Role of DOAC in PAD


Connie N. Hess, M.D., M.H.S.
University of Colorado School of Medicine
Aurora, Colorado, U.S.

Peripheral artery disease (PAD) commonly refers to atherosclerosis of the lower extremities and is associated with atherosclerotic disease in other vascular territories.  Patients with PAD are at heightened risk for major adverse cardiovascular events (MACEs), such as myocardial infarction, stroke, and cardiovascular death, as well as major adverse limb events (MALEs), including major amputation and acute limb ischemia (ALI).  Compared with patients without a history of peripheral revascularization, those who have undergone prior revascularization are at particularly high risk for ALI.  The risk for MALE is greatest immediately after a peripheral revascularization, whereas the risk for MACE increases steadily post-procedure. 

Given that many of these ischemic events are atherothrombotic in nature, different antithrombotic strategies to prevent these events have been investigated.  Recent data have demonstrated that in patients with chronic, stable PAD, the addition of a P2Y12 inhibitor to aspirin reduces MALE, and adding vorapaxar on top of P2Y12 inhibition and aspirin provides additional incremental benefit.  In PAD patients undergoing peripheral revascularization, the data are sparse, and until recently, there has been no proven therapy to reduce cardiovascular or limb ischemic risk in this setting. 

The strategy of dual pathway inhibition involving inhibition of thrombin generation with a low-dose factor Xa inhibitor and inhibition of platelet activation with low-dose aspirin has been studied in two large cardiovascular outcome trials.  In Cardiovascular Outcomes for People Using Anticoagulation Strategies (COMPASS), the regimen of rivaroxaban 2.5 mg twice daily plus low-dose aspirin versus aspirin alone reduced MACE and MALE in patients with stable atherosclerotic vascular disease, including a ~4,000-patient PAD subgroup.  The Vascular Outcomes Study of ASA (acetylsalicylic acid) Along with Rivaroxaban in Endovascular or Surgical Limb Revascularization for PAD (VOYAGER PAD) trial randomized over 6,500 patients with PAD undergoing lower extremity revascularization to rivaroxaban 2.5 mg twice daily plus aspirin versus aspirin alone.  In VOYAGER PAD, this combination therapy significantly reduced a composite primary endpoint including MACE and MALE, as well as ALI alone.  Although both COMPASS and VOYAGER PAD demonstrated increased bleeding with rivaroxaban plus aspirin versus aspirin alone, there was no increase in intracranial hemorrhage or fatal bleeding, and in both trials, the net clinical benefit favored use of this strategy.

Currently available data support the use of rivaroxaban plus aspirin for the prevention of ischemic events in PAD patients undergoing peripheral revascularization and in patients being treated for secondary prevention who are at low risk for bleeding but at high risk for MACE or MALE.  In cases of secondary prevention where there is an indication for dual antiplatelet therapy, this should be continued.  The data are not as robust for patients at low bleeding risk and low risk for MACE or MALE; treatment of this group of patients, as well as those at high bleeding risk, with monotherapy aspirin or clopidogrel is thus reasonable.




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