MANAGE Suggests Dabigatran Could Be Useful for Treating Myocardial Injury After Noncardiac Surgery

One expert called the trial results “provocative” but said its methods were “muddy,” making the findings difficult to interpret

MANAGE Suggests Dabigatran Could Be Useful for Treating Myocardial Injury After Noncardiac Surgery

ORLANDO, FL—New trial results suggest that dabigatran (Pradaxa; Boehringer Ingelheim) may be useful in patients with myocardial injury after noncardiac surgery (MINS), an entity identified by measuring troponin that carries a high risk of future events.

Compared with placebo, dabigatran 110 mg twice daily reduced the risk of a composite of major arterial and venous complications through an average follow-up of 16 months (11% vs 15%; HR 0.72; 95% CI 0.55-0.93), according to P.J. Devereaux, MD, PhD (Population Health Research Institute, Hamilton, Canada).

That benefit came without an increase in the combined risk of life-threatening, major, and critical organ bleeding (3% vs 4%; HR 0.92; 95% CI 0.55-1.53), although dabigatran-treated patients did have higher risks of minor and lower GI bleeding, he reported at the American College of Cardiology 2018 Scientific Session here.

Acknowledging some limitations of the trial—including a high rate of treatment discontinuation, the need to lower the target enrollment because of slow recruitment, and a change to the trial endpoints after the start of the study—Devereux said at a press conference: “Although it’s not perfect evidence, I certainly think that this helps us to hopefully get people measuring more troponins perioperatively and allowing us to actually treat these patients who have poor outcomes.”

But Kim Eagle, MD (University of Michigan, Ann Arbor), who commented on the study for TCTMD, looked at those same limitations and said the trial was “so muddy from the point of view of its method that I view it as completely uninterpretable.”

He was particular concerned with the high rate of study drug discontinuation, which was 43% with placebo and 46% with dabigatran. Rates higher than 5% to 10% raise questions about the validity of any conclusions you might draw from trial findings, Eagle said.

“That’s the biggest problem that the trial has and I come away from it without any confidence of knowing whether or not this strategy is helpful or not,” he said. “Obviously I commend the investigators for doing their best to try to make something from this when things changed dramatically midcourse, but this is not a practice-changing trial from my point of view.”

What to Do About MINS?

MINS—which includes clinical MI and isolated ischemic troponin elevations occurring in the first 30 days after surgery—is a relatively recently described condition associated with heightened risks of cardiovascular events and death. There are no established treatments.

Oral anticoagulation has been proven effective in nonoperative patients with elevated thrombotic risks, and in the perioperative setting, dabigatran has been shown to prevent venous thromboembolism (VTE).

The MANAGE trial was designed to test dabigatran’s safety and effectiveness in patients aged 45 and older with MINS. Investigators enrolled patients who had undergone noncardiac surgery and were within 35 days of developing MINS and randomized them to dabigatran or matching placebo. Patients who were not already taking a proton pump inhibitor were also randomized to omeprazole 20 mg daily or matching placebo.

The trial was initially designed to include 3,200 patients, but because recruitment was slower than expected and trial funding was cut back, the sample size was reduced to 1,750 patients. In addition, the COMPASS results and a desire to enhance statistical power led to a broadening of the primary efficacy outcome to include amputation and symptomatic proximal deep vein thrombosis. The final composite outcome encompassed vascular mortality and nonfatal MI, nonhemorrhagic stroke, peripheral arterial thrombosis, amputation, and symptomatic VTE.

Of the 1,754 patients ultimately enrolled in the trial, 20% met MINS criteria for MI and the rest were included because of isolated ischemic troponin elevations. The median time from MINS diagnosis to randomization was 5 days. The vast majority of patients (91%) did not have ischemic symptoms. Use of medical therapy aside from the study drug was similar in both trial arms.

Most of the drug discontinuations in the trial were due to patient request, and Devereux explained that publications of studies suggesting that dabigatran carried a greater risk of MI relative to other anticoagulants and a belief on the part of physicians that the drug might be dangerous in patients with subclinical troponin elevations played a major role in those decisions. In addition, he said, the risks associated with MINS were not widely appreciated.

Devereux defended the findings of the trial, saying that a high rate of discontinuation would be expected to add “noise” and obscure any treatment effects. Despite that, “we still did see an effect, which suggests, in fact, maybe the drug effect was bigger,” he said, pointing out that an exploratory, per protocol analysis that censored patients 7 days after drug discontinuation also indicated a benefit from dabigatran treatment.

‘Ultimately Practice May Change’

Erin Bohula, MD, DPhil (Brigham and Women’s Hospital, Boston, MA), who served as a discussant for the trial at a press conference, said MANAGE adds to the growing body of evidence indicating that anticoagulants are useful beyond the setting of A-fib.

Bohula told TCTMD that she was understanding of the obstacles the trial investigators faced in terms of recruitment because physicians may be hesitant to use a therapy associated with an increased risk of bleeding. She also understood the challenges regarding drug discontinuation because of the commitment patients make to take an oral anticoagulant. And, Bohula added, patients recruited during an acute event typically are more likely to discontinue drug treatment.

The fact that the trial showed a significant benefit from dabigatran is “encouraging and it speaks to a probably real result,” particularly when considered in the context of other studies showing the positive effects of oral anticoagulation in patients with vascular disease, Bohula said.

Standing in the way of implementing this type of approach in practice, however, is the fact that physicians outside of cardiology are not regularly checking troponins after surgery. “I think that that is—practically speaking—not likely to happen in the near future,” Bohula said. “I think ultimately practice may change, but tomorrow am I going to see the orthopedists checking troponins so that we can anticoagulate patients? Probably not.”

She said she hopes the MANAGE results will encourage people to start checking troponins more frequently after surgery even if there is no intention to start oral anticoagulation. That’s because there is evidence that these patients are at risk for future events and may benefit from standard therapies like aspirin, she said. “The average physician may not reach for an oral anticoagulant, but they probably should be reaching for some other well-established secondary preventive therapies.”

Eagle remained skeptical, however, and cautioned against a rush into more routinely measuring troponins after noncardiac surgery because of the risk of unintended consequences, including overtesting and overtreatment. The medical community needs a better understanding of what these troponin elevations mean before treatments can be initiated, he argued.

As for the approach evaluated in MANAGE, Eagle said, it’s going to need to be retested in a study with an equal or larger sample size with solid endpoints and high validation of patient compliance.

“Certainly for me, the idea of putting somebody on an anticoagulant for several years for this kind of a biological marker is far from proven,” he said. “It’s worthy of further research and certainly is provocative.”

Sources
  • Devereux PJ. The effect of dabigatran in patients suffering myocardial injury after noncardiac surgery. Presented at: ACC 2018. March 11, 2018. Orlando, FL.

Disclosures
  • Devereux reports receiving research grants from Abbott Diagnostics, Boehringer Ingelheim, Philips Healthcare, and Roche Diagnostics.
  • Eagle reports no relevant conflicts of interest.
  • Bohula reports receiving consulting fees/honoraria from Daiichi Sankyo, Merck, and Servier and research grants from Eisai.

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