Anticoagulation in Patients with Atrial Fibrillation and Coronary Artery Disease.

The management of antithrombotic therapy in patients with atrial fibrillation undergoing percutaneous coronary intervention for coronary artery disease remains a challenge in clinical practice. This group of patients has indications for both oral anticoagulation and antiplatelet therapy. Such combination will require careful considerations of both thromboembolic and bleeding risks. There have been several big trials looking at the rationale of treating those patients with an oral anticoagulant in combination with one (dual-therapy strategy) or two antiplatelet agents (triple-therapy strategy). Copyright:

INTRODUCTION

Atrial fibrillation (AF) is the most common heart arrhythmia worldwide. It is a rapidly growing problem with prevalence that increases with age and is expected to double by 2030.[1] It is estimated to occur in around 2% for population <65 years of age, and it jumps to 9% in patients >65 years of age.

AF increases stroke risk by 5 folds and responsible for at least one-third of all strokes.[2] AF-related strokes are usually more severe, with poorer long-term outcomes and higher recurrence rates compared to other etiologies.[3]

The incidence of AF in acute coronary syndrome (ACS) patients is ranging from 10% to 15%.[4] In this setting, AF is found to be a marker for increased long-term mortality postinfarct. Over the past 20 years, the relative mortality risk for patients with AF post-myocardial infarction (MI) has remained around 2.5 times higher than patients without AF.

It is estimated that 5%–10% of patients with AF will undergo percutaneous coronary intervention (PCI).[4] The choice of antithrombotic therapy in this population is tricky because there are indications for both oral anticoagulation and dual antiplatelet therapy (DAPT). Triple therapy incorporating an oral anticoagulant (OAC), aspirin, and a P2Y12 inhibitor has been commonly used, but concerns about bleeding have led to the search for a better option.

Up until recently, most guidelines recommended using triple therapy, but that approach has been associated with increased bleeding. Now, data are available from several big trials that studied the rationale of dual-therapy strategy (OAC + one antiplatelet) versus triple-therapy strategy (OAC + two antiplatelets).

This review article summarizes the current data about this topic. It also includes the recommendations and rationales for choosing the antithrombotic regimen for patients who have indications for OAC and antiplatelets after ACS or PCI. Of note, in AF patients with coronary artery disease and no prior stenting, long-term treatment with an OAC without antiplatelet therapy is recommended.

QUESTIONS THAT NEED TO BE ADDRESSED IN DECISION-MAKING PROCESS

It is very important to answer three questions in patients with an indication for combined anticoagulant and antiplatelet therapy:

What combination of antiplatelet and anticoagulant agents should be recommended?

How long should the P2Y12 receptor blocker agent be continued and does aspirin need to be used, and for how long?

Even though there is plenty of data now available to address those questions, the tailored treatment approach is important, and the clinicians must be able to evaluate the merit of each treatment strategy.

CURRENT DATA (MOVING TOWARDS NON-VITAMIN-K ORAL ANTICOAGULANTS AND DUAL THERAPY)

Up until 4 years ago, we had no randomized trial data about the use of non-Vitamin-K oral anticoagulants (NOACs) and antiplatelet agents around the time of coronary stenting. The use of triple therapy (using warfarin + DAPT) was the recommended initial therapy for some time in most stented patients taking long-term anticoagulation. However, with growing evidence and the publications of AUGUSTUS trial in 2019, aspirin use after PCI in patients who receive anticoagulant therapy is declining.

NEW TRIALS IN ANTICOAGULATION

The WOEST trial (An Open-Label, Randomized, Controlled, Multicenter trial from November 2008 to November 2011; n = 573) compared clopidogrel and warfarin (dual therapy) with acetylsalicylic acid (ASA) and clopidogrel with warfarin (triple therapy) in patients who need anticoagulation following PCI.

In the triple-therapy group, patients received aspirin 80 mg daily and clopidogrel 75 mg daily for at least 1 month after bare-metal stenting (BMS) and at least 1 year after drug-eluting stenting (DES). In the OAC and clopidogrel group, patients received clopidogrel 75 mg daily for at least 1 month after BMS (up to 1 year for patients with ACS) and for at least 1 year after DES. The indication for anticoagulant was AF in 69% of patients. After a median follow-up of 358 days, the combined secondary endpoints of death, MI, stroke, target vessel revascularization, and stent thrombosis were lower with clopidogrel and OAC (dual therapy; 11.1 vs. 17.6% for triple therapy; adjusted hazard ratio [HR] 0.56, 95% confidence interval [CI] 0.35–0.91), as was the secondary endpoint of all-cause death (2.5 vs. 6.3%; adjusted HR 0.39, 95% CI 0.16–0.93). The primary endpoint of bleeding was significantly lower with dual therapy. Bleeding episodes were seen in 54 (19.4%) patients receiving double therapy and in 126 (44.4%) receiving triple-therapy (HR 0.36, 95% CI 0.26–0.50, P < 0·0001).[5]

The PIONEER AF-PCI trial was a pioneering trial. It was the first randomized trial using NOAC and came after WOEST.

