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Blood pressure levels are strongly predictive of the risks of first-ever and recurrent stroke. The benefits of blood pressure-lowering therapy for the prevention of fatal and non-fatal stroke in middle-aged individuals are well established. However, until recently, there has been uncertainty about the consistency of such benefits across different patient groups and in particular, for older people and in those with a history of stroke. This paper discusses the evidence surrounding the effectiveness of blood pressure-lowering therapy, specifically in older patients with a history of stroke, with particular attention paid to the results from the Perindopril Protection Against Recurrent Stroke Study (PROGRESS). PROGRESS was a randomised, double-blind, placebo-controlled trial of 6105 individuals with a history of cerebrovascular disease recruited from 172 hospital outpatient clinics in ten countries. Participants (mean age 64 years; range 26-91 years) were randomly assigned to receive active treatment with an ACE inhibitor-based blood pressure-lowering regimen (perindopril) with or without addition of the diuretic indapamide, or matched placebo. At the end of follow up (mean of 4 years), active treatment reduced the incidence of total stroke by 28% (95% CI 17-38%) and the rate of major vascular events by 26% (95% CI 16-34%). Importantly, benefits of treatment were consistent across key patient subgroups, including those with and without hypertension, patients who were Asian and non-Asian, and for both ischaemic and haemorrhagic strokes subtypes. Current evidence is now strong for clinicians to consider blood pressure-lowering therapy as pivotal in the prevention of stroke, especially in patients with a known history of cerebrovascular disease (and vascular disease, in general), irrespective of blood pressure levels, as soon as patients are clinically stable after an acute stroke or other vascular event. Additional age-specific analyses of the PROGRESS data, together with those from other completed trials, will provide more reliable information about the size of the benefits of blood pressure-lowering therapy, specifically for different age groups, and particularly in the oldest old (those aged >80 years). In the meantime though, an ACE inhibitor plus diuretic treatment regimen that maximises the degree of blood pressure reduction has a good safety profile and is an effective treatment that should be considered in all patients with stroke, including the elderly.
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PMID:The Perindopril Protection Against Recurrent Stroke Study (PROGRESS): clinical implications for older patients with cerebrovascular disease. 1264 80

The burden of Type II diabetes is growing rapidly worldwide, across high-, middle- and low-income countries. This burden is associated primarily with increased risks of macrovascular and microvascular diseases, and it is agreed that multifactorial treatment regimens are required to reduce it. ADVANCE (Action in Diabetes and Vascular disease: Preterax and Diamicron-MR Controlled Evaluation) is a large-scale, 2 x 2 factorial, randomised clinical trial. It will investigate the potential benefits of blood pressure lowering, using a fixed low-dose combination of perindopril and indapamide vs placebo, and of tighter glucose control, using an intensive gliclazide-MR-based glucose control regimen vs a standard guidelines-based regimen, separately and together. The two primary outcomes are a composite macrovascular end point of nonfatal stroke, nonfatal myocardial infarction and cardiovascular death; and a composite microvascular end point of new or worsening nephropathy or microvascular eye disease. Following successful recruitment and randomisation of 11,140 participants by March 2003, the study is currently half way through its planned follow-up of 4.5 years. Adherence to randomised study treatment is good; and loss to follow-up is minimal. It is hoped that the study will answer a number of unresolved issues. The blood pressure lowering arm will investigate the possible reduction in major vascular disease in patients with Type II diabetes whether or not they have hypertension, and the possible benefits of blood pressure lowering in such patients already receiving background therapy with the ACE inhibitor perindopril. The glucose control arm will investigate the possible reduction in both macrovascular and microvascular disease achieved with tighter glucose control, targeting an HbA1c of 6.5% and a fasting blood glucose of 6.0 mmol/l. Finally, the factorial design will enable investigation of the combined effects of more intensive glucose control and tighter control of blood pressure.
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PMID:ADVANCE: action in diabetes and vascular disease. 1607 30

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.
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PMID:Managing hypertension in high-risk patients: lessons and promises from the STRATHE and ADVANCE trials. 1672 62

The year 2008 was rich in teachings and suspense in diabetology. Past studies, i.e. United Kingdom Prospective Diabetes Study (UKPDS) in type 2 diabetic patients and Diabetes Control and Complications Trial (DCCT) in type 1 diabetic patients, have shown that in the short term, intensive treatment reduces the incidence of microvascular complications linked to diabetes and in the long term that of both microvascular and macrovascular ones. The in-the-raw conclusions of the recent Action to Control Cardiovascular risk in Diabetes (ACCORD) study note an increase in mortality in type 2 diabetic patients treated intensively, while the Action in Diabetes and Vascular disease, Perindopril and Indapamide Controlled Evaluation (ADVANCE) study evidences a reduction in microvascular complications and the Veterans Affairs Diabetes Trial (VADT) study shows that intensive treatment has no significant effect. A well thought-out analysis of the studies published in 2008 (ACCORD, STENO 2 post-trial, ADVANCE, VADT, UKPDS post-trial, Epidemiology of Diabetes Interventions and Complications [EDIC]) is particularly instructive and highlights the existence of glycaemic memory, the non-existence of blood pressure memory, the need to control all cardiovascular risk factors and to treat diabetes early while avoiding hypoglycaemic incidents. The glycaemic target based on HbA1c must take into account the patient's age and the duration of his diabetes, as well as his cardiovascular risk factors and previous glycaemic control. All in all, the intensive treatment of type 2 diabetes must begin early; it must not be too rapid and must avoid hypoglycaemic incidents and be combined with a strict control of other cardiovascular risk factors.
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PMID:Glycaemic control and cardiovascular morbi-mortality: the contribution of the 2008 studies. 1919 63

