Treatment dilemmas in atrial fibrillation

Atrial fibrillation (AF) is the most common cardiac arrhythmia, affecting at least 3% of Irish adults over 60 and 6% over 70.¹ The worldwide prevalence has been rising and is approximately 600 in men and 375 in women per 100,000 population.²  For all that, we are still in a relative infancy in understanding its pathophysiology and association with risk of stroke and other illnesses. While much progress has been made in the past 10 years, in particular with collaborative interdisciplinary working and research between cardiologists and stroke physicians, nevertheless there are many unanswered questions and dilemmas in AF.

Risk of stroke

While the risk of stroke is a paramount consideration in AF and much has improved with successive iterations of vascular risk scores such as CHADS2 and CHA2 DS2-VASC, the C-statistic of such scores remains poor at a 0.60 average,³ and while addition of biomarkers NT Pro-BNP and troponin raises this predictability to a modestly healthier 0.71,⁴ they are still approximates of risk and do not assess an individual atrium’s thrombogenecity when fibrillating. 

Echocardiographic analysis of the fibrillating atrium including morphology of the left atrial appendage, left atrial reservoir strain and P-wave to A time on tissue Doppler imaging (PA-TDI) can give further useful clues as to what might be a highly thrombogenic atrium even on transthoracic echocardiography,⁵ but this is a time-expensive examination or invasive in the case of transoesophageal echocardiography, and imaging criteria are as of yet unproven as a population-based method of risk stratification.

The ‘zero sum’ game: AF and CHA2 DS2-VASC = 0

Current ESC guidelines recommend no treatment with a score of zero in men and one in women (the score for female sex only coming into play as a risk when over 65).⁶ The guidelines are clear that anti-platelets have no role in stroke prevention in AF, a view strongly supported in the ACTIVE-W study where dual anti-platelets (DAPT) were inferior to anticoagulation with vitamin-K antagonists (VKA), in stroke prevention.⁷   

However, this does not mean that patients with AF and a score of zero have no risk of stroke – they do. This annual risk is probably less than 1% in this overall population,⁸ although it has been reported as high as 2.4%.⁹ Within this ‘low risk’ population, however, it may be hard to assess the true risk accurately in the individual and of course such risk may change in circumstances where there is an added hypercoagulable state, such as a malignancy or undergoing surgery and even perhaps during infection. 

A dilemma remains therefore on how to treat such patients. As these patients are younger by definition, then lifestyle advice, weight reduction and careful monitoring of blood pressure may help reduce paroxysmal episodes or development of persistent AF, which is desirable. Ablation should be considered as an option in all symptomatic and younger patients without structural abnormality, but a decision to anticoagulate remains a difficult one.

Current guidance should be tempered with specialist cardiac opinion and transoesophageal echocardiographic evaluation, as while the risk of stroke is probably less than 1% in such patients it is not zero, a fact that needs explaining to patients as the relatively rare occurrence of stroke in this population is difficult to accept as ‘rare bad luck’ when a known risk was present and seemingly untreated. 

Certainly in the ‘zero’ CHA2 DS2-VASC patient where the risk of bleeding, as determined by HAS-BLED, is low and other factors are present that may increase thrombogenic risk, or where cardiac opinion or imaging is suggestive of a ‘dangerous’ atrium, then it seems reasonable to consider anticoagulation outside the guideline. It is important to document the discussion in all cases with an indicative risk of stroke and bleeding explained to patients, together with an explanation of the lack of individual certainty in this group with available risk scores. This will usually, in my experience, prompt a patient to ask your advice. That is all after all why patients are consulting you and not Google!

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Hearts or minds? CAD with AF

Between 5% and 15% of patients undergoing percutaneous coronary intervention (PCI) and stent insertion will have concomitant AF. There is good evidence that use of oral anticoagulation (OAC) only in the patient with coronary artery disease (CAD) leads to an excess of acute coronary syndrome (ACS) and conversely that dual antiplatelet therapy (DAPT) only in the AF patient leads to an excess of stroke.^7,10 A therapeutic combination is therefore needed in the patient with both conditions, but combining an antiplatelet with an OAC doubles the risk of bleeding, and adding two, further increases that risk.¹¹

