Left Atrial Appendage Closure vs. Novel Anticoagulation Agents in Atrial Fibrillation
Left Atrial Appendage Closure vs. Novel Anticoagulation Agents in Atrial Fibrillation
Atrial fibrillation (AF) is the most common cardiac arrhythmia with a prevalence of 1-2%.
 Without antithrombotic treatment, the annual risk of a cardioembolic event is 5-6%. The
 source of a cardioembolic event is a thrombus, which usually forms in the left atrial
 appendage (LAA). The prevention of cardioembolic events involves treatment with anticoagulant
 drugs, which were limited to, until recently, vitamin K antagonists (e.g. warfarin).
 Anticoagulant treatment with warfarin can lead to adverse bleeding events, some of which can
 be life threatening. Recently, two new options for thrombus prevention have been developed.
 The first is the novel anticoagulants (NOAC), which were associated with slightly better
 safety profiles due to a lower frequency of intracranial bleeding in large randomized trials
 . The second option involves interventional occlusion of the LAA. The aim of this project is
 to compare the LAA occlusion intervention to NOAC pharmacological treatment in a randomized
 multicenter study of AF patients at high risk of a cardioembolic event.
Interventional left atrial appendage closure vs. novel anticoagulation agents in high-risk
 patients with atrial fibrillation (PRAGUE-17 study)

 INTRODUCTION Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia with a
 prevalence of 1-2% in the general population; additionally, the incidence increases with age.
 (1) Among the elderly 75 years and older, its incidence is 12%. (2) AF is associated with a
 five-fold risk of a cardioembolic event; approximately 20% of all strokes are due to AF. (3)
 The annual risk of stroke in AF patients is 5 -6 % in AF patients without antithrombotic
 treatment. Moreover, a stroke due to AF is typically more severe, i.e. associated with worse
 neurological deficits. (4) Not only does the incidence of AF increase with age, the risk of
 strokes in AF patients also increases with age with age: in patients between 50-59 years, the
 risk of stroke is about 1.5%, while in patients between 80 - 90, the risk increases to about
 23%. (5) The source of an embolic stroke is a thrombus, which forms in the left atrium (LA)
 due to insufficient mechanical contraction of LA. Most often thrombi arise in the left atrial
 appendage (LAA); according to data from autopsies and findings from transesophageal
 echocardiography (TEE) in AF patients, approximately 90% of all left atrial thrombi arise in
 the LAA. (6) In addition to insufficient mechanical contraction of LA, the pro-coagulant
 status of patients also plays an important role in thrombus development. A patient's risk
 profile is characterized according to the CHA2DS2-VASc score. Each letter presents one
 recognized risk factor (C - congestive heart failure or left ventricular dysfunction, H -
 hypertension, A - age > 75 years (2 points), D - diabetes, S - history of stroke (2 points),
 V - present vascular disease (atherosclerosis), A - age > 65 years, Sc- female sex. In the
 CHA2DS2-VASc scoring system, each risk factor is evaluated as either 1 or 2 points. The sum
 of all points presents the annual risk of a cardioembolic event, in percent. The prevention
 of strokes or other systemic cardioembolic events (thrombus can embolize to peripheral artery
 of upper or lower extremity, artery supplying gastrointestinal tract, renal artery etc.)
 involve treatment using anticoagulant drugs, which were, until recently, vitamin K
 antagonists only (e.g. warfarin). These drugs block the effect of vitamin K in the liver,
 which in turn blocks the production of coagulant factors II, VII, IX, and X. As a result, the
 coagulation cascade is slowed. The efficacy of warfarin is estimated using International
 Normalized Ratio (INR); the effective INR to prevent thrombus formation in AF patients is
 between 2.0 and 3.0. The amount of vitamin K in food varies, which can lead to variations in
 INR despite a stable warfarin dose. This represent one of the disadvantages of warfarin
 treatment. In large randomized trials, in which all patients are very carefully followed,
 only 65% of INR values were successfully maintain between 2.0 and 3.0. (7) In real clinical
 praxis, it was shown that only 50% of all INR values are within the desired range. (8) This
 can easily lead to both overtreatment and undertreatment of patients. Vitamin K antagonism is
 thought to be effective when 70% of INR values are maintained in the therapeutic range. (9)
 Another disadvantage of warfarin treatment involves dietary restrictions.

