November 11, 2015

ORLANDO, FL — New results from long-term follow-up of the ACCORD trial support the position that the benefits of intensive blood-pressure lowering to a target of <120 mm Hg systolic for patients at high cardiovascular risk, as shown in the new SPRINT trial, should be extended to diabetic patients, the lead ACCORD author says[1].

The SPRINT trial, reported earlier this week at the American Heart Association (AHA) 2015 Scientific Sessions, showed lower rates of cardiovascular events and all-cause mortality with targeting systolic blood pressure to <120 mm Hg vs the standard target of <140 mm Hg in patients at increased CV risk. But the trial did not include diabetic patients.

Dr William Cushman

"This was because the ACCORD trial evaluating the same intervention in diabetics was already under way," ACCORD lead investigator Dr William C Cushman (VA Medical Center, Memphis, TN) told heartwire from Medscape. "As the main ACCORD trial showed a nonsignificant result for intensive blood-pressure control, this was not adopted into the guidelines. But now guidelines committees will have to grapple with whether to extend recommendations based on SPRINT to the diabetic population. By reexamining the ACCORD results, including long-term follow-up, we can find some clues that may help."

Cushman explained that after the 4.9 years of active treatment in the ACCORD trial, the main results showed a nonsignificant 12% reduction in the primary end point of composite cardiovascular events. "Although there was a significant effect on stroke, this was only one of eight secondary end points, and because the primary end point was not significant, it was not taken as strong enough evidence to support intensive treatment," he said.

However, the ACCORD trial was underpowered, with a much lower event rate than anticipated, and the confidence limits for the primary end point were wide and included the possibility of a 27% reduction in events—similar to what has just been reported in SPRINT—he noted.

In addition, there was a suggestion of an interaction with intensive glycemic control. "This was a 2x2 factorial study also evaluating intensive glycemic control, which turned out to be associated with a higher event rate, as also seen in several other large trials. We now know that intensive glycemic control is not advisable, and when we look at the patients in the standard glycemic-control arm alone, there did appear to be a benefit of intensive blood-pressure reduction, but the interaction P value in the main trial was not significant (P=0.08)," he reported.

ACCORDION: Long-term Follow-up of ACCORD Patients

Presenting new results from long-term follow-up of the ACCORD patients, dubbed the ACCORDION trial, at the AHA meeting, Cushman noted that 3957 patients were followed for an additional 54 to 60 months. During this time, patients who had been in the intensive blood-pressure arm in the main trial were no longer aiming for the lower blood-pressure goals, so the difference in blood pressures between the two groups narrowed—from 14.5 mm Hg at the end of the main trial to 4.2 mm Hg at the end of the follow-up period.

Results from the follow-up period showed a 9% nonsignificant reduction in the primary end point of major cardiovascular events over a median follow-up of 8.8 years from randomization.

However, Cushman reported that with long-term follow-up, the interaction between blood pressure and glycemia interventions has now become significant (P for interaction 0.037), with evidence of benefit for intensive blood-pressure lowering in participants randomized to standard glycemia therapy (HR=0.79, 95% CI 0.65–0.96).

In addition, the stroke benefit observed during the active intervention did not persist after blood-pressure differences waned. "This finding adds evidence that the blood-pressure/stroke relationship observed during the main ACCORD was real," he suggested.

"This is a secondary analysis, but it does put a different color on the results, especially given what SPRINT has shown," Cushman commented to heartwire .

"While these long-term results should be regarded as hypothesis generating, given that the main trial was neutral, it is unlikely that another trial of intensive blood-pressure lowering will be conducted in diabetic patients. And these long-term results do take on an enhanced importance when viewed alongside the SPRINT results," he said.

Cushman concluded: "The bottom-line message is we don't have level-A evidence to treat diabetics to a target of 120 mm Hg, but taking into account results from the standard-glycemic-control arm of ACCORD, including those from long-term follow-up, and the stroke benefit seen in the main trial, together with the SPRINT results, I would say it is appropriate to include diabetic patients when making recommendations on intensive blood-pressure control. In addition, we have to take into consideration the fact that in most trials the benefits of blood-pressure reduction in diabetics are at least as good if not better than in nondiabetics."

Bakris in Agreement

Discussant of the ACCORDION paper at the AHA meeting, Dr George Bakris (University of Chicago Medicine, IL), agreed with Cushman's interpretation. "Diabetics should not be treated differently from nondiabetics when considering intensive blood-pressure reduction," he told heartwire .

"These latest ACCORD results do fit in very well with the SPRINT results if you take into account the intensive glycemic-lowering interaction. I always suspected that the intensive-glycemic-control group detracted from the impact of the blood-pressure reduction in ACCORD. Now we are seeing the true colors."

Bakris added: "The ACCORD trial was dramatically underpowered but did show a trend toward benefit. And if you look at the 40 or so trials of blood-pressure reduction in diabetes, the take-home message is that there is a lower risk for most cardiovascular outcomes in the lower blood-pressure group.

"I think we can say from SPRINT and ACCORD together than we are back to advising patients to get down below 130, as this is where most patients in the intensive groups were. Also, the ACCORDION stroke results confirm there is no legacy effect of blood-pressure reduction—you need to keep the blood pressure down consistently," he concluded.

Both ACCORD and SPRINT were supported by the National Heart, Lung, and Blood Institute (NHLBI)/National Institutes of Health (NIH). Cushman reports receiving institutional grant support from the NHLBI/NIH, Eli Lilly, and Merck and participating in uncompensated consulting for Takeda. The coauthors report no relevant financial relationships.

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