylpyrrolydone/polyvinyl acetate might be considered incompatible with indapamide, and the implementation of this polymer career should be avoided in the case of the entitled development. The experimental data additionally have revealed that sorbitol is incompatible with indapamide. The obtained results afforded deeper insight in to the solid-state stability of the studied binary systems and pointed out directions for further development of indapamide sustained release solid-dosage formulation.

Development and in vitro Evaluation of Sustained Release Matrix Tablets of Indapamide from Methocel® K15 MCR and K100 LVCR

Indapamide, a low-dose thiazide-type diuretic, is used for the treatment of essential hypertension. In this study, we developed an indapamide sustained release formulation using Methocel K15 MCR (a modified hydroxypropyl methylcellulose), Methocel K100 LVCR (a modified hydroxypropyl methylcellulose), magnesium stearate, talc and starch 1500 by direct compression. The powders for tableting were evaluated for angle of repose, loose bulk density, tapped bulk density, compressibility index, total porosity etc. The tablets were subjected to thickness, weight variation test, hardness, friability and in vitro release studies. The in vitro dissolution study was carried out in the gastric medium (pH 1.3) for first two hours and then in the intestinal medium (pH 6.8) for 22 hours using United States Pharmacopoeia (USP) 22 paddle-type dissolution apparatus. The granules showed satisfactory flow properties, compressibility index etc. All the tablets complied with pharmacopoeial specifications. The results of dissolution studies indicated that the formulation F-5 and F-7 (up to 75.36 % drug release in 12 hours) could extend the drug release up to 12 hours. The drug release patterns were simulated in different kinetic orders such as Zero Order release kinetics, First Order release kinetics, Higuchi release kinetics, Korsmeyer-Peppas release kinetics and Hixson-Crowell release kinetics to assess the release mechanism. From the study we observed that Higuchi release kinetics was the predominant release mechanism than Zero Order and First Order kinetics. The drug release mechanism from the matrix tablets was found to be non Fickian mechanism. DOI: http://dx.doi.org/10.3329/dujps.v10i2.11785 Dhaka Univ. J. Pharm. Sci. 10(2): 87-92, 2011 (December)

Effects of short and long-term indapamide treatments on urinary calcium excretion in patients with calcium oxalate dihydrate urinary stone disease: A pilot study

The aim of this study was to determine the relative calcium-reducing effects of indapamide at 6 and 18 months using a dose of 1.5 mg/day. Twenty-two patients with idiopathic hypercalciuria and calcium oxalate dihydrate urinary stone disease (minimum one stone episode) were selected. Each patient began a therapy regime of 1.5 mg indapamide sustained release taken once a day in the evening. Under basal conditions and after 6 and 18 months of treatment, subjects submitted urine and blood samples for analysis. The primary aim of this study was to assess the effects on excretion and concentration of calcium in urine. For 2 h urine, there was a mean decrease in urinary calcium concentration of 47%, whereas urinary calcium concentrations decreased by 53% in 24 h urine (p < 0.05) at 6 months of treatment. Blood urate levels rose by 19% (p < 0.05). Treatment for 18 months resulted in significant reduction in urinary calcium levels, by approximately 48% (p < 0.05) in both 2 h and 24 h urine. A 21% increase in urate levels in the blood was observed (p < 0.05). The remaining parameters remained unaltered. Owing to the low effective dosage of indapamide (1.5 mg/day) and the lack of any severe side-effects, this drug would appear to be a good candidate for use in the control of hypercalciuria. As such, it could prove efficacious in the prevention of recurrent kidney stones that are often associated with this condition.

Comparison of liquid chromatography-ultraviolet and chromatography-tandem mass spectrometry for the determination of indapamide in human whole blood and their applications in bioequivalence studies

