Effects of a fixed combination of perindopril and indapamide on macrovascular and microvascular outcomes in patients with type 2 diabetes mellitus (the ADVANCE trial): a randomised controlled trial

Summary

Background

Blood pressure is an important determinant of the risks of macrovascular and microvascular complications of type 2 diabetes, and guidelines recommend intensive lowering of blood pressure for diabetic patients with hypertension. We assessed the effects of the routine administration of an angiotensin converting enzyme (ACE) inhibitor-diuretic combination on serious vascular events in patients with diabetes, irrespective of initial blood pressure levels or the use of other blood pressure lowering drugs.

Methods

The trial was done by 215 collaborating centres in 20 countries. After a 6-week active run-in period, 11 140 patients with type 2 diabetes were randomised to treatment with a fixed combination of perindopril and indapamide or matching placebo, in addition to current therapy. The primary endpoints were composites of major macrovascular and microvascular events, defined as death from cardiovascular disease, non-fatal stroke or non-fatal myocardial infarction, and new or worsening renal or diabetic eye disease, and analysis was by intention-to-treat. The macrovascular and microvascular composites were analysed jointly and separately. This trial is registered with ClinicalTrials.gov, number NCT00145925.

Findings

After a mean of 4·3 years of follow-up, 73% of those assigned active treatment and 74% of those assigned control remained on randomised treatment. Compared with patients assigned placebo, those assigned active therapy had a mean reduction in systolic blood pressure of 5·6 mm Hg and diastolic blood pressure of 2·2 mm Hg. The relative risk of a major macrovascular or microvascular event was reduced by 9% (861 [15·5%] active vs 938 [16·8%] placebo; hazard ratio 0·91, 95% CI 0·83–1·00, p=0·04). The separate reductions in macrovascular and microvascular events were similar but were not independently significant (macrovascular 0·92; 0·81–1·04, p=0·16; microvascular 0·91; 0·80–1·04, p=0·16). The relative risk of death from cardiovascular disease was reduced by 18% (211 [3·8%] active vs 257 [4·6%] placebo; 0·82, 0·68–0·98, p=0·03) and death from any cause was reduced by 14% (408 [7·3%] active vs 471 [8·5%] placebo; 0·86, 0·75–0·98, p=0·03). There was no evidence that the effects of the study treatment differed by initial blood pressure level or concomitant use of other treatments at baseline.

Interpretation

Routine administration of a fixed combination of perindopril and indapamide to patients with type 2 diabetes was well tolerated and reduced the risks of major vascular events, including death. Although the confidence limits were wide, the results suggest that over 5 years, one death due to any cause would be averted among every 79 patients assigned active therapy.

Introduction

Prevention of the vascular complications of type 2 diabetes mellitus is a global health priority. By 2030, an estimated 350 million people will be living with diabetes worldwide.¹ Most people with this condition will die or be disabled as a consequence of vascular complications. In patients with diabetes and hypertension, all the main classes of antihypertensive drugs seem to reduce the risks of stroke and coronary heart disease.² Moreover, there is evidence that more intensive treatment, targeting lower blood pressure values, confers greater protection against these macrovascular outcomes.³ Angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor blockers have also been shown to reduce the risk of development or progression of diabetic nephropathy.⁴ Additionally, there is some evidence that more intensive therapy, targeting lower blood pressure values, confers greater protection against diabetic eye disease.⁵

These findings suggest that prevention strategies designed to increase the use of treatments for lowering blood pressure, and to improve levels of blood pressure control, could produce worthwhile reductions in the risks of macrovascular and microvascular complications of diabetes. Traditional strategies set arbitrary blood pressure levels at which treatment is initiated and arbitrary goals against which treatment should be titrated. This strategy neglects those diabetic patients without what is typically defined as hypertension, and yet for whom blood pressure remains an important determinant of their risk of vascular disease.⁶ Additionally, this strategy is usually resource-intensive, needing multiple patient visits, careful monitoring of both blood pressure and side-effects, and the coordination of complex drug regimens. Perhaps partly as a consequence of such complexity, surveys of blood pressure control indicate that few patients receiving antihypertensive drugs achieve recommended goals for blood pressure.7, 8, 9, 10

An alternative approach, to increase the use and effectiveness of treatment for lowering blood pressure in patients with diabetes, is to add a fixed-dose combination of blood pressure lowering drugs irrespective of initial blood pressure level or the use of other antihypertensive drugs.¹¹ This approach is more inclusive and less resource-intensive than the target-setting strategy. Although this approach might not produce the largest blood pressure reductions possible, it will shift the entire distribution of blood pressure values down in patients with diabetes, with minimum requirements for titration and, potentially, with fewer side-effects.¹²