Furthermore, evidence suggests that OAC with VKA plus clopidogrel is associated with much less bleeding than traditional OAC+DAPT, with 19.4% patients receiving double therapy and 44.4% receiving triple therapy having significant bleeds (hazard ratio [HR] 0.36, 95% CI 0.26 to 0.50, p < 0.0001), without any excess of ACS or stent failure.¹²

More recent studies have looked at NOAC use in this setting. In PIONEER AF-PCI, two different rivaroxaban regimens were compared to ‘standard’ triple therapy with VKA and DAPT in over 2,000 patients undergoing PCI: low-dose rivaroxaban 15mg (10mg if creatine clearance  30-50ml/min) with clopidogrel and very low dose rivaroxaban 2.5mg twice daily combined with aspirin and clopidogrel.¹³ At 12 months 15mg rivaroxaban plus clopidogrel was compared to OAC with very-low dose rivaroxaban (2.5mg bd) or VKA and DAPT with clopidogrel and aspirin. DAPT durations of one, six and 12 months were examined in both these arms. Both rivaroxaban arms reduced the risk of significant bleeding at one year when compared to standard triple therapy with VKA (INR 2-3) in all DAPT durations with similar rates of myocardial infarction and stroke seen in all three arms.¹⁴ This is complicated however, as the trial was underpowered for efficacy and lower doses of rivaroxaban were not studied previously for stroke prevention in a large population. 

In RE-DUAL PCI, the safety of two doses of dabigatran (110mg or 150mg bid) in combination with clopidogrel or ticagrelor were compared with standard triple therapy (one or three months depending on stent used) with VKA, aspirin and either clopidogrel or ticagrelor in over 2,700 patients with AF undergoing PCI.¹⁵ Significant bleeding was reduced with both the 110mg and 150mg dabigatran dual therapy arms compared to the standard VKA triple therapy arm. Again the study was underpowered for efficacy and the majority of patients had clopidogrel rather than ticagrelor, but non-inferiority of dabigatran dual-therapy versus triple therapy was demonstrated in a composite endpoint of death, thromboembolic events and unplanned revascularisation. 

ESC guidelines emphasise that duration of DAPT is no longer dependent on the type of stent, ie. drug eluting stents (DES) or bare metal stents (BMS) but on the patient’s clinical scenario. As contemporary DES are as safe as BMS regarding risk of stent thrombosis, BMSs potentially no longer have an advantage in AF patients to reduce the duration of P2Y12 inhibitor therapy and risk of bleeding in patients also on OAC. DES also reduces the risk of restenosis and theoretically the likelihood of prolonged periods of OAC+DAPT or repeated interventions. Recent trials of modern DES suggest that short duration DAPT (ie. one month after elective stenting or six months after ACS) is a safe and effective strategy where there is a high bleeding risk and/or the patient is older.^16,17

Patients receiving (N)OAC in combination with DAPT are considered to be at high bleeding risk but the recent trials described above indicate rivaroxaban 15mg or dabigatran 110/150mg bid in dual therapy with clopidogrel mainly and without aspirin is safer in terms of bleeding risk than triple therapy with VKA, clopidogrel and low-dose aspirin. In addition rivaroxaban 2.5mg bid in triple therapy with aspirin and clopidogrel is safer in terms of bleeding risk than triple therapy with dose-adjusted VKA, clopidogrel and low-dose aspirin. Whether this lower dose rivaroxaban strategy constitutes enough evidence for a different guideline after ACS for AF patients on OAC for the first 12 months before reverting to conventional NOAC dosing remains to be seen. 

Prolonged antiplatelet therapy beyond one year after ACS or DES implantation has been suggested in patients not on an OAC based on large-scale randomised clinical trials such as the DAPT study trial, where patients were randomised 12 months after a PCI with DES to aspirin plus clopidogrel or aspirin alone for up to 30 months after the PCI. PEGASUS TIMI 54 trial randomised patients one to three years after an MI to aspirin plus ticagrelor or aspirin alone, and followed for a median of 33 months. While both studies showed a benefit on cardiovascular events at the expense of increased bleeding rates, patients in need of long-term OAC therapy were excluded and the results are of less relevance for treatment of AF patients.

Naturally there is a concern not to undo what has been achieved and to protect the repaired coronary artery, but our use of DAPT has historically probably been excessive in duration in the uncomplicated PCI and stent and the ongoing use of any antiplatelet in ‘remote’ and stable CAD while theoretically desirable, must be balanced against its additive risk with necessary anticoagulation in the AF patient.  