 Recently, several new drugs that can block coagulation have been discovered, and are
 appropriately named novel anticoagulants (NOAC). These new drugs include direct thrombin
 (factor IIa) inhibitors, such as dabigatran, and inhibitors of factor Xa, such as rivaroxaban
 and apixaban. In contrast to warfarin, they block a single step in the coagulation cascade.
 The dosing of these drugs does not have to be adjusted based on laboratory tests, like
 warfarin. Stable concentrations of these drugs are achieved by once or twice daily dosing,
 according to their half-lives. Dosing only needs to be adjusted when there is significant
 comorbidity (i.e. renal or liver function) and no dietary restrictions are needed. In large
 prospective multicenter studies, NOAC were non-inferior to warfarin, i.e. prevention of
 systemic cardioembolic events was similar between patients treated by warfarin and NOAC. (10)
 (11) (12) (13) Additionally, NOAC were associated with slightly better safety profiles
 relative to the lower frequency of intracranial bleeding. (10) (11) (12) (13)

 The prevention of thrombus formation in the fibrillating atrium by anticoagulation has been
 shown to be effective; however, adverse bleeding events can occur with both warfarin (even in
 the therapeutic range) and NOAC. The frequency of any (major or minor) bleeding during NOAC
 treatment is approximately 15-18% per year; severe bleeding can lead to hospitalization or
 even death.

 The risk of bleeding can be estimated using the HAS-BLED scoring system. Each letter presents
 a risk factor for bleeding (H - hypertension, A - abnormal liver or renal function, S -
 history of stroke, B - history of bleeding, L - labile INR, E - elderly patients, and D -
 drugs, alcohol consumption). Patients with HAS-BLED scores > 3 are considered to be at high
 risk of bleeding.

 The limitation of anticoagulative drugs was one of reasons behind the development of
 nonpharmacological treatments for AF. Because about 90% of left atrial thrombi occur in the
 LAA; (6) the occlusion of the LAA is the main non-pharmacological option for prevention of
 cardioembolic event from the LA. LAA occlusion is performed using a percutaneous approach;
 the catheter is inserted through the femoral vein via a transseptal puncture into the LA. The
 LAA is visualized and closed using a special device. Currently, two different devices are
 present on the market (Watchman, Boston Scientific and Amplatzer Cardiac Plug, St. Jude
 Medical). The largest trial published regarding LAA occlusion was the PROTECT trial. (14) In
 this prospective randomized multicenter trial, occlusion of the LAA using a Watchman device
 was compared with standard warfarin treatment. The LAA occlusion was non-inferior to
 warfarin; the incidence of cardioembolic events and death was similar in both groups (3% of
 patients per year in the LAA occlusion group vs. 4.9% of patients per year in the warfarin
 group). The major disadvantage of LAA occlusion was related to peri-procedural and
 device-related complications, which were present in 7.4% of patients per year. Fifty-five
 percent of the reported adverse event occurred on the day of the procedure and the most often
 was significant pericardial effusion, which was present in 4.8% patients. In summary, LAA
 occlusion can be associated with significant risk of peri-procedural complications;
 additionally, while it is reduced, the risk of thrombus formation in the LA is not
 eliminated. In other study assessing LAA occlusion, periprocedural and device-related
 complications occurred in 6 - 8%. (15) Despite the risk, LAA occlusion presents a very
 promising alternative to anticoagulant treatment for patients with a very high risk of
 bleeding, or in those contraindicated for warfarin or NOAC. For patients with the highest
 CHA2DS2-VASc and HAS-BLED scores, no studies have been published to date, and no studies are
 in progress according to the randomized trial study registry. The inclusion criterion in the
 PROTECT study was a CHADS2 score > 1, with approximately 1/3 of patients having a CHADS2 of 1
 only. (14) The anticoagulation treatment is well established in the majority of patients with
 AF in standard clinical practice; however, despite the anticoagulation treatment, systemic
 cardioembolic event can occur and bleeding risks can be very serious. In the largest study
 with rivaroxaban, the ROCKET study, in which the drug was compared to warfarin, the annual
 incidence of stroke was in 1.7 - 2.2% of patients and the annual incidence of any bleeding
 (both major and minor) was 15% (11) Similarly, in the ARISTOTLE study, in which another NOAC
 apixaban was compared to warfarin, the annual incidence of cardioembolic event was 1.27 -
 1.6%, and the annual risk of major or clinically significant bleeding was 4 - 6%.(10) The
 best treatment for those AF patients at highest risk, i.e.

 patients with high CHA2DS2-VASc scores and a very high bleeding risk, is still not known.
 Moreover, the number of such patients has been increasing due to the increasing age of the
 general population.

