Atrial fibrillation anticoagulation

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Cafer Zorkun, M.D., Ph.D. [2] George Leef, MD; Arzu Kalayci, M.D. [3], Syed Hassan A. Kazmi BSc, MD [4]; Sabawoon Mirwais, M.B.B.S, M.D.[5]

Overview

Oral anticoagulation to prevent stroke and systemic embolization is a mainstay of atrial fibrillation management. Anticoagulation is recommended for AF patients at high risk for stroke based on CHADS2-VASc score who do not have an unacceptable risk of bleeding (HAS-BLED score). Anticoagulation can be with warfarin, or one of the novel oral anticoagulants (NOACs).

Warfarin was the only option for oral anticoagulation until 2010. Four novel oral anticoagulants (NOACs) have been approved for use in nonvalvular AF as alternatives to warfarin since then. At present, either warfarin or a NOAC is a reasonable option for most AF patients. Anti-platelet therapy is not recommended for stroke reduction in AF.

CHADS2-VASc score

The CHADS2-VASc score is the currently recommended system for estimating stroke risk in AF [1]. Points are assigned as follows:

  • Congestive Heart Failure 1 point
  • Hypertension 1 point
  • Age 65-74 1 point
  • Diabetes 1 point
  • Stroke/TIA 2 points
  • Vascular disease (CAD, PAD) 1 point
  • Age > 75 1 point
  • Female sex 1 point

For CHADS2-VASc score of 0, stroke risk is low and no anticoagulation is recommended.

For CHADS2-VASc score of 2 or more, stroke risk is high, and anticoagulation is recommended.

For CHADS2-VASc score of 1, stroke risk is intermediate. Either anticoagulation or no anticoagulation is reasonable.

Anticoagulation Options

Warfarin

Warfarin is the traditional oral anticoagulant used in atrial fibrillation. For both primary and secondary prevention of stroke, there is a 61% relative risks reduction in the incidence of all cause stroke (both ischemic and hemorrhagic) associated with adjusted-dose warfarin.[2]

An INR between 2-3 has been found to be best for reducing stroke risk while balancing against bleeding risk.[2][3][4] [2][5] The optimal INR should obviously maximize efficacy in reducing the risk of stroke and simultaneously minimize the risk of bleeding. INRs lower than this, such as those in the range of 1.6 to 2.5, are associated with efficacy that is only 80% of that in the target range.[6][7] [8][9]

There are a number of problems with warfarin, including the high level of monitoring required and the numerous interactions with food and other medications.

Novel Oral Anticoagulants

Since 2010, four novel oral anticoagulants (NOACs) have been approved. These drugs are direct inhibitors of thrombin (factor II) or factor Xa. Unlike warfarin, they have quick onset, short half life, do not require INR monitoring, have fewer drug-drug and food interactions, and favorable safety profiles. The NOACs are approved for use in nonvalvular AF only.

  • Apixaban: factor Xa inhibitor, may be the best choice[10]. Compared to warfarin in ARISTOTLE trial [11]. Apixaban was found to have superior stroke protection and lower risk for major bleeding. Notably ARISTOTLE showed a decrease in total deaths compared to warfarin, which has not been seen with any other NOAC.
  • Dabigatran: direct thrombin inhibitor, compared to warfarin in RE-LY trial [12]. Dabigatran was found to have comparable stroke protection and lower risk for major bleeding, especially intracranial bleeding.
  • Rivaroxaban: factor Xa inhibitor, compared to warfarin in ROCKET-AF trial [13]. Rivaroxaban was found to have comparable stroke protection and similar risk for major bleeding. Risk of intracranial bleeding was lower with rivaroxaban.
  • Edoxaban: factor Xa inhibitor, compared to warfarin in ENGAGE trial [14]. Edoxaban was found to have comparable stroke protection and lower risk for major bleeding. Edoxaban was found to be inferior to warfarin for stroke prevention in patients with CrCl > 95mL/min based on subgroup analysis, so it is only approved for patients with CrCl between 30-95.

None of the NOACs have been tested in patients with severe renal impairment. Dabigatran was tested in patients with mechanical valves in the RE-ALIGN trial [15], but the trial had to be stopped early due to excess thrombotic events in the dabigatran arm. All NOACs are considered contraindicated in valvular AF.