The Action in Diabetes and Vascular disease: preterAx and diamicroN-MR Controlled Evaluation (ADVANCE) trial was designed to assess the effects on vascular disease of such an approach using a fixed combination of the ACE inhibitor, perindopril, and the diuretic, indapamide, in a diverse population of patients with type 2 diabetes and a broad range of blood pressure values. Using a factorial design, the study will also assess the effects on the same outcomes of an intensive gliclazide MR-based glucose lowering regimen (aiming for a haemoglobin A_1c [HbA_1c] level of 6·5% or lower) compared with standard glucose control. Follow-up in the glucose arm of the study will be completed in December, 2007. Here we report the principal results from the blood pressure lowering arm of the study, completed in June, 2007.

ADVANCE is a randomised controlled trial done by 215 collaborating centres in 20 countries from Asia, Australasia, Europe, and North America. Approval for the trial was obtained from the institutional ethics committee of each centre and all participants provided written informed consent. Detailed study methods are published elsewhere¹³ and are described here in brief. This trial is registered with ClinicalTrials.gov, number NCT00145925.

Patients were potentially eligible if they had been diagnosed with type 2 diabetes mellitus at the age of 30 years or older and were aged 55 years or older at entry to the study. Potentially eligible patients also needed to have at least one of the following: a history of major cardiovascular disease (stroke, myocardial infarction, hospital admission for transient ischaemic attack, hospital admission for unstable angina, coronary revascularisation, peripheral revascularisation, or amputation secondary to vascular disease), or at least one other risk factor for cardiovascular disease. Such risk factors were defined by the presence of at least one of the following: a history of major microvascular disease (macroalbuminuria [urinary albumin-creatinine ratio >300 μg/mg], proliferative diabetic retinopathy, retinal photocoagulation therapy, macular oedema, or blindness in one eye thought to be caused by diabetes), current cigarette smoking, total cholesterol more than 6·0 mmol/L, HDL cholesterol less than 1·0 mmol/L, microalbuminuria (urinary albumin-creatinine ratio 30–300 μg/mg), diagnosis of type 2 diabetes mellitus made 10 years or more before entry, or age 65 years or older at entry. Patients with an indication for an ACE inhibitor were eligible for inclusion, unless they had a specific indication for an ACE inhibitor other than perindopril at a maximum dose of 4 mg a day. There were no blood pressure criteria for inclusion.

Patients were ineligible if, in the opinion of the investigator, they met any of the following exclusion criteria: a definite indication for, or contraindication to, any of the study treatments or the HbA_1c target (≤6·5%); a definite indication for long-term insulin therapy at study entry; or current participation in another clinical trial.

Potentially eligible participants entered a 6-week pre-randomisation run-in period during which they received a fixed combination tablet consisting of perindopril (2 mg) and indapamide (0·625 mg). All other treatments were continued at the discretion of the responsible physician, with the exception of ACE-inhibitors; participants taking an ACE-inhibitor other than perindopril had this treatment withdrawn and were offered substitution with open-label perindopril at a dose of 2 mg or 4 mg a day. Those who adhered to, and tolerated, the run-in study drugs were randomly assigned, in a double-blind fashion, to combined perindopril (2 mg) and indapamide (0·625 mg) or matching placebo. After 3 months, the doses of randomised therapy were doubled to 4 mg for perindopril and 1·25 mg for indapamide, or matching placebo. Study treatments were allocated using a central, computer-based, randomisation service accessible by internet, telephone, and facsimile. Randomisation was stratified by study centre, history of macrovascular disease, history of microvascular disease, and background use of perindopril at baseline. The use of concomitant treatments during follow-up, including blood pressure lowering therapy, remained at the discretion of the responsible physician with two exceptions—the use of thiazide diuretics was not allowed, and open-label perindopril, to a maximum of 4 mg a day, was the only ACE-inhibitor allowed, thus ensuring that the maximum recommended dose of 8 mg for perindopril could not be exceeded by patients randomly assigned to active treatment. However, if at any time another ACE inhibitor or a thiazide diuretic was thought to be definitely indicated, study treatment could be withdrawn and alternate open-label treatment provided.

