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Table of Contents
ORIGINAL ARTICLE
Year : 2021  |  Volume : 11  |  Issue : 4  |  Page : 179-185

Nonvalvular atrial fibrillation and acute coronary syndrome: Present Indian perspective and assessment


1 Associate Consultant, Indraprastha Apollo Hospital, New Delhi, India
2 Consultant, Cardiology, Fortis Escorts Heart Institute, New Delhi, India
3 Consultant, Cardiology, Indraprastha Apollo Hospital, New Delhi, India

Date of Submission14-Oct-2020
Date of Decision14-Oct-2020
Date of Acceptance26-Nov-2020
Date of Web Publication25-Oct-2021

Correspondence Address:
Dr. Ranjan Modi
Indraprastha Apollo Hospitals, New Delhi - 110 076
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jicc.jicc_74_20

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  Abstract 


Background: The number of patients undergoing percutaneous coronary intervention (PCI) who mandate additional oral anticoagulant therapy, due to presence of Atrial Fibrillation (AF), has been increasing. Dual antiplatelet therapy (DAPT) is associated with reduced ischemic events including stent thrombosis, myocardial infarction and stroke following PCI. However, the trade-off is an increased risk for bleeding while on DAPT. The addition of an anticoagulation further increases the likelihood of bleeding while on antiplatelet therapy. Thus, the overall risks and benefits for each patient undergoing PCI on anticoagulation (VKA/ NOAC) must be assessed and therapy individualized to ensure optimal therapy for each unique situation. Aims and Objectives: The aim of the study was to determine the diversity in the antiplatelet and anticoagulation treatment of patients with nonvalvular AF or flutter who develop acute coronary syndrome (ACS) or undergo PCI in India.Materials and Methods: All patients who had AF and underwent PCI were included in the study. Results: In the study 100 patients of AF with PCI were evaluated, among who 95 % were started on triple therapy (TT) and 5 % on DAPT. The patients were followed up at 1 month, 3 months, 6 months, and 1 year for adjustment of antiplatelet, anticoagulation medicines, and their dosage. Conclusion: The study reviewed the best practices for the pharmacologic management of patients requiring anticoagulation with NOAC who are treated with PCI and require antiplatelet therapy.

Keywords: Antiplatelet therapy, non-Vitamin K antagonist oral anticoagulants, oral anticoagulant, percutaneous coronary intervention


How to cite this article:
Modi R, Jaswal A, Modi S. Nonvalvular atrial fibrillation and acute coronary syndrome: Present Indian perspective and assessment. J Indian coll cardiol 2021;11:179-85

How to cite this URL:
Modi R, Jaswal A, Modi S. Nonvalvular atrial fibrillation and acute coronary syndrome: Present Indian perspective and assessment. J Indian coll cardiol [serial online] 2021 [cited 2021 Dec 5];11:179-85. Available from: https://www.joicc.org/text.asp?2021/11/4/179/329152




  Introduction Top


Long-term oral anticoagulation (OAC) is an essential aspect of the treatment of patients with atrial fibrillation (AF). Approximately 70%–80% of all patients in AF have an indication for lifelong OAC, and coronary artery disease coexists in 20%–30% of these patients.[1],[2] Balancing the risk of bleeding and thromboembolism is crucial in the management of patients on OAC, even more in cases when AF is associated with percutaneous coronary intervention (PCI).

The availability of various antiplatelets and oral anticoagulants has continued to grow in the last decade. Hence, various combinations of these medications are used by clinicians. This leads to the uncertainity regarding the optimal combination therapy.

Given the high proportion of patients undergoing PCI on antiplatelets and requiring OAC for conditions, particularly like AF, it is important that physicians are aware of the clinical implications and management of these overlapping conditions. The periprocedural management of anticoagulated patients is critical, but clinical practice varies widely between clinicians, hospitals, and countries. The addition of these OAC often requires modification of the antiplatelet regimen to optimize patient outcomes by balancing the risk of bleeding with the risk for ischemic events.

