Comparison of Left Atrial Appendage Occlusion vs Standard Medical Therapy in Patients in AF Undergoing TAVI
Comparison of Left Atrial Appendage Occlusion vs Standard Medical Therapy in Patients in AF Undergoing TAVI
Study category and Rationale Clinical study, Category A.

 Clinical Phase: Post market study

 Background and Rationale: Left atrial appendage occlusion (LAAO) allows avoiding oral
 anticoagulation and provides at the same time an at least equally good protection from
 strokes and peripheral embolism. It may therefore be an attractive alternative to oral
 anticoagulation in the patient population undergoing transcatheter aortic valve implantation
 (TAVI): the concept of LAAO is based on the fact that thrombus formation in atrial
 fibrillation occurs in >90% in the left atrial appendage (LAA). Mechanical occlusion of the
 LAA reduces the stroke risk by eliminating the source of thrombus formation. In the here
 proposed "Randomized Comparison of Left Atrial Appendage Occlusion versus Standard Medical
 Therapy in Patients in Atrial Fibrillation Undergoing Transfemoral Transcatheter Aortic Valve
 Implantation", study we test the hypothesis, that LAAO is superior to standard medical
 therapy in the high-risk TAVI population. This hypothesis has not been investigated by
 previous studies so far.

 Overall Objective(s): Overall objective: to compare the safety (and efficacy) of LAAO using
 the St. Jude left atrial appendage closure device with standard medical therapy in a
 prospective, multi-center, randomized trial in patients undergoing TAVI in routine clinical
 practice.

 Primary Objective: To assess the safety of the device intervention with regard to stroke
 prevention and prevention of bleeding complications in a patients population at high risk of
 stroke and bleeding.

 Secondary Objectives: Short-term (procedural) safety of device intervention is assessed (rate
 of successful deployment of a left atrial appendage occluder; rate of kidney failure). As a
 further secondary objective, long-term effects of device intervention on stroke and bleeding
 prevention as well as mortality are assessed and compared to medical therapy.

 Outcome(s): Primary: Composite endpoint of ischemic and hemorrhagic neurologic events,
 peripheral embolism, life-threatening/disabling and major bleeding complications and
 cardiovascular mortality at 1 year

 Secondary: All deaths (cardiac and non-cardiac) at 30 days, 1, 3, and 5 years Device success
 at 30 days

 In-hospital acute kidney injury (AKI)

 Study design: An investigator-initiated, randomized, multicenter, non-blinded, all-comers
 study

 Measurements and Procedures: 80 patients in atrial fibrillation undergoing TAVI will be
 randomized in a non-blinded fashion (1:1 randomization) to LAAO (device group) or SMT at the
 operators' discretion (medical group; antiplatelet therapy and oral anticoagulation or oral
 anticoagulation alone). All patients will be followed for up to 5 years. The primary analysis
 will be performed at 30 days and after completion of a 1-year follow-up.

 80 patients in atrial fibrillation undergoing TAVI will be randomized in a non-blinded
 fashion (1:1 randomization) to LAAO (device group) or standard medical therapy (SMT) at the
 operators' discretion (medical group; antiplatelet therapy, oral anticoagulation or oral
 anticoagulation alone).

 Estimated duration for the main investigational plan from start of screening of first
 participant to last participant processed and finishing the study: 6 years
Background and Rationale

 Transcatheter aortic valve implantation (TAVI) is a minimally invasive treatment option for
 patients suffering from severe symptomatic aortic stenosis. Superiority of TAVI over medical
 treatment has been shown in the randomized PARTNER B trial followed by the PARTNER A trial
 showing non-inferiority over a more invasive open-heart surgical aortic valve replacement in
 high-risk patients. Over the last years, many patients have been successfully treated with
 TAVI worldwide.

 Peri- and post-procedural morbidity differed considerably between the surgical and
 interventional treatment group in the PARTNER A trial: while major bleeding (19.5% vs 9.3% at
 30 days) and new onset atrial fibrillation (16% vs 8.6% at 30 days) occur more often in
 surgically treated patients, vascular access complications (3.8 vs 17% at 30 days) and
 neurologic events (5.5% vs 2.4% at 30 days) are more frequently encountered in the TAVI
 population. The higher rate of neurologic events in the TAVI group was of particular concern,
 given its association with a higher mortality and the clinical impact of major neurologic
 events on patient's quality of life and daily functioning. Only about 40-50% of strokes occur
 intra-procedurally, followed by a higher hazard rate in the first week and a constant hazard
 thereafter. After 30 months, the surgical group experienced a numerically higher stroke rate,
 although not statistically significant. Measures to reduce procedural and post-procedural
 stroke rate were and are still looked for.

 While procedural strokes can be most likely reduced by improvements in valve delivery systems
 (smaller delivery systems) and more operator experience, cerebral protection devices are
 currently tested in trials but preliminary results are rather disappointing. Risk factors for
 post-procedural strokes after TAVI are a previous history of stroke, more extensive
 peripheral vascular disease, and higher functional class.

