Comparison of Pharmacokinetics and Bioavailability of Fixed-Dose Combination Tablet and Monotherapy Combination of Allisartan Isoproxil and Indapamide Sustained-Release in Healthy Chinese Volunteers.

This study aimed to compare the pharmacokinetics and bioavailability of 2 formulations: a fixed-dose combination tablet containing allisartan isoproxil (AI) and indapamide sustained-release (SR), and a monotherapy combination of AI and indapamide SR, in healthy Chinese subjects. A monocentric, open-label, single-dose, randomized, 2-way crossover study design was implemented. A total of 38 healthy male and female volunteers were equally divided into 2 treatment sequences. The analysis of plasma concentrations was conducted using a nonstereospecific liquid chromatography/tandem mass spectrometric method. The primary pharmacokinetic parameters were calculated using a noncompartmental model. Safety assessments were performed throughout the study. For the fixed-dose combination and monotherapy combination, the mean values of EXP3174 (metabolite of AI) Cmax , AUC0-t , and AUC0-∞ were 987 and 999 ng/mL, 8059 and 7749 ng/mL h, and 8332 and 8007 ng/mL h, respectively. The corresponding values for indapamide were 27 and 32 ng/mL, 1002 and 1105 ng/mL h, and 1080 and 1172 ng/mL h. No serious adverse events were reported during the study. The combination tablet containing 240 mg of AI and 1.5 mg of indapamide SR met the bioequivalence standards. Additionally, both formulations were tolerated and had good safety profiles in the research.

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.

Not So Innocent Indapamide.

A 58-year-old asymptomatic man was referred by his general practitioner for abnormal blood results. Routine blood tests to monitor blood count and kidney functions showed neutropenia and hyponatremia. He was euvolemic on examination. A further detailed investigation did not reveal any cause of neutropenia and hyponatremia. After careful assessment of their drug history, it transpired he recently started Indapamide for uncontrolled hypertension. Hyponatraemia is a common side effect of Indapamide and in addition, it can rarely cause agranulocytosis and leukopenia. Indapamide was stopped and the blood counts started to improve and became normal after two weeks.

[Intraoperative management of potentially fatal arrhythmias after anesthesia induced by severe hypokalemia: A case report].

Severe hypokalemia is defined as the concentration of serum potassium lower than 2.5 mmol/L, which may lead to serious arrhythmias and cause mortality. We report an unusual case of potentially fatal ventricular arrhythmias induced by severe hypokalemia in a patient undergoing laparoscopic partial nephrectomy in Peking University Third Hospital due to irregular use of indapamide before operation. Indapamide is a sulfonamide diuretic with vasodilative and calcium antagonistic effects, which enhances sodium delivery to the renal distal tubules resulting in a dose-related increase in urinary potassium excretion and decreases serum potassium concentrations. The electrolyte disorder caused by the diuretic is more likely to occur in the elderly patients, especially those with malnutrition or long-term fasting. Hence, the serum potassium concentration of the patients under indapamide therapy, especially elderly patients, should be monitored carefully. Meanwhile, the potassium concentration measured by arterial blood gas analysis is different from that measured by venous blood or laboratory test. According to the previous research, the concentration of potassium in venous blood was slightly higher than that in arterial blood, and the difference value was 0.1-0.5 mmol/L. This error should be taken into account when rapid intravenous potassium supplementation or reduction of blood potassium level was carried out clinically. In the correction of severe hypokalemia, the standard approach often did not work well for treating severe hypokalemia. The tailored rapid potassium supplementation strategy shortened the time of hypokalemia and was a safe and better treatment option to remedy life-threatening arrhythmias caused by severe hypokalemia with a high success rate. Through the anesthesia management of this case, we conclude that for the elderly patients who take indapamide or other potassium excretion diuretics, the electrolyte concentration and the general volume state of the patients should be comprehensively measured and fully evaluated before operation. It may be necessary for us to reexamine the serum electrolyte concentration before anesthesia induction on the morning of surgery in patients with the history of hypokalemia. For severe hypokalemia detected after anesthesia, central venous cannulation access for individualized rapid potassium supplementation is an effective approach to reverse the life-threatening arrhythmias caused by severe hypokalemia and ensure the safety of the patients.

Incidence of severe hypokalaemia in patients taking indapamide.

