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PubMed2003

Trials on blood pressure-lowering and secondary stroke prevention.

The risk of stroke is strongly and persistently related to the usual level of both systolic blood pressure (SBP) and diastolic blood pressure (DBP). This relation holds for primary and secondary stroke, both ischemic and hemorrhagic. The Perindopril Protection Against Recurrent Stroke Study (PROGRESS) has now provided definitive evidence that lowering the blood pressure of patients with preexisting cerebrovascular disease (prior stroke or transient ischemic attack [TIA]) also reduces the incidence of secondary stroke. PROGRESS showed that a flexible blood pressure-lowering regimen involving an angiotensin-converting enzyme inhibitor (perindopril) and a diuretic (indapamide) reduces the incidence of stroke, major coronary events, and major vascular events by 28%, 26%, and 26%, respectively. These benefits were associated with an average reduction of 9.0 mm Hg (SBP) and 4.0 mm Hg (DBP). The 28% reduction in stroke incidence translated into a 24% reduction in ischemic stroke and a 50% reduction in hemorrhagic stroke. Combination therapy with perindopril and indapamide decreased blood pressure more effectively than did perindopril monotherapy (mean reduction of 12.3 mm Hg [SBP] and 5.0 mm Hg [DBP] vs 4.9 mm Hg [SBP] and 2.8 mm Hg [DBP], respectively) and was equally effective in reducing stroke risk in patients with and without hypertension. In conclusion, blood pressure-lowering therapy is now established as the most important measure for primary and secondary stroke prevention. Results of PROGRESS suggest that antihypertensive treatment with a combination of perindopril plus indapamide should now be routinely considered for all patients with previous stroke or TIA.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed2002

Drug-induced long QT in isolated rabbit Purkinje fibers: importance of action potential duration, triangulation and early afterdepolarizations.

In the present study, we investigated three drug-induced long-QT syndromes in isolated rabbit Purkinje fibers in order to identify the relationship of action potential duration (APD), triangulation of action potentials (APD(90)-APD(40)) and early afterdepolarizations. Isolated rabbit Purkinje fibers were superperfused in Tyrode solution with solvent, indapamide (1 x 10 (-4) M, an I(ks) blocker mimicking long QT1), dofetilide (1 x 10 (-9), 1 x 10 (-8) or 1 x 10 (-7) M, an I(kr) blocker mimicking long QT2) or anthopleurin (1 x 10 (-8) M, an inhibitor of the inactivation of the I(Na(+)) current mimicking long QT3) (n=8 per group) for 25 min, and stimulated at 1 Hz for 20 min and at 0.2 Hz for another 5 min. Indapamide did not change APD and triangulation or elicit early afterdepolarizations even in the presence of beta-adrenergic stimulation with isoproterenol. Dofetilide concentration-dependently prolonged APD(90), increased triangulation and elicited early afterdepolarizations. Anthopleurin markedly increased APD(90) as well as triangulation and elicited early afterdepolarizations. The induction of early afterdepolarizations by dofetilide and anthopleurin was associated with a prolongation of APD(90) or an increase in triangulation, but not with a change in APD(40). Moreover, the degree of the increase in the triangulation was larger than that of APD(90) in long QT2 (dofetilide-induced) and long QT3 (anthopleurin-induced) models in isolated rabbit Purkinje fibers. Our present study indicates that rabbit Purkinje fibers can be used as long QT2 (dofetilide-mimicking) and LQT3 (anthopleurin-mimicking) syndrome models, and confirms that drug-induced long QT1 (indapamide-mimicking) is absent. Our present study also shows the relationship between a prolongation of APD(90) or increase in triangulation and the induction of early afterdepolarizations with dofetilide (I(kr) blocker) and anthopleurin (I(Na) modulator) in isolated rabbit Purkinje fibers.

Action Potentials↗
PubMed2003

Perindopril pROtection aGainst REcurrent Stroke Study (PROGRESS): interpretation and implementation.

