Anticoagulation for Non-Valvular Atrial Fibrillation: Why is it So Difficult to Accept an Alternative?
Atrial Fibrillation (AF) is well recognized as the most common arrhythmia in clinical practice, estimated to occur in 1-2% of the general population. With millions affected in the US alone and nearly ten million estimated worldwide, the projected numbers over the next decade are staggering. The prevalence is expected to double by 2050.1-4
Regardless of the type, AF confers a five-fold risk of stroke.5 Nearly 20% of all strokes are attributed to this arrhythmia. Patients with a history of stroke have a significantly higher risk of recurrent stroke. These AF associated strokes tend to cause greater morbidity and mortality than strokes from other causes.6
Since the introduction of warfarin over 50 years ago, anticoagulation (AC) has been the primary mode of therapy for embolic stroke risk reduction. The struggles with warfarin use remain, with the ability to maintain time in the therapeutic range in clinical trials ranging from 55-65%.7,8 This compounded by underutilization of AC in the elderly, those at highest risk of embolic events, mandates the need for alternative strategies.9 Novel drugs (non-vitamin K dependant) have increased the AC options but an inability to monitor AC effect, potential increased risks of bleeding in the elderly and lack of reversibility still limit their use in patients at high risk for bleeding.10 "Why should I take a medicine that thins the blood in my whole body if the blood clots are only coming from my heart?" is a seemingly logical question often asked by many patients.
Irrespective of one's opinion in the matter of source of cardiac emboli in nonvalvular AF, randomized control study directed at local therapy alone with left atrial appendage (LAA) occlusion (Watchman, Boston Scientific Corp.) versus systemic AC validate the effectiveness of local therapy with a LAA occlusion strategy.11 This initial short term analysis showed noninferiority to warfarin. As expected, longer follow-up revealed gradual increases in event rates of stroke, systemic embolism and cardiovascular death in the warfarin (control) arm12 and with a mean follow-up of four years, statistically significant reductions in all three metrics were observed with this LAA occlusion strategy with superiority in primary efficacy (hazard ratio of 0.61) and reduction in cardiovascular mortality (p=0.0045) and all cause mortality (p=0.0379).13
While recognizing a procedural complication rate, safety data from the Protect-AF trial and the subsequent continued access registry (CAP) of more experienced implanters has shown clear evidence of a learning curve.14 There was a significant decline in the rate of procedure- or device-related safety events within seven days of the procedure across the two studies, with 7.7% and 3.7% of patients, respectively, experiencing events (P=0.007). The rate of serious pericardial effusion within seven days of implantation, which had made up > 50% of the safety events in Protect AF, was lower in the CAP Registry (5.0% vs. 2.2%, respectively; P=0.019). There was a similar experience-related improvement in procedure-related stroke (0.9% vs. 0%, respectively; P=0.039). In the confirmatory safety trial, the Prevail study, 40% of the patients were enrolled at new sites by new operators. Not only were the Watchman implant success rates the highest at 95%, but the acute primary endpoint of seven-day procedural safety was met.15
When the functional impact of the primary efficacy and safety events (including both device-related and nonprocedural events) was considered in terms of disability or death, device based therapy was associated with improved outcomes and quality of life.12,16 All analyses (including the intention-to-treat and the secondary analyses) demonstrated a statistically improved clinical outcome in the LAA closure group over the control group. In patients at highest risk, those with previous stroke or transient ischemic attack (131 patients, 19%, who met this criterion at entry) the rate of primary efficacy events was 5.3% per year in the group assigned to LAA closure vs. 8.2% per year in those randomized to ongoing AC.
A net clinical benefit (NCB) analysis of the Protect AF trial and CAP registry examined the annualized rates of ischemic stroke, intracranial hemorrhage, major extracranial bleeding, pericardial effusion, and death.17 The results shed light on optimum selection of patients with AF for percutaneous LAA closure as an alternative to long-term AC. Analysis of the randomized trial cohort found the NCB of closure greatest for patients at highest risk for stroke — most notably those with higher CHADS2 scores, and those in whom LAA closure was employed as secondary prevention. As complication rates decreased in the CAP registry, the NCB more clearly favored intervention.
