Dabigatran after noncardiac surgery reduces major CV complications in patients with myocardial injury
ORLANDO, Fla. — Treatment with dabigatran significantly reduced the risk for death, MI, stroke and other CV complications among patients with elevated risk for these events as a result of myocardial injury after noncardiac surgery.
In a group of 1,754 patients treated with twice-daily dabigatran 110 mg or placebo, the primary efficacy outcome of major vascular complications occurred in 11% of the dabigatran group vs. 15% of the placebo group (HR = 0.72; 95% CI, 0.55-0.93). This translates to a 28% reduction in risk for patients receiving dabigatran, according to P.J. Devereaux, MD, PhD, FRCP, director of the division of cardiology at McMaster University. Major vascular complications included a composite of vascular death, nonfatal MI, nonhemorrhagic stroke, peripheral arterial thrombosis, amputation and symptomatic venous thromboembolism.
The primary safety outcome of life-threatening, major and critical organ bleeding was similar at 3% in the dabigatran group vs. 4% of the placebo group (HR = 0.92; 95% CI, 0.55-1.53). More patients assigned dabigatran experienced bleeding in the lower gastrointestinal tract and minor bleeding.
Trial design, adherence
The MANAGE study enrolled patients in 19 countries (mean age, 70 years; 50% men). Patients were treated with twice-daily dabigatran 110 mg (n = 1,754) or placebo (n = 556). The primary safety outcome was the combined rate of life-threatening, major and critical organ bleeding. Patients were followed for a maximum of 2 years or until the trial was terminated on Nov. 30, 2017.
The MANAGE trial design changed over time. The initial design was to randomly assign 3,200 patients with a primary composite outcome of vascular mortality and nonfatal MI, stroke, peripheral arterial thrombosis and symptomatic pulmonary embolism. However, recruitment was slower than anticipated and funding was curtailed during conduct of the trial. Without knowledge of the trial results, the sample size was reduced to 1,750 and, further, based on findings of the COMPASS trial the primary efficacy outcome was broadened to incorporate amputation and symptomatic proximal deep vein thrombosis, according to the presentation.
Nearly all patients completed follow-up, but 45% of those assigned dabigatran had discontinued the study drug. Patient request was the most common reason for drug discontinuation. However, 14% of these patients had a major complication. Devereaux noted that analyses that counted patients up to 1 week after discontinuation of study drug showed even greater treatment effects, including a 46% reduction in major CV complications with dabigatran and no excess life-threatening, major or critical organ bleeding.
Challenge of myocardial injury after noncardiac surgery
It is estimated that myocardial injury after noncardiac surgery, also referred to as MINS, occurs in more than 8 million adults each year and is associated with increased risk for major CV complications and death in the first 2 years after noncardiac surgery, according to Devereaux. However, he said, no published trial has evaluated treatment for myocardial injury after noncardiac surgery.
Myocardial injury after noncardiac surgery includes MI and isolated ischemic troponin elevation that occur within the first 30 days after surgery. Many cases of myocardial injury after noncardiac surgery are undetected because it is currently not standard practice at most centers to monitor troponin in patients who underwent major noncardiac surgery, according to Devereaux. He said in a press release he is hopeful that this will change now that this study has shown treatment with dabigatran can improve outcomes for patients with myocardial injury after noncardiac surgery.
The investigators tested dabigatran in patients with myocardial injury after noncardiac surgery because it “has the potential to reduce a broad range of vascular complications without causing substantial bleeding,” he said.
“The implications are that patients with MINS are at high risk,” Devereaux said. “One in seven patients in the placebo group suffered a major vascular complication during a 16-month follow-up [and] 91% of the MINS patients were only detected through troponin screening after noncardiac surgery. Clinicians will not recognize most MINS events without routine perioperative troponin measurements.” – by Dave Quaile
Devereaux, PJ. Joint American College of Cardiology/Journal of the American Medical Association Late-Breaking Clinical Trials. Presented at: American College of Cardiology Scientific Session; March 10-12, 2018; Orlando, Fla.
Disclosures: The study was funded by grants from Boehringer Ingelheim and the Canadian Institutes of Health Research. Devereaux reports he receives research grants from Abbott Diagnostics, Boehringer Ingelheim, Philips and Roche Diagnostics.