New Orleans, LA - Despite the current recommendations calling for the use of perioperative beta blockers in patients with type 2 diabetes undergoing noncardiac surgery, a new randomized trial shows no benefit from treatment with metoprolol vs placebo in this population.

Results of the Diabetic Postoperative Mortality and Morbidity (DIPOM) trial were presented here today at the American Heart Association Scientific Sessions 2004.

Dr Anne Benedicte Juul

"The DIPOM trial showed no statistically significant effect of short-term metoprolol treatment on cardiac morbidity and mortality in diabetic patients undergoing major noncardiac surgery," Dr Anne Benedicte Juul (Copenhagen Trial Unit, Center for Clinical Intervention Research, Denmark) told doctors here. "There is no evidence to recommend beta blockers on the sole indication of diabetes in the perioperative setting. Therapeutic recommendations and guidelines need to be updated."

Prior trials have shown that treating patients with beta blockers before surgery can reduce cardiac events in patients undergoing noncardiac surgery, particularly in patients with diabetes, considered a coronary heart disease equivalent.[1, 2] It's not clear what the positive effect of beta blockers are in this setting, Juul said, but they lower heart rate and blood pressure, which might diminish perioperative stress.

These positive findings led to recommendations by the American College of Cardiology, American Heart Association, and the American College of Physicians that beta blockers be used in this setting. However, they had also recommended further research, because these trials were relatively small and had some limitations. For example, in one study,[2] there was no intention-to-treat analysis; only those who survived to discharge were analyzed, and those previously on beta blockers were randomized, Juul said.

There is no evidence to recommend beta blockers on the sole indication of diabetes in the perioperative setting. Therapeutic recommendations and guidelines need to be updated.

In DIPOM, 921 patients with type 2 diabetes undergoing noncardiac surgeries, including orthopedic, gynaecologic, and neurologic procedures, and not already taking beta blockers were randomized to receive placebo or 100 mg/day of metoprolol for a maximum of eight days. The primary end point was a composite of all-cause mortality, acute MI, unstable angina, or congestive heart failure.

If patients tolerated a 50-mg test dose, 100 mg was given about two hours before surgery. The 100-mg dose was given daily until discharge, and if oral medication could not be taken, 5 mg was given intravenously every six hours until patients recovered sufficiently to take the oral medication again.

Mean treatment duration was about five days in each group. Juul reported that heart rate was significantly lower with metoprolol treatment vs placebo.

After a median follow-up of 18 months, there was no significant difference in the occurrence of primary end-point events between the groups on the intention-to-treat analysis, although results were also similar on the per-protocol analysis, she noted.

All-cause mortality was also not different, occurring in 16% of both treatment groups, Juul said (p=0.88). Serious adverse events occurred in 7.1% of metoprolol and 5.2% of placebo patients.

Although DIPOM is now the largest trial looking at this topic, there is room for further investigation on this question, Juul told heartwire. It may be that a different dose or different duration of treatment might have some benefit, she noted, although the level of heart-rate lowering achieved in this study was comparable to that in the previous studies that showed benefit.

The POISE trial, now ongoing, has randomized about 10 000 patients to 200 mg of metoprolol for three weeks and should provide more information on the efficacy of this treatment, she said.

Invited discussant for the DIPOM trial during the session here was Dr Dennis T Mangano (Ischemia Research and Education Foundation, San Francisco Veterans Affairs Medical Center and University of California), who was the lead author on one of the previous trials showing benefit from the use of beta blockers in this setting.

He pointed out that the population in the DIPOM study was apparently low risk and had an uncomplicated course to surgery. Patients received metoprolol in a relatively low dose, and they received it orally, which in postoperative patients could be highly variably absorbed, and many received no drug or only 50 mg.

The final research question in DIPOM, then, might be phrased, "In diabetic patients with few other risk factors who undergo lower-risk, generally uncomplicated noncardiac surgery, will low-dose orally administered and widely variably absorbed metoprolol succinate given for four days in 40% to 70% of the metoprolol group reduce long-term fatal or nonfatal events? The study answer is no," Mangano said.The negative result, given this modified research question, is not a surprise, he said, but the investigators are to be complimented in establishing that this lower-dose approach "to this excruciating stress" is ineffective.

Future trials should include higher-risk populations, higher-risk surgery, and more intensive beta-blockade administration, given intravenously for several days and only then given orally, as well as more direct long-term follow-up, he said.