Victor J. Del Brutto, MD

Knijnik L, Rivera M, Blumer V, Cardoso R, Fernandes A, Fernandes G, et al. Prevention of Stroke in Atrial Fibrillation After Coronary Stenting: Systematic Review and Network Meta-Analysis. Stroke. 2019;50:2125–2132

Approximately one-fourth of patients with atrial fibrillation (AF) have coronary artery disease (CAD), and a significant number of them undergo percutaneous coronary intervention (PCI) and stent placement. This clinical scenario represents a special circumstance in which a combined antithrombotic regimen with platelet anti-aggregation (to prevent stent thrombosis and myocardial ischemia) and anticoagulation (to prevent AF-related cardioembolic stroke) is warranted. Previously, in the absence of randomized controlled trials, guidelines supported the use of a Vitamin K antagonist (VKA) and dual antiplatelet (DAPT), especially when drug eluting stents were used. This regimen known as “triple therapy” has shown to have a fourfold risk of bleeding complications when compared to oral anticoagulation alone.

One of the first randomized controlled trials to challenge this practice was the WOEST study in 2013. This trial showed that patients on oral anticoagulation who underwent PCI had a lower rate of major bleeding without an increase in ischemic events when treated with clopidogrel alone rather than clopidogrel and aspirin. Subsequently, the appearance of direct oral anticoagulants (DOACs) with safer pharmacological profiles encouraged investigators to compare substitute antithrombotic regimens. PIONEER AF-PCI in 2016 and RE-DUAL in 2017 reported lower rates of clinically relevant bleeding complications with DOACs and a single antiplatelet agent (SAPT) compared to triple therapy (VKA + DAPT). There was no difference in mortality and ischemic events among groups. Of notice, these trials were not designed to assess whether the bleeding reduction was due to the use of a DOAC or the use of SAPT. Additionally, in both studies, lower doses of DOACs were associated with numerically higher rates of ischemic events. In light of this new evidence, newer guidelines favor the use of DOACs over VKA and double therapy over triple therapy (recommendation IIb, level of evidence B-R). More recently, the AUGUSTUS trial utilized a two-by-two factorial design to assess the efficacy and safety of Apixaban vs. Warfarin, as well as a P2Y12 inhibitor alone vs. DAPT. The authors found that a regimen of P2Y12 inhibitor (without aspirin) plus Apixaban was associated with significant lower bleeding complications and appeared to be as effective as triple therapy in preventing ischemic events.

Considering that the aforementioned trials were mainly designed to assess reduced rate of bleeding complications rather than the efficacy in preventing ischemic events, Knijnik et al. conducted a systematic review and network meta-analysis to evaluate the efficacy-safety profile of different antithrombotic regimens among patients with AF who underwent PCI and stent placement. The authors found that stroke is better prevented with double therapy-based regimens (VKA + SAPT and DOAC + SAPT), likely due to a reduced rate of hemorrhagic strokes. As expected, DOAC + SAPT had the lowest rate of bleeding complications. DOAC-based regimens were better in preventing cardiac events when compared to VKA, and DAPT seems better that SAPT in reducing major cardiovascular adverse events. Despite being associated with the highest rates in bleeding complications, triple therapy regimens (VKA + DAPT and DOAC + DAPT) had the lower risk for all-cause mortality. The latter is probably the most difficult finding to be rationalized. Improved mortality among patients on triple therapy does not seem to be explained by s decrease in cardiac or neurological complications. The findings could be influenced by bias incorporated by non-randomized trials included in the analysis; however, this is an observation that would require further investigation.

Overall, it is reasonable to say that a regimen of DOAC plus SAPT (P2Y12 inhibitor) has the best risk-benefit profile. The temporary addition of aspirin (DOAC + DAPT) in patients with low bleeding risk might add extra protection for ischemic complications (and potentially lower mortality); however, this remains a matter of debate.