 Therefore, treatment of these patients presents a serious problem for clinical practice and a
 search for the optimal solution is warranted. The safety profile for NOAC seems to be
 slightly better than warfarin; nonetheless, the bleeding risk with NOAC is not negligible,
 which is evident by comparing the CHA2DS2-VASc and HAS-BLED scoring systems: some factors
 increase the risk for both thrombotic and bleeding events.

 The Aim of our project is to compare LAA occlusion with NOAC in a randomized multicenter
 study of AF patients at the greatest risk. Such randomized study has never been done.

 PATIENTS AND METHODS Patients with AF with an indication for anticoagulation will be eligible
 for the study. Inclusion criteria will be the presence of AF (paroxysmal, persistent or
 permanent), signed informed consent and one of the following criteria

 1. history of significant bleeding (i.e. bleeding which required intervention or
 hospitalization), even in the absence of anticoagulation treatment at the time of the
 bleeding event, or

 2. a cardioembolic event, which occurred on anticoagulation, or

 3. a high risk profile of the patient, defined as a CHA2DS2-VASc score ≥ 3 and a HAS-BLED
 score ≥ 2

 Exclusion criteria will be as follows:

 1. thrombus in the LA or LAA;

 2. mechanical valve prosthesis;

 3. mitral stenosis;

 4. previous LAA ligation during cardiac surgery;

 5. life expectancy less than 2 years;

 6. comorbidities other than AF, which present an indication for anticoagulation;

 7. patent foramen ovale with atrial septal aneurysm

 8. mobile plaque in the aorta;

 9. symptomatic atherosclerosis of the carotid artery;

 10. pericardial effusion greater than 10 mm;

 11. clinically significant bleeding within the 30 days prior to the scheduled procedure;

 12. stroke or other cardioembolic event within the 30 days prior to the scheduled procedure;

 13. acute coronary syndrome within the 90 days prior to the scheduled procedure,

 14. gravidity,

 15. significant valvular disease,

 16. creatinine clearance less than 30 ml/min

 A routine TEE will not be done on all patients before randomization. If the patient is
 randomized to the LAA occlusion arm, a TEE examination will be done to exclude the presence
 of a thrombus in the LA or LAA before the invasive procedure. The presence of a thrombus in
 the LAA or LA is an additional exclusion criterion (patients with a thrombus in the LAA will
 be removed from analyses).

 Next, a cardiac CT will be done to assess the morphology of the LAA, and a blood sample will
 be drawn for assessment of natriuretic peptides and cytokines.

 Patients will be randomized to the interventional LAA occlusion (group A) or NOAC treatment
 (group B) in a 1/1 ratio, the randomization will be done using web-based randomization
 software. The software is designed to respect the CHA2DS2VASc characteristics of patients,
 i.e., the goal is to have comparable CHA2DS2VASc in both arms at the end of the study. The
 randomization process will be done outside all participating centers and therefore it will be
 masked from study subjects and site personnel.

 For those randomized to group A (LAAO group), an interventional LAA occlusion will be
 performed. The type of LAA occlusion system will be left on the discretion of the implant
 center; however, only Amulet device (St. Jude Medical) and the Watchman device (Boston
 Scientific) are available for use in this study. The goal will be to achieve approximately
 half of patients implanted with the Watchman system (Boston Scientific) and the other half
 implanted with the Amulet system (St. Jude Medical). The protocol and LAA imaging for the
 procedure will use the current praxis of the surgeon: the procedure can be done under TEE,
 ICE, or angiographic visualization and control, depending on the experience and preference of
 the particular center and surgeon.

 After the procedure, all patients will be treated with a combination of aspirin 100 mg (once
 daily) and clopidogrel 75 mg (once daily) for three months. After three months, a control TEE
 will be done. If the TEE finding is satisfactory (i.e., the absence of a thrombus on the
 device, and the absence of peri-device leakage or a leakage line of less than 5 mm, and a
 satisfactory position of the device as assessed by the surgeon), the clopidogrel will be
 discontinued, however, the aspirin (100 mg, once daily) will be continued. Additional
 transesophageal echocardiographies are not planed unless indicated by the clinical status of
 the patient.

