Fewer Events on Dabigatran After Post–Noncardiac Surgery Myocardial Injury: MANAGE

Marlene Busko

March 23, 2018

ORLANDO, Florida — Among patients with ischemic myocardial injury after noncardiac surgery (MINS), those who then received daily dabigatran (Pradaxa, Boehringer Ingelheim) showed a significant 28% reduction in risk for cardiovascular events over a mean 16 months in a placebo-controlled trial.

The risk reduction was achieved without more major bleeds for the patients assigned to take the oral direct thrombin inhibitor in the study, called Management of Myocardial Injury After Noncardiac Surgery (MANAGE).

On the other hand, patients taking dabigatran showed an increased risk for minor bleeding, said PJ Devereaux, MD, PhD, McMaster University, Hamilton, Ontario, Canada, on presenting the results of MANAGE here at the American College of Cardiology (ACC) 2018 Annual Scientific Sessions.

MINS, which is defined as being ischemic in origin, whether or not there are symptoms, was diagnosed on the basis of isolated troponin elevations in 80% of the patients. The remaining 20% were found to have had a myocardial infarction (MI) according to standard definitions.

Most patients (91%) did not have symptoms of ischemia, Devereaux pointed out, so the diagnosis would likely have been missed without troponin measurement.

Clinical Implications

Panelists after Devereaux's presentation queried him about the potentially major implications of the study, which puts a spotlight on this novel syndrome.

Does the MANAGE trial argue in favor of routine troponin determinations on every patient undergoing noncardiac surgery, "and then every single one of them should be treated with a year of dabigatran? Which intuitively seems a little excessive," asked panelist Glenn N Levine, MD, Baylor College of Medicine, Houston, Texas.

"They're essentially the same patients they were before surgery, where certainly we wouldn't be treating them so aggressively," Levine continued. "Such a strategy to me seems a complete paradigm shift in how we treat patients and will result in a tremendous number of patients being labelled as MI."

Devereaux replied that he would recommend troponin screening for patients who undergo noncardiac surgery and have known vascular disease or are aged 65 years or older. That would likely be cost-effective, he said. For patients with MINS, he would "strongly encourage" prophylaxis with aspirin and a statin.

Patients like these have not been systematically followed, so "it's easy to assume" that they are faring well, Devereaux said. "But all the epidemiological data and MANAGE support that many of them don't do okay, and we should be a lot more assertive about secondary prophylaxis and following them up."

Moreover, he said, "MANAGE offers encouraging evidence, similar to COMPASS, that a low-to-intermediate dose of an anticoagulant, likely with an antiplatelet, is likely an attractive option for patients with vascular disease in terms of preventing subsequent cardiovascular complications."

The trial showed that patients who may not meet classic definitions for an MI had an extremely high short-term risk for a range of cardiovascular events, observed Erin Bohula, MD, DPhil, Brigham and Women's Hospital, Boston, Massachusetts, for theheart.org | Medscape Cardiology.

"Recognition of that high risk definitely argues for identifying individuals so you can start secondary preventative therapy to minimize these bad outcomes," said Bohula, who isn't with MANAGE but had been invited to comment on it an ACC media briefing.

MINS Within the Past 35 Days

The trial entered 1754 patients at 84 centers in 19 countries between January 2013 and July 2017; 48% were women. They had undergone noncardiac surgery, and MINS was diagnosed within the previous 35 days; the mean ultimately was 5 days.

They were randomly assigned to receive 110 mg dabigatran twice a day or placebo. The trial also assigned 556 patients to receive omeprazole or placebo in a separate randomization; that part of the study was not reported at the ACC session.

Importantly, the sample target had been reduced from the planned 3200 patients because of slow enrollment and funding restrictions, Devereaux noted. Taking a cue from the COMPASS trial, he said, amputation and symptomatic proximal deep-vein thrombosis were added to the primary efficacy outcome.

Three fourths of the patients were receiving aspirin during the follow-up, but only 7% were receiving dual antiplatelet therapy; 69% were taking a statin.

The primary efficacy outcome occurred in 11% of the dabigatran group vs 15% of the controls; it consisted of vascular death, MI, nonhemorrhagic stroke, peripheral arterial thrombosis, amputation, or symptomatic venous thromboembolism.

