Reducing CV Risk With Dual Antiplatelet/Anticoagulation Therapy

Implications for treating patients at risk of cardiovascular disease with rivaroxaban plus aspirin based on the COMPASS and VOYAGER PAD clinical trials.

Manesh R. Patel, MD: One of the most telling trials recently is the COMPASS trial, which studied patients with stable CAD [coronary artery disease] and PAD [peripheral artery disease]. It took 24,000 patients who had coronary artery disease from roughly 558 centers, and it randomized them into 1 of 3 regimens. One was just aspirin therapy, another was 5 mg of rivaroxaban twice daily, and the third was 2.5 mg of rivaroxaban plus low-dose aspirin. That trial stopped early, showing that there was a significant reduction in MACE [major adverse cardiovascular events] for those patients—a relative risk reduction of about 25% to 26% for a hazard ratio of 0.76 in patients who got the 2.5 mg twice daily of rivaroxaban plus aspirin. Significantly, that showed not only a reduction in some myocardial infarction [MI] and significant reduction in CV [cardiovascular] death but also a reduction in stroke, which was fairly telling. What that did was open our eyes. I started talking about platelets leading to clots in that vessel, but there’s also that other pathway of antithrombotic therapy, the clotting that happens through the thrombin pathway.” This dose is potentially the most studied dose of rivaroxaban because it was studied in ATLAS and now COMPASS. The 2.5 mg twice-daily dose of rivaroxaban, when coupled with low-dose aspirin, seems to reduce the cardiovascular events the most; there’s no free lunch.

People often ask, how did that do compared with bleeding. Just to highlight again, it was roughly a 4% rate in the population for those who got 2.5 mg of rivaroxaban twice daily plus aspirin, and the 2.5 mg twice daily plus aspirin once daily. Comparing that with aspirin alone once daily, the event rate was 4% vs 6% in the CAD population. If I look at the CAD population from Stuart Connolly’s publication in The Lancet, there’s a 2% absolute-risk reduction, or a hazard ratio of 0.74. I have to treat about 50 patients broadly who have coronary disease, in some of these elevated-risk factors, chronically with this therapy to prevent 1 of these MACE events. That’s a pretty powerful therapy in those patients.

How do we reduce the risk of our patients with a high risk for cardiovascular events who have diabetes. The COMPASS trial, as I highlighted, showed some really interesting findings. I took home the COMPASS trial by saying, “The more your burden of vascular disease, the more benefit you got.” If you have coronary artery disease—CAD and PAD, 2 vascular beds—you got a bigger benefit. If you had coronary disease, lower-extremity disease, and carotid disease counted in the PAD group, it seemed like you got more of a benefit. 

Who else benefits? They said CAD plus kidney disease. Kidney disease is another vascular bed to me. We just happen to figure it out with the creatinine. The other high-risk group were people who had diabetes and coronary disease. I think about diabetes as multivessel disease because it affects everything, so diabetes can also be considered as a polyvascular component. For people with diabetes, which affects all vessels and coronary disease, it’s just another vascular bed. When I put those populations together, those findings have shown us that the patients with diabetes, just like the polyvascular patients, had a significant reduction with aspirin and 2.5 mg twice daily of rivaroxaban compared with aspirin. It had a hazard ratio of 0.74, almost a 2% absolute-risk reduction and a significant reduction in MACEs, although small numbers, and also in limb events. There were some small numbers, but they were at least 50% less than the rivaroxaban-treated group.

Marc P. Bonaca, MD, MPH: The VOYAGER PAD trial looked at the combination of low-dose aspirin and a low-dose anticoagulant, rivaroxaban 2.5 mg twice daily, in a very specific population. This was a PAD population undergoing revascularization for either clot occasion or critical limb ischemia, and it looked at the reduction or the benefit in terms of both major adverse limb events and cardiovascular events, what I like to call irreversible harm events of the heart, limb, or brain. What we learned from VOYAGER PAD was that that combination, which had been shown to be efficacious in chronic coronary and peripheral artery disease in the COMPASS trial and even in patients with acute coronary syndrome in the ATLAS trial, was that it was again efficacious for this broader outcome in patients with peripheral artery disease with efficacy apparent both early and long term—even 3 years after the intervention.

An additional thing we learned from VOYAGER PAD has to do with the safety of combining the strategy with antiplatelet therapy. Patients who get stenting in the coronary or periphery—here we’re talking about PAD—often will get a short course of dual-antiplatelet therapy [DAPT] for stent protection. That’s not really data driven in PAD, but it’s often done. What we learned was that adding rivaroxaban—starting at the time of revascularization shortly after with DAPT and then just stopping DAPT when you no longer needed it but continuing rivaroxaban long term—was safe. Overall, there was no interaction for bleeding on the basis of clopidogrel, and the benefit of the low-dose anticoagulant was very clear on top of clopidogrel. The way I take that is that DAPT is not enough to prevent acute limb ischemia. It’s not enough to prevent MIs and strokes in this population. The benefit of rivaroxaban in relative and absolute terms was consistent whether you choose to use it, and it was safe to follow that strategy and initiate the rivaroxaban right away. We did see a trend for less bleeding in those who had shorter durations of DAPT, a month or less rather than longer durations, but obviously that’s something you need to individualize for each patient.

Transcript Edited for Clarity

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