The aim of this study was to compare two methods which were based on liquid chromatography with ultraviolet detection (LC-UV) and liquid chromatography-tandem mass spectrometry (LC-MS/MS), respectively, to determine indapamide (CAS 26807-65-8) and to apply them to bioequivalence studies. The universal parameters, including selectivity, linearity, precision, and quantification limit, served as gold standard for the comparison of the two methods. As a result, the two methods were both very consistent and reliable. Furthermore, the LC-MS/MS method required only one-fifth the blood volume needed by the other method and was approximately 25 times more sensitive than the other method. The total run time of the LC-MS/MS method was 3.5 min per sample as opposed to 11 min for the other method. Forty healthy male Chinese volunteers were selected as subjects. One half were orally administrered 2.5 mg indapamide immediate release tablets while the other half were orally administered 1.5 mg indapamide sus-tained release coated tablets. The collected blood samples were determined with the two methods described above. The pharmacokinetic parameters were determined using a noncompartmental method. For the bioequivalence studies, the pharmacokinetic parameters acquired here were in line with the literature and parameters met the criteria set by the State Food and Drug Administration of China (SFDA) for bioequivalence study, indicating that generic drugs are bioequivalent to branded drugs. The present study suggests that the two methods based on LC-UV and LC-MS/MS were suitable for bioavailability studies of indapamide with different pharmaceutical formulations. Consequently, it can be believed that the criterion that each individual expected concentration range would need a given bioassay with the requested sensitivity is not absolutely right. In practice, most of the time, the highest sensitivity allows to bioassay concentrations in a higher range.

Effect of Antihypertensive Agents on Blood Pressure Variability

To investigate the effect of different antihypertensive agents on blood pressure (BP) variability (BPV) and the underlying mechanism, we analyzed the ambulatory BP monitoring data of 577 patients before and after 3-month antihypertensive treatment, in the Natrilix SR Versus Candesartan and Amlodipine in the Reduction of Systolic Blood Pressure in Hypertensive Patients (X-CELLENT) Study, a multicenter, multinational, randomized, double-blind, placebo-controlled study with 4 parallel treatment arms (placebo, candesartan, indapamide sustained release, and amlodipine). Within-subject mean and SD of 24-hour BP, weighted by time interval between consecutive readings, were calculated in 3 time frames (daytime, nighttime, and 24 hours) to evaluate BP and BPV. The mean 24-hour heart rate (HR) and HR variability were calculated with the same algorithms. We found that the 3 antihypertensive drugs had a similar BP-lowering effect (P<0.001 for all), but amlodipine (P<0.007) and indapamide sustained release (P<0.04) were the only agents associated with a significantly decreased BPV after 3-month treatment. On the other hand, the major determinants of BPV at baseline were age, mean BP, and the corresponding HR variability. However, the reduction in BPV by amlodipine was significantly associated with the reduction in BP (P<0.006) and the reduction in HR variability (P<0.02), whereas the corresponding reduction by indapamide sustained release was only associated with the reduction in HR variability at night (P=0.004). In summary, 3-month amlodipine or indapamide sustained release treatment was associated with a significant reduction in BPV, and the mechanism of those reductions was possibly attributable to lowering BP or ameliorating the autonomic nervous system regulation or both. The combination of the 2 agents might help to optimize such properties.

Severe Hyponatremia and Other Electrolyte Disturbances Associated with Indapamide

The aim of this study is to evaluate patients' demographics, patterns of presentation and outcomes of admissions with severe hyponatremia and other electrolyte disturbances that are related to indapamide. Patients with severe indapamide-related hyponatremia (defined as serum sodium <125 mmol/L) admitted to the Department of General Medicine of a tertiary teaching hospital between 1 July 2006 and 30 June 2009 were evaluated in this study. Patients' characteristics, clinical features of their presentation and other electrolyte disturbances were analyzed retrospectively. Eleven patients were admitted with severe hyponatremia and other electrolyte disturbances associated with indapamide use. All patients were female and elderly (age: 81.7 ± 5.8 years). Their mean weight was 59.0 ± 8.8 kg. Indapamide sustained release (SR) 1.5 mg daily was taken by eight of eleven patients and the others took indapamide 2.5 mg in combination with perindopril. The mean serum sodium concentration on presentation was 110.9 ± 5.9 mmol/L and was associated with findings of hypokalemia in ten patients and hypomagnesemia in eight patients. All patients presented predominantly with neurological manifestations, delirium (six patients) being the most common. Electrocardiographic changes were common (nine patients) including prolonged QT interval in six patients. All the patients' electrolyte abnormalities were corrected without any life-threatening complications. This study highlights that the use of indapamide is associated with severe hyponatremia and other electrolyte disturbances. Therefore clinicians should be aware of severe electrolyte disturbances arising from indapamide. New onset of neurological symptoms such as delirium and unsteady gait in the elderly taking indapamide should prompt evaluation of their electrolyte profile.