Notwithstanding recent advances in our research and understanding, some gaps remain and several key principles are re-enforced by the current ESC guidelines: 

All AF patients with high risk of stroke and/or mechanical heart valves need to continue their oral anticoagulation (OAC) up to, during and after PCI and stenting

ACS patients with AF will require a period on OAC and DAPT which should be kept to one to six months depending on relative risk of bleeding and risk of further ACS/stent thrombosis (see Figure 1)

Patients should not continue on both OAC and an antiplatelet (APT) beyond 12 months in most cases

When choosing an OAC, preference should be for a NOAC at the lowest effective dose licensed for stroke prevention (unless patient has a mechanical heart valve or renal failure precluding their use, in which case a VKA such as warfarin must be employed)

As data on their use is still limited, prasugrel or ticagrelor should be avoided as part of the triple therapy in the AF patient with ACS unless there is a clear advantage to their use (such as stent thrombosis previously on aspirin + clopidogrel). 

See Figure 2 for ESC guideline on use of antiplatelets after ACS in AF patients in need of OAC.

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Russian roulette: the risk of stopping anticoagulation for a procedure?

Common questions that cross my desk are: 

“Is it is safe to stop anticoagulation in this AF patient in order to do procedure ‘x’?

“When should I stop anticoagulation before doing x?”

The answer to the former is a nuanced one while that to the latter largely depends on the risk of bleeding and is best answered by the person doing the procedure with a little guidance.

 Bridging studies involving VKAs showed  there is no benefit to be gained by bridging with low-molecular-weight heparin (LMWH) while transitioning off warfarin with INR monitoring pre-surgery²⁰ and such a strategy doubled the risk of bleeding. The risk of stroke however in such circumstances is not zero and this trial and others suggest it is in fact between 0.3-1% while off anticoagulation. In this regard it can never be totally safe to stop anticoagulation in an AF patient at risk of stroke and it is the patient themselves that must weigh up the necessity and benefit of the procedure versus the small risk of stroke while off anticoagulation. 

While only the patient can really make this judgement, in looking for guidance our advice must emphasise the low risk of stroke where surgery is very necessary in our opinion, and conversely urge a little caution where surgery may be an equivocal call on benefit to life or quality of life, though the latter is very patient determined. Again clear documentation of the discussion is important as a peri-procedural stroke is difficult for everyone concerned. It is probably also good advice to AF patients to ensure that the hospital in which they are planning to have any major procedures has a good  pathway of care in the event of a stroke.

When stopping anticoagulation before a procedure the matter is somewhat more straightforward for patients still using warfarin as INR can be measured to reassure surgeons that they are operating at a level of anticoagulant effect they are comfortable with. For many minor procedures such as removal of skin lesions or simple dental extractions  an operator may be happy to proceed as long as the INR is not excessively above 2. 

In the case of NOAC medication, a little knowledge of individual pharmacokinetics and renal function is needed  (see Table 1)  but in general if the procedure carries a low risk of bleeding and renal function (as estimated by  the Cockroft-Gault equation) is normal then all the factor Xa inhibitors (apixiban, edoxaban, rivaroxaban) can be safely stopped 24 hours pre-procedure. If the procedure carries a high risk of bleeding they should be stopped 48 hours pre-procedure. These intervals rise to 36 before low risk and 48 hours before high risk procedures where creatinine clearance is estimated to be less than 30ml/min. As dabigatran is more dependent on renal excretion, the interval of cessation before high or low risk procedure is more closely linked with eGFR stratification as outlined Table 2.