In spite of this convincing evidence, there is still some skepticism an interventional approach is best for the patient due to persistent safety concerns. The data showing the safety of LAA closure with the Watchman device is essentially based on an early generation device and first in man experience by most operators. In historical context and comparison, initial 3.5-year clinical experience on the safety of PTCA reported success in only 63% of patients with major complications in 9%.18 Yet another example, the early experience of permanent transvenous pacemaker implantation, was also consistent with high complication rates as seven of the first 33 patients reported in 1967 had major complications.19 Fortunately, in the aforementioned procedural examples, there was substantial foresight at the time, which set the groundwork for continuous improvement. These didactics must be applied to the LAA closure arena to encourage a more universal acceptance of this progressive technology.
LAA closure represents a paradigm shift in the management of high risk patients with AF. While the Protect AF data using the Watchman device cannot be applied to other LAA closure technology due to device and technique variances, it represents a proof of concept of a LAA closure strategy. As these novel devices and techniques are developed, studied and refined,20,21 LAA closure can develop as a primary therapy in the majority of these patients.
- Wolf PA, Abbott RD, Kannel WB. Atrial fibrillation as an independent risk factor for stroke: The Framingham Study. Stroke 1991;22:983–988.
- Lloyd-Jones DM, Wang TJ, Leip EP, Larson MG, Levy D, Ramachandran SV, D'Agostino RB, Massaro JM, Beiser A, Wolf PA, Benjamin EJ. Lifetime risk for development of atrial fibrillation: The Framingham Heart Study. Circulation 2004;110:1042-1046.
- Go AS, Hylek EM, Phillips KA, Chang Y, Henault LE, Selby JV, Singer DE. Prevalence of diagnosed atrial fibrillation in adults: national implications for rhythm management and stroke prevention: the AnTicoagulation and Risk Factors in Atrial Fibrillation (ATRIA) Study. JAMA 2001;285:2370–2375.
- The Task Force for the Management of Atrial Fibrillation of the European Society of Cardiology (ESC). Guidelines for the management of atrialfibrillation. Eur Heart J 2010;31:2369–2429
- Kirchhof P, Auricchio A, Bax J, Crijns H, Camm J, Diener HC, Goette A, Hindricks G, Hohnloser S, Kappenberger L, Kuck KH, Lip GY, Olsson B, Meinertz T, Priori S, Ravens U, Steinbeck G, Svernhage E, Tijssen J, Vincent A, Breithardt G. Outcome parameters for trials in atrial fibrillation: executive summary. Recommendations from a consensus conference organized by the German Atrial Fibrillation Competence NETwork (AFNET) and the European Heart Rhythm Association (EHRA). Eur Heart J 2007;28:2803–2817.
- Stewart S, Hart CL, Hole DJ, McMurray JJ. A population-based study of the long term risks associated with atrial fibrillation: 20-year follow-up of the Renfrew/ Paisley study. Am J Med 2002;113:359–364.
- Connolly SJ, Ezekowitz MD, Yusuf S, Eikelboom J, Oldgren J, Parekh A, Pogue J, Reilly PA, Themeles E, Varrone J, Wang S, Alings M, Xavier D, Zhu J, Diaz R, Lewis BS, Darius H, Diener HC, Joyner CD, Wallentin L; RE-LY Steering Committee and Investigators. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009;361:1139–1151.
- Patel MR, Mahaffey KW, Garg J, Pan G, Singer DE, Hacke W, Breithardt G, Halperin JL, Hankey GJ, Piccini JP, Becker RC, Nessel CC, Paolini JF, Berkowitz SD, Fox KA, Califf RM; ROCKET AF Investigators ROCKET AF Investigators. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 2011;365:883–891.
- Go AS, Hylek EM, Borowsky LH, Phillips KA, Selby JV, Singer DE. Warfarin use among ambulatory patients with nonvalvular atrial fibrillation: the anticoagulation and risk factors in atrial fibrillation (ATRIA) study. Ann Intern Med 1999;131:927-34.
