Antithrombotic Therapy Following Stent Placement in Patients with A-Fib: Should DOACs Be Preferred?

Many patients with atrial fibrillation (AF) received triple antithrombotic therapy after undergoing a percutaneous coronary intervention (PCI) and receiving cardiac stent. Triple therapy consists of warfarin plus dual antiplatelet therapy (DAPT) with a P2Y₁₂ inhibitor and low-dose aspirin. But is triple therapy the best approach? This practice, while widely employed, is not entirely evidence-based. It’s actually the result of combining two evidence-based strategies – one to prevent strokes in patients with AF and the second to prevent stent thrombosis. The ACTIVE W trial demonstrated that oral anticoagulation therapy is superior to DAPT for preventing stroke in patients with AF.¹ But for patients undergoing coronary stenting, aspirin plus ticlopidine reduced the risk of stent thrombosis compared to aspirin alone or aspirin plus warfarin.²  

In the WOEST trial, triple therapy was associated with higher rates of bleeding; however, this study did not aim to assess thromboembolic events or stent rethrombosis.³ The duration of treatment with triple therapy is also controversial and requires balancing the risk for thrombosis with the risk for bleeding. The 2016 AHA/ACC guidelines provide a Class I recommendation suggesting that patients undergoing PCI with a bare metal stent (BMS) or drug eluting stent (DES) for acute or recent acute coronary syndrome (ACS) receive at least 12 months of DAPT.⁴ Moreover, patients with stable ischemic heart disease who recieve a BMS or DES should receive at least 1 and 6 months of DAPT, respectively.⁴

While triple therapy with warfarin is often used in patients with AF undergoing PCI, the effectiveness and safety of the direct oral anticoagulants (DOACs) in this patient population is unknown. In previous trials comparing DOACs to warfarin in patients with nonvalvular AF, rivaroxaban and apixaban had lower rates of clinically significant bleeding compared to warfarin.^5,6  Thus, the PIONEER AF-PCI study set out to assess the safety of two treatment strategies involving rivaroxaban as compared with triple therapy in patients with nonvalvular AF who receive an intracoronary stent.

PIONEER AF-PCI was an open-label, randomized, controlled study that enrolled 2124 patients with nonvalvular AF who had received an intracoronary stent. Patients were randomly assigned to one of three treatment groups:

• Group #1: Rivaroxaban 15 mg daily (or rivaroxaban 10 mg daily if CrCl 30-50 mL/min) plus a P2Y₁₂ inhibitor for 12 months
• Group #2: Rivaroxaban 2.5 mg twice daily with a prespecified duration of DAPT (1, 6, or 12 months)
• Group #3: Dose-adjusted warfarin (INR goal 2-3) with a prespecified duration of DAPT (1, 6, or 12 months)

DAPT consisted of a P2Y₁₂ inhibitor (clopidogrel, ticagrelor, or prasugrel) plus low-dose aspirin for a 1, 6, or 12 month duration based on clinician preference. The results of the primary analysis demonstrated that treatment with rivaroxaban 15 mg daily plus P2Y₁₂ inhibitor or rivaroxaban 2.5 mg twice daily plus DAPT significantly reduced the risk of clinically important bleeding events compared to triple therapy.⁷ While bleeding is a relevant endpoint, the treatment strategies for patients with AF and intracoronary stents must weigh both the risk of bleeding AND the risk for thrombotic events.

In a post-hoc, secondary analysis of the PIONEER AF-PCI, trial investigators aimed to determine the effects of these treatment strategies on all-cause mortality and recurrent hospitalization.⁸ The primary end point of the secondary analysis was the occurrence of all-cause death or first rehospitalization for an adverse event. Rehospitalizations were classified as being attributed to bleeding, cardiovascular causes, or other causes. Cardiovascular causes for hospitalization included, but were not limited to, heart failure, AF, unstable angina, dyspnea, chest pain, myocardial infarction, and ischemic stroke. Bleeding causes for hospitalization included epistaxis, hematuria, anemia, hemorrhagic stroke, and others.