The need of this study was to determine the diversity in the antiplatelet and anticoagulation treatment of patients with nonvalvular AF or flutter who develop acute coronary syndrome (ACS) or undergo PCI in India. The study also helped to guide the management of these patients in India.

Materials and Methods

All patients who had AF and underwent PCI were included in the study.

Inclusion criteria

  • Adults >18 years of age (male or female)
  • Active or history of nonvalvular atrial fibrillation or flutter on anticoagulation
  • PCI with stenting (drug-eluting stent [DES]).



  Results Top


In our study, the majority of the subjects were males with a male-to-female ratio of 1.6:1. The mean age was 61 ± 4.2 years. The risk factors included diabetes (65%), hypertension (58%), dyslipidemia (57%), and smoking (32%). The most common cardiac presentation in the patients was unstable angina in 61 patients, followed by non-ST elevation MI (NSTEMI) in 25 patients, ST elevation MI (STEMI) in 8 patients, and stable angina in 6 patients. Echocardiography revealed normal left ventricular (LV) function in 47 patients, mild LV dysfunction in 31 patients, moderate in 12 patients, and severe LV dysfunction in 10 patients.

The mean CHA2DS2VASc score was 2.46 ± 1.32 Patients presenting with persistent AF were 53 patients, paroxysmal AF in 35 patients, and permanent AF in 12 patients. The patients were treated for single-vessel disease in 51 cases, double-vessel disease in 38 cases, and triple-vessel disease was noted in 11 patients.

The patients were started on triple therapy (TT) (dual antiplatelet and anticoagulant) in 95% of cases with dual antiplatelet therapy (DAPT) only seen in 5% of cases. Among the anticoagulant therapy, most of the patients were initiated on non-Vitamin K oral anticoagulants (NOACs), 85%, with a few on Vitamin K antagonist (VKA) (acitrom), 15%. None of the patients were started on warfarin. The bleeding manifestation was measured using BARC definitions which showed majority of the cases 78 in BARC 0, 14 in BARC 1, 6 in BARC 2, and 2 in BARC 3. No cases were reported in BARC 4 and 5 groups.

A number of patients who presented with STEMI (8 patients) and unstable angina (10 patients) were initially loaded with ticagrelor, but with the advent of AF postloading dose, they were later shifted to clopidogrel the next day in view of the initiation of anticoagulation as well. Only one patient was loaded with prasugrel outside which was shifted to clopidogrel as per the same protocol.

The patients were followed up at 1 month, 3 months, 6 months, and 1 year for adjustment of antiplatelet, anticoagulation medicines, and their dosage.

The study analyzed the evolving dilemma of periprocedural and postprocedural management of anticoagulated patients, burden of the disease, available data, and risk factors that could identify high-risk patients and propose a best well-balanced management strategy of antiplatelets and anticoagulation in patients with PCI and AF.

In our study of patients with AF and ACS, we came across these scenarios. The management of the patients with antiplatelets, anticoagulants, and their dosage differed in the groups with changes at initiation and follow-up.

  1. Recent ACS (STEMI) with recent AF
  2. Recent ACS (NSTEMI) with recent AF
  3. Recent ACS (STEMI/NSTEMI) with old AF on anticoagulation



  Discussion Top


AF is associated with a small but significant incidence of stroke and systemic thromboembolism.[3] Oral anticoagulants (NOACs) reduce the incidence of stroke and systemic embolism in these patients.[4] A meta-analysis of 29 trials on the use of antithrombotic therapy to prevent stroke in patients who have nonvalvular AF showed that anticoagulation reduced stroke by 64% as compared with placebo and by 39% as compared with aspirin in patients with nonvalvular AF.[5]

Furthermore, several trials including ACTIVE-W have confirmed the superiority of anticoagulation in reducing embolic events over DAPT with aspirin and clopidogrel in patients with both paroxysmal and sustained AF and at least one additional stroke risk factor.[6] As a result, the ACC/AHA guidelines recommended oral anticoagulant therapy for those patients with at least one additional risk factor for stroke and suggested the use of aspirin only for those at low risk for stroke such as patients without risk factors.[3]

Three antithrombotic drug combinations have been used most in practice in patients with AF and PCI: TT (OAC and DAPT with aspirin and clopidogrel), OAC, and one antiplatelet agent (aspirin or clopidogrel), or rarely, DAPT alone without oral anticoagulants. Although there are wide variations in type and duration of therapy in practice, initially, TT is the most common treatment regimen in this setting. Antiplatelets other than clopidogrel like prasugrel and ticagrelor have been sparingly used in combination with anticoagulants due to increased chance of bleeding events.