It was an open-label, randomized multicenter trial that looked at a conventional strategy of Vitamin-K antagonist using DAPT and then titrating down the duration of DAPT versus 2 rivaroxaban-based strategies. One in which the intensity of rivaroxaban was standard (even the standard dose was decreased from 20 to 15 mg) and there was somewhat of a lower intensity of antiplatelet therapy and then one in which there was a low dose of rivaroxaban (2.5 mg twice daily) combined with DAPT.[6]

The group receiving triple therapy had significantly higher (26.7%) bleeding rate, whereas the 2 rivaroxaban-based arms had approximately similar (16.8% and 18%) rates of clinically significant bleeding, but lower than the triple therapy. The composite deaths from cardiovascular causes and ischemic stroke were quite similar in the 3 arms, and the numbers of major adverse cardiovascular events were 6.0, 5.6, and 6.5, respectively.

Although PIONEER was a sizeable study, it was still one of the smallest trials with pretty wide CI. It could not exclude a potential loss of efficacy. However, it was pioneering the idea of replacing warfarin with NOAC in AF patients undergoing PCI.

The RE-DUAL PCI trial was next in line after PIONEER with a quite similar design involving 2700 patients. It was an open-label, randomized, controlled, multicenter trial from July 21, 2014, to October 31, 2016. It was looking at the use of dabigatran in AF population who had undergone coronary stenting. The standard arm was the triple therapy with warfarin (+ASA + P2Y12), and on the other, 2 experimental arms using 2 doses of dabigatran (+P2Y12) 110 mg and 150 mg. There was about a 50% reduction in clinically relevant bleeding with the 110 mg of dabigatran arm, and about a 30% reduction with the 150 mg of dabigatran arm.[7]

There were comparable rates of ischemic outcomes in the 2 arms. Interestingly, there was a tendency for more stent thrombosis and MI in the 110-mg dabigatran without aspirin compared to the warfarin triple therapy. This raises the question: does one need to use triple therapy for some period, especially during that period of vulnerability?

The AUGUSTUS Trial has helped to clear the doubt by its large size and design. It enrolled over 4000 patients using 2-by-2 factorial design.[8] PIONEER and RE-DUAL trials left unanswered questions about the reasons for reduced bleeding rate. Was it because the use of direct OAC (DOAC) instead of Vitamin K antagonist (VKA); or reducing the dose of DOAC (e.g., rivaroxaban 2.5 mg twice daily); or dropping the aspirin?

The 2-by-2 study design comparing apixaban or VKA, combining with aspirin or placebo. Patients were randomized to those regimens within a week on average of their PCI. Therefore, day seven after PCI was the median where patients were randomized, and at that stage received either apixaban or VKA, and received aspirin or placebo. The study showed that there was a reduction in bleeding with apixaban compared to VKA (10.5% vs. 14.7%, HR 0.69; 95% CI 0.58–0.81; P < 0.001) and in the patients receiving placebo compared with aspirin (9.0% vs. 16.1%, HR 1.89; 95% CI 1.59–2.24; P < 0.001). The rate of death or hospitalization, a secondary endpoint, was lower with apixaban versus VKA (23.5% vs. 27.4%) but similar in aspirin and placebo group.

There was no significant difference in the rate of ischemic events comparing apixaban with VKA or comparing aspirin with placebo.

ASPIRIN TO KEEP OR TO DROP?

The other strength of AUGUSTUS trial was looking at aspirin in a double-blinded design at what does it do in terms of harm with bleeding and benefit in terms of ischemic events. It showed that including aspirin for the long-term treatment after PCI led to a much higher bleeding rate than omitting aspirin.

There was no significant difference in mortality or MI. However, a numerical trend in more coronary thrombotic events (MI, urgent revascularization, and stent thrombosis) with placebo versus aspirin. Definite or probable stent thrombosis in particular was doubled in the placebo group (0.5% vs. 0.9%), though the difference was not significant.[8]

Looking at the result of AUGUSTUS in a broad way, it gives us confidence to use NOAC and double therapy instead of triple therapy. However, the numerical increase of stent thrombosis still leaves some doubt and hence the role of individualization by the interventionist. The assessment of the risk of stent thrombosis plays a major role, especially in the first 30 days post-PCI, where most of the stent thrombosis occurred. It is also worth to mention that all of these procedures were done on aspirin, and patients were on aspirin for a median of 6 days following the procedure, which means they received blockade of that pathway for approximately 2 weeks' postprocedure. Therefore, the result could be different if aspirin was stopped prior or at the time of the procedure.