The primary safety outcome was seen in 3% of patients receiving dabigatran vs 4% of those assigned to placebo; that endpoint included life-threatening, major, or critical-organ bleeding.

Table. MANAGE: Risk for Primary Outcomes, Dabigatran vs Placebo

Endpoint Hazard Ratio (95% CI) P Value
Primary efficacy (vascular death, MI, nonhemorrhagic stroke, peripheral arterial thrombosis, amputation, or symptomatic venous thromboembolism) 0.72 (0.55 - 0.93) .012
Primary safety (life-threatening, major, and critical-organ bleeding) 0.92 (0.55 - 1.53) .79


Praise and Concerns

"Thank you for this terrific explanation of what I've seen in my whole career: people who get into trouble after noncardiac surgery, and you're called to see them, the troponins are up," said panelist Neil J Stone, MD, Northwestern University Feinberg School of Medicine, Chicago, Illinois, about MINS.

Stone wondered, however, why the study's dropout rate was high, since this can hide important details. Devereaux had noted that 45% of patients in both groups had discontinued their assigned agent;  in 60% of cases, this was because of patient request.

Devereaux replied that some reports had linked dabigatran to a possible increased MI risk. Some patients would "go home, talk to another physician, look online, and...come back and say, 'Boy, there seems to be this concern about using dabigatran.' " Then they would drop out of the study.

Because MINS is relatively new as a defined syndrome, physicians may have thought that "it doesn't matter" in patients who don't have symptoms, he speculated. So they may have advised patients of the bleeding risk with dabigatran and suggested that they withdraw from the study.

Bleeding Outcomes

"You had to be surprised you had an efficacy signal but no bleeding signal," said briefing moderator Kim Eagle, MD, University of Michigan, Ann Arbor, to Devereaux. "I was surprised."

Eagle said he had reservations about MANAGE because it might imply that such patients be put on a novel oral anticoagulant (NOAC) for up to 2 years, all "for a little troponin release."

Despite possible worries about bleeding under those circumstances, Eagle observed, "your trial suggested it went in the direction of safety."

Later in an interview, Eagle also expressed concerns about the trial's methods. MANAGE is "a difficult trial for me to reconcile," he told theheart.org | Medscape Cardiology.

For example, he noted, the study planned to enroll a much larger group of patients, in the middle of the trial the major primary endpoint was changed, and nearly half the patients reported stopping the study drug or placebo.

"And yet we saw potentially a signal both towards benefit but also safety of taking anticoagulant," he said. "It's a messy trial for me."

MANAGE "is not a trial that will change my practice," he said. "But I certainly think it's interesting and something we need to further explore."

The "gorilla in the room" is whether all patients getting noncardiac surgery should have their troponins measured, he said. Then the question becomes, what should be done with that information? "Put everybody on a NOAC? I don't think so," he said.

Eagle also said he's concerned that as an unintended consequence, MINS could increasingly be treated as a silent MI. "Suddenly all these people are getting stress tests or coronary angiography. You can imagine the wash that this could have in testing, treatment, and financial implications."

Bohula agreed that "whether troponin screening of patients having noncardiac surgery would be applied will probably take some time," and "it would be nice to have additional studies that support this, with the same strategy, maybe with a different agent."

Devereaux agreed that further research is needed. But the results of MANAGE added to epidemiologic findings, he said, may "get people to recognize these patients have very poor outcomes, to start measuring troponins, and start using better secondary prophylactic measures, and to undertake more trials to figure out how to improve the outcome for this patient population."

MANAGE was funded by Boehringer Ingelheim and the Canadian Institutes of Health Research. Devereaux discloses receiving research grants from Abbott Diagnostics, Boehringer Ingelheim, Philip Healthcare, and Roche Diagnostics. Eagle discloses receiving research grants from Gore and Medtronic. Bohula discloses receiving consultant fees or honoraria from Daiichi Sankyo, Merck, and Servier and research grants from Eisai. Levine and Stone had no relevant disclosures.

American College of Cardiology (ACC) 2018 Annual Scientific Session. Abstract 404-14. Presented March 11, 2018.

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