DOACs for AF and PAD Associated With Reduced Risk for Major Adverse Limb Events

Anticoagulation therapy decreases risk for major adverse limb events in patients with nonvalvular AF and peripheral artery disease.

Among patients with nonvalvular atrial fibrillation (NVAF) and concomitant peripheral artery disease (PAD), the incidence of major adverse limb events (MALE) is significantly lower in those who used direct oral anticoagulants (DOACs) compared with those who used vitamin K antagonists (VKAs), according to a study in the Journal of Cardiovascular Development and Disease.

The systematic review and meta-analysis assessed the efficacy and safety of DOACs vs VKA therapy in patients with NVAF and PAD, focusing on mortality, MALE, major adverse cardiovascular events, and major bleeding.

A comprehensive literature search was conducted in Medline, EMBASE, Scopus, Web of Science, and CENTRAL databases in September 2021. A total of 12 articles (3 post hoc analyses from randomized controlled trials and 9 observational cohorts) published from 2013 to 2020 were included.

The primary point of interest was lower-limb events, which were reported as a composite outcome of MALE. The analysis included 3 studies with 13,561 total patients with PAD who received anticoagulation therapy for concomitant NVAF. Patients in the DOAC group were significantly less likely to have a MALE compared with those in the VKA group, with moderate heterogeneity (hazard ratio [HR], 0.58; 95% CI, 0.39-0.86; P <.01; I2 =32%).

Analysis of patients with PAD without AF was based on 4 studies, in which the need for reoperation was a separate outcome. Among 2323 patients, no significant difference was observed between the 2 treatment groups, without any evidence of heterogeneity (odds ratio [OR], 1.49; 95% CI, 0.79-2.79; P =.14; I2 =6%).

Using DOACs in patients undergoing lower-extremity arterial procedures may play a more significant role in the future, but further investigations are needed for definitive results and safe decision-making.

Regarding efficacy outcomes in patients with PAD and AF, compared with VKAs, the use of DOACs was associated with a significantly decreased risk for stroke/systemic embolism (HR, 0.76; 95% CI, 0.61-0.95; P <.01; I2 =64%) and all-cause mortality (HR, 0.78; 95% CI, 0.66-0.92; P <.01; I2 =86%), with substantial heterogeneity. No statistically significant difference occurred between the DOAC and VKA groups for the incidence of myocardial infarction (HR, 0.81; 95% CI, 0.59-1.11; P =.21; I2 =18%) and cardiovascular mortality (HR, 0.77; 95% CI, 0.58-1.02; P =.07; I2 =.17).

Major bleeding was reported in most of the studies in patients with PAD and AF. Similar risks (HR, 0.91; 95% CI, 0.74-1.12; P <.01; I2 =91%) were found for major bleeding episodes in DOACs vs VKAs. These results were analyzed separately owing to the considerable heterogeneity. Rivaroxaban at higher doses significantly increased the risk for bleeding (HR, 1.16; 95% CI, 1.07-1.25; P <.01; I2 =12%). A significantly lower risk for major bleeding was observed in the composite group of other DOAC drugs at conventional dosages and rivaroxaban administered at a reduced dose (HR, 0.71; 95% CI, 0.63-0.79; P <.01; I2 =35%).

Study limitations include the residual confounding results are related to unmeasured factors, and misclassification or miscoding of baseline comorbidities is possible. Also, there was significant overlap between the meanings of coronary artery disease, lower-extremity artery disease, and PAD. In addition, the researchers were unable to conduct a subgroup analysis by age, comorbidities, or medication.

“Using DOACs in patients undergoing lower-extremity arterial procedures may play a more significant role in the future, but further investigations are needed for definitive results and safe decision-making,” the investigators stated.


Pomozi E, Nagy R, Fehérvári P, et al. Direct oral anticoagulants as the first choice of anticoagulation for patients with peripheral artery disease to prevent adverse vascular events: a systematic review and meta-analysis. J Cardiovasc Dev Dis. Published online February 3, 2023. doi: 10.3390/jcdd10020065