By Jeffrey Zimmet, MD, PhD

Associate Professor of Medicine, University of California, San Francisco; Director, Cardiac Catheterization Laboratory, San Francisco VA Medical Center

Dr. Zimmet reports no financial relationships relevant to this field of study.

SYNOPSIS: The PIONEER study of atrial fibrillation patients post-percutaneous coronary intervention showed that regimens of clopidogrel plus reduced-dose regimens of rivaroxaban demonstrated lower bleeding and similar rates of stroke and adverse cardiac events compared with traditional warfarin triple therapy.

SOURCES: Gibson CM, Mehran R, Bode C, et al. Prevention of bleeding in patients with atrial fibrillation undergoing PCI. N Engl J Med 2016;375:2423-2434.

Jolly SS, Natarajan MK. Atrial fibrillation and PCI — Do we still need aspirin? N Engl J Med 2016;375:2490-2492.

Patients requiring long-term antithrombotic therapy have long presented a safety problem post-percutaneous coronary intervention (PCI). The guideline-directed addition of dual antiplatelet therapy (DAPT) to anticoagulation with either warfarin or one of the new oral anticoagulant (NOAC) drugs carries a significant hazard of serious bleeding that can be several times that posed by the anticoagulant alone. Until recently, strategies to reduce bleeding in this population have received limited attention in clinical trials. In addition, there has been virtually no trial information regarding the safety of NOAC use in the post-PCI setting. The PIONEER AF-PCI trial is the first in a much-anticipated series of trials to tackle this problem.

The trial investigators enrolled 2,124 patients presenting with nonvalvular atrial fibrillation who underwent PCI with stent placement. Patients were randomized 1:1:1 to one of three treatment regimens. In each case, the investigators pre-specified the intended duration of DAPT (one, six, or 12 months) depending on clinical scenario, and patients were distributed evenly among the three groups, depending on DAPT duration. Patients in group one received rivaroxaban at a dose of 15 mg daily, along with a single standard-dose P2Y12 inhibitor (of which clopidogrel represented the majority). Aspirin was withheld in all group one patients after randomization. Patients in group two received DAPT in addition to rivaroxaban at a dose of 2.5 mg twice daily, which corresponds to the regimen used in the low-dose arm of the ATLAS2 TIMI 51 trial. Group three patients received full-dose warfarin (international normalized ratio goal, 2-3) in addition to standard DAPT. Both rivaroxaban groups used reduced dosing compared with the approved dose for nonvalvular atrial fibrillation. The standard dosing for such patients with preserved renal function is 20 mg once daily. The primary safety endpoint was the occurrence of clinically significant bleeding during the trial medication period. Major adverse cardiac events (MACE), including cardiac death, myocardial infarction, stroke, and stent thrombosis, were included as secondary endpoints.

The rates of clinically significant bleeding were lower in the two rivaroxaban arms compared with the warfarin group. At 12 months, bleeding rates were 16.8% in group one, 18.0% in group two, and 26.7% in group three (hazard ratio [HR] for group one vs. group three, 0.59; 95% confidence interval [CI], 0.47-0.76; P < 0.001; HR for group 2 vs. group 3, 0.63; 95% CI, 0.50-0.80; P < 0.001). The majority of these events met criteria for neither TIMI major nor TIMI minor bleeding, but fell under the category of bleeding requiring medical attention. Although early discontinuation rates were > 20% in each group, results were not significantly different in the modified intention-to-treat analysis. MACE rates were low and were not significantly different among the three groups: 6.5% in group one, 5.6% in group two, and 6.0% in group three. Stent thrombosis was rare, occurring in five patients (0.7%) in group one, six patients (0.9%) in group two, and four patients (0.6%) in group three. The authors concluded that in patients with atrial fibrillation post-PCI with stent placement, the studied regimens, including low-dose or very low-dose rivaroxaban, conferred a significantly lower risk of clinically important bleeding compared to standard triple therapy with full-dose warfarin. Although the efficacy endpoints of MACE and stent thrombosis were similar among groups, the authors cautioned that statistical power was insufficient to evaluate these events.

COMMENTARY

Kudos to the study team for contributing significantly to the knowledge base in this area, and for performing the first randomized study of a NOAC agent in atrial fibrillation patients post-PCI. The studied rivaroxaban regimens, as compared with triple therapy, reduced bleeding without an apparent increase in stroke or myocardial infarction. Warfarin always was slated to lose this contest, and as a matter of trial design was set up to fail. Only warfarin was used at full dose, and on a background of full DAPT. On the other hand, rivaroxaban was used either in a reduced 15 mg dose with aspirin omitted, or at a very low dose on a background of DAPT. There was no WOEST trial-like strategy of omitting aspirin in a warfarin arm. It should come as no surprise that reducing the anticoagulant dose and omitting aspirin from the regimens would reduce bleeding. In this trial, that was powered only for bleeding; therefore, it should come as no surprise that the watered-down rivaroxaban regimens came out on top. The lack of a WOEST-like arm was a significant shortcoming. Notably, WOEST also showed a reduction in MACE and all-cause mortality with warfarin, which was not demonstrated in this trial with rivaroxaban, although WOEST was a smaller trial.

The very low-dose rivaroxaban group was administered on a background of DAPT. It is unclear if the addition of this dose of rivaroxaban produces additional efficacy over DAPT alone for prevention of stroke in atrial fibrillation. As was demonstrated in the ATLAS2 trial, however, it certainly increases bleeding. In this vein, we should note that approximately 10% of the patients were classified as exhibiting CHA2DS2-VASc scores of 0 or 1, and typically would not be treated with anticoagulant therapy. The clustering of patients in the lower stroke risk categories again skews the results in favor of lower-intensity and, therefore, lower bleeding risk regimens, with little chance that a stroke difference will be detected. The authors emphasized that the study was underpowered for efficacy (detection of stroke and cardiac events) endpoints. The authors estimated that a sample size of more than 13,500 patients per group — nearly 41,000 patients total — would be required to reach 90% power to detect a 15% difference between treatment groups in terms of MACE.

Despite these flaws, this trial demonstrates that in average PCI patients, rivaroxaban and clopidogrel without aspirin exhibits an acceptable baseline level of safety. An accompanying editorial asked pointedly whether aspirin is still necessary for atrial fibrillation patients post-PCI. I agree with their assertion that cardiologists should individualize therapy on the basis of each patient’s balance of risk for bleeding and stent thrombosis. At least three other NOAC studies are in the works for this population. Of these, the most eagerly anticipated is the AUGUSTUS trial, which is the largest study in this group and pits apixaban against warfarin in a 2x2 design in combination with either aspirin or placebo. Until then, PIONEER has added to the array of options for patients in this challenging group.