March 14, 2010

March 13, 2010 (Atlanta, Georgia) — New data from the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study show that there is no benefit to be gained in diabetics from intensively lowering their systolic blood pressure to a goal of <120 mm Hg [1].

There was no difference in the primary end point--a composite of fatal and nonfatal major cardiovascular events--between this group and those who received standard antihypertensive therapy to get their pressure down to <140 mm Hg, said lead author Dr William C Cushman (Veterans Affairs Medical Center, Memphis, TN), who presented the results at a late-breaking clinical-trials session here at the American College of Cardiology (ACC) 2010 Scientific Sessions; they were simultaneously published online in the New England Journal of Medicine.

I've said all along, that whichever the answer is, it is extremely important.

To heartwire , Cushman admitted he was surprised by the results: "We wouldn't have done the study if we didn't think there was a reason to think it might be beneficial." But he countered, "I've said all along, that whichever the answer is, it is extremely important. If it doesn't show benefit, we should not be aggressive, because it's hard enough to get diabetics to below 140 mm Hg, so this is a good answer."

In an accompanying editorial [2] in the journal, Dr Peter M Nilsson (University Hospital, Malmö, Sweden) agrees: "The main conclusion to draw from this study must be that a systolic BP target below 120 mm Hg in patients with type 2 diabetes is not justified by the evidence."

Nilsson added that with the conclusion of the ACCORD study--which as well as this ACCORD BP trial included the ACCORD lipid trial, also reported here at the ACC meeting--a period of three landmark studies (UKPDS, ADVANCE, and ACCORD) has now come to an end. "We learn from the completed ACCORD study that flexible goals should probably be applied to the control of hyperglycemia, blood pressure, and dyslipidemia in patients with type 2 diabetes, taking into account individual clinical factors of importance," he states.

Stroke Benefit; But 89 People Must Be Treated for Five Years to Prevent One

The ACCORD trial was conducted in the US and Canada in 10 251 high-risk patients with type 2 diabetes who were randomly assigned to either intensive or standard glycemic control (ACCORD glycemia trial). In addition, 4733 of the participants were also randomized to either intensive or standard blood-pressure control (ACCORD BP) and the remaining 5518 patients were randomly assigned to simvastatin plus fenofibrate or simvastatin plus placebo in the ACCORD lipid trial.

As reported extensively on heartwire , the ACCORD glycemia trial was stopped early, in February 2008, because of higher mortality in the intensive-glycemic-control group, sparking much debate about the ideal HbA1c level to aim for in diabetics. All patients, whether they were participating in the ACCORD BP or ACCORD lipid trial, were then transferred to the standard glycemia-control regimen, and the studies continued for their planned duration of around five years, Cushman explained.

The ACCORD BP trial was conducted because there was no clinical-trial evidence to support recommendations to lower systolic BP below 130 mm Hg in type 2 diabetes--as is advised in the JNC 7 guidelines--Cushman explained. Instead, this recommendation was based on observational studies and "best guesses" by experts, he noted.

In the ACCORD BP trial, the 4733 patients were randomized, in a nonblinded fashion, to an intensive BP-lowering regimen with a target systolic BP goal of <120 mm Hg--with patients on average taking three and a half antihypertensives--or standard BP lowering, where the goal was <140 mm Hg. The primary composite outcome was nonfatal MI, nonfatal stroke, or death from cardiovascular causes, and the mean follow-up was 4.7 years.

After one year, the mean systolic pressure was 119.3 mm Hg in the intensive-BP-lowering group and 133.5 mm Hg in the standard group.

There was no significant difference in the primary end point between the groups. There was also no difference between the groups in terms of prespecified secondary end points--bar one, stroke--and these included: the primary outcome plus revascularization or nonfatal heart failure; major coronary disease events; and fatal or nonfatal heart failure.

Primary and Secondary Outcomes of ACCORD BP

Outcome Intensive therapy (n=2363), events, n Intensive therapy (n=2363),

%/y

Standard therapy (n=2371), events, n Standard therapy (n=2371), %/y Hazard ratio p
Primary outcome 208 1.87 237 2.09 0.88 0.20
Prespecified secondary outcomes            
Nonfatal MI 126 1.13 146 1.28 0.87 0.25
Stroke            
--Any 36 0.32 62 0.53 0.59 0.01
--Nonfatal 34 0.30 55 0.47 0.63 0.03
Death            
--Any cause 150 1.28 144 1.19 1.07 0.55
--Cardiovascular cause 60 0.52 58 0.49 1.06 0.74

The significant difference in stroke between the intensive and standard BP-lowering arms "is very interesting because it's consistent with what has been seen in other hypertension trials with treatment vs placebo, ie, about a 40% reduction in stroke for a 5- to 10-mm-Hg reduction in BP," Cushman told heartwire .

He said the stroke reduction "could have happened by chance," but the fact that it is "consistent with a whole lot of other data" suggests otherwise. But even if it is a real finding, "stroke was relatively uncommon, and you have to treat 89 people for five years to prevent one stroke," he observed.

And those assigned to the intensive-therapy group were more likely to suffer adverse events due to antihypertensive therapy--3.3% compared with 1.3% in the standard-therapy group (p<0.001).

Treat Hypertension in Diabetics, But Not Excessively

Cushman told heartwire : "In my opinion it's now probably reasonable to forget all about the 130-mm-Hg goal [in diabetics], even though we didn't test that. Everything in terms of clinical-trial evidence would suggest that 140 mm Hg is an appropriate goal."

"There is no reason to say that we shouldn't treat [high] blood pressure in diabetics--we should, it's extremely important to get them down to the levels at which we have shown benefit, consistent with our standard group." He pointed out that those on the standard BP-lowering regimen in the ACCORD BP trial "did much better than predicted, with event rates half of what were expected."

In his editorial, Nilsson says, "Unfortunately, the design and results of the ACCORD BP study leave unresolved the issue of the optimal blood-pressure target in patients with diabetes." The ACCORD BP investigators "may be able to shed more light on this question in subsequent post hoc analyses of their data."

In response to this, Cushman says: "I don't think we are in a no-man's-land. I think we have good evidence to get either around or below 140 mm Hg in diabetics.

"It doesn't make a lot of sense that 130 mm Hg would be better," Cushman adds, "and it's not practical to do a [trial testing] 140 mm Hg vs 130 mm Hg, because that study would have to be huge." In retrospect, it may have been better to compare 150 mm Hg with 130 mm Hg, he says, but "the 150 mm Hg would not have been acceptable ethically in the US, because the guidelines have been saying for years to treat everybody below 140 mm Hg."

Disclosures for the ACCORD authors are listed online . Nilsson has acted as a consultant to Merck and Novartis; as a speaker for Merck, Novartis, Lilly, GlaxoSmithKline, Pfizer, AstraZeneca, and Novo Nordisk; and has received honoraria from Berlin-Chemie and Menarini.

Comments

3090D553-9492-4563-8681-AD288FA52ACE

processing....