Rivaroxaban-Based Double or Triple Therapy Cuts Bleeding in Patients With A-fib Undergoing PCI: PIONEER AF-PCI

NEW ORLEANS, LA—Using lower-dose rivaroxaban with a single P2Y12 inhibitor or with standard dual antiplatelet therapy (DAPT) lowers rates of clinically significant bleeding compared with conventional triple therapy involving warfarin plus DAPT in patients with A-fib undergoing PCI, results of the PIONEER AF-PCI trial show.

Just 11 or 12 patients would need to be treated with one of the regimens based on rivaroxaban (Xarelto; Bayer/Janssen Pharmaceuticals) instead of the warfarin-based strategy to prevent one bleeding event, C. Michael Gibson, MD (Beth Israel Deaconess Medical Center, Boston, MA), reported here at the American Heart Association (AHA) Scientific Sessions 2016.

There were no differences across study arms in rates of the composite of cardiovascular death, MI, or stroke, he said, although event rates were low and the trial was not powered for efficacy. Post hoc analysis, however, suggested that the rivaroxaban-based approaches reduced all-cause hospitalizations and hospitalizations resulting from either cardiovascular events or bleeding, with numbers needed to treat of 10 to 25.

The results, which were published simultaneously online in the New England Journal of Medicine (main results) and Circulation (hospitalization results), should change practice, Gibson told TCTMD. He noted that full-dose triple therapy with warfarin, a P2Y12 inhibitor, and aspirin is routinely used in this patient population.

The trial indicates that if warfarin is used as one of the options in antithrombotic therapy after PCI in patients with A-fib, there will be excess bleeding, Gibson said. “So I think it kind of takes that option off the table.”

Discussing the study at a press conference, Philippe Gabriel Steg, MD (Hôpital Bichat, Paris, France), said, “This is an important and robust contribution to the evidence base in this area, which is actually very limited, and given that we have nothing, having this piece of evidence may very well change practice.”

Although he raised some issues that should be considered when interpreting the results of the trial, he noted that the non-vitamin K antagonist oral anticoagulants (NOACs) have some advantages over warfarin in that they are more convenient to use and safer. Thus, now that there is a study showing that a NOAC reduces bleeding without an obvious excess in stroke and MACE in patients with A-fib undergoing PCI, “I’m sure it’s going to impact practice,” Steg said.

Clarifying Post-PCI Therapy in Patients With A-fib

Gibson noted that about 5% to 10% of patients coming into the cath lab have both A-fib and a requirement for stenting, indicating a need for both oral anticoagulation and DAPT. The tendency, he said, has been to combine both strategies, but that results in excess bleeding.

Prior studies—including ATLAS ACS 2-TIMI 51—have provided evidence that lower anticoagulant doses may remain effective while mitigating bleeding risks. Another option would be to remove aspirin from the regimen and treat only with an anticoagulant and a P2Y12 inhibitor. That approach was studied in WOEST, which showed that warfarin plus clopidogrel reduced bleeding and improved efficacy versus triple therapy.

But Gibson highlighted the uncertainty about the optimal approach to treating patients who require both oral anticoagulation and antiplatelet therapy, noting that numerous options are available.

PIONEER AF-PCI was designed to provide some clarity about some of the treatment possibilities. The trial, conducted at 426 sites in 26 countries, enrolled 2,124 patients with nonvalvular A-fib who required stent implantation. Before randomization, treating physicians decided on a duration of DAPT—1, 6, or 12 months. Patients were then randomized to one of three arms:

• Rivaroxaban 15 mg (or 10 mg for those with moderate renal impairment) once-daily plus P2Y12 inhibitor once-daily for 1 year
• Rivaroxaban 2.5 mg twice-daily, P2Y12 inhibitor, and aspirin 75 to 100 mg/day (after DAPT discontinuation, patients continued on rivaroxaban 15 mg once-daily plus aspirin)
• Warfarin (target INR 2.0 to 3.0), P2Y12 inhibitor, and aspirin 75 to 100 mg/day (after DAPT discontinuation, patients continued on warfarin plus aspirin)

DAPT duration was 1 month in 16%, 6 months in 35%, and 12 months in 49%. Clopidogrel was the P2Y12 inhibitor used in 95% of patients, with ticagrelor (Brilinta; AstraZeneca) and prasugrel (Effient; Eli Lilly) used in the rest. The time in therapeutic range for warfarin-treated patients was 65%.