OBJECTIVES: To determine the effects of a perindopril-based blood pressure lowering regimen in hypertensive and non-hypertensive patients with a history of stroke or transient ischaemic attack (TIA). DESIGN AND METHODS: 6105 subjects from 172 centres in Asia, Australasia, and Europe were randomised to receive active treatment (n = 3051) or placebo (n = 3054). Active treatment consisted of a flexible regimen based on the angiotensin-converting enzyme inhibitor perindopril (4 mg daily), with the addition of the diuretic indapamide, at the discretion of treating physicians. The primary outcome was total stroke (fatal or non-fatal). Analysis was by intention to treat. RESULTS: Active treatment reduced blood pressure by 9/4 mmHg over 4 years of follow-up. 307 (10%) individuals assigned active treatment suffered a stroke, compared with 420 (14%) assigned placebo [relative risk reduction 28% (95% confidence interval 17-38), P < 0.0001]. Active treatment also reduced the risks of total major vascular events [26% (16-34)] including non-fatal myocardial infarction [38% (14-55)], severe cognitive decline [19% (4-32)], stroke-related dementia [34% (3-55)] and disability [18% (8-28)]. There were similar reductions in the risk of stroke in hypertensive and non-hypertensive subgroups (P < 0.01). Combination therapy with perindopril plus indapamide lowered blood pressure by 12/5 mmHg and stroke risk by 43%. Single-drug therapy lowered blood pressure by 5/3 mmHg and produced no significant fall in the risk of stroke. CONCLUSIONS: The blood-pressure lowering regimen used in Perindopril pROtection aGainst REcurrent Stroke Study (PROGRESS) reduced the risks of stroke and other serious events in hypertensive and non-hypertensive subjects with a history of stroke (whatever the subtype) or transient ischaemic attack. Combination therapy with perindopril and indapamide produced larger blood pressure reductions and larger stroke reductions than monotherapy with perindopril alone. Treatment with these two agents should be considered routinely for all patients with a history of previous stroke or TIA, whether hypertensive or normotensive.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1987

Interactions of diuretics with the peripheral-type benzodiazepine receptor in rat kidney.

The peripheral-type benzodiazepine receptor (PBR) has been autoradiographically localized to the thick ascending limb and early distal tubule. To elucidate further the role of this receptor in kidney function, we have examined the effects of all classes of diuretics on the binding of labeled PBR-specific ligands (R05-4864, PK 11195) to rat kidney membranes (13,000 X g X 10 min). Drugs capable of inhibiting R05-4864 binding by 50% at less than 200 microM included: metolazone (IC50 = 1 microM), indacrinone (IC50 = 42 microM), indapamide (IC50 = 58 microM), hydrochlorothiazide (HCTZ; IC50 = 117 microM) and trichloromethiazide (IC50 = 175 microM). Conversely, diuretics of the loop (e.g., furosemide), K+-sparing (e.g., triamterene), and carbonic anhydrase inhibitor (e.g., acetazolamide) classes exerted no significant effects on R05-4864 binding (IC50S greater than or equal to 1 mM). Inhibition by indacrinone was stereoselective. Thiazide-like compounds inhibited R05-4864 binding with a rank-order of potencies similar to that for their enhancement of in vivo natriuresis (metolazone greater than HCTZ approximately equal to trichlormethiazide greater than chlorothiazide). Scatchard analysis revealed that metolazone, indacrinone, indapamide and HCTZ inhibited R05-4864 binding by reducing Kd, with no effect on maximum binding. The apparent Kd of metolazone for the renal PBR was 3.8 X 10(-7) M. IC50 values of 14 metolazone derivatives for inhibition of R05-4864 binding correlated well (r = .71, P less than .01) with their natriuretic efficacies. PK 11195 binding to digitonin (1.2 mg/mg of protein)-solubilized membranes displayed the same rank-order of, but was twice as sensitive to inhibition by metolazone, indacrinone, indapamide and HCTZ.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Acute and chronic diuretic treatment selectively affects vascular permeability in the unanesthetized normal rat.