BACKGROUND: Diuretics are commonly used for the treatment of hypertension. Yet, hypokalaemia is a well-recognised adverse effect. We conducted a retrospective study to evaluate the incidence of severe hypokalaemia, defined as requiring hospitalisation, among patients on indapamide. METHODS: We searched a territory-wide database, Clinical Data Analysis and Reporting System of the Hong Kong Hospital Authority. We traced all hypertensive patients who had been prescribed indapamide in 2007-2016 and all admissions due to hypokalaemia in 2007-2018. Factors associated with hospitalisation were studied using multivariable logistic regression. RESULTS: During the period studied, 62,881 patients were started on indapamide and 509 (0.8%) were hospitalised for hypokalaemia. 53% of these hospitalisations occurred within the first year of treatment, and half of those in the first year occurred during the first 16 weeks. Female sex (adjusted OR, 1.75; 95%CI, 1.45-2.12) and immediate-release formulation (adjusted OR, 1.41; 95%CI, 1.14-1.75) were associated with hospitalisation. In the multivariable model, advanced age was not a significant predictor. There were no deaths during hospitalisation and the median length of hospital stay was one day. CONCLUSIONS: In this large population-based study with 147,319 person-years of follow-up, severe hypokalaemia requiring hospitalisation was uncommon among hypertensive patients on indapamide. The risk is higher in women and in the initial weeks and months after starting therapy. The use of the sustained-release formulation reduces the risk. We conclude that using indapamide to treat hypertension is safe, even in the elderly, especially if the sustained-release formulation is used and electrolytes are monitored periodically.

Intraoperative management of potentially fatal arrhythmias after anesthesia induced by severe hypokalemia: A case report / 北京大学学报(医学版)

Severe hypokalemia is defined as the concentration of serum potassium lower than 2.5 mmol/L, which may lead to serious arrhythmias and cause mortality. We report an unusual case of potentially fatal ventricular arrhythmias induced by severe hypokalemia in a patient undergoing laparoscopic partial nephrectomy in Peking University Third Hospital due to irregular use of indapamide before operation. Indapamide is a sulfonamide diuretic with vasodilative and calcium antagonistic effects, which enhances sodium delivery to the renal distal tubules resulting in a dose-related increase in urinary potassium excretion and decreases serum potassium concentrations. The electrolyte disorder caused by the diuretic is more likely to occur in the elderly patients, especially those with malnutrition or long-term fasting. Hence, the serum potassium concentration of the patients under indapamide therapy, especially elderly patients, should be monitored carefully. Meanwhile, the potassium concentration measured by arterial blood gas analysis is different from that measured by venous blood or laboratory test. According to the previous research, the concentration of potassium in venous blood was slightly higher than that in arterial blood, and the difference value was 0.1-0.5 mmol/L. This error should be taken into account when rapid intravenous potassium supplementation or reduction of blood potassium level was carried out clinically. In the correction of severe hypokalemia, the standard approach often did not work well for treating severe hypokalemia. The tailored rapid potassium supplementation strategy shortened the time of hypokalemia and was a safe and better treatment option to remedy life-threatening arrhythmias caused by severe hypokalemia with a high success rate. Through the anesthesia management of this case, we conclude that for the elderly patients who take indapamide or other potassium excretion diuretics, the electrolyte concentration and the general volume state of the patients should be comprehensively measured and fully evaluated before operation. It may be necessary for us to reexamine the serum electrolyte concentration before anesthesia induction on the morning of surgery in patients with the history of hypokalemia. For severe hypokalemia detected after anesthesia, central venous cannulation access for individualized rapid potassium supplementation is an effective approach to reverse the life-threatening arrhythmias caused by severe hypokalemia and ensure the safety of the patients.

Efficacy of Single-Pill, Triple Antihypertensive Therapy in Patients with Uncontrolled Hypertension: A Systematic Review and Meta-analysis.

