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Background and Purpose: Observational studies demonstrate strong associations between blood pressure and bleeding complications of antithrombotic therapy. The objective was to determine whether blood pressure lowering reduces risks of bleeding in patients on antithrombotic therapy., Methods: This is a subsidiary analysis of the Perindopril Protection Against Recurrent Stroke Study (PROGRESS) trial, a randomized, placebo-controlled trial. A total of 6105 patients with cerebrovascular disease were randomly assigned to either active treatment (perindopril ± indapamide) or placebo(s). The outcomes were intracranial and extracranial bleeding., Results: There were 4876 (80%) patients on antithrombotic therapy at baseline. Over a mean follow-up of 3.9 years, 119 intracranial and 123 extracranial bleeding events were observed. Among patients with and without antithrombotic therapy, active treatment lowered blood pressure by 8.9/4.0 and 9.3/3.8 mm Hg and reduced the risks of intracranial bleeding by 46% (95% CI, 7%-69%) and 70% (39%-85%), respectively. However, active treatment did not reduce the risks of extracranial bleeding significantly in either group. Among patients on antithrombotic therapy, the lowest risk of intracranial bleeding was observed in participants with the lowest follow-up systolic blood pressure levels (median, 113 mm Hg)., Conclusions: Blood pressure lowering provides protection against intracranial bleeding among patients with cerebrovascular disease including those receiving antithrombotic therapy.

To determine whether the persistent antihypertensive effect observed after withdrawal of angiotensin-converting enzyme inhibition was specific and whether it was associated with durable improvement of renal function. Lyon hypertensive (LH) rats were treated from 3 and 12 weeks of age with perindopril at the dose of 0.4 (P0.4) or 1.5 (P1.5) mg·kg(-1)·d(-1), with double (hydralazine 75 mg·kg(-1)·d(-1) and hydrochlorothiazide 15 mg·kg(-1)·d(-1)), or triple antihypertensive therapy (reserpine 0.75 mg·kg(-1)·d(-1) was added). Blood pressure (BP) was recorded by telemetry, and renal functions were evaluated in freely moving rats. Despite similar BP reduction after perindopril withdrawal in P0.4 and P1.5 groups, greater decrease in proteinuria was observed in P1.5 group. Double or triple therapy prevented the hypertension of LH rats, but without any persistent antihypertensive or antiproteinuric effect after its withdrawal. Salt load elicited an increase in BP that was similar in untreated LH and both perindopril-pretreated groups (+30 mm Hg), but more pronounced in double therapy–pretreated or triple therapy–pretreated groups (+50 mm Hg). The pressure–natriuresis curve shifted to lower BP levels in P0.4 and P1.5 groups, whereas it was blunted in double and triple therapy groups. Angiotensin-converting enzyme inhibition has a durable renoprotection after treatment withdrawal that is independent of BP lowing.

Background and Purpose: Patients with cerebral amyloid angiopathy (CAA) are at high risk for intracerebral hemorrhage (ICH), but no effective prevention strategies have been established. The objective is to determine whether lowering of blood pressure (BP) provides protection for this high-risk patient group., Methods: This study is a subsidiary analysis of the PROGRESS trial-a randomized, placebo-controlled trial that established the beneficial effects of BP lowering in patients with cerebrovascular disease; 6105 patients were randomly assigned to either active treatment (perindopril for all participants plus indapamide for those with neither an indication for nor a contraindication to a diuretic) or matching placebo. Outcomes were probable CAA-related ICH as defined by the Boston criteria, probable hypertension-related ICH, and unclassified ICH., Results: Over a mean follow-up of 3.9 years, 16 probable CAA-related ICH, 51 probable hypertension-related ICH, and 44 unclassified ICH occurred. Active treatment reduced the risk of CAA-related ICH by 77% (95% CI, 19%-93%), that of hypertension-related ICH by 46% (95% CI, 4%-69%), and that of unclassified ICH by 43% (95% CI, -5%-69%). There was no evidence of differences in the magnitude of the effects of treatment among different types of ICH (P homogeneity=0.4)., Conclusions: BP-lowering treatment is likely to provide protection against all types of ICH.