 In some patients, the duration of dual antiplatelet treatment could be individualized taking
 into consideration the particular risks of that patients. In patients with very high bleeding
 risk (e.g. patients with a history of repeated bleedings), the duration of dual antiplatelet
 treatment could be shortened to 6 weeks. After that, if a control TEE yields satisfactory
 results, clopidogrel could be discontinued and patients could be left on aspirin monotherapy
 only. Six-weeks of dual antiplatelet treatment has been recently shown to be sufficient after
 LAA occlusion. (16) On the other hand, in patients with a significant thrombotic risk (e.g.
 with a history of repeated cardioembolic events, but without a history of overt bleeding),
 the duration of dual antiplatelet treatment could be prolonged to 6 months. The decision
 (i.e., the assessment of the individual risk profile of an implanted patient) and the
 patient-specific approach will be left to the discretion of the treating physician.

 Experience with the LAA occlusion procedure In studies published regarding LAA occlusion, the
 experience of the interventional cardiologist (learning curve) and staff was shown to be very
 important; i.e. the number of complications during the first implantations were significantly
 higher compared to those that followed. (14, 17) To prevent interventional lack of experience
 from affecting outcomes, the other two teams will start performing the procedures before the
 initiation of the study, with the goal of doing at least 5- 10 LAA occlusions before the
 start of the study. This first 5-10 LAA occlusion will be done not according to the inclusion
 criteria of our study, but the patients will be enrolled according to the current standard
 criteria and guidelines for LAA occlusion. Additionally, the first 5-10 procedures in the
 study will be done with the assistance of an interventional cardiologist experienced with LAA
 occlusion.

 For those randomized to group B (NOAC group), patients will be treated using a registered
 NOAC (rivaroxaban, apixaban or dabigatran, but preferentionally apixaban) at the dose
 recommended by the manufacturer (in a case of apixaban 5 mg or 2.5 mg twice daily) and
 adjusted relative to comorbidities (body weight, age, and renal function).

 Outpatient follow-up will be done at 6 weeks, 3, 6, 9, and 12 months after randomization and
 then every 6 months. At the 6-month follow-up, a blood sample will be drawn for cytokines
 measurement.

 Endpoints: The primary endpoint of the study will be the occurrence of any of the following
 events within 24 months following randomization:

 (1) stroke or TIA (any type), (2) systemic cardioembolic event, (3) clinically significant
 bleeding 4) cardiovascular death (5) a significant peri-procedural or device-related
 complication.

 A stroke is defined as the sudden onset of a focal neurologic deficit, from a nontraumatic
 cause, in a location consistent with the territory of a major cerebral artery and categorized
 as either ischemic, hemorrhagic, or unspecified. An imaging examination (CR, MRI) will be
 recommended. A TIA is defined according to current standard criteria, i.e., as a stroke with
 relief of symptoms within 24 hours. Systemic cardioembolic events will be defined as an acute
 vascular occlusion of an extremity or organ, documented with imaging (CT angiography,
 percutaneous interventional angiography), surgery, or autopsy.

 Clinically significant bleeding will be a composite of major and non-major clinically
 significant bleeding. Clinically significant major bleeding will be defined according to the
 criteria of the International Society on Thrombosis and Hemostasis (ISTH), as clinically
 overt bleeding accompanied by one or more of the following: a decrease in hemoglobin level ≥
 20 g/l over a 24-hour period, transfusion of 2 or more units of packed red cells, bleeding at
 a critical site (intracranial, intraspinal, intraocular, pericardial, intramuscular with
 compartment syndrome, or retroperitoneal), or fatal bleeding. (18) This definition is the
 same as that used recently in all trials comparing NOAC with warfarin. Clinically significant
 non-major bleeding will be defined similarly as it was in the ROCKET trial, i.e., any
 bleeding requiring hospitalization or invasive procedure, which doesn´t meet the ISTH major
 criteria.

 Peri-procedural and device-related complications will be evaluated as significant if there is
 (1) a pericardial effusion requiring drainage, surgery, or pericardiocentesis, (2) a
 cardioembolic event during the procedure, (3) significant peri-procedural bleeding (i.e.,
 major vascular bleeding requiring surgical revision, or blood concentrate transfusion), (4)
 device embolization, or (5) a thrombus on the device with a consequent cardioembolic event.

 The secondary endpoints will be the incidence of each component of the primary end-point;
 quality of life (assessed by patients using Health-related quality of life questionnaire,
 i.e. the questionnaire which was used in the PROTECT study)(19), minor bleeding, a comparison
 of economic costs, an analysis of changes in cytokine concentrations (natriuretic peptides
 and other inflammatory and pro-thrombotic cytokines) before the procedure and at 6 months,
 and the relationship of LAA morphology to success of the LAA occlusion and the risk of
 systemic cardioembolic events.