Blood pressure is an important determinant of the risk of macro- and microvascular vascular complications in patients with type 2 diabetes. Current European guidelines for the management of hypertension recommend lowering blood pressure in patients with type 2 diabetes to reduce the risk of cardiovascular events. The Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation (ADVANCE) trial (n = 11,140), is the first trial designed to address the issue of whether routine blood pressure lowering with the fixed combination of perindopril/indapamide is beneficial in patients with diabetes with a broad range of baseline blood pressure values. In addition, it aimed to determine if clinical benefit is achieved over and above that observed with background angiotension-converting enzyme inhibitor therapy. In the perindopril/indapamide arm, the reduction in blood pressure led to significant clinical benefits in patients with type 2 diabetes, irrespective of baseline blood pressure values, and subsequently improved mortality rates, and macro- and microvascular outcomes, beyond the improvements associated with patients' existing antihypertensive therapies. ADVANCE is a robust well-designed trial, the results of which are directly applicable to current clinical practice. The ADVANCE study defines the relevant blood pressure goals for patients with type 2 diabetes who are at high risk of cardiovascular events and underscores the benefits of aggressive blood pressure reduction even in normotensive patients with diabetes. It is likely that these findings will have a significant impact on the management of patients with type 2 diabetes. In view of the evidence indicating that clinical benefits obtained with the perindopril/indapamide combination can be expected even in patients who are normotensive, vascular risk rather than initial blood pressure should be employed to determine appropriate treatment protocols in patients with type 2 diabetes.
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PMID:Implications of the ADVANCE study for clinical practice. 1936 50

Whether glycaemic control may result in a reduction of cardiovascular (CV) risk has been a matter of continuous discussion and investigation. Epidemiological analyses have extensively suggested a relationship between glycaemic control and CV events; however, the results of intervention trials have been less conclusive. The UKPDS reported a 16% reduction in the risk of myocardial infarction, but this reduction was not statistically significant. The results of the Kumamoto and PROactive studies could not allow any firm conclusions to be drawn either, because of limited size and the defined primary endpoint, respectively. The results of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) and Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) trials and the Veteran Administration Diabetes Trial (VADT) were published in rapid succession over the second half of 2008 and at the beginning of 2009. A total number of almost 25,000 type 2 diabetic patients were recruited in these three trials, which assessed the effect of intensive glycaemic control vs conventional treatment on well-defined CV endpoints. In spite of the achievement and maintenance of strict glycaemic control (HbA(1c) <7.0%), no beneficial effect of intensive therapy was apparent in any of the studies. At the same time these results were presented, the results of an analysis of the 10 year follow-up of the UKPDS also became available and provided a more optimistic view of the potential benefit of achieving good glycaemic control. The relative risk reductions for myocardial infarction and all-cause mortality were significantly lower in the patients who initially received the intensive treatment compared with those in the conventional treatment arm. Moreover, the initial benefit in terms of microvascular complications observed at the end of the intervention trial remained unaltered at follow-up. Once again the debate on the importance of glycaemic control in preventing macrovascular complications remains unsettled. These results, however, require some reconciliation, and the objective of this commentary is to analyse a series of elements, including the changes in the treatment approach to CV risk factors in type 2 diabetes, the effect of glucose-lowering agents, and the characteristics of the patients included in the different trials, that should be taken into account when interpreting the results of intervention trials in type 2 diabetes.
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PMID:Megatrials in type 2 diabetes. From excitement to frustration? 1937 46

