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.

References

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Clinical Topics: Anticoagulation Management, Arrhythmias and Clinical EP, Pericardial Disease, Anticoagulation Management and Atrial Fibrillation, Atrial Fibrillation/Supraventricular Arrhythmias

Keywords: Atrial Appendage, Atrial Fibrillation, Boston, Hemorrhage, Pericardial Effusion, Stroke, Warfarin


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