Diuretics are widely used antihypertensive agents, and although their renal actions have been well characterized, the extent of their vascular effects remains to be defined. Because hypertension is associated with numerous vascular complications whose incidences are not always lowered once blood pressure is regulated, this study was undertaken to evaluate the effects of five selected diuretics on capillary permeability to see if they could contribute in some way to these vascular abnormalities. Extravasation of Evans blue dye (EB: 20 mg/kg) injected in the caudal vein of male Wistar rats was used to assess capillary permeability to albumin. Indapamide (0.04 mg/kg), cicletanine (2.0 mg/kg), amiloride (0.3 mg/kg), hydrochlorothiazide (0.5 mg/kg) and furosemide (0.5 mg/kg) were administered by acute i.v. injection or by 10-day "chronic" gavage. EB extravasation was increased in the upper bronchi, lung parenchyma and kidney after acute administration of indapamide (54, 41 and 31%, respectively) and hydrochlorothiazide (45, 41 and 19%, respectively), and increased in all tissues but the duodenum (upper bronchi, lung parenchyma, heart, liver, kidney and muscle; 57-118%) after furosemide. In contrast, capillary permeability was reduced after acute cicletanine in the heart (31%), duodenum (49%) and muscle (58%) and after amiloride in the heart (25%) and muscle (63%). Pretreatment with indomethacin abolished most changes in EB extravasation induced by acute injection of the diuretics. After 10-day gavage, however, changes in capillary permeability were null after amiloride or hydrochlorothiazide treatment, attenuated after cicletanine or furosemide or even reversed after indapamide. Arterial pressure was not affected by diuretic treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1996

PROGRESS--perindopril protection against recurrent stroke study: status in July 1996. PROGRESS Management Committee.

OBJECTIVES: The primary objective of PROGRESS is to determine reliably the efficacy of lowering blood pressure for the prevention of stroke in patients with a history of cerebrovascular disease. DESIGN: PROGRESS is a randomized, double-blind, placebo-controlled trial investigating the effects on the incidence of stroke and other major cardiovascular events and dementia of treatment with the angiotensin-converting enzyme inhibitor perindopril, alone or in combination with the diuretic indapamide. METHODS: The study population comprises 6000 normotensive or hypertensive patients with a history of stroke or transient ischaemic attack within the previous 5 years. The study is being conducted in over 160 centres in seven regions: Australia and New Zealand, The People's Republic of China, France and Belgium, Italy, Japan, Sweden and the United Kingdom. Computerized randomization to active treatment or placebo is performed by fax direct to Auckland, New Zealand. The primary study outcome is total stroke and secondary outcomes include fatal or non-fatal stroke, total major cardiovascular events and deaths, cognitive function and disability. Patients will be followed for a minimum of 4 years after randomization. RESULTS: By 16 July 1996, 162 local clinical centres had been registered across the seven regions, and 1682 patients, 49% with a history of hypertension, had been randomly assigned to receive active treatment or placebo, with 65% allocated to the combination of perindopril and indapamide or double placebo, and 35% to perindopril alone or single placebo. Three months after randomization, the blood pressure difference between the treatment and control groups among the first 182 patients randomized was 11.9 mmHg (systolic) and 3.9 mmHg (diastolic). Six strokes and two non-stroke cardiovascular deaths have been recorded after a total of 3174 patient-months of follow-up. CONCLUSIONS: Observations made so far confirm that full recruitment into the study is feasible and that treatment with perindopril and indapamide is well tolerated in the study population. The blood pressure differences between control and treatment groups recorded so far suggest that the study should have the power to achieve its primary objectives, provided compliance with treatment is satisfactory and 6000 patients are successfully recruited and followed for 4-5 years.

Adult↗
PubMedDate not supplied

Role of dual pacemaker mechanisms in sinoatrial node discharge.

We investigated whether in the sinoatrial node (SAN) there are two different pacemaker mechanisms and whether either one can maintain spontaneous discharge. These questions were studied by means of an electrophysiological technique and of blockers of different diastolic currents in rabbit and guinea pig isolated SAN. In SAN subsidiary pacemakers of both species, Cs(+) (5-10 mM) or high [K(+)](o) (10-12 mM) decreased the maximum diastolic potential, abolished diastolic depolarization (DD) at polarized levels (subsidiary DD), unmasked a U-shaped dominant DD at depolarized levels, but did not stop the SAN. In rabbit SAN, E4031 (1 microM) and d-sotalol (100 microM) did not stop discharge, but did so after block of subsidiary DD by high [K(+)](o) or Cs(+). In guinea pig SAN, in Tyrode solution E4031, d-sotalol or indapamide (100 microM) did not stop SAN discharge. In the presence of Cs(+) or high [K(+)](o) indapamide (but not E4031 or d-sotalol) stopped the SAN. Ba(2+) (1-5 mM) led to stoppage of discharge both in Tyrode solution and in high [K(+)](o) or Cs(+). Depolarization by blockers of DD unmasked sinusoidal fluctuations, which during recovery were responsible for resumption of discharge. We conclude that in rabbit and guinea pig SAN, two different pacemaker mechanisms (Cs(+)- and K(+)-sensitive subsidiary DD, and Cs(+)- and K(+)-insensitive dominant DD) can independently sustain discharge, but block of both mechanisms leads to quiescence. Abolition of dominant DD by blockers of I(K) is consistent with a decay of I(K) as the dominant pacemaking mechanism, I(Kr) being more important in rabbit and I(Ks) in guinea pig. Sinusoidal fluctuations appear to be an essential component of the pacemaking process.

