Dabigatran in patients with myocardial injury after non-cardiac surgery (MANAGE): an international, randomised, placebo-controlled trial

In this study (n=1,754), the incidence of the primary composite endpoint was lower in those randomised to dabigatran 110mg BD (11% vs 15% with placebo; HR 0.72; 95% CI 0.55-0.93; p=0.0115), with no significant increase in major bleeding (3% v 4%; HR 0.92; 0.55-1.53; p=0.76).

The primary efficacy outcome was the occurrence of a major vascular complication, a composite of vascular mortality and non-fatal myocardial infarction, non-haemorrhagic stroke, peripheral arterial thrombosis, amputation, and symptomatic venous thromboembolism. The primary safety outcome was a composite of life-threatening, major, and critical organ bleeding.

 

According to a related comment, myocardial injury after non-cardiac surgery (MINS), detected by elevated troponin measurement, is a common postoperative complication and increases the risk of 30-day mortality three-fold.

 

The following issues are discussed:

 

·         There was a lower than expected recruitment rate and the primary outcome was broadened during the trial to increase power. The low enrolment rate, considering the frequency of MINS, may in part indicate physician reluctance to screen post-operative patients for elevated troponin and/or expose them to dabigatran.

 

·         Troponin was predominantly measured in a-priori high-risk patients, and those without bleeding issues, implying the results of the trial cannot necessarily be generalised to all postoperative patients.

 

·         In daily practice, it might prove challenging to pinpoint MINS among the many other conditions associated with elevated troponin levels, and to discriminate MINS from chronic stable troponin elevation.

 

·         The primary safety endpoint was a composite of life-threatening, major, or critical organ bleeding. Many patients with important bleeding problems, even requiring transfusion, did not qualify for this definition. For example dabigatran increased the secondary outcomes of risk of minor bleeding (15% v 10%; HR 1.64; 1.25-2.15), clinically non-significant lower gastrointestinal bleeding (4% v 1%; HR 4.77; 2.11-10.80), and dyspepsia (15% v 11%; HR 1.33; 1.02-1.73). According to the commentary “it is important to state that, without doubt, adding a direct oral anticoagulant increases bleeding risk in the postoperative period.”

 

The commentary concludes that “whether the results of MANAGE will affect postoperative management of MINS depends on additional analyses and future studies. The optimal strategy of detecting and treating coronary artery disease, atrial fibrillation, and other cardiovascular diseases in postoperative patients with elevated troponin needs further exploration into the optimal risk-to-benefit balance with antiplatelet or anticoagulant therapies, or their combinations.”