Aortic valve replacement (AVR) is the only life-saving treatment for patients with severe symptomatic aortic stenosis. Bioprosthetic valves are used in 90% of AVRs because they do not require lifelong anticoagulation. The major limitation of bioprosthetic valves is their limited durability compared to mechanical valves. In addition, bioprosthetic valves still carry a 2-3% risk of symptomatic valve thrombosis, stroke, and thromboembolism in the first 30 days after implantation, and a 1% annual risk thereafter. The risk of subclinical valve thrombosis is around 10% at 30 days and 25% at 1 year, and prevention of subclinical valve thrombosis is hypothesized to reduce the risk of clinical thrombotic events and perhaps even improve valve durability, although high-quality evidence is lacking. This doctoral thesis comprises 7 chapters of varied methodology that summarize the evidence behind current recommendations for antithrombotic therapy after bioprosthetic AVR, identify evidence gaps, and present the design a randomized trial that aims to address some of these evidence gaps. Chapter 1 introduces each included study with a brief summary. Chapter 2 is a narrative review summarizing guideline recommendation for antithrombotic therapy after bioprosthetic AVR and the evidence upon which they are based. Chapter 3 is an observational study describing antithrombotic prescribing practices in the VISION Cardiac Surgery cohort study. Chapter 4 is a systematic review and network meta-analysis of randomized studies of antithrombotic therapy after transcatheter aortic valve replacement. Chapter 5 is a systematic review and meta-analysis of randomized and observational studies of subclinical valve thrombosis. Chapter 6 presents the design and rationale of a feasibility trial of direct oral anticoagulants versus vitamin K antagonists in patients with a new surgical bioprosthetic AVR and atrial fibrillation. Chapter 7 discusses the implications, limitations, and future avenues of the research presented in this doctoral thesis. / Thesis / Doctor of Philosophy (PhD) / More than 10,000 Canadians require aortic valve replacement each year. Bioprosthetic valves (made out of cow or pig tissue) are often preferred over mechanical valves (made out of metal) because the risk of blood clots forming on the valve or causing a stroke is lower. The disadvantage of bioprosthetic valves is that they can wear out and require re-replacement. The reason why bioprosthetic valves wear out is uncertain, but it may be related to small blood clots on the valve that are only detectable on a CT scan. This doctoral thesis explores the use of blood thinners for patients with bioprosthetic aortic valve replacement. Ideally, blood thinners would be able to prevent blood clots and stroke, and to improve the durability of bioprosthetic valves, without causing too much bleeding. The thesis reviews the available evidence, identifies unanswered questions, and ends with a proposal for a study to generate new data.

Objective: A systematic review and meta-analysis was performed to evaluate the safety and efficacy of drug-eluting stents (DES) vs bare-metal stents (BMS) in atrial fibrillation (AF) patients. Methods: We systematically searched 5 engines until May 2019 for cohort studies and randomized controlled trials (RCTs). Primary outcomes were major bleeding and major adverse cardiac events (MACE) including cardiac death, myocardial infarction, target vessel revascularization (TVR) or stent thrombosis. Effects of inverse variance random meta-analyses were described with relative risks (RR) and their 95% confidence intervals (CI). We also stratified analyses by type (triple [TAT] vs dual [DAT]) and duration (short-vs long-term) of antithrombotic therapy. Results: Ten studies (3 RCTs; 7 cohorts) including 10,353 patients (DES: 59.6%) were identified. DES did not show higher risk of major bleeding than BMS (5.6% vs 6.9%, RR 1.07; 95%CI, 0.89–1.28, p = 0.47; I2 = 0%) or MACE (12% vs 13.6%; RR 0.96; 95%CI 0.81–1.13, p = 0.60; I2 = 44%). Although, DES almost decreased TVR risk (6.4% vs 8.4%, RR 0.78; 95%CI, 0.61–1.01, p = 0.06; I2 = 15%). Stratified analyses by type and duration of antithrombotic therapy showed no differences in major bleeding or MACE between both types of stents. In DES, long-term TAT showed higher major bleeding risk than long-term DAT (7.7% vs 4.7%, RR 1.48, 95%CI 1.08–2.03, p = 0.01; I2 = 12%). For both types of stents, MACE risk was similar between TAT and DAT. Conclusions: In patients with AF undergoing PCI, DES had similar rate of major bleeding and MACE than BMS. DAT seems to be a safer antithrombotic therapy compared with TAT. / Janssen Pharmaceuticals / Revisión por pares

Coronary artery disease (CAD) is the leading cause of mortality worldwide and atrial fibrillation (AF) is a prevalent arrhythmia associated with increased risk of mortality and morbidity. Despite improved outcome in both diseases, there is a need to further describe the prevalence, outcome and management of CAD in patients with concomitant AF. AF was a common finding among patients with MI, with 16% having new-onset, paroxysmal or chronic AF. Patients post-MI with concomitant AF, regardless of subtype, were at increased risk of composite cardiovascular outcome of mortality, MI or ischemic stroke, including mortality and ischemic stroke alone. No major difference in outcome was observed between AF subtypes. At discharge, an oral anticoagulant was prescribed to 27% of the patients with MI and AF undergoing percutaneous coronary intervention (PCI). Aspirin or clopidogrel plus warfarin versus dual antiplatelet therapy with aspirin plus clopidogrel were associated with similar 0-90-day and lower 91-365-day risk of cardiovascular outcome, without increased risk of major bleeding events. Triple therapy with aspirin, clopidogrel plus warfarin versus dual antiplatelet therapy was associated with non-significant lower risk of cardiovascular outcome, but with increased risk of bleeding events. Treatment with renin-angiotensin system (RAS) inhibitors post-MI was associated with lower risk of all-cause and cardiovascular mortality in patients with and without congestive heart failure and/or AF. However, RAS inhibition in patients without AF was not associated with lower risk of new-onset AF. Approximately 1 in 3 patients undergoing isolated coronary artery bypass grafting (CABG) had pre- or postoperative AF. Patients with AF, regardless of subtype, were at higher risk of all-cause mortality, cardiovascular mortality and congestive heart failure. Furthermore, postoperative AF was associated with higher risk of recurrent AF. In conclusion, AF was a common finding in the setting of MI and CABG. AF, irrespectively if in the setting of MI or CABG was associated with higher risk of ischemic events and mortality. Also, postoperative AF was associated with recurrent AF. Oral anticoagulants post-MI and PCI in patients with AF was underutilized, however, optimal antithrombotic therapy is still unknown. RAS inhibition post-MI seems beneficial, however, it was not associated with lower incidence of new-onset AF.