In a study of 21,443 elderly patients on bleeding complications associated with combinations of aspirin, thienopyridine derivatives, and warfarin in elderly patients following acute myocardial infarction, when followed on average for 22 months after an acute MI, bleeding was 1.7 times more frequent with DAPT and 1.9 times more frequent with aspirin plus warfarin when compared with aspirin monotherapy.[7] Similarly, in a nationwide registry of 40,812 patients with acute MI in Denmark, the risk of bleeding was 2.6% for aspirin, 4.6% for clopidogrel, 4.3% for DAPT, 5.1% for aspirin plus an oral anticoagulant, 12.3% for clopidogrel plus an oral anticoagulant, and 12.0% for TT over a mean follow-up of 16 months.[8]

Thus, the literature suggests that taking a combination of oral anticoagulants with aspirin and clopidogrel (“triple therapy”) poses a significant dilemma for the cardiologist because of the increased risk of major bleeding. Although the bleeding risk is higher, as noted in various studies, still, TT was the most common regimen used in the setting of AF patients requiring PCI (Data from CRUSADE Registry).[9] Similarly, data from Society for Cardiac Angiography and Interventions survey (2011) revealed that 86% of interventionists prefer TT for 1 month followed by warfarin and aspirin in case of bare-metal stent and 47.4% recommend at least 6 months of TT after DES implantation.

According to the guidelines DAPT alone is inferior to warfarin for prevention of thromboembolic events in patients with AF.[10] Various trials addressed this issue of dual therapy (warfarin + clopidogrel) versus TT. The results from the single-center WOEST trial involving 573 patients who underwent PCI with a mean follow-up of 1 year clearly show that the use of dual therapy (warfarin and clopidogrel without aspirin) was associated with a significant reduction in bleeding complications with no increase in the rate of thrombotic events being observed.[11]

Furthermore, the use of TT was associated with higher mortality and morbidity.[12] Although data on the efficiency and safety of warfarin plus clopidogrel combination are limited, this combination may be an alternative in patients with high bleeding risk and/or absent risk factors for stent thrombosis. The study did conclude that anticoagulants and clopidogrel were associated with a significant reduction in major bleeding and no increase in thrombotic events compared to TT with anticoagulation, aspirin, and clopidogrel.[12]

In the past, these patients received a (TT) for 3–12 months. This TT has never been studied for efficacy; however, the rate of bleeding complications in comparison to a simple OAC or DAPT is significantly higher. Registries and smaller trials showed that DAPT with an OAC plus a platelet inhibitor may be sufficient to prevent stroke and stent thromboses/myocardial infarctions.

In the past, anticoagulation was limited to VKAs, but with the recent addition of NOAC in the treatment regimen of AF, the combination of antiplatelets and anticoagulants has become more wide range.

These questions were investigated in various prospective and randomized studies involving all four NOACs approved for stroke prevention in AF. The NOACs were tested against VKAs involving single antiplatelet therapy without using DAPT. The trials with rivaroxaban (PIONEER AF-PCI), dabigatran (RE-DUAL PCI), apixaban (AUGUSTUS), and edoxaban (ENTRUST-AF PCI) are instrumental in determining the management. The current status is that a NOAC plus a single antiplatelet agent, mostly clopidogrel, is superior to TT with VKA with respect to bleeding complications without any obvious disadvantage due to increases in stroke cases or cardiac ischemia. The international guidelines already permit treatment without TT in cases where the bleeding risk is prevalent. In this situation, it is recommended to prescribe a NOAC plus a single antiplatelet therapy. Thus, TT no longer seems to be indicated for most patients with AF and after ACS or PCI with exception of patients in high-risk categories such as left main PCI, multivessel stenting PCI, diabetes, and multiple stents.