INTRODUCTION: Systemic arterial hypertension is the most common preventable risk factor for all causes of morbidity and mortality worldwide with a prevalence of 35-40% of the adults. Despite the wide variety of effective antihypertensive medications, most hypertensive patients remain uncontrolled. However, the combination of ACE inhibitor, diuretics, and calcium antagonist for the triple therapy in a single Pill Combination (SPC) is an efficient regimen in hypertension management. It is recommended by the ESH 2018 guideline, which offers better efficacy and compliance to treatment. AIM: To evaluate the efficacy of perindopril/indapamide/amlodipine single-pill combination in patients with uncontrolled hypertension. METHODS: We searched PubMed, Scopus, Web of Science, and Cochrane CENTRAL for relevant clinical trials. We conducted the risk of bias assessment using Cochrane's risk of bias tool. We performed the analysis of continuous data using mean difference (MD) and relative 95% confidence interval (CI), while dichotomous data were analyzed using risk ratio (RR) and relative 95% CI. We included the analysis of the following outcomes: systolic blood pressure (SBP), Diastolic blood pressure (DBP), Heart rate (HR), 24 h Ambulatory blood pressure monitoring (ABPM) for SBP, and 24 h ABPM for DBP. RESULTS: We included six clinical trials. We found that the triple therapy significantly reduces SBP by 24 mmHg (MD = - 24.65 [22.41, 26.89], (P < 0.01)), DBP by 12 mmHg (MD = 12.41 [11.53, 13.29], (P < 0.01)), 24-h ABPM for SBP by 14 mmHg (MD = 14.08 [9.10, 19.05], (P < 0.01)), and ABPM 24 h DBP by 7 mmHg (MD = 7.01 [5.37, 8.65], (P < 0.01)). We noted no significant difference of the single pill on heart rate (MD = 0.81 [- 0.04, 1.67], (P = 0.06). CONCLUSION: perindopril/indapamide/amlodipine is effective in reducing systolic and diastolic blood pressures by 24 and 12 mmHg respectively. Over 24 h, the combination reduced systolic and diastolic blood pressures by 14 and 7 mmHg respectively.

Perindopril/Indapamide/Amlodipine in Hypertension: A Profile of Its Use.

The single-pill combination (SPC) of perindopril (PER)/indapamide (IND)/amlodipine (AML) is a valuable and convenient treatment option for patients with hypertension controlled with two-drug SPC of PER/IND + AML given as two separate pills at the same dose level. PER [an angiotensin-converting enzyme (ACE) inhibitor], IND (a thiazide-like diuretic) and AML (a calcium channel blocker) are well established antihypertensive agents, which have been available for a long time as monotherapies and dual SPCs and have complementary mechanisms of action. Once-daily PER/IND/AML provided effective BP control, with good tolerability, in patients with uncontrolled hypertension in clinical trials and in large observational prospective studies. The efficacy and tolerability of PER/IND/AML was similar to that of PER/IND + AML in a randomized clinical trial. The therapeutic effect of PER/IND/AML was associated with improved health-related quality of life. Thus, switching from the two-pill PER/IND + AML regimen to single-pill PER/IND/AML reduces pill burden and simplifies drug administration, which may improve adherence to treatment, leading to better BP control and clinical outcomes.

Approximately one-quarter of patients with hypertension require three antihypertensive agents to achieve BP control. However, complex treatment regimens and high pill burden reduce treatment adherence, which in turn leads to poor BP control. Perindopril (PER), indapamide (IND), amlodipine (AML) belong to the core drug classes for the treatment of hypertension. These drugs have been available for a long time as monotherapies and two-drug single-pill combinations. Once-daily PER/IND/AML provides very good BP control in patients with uncontrolled hypertension and is generally well tolerated. The single-pill PER/IND/AML has similar efficacy and tolerability to PER/IND + AML given as two separate pills. Therefore, switching from PER/IND + AML to PER/IND/AML reduces pill burden and simplifies the treatment regimen, which may improve adherence to treatment, leading to better BP control and clinical outcomes. Thus, PER/IND/AML is a valuable and convenient treatment option for patients with hypertension controlled with PER/IND + AML at the same dose level.

Effectiveness of indapamide/amlodipine single-pill combination in patients with isolated systolic hypertension: post-hoc analysis of the ARBALET study.