 Minor bleeding will be defined as any bleeding reported by the patient, which did not meet
 the criteria for major or clinically significant non-major bleeding. Economical comparisons
 will involve comparing all costs for treatment in both groups (i.e. drugs, device, and all
 hospitalizations) for the whole study period. Because the LAA is an important source of
 natriuretic peptides, and in some patients, the production of these hormones can be
 eliminated after LAA occlusion, natriuretic peptides and other inflammatory and thrombotic
 cytokines will be measured before, and 6 months after randomization and the concentrations
 will be compared.

 Statistics For any randomized trial, the power and sample size calculation are critical
 determinants of the overall success of the trial and the interpretation of findings. The
 sample size calculation was based on the following assumptions: the power of the test = 0.8,
 statistical significance border = 0.05. Based on information from large previous trials with
 NOAC, the investigators assume that 13% of patients in the NOAC group and 10% of patients in
 the interventional group will achieve the primary endpoint per year. (15) With regard to the
 border for non-inferiority, the investigators expect 18% of patients to achieve the primary
 endpoint per year. This means, that for the non-inferiority hypothesis, 198 patients will
 have to be enrolled in each group, i.e. a total of 396 study participants. Data analysis will
 be performed based on intention-to-treat principles. For data description, standard
 descriptive statistical methods will be used: absolute and relative frequencies for
 categorical data and the median with 5-95% percentiles for continuous data. For categorical
 variables, statistical analysis will be done using the χ2 or the Fisher exact test; for
 continuous variables, the Student t-test or Mann-Whitney U test will be used. Kaplan-Meier
 curves will be calculated for visualizing the occurrence of end-points during follow-up. The
 influence of patient characteristics on the occurrence of end-points will be calculated using
 logistic regression and the Cox proportional risk model, when appropriate. Statistical
 analyses will be done using SPSS 22 software (IBM Corporation, 2013).

 DISCUSSION: The incidence of AF increases with the increasing age of the population. In a
 cohort of 4000 people in the Framingham study, who were followed for more than 30 years, the
 lifetime risk of the occurrence of AF in a 40 year old man (without previous AF) was 26% and
 it was 23% for women. (20). The CHA2DS2-VASc score also rises with increasing age, which
 means the risk of cardioembolic (as well as bleeding) events also increase with age;
 therefore, the number of patients with a need for, but concurrently with a risk of
 anticoagulant treatment, increases. The safety profile of NOAC has been shown in large
 randomized studies to be slightly better compared to warfarin, mainly due to the slightly
 lower incidence of intracranial bleeding. LAA occlusion, which has been shown to be
 non-inferior to warfarin in a large study (14), can be a possible alternative in patients at
 high risk for bleeding. However, LAA occlusion has been associated with a significant number
 of complications, and therefore, the risk of interventional LAA occlusion is "acceptable"
 mainly in patients at highest risk for bleeding and stroke.Until now, published and ongoing
 studies have not focused on this particular group of high-risk patients; for example, an
 inclusion criterion for the PROTECT trial was only a CHADS2 >1 and 34% of all PROTECT
 patients had a CHADS2 score of 1.

 (14) No studies comparing treatment with NOAC vs. LAA occlusion have been published. Because
 treatment for these particular patients is very complicated, any progress relative to this
 very complex set of patients is warranted and much needed.
Inclusion Criteria:

 1. history of significant bleeding (i.e. bleeding which required intervention or
 hospitalization), even in the absence of anticoagulation treatment at the time of the
 bleeding event, or

 2. a cardioembolic event, which occurred on anticoagulation, or

 3. a high risk profile of the patient, defined as a CHA2DS2-VASc score ≥ 3 and a HAS-BLED
 score ≥ 2

 Exclusion Criteria:

 1. thrombus in the LA or LAA;

 2. mechanical valve prosthesis;

 3. mitral stenosis;

 4. previous LAA ligation during cardiac surgery;

 5. life expectancy less than 2 years;

 6. comorbidities other than AF, which present an indication for anticoagulation;

 7. patent foramen ovale with atrial septal aneurysm

 8. mobile plaque in the aorta;

 9. symptomatic atherosclerosis of the carotid artery;

 10. pericardial effusion greater than 10 mm;

 11. clinically significant bleeding within the 30 days prior to the scheduled procedure;

 12. stroke or other cardioembolic event within the 30 days prior to the scheduled
 procedure;

 13. acute coronary syndrome within the 90 days prior to the scheduled procedure,

 14. gravidity,

 15. significant valvular disease,

 16. creatinine clearance less than 30 ml/min