Novel oral anticoagulants

NOAC has become widely adopted since the initial approval. They represent a class of drugs that have two unique mechanisms of action; both directly inhibit a single coagulation factor with the distinction between individual types of agents occurring based on the coagulation factor that is inhibited. Among the NOACs- Apixaban, Edoxaban, Rivaroxaban all inhibit factor Xa, whereas the direct thrombin inhibitor dabigatran inhibits factor IIa (thrombin).

The introduction and rise of NOAC were in response to numerous limitations and challenges with the preexisting therapy of VKAs, which requires frequent monitoring and has numerous drug and dietary interactions. NOAC provides a potent and a predictable therapeutic effect with comparatively minimal routine laboratory monitoring required.

Multiple risk prediction scores have been introduced to assist in the assessment and stratification of bleeding risk. The hypertension, abnormal renal/liver function, stroke, bleeding history or predisposition, labile international normalized ratio, elderly, drugs/alcohol concomitantly (HAS-BLED) score is among the most commonly used scores for bleeding risk stratification and is used to assess bleeding risk in patients with AF. A patient with a HAS-BLED score ≥3 is considered to be at high risk for bleeding.[13] The use of the HAS-BLED score specifically for patients on concomitant DAPT however has not been validated. The PREdicting bleeding Complications In patients undergoing Stent implantation and subsequent (PRECISE)-DAPT score was introduced to assess bleeding risk for patients on DAPT. A longer duration of DAPT is associated with significantly increased bleeding in patients at high PRECISE-DAPT risk (score ≥25).[14] Data support an ischemic benefit of DAPT only in patients with a PRECISE-DAPT score <25.[16] Both bleeding risk prediction models have utility for predicting future significant bleeding events in patients taking oral anticoagulants (OAC) and undergoing PCI.[15]

An overview of the pivotal NOAC trials in patients with nonvalvular AF is summarized in [Table 1]. In the Randomized Evaluation of Long-term anticoagulant therapy (RE-LY) trial, dabigatran was compared to warfarin in 18,113 patients with results first published in 2009.[16] In 2011, results were published from the pivotal Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in AF (ROCKET-AF) trial of 14,246 patients comparing rivaroxaban to warfarin.[17] The Apixaban for Reduction in Stroke and Other Thromboembolic Events in AF (ARISTOTLE) trial compared apixaban to warfarin and assessed outcomes in 18,201 patients.[18] Effective Anticoagulation with Factor Xa Next Generation in AF (ENGAGE-AF) compared edoxaban to warfarin in 21,105 patients with results reported in 2013.[19]
Table 1: Schematic diagram for use of long-term antiplatelet and novel oral anticoagulant therapy

Click here to view


As discussed earlier, the PIONEER AF-PCI trial and the RE-DUAL trial both compared a NOAC plus single antiplatelet therapy with TT with a VKA plus DAPT. Both the pivotal trials reported significantly lower bleeding with the dual antithrombotic regimen compared with TT.[20],[21],[22]

In the RE DUAL PCI AF, patients with AF who had undergone PCI, the risk of bleeding was lower among those who received dual therapy with dabigatran and a P2Y12inhibitor than among those who received TT with warfarin, a P2Y12 inhibitor, and aspirin. Dual therapy was noninferior to TT with respect to the risk of thromboembolic events. In the trial, dabigatran compared to TT with VKA in 2,725 randomized patients was associated with a significant reduction of bleeding events at both 150 mg and 110 mg twice daily dosing with dabigatran.[20],[21] Due to a concern for potential increased risk for ischemic events with the lower dabigatran dose (110 mg twice daily), 150 mg twice daily dosing with dabigatran is preferred with single antiplatelet therapy.