Antiplatelet Therapy for Atrial Fibrillation (not recommended)

Aspirin Monotherapy

Aspirin monotherapy is associated with only a modest and inconsistent reduction in the risk of stroke associated with atrial fibrillation.[9][16] Studies suggest that the efficacy of aspirin may be greater in patients with hypertension or diabetes. Aspirin may also be more efficacious in reducing the risk of non-cardioembolic stroke as opposed to the more disabling cardioembolic form of stroke.[17][18] Apixaban was compared to aspirin for prevention of stroke in the AVERROES trial, which showed that apixaban was more effective than aspirin for stroke prevention with a comparable bleeding risk [19]. There seems to be little reason to use aspirin monotherapy in AF given the availability of clearly superior alternatives.

Dual Antiplatelet Therapy

Among patients who are not deemed candidates for Coumadin therapy (estimated to be approximately 40-50% of patients), dual antiplatelet therapy with both aspirin and clopidogrel (at a maintenance dose of 75 mg/day) was superior to aspirin monotherapy in the ACTIVE-A trial. The primary endpoint of the trial was the composite of stroke, myocardial infarction, non–central nervous system systemic embolism, or death from vascular causes. After a median of 3.6 years of follow-up in 7,554 randomized patients, the addition of clopidogrel to aspirin alone yielded a reduction in events from 7.6% to 6.8% (relative risk reduction with clopidogrel, 0.89; 95% confidence interval [CI], 0.81 to 0.98; P=0.01). The addition of clopidogrel to aspirin alone reduced the risk of stroke by 28% (from 3.3% to 2.4%, p<0.001) and reduced the risk of MI by 22% (from 0.9% per year to 0.7% per year, p=0.08). The risk of major bleeding among patients treated with aspirin and clopidogrel was 2.0% per year whereas it was 1.3% per year among patients treated with aspirin alone (relative risk, 1.57; 95% CI, 1.29 to 1.92; P<0.001). If 1000 patients were treated for 3 years, the combination of aspirin plus clopidogrel would prevent 28 strokes (17 disabling or fatal), and 6 myocardial infarctions, at a cost of 20 major bleeds compared to aspirin alone.

These trials were all conducted in the pre-NOAC era. With the availability of alternatives to warfarin, there should be very few patients who cannot be anticoagulated. Dual antiplatelet therapy is not routinely recommended.

Anticoagulation in end stage renal disease

Patients with end stage renal disease were excluded from the trials of warfarin in AF, as well as from the trials of the NOACs in AF. There is no high quality randomized data looking at anticoagulation in patients with AF and ESRD. Given the risk factors for kidney disease, most patients with AF and ESRD will have high CHADS2-VASc scores as well as high HAS-BLED scores. Several observational studies have suggested that warfarin may not be beneficial in ESRD given a markedly increased risk for intracranial bleeding [20][21][22][23]. This may be related to baseline bleeding propensity in ESRD from uremic platelet dysfunction as well as issues with maintaining a therapeutic INR. Use of warfarin in ESRD patients requires additional study and higher quality data, but based on current data it is not clearly beneficial. AHA/ACC still gives warfarin a weak recommendation in dialysis patients based on the 2014 guidelines, but KDIGO recommends against routine anticoagulation in dialysis patients given the uncertainty that benefits outweigh risks. Warfarin is still necessary in very high risk situations, such as mechanical valve or known LV thrombus.

There is no clear alternative to warfarin, since low molecular weight heparin is cleared by the kidney and the novel oral anticoagulants have not been studied in advanced kidney disease. Apixaban has dosing recommendations in ESRD, but these are based on pharmacokinetic data only. Currently there is no published outcomes data for apixaban in advanced kidney disease.

Interruption of Anticoagulation

  • No mechanical valve, high risk of bleeding with procedure: Coumadin can be discontinued for one week without heparin bridging.
  • Presence of mechanical valve, patients with AF who are at high risk of stroke, or patients in whom coumadin must be interrupted for over a week: These patients should be administered either unfractionated heparin or low molecular weight heparin.

2019 AHA/ACC Focused Update of the 2014 AHA/ACC Guideline


Class of Recommendation Recommendation Comment/Rationale
I
  • Oral anticoagulants recommended for high risk patients now have edoxaban included
  • Exclusion criteria for CHA2DS2-VASc assessment and use of NOACs now defined as moderate to severe mitral stenosis or a mechanical heart valve
  • For Afib or Aflutter of greater than or equal to 48 hours or of unknown duration, anticoagulation with warfarin (INR 2-3), a factor Xa inhibitor or direct oral anticoagulant is recommended for at least 3 weeks before and at least 4 weeks after cardioversion
  • NOACs are recommended over warfarin where eligible except in those patients with moderate - severe mitral stenosis or a mechanical heart valve
  • Idarucizumab is the reversal agent for dabigatran in the event of life-threatening bleeding or an urgent procedure
  • In patients with cardiac implantable electronic devices, atrial high rate episodes (AHREs) should prompt further evaluation
  • Weight loss and risk factor modification is recommended for overweight/obese patients with AF.
  • Further evaluation should be performed in patients with AHREs who have received cardiac implantable electronic devices
  • Weight loss and risk factor modification is recommended for overweight/obese patients with AF.