 A subgroup of patients of particular concern are patients suffering from atrial fibrillation:
 predictor of early (day 1-30) cerebrovascular events was new-onset atrial fibrillation (OR
 2.76), whereas chronic atrial fibrillation was a predictor (OR 2.84) for the occurrence of
 late (>30 days) cerebrovascular events. Amat-Santos reported a higher rate of
 strokes/systemic embolism in patients with in hospital new onset atrial fibrillation after
 TAVI (13.6% vs 3.2% after 30 days). Patients diagnosed with new onset atrial fibrillation
 during or after the procedure in which no anticoagulation was initiated experienced an
 alarmingly high 30-day stroke rate of 40%.

 Despite these results and the high prevalence of atrial fibrillation (AF) of about 33% in the
 overall TAVI population, only 30% of AF patients were on vitamin K antagonists (VKA) before,
 and only 70% after TAVI. While oral anticoagulation is an effective medical treatment for
 ischemic stroke prevention in these patients, it is often withheld from patients given their
 high risk of bleeding. TAVI patients typically not only suffer from much co-morbidity and are
 poly-medicated, but also suffer from a lot of bleeding risk factors. The bleeding risk score
 (HASBLED score) expresses the risk of major bleeding with a scoring system consisting of 9
 individual risk factors for bleeding; a patient is at high risk for bleeding, if 3 or more
 factors are present. The stroke risk score (CHA2DS2-Vasc score) comprises of 9 individual
 risk scores for stroke in patients suffering from atrial fibrillation. Both risk scores share
 common risk factors, such as age, hypertension and previous stroke. It is therefore not
 surprising that patients at highest risk for stroke are at the same time at highest risk for
 major bleedings. The TAVI population forms such a high risk group with a high prevalence of
 the above risk factors: average patients age in the PARTNER trial was 84 years, with 11%
 showing severe renal impairment, about 75% had an indication for concomitant acetylsalicylic
 acid use and all suffered per definition from heart failure. In Stortecky's study on TAVI
 patients suffering AF, the average CHA2DS2-Vasc score was 4.5, with >95% of patients having a
 score >3.

 Left atrial appendage occlusion (LAAO) allows avoiding oral anticoagulation and provides at
 the same time an at least equally good protection from strokes and peripheral embolism. It
 may therefore be an attractive alternative to oral anticoagulation in the TAVI patient
 population: the concept of LAAO is based on the fact that thrombus formation in atrial
 fibrillation occurs in >90% in the left atrial appendage (LAA). Mechanical occlusion of the
 LAA reduces the stroke risk by eliminating the source of thrombus formation.

 Clinical studies proved this concept to be true: the PROTECT-AF study randomized >700
 patients to either LAA occlusion or medical therapy (VKA). At one year, non-inferiority of
 LAAO was proven, with numerically less embolic events in the LAAO group. At a European
 conference (EuroPCR conference) 2013, Holmes (principal investigator of the PROTECT-AF trial)
 reported 4-year follow-up data with a significant 40% reduction of the composite of
 stroke/peripheral embolism/cardiovascular death and a 34% reduction of all cause mortality in
 the LAAO group as compared to oral anticoagulation. By reducing bleeding complications, it
 can be anticipated that morbidity and mortality will continue to diverge between the two
 groups. Comparable results from a large registry using Amplatzer devices (St. Jude Medical,
 St. Paul, USA) for LAAO were reported: after an average follow-up of 32 months,
 cardiovascular death, stroke, and peripheral embolism occurred in 7% of patients. In the
 latter study, oral anticoagulation was instantly stopped after LAAO in all patients.

 In the here proposed "Randomized Comparison of Left Atrial Appendage Occlusion versus
 Standard Medical Therapy of Atrial Fibrillation in Patients Undergoing Transfemoral
 Transcatheter Aortic Valve Implantation", study the investigators test the hypothesis, that
 LAAO is superior to standard medical therapy in the high-risk TAVI population. This
 hypothesis has not been investigated by previous studies so far. The design is an
 investigator-initiated, randomized, multicenter, non-blinded, all-comers study. It is
 understood, that this is a pilot trial with the intention to prove safety, but which is
 underpowered to show superiority over medical therapy.
Inclusion Criteria:

 -  Severe aortic valve stenosis with an indication for aortic valve replacement (e.g.,
 symptomatic patient, decreased left ventricular (LV) function)

 -  Suitable anatomy for transfemoral TAVI with the Portico Transcatheter Aortic Valve
 System (ileofemoral arterial diameter, annulus-coronary distance, annulus diameter)

 -  No mobile thrombus in the LA or LAA precluding LAAO

 -  Atrial fibrillation with a CHA2DS2-Vasc-Score >=1. No limitation regarding the nature
 of atrial fibrillation (paroxysmal, permanent, persistent)

 Exclusion Criteria:

 -  Pregnancy

 -  Known intolerance to aspirin, heparin, contrast media or clinically manifest nickel
 allergy

 -  Inability to provide informed consent

 -  Mechanical heart valve or other indication for oral anticoagulation (i.e. recent
 pulmonary embolism)

 -  Contraindication for oral anticoagulation

 -  Currently participating in another trial