The angiotensin-converting enzyme (ACE) inhibitor perindopril (Coversyl) is a long-acting lipophilic drug with a high-tissue affinity for the ACE. ACE inhibition by perindopril has two main effects: it inhibits the angiotensin II formation and potentiates bradykinin. Perindopril is one of the ACE inhibitors that has been extensively studied in randomized clinical trials within various patient populations. The clinical efficacy has been demonstrated in patients with hypertension, diabetes mellitus, cerebrovascular disease, stable coronary artery disease (CAD) and heart failure. Perindopril has a positive safety and tolerability profile. Therefore, perindopril, as an ACE inhibitor, has an established place in the major clinical treatment guidelines. This article discusses several studies that have shown that an antihypertensive treatment with perindopril reduces and prevents cardiovascular events in a large range of patients with established vascular disease. The observed cardioprotective benefits of perindopril were independent of blood pressure. The outcome of these and other trials support the concept of specific cardioprotective properties of ACE inhibition by perindopril in addition to the blood pressure-lowering effects, such as anti-atherosclerotic, anti-inflammatory and antithrombotic properties. In addition, the observed consistency of the treatment benefit across subgroups indicates that the absolute benefits conferred by treatment are mainly established by each patient's future risk of vascular complications, rather than their initial blood pressure level or other risk factors. This article describes these issues according to the main studies with perindopril or perindopril-based regimens, concluding that the blood pressure-dependent and -independent cardioprotective effects extend to all patients with vascular disease. This concept supports the provision of ACE inhibitor-based treatment, not on the basis of arbitrary cut-off points for blood pressure but rather on assessment of vascular risk, which is raised in patients with stable CAD, diabetes and stroke.
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PMID:Angiotensin-converting enzyme inhibition by perindopril in the treatment of cardiovascular disease. 1937 59

Cardiovascular disease is the predominant cause of death in diabetic patients, and reducing the risk of cardiovascular disease in diabetics has recently been the focus of several highly publicized large trials, including ACCORD (Action To Control Cardiovascular Risk in Diabetes), ADVANCE (Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation), and VADT (Veterans Affairs Diabetes Trial). These studies randomized high-risk diabetic patients into either intensive treatment or standard treatment. The glycemic control arm of ACCORD was terminated 17 months before the planned end of the study because of a finding of significantly increased all-cause and cardiovascular mortality in the intensive treatment group. These findings were not duplicated in either ADVANCE or VADT. Multiple possible explanations have been brought forward, including a higher incidence of death from unrecognized hypoglycemia, effects due to increased exposure to particular antidiabetic medications, adverse effects of rapid correction of hyperglycemia, weight gain, and differences in baseline characteristics. None of these were validated in post hoc analyses of the trial data, and the cause of the increased mortality remains elusive. Subgroup analyses suggest that those who start off with better control of their diabetes or without preexisting cardiovascular disease may have the most to gain from tight glycemic control. Reducing the risk of macrovascular disease and death in diabetic patients requires not only attention to glucose control but also meticulous attention to control of nonglycemic risk factors, including hypertension, hyperlipidemia, smoking, lack of exercise, and unhealthy diet as well as timely prescription of medications with proven preventative benefits, such as aspirin and statins.
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PMID:Glycemic targets for patients with type 2 diabetes mellitus. 1942 66

The relative importance of various blood pressure indices on cardiovascular risk in people with type 2 diabetes mellitus has not been established. This study compares the strengths of the associations between different baseline blood pressure variables (systolic blood pressure [SBP], diastolic blood pressure [DBP], pulse pressure [PP], and mean arterial pressure) and the 4.3-year risk of major cardiovascular events in the Action in Diabetes and Vascular Disease: Preterax and Diamicron-Modified Release Controlled Evaluation Study. Mean (SD) age for the 11 140 participants was 65.8 years (6.4 years). During follow-up, 1000 major cardiovascular events, 559 major coronary events, and 468 cardiovascular deaths were recorded. After adjustment for age, sex, and treatment allocation, the hazard ratios (95% CIs) associated with 1 increment in SD for the risk of major cardiovascular events were 1.17 (1.10 to 1.24) for SBP; 1.20 (1.13 to 1.28) for PP; 1.12 (1.05 to 1.19) for mean arterial pressure; and 1.04 (0.98 to 1.11) for DBP. The areas under the receiver operating characteristic curve were slightly higher for SBP and PP compared with mean arterial pressure and DBP for major cardiovascular and coronary events. Using achieved instead of baseline blood pressure values marginally improved the effect estimates for SBP, DBP, and mean arterial pressure, with no significant differences in the areas under the receiver operating characteristic curve between models with SBP and those with PP. In conclusion, SBP and PP are the 2 best and DBP is the least effective determinant of the risk of major cardiovascular outcomes in the relatively old patients with type 2 diabetes mellitus participating in the Action in Diabetes and Vascular Disease: Preterax and Diamicron-Modified Release Controlled Evaluation Study. However, SBP may be the simplest and most useful predictor across a wider range of age groups and populations.
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PMID:Blood pressure variables and cardiovascular risk: new findings from ADVANCE. 1947 Aug 69

Patients with type 2 diabetes mellitus are at increased risk for complications related to both microvascular and macrovascular events. Although glycemic control has been shown to lower the risk of microvascular events, the effect of intensive glycemic control on macrovascular outcomes is less clear. Recently, 3 large randomized controlled trials (Action to Control Cardiovascular Risk in Diabetes [ACCORD], Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation [ADVANCE], and the Veterans Affairs Diabetes Trial [VADT]) have been published to assess the effect of intensive glucose-lowering efforts on macrovascular outcomes, including myocardial infarction, stroke, and death. This article highlights the similarities and differences between the 3 trials with an emphasis on their impact on patient care.
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PMID:Implications of new diabetes treatment trials: should current clinical practice be altered? 1949 42

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