The patients included in this analysis were, on average, 70 years old and primarily Caucasian men with a mean CHA₂DS₂-VASc of 4 and a mean HAS-BLED score of 3. The majority of patients enrolled had a DES placed for NSTEMI, STEMI, and unstable or stable angina.  A majority were on clopidogrel at baseline. Patients were excluded if they had a past medical history significant for stroke or transient ischemic attack. After the patient completed the prespecified duration of DAPT, low-dose aspirin was continued for the remainder of the follow-up period.

The primary composite endpoint was experienced by 34.9% of subjects using the rivaroxaban + P2Y₁₂ strategy, 31.9% of subjects in the low-dose rivaroxaban + DAPT group, and 41.9% of subjects receiving triple therapy. Table 1 shows the results for the primary composite outcome as well as the individual components of the primary outcome.

Table 1. All-cause death and First Recurrent Hospitalization for Three Treatment Strategies

^{CV: Cardiovascular}

^{NNT: Number-needed-to-treat}

^{Statistical significance: p<0.05}

Patients treated with either rivaroxaban strategy had fewer occurrences of all-cause death or first recurrent hospitalization when compared to triple therapy. No difference was observed between the two rivaroxaban treatment strategies. For both rivaroxaban-based strategies, the numbers-needed-to-treat (NNT) were low at 15 and 10 for the two approaches.

Although low-dose rivaroxaban + DAPT treatment strategy resulted in the fewest events, the focus of this commentary will be on the results comparing rivaroxaban 15 mg daily plus P2Y₁₂ inhibitor versus triple therapy due to the fact that rivaroxaban 2.5 mg tablets are not available in the United States. For this comparison, the primary composite outcome was driven by first recurrent hospitalization. While no mortality benefit was seen when comparing these two treatment strategies, are these results clinically important?

To answer this question, let’s examine some aspects of the study that impact clinical applicability. First, the investigators chose a treatment strategy that is not currently recommended for AF in the United States. Typically, patients with AF are treated with rivaroxaban 20 mg daily with a dose reduction to 15 mg daily if a patient’s creatinine clearance is 15-50 mL/min. Instead this trial started with rivaroxaban 15 mg daily with a dose reduction to 10 mg daily for a creatinine clearance of 30-50 mL/min. This dose reduction, while not common practice, was likely selected to decrease the risk of bleeding. It does not appear that reducing the dose increased hospitalizations for cardiovascular causes. Currently, rivaroxaban 10 mg tablets are available in the United States and are currently recommended for postoperative deep vein thrombosis (DVT) prophylaxis after hip or knee replacement.

Second, while clinician-determined duration of DAPT may pose some limitations, it allows a comparison of a real-life approach (triple therapy requiring clinician discretion for duration of DAPT) to a new, less complex approach (rivaroxaban plus P2Y₁₂ inhibitor for 12 months).  There was a statistically significant difference seen in HAS-BLED scores for patients receiving 1, 6, or 12 month DAPT in the triple therapy arm (p=0.031) with 76%, 70.9% and 66% of subjects at high-risk for bleeding (HAS-BLED score of 3 or higher), respectively. This difference in HAS-BLED scores mimics real world decision-making, weighing risks of bleeding and thrombosis. Additionally, the time in therapeutic range (TTR) achieved in the patients in the triple therapy arm was 65%, which is comparable to the real world management of patients on warfarin.

Although this is a post hoc analysis, these results draw into question the acceptability of triple therapy.  Triple therapy resulted in more hospitalizations for bleeding and cardiovascular causes when compared to rivaroxaban 15 mg daily plus a P2Y₁₂ inhibitor. While some differences exist between the trial intervention and current recommendations, the differences seen in recurrent hospitalizations are significant.  Although mortality rates were not different between the treatment groups, it is important to consider the economic implications that even a modest reduction in hospitalizations has on healthcare expenditure.

Based on the results of this analysis, a rivaroxaban-based strategy appears to be a reasonable option to consider in patients with AF undergoing PCI. Of course, it is important to consider the clinical status of the patient and to weigh the risks and benefits of each treatment option. What do you think? Are you convinced? Should rivaroxaban 15 mg daily with a P2Y₁₂ inhibitor for 12 months after PCI in patients with AF replace triple therapy? How would you manage patients after 12 months of therapy with rivaroxaban plus clopidogrel?