Action Potentials↗
PubMed2001

Study rationale and design of ADVANCE: action in diabetes and vascular disease--preterax and diamicron MR controlled evaluation.

AIMS/HYPOTHESIS: Patients with Type II (non-insulin-dependent) diabetes mellitus are at increased risk of macrovascular and microvascular disease, both of which are reduced by controlling raised blood pressure in hypertensive patients. Intensive glycaemic control has also been shown to reduce microvascular disease but the effects on macrovascular disease remain uncertain. This study will examine the hypotheses that lowering blood pressure with an ACE inhibitor-diuretic combination and intensively controlling gylcaemia with a sulphonylurea-based regimen in high-risk patients with Type II diabetes (both hypertensive and non-hypertensive) reduces the incidence of macrovascular and microvascular disease. METHODS: The study is a 2 x 2 factorial randomised controlled trial that will include 10000 adults with Type II diabetes at high risk of vascular disease. Following 6 weeks on open label perindopril-indapamide combination, eligible patients are randomised to continued perindopril-indapamide or matching placebo, and to an intensive gliclazide MR-based glucose control regimen or usual guidelines-based therapy. Primary outcomes are, first, the composite of nonfatal stroke, non-fatal myocardial infarction or cardiovascular death and, second, the composite of new or worsening nephropathy or diabetic eye disease. The scheduled average duration of treatment and follow-up is 4.5 years. The study will be conducted in approximately 200 centres in Australasia, Asia, Europe and North America. CONCLUSION/INTERPRETATION: ADVANCE is designed to provide reliable evidence on the balance of benefits and risks conferred by blood pressure lowering therapy and intensive glucose control therapy in high-risk diabetic patients, regardless of initial blood pressure or glucose concentrations.

Aged↗
PubMed2001

Coronary microvasculature alteration in hypertensive rats. Effect of treatment with a diuretic and an ACE inhibitor.

The development of hypertension is accompanied by rarefaction of arterioles and capillaries in both animal models and humans. Although many studies have examined the effects of antihypertensive therapies on hemodynamics, cardiac hypertrophy, and large vessel structure, the question of whether changes in microvascular density induced by hypertension can be restored by pharmacologic treatment has yet to be answered. We report a series of experiments performed in rats with renovascular hypertension induced by unilateral nephrectomy and renal artery stenosis (Goldblatt one-kidney, one-clip model). Animals were treated for 4 weeks, after renal artery clipping, either with an angiotensin converting enzyme inhibitor (perindopril [PER], 0.76 mg/kg/day), or with an indol derivative diuretic with specific vascular properties (indapamide [IDP], 0.24 mg/kg/day) or with the combination of both drugs at the same doses as during monotherapy. Coronary microvessel densities (arterioles and capillaries) were evaluated by double immunolabeling in nonserial cryostat sections of the left ventricular inner myocardium. After 4 weeks of hypertension (mean arterial pressure, 174+/-11 v 124+/-5 mm Hg in normotensive (NT) controls, P < .01), cardiac hypertrophy (+59%, P < .001) was associated with a significant increase in myocardial arteriolar density (+27%, P < .01), and a decrease in capillary density (-12%, P < .05). Treatment with PER prevented the increase in arterial pressure, heart weight, and arteriolar density, but did not significantly affect the low coronary capillary density in comparison with that measured in untreated hypertensive (HT) rats. Treatment with IDP preserved normal capillary myocardial density but did not significantly lower the blood pressure (BP) (169+/-9 mm Hg) and only slightly reduced the cardiac ventricular hypertrophy: - 14% v untreated HT (P < .05) and +37% v NT (P < .01). In the same way, IDP normalized the left ventricular capillary density in spontaneously HT rats (+18% v untreated rats, P < .01). The combination of both drugs, PER and IDP, at the same low doses as during monotherapy, resulted in normal levels of arterial pressure and complete normalization of cardiac hypertrophy and arteriolar and capillary myocardial densities. In conclusion, the results observed after PER suggest that blockade of the renin-angiotensin system could inhibit large coronary vessel growth but minimally affects the capillary density despite complete normalization of BP. Indapamide could have beneficial effect on myocardial capillary density. The combination of IDP and PER has additional effects and prevents the increase in BP and cardiac weight, and reverses microvascular rarefaction, specifically arteriolar and capillary densities.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed2006