Treating hypertension by rational use of diuretics: results of the Russian ARGUS-2 study

ABSTRACTObjective: Insufficient use of diuretics in combination antihypertensive therapy is a main cause of poor blood pressure (BP) control in Russia. The objective of the ARGUS-2 study was to demonstrate that a rational use of a thiazide-like diuretic, indapamide sustained release (SR), alone or in combination, improves BP control in patients with arterial hypertension difficult to control due to isolated systolic hypertension (ISH), diabetes mellitus (DM), chronic nephropathy, or metabolic syndrome.Methods: The open-label, non-comparative, 3-month study without preliminary washout included 1438 hypertensive patients (mean age: 57.3 ± 10.7 years, mean BP: 158.8 ± 14.2/93.4 ± 10.0 mmHg), with difficult-to-control arterial hypertension and who had never been treated with diuretics previously. Throughout the study, patients received indapamide SR 1.5 mg OD. BP control was defined as <140/90 mmHg for all patients and <130/80 mmHg for those with diabetes mellitus or chronic nephropathy.Results: Indapamide SR was given as initiation monotherapy to 13.7% of the patients, as substitutive monotherapy to 6.8% of the patients uncontrolled by a previous monotherapy, as additive therapy to 31.9% of the patients uncontrolled by previous monotherapy, and as additive therapy to 47.6% uncontrolled by previous combination therapy without a diuretic. Among included patients 75.7% received also an ACE inhibitor or an angiotensin II receptors blocker, 43.9% a calcium channel blocker, and 32.8% a beta-blocker. In 3 months after indapamide SR administration, average BP level decreased to 131.8 ± 9.7/80.5 ± 6.9 mmHg and 84.5% of the study population achieved BP control. BP was controlled in 91.9% of patients with ISH (n = 477), 74.8% of those with diabetes (n = 214), 75.6% of those with chronic nephropathy (n = 82), and 85.1% of patients with metabolic syndrome (n = 745). No case of hypokalemia was reported.Conclusion: The study demonstrates the value of including the thiazide-like diuretic indapamide SR in a combined antihypertensive regimen to control BP in hypertensive patients with added cardiovascular risk factors whose hypertension is difficult to treat. Methodological limitations of this study are its open-label design and the possibility of a change in concomitant antihypertensive treatment during the study.

Final Results from HYVET Show Benefit of Treating Hypertension in Older Patients

Final results of the Hypertension in the Very Elderly Trial [HYVET] demonstrated that treatment of hypertension based on indapamide sustained release tended to reduce strokes and all-cause mortality in the elderly.

Efficacy and Acceptability of Indapamide Sustained Release in Elderly High-Risk Hypertensive Patients

To assess the efficacy and acceptability of indapamide sustained-release (SR) monotherapy in elderly high-risk patients with moderate to severe hypertension. 1277 hypertensive patients older than 55 years with moderate to severe hypertension, including 91% with systolic blood pressure (SBP) >160 mmHg and at least one cardiovascular risk factor (age >65 years, male, diabetes mellitus, coronary heart disease [CHD], cerebrovascular disease, dyslipidaemia, obesity, smoking) were enrolled in this observational study. They received indapamide SR 1.5 mg, one tablet daily, for 3 months. Blood pressure (BP) was assessed monthly by sphygmomanometer. Statistical analyses were performed using the χ(2) test, analysis of variance, and the Newman-Keuls test. After 3 months of treatment with indapamide SR, SBP had decreased by 34 ± 3 mmHg and diastolic BP (DBP) by 12 ± 6 mmHg (both p < 0.001). Ninety-two percent of patients responded to therapy (SBP/DBP reduction >20/10 mmHg) and 52% were normalized (SBP <140 mmHg and DBP <90 mmHg). BP targets were reached in 48% of patients older than 65 years, 31% of diabetic patients, and 33% of patients with CHD. There were no changes in serum creatinine, glucose or lipid parameters, and 3% of patients had hypokalaemia (<3.5 mmol/L). The patients self-assessment scores regarding general state of health improved and 34% of patients reported 'excellent' health after treatment. In the high-risk patients of the ARGUS study, monotherapy with indapamide SR showed antihypertensive efficacy with good acceptability and no changes in metabolic parameters over a 3-month period. Indapamide SR monotherapy normalized BP in half of the patients treated and proved an appropriate first-line treatment in hypertensive patients older than 55 years with added cardiovascular risk factors.