DOAC reversal agents work but what comes next needs more data

The risk of death after severe DOAC-related bleeding remains significant despite a high rate of effective haemostasis with reversal agents.

That’s the conclusion from a systematic review and meta-analysis of the evidence for clinical outcomes following bleeding and use of 4-factor prothrombin complex concentrates (4PCC) or specific reversal agents idarucizumab and andexanet alfa.

The meta-analysis, published in the JACC, comprised 60 relevant articles representing 4,735 patients with severe or uncontrolled bleeding associated with DOAC use.

There were 623 deaths – an overall mortality rate of 17.7% but with significant heterogeneity between studies. For example, mortality following an ICH was 20.2%.

Where causes of death were available, most (67.8%) were adjudicated to the underlying index bleeding event.

The overall rate of thromboembolic events following control of the bleeding event was 4.6% but higher with andexanet (10.7%) compared to 4PCC (4.3%) and idarucizumab (3.8%).

“A prothrombotic rebound effect cannot be ruled out with andexanet within the first days after reversal since andexanet has shown to transiently increase thrombin generation.”

The meta-analysis found effective haemostasis was achieved in 78.5% of patients.

“The rate of haemostatic efficacy was high with 4PCC (80.1%; 95% CI: 75.9% to 84.2%), idarucizumab (76.7%; 95% CI: 68.5% to 85%), and andexanet (80.7%; 95% CI: 73.5% to 87.9%),” it said.

“Failure to achieve effective haemostasis resulted in a more than a 3-fold increase of death compared to achieving effective haemostasis (RR: 3.63; 95% CI: 2.56 to 5.16; I2 ¼ 0%).”

The meta-analysis also revealed a high rate of patients (52.6%) who had moderate/severe disability at discharge (mRS: 3 to 5) and 66.2% of patients with poor outcomes (mRS: 4 to 6).

“Therefore, although the mortality rates from DOAC-related ICH appear to have decreased with the introduction of reversal agents over the past decade, the rates of moderate/severe disability and poor prognosis remain very high.”

The authors said an ESC consensus recommends resumption of anticoagulation after major bleeding as soon as the thrombotic risk exceeds the rebleeding risk, in most cases within 1 week.

“In our review, anticoagulation was resumed on average 11 days after admission. The rebleeding rate was 13.2%, and 78% of rebleeds occurred after resumption of anticoagulant therapy. Eighty-two percent of rebleeds were described as an ICH. Therefore, caution with anticoagulant resumption is advised.”

They noted that comparative studies were needed to determine if specific reversal agents were more effective and/or safer than nonspecific reversal with 4PCC.

An editorial comment in the journal said concern about bleeding was the most common reason providers do not treat patients with AF with an OAC.

“Even among patients treated with DOACs, patients are often underdosed relative to treatment recommendations, in large part based on fear of bleeding events,” it said.

However they noted that DOACs are relatively safe and reversal agents were rarely needed.

“The best way to deal with bleeding is to prevent it,” they said.

“Guidelines stress the need to minimise bleeding risk for all patients on OACs by addressing modifiable factors increasing the risk of bleeding, such as concomitant use of aspirin, which increases the hazard for major bleeding events by at least 50%.”

They concluded that the availability of reversal agents should provide reassurance to providers to prescribe OACs for stroke prevention.

Australian and New Zealand data to come

Commenting on the meta-analysis, Professor Ross Baker from the Perth Blood Institute, told the limbic that anticoagulant related bleeding was a sentinel event for death.

“One in six will die and exactly what we should do when someone presents is an important consideration and perhaps a bit underestimated,” he said.

“If someone comes in with an intracerebral haemorrhage, it’s a catastrophic event and you may not be able to avoid further trouble.”

He said it was clear that all the reversal agents used for DOACs were effective.

“We can stop the haemorrhage but it is really the timing of anticoagulation that is the critical decision point after that initial event.”

“There is really not too much research in that – when to start, what sort of dose – but you can see from the meta-analysis that the rebleeding rate is an issue.”

“We know with perioperative bleeding that if you start too strongly too soon you are going to struggle with haemorrhage. But if you leave it too long without anticoagulation, because of all the events and the inflammatory reactions that happen, you are at higher risk for further thromboembolism.”

Professor Baker said haematology should be involved in decisions about restarting anticoagulation.

“It’s a difficult decision…getting that balance right between bleeding and stroke. It is good to have more hands on deck to try and solve the problem.”

He said there were protocols for major haemorrhage with a focus on managing the initial bleeding.

“..but then if they go to the ward, the information about rebleeding and the subsequent management may or may not be thoroughly considered in the complexity of the patient. There are always lots of things going on.”

“This decision about anticoagulation needs to be seriously considered to get the timing right….not too much too early and not too little too late.

The Anticoagulation Reversal and Events Study (ARES) which will report soon will provide more information on management of anticoagulant-related bleeding.

Professor Baker reinforced the message that people who are on a DOAC are on it for a good reason.

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