The primary endpoint was clinically significant bleeding, defined as TIMI major and TIMI minor bleeding or bleeding requiring medical attention. The rate was 26.7% in the warfarin arm, with lower rates observed with rivaroxaban-based double therapy (16.8%; HR 0.59; 95% CI 0.47-0.76) and triple therapy (18.0%; HR 0.63; 95% CI 0.50-0.80). The findings were consistent across subgroups.

Reductions were also seen in other types of bleeding, including GUSTO severe, ISTH major, and BARC definite fatal.

In terms of efficacy outcomes, cardiovascular death, MI, or stroke occurred in 6.0% of warfarin-treated patients, 6.5% of those receiving rivaroxaban-based double therapy, and 5.6% of those receiving rivaroxaban-based triple therapy. The between-group differences in that composite and the individual components were not significant.

In the post hoc analysis of hospitalizations, the rate of all-cause death or all-cause hospitalization for adverse events was 41.9% in the warfarin arm, with lower rates seen with rivaroxaban-based double therapy (34.9%; HR 0.79; 95% CI 0.66-0.94) and triple therapy (31.9%; HR 0.75; 95% CI 0.62-0.90).

What About the WOEST Strategy?

Gibson anticipated comparisons between PIONEER AF-PCI and WOEST, and he pointed out some important differences between the trials. First, only 69% of WOEST participants had A-fib, whereas all of the patients in PIONEER AF-PCI had the arrhythmia. In the former trial, the plan was to use triple therapy for 1 year, and about two-thirds of patients reached that goal. In the current trial, only 22.7% of patients were on triple therapy for 1 year.

Although the WOEST strategy of warfarin plus clopidogrel was not one of the approaches studied in PIONEER AF-PCI, Gibson pointed out that by about 6 months, many of the patients in the warfarin arm were on double therapy after discontinuing P2Y12 inhibitor therapy.

In his comments, Steg highlighted the lack of a WOEST-like arm as one of the issues to consider when interpreting the new results, noting that both trials showed reductions in bleeding with the tested approach, but that only WOEST showed a reduction in MACE and all-cause mortality, as well. “This begs the question of which is the best strategy,” Steg said.

Additionally, Steg said the findings of PIONEER AF-PCI should be interpreted in the context of other factors, including the fact that reduced doses of rivaroxaban, but not warfarin, were used and that there was no formal testing of the noninferiority of the rivaroxaban-based regimens compared with warfarin-based triple therapy. He noted that the upper end of the confidence intervals surrounding the point estimates of the hazard ratios suggest the possibility of a three-fold increase in the risk of cardiovascular death, MI, or stroke with the rivaroxaban-based approaches.

The low events rates in all three arms, however, were reassuring, Steg continued. “But I think formally we haven’t fully established noninferiority or clinical equivalence of these strategies.”

One final point, Steg said, is that even though the data on hospitalizations are intriguing, “we have to remember that they come from a post hoc analysis and therefore must be viewed as hypothesis-generating.”

For Gibson, though, the hospitalization information is important. “Hospital admissions are costly, and I think that this will also be a finding that will accelerate adoption of the [rivaroxaban-based] strategies,” he said, calling the low numbers needed to treat “kind of unheard of.”

Note: Study co-author Roxana Mehran, MD, is a faculty member of the Cardiovascular Research Foundation, the publisher of TCTMD.