Which ASCVD Patients Will Benefit Most From Rivaroxaban Plus Aspirin? Some Clues

Simple clinical characteristics can be used to pick patients with stable atherosclerotic vascular disease who are likely to have the best balance between ischemic and bleeding risk when treated with low-dose rivaroxaban plus aspirin versus aspirin alone, as in the COMPASS trial, two analyses show.

In an analysis of COMPASS trial data, the net clinical benefit was greatest in patients who had disease in more than one vascular bed, a history of heart failure, renal insufficiency, or diabetes, researchers led by Sonia Anand, MD, PhD (Population Health Research Institute, McMaster University, Hamilton, Canada), report.

Supportive of those findings is an analysis from the international REACH Registry showing that an increasing number of “enrichment criteria”—or high-risk features—used in COMPASS was associated with a marked rise in ischemic risk accompanied by a more modest uptick in bleeding risk. The net clinical benefit of using a combination of low-dose rivaroxaban and aspirin would be expected to be greater in patients with more than one of these characteristics.

The results of both studies, published online ahead of the July 2, 2019, issue of the Journal of the American College of Cardiology, might help guide clinicians who have been uncertain about how to apply the main COMPASS results to their practice when selecting the best patients for the therapy, Anand told TCTMD.

“We could think of these groups as the low-hanging fruit, and it will enable physicians to get started using this therapy because there is this concept of therapeutic inertia where, whenever there’s a new medication or a new finding, it takes physicians time to get used to it in terms of understanding the data as well as getting their own experience using it in patients,” she said.

Commenting for TCTMD, William Hiatt, MD (University of Colorado School of Medicine, Aurora), said he hoped these latest data would have that effect, “because I think one of the problems we face these days is you have new exciting publications like COMPASS and then there’s not a lot of uptake.

“And I think that’s unfortunate because that means patients are going around untreated who might benefit from additional therapy and might in fact benefit a lot more by dual-pathway inhibition than by dual antiplatelet therapy,” he continued. “Changing how people think about that is always hard and these papers give us key risk enhancers that are easily clinically identified and allow you to make a decision to add low-dose rivaroxaban instead of a second antiplatelet drug and maybe even stop clopidogrel and switch to dual-pathway inhibition..”

Clinical Benefit Increases Over Time

The COMPASS trial—which was stopped early due to “overwhelming efficacy”—showed that the combination of rivaroxaban (Xarelto; Bayer/Janssen) 2.5 mg twice daily and aspirin 100 mg once daily significantly reduced major vascular events at the cost of increased major bleeding when compared with aspirin alone in patients with stable CAD, PAD, or both. That dose of rivaroxaban was approved by both US and European regulators on the strength of the results.

But, Anand said, physicians have questioned who among the rather large potentially eligible patient population should receive the combination studied in the trial.

So she and her colleagues took a more detailed look at the trial data to identify subgroups to target. They identified high-risk patients using a modified atherothrombosis risk score derived from the REACH Registry of patients with known vascular disease or a high risk for ischemic vascular events and using classification and regression tree (CART) analysis.

High-risk features identified using the REACH score were having more than one vascular bed affected, a history of heart failure, and renal insufficiency. The CART analysis identified similar features and added diabetes to the list. Overall, the proportion of patients with at least one high-risk feature was 50.2% based on the REACH score and 59.6% based on the CART analysis.

Compared with aspirin monotherapy, the combination of low-dose rivaroxaban and aspirin reduced the risk of a composite endpoint of cardiovascular death, MI, stroke, acute limb ischemia, or vascular amputation through 30 months (4.48% vs 5.95%; HR 0.75; 95% CI 0.66-0.85). That works out to 23 events prevented for every 1,000 treated. There was only a nonsignificant increase in severe bleeding (0.85% vs 0.64%; HR 1.34; 95% CI 0.95-1.88), working out to two events for every 1,000 treated.

Patients with high-risk features had larger event rates and thus greater absolute reductions in ischemic risk. For high-risk patients by REACH and CART criteria, combination therapy prevented 36 and 33 serious vascular events, respectively; increases in severe bleeding were three and one per 1,000 treated.

Lower-risk patients derived a benefit from rivaroxaban plus aspirin, too, with the combination preventing roughly 10 serious vascular events for every 1,000 patients treated at the cost of two to four severe bleeds.

The net clinical benefit of combination therapy increased over time, especially in the high-risk groups.

The study “kind of paves the way to start off getting comfortable prescribing this therapy by starting off with the higher-risk groups,” Anand said, noting that other considerations like a patient’s ability to pay and drug-drug interactions will come into play as well.

More ‘Enrichment Criteria,’ More Risk

The analysis from the REACH Registry, led by Arthur Darmon, MD (Hôpital Bichat, Paris, France), is largely consistent with the findings the study by Anand et al.

The investigators identified 16,875 COMPASS-eligible patients enrolled in the registry using the trial’s inclusion and exclusion criteria and then examined how various enrichment criteria—and the number of them—related to ischemic and bleeding risks. Those criteria (and the proportion of patients with the characteristics) were:

• Age over 65 (81.5%)
• Diabetes (41.0%)
• Chronic kidney disease (40.2%)
• PAD (33.7%)
• Current smoking (13.8%)
• Heart failure (13.3%)
• Ischemic stroke (11.1%)
• Asymptomatic carotid stenosis (8.7%)

The number of high-risk features strongly influenced risks of adverse outcomes at 4 years. The rates of ischemic events (cardiovascular death, MI, or stroke) were 7.0%, 12.5%, 16.6%, and 21.8% for patients with one, two, three, or four or more criteria, respectively. Serious bleeding (hemorrhagic stroke, hospitalization for bleeding, or transfusion) increased more modestly across groups—1.5%, 1.8%, 2.0%, and 3.2%.

“Taken separately, no single enrichment criterion appeared associated with a more favorable trade-off between ischemic and bleeding risks than in the overall COMPASS population,” the authors write. “However, the subgroup with multiple enrichment criteria had a higher absolute increase in ischemic than in bleeding risk, and appears to potentially be a good group for the addition of low-dose rivaroxaban to the standard regimen of aspirin for secondary prevention.”

Looking for More Answers in PAD

Hiatt, who co-authored an accompanying editorial in JACC with Connie Hess, MD, and Marc Bonaca, MD (both University of Colorado School of Medicine), said the contribution of the two studies is in identifying features of patients who might benefit more from low-dose rivaroxaban plus aspirin “and allowing clinicians to more carefully individualize therapy for patients in their practice.”

He said, however, that he would have liked to see more detailed information on the patients with PAD specifically and questioned the decision of Anand et al to mix cardiovascular and limb outcomes in their ischemic endpoint, which muddied the waters a bit. “I think that was the missed opportunity,” Hiatt said, noting that the ongoing VOYAGER PAD trial he’s running should help clarify some of those issues. The trial is testing low-dose rivaroxaban plus aspirin in patients with PAD who are undergoing lower-extremity revascularization.

Still, the findings of these two analyses should have an impact on use of low-dose rivaroxaban plus aspirin clinically, Hiatt indicated. “The uptake has been challenging. I think clinicians look at their stable populations of patients and really puzzle over when to add a low dose of an antithrombotic agent and what is something that would compel you to make that decision. And so I think these results give us more discrimination.”