BACKGROUND: This study evaluated the effectiveness of treatment with an indapamide/amlodipine single-pill combination (SPC) in outpatients with uncontrolled isolated systolic hypertension (ISH) aged over 55 years in real-life clinical practice. METHODS: This was a post-hoc analysis of the subgroup of patients with ISH from ARBALET, a 3-month, multicenter, observational, open-label study conducted in Russia among patients with grade I or II hypertension who were either uncontrolled on previous antihypertensive treatment or treatment-naïve. The effectiveness of indapamide/amlodipine SPC was assessed by the change in office systolic blood pressure (SBP) and the rate of target SBP (< 140 mmHg) achievement at 2 weeks, 1 month and 3 months, in four age groups: 55-59 years, 60-69 years, 70-79 years, and 80 years or older. RESULTS: The ARBALET study recruited 2217 patients, of whom 626 had ISH and were included in this post-hoc analysis (mean age 66.1 ± 7.8 years; 165 men [26.4%] and 461 women [73.6%]). Target SBP < 140 mmHg was achieved in 43%, 75% and 93% of patients at 2 weeks, 1 and 3 months, respectively. SBP decreased from baseline by 18.8 ± 10.5 mmHg, 27.2 ± 10.6 mmHg and 31.8 ± 9.9 mmHg at 2 weeks, 1 month and 3 months, respectively. In the groups of patients aged 55-59, 60-69, 70-79, and ≥ 80 years, SBP reductions at 3 months compared with baseline were - 30.3 ± 9.4, - 32.4 ± 9.7, - 32.5 ± 10.7, and - 28.9 ± 9.6 mmHg, respectively. CONCLUSION: This post-hoc analysis of the observational ARBALET study showed that indapamide/amlodipine SPC was associated with significant reductions in BP and high rates of target BP achievement in a broad age range of patients with ISH treated in routine clinical practice. STUDY REGISTRATION NUMBER: ISRCTN40812831.

The Efficacy and Tolerability of a Fixed Combination of Perindopril and Indapamide in the Treatment of Unregulated Essential Hypertension - a Postmarketing Study.

OBJECTIVE: The objective of this non-interventional post-marketing clinical trial was to analyze the antihypertensive effect and safety of a fixed combination of perindopril and indapamide in the treatment of unregulated essential hypertension. PATIENTS AND METHODS: The prospective clinical trial included patients aged 20 to 75 years with essential hypertension and blood pressure values ≥ 140/90 mmHg at baseline. On the basis of the investigator's decision, patients received 2 mg perindopril + 0.625 mg indapamide (group 2+0.625) or 4 mg perindopril + 1.25 mg indapamide (group 4+1.25). RESULTS: The study included 1173 patients (426 patients in group 2+0.625 and 747 patients in group 4+1.25) at 27 investigational centers in Bosnia and Herzegovina. Mean blood pressure values at baseline and visits after nine months were significantly higher in the 4+1.25 group compared to the 2+0.625 group. There was a significant drop in systolic and diastolic blood pressure in both groups. The target values of systolic and diastolic blood pressure, according to the European Society of Cardiology (2018), were reached after nine months of therapy by more than 80% of patients in the 2+0.625 group, and this number was significantly higher compared to the 4+1.25 group where more than 60% of patients reached target values. Newly diagnosed patients had a better response to therapy. The percentage of patients receiving additional antihypertensive therapy decreased by the end of the study. Age, gender and the existence of diabetes mellitus were identified as negative predictors of target blood pressure achievement. The therapy showed a good safety profile. CONCLUSION: A fixed combination of perindopril and indapamide was effective and safe in the treatment of unregulated essential hypertension.

[Tactics of antihypertensive therapy during COVID-19 pandemic].

Results of foreign and Russian studies indicate a higher mortality rate of patients with concomitant cardiovascular diseases (CVD) due to the new coronavirus infection COVID-19. It has been proven that arterial hypertension, as one of the significant risk factors for the development of concomitant cardiovascular diseases, is associated with a more severe prognosis of COVID-19. This article presents the results of modern studies and large meta-analyzes of necessity and safety of the use of blockers of the renin-angiotensin-aldosterone system in patients with arterial hypertension and COVID-19. The data of studies show that an angiotensin-converting enzyme inhibitor (ACE inhibitor) and a thiazide-like diuretic is a pathogenetically rational combination. It realizes various ways of lowering blood pressure by reducing the activity of the renin-angiotensin-aldosterone system, which is achieved by using an ACE inhibitor, and natriuresis due to diuretics. As an example, a highly effective fixed combination of drugs is considered, characterized by good tolerance, which consists of an ACE inhibitor lisinopril and a thiazide-like diuretic indapamide of prolonged action. The authors expressed the opinion that the appointment of the fixed combination drug Diroton Plus (Gedeon Richter) will contribute to effective control of blood pressure and organoprotection in conditions of increased thrombogenic and prooxidative potential, characteristic of COVID-19 both in the acute stage and within the post-COVID Syndrome.

Unilateral Idiopathic Choroidal Effusion in a Patient Who Takes Sulfonamides.

