‘1-2-3-4-day rule’: Initiating DOACs according to stroke severity may be the way to go

Following nonvalvular atrial fibrillation (NVAF)-associated stroke events, a graded increase in delay in direct oral anticoagulants (DOACs) initiation of between 1 and 4 days, depending on the severity of the index event, appears to be effective for recurrent stroke prevention and does not compromise safety both in Asians and Europeans, according to a recent study.

As compared with later DOAC initiation, early initiation by the so-called 1-2-3-4-day rule reduced the risk of the composite of recurrent stroke or systemic embolism (adjusted hazard ratio [aHR], 0.50, 95 percent confidence interval [CI], 0.27–0.89; p=0.019) and ischaemic stroke (IS; aHR, 0.54, 95 percent CI, 0.27–0.999; p=0.049) in Japanese populations. Based on the rule, DOACs were initiated within 1 day after transient ischaemic attack (TIA), within 2 days after mild IS, within 3 days after moderate IS, and within 4 days after severe IS. [Stroke 2022;53:1540-1549]

With regard to safety, there was no significant difference in the incidence of major bleeding between the early and late treatment groups (aHR, 0.81, 95 percent CI, 0.28–2.19; p=0.687).

The efficacy and safety data of the 1-2-3-4-day rule in Japanese patients were validated in an analysis involving European patients (n=2,036; early group n=547, late group n=1,489, median age 78 years, 51 percent women).

Discussing the results, the investigators said: “Both the risks of stroke/systemic embolism and IS were halved in the early group compared with the late group presumably because of the prevention of recurrent thromboembolism within the initial days.”

They also acknowledged the possibility that patients at high risk for both ischaemia and bleeding, who might not be the best candidates for early anticoagulation, might have been more commonly assigned to the late treatment group, although CHADS₂-VASc and HAS-BLED scores were similar in the two groups.

The current analysis included 1,797 patients (early group n=785; late group, 1,012) from two prospective registries in Japan, namely SAMURAI-NVAF (September 2011 to March 2014) and RELAXED (February 2014 to April 2016). The median age was 77 years, and 41 percent were women. DOACs were started at a median of 4 days after the index IS/TIA overall, 2 days after TIA, 3 days after mild IS, 4 days after moderate IS, and 5 days after severe IS.

The optimal timing

The current consensus for starting DOACs following NVAF-related acute IS/TIA is based on the ‘1-3-6-12-day rule,’ with graded increase in delay in anticoagulation of between 1 and 12 days after onset of IS/TIA and varying according to neurological severity. For example, it is recommended that DOAC treatment be initiated 12 days after onset of severe IS. [Eur Heart J 2016;37:2893-2962]

However, the investigators pointed out that the timings involved in the 1-3-6-12-day rule might be somewhat later than currently used in a real-world practical setting. Furthermore, there are pieces of evidence that indicate that early initiation of anticoagulation with DOACs lowers the risk of poor clinical outcomes compared with warfarin in practical clinical settings. [Ann Neurol 2019;85:823-834; J Thromb Thrombolysis 2019;47:292-300; JAMA Neurol 2019;76:1192-1202]

Then again, later DOAC initiation may be more practical for some patients, according to the investigators. This is especially true for those with cardiac thrombi on ultrasound, who require major surgical intervention, have haemorrhagic transformation, with neurological instability, who are older, and have uncontrolled blood pressure. [N Engl J Med 2009;361:1139-1151; N Engl J Med 2011;365:883–891; N Engl J Med 2011;365:981-992; N Engl J Med 2013;369:2093-2104]

The present ‘1-2-3-4-day rule’ can therefore work in the real-world clinical setting by careful selection of patients, excluding those who present with conditions that favour delayed initiation of DOACS, the investigators said. 

However, it goes without saying that before any changes to clinical practice or guidelines can be made, more randomized controlled trials should be conducted, they added.