Urinary N-acetyl B glucosaminidase as an earlier marker of diabetic nephropathy and influence of low-dose perindopril/indapamide combination.

INTRODUCTION: Tubulointerstitial injury is both a key feature of diabetic nephropathy and an important predictor of renal dysfunction. N-Acetyl B glucosaminidase (NAG) is derived from proximal tubular cells and is widely used to evaluate tubular renal function. OBJECTIVE: The objective of this study is whether NAG can be used as an early marker of diabetic nephropathy by comparing the urinary NAG levels between healthy controls and diabetic patients and determining changes in urinary NAG excretion after treatment with low-dose combination perindopril (2 mg)/ indapamide (0.625 mg)/o.d. MATERIALS AND METHODS: A total of 50 patients (29 female) with type II diabetes mellitus applying to our diabetes outpatient clinics for the first time were included in our study (Group 1). Diabetic patients were classified into three subgroups on the basis of their duration of diabetes: Group 1A (n = 15) < or = 3 years, Group 1B (n = 19) 3 to 5 years, and Group 1c (n = 16) > 5 years. The inclusion criteria were no prior use of antihypertensive agents; blood pressure < 130/85 mmHg; urinary albumin excretion < 30 mg/day; and absence of renal failure, diabetietes, and hypertensive retinopathy. A total of 30 healthy individuals (16 female) (Group 2) were assessed as the control group. Systolic and diastolic blood pressures, HbA1c, body mass index, 24-h microalbuminuria (MAU), and NAG measurements in urine samples were performed by using colorimetric assay method in an analyzer (Roche Cobas Mira). The assay defined as fragmentation of 3-cresolsulfonphthaleinyl-N-acetyl-beta-D-glucosaminide molecule by NAG to 3-cresolsulphonphthalein and N-acetylglucosamine molecules and serum creatinine were measured in all groups. Type II diabetic patients were administered perindopril (2 mg)/indapamide (0.625 mg) combination once daily for 4 months, and urinary NAG levels were measured at the end of treatment. RESULTS: Statistically significant differences were observed between the groups 1 and 2 with respect to the levels of NAG and HbA1c (p < 0.05). In the treatment group, NAG levels decreased significantly (p < 0.05), whereas blood pressure and HbA1c levels did not change significantly (p > 0.05). In diabetic patients, pretreatment NAG were lowest in Group 1A and highest in Group 1c, although the difference between the treatment subgroups was not statistically significant (p > 0.05). CONCLUSION: Urinary NAG excretion is elevated in type II diabetic patients as compared with the healthy individuals. Perindopril/indapamide administration is effective in reducing urinary NAG excretion in these patients, and this effect seems to be independent from blood pressure and glycemia control. Presence of tubular proteinuria may be an early indicator of diabetic renal disease in patients without microalbuminuria. Perindopril (2 mg)/ indapamide (0.625 mg)/o.d. treatment may have beneficial effect on the tubulointerstitial damage in diabetic kidney disease.

Acetylglucosaminidase↗
PubMed1998

Centralized echocardiogram quality control in a multicenter study of regression of left ventricular hypertrophy in hypertension.

