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Antithrombotic therapy continues to evolve for patients with PAD

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Ian Del Conde

Researchers continue to learn more about how best to treat patients with peripheral artery disease with antithrombotic therapies without increasing their risk for bleeding, according to a presentation at the International Symposium on Endovascular Therapy.

“The sobering fact is that despite these patients being on guideline-mandated therapies, as much as can be expected in the real world, there is a substantial residual cardiac risk,” Ian Del Conde, MD, FACC, director of vascular medicine at Miami Cardiac and Vascular Institute, said during the presentation.

As shown in the REACH registry, the risk for MACE increased in patients with PAD who were on guideline-mandated therapies from 21.1% in year 1 to 40.4% in year 3. This increase was also seen for limb events, with 18.2% of patients requiring any peripheral revascularization and 3.8% requiring amputation at 4 years.

“At the fundamental level, what we’re dealing with is thrombosis, which is really a system that is contributed by two different systems: the platelets and the coagulation proteins that work hand-in-hand to produce a thrombus,” Del Conde said.

Although some may think that antiplatelet and anticoagulation therapies would work well together as an antithrombotic strategy for patients with an increased risk for thrombotic and ischemic complications, available evidence about this combination has shown that it can lead to serious bleeding, including intracranial hemorrhage, as shown in two studies published in 2006 and 2007.

In the WAVE study published in The New England Journal of Medicine in 2006, patients were assigned warfarin with aspirin or aspirin alone. During 35 months of follow-up, there was no benefit for MACE nor limb events. In addition, there was also a threefold increase in the risk for life-threatening bleeding. Similar results were seen in the study published in 2006 in the Journal of Vascular Surgery.

Del Conde said: “It was on this basis that every single guideline recommendation that has been published since those studies has warned clinicians against the combination of anticoagulation therapy plus antiplatelet therapy, giving it a class III indication. In other words, you would be harming patients.”

The field of anticoagulants is changing now that there are several nonvitamin K-dependent oral anticoagulants such as rivaroxaban (Xarelto, Janssen/Bayer) and apixaban (Eliquis, Bristol-Myers Squibb/Pfizer). These new medications have numerous benefits, including rapid onset, fixed dosing, few drug interactions, no food interactions, no need for monitoring and a short half-life, Del Conde said.

In a meta-analysis published in Blood in 2014, researchers found these newer oral anticoagulants result in less bleeding and less intracranial hemorrhage compared with warfarin.

The COMPASS trial, which was published in NEJM in 2017, enrolled patients with stable CAD and/or PAD. The trial was discontinued due to a 24% RR reduction for MACE in patients assigned 2.5 mg rivaroxaban twice per day and 100 mg aspirin compared with patients assigned aspirin alone (HR = 0.76; 95% CI, 0.66-0.86). In addition, patients with PAD who were assigned 2.5 mg rivaroxaban twice per day with aspirin had 28% fewer MACE and 46% fewer major adverse limb events compared with those assigned aspirin alone. There was also a benefit for all-cause mortality in patients assigned the combination therapy (4.1% vs. 3.4%; HR = 0.82; 95% CI, 0.71-0.96).

In the small ePAD study published in the Journal of Endovascular Therapy in 2018, researchers assessed the effects of edoxaban (Savaysa, Daiichi Sankyo) in patients with PAD after they underwent an intervention. Patients assigned edoxaban plus aspirin had similar thrombotic and bleeding outcomes compared with patients assigned clopidogrel plus aspirin. The VOYAGER-PAD trial, which just completed enrollment, will be assessing the safety and efficacy of rivaroxaban in patients with PAD who are undergoing peripheral revascularization procedures.

“The field of antithrombotic therapy in PAD is being reborn,” Del Conde said. – by Darlene Dobkowski

References:

Del Conde I. Saving lives and limbs: The critical role of medical therapies in PAD today and tomorrow. Presented at: the International Symposium on Endovascular Therapy (ISET); Jan. 27-30, 2019; Hollywood, Fla.

Anand S, et al. N Engl J Med. 2007;doi:10.1056/NEJMoa065959.

Chai-Adisaksopha C, et al. Blood. 2014;doi:10.1182/blood-2014-07-590323.

Eikelboom JW, et al. N Engl J Med. 2017;doi:10.1056/NEJMoa1709118.

Fihn SD, et al. Circulation. 2012;doi:10.1161/CIR.0b013e318277d6a0.

Gerhard-Herman MD, et al. Circulation. 2016;doi:10.1161/CIR.0000000000000471.

Koppensteiner R, et al. J Vasc Surg. 2006;doi:10.1016/j.jvs.2006.07.044.

Moll F, et al. J Endovasc Ther. 2018;doi:10.1177/1526602818760488.

Disclosure: Del Conde reports he consults for Bristol-Myers Squibb and Merck and serves on the speakers bureau for Bristol-Myers Squibb, Janssen, Pfizer and Portola.