Cardiovascular disease is responsible for 70% of all mortality among patients with type 2 diabetes and is also a major contributor to diabetes-related healthcare costs. The ADVANCE trial clearly demonstrated that a simple and easily applicable pharmacological strategy based on perindopril/indapamide fixed combination could substantially reduce total and cardiovascular mortality (-14% and -18%, respectively). The observed benefits were largely caused by a substantial decrease in systolic blood pressure (SBP), confirming the need to have ambitious therapeutic goals in such high-risk patients. This point is of importance because most of the patients included in the trial were being treated for hypertension, and baseline brachial SBP and diastolic blood pressure at inclusion were very close to normal. Previous mechanistic studies have highlighted the positive effect of perindopril/indapamide fixed combination on large artery function as well as on microvascular structure. For example, in the REASON trial, in patients treated with perindopril/indapamide, the decrease in central aortic SBP, which closely correlated with the decrease in left ventricular hypertrophy, reflected a significant improvement in large artery function and a changing pattern in both peripheral reflection coefficients and structural arteriolar network. These data are supported by those from other studies, which show increases in coronary blood flow reserve with perindopril/indapamide treatment. In conclusion, normalization of SBP, pulse pressure, arterial function and myocardial perfusion, a haemodynamic profile known to improve survival in the hypertensive populations at high cardiovascular risk, seems to be more easily achieved when a strategy based on the perindopril/indapamide combination is applied.

Difficulties in achieving a reduction in morbidity and mortality in patients with diabetes are a result of the complexity of the disease and its intertwined relationship with hypertension and renal impairment. In the recently published Action in Diabetes and Vascular disease: PreterAx and DiamicroN-MR Controlled Evaluation (ADVANCE) trial, treatment of patients with diabetes with the fixed combination perindopril/indapamide on top of background treatments provided clinically and statistically significant reductions in blood pressure (from 145/81 to 136/73 mmHg), all-cause mortality (-14%), cardiovascular mortality (-18%), major cardiovascular events (-9%), renal events (-21%) and new-onset microalbuminuria (-21%) when compared with placebo. As the ADVANCE trial included both hypertensive and normotensive patients, its results suggest that systematically treating all patients with diabetes with perindopril/indapamide, independently of their baseline blood pressure, may have significant long-term value that can be explained partly by the reversal of end-organ damage to the kidney and the heart. Considering that patients with both hypertension and diabetes are characterized by generalized macro- and microvascular disease, the results of the ADVANCE trial, taken together with results of other perindopril/indapamide hypertension studies, support a broad use of perindopril/indapamide treatment for the long-term improvement of prognosis in hypertensive patients as well as in patients with 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.

Pharmacological treatment of hypertension represents a cost-effective way of preventing cardiovascular and renal complications. To benefit maximally from antihypertensive treatment, blood pressure should be brought to below 140/90 mmHg in every hypertensive patient, and even lower (< 130/80 mmHg) if diabetes or renal disease co-exists. Such targets cannot usually be reached using monotherapies. This is especially true in patients who present with a high cardiovascular risk. The co-administration of two agents acting by different mechanisms considerably increases the blood pressure control rate. Such combinations are not only efficacious, but are also well tolerated, and some fixed low-dose combinations even have a placebo-like tolerability. This is the case for the preparation containing the angiotensin-converting enzyme inhibitor perindopril (2 mg) and the diuretic indapamide (0.625 mg), a fixed low-dose combination that has been shown in controlled trials to be more effective than monotherapies in reducing albuminuria, regressing cardiac hypertrophy and improving the stiffness of large arteries. Using this combination to initiate antihypertensive therapy has been shown in a double-blind trial (Strategies of Treatment in Hypertension: Evaluation; STRATHE) to normalize blood pressure (< 140/90 mmHg) in significantly more patients (62%) than a sequential monotherapy approach based on atenolol, losartan and amlodipine (49%) and a stepped-care strategy based on valsartan and hydrochlorothiazide (47%), with no difference between the three arm groups in terms of tolerability. An ongoing randomized trial (Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation; ADVANCE) is a study with a 2 x 2 factorial design assessing the effects of the fixed-dose perindopril-indapamide combination and of the intensive gliclazide modified release-based glucose control regimen in type 2 diabetic patients, with or without hypertension. A total of 11 140 patients were randomly selected. Within the first 6 weeks of treatment (run-in phase), the perindopril-indapamide combination lowered blood pressure from 145/81 +/- 22/11 mmHg (mean +/- SD) to 137/78 +/- 20/10 mmHg. Fixed-dose combinations are becoming more and more popular for the management of hypertension, and are even proposed by hypertension guidelines as a first-line option to treat hypertensive patients.