OBJECTIVE: To test the feasibility and utility of instituting centralized echocardiographic quality control during a multicenter study of regression of left ventricular hypertrophy in hypertension. DESIGN AND METHODS: The LIVE (Left Ventricular Hypertrophy: Indapamide Versus Enalapril) study is an ongoing multicenter, double-blind, controlled study of regression of echocardiographic left ventricular mass index in hypertensive patients with left ventricular hypertrophy (left ventricular mass indexes > 100 g/m2 for women and > 120 g/m2 for men) treated for 1 year with 1.5 mg indapamide sustained-release coated tablets versus 20 mg enalapril. A centralized evaluation committee has validated a prestudy sample echocardiogram from each center, and is now reviewing all videotapes recorded during this study for quality control; final results will be based on a further randomized blinded analysis by this centralized evaluation committee. RESULTS: Since December 1994, 878 patients have been preselected (videoechocardiographic recordings sent for assessment), 645 selected (videoechocardiographic recordings validated), and 576 randomly allocated to treatment. After preliminary quality control, 27% (233) of baseline echocardiograms were rejected by our centralized evaluation committee, and 22% (142) of postinclusion echocardiographic measurements had to be repeated, mainly because they were of poor echogenic quality. Analysis of approved baseline echocardiograms for the first 274 randomly allocated patients with digitized data showed that there was a significant correlation between centralized evaluation committee and investigator calculations of left ventricular mass index (r = 0.76, P < 0.001), with consistently higher values for investigator calculations, independently of level of left ventricular mass index (correlation between difference and mean of investigator and centralized evaluation committee measurements, r = 0.08, P = 0.28). The mean difference was 8 +/- 20 g/m2 (P < 0.001). CONCLUSION: Early results of the LIVE study quality control showed that real-time 'live', centralized echocardiographic reading was not only feasible, but also useful for avoiding unquantifiable echocardiograms and overestimation of left ventricular mass index. Thus, real-time, centralized echocardiographic quality control should be recommended for multicenter studies of regression of left ventricular hypertrophy.

Adult↗
PubMed2004

Comparison of different therapeutic strategies in hypertension: a low-dose combination of perindopril/indapamide versus a sequential monotherapy or a stepped-care approach.

OBJECTIVE: To compare the efficacy and the tolerability of three different strategies in the treatment of hypertension (low-dose combination, sequential monotherapy and stepped-care). DESIGN: Hypertensive patients were randomized to a 9-month treatment with the aim to lower blood pressure below 140/90 mmHg. Treatment adjustments were allowed at months 3 and 6. The study was discontinued for patients with normal blood pressure at month 6. In the 'low-dose combination' group, perindopril (2 mg) and indapamide (0.625 mg) were first administered with the possibility to increase the doses in two steps up to respectively, 4 and 1.25 mg. In the 'sequential monotherapy' group, the treatment was initiated with atenolol (50 mg), replaced if necessary by losartan (50 mg), and then by amlodipine (5 mg). In the 'stepped-care' group, valsartan, was given first at a 40 mg dose, then at a 80 mg dose, to be co-administered finally if needed with hydrochlorothiazide, 12.5 mg. All study tablets were encapsulated to conceal their identity and had to be taken once a day. PATIENTS: Patients with uncomplicated essential hypertension were recruited (n = 180 in the 'low-dose combination' group, n = 176 in the 'sequential monotherapy' group and n = 177 in the 'stepped-care' group). RESULTS: The percentage of patients having achieved the target blood pressure was significantly greater in the 'low-dose combination' group (62%) than in the 'sequential monotherapy' (49%, P = 0.02) and the 'stepped-care' group (47%, P = 0.005). The percentage of patients having normalized their blood pressure without experiencing drug-related adverse events was also significantly higher in the 'low-dose combination' group (56%) than in the 'sequential monotherapy' (42%, P = 0.002) and the 'stepped-care' group (42%, P = 0.004). CONCLUSIONS: A first line management of hypertension based on a low-dose combination of perindopril and indapamide allows the normalization of blood pressure in significantly more patients than a 'sequential monotherapy' strategy involving atenolol, losartan and amlodipine, and a 'stepped-care' strategy involving valsartan and hydrochlorothiazide. These better blood pressure results were not obtained at the expense of a worsening of tolerability.

Aged↗
PubMed2006

ADVANCE: breaking new ground in type 2 diabetes.