- Cullen MW, Kim S, Piccini JP Sr, Ansell JE, Fonarow GC, Hylek EM, Singer DE, Mahaffey KW, Kowey PR, Thomas L, Go AS, Lopes RD, Chang P, Peterson ED, Gersh BJ; on behalf of the ORBIT-AF Investigators. Risks and Benefits of Anticoagulation in Atrial Fibrillation: Insights From the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF) Registry. Circ Cardiovasc Qual Outcomes 2013 Jun 11. [Epub ahead of print]
- Holmes DR, Reddy VY, Turi ZG, Doshi SK, Sievert H, Buchbinder M, Mullin CM, Sick P; PROTECT AF Investigators. Percutaneous closure of the left atrial appendage versus warfarin therapy for prevention of stroke in patients with atrial fibrillation: a randomised non-inferiority trial. Lancet 2009;374:534-42.
- Reddy VY, Doshi SK, Sievert H, Buchbinder M, Neuzil P, Huber K, Halperin JL, Holmes D; PROTECT AF Investigators. Percutaneous Left Atrial Appendage Closure for Stroke Prophylaxis in Patients with Atrial Fibrillation: 2.3-Year Follow-up of the PROTECT AF (Watchman Left Atrial Appendage System for Embolic Protection in Patients with Atrial Fibrillation) Trial. Circulation 2013;127:720-9.
- Reddy VY, Doshi SK, Sievert H, Buchbinder M, Neuzil P, Huber K, Kar S, Halperin J, Whisenant B, Swarup V, Holmes D. Long Term Results Of Protect AF: The Mortality Effects Of Left Atrial Appendage Closure Versus Warfarin For Stroke Prophylaxis In AF. Presented at the 2013 Annual Scientific Sessions of the Heart Rhythm Society. LB01-03 Session Number: SP21, May 9, 2013.
- Reddy VY, Holmes D, Doshi SK, Neuzil P, Kar S. Safety of Percutaneous Left Atrial Appendage Closure: Results from the Watchman Left Atrial Appendage System for Embolic Protection in Patients with AF (PROTECT AF) Clinical Trial and the Continued Access Registry. Circulation 2011;123:417-24.
- Holmes DR, Doshi SK, Kar S, Sanchez J, Swarup V, Whisenant B, Valderrabano M, Huber K, Lustgarten D, Reddy VR on behalf of the PREVAIL investigators. Results of Randomized Trial of LAA Closure vs Warfarin for Stroke/ Thromboembolic Prevention in Patients with Non-valvular Atrial Fibrillation (PREVAIL). CIT. Beijing, China. April 2013. Invited Presentation.
- Alli O, Doshi S, Kar S, Reddy V, Sievert H, Mullin C, Swarup V, Whisenant B, Holmes D Jr. Quality of Life Assessment in the Randomized PROTECT AF (Percutaneous Closure of the Left Atrial Appendage Versus Warfarin Therapy for Prevention of Stroke in Patients With Atrial Fibrillation) Trial of Patients at Risk for Stroke with Nonvalvular Atrial Fibrillation. J Am Coll Cardiol 2013;61:1790-8.
- Gangireddy SR, Halperin JL, Fuster VL, Reddy VR. Percutaneous left atrial appendage closure for stroke prevention in patients with atrial fibrillation: an assessment of net clinical benefit. Eur Heart J 2012;33:2700-8.
- LG, Block PC, Bourassa M, Detre K, Gosselin AJ, Grüntzig AR, Kelsey SF, Kent KM, Mock MB, Mullin SM, Myler RK, Passamani ER, Stertzer SH, Williams DO. Percutaneous transluminal coronary angioplasty: report of complications from the National Heart, Lung, and Blood Institute PTCA Registry. Circulation 1983;67:723-30.
- Firor WB, Goldman BS. Initial experience with the permanent implantable transvenous pacemaker: a report of 33 patients. Can Med Assoc J 1967;96:144-7.
- Singh SM, Dukkipati SR, d'Avila A, Doshi SK, Reddy VR. Percutaneous left atrial appendage closure with an epicardial suture ligation approach: A prospective randomized pre-clinical feasibility study. Heart Rhythm 2010;7:370-6.
- Park JW, Bethencourt A, Sievert H, Santoro G, Meier B, Walsh K, Lopez-Minquez JR, Meerkin D, Valdés M, Ormerod O, Leithäuser B. Left atrial appendage closure with Amplatzer cardiac plug in atrial fibrillation: initial European experience. Catheter Cardiovasc Interv 2011;77:700–706.
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