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Action in Diabetes and Vascular Disease - ADVANCE BP
Description:
The goal of the trial was to evaluate blood pressure lowering and intensive glucose control for the prevention of vascular disease among high-risk patients with type 2 diabetes; the present summary describes the results of the blood pressure intervention.
Study Design
Patients Enrolled: 11,140
Mean Follow Up: 4.3 years, 9.9 years
Mean Patient Age: 66 years
Female: 43%
Patient Populations:
Type 2 diabetes; age 55 years or older; elevated risk of vascular disease defined as ≥1 of the following: Age ≥65 years, history of major macrovascular or microvascular disease, first diagnosis of diabetes >10 years prior to entry, and other major risk factors
Primary Endpoints:
Major vascular events defined as a composite of cardiovascular death, nonfatal stroke, nonfatal myocardial infarction, or new or worsening nephropathy or retinopathy
Drug/Procedures Used:
Following a 6-week run-in period of active therapy with perindopril and indapamide, patients were randomized to a fixed combination of perindopril and indapamide once daily (n = 5,569) or placebo (n = 5,571). The dose for the first 3 months was 2.0 mg of perindopril and 0.625 mg of indapamide, which was increased to 4.0 mg and 1.25 mg, respectively thereafter. In a factorial design, patients were also randomized to intensive or standard glucose control.
Principal Findings:
Mean blood pressure at study entry was 145/81 mm Hg. Approximately two-thirds of patients had a history of hypertension, and 75% were already on blood pressure lowering therapy. At the end of follow-up, 73% of the active treatment group and 74% of the placebo group remained on study drug.
Blood pressure was an average of 5.6/2.2 mm Hg lower in the treatment group compared with the placebo group (p < 0.001). The final blood pressure in the active treatment group was 134.7/74.8 mm Hg compared with 140.3/77.0 mm Hg in the placebo group. All-cause mortality was significantly lower in the perindopril/indapamide group (7.3% vs. 8.5%, relative risk reduction [RRR] 14%, p = 0.025), driven by a reduction in cardiovascular death (3.8% vs. 4.6%, RRR 18%, p = 0.027). The primary endpoint of vascular events was also significantly lower in the perindopril/indapamide group (15.5% vs. 16.8%, RRR 9%, p = 0.041), with similar reductions in macrovascular events (8.6% vs. 9.3%, RRR 8%) and microvascular events (7.9% vs. 8.6%, RRR 9%).
Coronary heart disease events were reduced by 14% (8.4% vs. 9.6%) and renal events by 21% (22.3% vs. 26.9%), the majority of which were new onset microalbuminuria. There was no difference in cerebrovascular events (5.1% vs. 5.8%) or eye events (45.4% vs. 46.9%). Findings were consistent in several key subgroups, including those with and without hypertension, and in patients on angiotensin-converting enzyme inhibitors and other blood pressure lowering medications.
After the initial follow-up period, participants went back to usual care at the discretion of their treating physician. These patients continued to be followed to assess clinical outcomes (ADVANCE-ON). Post-trial mean systolic blood pressure was 137 mm Hg in the initial active treatment group vs. 138 mm Hg in the initial placebo treatment group. At a median of 9.9 years of follow-up, a reduction in all-cause mortality was still observed in the initial active treatment vs. initial placebo group (hazard ratio [HR] 0.91, p = 0.03). Cardiovascular mortality (HR 0.88, p = 0.04) and macrovascular events (HR 0.92, p = 0.06) were also lower in the initial active treatment group.
Interpretation:
Among high-risk patients with type 2 diabetes, use of a blood pressure intervention program with the combination of perindopril and indapamide was associated with a significant reduction in death and vascular events compared with placebo through a mean follow-up of 4.3 years. Benefit persisted late into follow-up, which suggests a memory effect (or carry forward) from active control of blood pressure among type 2 diabetics.
The UKPDS trial demonstrated that treating hypertensive diabetic patients to reduce blood pressure resulted in reduced vascular events; the present study extends these findings to patients with or without hypertension. The final blood pressure was also lower in the present study with active therapy at a mean of 135 mm Hg compared with UKPDS, which was in the 145 mm Hg range, suggesting that even lower blood pressure results in a further reduction in events.
The ACCORD BP trial found no benefit to treating patients to a target goal of systolic blood pressure at 120 mm Hg compared with a target goal of systolic blood pressure at 140 mm Hg.
References:
Presented by Dr. John Chalmers at the European Society of Cardiology Congress, Barcelona, Spain, September 1, 2014.
ADVANCE Collaborative Group. 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. Lancet 2007; epub before print.
Presented by Dr. Stephen MacMahon at the European Society of Cardiology Congress, September 2007, Vienna, Austria.
Keywords: Risk, Perindopril, Drug Combinations, Follow-Up Studies, Diabetes Mellitus, Type 2, Diuretics, Coronary Disease, Blood Pressure, Indapamide, Hypertension, Glucose, ESC Congress
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