Purpose: To report a challenging case of unilateral choroidal effusion.Methods: A case report about patient who presented with unilateral choroidal effusion and who was taking sulfonamides. Patient has been under care of a multidisciplinary team of uveitis consultant, ocular oncology consultant, and systemic oncology consultant. A comprehensive workup was done (blood tests, Spectralis OCT, FFA, chest X-rays, MRI, PETCT).Results: Baseline visual acuity on the affected (right) eye was 6/12. Patient is amblyopic and hypermetropic on that eye. Blood test results were negative on syphilis, tuberculosis, or sarcoidosis. MRI showed no mass lesions. PETCT scan showed no signs of malignant process out of the eye. Suprachoroidal drainage was done and analysis of the drainaged fluid showed no presence of malignant cells. Overall workup period patient's vision was stable.Conclusion: Definite diagnosis of unilateral choroidal effusion was done. A comprehensive workup is needed to exclude potential malignant process.

Comparing the sodium excreting efficacy of furosemide and indapamide combination against furosemide and metolazone combination in congestive heart failure patients: A randomized control trial.

OBJECTIVE: To compare efficacy and safety of indapamide-furosemide combination against metolazone-furosemide combination in refractory heart failure patients. METHODS: The randomised controlled trial was conducted at Rehman Medical Institute, Peshawar, Pakistan, from January 1 to June 30, 2018, and comprised refractory heart failure patients who were randomised into two groups using lottery method Group 1 received intravenous furosemide 40mg Q12hr with metolazone 5mg Q24hr, while group 2 received intravenous furosemide 40mg Q12hr with indapamide 2.5mg Q24hr. Both groups were assessed for urinary sodium excretion, total urine output and decrease in weight on day one, day three and day five of admission. SPSS 22 was used for data analysis. RESULTS: Of the 150 patients, there were 75(50%) in each of the two groups. Mean age in group 1 was 64.8}11.2 years, while it was 66.3}12.9 years in group 2. Both groups showed increased urinary sodium excretion and total urine output (p>0.05). Hypokalaemia was the most common adverse event 66%. Mean hospital stay was not significantly different between the groups (p>0.05). CONCLUSIONS: There was no significant differences between adverse events and efficacy between patients receiving either indapamide-furosemide combination or metolazone-furosemide combination.

A review of the prescribing trend of thiazide-type and thiazide-like diuretics in hypertension: A UK perspective.

Thiazide diuretics have been the cornerstone of hypertension treatment for >5 decades. Most recent European and American guidelines recommend both thiazide-type and thiazide-like diuretics as first-line drugs for all patients with hypertension. In contrast, diuretics are not regarded as first-line treatment in the UK and in patients who are to be initiated on a diuretic treatment, thiazide-like molecules, such as chlortalidone and indapamide are the preferred option. This review examines the prescribing trend of the 4 most commonly prescribed thiazide diuretics for the treatment of hypertension in the UK. Prescription cost analysis data were obtained for both 2010 and 2016/2017 for each region of the UK to analyse the impact of the 2011 National Institute for Health and Care Excellence hypertension guidelines on the trend in thiazide diuretic prescribing. Overall, the prescriptions of thiazide diuretics declined over the years. Bendroflumethiazide is the most commonly prescribed diuretic in the UK and despite some geographical differences, thiazide-type diuretics are more widely used than thiazide-like. The use of indapamide increased significantly between 2010 and 2016/2017 while chlortalidone was rarely employed. Of the many factors affecting trends in prescriptions, clinical inertia, treatment adherence, availability of the products and the lack of fixed dose combinations may play a role.

Plasmapheresis to treat Osmotic Demyelination Syndrome from overly rapid plasma sodium correction.

Osmotic demyelination syndrome results from overly rapid serum sodium correction and is often iatrogenic. We report a 50-year-old hypertensive woman on Indapamide presenting with malaise, dizziness and serum sodium less than 100mmol/l who developed osmotic demyelination syndrome after correction of the hyponatremia. Good neurological recovery was seen after plasmapheresis.

Short-term effects of perindopril-amlodipine vs perindopril-indapamide on blood pressure control in sub-Saharan type 2 diabetic individuals newly diagnosed for hypertension: A double-blinded randomized controlled trial.

