More Support for DOAC-Based Double Therapy After PCI for A-fib Patients

There is high certainty that double therapy with a direct oral anticoagulant (DOAC) and a P2Y12 inhibitor reduces bleeding in A-fib patients who have undergone PCI compared with triple therapy that includes warfarin, a P2Y12 inhibitor, and aspirin, a meta-analysis of recent randomized trials affirms.

Less certain, however, is the impact on risks of mortality and ischemic events, which do not significantly differ between groups, albeit with wide confidence intervals, researchers led by Safi Khan, MD (West Virginia University, Morgantown), report.

“That simply tells you that we still do not have adequate data to make any opinion regarding the effects on ischemic endpoints, and we need more clinical trials perhaps, to guide us in that direction,” Khan told TCTMD.

In a paper published online March 16, 2020, ahead of print in the Annals of Internal Medicine, he and his colleagues note that future trials—including COACH-AF-PCI, APPROACH-ACS-AF, OPTIMAL, and SAFE-A—will provide additional insights.

Clearing Up a Clinical Quandary

Management of patients who have indications both for dual antiplatelet therapy (DAPT) and chronic oral anticoagulation--like those with A-fib who are undergoing PCI or have ACS--has long been a challenge for clinicians seeking to balance risks of bleeding and ischemic events. Recent trials focusing on regimens that combine a DOAC with a P2Y12 inhibitor and drop aspirin early on—including PIONEER AF-PCI, RE-DUAL PCI, AUGUSTUS, and ENTRUST-AF PCI—have provided some guidance.

The meta-analysis by Khan et al is not the first to pool those data to get a better handle on the impact of double versus triple therapy in A-fib patients undergoing PCI. In December 2019, a meta-analysis in the European Heart Journal showed that DOAC-based double therapy reduced bleeding without a significant effect on most ischemic outcomes; the exception was stent thrombosis, for which there was a significantly greater risk with double therapy. More recently, a meta-analysis that also included the WOEST trial demonstrated a lower risk of bleeding with double therapy, without an increased risk of any ischemic events.

This latest meta-analysis, which did not include WOEST, employed more-robust statistical methods to pool data from the other four trials, Khan said. The investigators assessed the certainty of evidence and used methods that took into account the small number of trials and limited sample size. All patients underwent PCI, except for the 23.9% of AUGUSTUS participants who were treated with medical therapy.

There was high-certainty evidence that using DOAC-based double therapy reduced TIMI major bleeding through a median follow-up of 1 year (risk difference -0.013; 95% CI -0.025 to -0.002), with significant reductions in TIMI major/minor bleeding and trial-defined bleeding.

No significant differences were seen between groups for all-cause or CV mortality, stent thrombosis, MI, or stroke, although evidence was deemed “low-certainty.” The authors say that “the upper bounds of the CIs for these effects were compatible with possible increased risks with dual therapy.”

Some Individualization Necessary

Speaking with TCTMD, Renato Lopes, MD, PhD (Duke Clinical Research Institute, Durham, NC), lead author of a similar meta-analysis published last month, took issue with the wording of the researchers’ conclusion around the impact of double versus triple therapy on ischemic risks in these trials (ie, low-certainty evidence) while pointing out that the findings are similar.

“The conclusions are aligned and the results are aligned. Avoiding aspirin is the safest way. Using a NOAC [rather] than warfarin is a better option. Triple therapy with aspirin, clopidogrel, and warfarin should generally be avoided in clinical practice,” Lopes said.

As for the impact on ischemic events, “I prefer to say that we did not find any significant increase in MACE by dropping aspirin [rather] than saying that there is uncertainty around that because uncertainty is when we have no data,” he added. “And here we have five randomized trials showing . . . in a very robust way that there is no significant increase in MACE, so I think that these findings should not be ignored.”

John Doherty, MD (Jefferson Heart Institute, Philadelphia, PA), who wrote an editorial accompanying the meta-analysis by Khan et al, told TCTMD that “the question really is do these simpler regimens reduce bleeding—which they pretty convincingly do—and are you paying a price or not paying a price for thrombotic events.”

The conclusion looking at all this, he continued, “is that you’re probably not going to be doing triple therapy with warfarin anymore in such patients. You’re probably going to be using a DOAC-based regimen.”

There is still some question about how long aspirin should be used initially, and guidance documents from the US and Europe differ somewhat on this issue. That decision comes down to characteristics of specific patients, Doherty said—based on whether they are being treated electively or for ACS, the complexity of disease, and the level of bleeding risk, for instance. If a patient has a low bleeding risk and complex disease, aspirin might be kept in the regimen for a little longer, he said. “Whereas, conversely, if it’s not an acute coronary syndrome, if it’s not complex angiographically, and the patient is at increased bleeding risk, then you would probably have the dual antiplatelet therapy on board for a shorter period of time,” he said.

“The bottom line is this is really the wave of the future,” Doherty said, referring to DOAC-based double therapy, “but the caveat would be you sometimes have to individualize therapy depending on the specific characteristics of the patient under question.”

The important thing, Doherty added, is to maintain communication across all members of the care team, which can include interventional and general cardiologists, electrophysiologists, and the patients themselves, whenever the regimen will be changed.