In the PIONEER AF PCI, participants with AF undergoing PCI with placement of stents, the administration of either low-dose rivaroxaban plus a P2Y12 inhibitor for 12 months or very-low-dose rivaroxaban plus DAPT for 1, 6, or 12 months was associated with a lower rate of clinically significant bleeding than was standard therapy with a VKA plus DAPT for 1, 6, or 12 months. The three groups had similar efficacy rates, but the clinical efficacy is uncertain as the study was not powered to evaluate thrombotic events (stent thrombosis, ischemic stroke).

The trial randomized 2,124 patients with nonvalvular AF were treated with PCI to receive 1 of 3 treatment strategies of antiplatelet therapy and OAC. The investigators reported that the use of either low-dose rivaroxaban plus a P2Y12 inhibitor for 12 months or very-low-dose rivaroxaban plus DAPT was associated with lower clinically significant bleeding compared with VKA plus DAPT.[22]

The AUGUSTUS trial reported the impact of apixaban with and without aspirin in 4,614 patients with AF and an ACS or PCI. The use of a P2Y12 inhibitor and apixaban without aspirin resulted in less bleeding and fewer hospitalizations without significant differences in the incidence of ischemic events compared with drug regimens that included a VKA, aspirin, or both.[23] Edoxaban is currently being studied as part of a TT regimen in the Edoxaban Treatment Versus VKA in Patients With AF Undergoing PCI (ENTRUST-AF) trial.

There are a few highlights regarding NOACs which are important to be considered. The various RCT data have concluded:

  1. Apixaban 5 mg twice a day and dabigatran 150 mg twice a day are most efficacious in the prevention of stroke/systemic embolism. Among the two, dabigatran 150 mg has shown most efficacy
  2. Apixaban has shown the most favorable outcomes in major bleeding and intracranial hemorrhage in the elderly population, making it the safest drug for this group of population
  3. Apixaban should be preferred for patients with renal impairment
  4. Apixaban 2.5 mg are considered in patients with any of the two present: Age >80 years, weight <60 kg and serum creatinine >1.5 mg.


Guideline recommendations

The 2016 American College of Cardiology/American Heart Association (ACC/AHA) focused update on duration of DAPT in patients with coronary artery disease guideline recommendations for patients at high bleeding risk treated with PCI supports clopidogrel as the P2Y12 inhibitor of choice in patients on OAC therapy.[24] The duration of DAPT recommended by the ACC/AHA guidelines is based on the indication for PCI. In patients with stable coronary artery disease, discontinuation of the P2Y12 inhibitor at 3 months is recommended, whereas for patients treated for ACS, P2Y12 inhibitors should be continued for at least 6 months.[24]

The 2018 ESC guidelines similarly recommend clopidogrel as the P2Y12 inhibitor of choice, with low dose (≤100 mg daily) aspirin, however recommend keeping the duration of TT as short as possible.[25]

ESC guidelines recommend TT with aspirin, clopidogrel, and OAC for 1 month and up to 6 months in patients at higher ischemic risk due to ACS or procedural characteristics that outweigh bleeding risk (Class IIa, level of evidence B).

When a NOAC is added to either aspirin or clopidogrel, the lowest approved effective dose for stroke prevention tested in AF trials should be considered (Class IIa, level of evidence C).

The ESC cautions that the use of ticagrelor or prasugrel is not recommended as part of triple antithrombotic therapy with aspirin and OAC (Class III, level of evidence C).

As per literature and evidence, we noted that majority of the patients were initiated on NOACs by physicians, but the duration, dosage, and recommendations were varied.

The following are key perspectives from the state-of-the-art review on the management of antithrombotic therapy in AF patients undergoing PCI published in 2019:[26]