IIa
  • For patients with AF or atrial flutter of <48 hours' duration with a CHA2DS2-VASc score of ≥2 in men and ≥3 in women:
    • Heparin, a factor Xa inhibitor, or a direct thrombin inhibitor as close to starting cardioversion
    • Long term anticoagulation recommended after cardioversion
  • Andexanet Alfa recommended as a reversal agent for apixaban and rivaroxaban induced bleeding episodes
  • Catheter ablation of AF is reasonable in symptomatic AF patients with HF and reduced LVEF.
  • Clopidogrel preferred over prausgrel as a part of triple therapy post-stenting
  • Double therapy with a P2Y12 inhibitor and dose adjusted vitamin K antagonist is reasonable post-stenting
  • Double therapy with clopidogrel and low-dose rivaroxaban (15 mg daily) may be reasonable post-stenting
  • Double therapy with a P2Y12 inhibitor and dabigatran 150 mg twice daily is reasonable post-stenting.
  • For detection of silent AF in patients with cryptogenic stroke in whom long-term external ambulatory monitoring is equivocal, implantation of a cardiac monitor is reasonable


IIb
  • Percutaneous LAAO should be considered for those AF patients at an increased risk of stroke who have contraindications to long-term anticoagulation and who are at high risk of thromboembolic events.
  • After initial 4-6 weeks of triple therapy for AF patients at high risk for stroke and those who have undergone PCI for stenting post-ACS, switch to double therapy should be considered
III
  • The direct thrombin inhibitor dabigatran should not be used in patients with AF and a mechanical heart valve
  • In patients with AF and end-stage CKD or on dialysis, the direct thrombin inhibitor dabigatran or the factor Xa inhibitors rivaroxaban or edoxaban are not recommended because of the lack of evidence from clinical trials that benefit exceeds risk.

2017 AHA/ACC Focused Update of the 2014 AHA/ACC Guideline for the Management of Patients With Valvular Heart Disease (VHD)

Recommendation for Anticoagulation for Atrial Fibrillation (AF) in Patients with VHD

COR LOE RECOMMENDATION COMMENT/RATIONALE
I B-NR Anticoagulation with a vitamin K antagonist (VKA) is indicated for patients with rheumatic mitral stenosis (MS) and AF. MODIFIED: VKA as opposed to the direct oral anticoagulants (DOACs) are indicated in patients with AF and rheumatic MS to prevent thromboembolic events. The RCTs of DOACs versus VKA have not included patients with MS. The specific recommendation for anticoagulation of patients with MS is contained in a subsection of the topic on anticoagulation.
I C-LD Anticoagulation is indicated in patients with AF and a CHA2DS2-VASc score of 2 or greater with native aortic valve disease, tricuspid valve disease, or mitral regurgitation. NEW: Post hoc subgroup analyses of large RCTs comparing DOAC versus warfarin in patients with AF have analyzed patients with native valve disease other than MS and patients who have undergone cardiac surgery. These analyses consistently demonstrated that the risk of stroke is similar to or higher than that of patients without VHD. Thus, the indication for anticoagulation in these patients should follow Guideline Determined Medical Therapy (GDMT) according to the CHA2DS2-VASc score.
IIa C-LD It is reasonable to use a DOAC as an alternative to a VKA in patients with AF and native aortic valve disease, tricuspid valve disease, or MR and a CHA2DS2-VASc score of 2 or greater. NEW: Several thousand patients with native VHD (exclusive of more than mild rheumatic MS) have been evaluated in RCTs comparing DOACs versus warfarin. Subgroup analyses have demonstrated that DOACs, when compared with warfarin, appear as effective and safe in patients with VHD as in those without VHD.

