NPC Archive Item: A key message on intensive blood-pressure control in type 2 diabetes mellitus from ACCORD

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20 April 2010

The ACCORD blood-pressure (BP) study conducted in patients with type 2 diabetes at high risk for cardiovascular (CV) disease concluded that intensive BP control to a target systolic blood-pressure of 120mm Hg, as compared with a target of 140mm Hg, did not reduce the rate of a composite outcome of fatal and nonfatal major CV events. There were significantly more serious adverse events attributed to antihypertensive treatment in the intensive-therapy group compared with the standard-therapy group; number needed to harm [NNH] 50 over 5 years.

Both the ACCORD BP and lipid trials add to ACCORD’s message on glycaemic control; over-intensification of treatment in type 2 diabetes mellitus provides limited or no overall benefit, and may increase the risk of adverse events.

Level of evidence: Level 2 (limited quality patient-oriented evidence) according to the SORT criteria.

Action
Health professionals should continue to follow NICE guidance on the management of type 2 diabetes. The ACCORD BP trial suggests that targeting a systolic BP of less than 120mmHg, as compared with less than 140mmHg, does not reduce the rate of a composite of major CV events in patients with type 2 diabetes at high CV risk. NICE guidance recommends to reduce BP to below 140/80 mmHg (below 130/80 mmHg if there is kidney, eye or cerebrovascular damage). Health professionals may wish to consider the implications of the ACCORD BP trial, with respect to the risk and benefits of intensifying BP control, especially if aiming for BP targets below the standard target levels set by NICE.

What is the background to this?
As the NICE full guideline for diabetes notes, people with type 2 diabetes are at increased CV risk which is reduced by lowering BP. There is limited evidence from previous randomised trials to demonstrate whether or not reduction in BP below the recommended standard targets provides additional benefit. The ACCORD study evaluated the effect of intensive treatment of blood glucose on CV outcomes in 10,251 patients with type 2 diabetes who were at high risk for CV disease (see previous blog). From within the cohort of patients recruited to the ACCORD blood glucose study, patients were also recruited to two other trials to evaluate the effect of intensifying either systolic BP control (ACCORD BP trial) or lipid-modification therapy (ACCORD lipid trial) in people with type 2 diabetes.

What does this study claim
The ACCORD BP trial concluded that in people with type 2 diabetes at high risk of CV events, intensive BP control to a systolic blood-pressure target of less than 120mmHg, as compared with less than 140mmHg (standard therapy), did not reduce the rate of a composite outcome of fatal and non-fatal CV events significantly over a mean follow-up of 4.7 years. The annual rate of the primary outcome was 1.87% in the intensive-therapy group and 2.09% in the standard-therapy group (hazard ratio [HR] with intensive therapy, 0.88; 95% confidence interval [CI] 0.73 to 1.06; P=0.20). Statistically significant, small differences were seen in the rate of total stroke (0.32% per year in the intensive-therapy group vs. 0.53% per year in the standard-therapy group; HR 0.59; 95% CI 0.39 to 0.89; P=0.01) and in the rate of non-fatal stroke (0.30% per year in the intensive-therapy group vs. 0.47% per year in the standard-therapy group; HR 0.63; 95% CI 0.41 to 0.96; P=0.03). There were significantly more serious adverse events attributed to antihypertensive treatment in the intensive-therapy group (3.3%) compared with the standard-therapy group (1.3%) (P<0.001; number needed to harm [NNH] 50 over 5 years).

How does this relate to other studies?
The UKPDS and a post hoc subgroup analysis of the HOT trial showed reductions in CV events with antihypertensive therapy amongst patients with type 2 diabetes mellitus. The intensive treatment arms for both these trials achieved a mean systolic BP of 144mmHg, which is much higher than those for the ACCORD BP trial. The ADVANCE trial had no specific BP goals, and the mean systolic BP in the intensive group (135mmHg) was not as low as the mean systolic BP even in the ACCORD standard-therapy group. As there is limited evidence from randomised trials to support a strategy of lowering systolic BP below 135 to 140mmHg in patients with type 2 diabetes mellitus, the ACCORD BP trial investigated whether intensively targeting systolic BP to <120mmHg reduces major CV events.