Objective: An elevated free fatty acid (FFA) level impairs endothelium-dependent vasodilation in humans, which may be pathophysiologically relevant to the development of endothelial dysfunction in patients with insulin resistance. We investigated the effect of inhibition of the renin-angiotensin system (RAS) on FFA-induced endothelial dysfunction., Methods and Results: Changes in forearm blood flow during intra-arterial infusion of acetylcholine were measured by plethysmography before and after systemic infusion of lipid/heparin in 10 healthy subjects given a single dose of placebo, losartan (50 mg), or perindopril (8 mg). Endothelial function after lipid/heparin infusion was also investigated with the coinfusion of vitamin C or NG-monomethyl-L-arginine (L-NMMA). Elevated FFA significantly reduced the response to acetylcholine by 37.7% (P=0.0096) without L-NMMA, but not the response with L-NMMA, whereas FFA did not affect the response to nitroprusside. The single dose of either losartan or perindopril completely prevented FFA-induced endothelial dysfunction. Vitamin C also prevented FFA-induced endothelial dysfunction., Conclusions: Elevated FFA levels by lipid/heparin infusion, which may partly mimic the abnormal lipid profile in patients with insulin resistance, caused endothelial dysfunction via RAS activation and the presumably resultant oxidative stress in humans. Our results suggest the therapeutic rationale for RAS inhibition in patients with high FFA levels.

Background and Purpose: Angiotensin-converting enzyme (ACE) inhibitor-based therapy reduces the recurrence of stroke. The present study assessed the effects of long-term ACE inhibitor therapy on cerebral circulation in patients with previous minor stroke., Methods: After a run-in period, 19 patients were randomized to ACE inhibitor therapy (n=9; 4 mg of perindopril daily; mean age, 64+/-8 years; mean systolic/diastolic blood pressure [BP]+/-SD, 133+/-12/77+/-9 mm Hg) or placebo therapy (n=10; mean age, 66+/-9 years; mean BP, 139+/-10/78+/-8 mm Hg). Cerebral blood flow (CBF) was measured during hypercapnia, normocapnia, and hypocapnia using a positron emission tomography with H2(15)O at entry into the study and after 3 to 12 months. Cerebral perfusion reserve (CPR) was defined as percent CBF response to a 1 mm Hg change in arterial partial pressure of CO2 between hypercapnia and hypocapnia., Results: Systolic/diastolic BP and CBF during normocapnia showed no significant changes between entry and completion of the trial in the perindopril and placebo groups. Mean value of CPR showed a significant increase in the perindopril group (from 3.7+/-1.7%/mm Hg to 4.8+/-1.7%/mm Hg; P<0.05) but not in the placebo group (from 4.1+/-0.8%/mm Hg to 4.2+/-0.6%/mm Hg; NS). Statistical parametric mapping analysis also showed global and significant increase (P<0.01, uncorrected) in CPR in the perindopril group alone., Conclusions: Long-term ACE inhibitor-based therapy had a beneficial effect on the cerebral circulation by improving CPR in patients with previous minor stroke.

Angiotensin-converting enzyme inhibitors have been shown to reduce morbidity and mortality in patients with heart failure. The angiotensin type-1 blocking and cardioprotective properties of perindopril and enalapril were studied in a rat model of dilated cardiomyopathy after autoimmune myocarditis. Enalapril at 20 mg/kg showed the same angiotensin type-1 blocking action as perindopril at 2 mg/kg in rats with heart failure. Twenty-eight days after immunization, surviving Lewis rats (90/120 = 75%) were divided into six groups and administered perindopril at 0.02, 0.2 and 2 mg/kg per day (Groups P0.02, P0.2 and P2), enalapril at 2 and 20 mg/kg per day (Groups E2 and E20) or vehicle alone (Group V, all groups n = 15). After oral administration for 1 month, four of 15 (27%) rats in Group V, and two (13%) in Groups P0.02 and E2 died. None of the animals in Groups P0.2, P2 and E20, or normal rats (Group N) died. Although both angiotensin-converting enzyme inhibitors improved ventricular function in a dose-dependent manner, the left ventricular end-diastolic pressure and area of myocardial fibrosis were lower, and +/- dP/dt was higher in Group P2 (4.9 +/- 0.6 mmHg, 7.5 +/- 1.4% and +2651 +/- 254/-2622 +/- 189 mmHg/s, respectively) than in Group V (16.7 +/- 1.3, 36 +/- 2.6 and +2659 +/- 176/-2516 +/- 205, respectively) and Group E20 (7.5 +/- 2.5, 15.6 +/- 2.0 and +2018 +/- 110/-2097 +/- 102, respectively). Although the expression levels of transforming growth factor-beta1 and collagen-III mRNA in Group V (36.3 +/- 5.7 and 157.6 +/- 12.7%) were significantly higher than those in Group N (19.6 +/- 3.0 and 65.2 +/- 1.5%, both p < 0.01), they were reduced in Group P2 (21.4 +/- 5.9 and 75.2 +/- 9.3%, both p < 0.01). These results suggest that although enalapril can block increases in blood pressure caused by circulating angiotensin type-1, perindopril at 2 mg/kg may confer greater protection than enalapril at 20 mg/kg against injury from the renin-angiotensin system in heart failure.