2017 ESC/EACTS Guidelines for the Management of Atrial Fibrillation in Patients With Valvular Heart Disease (VHD)

Recommendations Class of

Recommendation

Level of

Evidence

Anticoagulation
NOACs should be considered as an alternative to VKAs in patients with aortic stenosis, aortic regurgitation and mitral regurgitation presenting with atrial fibrillation[24] IIa B
NOACs should be considered as an alternative to VKAs after the third month of implantation in patients who have atrial fibrillation associated with a surgical or transcatheter aortic valve bioprosthesis IIa C
The use of NOACs is not recommended in patients with atrial fibrillation and moderate to severe mitral stenosis III C
NOACS are contraindicated in patients with a mechanical valve[25] III B
Surgical Interventions
Surgical ablation of atrial fibrillation should be considered in patients with symptomatic atrial fibrillation who undergo valve surgery[26] IIa A
Surgical ablation of atrial fibrillation may be considered in patients with asymptomatic atrial fibrillation who undergo valve surgery, if feasible, with minimal risk IIb C
Surgical excision or external clipping of the LA appendage may be considered in patients undergoing valve surgery[27] IIb B
  • LA = left atrial
  • NOAC = non-vitamin K antagonist oral anticoagulant
  • VHD = valvular heart disease
  • VKA = vitamin K antagonist

2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation (DO NOT EDIT)[1]

Prevention of Thromboembolism

Risk-Based Antithrombotic Therapy

Class I
"1. In patients with AF, antithrombotic therapy should be individualized based on shared decision-making after discussion of the absolute and RRs of stroke and bleeding, and the patient’s values and preferences. (Level of Evidence: C) "
"2. Selection of antithrombotic therapy should be based on the risk of thromboembolism irrespective of whether the AF pattern is paroxysmal, persistent, or permanent. (Level of Evidence: B) "
"3. In patients with nonvalvular AF, the CHA2DS2-VASc score is recommended for assessment of stroke risk. (Level of Evidence: B) "
"4. For patients with AF who have mechanical heart valves, warfarin is recommended and the target international normalized ratio (INR) intensity (2.0 to 3.0 or 2.5 to 3.5) should be based on the type and location of the prosthesis. (Level of Evidence: B) "
"5. For patients with nonvalvular AF with prior stroke, transient ischemic attack (TIA), or a CHA2DS2-VASc score of 2 or greater, oral anticoagulants are recommended. Options include: warfarin (INR 2.0 to 3.0) (Level of Evidence: A), dabigatran (Level of Evidence: B), rivaroxaban (Level of Evidence: B), or apixaban (Level of Evidence: B)."
"6. Among patients treated with warfarin, the INR should be determined at least weekly during initiation of antithrombotic therapy and at least monthly when anticoagulation (INR in range) is stable. (Level of Evidence: A) "
"7. For patients with nonvalvular AF unable to maintain a therapeutic INR level with warfarin, use of a direct thrombin or factor Xa inhibitor (dabigatran, rivaroxaban, or apixaban) is recommended. (Level of Evidence: C) "
"8. Re-evaluation of the need for and choice of antithrombotic therapy at periodic intervals is recommended to reassess stroke and bleeding risks. (Level of Evidence: C) "
"9. Bridging therapy with unfractionated heparin (UFH) or low-molecular-weight heparin (LMWH) is recommended for patients with AF and a mechanical heart valve undergoing procedures that require interruption of warfarin. Decisions regarding bridging therapy should balance the risks of stroke and bleeding. (Level of Evidence: C) "
"10. For patients with AF without mechanical heart valves who require interruption of warfarin or newer anticoagulants for procedures, decisions about bridging therapy (LMWH or UFH) should balance the risks of stroke and bleeding and the duration of time a patient will not be anticoagulated. (Level of Evidence: C) "
"11. Renal function should be evaluated prior to initiation of direct thrombin or factor Xa inhibitors and should be re-evaluated when clinically indicated and at least annually. (Level of Evidence: B) "
"12. For patients with atrial flutter, antithrombotic therapy is recommended according to the same risk profile used for AF. (Level of Evidence: C) "
Class III: No Benefit
"1. The direct thrombin inhibitor, dabigatran, and the factor Xa inhibitor, rivaroxaban, are not recommended in patients with AF and end-stage CKD or on hemodialysis because of the lack of evidence from clinical trials regarding the balance of risks and benefits. (Level of Evidence: C) "
Class III: Harm
"1. The direct thrombin inhibitor, dabigatran, should not be used in patients with AF and a mechanical heart valve. (Level of Evidence: B) "
Class IIa
"1. For patients with nonvalvular AF and a CHA2DS2-VASc score of 0, it is reasonable to omit antithrombotic therapy. (Level of Evidence: B) "
"2. For patients with nonvalvular AF with a CHA2DS2-VASc score of 2 or greater and who have end-stage CKD (creatinine clearance [CrCl] <15 mL/min) or are on hemodialysis, it is reasonable to prescribe warfarin (INR 2.0 to 3.0) for oral anticoagulation. (Level of Evidence: B) "
Class IIb
"1. For patients with nonvalvular AF and a CHA2DS2-VASc score of 1, no antithrombotic therapy or treatment with an oral anticoagulant or aspirin may be considered. (Level of Evidence: C) "
"2. For patients with nonvalvular AF and moderate-to-severe CKD with CHA2DS2-VASc scores of 2 or greater, treatment with reduced doses of direct thrombin or factor Xa inhibitors may be considered (e.g., dabigatran, rivaroxaban, or apixaban), but safety and efficacy have not been established. (Level of Evidence: C) "
"3. In patients with AF undergoing percutaneous coronary intervention, bare-metal stents may be considered to minimize the required duration of dual antiplatelet therapy. Anticoagulation may be interrupted at the time of the procedure to reduce the risk of bleeding at the site of peripheral arterial puncture. (Level of Evidence: C) "
"4. Following coronary revascularization (percutaneous or surgical) in patients with AF and a CHA2DS2-VASc score of 2 or greater, it may be reasonable to use clopidogrel (75 mg once daily) concurrently with oral anticoagulants but without aspirin. (Level of Evidence: B) "

