Action in Diabetes and Vascular Disease - ADVANCE BP
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.
Patients Enrolled: 11,140
Mean Follow Up: 4.3 years, 9.9 years
Mean Patient Age: 66 years
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
Major vascular events defined as a composite of cardiovascular death, nonfatal stroke, nonfatal myocardial infarction, or new or worsening nephropathy or retinopathy
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.
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.
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.
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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