Macrophage colony-stimulating factor, which induces proliferation and differentiation, and activation of monocytes and macrophages, plays an important role in the vulnerability of atheromatous plaques as well as the formation of atherosclerotic lesions. We measured serum concentrations of macrophage colony-stimulating factor in patients with acute myocardial infarction and also investigated the effects of early administration of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker on circulating macrophage colony-stimulating factor levels in these patients. The patients were divided randomly into 3 therapeutic groups; perindopril, candesartan, and control (without perindopril and candesartan) groups, and the drugs were administered within 24 to 36 hours after the onset of acute myocardial infarction. Serum macrophage colony-stimulating factor concentrations in acute myocardial infarction patients at the time of admission were significantly higher than those in healthy control subjects. The macrophage colony-stimulating factor levels in the patients decreased gradually after admission, but remained significantly higher than those in control subjects for 14 days. There were no significant differences in serum macrophage colony-stimulating factor levels among the 3 therapeutic groups during this study period. In conclusion, circulating macrophage colony-stimulating factor levels are elevated during the course of acute myocardial infarction, and inhibition of the renin-angiotensin system by angiotensin-converting enzyme inhibitor or angiotensin receptor blocker does not affect these levels.

Essential hypertension is a very heterogeneous disease and different pressor mechanisms might interact to increase blood pressure. It is therefore not surprising that antihypertensive drugs given as monotherapies normalize blood pressure in only a proportion of hypertensive patients. This is, for instance, the case for diuretics, angiotensin-converting enzyme (ACE) inhibitors and angiotensin II type 1 (AT1) receptor antagonists administered as single agents. The rationale for combining antihypertensive agents relates in part to the concept that the blood pressure-decreasing effect may be enhanced when two classes are coadministered. Also, combination treatment serves to counteract the counter-regulatory mechanisms that are triggered whenever pharmacologic intervention is initiated and act to limit the efficacy of the antihypertensive medication. For example, the compensatory increase in renin secretion induced by sodium depletion may become the predominant factor sustaining high blood pressure. Simultaneous blockade of the renin-angiotensin system, with either an ACE inhibitor or an AT1 receptor blocker, makes this compensatory hyper-reninaemia ineffective and allows maximum benefit from sodium depletion. The increased effectiveness obtained by combining a blocker of the renin-angiotensin system with a low dose of a diuretic is not obtained at the expense of reduced tolerability compared with the individual components administered alone. Fixed very-low-dose combinations containing an ACE inhibitor or an AT1 receptor blocker and a diuretic are therefore likely to become increasingly used, not only as second-line therapy, but also as first-line treatment. This is the case, for instance, for the fixed very-low-dose combination of the ACE inhibitor perindopril (2 mg) and the diuretic indapamide (0.625 mg), as this preparation is very effective in decreasing blood pressure while maintaining a tolerability that is similar to that of placebo.