A 2018 meta-analysis that included only these four trials WOEST, ISAR-TRIPLE, PIONEER AF-PCI, RE-DUAL PCI found that the use of OAC plus one P2Y12 receptor blocker, compared with triple therapy, led to a lower rate of thrombolysis in MI major or minor bleeding (4.3% vs. 9.0%; HR 0.53, 95% credible interval 0.36–0.85) and a similar rate of major adverse cardiac events (10.4% vs. 10.0%; HR 0.85, 95% credible interval 0.48–1.29).[910]

NON-VITAMIN-K ORAL ANTICOAGULANT SELECTION AND DOSING

There are enough data by now supporting the use of NOAC over warfarin. Most of the experts use a dose or doses tested in the mentioned randomized trials and approved by regulatory agencies.

For dabigatran, this includes both the 150 mg twice daily and the 110 mg twice daily dose. Dabigatran 110 mg twice daily was tested in the RE-LY trial and RE-DUAL PCI and it is used widely by many countries. However, the 110-mg option is not approved for this indication in the United States, where 150 mg is the standard dose approved for everyone.

The dose of apixaban is 5 mg twice daily as studied in the AUGUSTUS trial, which is the same dose that was licensed for atrial fibrillation in ARISTOTLE trial. Although in clinical practice, despite a lack of randomized trial data, 2.5 mg twice daily is sometimes used when a triple antithrombotic therapy is given.

For rivaroxaban, some experts recommend 15 mg daily (the dose tested in the PIONEER-AF PCI trial) while others recommend the full dose of 20 mg daily, which has been shown to provide stroke risk prevention similar to warfarin in the ROCKET-AF trial.[6] While a lower dose of rivaroxaban (15 mg once daily) plus a P2Y12 receptor blocker appears to be a rational choice, the PIONEER AF-PCI trial was underpowered to exclude an increased risk for stroke.[11] If rivaroxaban 15 mg has been selected as the anticoagulant, it should be increased to 20 mg when clopidogrel is discontinued.

Rivaroxaban 2.5 twice daily plus DAPT has also been evaluated and appeared to have a similar overall risk of thrombotic events as warfarin triple therapy. It should be noted that this strategy has not been proven to provide stroke prevention in AF.

CURRENT GUIDELINES

2019 focus update of 2014 American Heart Association/American College of Cardiology/Heart Rhythm Society Atrial Fibrillation guidelines[12]

If triple therapy is prescribed poststent placement, clopidogrel is preferred over prasugrel (Class IIa)

If triple therapy is prescribed for patients with AF who are at increased risk of stroke and who have undergone PCI with stenting for ACS, a transition to double therapy at 4–6 weeks may be considered (Class IIb)

Double therapy with clopidogrel and low-dose rivaroxaban (15 mg daily) may be reasonable poststenting (Class IIa)

Double therapy with P2Y12 and dabigatran 150 mg twice daily is reasonable poststenting (Class IIa).

The 2016 European Society of Cardiology guidelines recommend triple antithrombotic therapy with a NOAC, aspirin, and clopidogrel for 3 months in patients with atrial fibrillation who have an ACS and undergo PCI, and 1 month if he has a high risk of bleeding. Then to continue with dual therapy until completion of 1 year.[13]

The dual antithrombotic therapy is a default approach for most of the patients, based on the results of PIONEER-AF, RE-DUAL PCI, and AUGUSTUS. However, both the US and European guidelines leave room to physicians to follow a personalized strategy based on the individual risks of ischemia and bleeding.

Stent technology in optimizing dual antiplatelet therapy duration in patients post-percutaneous coronary intervention with high risk of bleeding

Certainly, there is a significant improvement of stents designs and backbone, struts thickness, and polymers. Compare to the first-generation stents where the polymers are durable that require long duration of DAPT up to 1 year, the newer generation of stents allows the safe use of shorter duration of DAPT. For example, the new Synergy™ stents have thin struts and bioabsorbable polymers with relatively short duration of drug release to 3 months. In contrast to durable polymers stents, the healing is faster and hence DAPT can be shorten to 1 month. In the animal model, synergy stents showed complete healing of endothelium by 150 days. In human, the EVOLVE trial demonstrated its safety and efficacy for the treatment of selected de novo atherosclerotic lesions up to 5 years. This gives the operator options to manage the antiplatelets duration for a patient who requires chronic anticoagulation by choosing the type of stent according to the risk of bleeding post-PCI.[14]

CONCLUSION

AF is a common arrhythmia which can lead to serious disability and mortality. In the presence of acute coronary syndrome, the serious risks posed by AF multiply. It is, therefore, crucial for physicians to know the proper way to manage these patients. Over the last decade, there have been robust data derived from randomized control trials to guide physician's decision-making. Nevertheless, because there are so many confounding factors that influence bleeding, ischemia and thromboembolic risks, and translation of these data in clinical practice are complicated.

Factors need to be considered including demographic (e.g., sex, age, body weight), procedural (size and location of stent, severity of disease), bleeding risks, and ischemic risk factors. The decision for triple or dual therapy, the choice and duration of antiplatelets, and the dose of DOAC must take into consideration all these factors. A good clinician should be able to weigh the risks of bleeding versus ischemia to reach the right balance of anticoagulation and antiplatelets, and institute a proper short- and long-term management plan.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.