Participants were seen 3, 4, and 6 months after randomisation, and subsequently, every 6 months. At study visits, information on adherence to, and tolerability of, study treatments, blood pressure, blood glucose, HbA_1c, lipid levels, and occurrence of study outcomes was obtained. Blood pressure was recorded as the mean of two measurements made after the patient was rested for at least 5 min in the seated position, using a standardised automated sphygmomanometer (Omron HEM-705CP, Tokyo, Japan). Additional information was obtained at the 2-year and 4-year follow-up visits, and included the urinary albumin-creatinine ratio, a formal retinal examination, a mini mental state examination, and a quality of life assessment.

The primary study outcomes were composites of major macrovascular and microvascular events. Major macrovascular events were cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke. Major microvascular events were new or worsening nephropathy [development of macroalbuminuria, doubling of serum creatinine to a level of at least 200 μmol/L, need for renal replacement therapy, or death due to renal disease] or retinopathy [development of proliferative retinopathy, macular oedema, or diabetes-related blindness, or retinal photocoagulation therapy]).

The secondary outcomes included all-cause mortality, cardiovascular death, major coronary events (death due to coronary heart disease [including sudden death] and non-fatal myocardial infarction), total coronary events (major coronary events, silent myocardial infarction, coronary revascularisation, or hospital admission for unstable angina), major cerebrovascular events (death due to cerebrovascular disease or non-fatal stroke), and total cerebrovascular events (major cerebrovascular events, transient ischaemic attack, or subarachnoid haemorrhage). Other secondary outcomes were heart failure (death due to heart failure, hospitalisation due to heart failure, or worsening New York Heart Association class), peripheral vascular disease, new or worsening nephropathy, new or worsening retinopathy, development of microalbuminuria, visual deterioration, new or worsening neuropathy, cognitive function, dementia, and hospitalisations. Results for all pre-specified outcomes are reported.

An Endpoint Adjudication Committee, masked to treatment allocation, reviewed source documentation for all individuals who had a suspected primary endpoint or who died during follow-up. Outcomes were coded according to the 10th revision of the International Classification of Diseases. An independent Data and Safety Monitoring Committee reviewed unblinded data at yearly intervals throughout follow-up. This committee was charged with informing the study investigators if, at any time, there emerged evidence, beyond reasonable doubt, of a difference between randomised groups in survival or evidence that was likely to materially alter the management of patients with diabetes.

ADVANCE was originally designed to provide at least 90% power to detect a 16% or greater reduction in the relative risks of both major macrovascular events and major microvascular events using a 5% two-tailed test with equal numbers allocated to active blood pressure treatment and placebo. Half-way through follow-up, the overall event rates (in active and placebo groups combined) were lower than expected. To enhance the statistical power of the trial to detect plausible treatment effects, two amendments dated Nov 30, 2005, were made to the study protocol: first, analyses of the primary outcomes were extended to include consideration of major macrovascular and microvascular events jointly as well as separately; and second, treatment and follow-up in the blood pressure arm was extended by 12 months.

Thus, the protocol pre-specified that the composite of major mascrovascular and microvasular outcomes would be included in the analyses of the primary outcomes. All analyses would also be by intention to treat. The effects of treatment on the primary and secondary endpoints were estimated from unadjusted Cox proportional hazard models. For participants with more than one outcome event during follow-up, survival time to the first relevant endpoint was used in each analysis. Participants were censored at their date of death or, for those still alive at the end of follow-up, the date of their last visit. Patients with an unknown vital status were censored when they were last known to be alive. Relative risk reductions are described in the text and figures as percentage reductions ([1–hazard ratio]×100). Differences between randomised groups during follow-up, in blood pressure and other continuous variables, were estimated from linear mixed models. Numbers needed to treat were calculated as reciprocals of the absolute risk differences with their normally-approximated 95% CIs.¹⁴ All p values were calculated from two-tailed tests of statistical significance with a Type I error rate of 5%. As is common practice in the analysis of data from large scale trials in which all major outcomes are reported (many of which are correlated), no adjustment for multiple statistical testing was done.¹⁵

Separate estimates for treatment effects were obtained among subgroups of participants defined by age, sex, history of vascular disease, ancillary treatments, blood pressure, and HbA_1c at study entry. No subgroup analyses were pre-specified. Homogeneity of treatment effects for both categorical and continuous variables was tested by adding interaction terms to the relevant Cox models. All analyses were done using SAS version 9.1.

ADVANCE was funded by grants from Servier and the National Health and Medical Research Council of Australia. The sponsor of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report. The corresponding author had full access to all data in the study. The Management Committee had final responsibility for the decision to submit for publication.