  1. Most patients with AF and stroke risk factors require OAC to decrease their risk of stroke or systemic embolism. This is now best achieved using direct oral anticoagulants (DOACs) due to lower rates of intracranial hemorrhage as compared to VKAs (e.g., warfarin)
  2. Approximately 5%–10% of patients undergoing PCI have comorbid AF, which complicates antithrombotic therapy decisions. While guidelines recommend DAPT for patients following PCI, this in combination with OAC therapy places patients at high risk for bleeding complications
  3. Several randomized trials have demonstrated that a regimen of a DOAC plus a single antiplatelet agent (usual clopidogrel) provides better safety than a TT regimen of VKA plus DAPT
  4. For patients undergoing PCI with comorbid AF, strategies such as radial access and a brief anticoagulation washout prior to PCI may be considered to help reduce procedure-related bleeding risk. New-generation DESs are also preferable, as they require shorter courses of antiplatelet therapy and are associated with a lower risk of stent thrombosis
  5. For patients undergoing PCI with comorbid AF, the use of DOACs is preferred over VKAs. DOACs should be prescribed at stroke prevention doses (e.g., apixaban 5 mg BID) or doses specifically tested in AF plus PCI randomized trials (e.g., rivaroxaban 15 mg daily) when possible. Dose reduction with dabigatran (110 mg BID) may be considered in patients at higher bleeding risk
  6. Use of triple antithrombotic therapy (OAC plus DAPT) should be limited in duration as much as possible. In many cases, this can be limited to the peri-PCI period only. Patients at high thrombotic risk may be considered for up to 1 month
  7. When combining OAC and antiplatelet therapy, the use of low-dose aspirin (81–100 mg) is preferred. The use of clopidogrel is also preferred over other P2Y12 inhibitor medications and over aspirin in most patients
  8. Most patients with AF who undergo PCI can discontinue antiplatelet therapy 12 months following stent placement. They should continue on OAC therapy long term.


Recommendations

Our recommendations based on current evidence-based medicine, best practices, clinical experience, and available pharmacologic therapies are the following:

  • The approach to a patient with AF and PCI is summarized in various [Table 1], [Table 2], [Table 3]
  • Prognosis is worse in those experiencing an adverse event whether it is an ischemic or bleeding event following PCI, so efforts are needed to balance these competing risks.
  • DES should be used as the default choice of stent
  • Aspirin therapy should be limited to the minimal duration required post PCI, with the dose restricted to low-dose aspirin
  • NOAC's offer significant advantages over VKA including less drug and dietary interactions, less routine monitoring of blood work, and greater time in therapeutic range, thus they should be the drug of choice in patients of AF and PCI
  • Potent thienopyridine therapy should be used following stent implantation in the absence of routine P2Y12 testing prior to initiating antiplatelet monotherapy
  • Amongst P2Y12 inhibitors prasugrel is not the preferred drug; clopidogrel or ticagrelor may be used with clopidogrel given preference in view of the enormous literature
  • Patients on anticoagulation undergoing PCI should undergo routine assessment with intravascular imaging as the role of high-risk lesion-related features have increased importance prior to determining the optimal duration of treatment with DAPT
  • In RE-DUAL trial, it was shown that without aspirin, the use of 110 mg dabigatran was associated with a numerical increase in death, myocardial infarction, stroke, and stent thrombosis. Thus, keeping the ischemic and bleeding risks in mind, dabigatran 110 mg can be used when patients are in TT treatment which can be switched to Dabigatran 150 mg when on dual therapy without aspirin
  • Dabigatran 150 mg and Apixaban 5 mg both are significantly efficacious in the prevention of ischemic stroke, with the former more than the latter
  • Apixaban 2.5 mg should be considered in patients of AF with PCI if age >80 years, weight <60 kg, and serum creatinine >1.5 mg/dl
  • Although studies on rivaroxaban did provide evidence on a decrease in bleeding events efficacy in view of stent thrombosis and ischemic stroke was uncertain
  • Although the choice of NOACs amongst patients with AF and PCI are subjective to the patient and treating physician, evidence does support dabigatran 150 mg and apixaban 5 mg with minimal but significant room for dabigatran 110 mg and apixaban 2.5 mg.
Table 2: Diagram depicting the approach for new-onset atrial fibrillation and anticoagulants

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Table 3: Diagram depicting the approach for the patient of anticoagulants and old atrial fibrillation on treatment (novel oral anticoagulant/Vitamin K antagonist)

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Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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  [Table 1], [Table 2], [Table 3]



 

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