OBJECTIVE AND RATIONALE: ADVANCE (Action in Diabetes and Vascular disease: preterAx and diamicroN-MR Controlled Evaluation) is a large-scale trial designed to investigate the benefits of blood pressure lowering and intensive glucose control in patients with type 2 diabetes, and to address a number of unresolved issues: whether blood pressure-lowering therapy and intensive glucose control therapy will reduce the risk of major vascular disease regardless of initial blood pressure or glucose concentration; whether more intensive glucose control targeting a haemoglobin A1c (HbA1c) level of 6.5% or less will confer greater protection against microvascular disease; and whether the benefits of the two interventions are additive. DESIGN AND METHODS: ADVANCE is a 2 x 2 factorial randomized clinical trial evaluating the risks and benefits of the low-dose fixed combination of perindopril and indapamide versus placebo to lower blood pressure and of an intensive gliclazide-MR-based glucose control regimen, targeting an HbA1c of 6.5% or less versus standard guidelines based therapy for glucose control. There are two primary outcomes: a composite macrovascular endpoint and a composite microvascular endpoint. RESULTS: A total of 12 878 participants from 215 centres in 20 countries entered a 6-week run-in phase between June 2001 and January 2003, and 11 140 patients were randomly assigned by March 2003. The average (SD) systolic and diastolic blood pressure fell from 145 (22)/81 (11) to 137 (20)/78 (10) mmHg during the 6-week run-in phase, during which participants received one tablet of open-labelled perindopril 2 mg/indapamide 0.625 mg. Of the 12 878 patients who entered the run-in, only 3.6% withdrew because of suspected intolerance to perindopril/indapamide. The study is half way through follow-up and both the study medications (perindopril 2 mg/indapamide 0.625 mg and gliclazide-MR) continue to be well tolerated. Completion is expected in 2007. CONCLUSION: Safe and effective blood pressure lowering with the fixed low-dose combination of perindopril and indapamide was confirmed during the run-in phase in 11 140 patients with type 2 diabetes, who were subsequently randomly assigned. Post-randomization study treatments have been well tolerated, and the completion of follow-up is scheduled in 2007.

Aged↗
PubMed2001

Perindopril/indapamide 2/0.625 mg/day: a review of its place in the management of hypertension.

The fixed low-dose combination of the ACE inhibitor perindopril and the non-thiazide diuretic indapamide has been evaluated in the management of patients with mild to moderate hypertension. Combination therapy aims to improve overall therapeutic efficacy while minimising adverse effects. In well-designed multicentre clinical trials, perindopril/indapamide at doses ranging from 2/0.625 to 8/2.5 mg/day was significantly more effective than placebo in achieving adequate blood pressure (BP) control. A similar reduction in supine BP was observed when combined perindopril/indapamide 2/0.625 mg/day was compared with losartan 50 mg/day or atenolol 50 mg/day. Similar reductions in 24-hour ambulatory BP were also seen with perindopril/indapamide 2/0.625 mg/day and irbesartan 150 mg/day. However, response and normalisation rates were significantly higher with combination therapy than with losartan or irbesartan monotherapy. Combined perindopril/indapamide 2/0.625 mg/day therapy effectively reduced BP in elderly patients aged 65 to 85 years to a significantly greater extent than either atenolol 50 mg/day or placebo. Supine BP was also normalised in approximately two-thirds of patients in a small noncomparative trial in patients with hypertension and renal impairment. Low-dose perindopril/indapamide 2/0.625 mg/day was well tolerated in clinical trials; the most common adverse events were headache and cough. Hypokalaemia, associated with the use of diuretics, occurred with a higher incidence with combined perindopril/indapamide 2/0.625 mg/day therapy than with either atenolol 50 mg/day or placebo. Perindopril/indapamide 2/0.625 mg/day has shown efficacy in well designed comparative trials with atenolol, losartan and irbesartan including elderly patients and patients with renal impairment. Studies comparing this dosage of perindopril/ indapamide with other combination therapies would be beneficial in allowing the place of perindopril/indapamide to be more accurately determined. The fixed-low dose combination of perindopril/indapamide provides a promising and well tolerated treatment option in the management of patients with mild to moderate hypertension.

Adult↗
PubMed1999

Vasodilatory effect of diuretics is dependent on inhibition of vascular smooth muscle carbonic anhydrase by a direct mechanism of action.