2011 ACCF/AHA/HRS Focused Update on the Management of Patients With Atrial Fibrillation (Updating the 2006 Guideline) (DO NOT EDIT)[28]

Combining Anticoagulant with Antiplatelet Therapy

Class IIb
"1. The addition of clopidogrel to aspirin (ASA) to reduce the risk of major vascular events, including stroke, might be considered in patients with AF in whom oral anticoagulation with warfarin is considered unsuitable due to patient preference or the physician’s assessment of the patient’s ability to safely sustain anticoagulation. (Level of Evidence: B) "

2010 ACCF/ACG/AHA Expert Consensus Document on the Concomitant Use of Proton Pump Inhibitors and Thienopyridines - Summary of Findings and Consensus Recommendations[29] (DO NOT EDIT)

  1. Clopidogrel reduces major CV events compared with placebo or aspirin.
  2. Dual antiplatelet therapy with clopidogrel and aspirin, compared with aspirin alone, reduces major CV events in patients with established ischemic heart disease, and it reduces coronary stent thrombosis but is not routinely recommended for patients with prior ischemic stroke because of the risk of bleeding.
  3. Clopidogrel alone, aspirin alone, and their combination are all associated with increased risk of GI bleeding.
  4. Patients with prior GI bleeding are at highest risk for recurrent bleeding on antiplatelet therapy. Other clinical characteristics that increase the risk of GI bleeding include advanced age; concurrent use of anticoagulants, steroids, or nonsteroidal anti-inflammatory drugs (NSAIDs) including aspirin; and Helicobacter pylori infection. The risk of GI bleeding increases as the number of risk factors increases.
  5. Use of a PPI or histamine H2 receptor antagonist (H2RA) reduces the risk of upper GI bleeding compared with no therapy. PPIs reduce upper GI bleeding to a greater degree than do H2RAs.
  6. PPIs are recommended to reduce GI bleeding among patients with a history of upper GI bleeding. PPIs are appropriate in patients with multiple risk factors for GI bleeding who require antiplatelet therapy.
  7. Routine use of either a PPI or an H2RA is not recommended for patients at lower risk of upper GI bleeding, who have much less potential to benefit from prophylactic therapy.
  8. Clinical decisions regarding concomitant use of PPIs and thienopyridines must balance overall risks and benefits, considering both CV and GI complications.
  9. Pharmacokinetic and pharmacodynamic studies, using platelet assays as surrogate endpoints, suggest that concomitant use of clopidogrel and a PPI reduces the antiplatelet effects of clopidogrel. The strongest evidence for an interaction is between omeprazole and clopidogrel. It is not established that changes in these surrogate endpoints translate into clinically meaningful differences.
  10. Observational studies and a single randomized clinical trial (RCT) have shown inconsistent effects on CV outcomes of concomitant use of thienopyridines and PPIs. A clinically important interaction cannot be excluded, particularly in certain subgroups, such as poor metabolizers of clopidogrel.
  11. The role of either pharmacogenomic testing or platelet function testing in managing therapy with thienopyridines and PPIs has not yet been established.

Sources

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