Objective: To review the safety and efficacy of the very-low-dose combination of perindopril 2 mg and indapamide 0.625 mg (Per2/Ind0.625) in essential hypertension, in relation to blood pressure control and target-organ damage., Study Selection: We included in this review several double-blind, randomized studies in hypertensive patients, including five main studies from the European registration file and two clinical trials on regression of target-organ damage [large artery stiffness: the Preterax in Regression of Arterial Stiffness in a Controlled Double-Blind Study (REASON); microalbuminuria in patients with type 2 diabetes: the Preterax in Albuminuria Regression (PREMIER) study]., Main Outcome Measures: Systolic (SBP) and diastolic (DBP) blood pressures measured at trough with a mercury sphygmomanometer, an automatic device (OMRON), and 24-h ambulatory blood pressure measurements (ABPM). Arterial stiffness, assessed from pulse wave velocity measurement and augmentation index (REASON study). Microalbuminuria (PREMIER study)., Results: The Per2/Ind0.625 combination was selected from the dose-finding studies. Twelve weeks after the participants were assigned to study groups, the reductions in SBP, measured with an OMRON device, were 12.3 +/- 15.0 mmHg with Per2/Ind0.625, 8.0 +/- 16.5 mmHg with perindopril 2 mg (P = 0.001), 9.4 +/- 14.3 mmHg with indapamide 0.625 mg (P = 0.023) and 2.1 +/- 16.8 mmHg with placebo (P < 0.001) (mean +/- SD; all P values are for comparisons with Per2/Ind0.625). The reductions in DBP were 6.8 +/- 9.2 mmHg, 5.0 +/- 9.5 mmHg (P = 0.02), 4.7 +/- 8.2 mmHg (P = 0.004) and 2.4 +/- 9.6 mmHg (P < 0.001) in the Per2/Ind0.625, perindopril 2 mg, indapamide 0.625 mg and placebo groups, respectively. During the long-term study, among 235 patients who achieved initial blood pressure normalization with the fixed combination, 79.8% sustained their normalized status over 1 year, with no significant difference regarding safety criteria. During the REASON study, Per/Ind reduced pulse wave velocity to a similar extent as atenolol, and augmentation index to a greater extent. During the PREMIER study, Per/Ind reduced microalbuminuria to a greater extent than did enalapril., Conclusions: The proven efficacy on blood pressure and regression of target-organ damage with a good safety profile confirm that the new fixed-low-dose combination Per2/Ind0.625 is a valuable option in the first-line treatment of hypertension.

Objective: To review the efficacy and safety of the very-low-dose combination of 2 mg perindopril and 0.625 mg indapamide in essential hypertension., Study Selection: The five main studies from the European registration file were performed in hypertensive outpatients and included two phase II double-blind randomised dose-ranging studies, and three phase III double-blind randomised studies (one study comparing placebo with each of the components, one long-term study over 15 months and one study comparing the combination and losartan)., Main Outcome Measures: Decreases in systolic (SBP) and diastolic (DBP) blood pressures measured at trough with a mercury sphygmomanometer, an automatic device (Omron), and 24 h ambulatory blood pressure measurements (ABPM)., Results: The combination 2 mg perindopril and 0.625 mg indapamide was selected from the dose-finding studies. Twelve weeks after participants in the randomised studies were allocated to groups, the reductions in SBP, measured with an Omron device, were 12.3 +/- 15.0 mmHg with the combination, 8.0 +/- 16.5 mmHg with 2 mg perindopril (P = 0.001), 9.4 +/- 14.3 mmHg with 0.625 mg indapamide (P = 0.023), and 2.1 +/- 16.8 mmHg with placebo (P < 0.001) (mean +/- SD; all P values are for comparisons with the combination). The reductions in DBP were 6.8 +/- 9.2 mmHg, 5.0 +/- 9.5 mmHg (P = 0.02), 4.7 +/- 8.2 mmHg (P = 0.004), and 2.4 +/- 9.6 mmHg (P < 0.001) in the combination, 2 mg perindopril, 0.625 mg indapamide and placebo groups, respectively. During the long-term study, among 235 patients who achieved initial blood pressure normalisation with the fixed combination, 79.8% sustained their normalisation over 1 year, with no significant difference regarding safety criteria: the occurrence of adverse drug reactions per patient per year was 0.37 and 0.28 in the combination and placebo groups, respectively. A significantly (P < 0.05) larger blood pressure decreasing effect on nocturnal mean SBP (by ABPM) was demonstrated for the combination compared with that achieved with losartan, with no difference in safety., Conclusions: The proven efficacy on DBP and SBP, and the good safety profile, confirm that the new low-dose combination of 2 mg perindopril and 0.625 mg indapamide is a valuable option in the first-line treatment of hypertension.