Five years ago, our in vitro and in vivo studies demonstrated for the first time that diuretic agents such as furosemide, hydrochlorothiazide, amiloride, triamterene and spironolactone inhibit carbonic anhydrase (CA) I, II and renal CA IV by a direct mechanism of action. In this paper we investigate the relationship between diuretics and CA I in the vasodilatory mechanism. Both in vitro (on purified CA I, erythrocyte CA I and smooth muscle CA I) and in vivo (in human and rabbits) we studied the effect of acetazolamide, hydrochlorothiazide, indapamide, furosemide, amiloride and triamterene on purified CA I, on human erythrocyte CA I, as well as on CA I isolated from vascular smooth muscle. Our results demonstrate that in vitro all diuretics inhibit CA I by a direct mechanism of action. Inhibition reached 100% with acetazolamide, 45% with hydrochlorothiazide, 82% with indapamide, 85% with furosemide, 68% with amiloride and 58% with triamterene. In vivo, similar inhibition of erythrocyte and smooth muscle CA I was obtained, being parallel with a reduction in arterial blood pressure values. Our data show that in addition to their already known mechanisms, diuretics also inhibit CA in vascular smooth muscle. Our results suggest that this mechanism is achieved by means of pH changes induced by CA I inhibition.

Acetazolamide↗
PubMed2001

[Clinical study of the month. Secondary prevention of cerebrovascular accident with perindopril: the PROGRESS study].

PROGRESS ("Perindopril pROtection aGainst REcurrent Stroke Study") demonstrated that blood-pressure lowering treatment with perindopril, an angiotensin converting enzyme inhibitor (combined with the diuretic agent indapamide when necessary), reduces the risk of stroke by 28% (95% CI: 17-38, p < 0.0001) among patients with a history of stroke or transient ischaemic attack. This protective effect was observed among both hypertensive and non-hypertensive individuals. It was more marked in the patients receiving combined perindopril + indapamide treatment (-43%; 95% CI 30-54) who were those who showed the greatest reduction in arterial blood pressure (-12/5 mm Hg). According to these observations, the authors concluded that treatment with these two agents should now be considered routinely for patients with a history of stroke or transient ischaemic attack, irrespective of their blood pressure.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed2002

[Efficacy of 12-week monotherapy with arifon-retard of patients with isolated systolic hypertension].

AIM: To evaluate the effect of arifon-retard (Servie, France) in patients with isolated systolic arterial hypertension (ISAH). MATERIAL AND METHODS: The efficiency of 12-week monotherapy with indapamid (arifon-retard) in a daily dose of 1.5 mg on systolic, diastolic, and pulse arterial pressure (SAP, DAP, and PAP, respectively) was studied in 20 patients with ISAH. RESULTS: SAP decreased by 25.1 +/- 1.8, (p < 0.00009), DAP by 4.2 +/- 0.9 (p < 0.0008), and PAP by 20.9 +/- 2.1 mm Hg (p < 0.00009). Antihypertensive effect was observed in all patients, AP normalized in 30% after 4 weeks of therapy and in 70% after 12 weeks, DAP not decreasing below 70 mm Hg in any of the patients. Antihypertensive effect of indapamid on SAP and PAP additionally increased from week 4 to week 12. With sufficient antihypertensive effect on SAP, the drug did not induce an excessive decrease of DAP and did not affect heart rate and blood biochemistry. The drug was well tolerated, no side effects were observed.

Aged↗
PubMed2002

[Treatment of hypertensive type 2 diabetes patients with microalbuminuria].

PRIMARY OBJECTIVE: The first fundamental study devoted to the reduction of microalbuminuria with a antihypertensive diuretic (indapamide SR) in type 2 diabetes with hypertension, the Marre study (NESTOR) was designed to demonstrate that this antihypertension agent could be an interesting therapeutic alternative by comparing its efficacy on microalbuminuria with that of enalapril 10 mg during a treatment period of 52 weeks. RESULTS: It was demonstrated that indapamide SR is the only diuretic providing a significant reduction (35%) in the microalbuminuria observed in hypertensive patients with type 2 diabetes. At the endpoint, comparison with the group of patients treated with enalapril, showed no significant difference in fractionated albumin clearance or in the percentage of patients with normoalbuminuria, microalbuminuria or gross proteinuria. Safety and tolerance were comparable for the two treatments.

Albuminuria↗