Poor blood pressure (BP) control contributes to complications in sub-Saharan African (SSA) type 2 diabetic individuals. Experts have advocated the use of combination therapies for effective BP control in these patients. The suggested combinations should include a RAAS antagonist and either a CCB or a thiazide diuretic; however, their efficacy is yet to be established in SSA. We investigated the short-term effects of two combination therapies on BP control in SSA type 2 diabetic individuals. This was a double-blinded randomized controlled trial conducted at the Yaoundé Central Hospital (Cameroon) from October 2016 to May 2017. We included type 2 diabetic patients, newly diagnosed for hypertension. After baseline assessment and 24-hour ABPM, participants were allocated to receive either a fixed combination of perindopril + amlodipine or perindopril + indapamide for 42 days. Data analyses followed the intention-to-treat principle. We included fifteen participants (8 being females) in each group. Both combinations provided good circadian BP control after 6 weeks with similar efficacy. Twenty-four-hour SBP dropped from 144 to 145 mm Hg vs 128 to 126 mm Hg with perindopril-amlodipine and perindopril-indapamide, respectively (P = 0.003 for both groups). Twenty-four-hour DBP dropped from 85 to 78 mm Hg (P = 0.013) vs 89 to 79 mm Hg (P = 0.006) in the same respective groups. No significant adverse effect was reported. A fixed initial combination of perindopril-amlodipine or perindopril-indapamide achieved similar effective BP control after 6 weeks in SSA type 2 diabetic individuals with newly diagnosed hypertension. Therefore, these combinations can be used interchangeably in this indication.

The effect of indapamide vs. bendroflumethiazide for primary hypertension: a systematic review.

The aims of the current review were to compare the efficacy of monotherapy with bendroflumethiazide vs. indapamide on mortality, cardiovascular outcomes, blood pressure, need for intensification of treatment and treatment withdrawal. Two authors independently screened the results of a literature search, assessed the risk of bias and extracted relevant data. Randomized clinical trials of hypertensive patients of at least a 1-year duration were included. When there was disagreement, a third reviewer was consulted. Risk ratio (RR) and mean differences were used as measures of effect. Two trials comparing bendroflumethiazide against placebo, one comparing indapamide with placebo and three of short duration directly comparing indapamide and Bendroflumethiazide, were included. No statistically significant difference was found between indapamide and bendroflumethiazide for all deaths [RR 0.82; 95% confidence interval (CI) 0.57, 1.18], cardiovascular deaths (RR 0.82; 95% CI 0.55, 1.20), noncardiovascular deaths (0.81; 95% CI 0.54, 1.22), coronary events (RR 0.73; 95% CI 0.30, 1.79) or all cardiovascular events (RR 0.89; 95% CI 0.67, 1.18). Indapamide performed worse for stroke (RR 2.21; 95% CI 1.19, 4.11), even though a reduction in RR compared with placebo was observed in both groups. There was no statistically or clinically significant difference between indapamide and bendroflumethiazide in blood pressure reduction (mean absolute difference <1 mmHg). The present review highlights a lack of studies to answer the review question but also a lack of evidence of superiority of one drug over the other. Therefore, there is a clear need for new studies directly comparing the effect of these drugs on the outcomes of interest.

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

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

[Combined Therapy of Arterial Hypertension With Triple Fixed-Dose Combination of Amlodipine/Indapamide/Perindopril Arginine in Real Clinical Practice: the Organization and the Main Results of the DOKAZATEL'STVO (Proof) Study].

AIM: to assess antihypertensive efficacy of the fixed-dose amlodipine/indapamide/perindopril arginine combination in hypertensive patients in real clinical setting. METHODS: We included in the 3­month clinical program 1 599 patients with arterial hypertension (AH) (38.8 % men, mean age 61.6±10 years). Primary outcomes were change of office and ambulatory (home blood pressure monitoring) systolic and diastolic blood pressure (SBP and DBP) from baseline to 3 months and rate of achievement of target BP.

Indapamide-induced bilateral choroidal effusion in pseudophakic patient.

We describe a case of indapamide-induced bilateral choroidal effusion, first time reported in pseudophakic patient, associated with no change in visual acuity and stable refraction.A 70-year-old man was referred for ophthalmic assessment, with binasal visual field defect for 2 days. He had been started on treatment with indapamide 3 weeks earlier. His ophthalmic history included bilateral cataract surgery and intraocular lens implant. Fundal examination revealed bilateral choroidal effusions; B-scan ultrasonography was used to measure the extent of the choroidal detachment and the anterior chamber depth. Discontinuation of indapamide resulted in spontaneous resolution of choroidal effusion after 3 days. Our case is the first in the literature that describes bilateral choroidal effusion induced by indapamide in a pseudophakic patient. The lack of myopic shift likely resulted in a later presentation, enhancing the theory that lens thickening and/or accommodative spasm may play a crucial role in pathophysiology.