Background: Epidemiological studies have shown that increased arterial stiffness and wave reflections, major determinants of systolic and pulse pressure, are associated with morbidity and mortality. Therapeutic trials based on cardiovascular mortality have recently shown that reduction of systolic blood pressure (SBP) requires normalization of both large-artery stiffness and wave reflections., Aims: To compare the antihypertensive effects of the very-low-dose combination of perindopril (2 mg) and indapamide (0.625 mg) (one or two tablets per day) with the beta-blocking agent atenolol (50 mg; one or two tablets per day) in order to determine whether the combination decreased SBP and pulse pressure more than did atenolol, and whether this decrease occurred in relation to a reduction in arterial stiffness [aortic pulse wave velocity (PWV)] or a decrease in the intensity of, or delay in, wave reflections (augmentation index, measured by applanation tonometry) or a combination of both., Material and Methods: This was a double-blind randomized study in 471 individuals with essential hypertension followed for 12 months. Arterial pressure was measured in the brachial artery (mercury sphygmomanometer) and in the carotid artery (applanation tonometry)., Results: For the same reduction in diastolic blood pressure (DBP), the combination of perindopril and indapamide decreased brachial SBP and pulse pressure significantly more than did atenolol (adjusted differences between groups -6.2 +/- 1.5 and -5.5 +/- 1.0 mmHg, respectively; P < 0.001). This difference was even more pronounced for the carotid than for the brachial artery. Whereas both antihypertensive agents similarly decreased PWV, only the combination significantly attenuated wave reflections., Conclusion: Normalization of SBP, pulse pressure and arterial function--a haemodynamic profile known to improve survival significantly in hypertensive populations at high cardiovascular risk--was achieved to a greater extent with a very-low-dose combination of perindopril and indapamide than with atenolol.

Background and Purpose: The purpose of this study was to investigate the effect of the angiotensin-converting enzyme inhibitor perindopril on mean arterial blood pressure (MABP), cerebral blood flow (CBF), and glomerular filtration rate in hypertensive stroke patients with moderate to severe internal carotid artery (ICA) disease or ICA occlusion., Methods: Twenty-four nonacute ischemic stroke patients who had MABP readings >100 mm Hg and moderate to severe ICA stenosis or occlusion were randomized to receive perindopril 4 mg daily or placebo for 14 days. MABP, ICA flow, and both middle cerebral artery (MCA) velocity and resistance index were measured before dose, at 5 time points over the subsequent 24 hours, and finally at 2 weeks. Brain hexamethyl propylene amine oxide single photon emission computed tomography scans were performed before drug administration and at time of peak drug effect (6 to 8 hours) after the first dose. Glomerular filtration rate was measured with (51)Cr EDTA before medication and at 14 days., Results: A placebo-corrected BP fall of 17/10 mm Hg was seen (P:=0.017), which was maximal at 5.5 hours. No significant change in ICA flow or MCA velocity was seen between groups. No significant change in hemispheric CBF was seen. The mean change from baseline in the treated group was -0.79 mL. 100 g(-1). min(-1) (95% confidence interval [CI], 1.65 to -3.23); mean change in the placebo group was -1.9 mL. 100 g(-1). min(-1) (95%CI, 3.02 to -6.92). Peri-infarct CBF was similarly unaffected. One of the treated patients developed transient acute renal impairment and was withdrawn from the study on day 4., Conclusions: Perindopril lowers BP without lowering CBF in hypertensive stroke patients with moderate to severe ICA stenosis or occlusion; monitoring of this patient population for the complications of renal artery stenosis should be considered.

Objective: To determine the effects of an angiotensin-converting enzyme (ACE) inhibitor-based blood pressure lowering regimen on the risk of stroke among patients with a history of cerebrovascular disease. Secondary aims include investigation of the effects of treatment on other cardiovascular events, dementia, and disability., Design and Methods: PROGRESS (Perindopril Protection Against Recurrent Stroke Study) is a double-blind, placebo-controlled, randomized trial being conducted in 172 centres in 10 countries (Australia, Belgium, China, France, Italy, Ireland, Japan, New Zealand, Sweden, and the United Kingdom). Patients were randomly assigned to treatment with the ACE inhibitor perindopril (and the diuretic indapamide for those with no definite indication for or contraindication to treatment with a diuretic) or matching placebo(s). Both hypertensive and normotensive patients were eligible for inclusion. Follow-up is scheduled for completion in 2001., Results: Of 6105 patients randomly allocated to study groups on completion of recruitment in November 1997, 1110 were recruited from Australia and New Zealand, 1520 from China, 713 from France and Belgium, 557 from Italy, 815 from Japan, 675 from Sweden, and 715 from the UK and Ireland. Regional differences in the baseline characteristics included a greater rate of diabetes, lacunar infarction, and cerebral haemorrhage in patients from China and Japan, and a more frequent history of myocardial infarction in Australia and New Zealand. Previous treatment with calcium antagonists was very frequent in Japan and China, whereas diuretic treatment was most often documented in the UK and Ireland., Conclusions: Analysis of baseline characteristics of patients recruited from seven distinct geographic regions revealed some interesting differences, but more striking was the consistency of characteristics of patients recruited from many different countries across the world.