So what?
Intensive antihypertensive therapy was not shown to significantly reduce the primary outcome or the rate of all-cause mortality, despite significant and sustained differences between the mean systolic BP of the intensive therapy group and the standard therapy group. Furthermore, no significant benefit of intensive BP control was seen with all of the secondary trial outcomes, with the exception of total and non-fatal stroke where there was a reduced rate with intensive antihypertensive therapy.

The trial showed signs of increased possible harm (including the rate of adverse events) associated with intensive BP control, compared with the standard therapy group. Both estimated glomerular filtration rate and macroalbuminuria were reduced in the intensive-therapy group, but the implications of these changes on CV and renal outcomes are uncertain. It is possible that the open-label design of the trial may have contributed as a potential source of bias in the reporting of adverse events.  As the trial focussed on evaluating the impact of specific BP targets, it remains unclear what contribution individual antihypertensive agents may have had on outcome measures and adverse events.

The observed primary outcome event rate was almost 50% lower than expected in the standard BP therapy group. This may have been due to the frequent use of statins and of inclusion criteria that directed participants with dyslipidaemia into the ACCORD lipid trial, potentially leaving lower CV risk participants in the BP trial.  Further limitations of the ACCORD BP trial include the possibility that 5 years is not long enough to see significant cardiac benefits from normalisation of systolic BP in patients with diabetes, especially if all other parameters (smoking status, glycaemic control, statins, aspirin etc.) are optimised.

NICE guidance on the management of type 2 diabetes recommends reducing BP to below 140/80 mmHg (below 130/80 mmHg if there is kidney, eye or cerebrovascular damage). The ACCORD BP trial concluded that there is no evidence that the strategy of intensive BP control, below NICE targets, reduces the rate of a composite of major CV events amongst patients with type 2 diabetes mellitus.

The ACCORD lipid trial concluded that the strategy of intensifying lipid modification therapy through combination use of fenofibrate and simvastatin (at a daily dose of 40mg or less) did not reduce rates of CV disease, as compared with simvastatin alone (see related blog ).

Study details
The Accord Study Group. Effects of intensive blood-pressure control in type 2 diabetes mellitus. New Engl J Med 2010; published online March 14th (10.1056/NEJMoa1001286)

Design: Open-label, randomised controlled trial. Mean follow up 4.7 years.

Patients: Baseline characteristics were essentially similar between the two groups. The mean age of the participants was 62.2 years; 47.7% were women and 33.7% had CV disease at baseline. The mean BP of the participants at baseline was 139.2/76.0 mmHg.

Intervention and comparison: Of the 10,251 patients who were eligible for the ACCORD study, 4733 participants were enrolled in the ACCORD BP trial. Of these, 2362 were randomly assigned to intensive BP control and 2371 were assigned to standard therapy. Patients were randomised to intensive targeting of systolic BP to <120mmHg versus standard targeting of systolic BP control to <140mmHg. The primary outcome was a composite of major non-fatal myocardial infarction , stroke  or CV death.

Outcomes and results: After one year, the mean systolic BP was 119.3 mm Hg in the intensive-therapy group and 133.5 mm Hg in the standard-therapy group. The annual rate of the primary outcome was 1.87% in the intensive-therapy group and 2.09% in the standard-therapy group (hazard ratio with intensive therapy, 0.88; 95% CI 0.73 to 1.06; P=0.20). The annual rates of death from any cause were 1.28% and 1.19% in the two groups, respectively (HR 1.07; 95%CI 0.85 to 1.35; P=0.55). The annual rates of stroke, a pre-specified secondary outcome, were 0.32% and 0.53% in the two groups, respectively (HR 0.59; 95% CI, 0.39 to 0.89; P=0.01). Serious adverse events attributed to antihypertensive treatment occurred in 77 of the 2362 participants in the intensive-therapy group (3.3%) and 30 of the 2371 participants in the standard-therapy group (1.3%) (P<0.001).

Sponsorship: The studies were supported by grants from the National Heart, Lung, and Blood Institute and other components of the National Institutes of Health. Several pharmaceutical companies provided study medications, equipment, or supplies.

More information on in the management of type 2 diabetes can be found on the type 2 diabetes section of NPC.

You can find more information on management of hyperlipidaemia, and the rest of the evidence base for fibrates, on the lipids section of NPC.

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