Randomized Trial Finds Rivaroxaban a Safer Option Than Warfarin for Patients With Atrial Fibrillation Undergoing PCI

The “triple-therapy” anticoagulation regimen (consisting of a vitamin K antagonist [VKA] plus dual antiplatelet therapy [DAPT] with a P2Y12 inhibitor and aspirin) has been shown to reduce thrombotic and stroke risk in patients with atrial fibrillation (AF) undergoing percutaneous intervention (PCI) with stent placement. However, this regimen does increase bleeding risk.

According to results from the PIONEER AF-PCI trial published in the New England Journal of Medicine, the oral factor Xa inhibitor rivaroxaban, when added to a P2Y12 inhibitor or DAPT, leads to similar efficacy, but a lower risk of bleeding, compared with standard VKA-based triple therapy.

C. Michael Gibson, MD, of the Department of Medicine at Beth Israel Deaconess Medical Center and Harvard Medical School, in Boston, Massachusetts, and authors enrolled 2,124 adult patients between May 2013 and July 2015 to this international, multicenter, randomized, controlled, open-label trial.

Patients with paroxysmal, persistent, or permanent nonvalvular AF (defined as AF not considered to be caused by a primary valve stenosis) who had undergone PCI with stent placement were eligible for inclusion. Patients were excluded if they had any condition known to increase the risk of bleeding (including a history of stroke or transient ischemic attack or anemia of an unknown cause with a hemoglobin concentration <10 g/dL).

Patients were randomized 1:1:1 to the following three groups:

  • group 1: low-dose rivaroxaban (15 mg once daily) plus a P2Y12 inhibitor for 12 months (n=709; mean age = 70.4 years)
  • group 2: very–low-dose rivaroxaban (2.5 mg twice daily) plus DAPT for 1, 6, or 12 months (n=709; mean age = 70.0 years)
  • group 3: standard therapy with a dose-adjusted VKA (once daily) plus DAPT for 1, 6, or 12 months (n=706; mean age = 69.9 years)

Randomization occurred within 72 hours after stent sheath removal, once the international normalized ratio was ≤2.5. Investigators selected the duration of DAPT (1, 6, or 12 months) and intended P2Y12 inhibitor (clopidogrel, prasugrel, or ticagrelor) for each patient.

At 12 months of follow-up, Dr. Gibson and authors found that “treatment that included either low-dose or very–low-dose rivaroxaban was associated with a lower risk of clinically significant bleeding – the study’s primary endpoint – compared with standard triple therapy that included a [VKA].”

Clinically significant bleeding (defined as a composite of major bleeding or minor bleeding per Thrombolysis in Myocardial Infarction criteria or bleeding requiring medical attention) occurred in 16.8 percent of patients in group 1, 18 percent in group 2, and 26.7 percent in group 3.

Hazard ratios for clinically significant bleeding between the rivaroxaban-based regimens and the VKA-based regimens were:

  • 0.59 for group 1 vs. group 3 (95% CI 0.47-0.76; p<0.001)
  • 0.63 for group 2 vs. group 3 (95% CI 0.50-0.80; p<0.001)
  • 0.61 for groups 1 and 2 vs. group 3 (95% CI 0.50-0.75; p<0.001; TABLE 1)

“The lower rate of bleeding in the two groups receiving rivaroxaban compared with the group receiving the VKA was consistent across multiple subgroups,” the authors noted, which examined factors such as the type of stent used, type of P2Y12 inhibitor used, and patients’ HAS-BLED score (a bleeding risk assessment tool).

Rates of death related to cardiovascular events (secondary endpoint; defined as a composite of death from cardiovascular cases, myocardial infarction, or stroke) also were similar among the three groups (6.5%, 5.6%, and 6% for groups 1, 2, and 3, respectively, TABLE 2).

“The three groups had similar efficacy rates, although the observed broad confidence intervals diminish the surety of any conclusions regarding efficacy,” the authors noted, adding that this study was not powered to establish either superiority or noninferiority of the rivaroxaban-based regimen.

Other potential limitations of the study include investigator’s choice of DAPT duration (rather than random assignment) and an imbalance in patient characteristics across these groups.


Reference

Gibson CM, Mehran R, Bode C, et al. Prevention of bleeding in patients with atrial fibrillation undergoing PCI. N Engl J Med. 2016;375:2423-34.

TABLE 1. Safety Outcomes Associated With Each Treatment Cohort (Primary Endpoint)
  Group 1 Group 2 Groups 1 and 2 Group 3 Group 1 vs. Group 3 Group 2 vs. Group 3 Groups 1 and 2 vs. Group 3
HR p value HR p value HR p value
All patients* 696 706 1,402 697
Clinically significant bleeding 109

(16.8%)

117

(18%)

226

(17.4%)

167

(26.7%)

0.59

(95% CI 0.47-0.76)

<0.001 0.63

(95% CI 0.50-0.80)

<0.001 0.61

(95% CI 0.50-0.75)

<0.001
   Major
bleeding
14

(2.1%)

12

(1.9%)

26

(2%)

20

(3.3%)

0.66

(95% CI 0.33-1.31)

0.23 0.57

(95% CI 0.28-1.16)

0.11 0.61

(95% CI 0.34-1.09)

0.09
   Minor
bleeding
7

(1.1%)

7

(1.1%)

14

(1.1%)

13

(2.2%)

0.51

(95% CI 0.20-1.28)

0.14 0.50

(95% CI 0.20-1.26)

0.13 0.51

(95% CI 0.24-1.08)

0.07
  Bleeding
that
requires
medical
attention
93

(14.6%)

102

(15.8%)

195

(15.2%)

139

(22.6)

0.61

(95% CI 0.47-0.80)

<0.001 0.67

(95% CI 0.52-0.86)

0.002 0.64

(95% CI 0.51-0.80)

<0.001
*Data are for all participants who underwent randomization and received at least one dose of the trial regimen during the treatment period.

HR = hazard ratio

TABLE 2. Efficacy Outcomes Associated With Each Treatment Cohort (Secondary Endpoint)
Group 1 Group 2 Group 3 Group 1 vs. Group 3 Group 2 vs. Group 3
HR p value HR p value
All patients 694 704 695
Major adverse cardiovascular event 41

(6.5%)

36

(5.6%)

36

(6%)

1.08

(95% CI 0.69-1.68)

0.75 0.93

(95% CI 0.59-1.48)

0.76
   Death from
cardiovascular
causes
15

(2.4%)

14

(2.2%)

11

(1.9%)

1.29

(95% CI 0.59-2.80)

0.52 1.19

(95% CI 0.54-2.62)

0.66
   Myocardial
infarction
19

(3%)

17

(2.7%)

21

(3.5%)

0.86

(95% CI 0.46-1.59)

0.62 0.75

(95% CI 0.40-1.42)

0.37
   Stroke 8

(1.3%)

10

(1.5%)

7

(1.2%)

1.07

(95% CI 0.39-2.96)

0.89 1.36

(95% CI 0.52-3.58)

0.53
Stent thrombosis 5

(0.8%)

6

(0.9%)

4

(0.7%)

1.20

(95% CI 0.32-4.45)

0.79 1.44

(95% CI 0.40-5.09)

0.57
Major adverse cardiovascular event or stent thrombosis 41

(6.5%)

36

(5.6%)

36

(6%)

1.08

(95% CI 0.69-1.68)

0.75 0.93

(95% CI 0.59-1.48)

0.76
HR = hazard ratio

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