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References 

1. Donoghue OA, Jansen S, Dooley C et al. Atrial fibrillation is associated with impaired mobility in community-dwelling older adults. J Am Med Dir Assoc 2014 Dec; 15(12):929-33
2. Chugh SS, Havmoeller R, Narayanan K et al. Worldwide epidemiology of atrial fibrillation: a Global Burden of Disease 2010 Study. Circulation 2014; 129(8):837-47
3. Fang MC, Go AS, Chang Y et al (ATRIA Study Group). Comparison of risk stratification schemes to predict thromboembolism in people with nonvalvular atrial fibrillation. J Am Coll Cardiol 2008; 51(8):810-5
4. Ruff CT, Giugliano RP, Braunwald E et al. Cardiovascular Biomarker Score and Clinical Outcomes in Patients With Atrial Fibrillation: A Subanalysis of the ENGAGE AF-TIMI 48 Randomized Clinical Trial. JAMA Cardiol 20161; 1(9):999-1006
5. Leung M, van Rosendael PJ, Abou R et al. Left atrial function to identify patients with atrial fibrillation at high risk of stroke: new insights from a large registry. Eur Heart J 2017 Dec 28. doi: 10.1093/eurheartj/ehx736
6. Kirchhof P, Benussi S, Kotecha D et al. 2016 ESC Guidelines for the management of atrial fibrillation developed in collaboration with EACTS. Europace 2016; 18(11): 1609-1678
7. ACTIVE Writing Group of the ACTIVE Investigators. Clopidogrel plus aspirin versus oral anticoagulation for atrial fibrillation in the Atrial fibrillation Clopidogrel Trial with Irbesartan for prevention of Vascular Events (ACTIVE W): a randomised controlled trial. Lancet 2006  10; 367(9526):1903-12.
8. Manolis AS, Manolis TA, Manolis AA, Melita H. Stroke risk stratification schemes in atrial fibrillation in the era of non-vitamin K anticoagulants: misleading and obsolete, at least for the ‘low-risk’ patients? Curr Drug Targets 2017; 18(16):1852-1865
9. Huang D, Anguo L, Yue WS, Yin L, Tse HF, Siu CW. Refinement of ischemic stroke risk in patients with atrial fibrillation and CHA2 DS2 -VASc score of 1. Pacing Clin Electrophysiol 2014 Nov; 37(11):1442-7 
10. Rubboli A, Colletta M, Valencia J et al (WARfarin and Coronary STENTing (WAR-STENT) Study Group). Periprocedural management and in-hospital outcome of patients with indication for oral anticoagulation undergoing coronary artery stenting. J Interv Cardiol 2009 Aug; 22(4):390-7. 
11. Hansen ML, Sørensen R, Clausen MT et al. Risk of bleeding with single, dual, or triple therapy with warfarin, aspirin, and clopidogrel in patients with atrial fibrillation. Arch Intern Med. 2010 Sep 13; 170(16):1433-41 
12. Dewilde WJ, Oirbans T, Verheugt FW et al (WOEST study investigators). Use of clopidogrel with or without aspirin in patients taking oral anticoagulant therapy and undergoing percutaneous coronary intervention: an open-label, randomised, controlled trial. Lancet 2013 Mar 30; 381(9872):1107-15
13. Gibson CM, Mehran R, Bode C et al. An open-label, randomized, controlled, multicenter study exploring two treatment strategies of rivaroxaban and a dose-adjusted oral vitamin K antagonist treatment strategy in subjects with atrial fibrillation who undergo percutaneous coronary intervention (PIONEER AF-PCI). Am Heart J 2015; 169(4):472-8 e5
14. Gibson CM, Mehran R, Bode C et al. Prevention of bleeding in patients with atrial fibrillation undergoing PCI. N Engl J Med 2016; 375(25):2423-2434
15. Cannon CP, Bhatt DL, Oldgren J et al. Dual antithrombotic therapy with dabigatran after PCI in atrial fibrillation. N Engl J Med 2017; 377(16):1513-24
16. Urban P, Meredith IT, Abizaid A et al. Polymer-free Drug-Coated Coronary Stents in Patients at High Bleeding Risk. N Engl J Med 2015; 373(21):2038-47
17. Varenne O, Cook S, Sideris G et al. Drug-eluting stents in elderly patients with coronary artery disease (SENIOR): a randomised single-blind trial. Lancet 2017; 391(10115):41-50
18. Mauri L, Kereiakes DJ, Yeh RW et al. Twelve or 30 Months of Dual Antiplatelet Therapy after Drug-Eluting Stents. N Engl J Med 2014; 371(23):2155-2166
19. Bonaca MP, Bhatt DL, Cohen M et al. Long-term use of ticagrelor in patients with prior myocardial infarction. N Engl J Med 2015; 372(19):1791-800
20. Douketis JD, Spyropoulos AC, Kaatz S et al (BRIDGE Investigators).Perioperative Bridging Anticoagulation in Patients with Atrial Fibrillation. N Engl J Med. 2015 Aug 27;373(9):823-33