Evolution of antithrombotics over a decade - a rollercoaster for elderly patients with atrial fibrillation

Background

Elderly individuals with atrial fibrillation (AF) face a dual risk of thromboembolic- and bleeding events. Therefore, preventing thromboembolism with oral anticoagulation (OAC) is equally challenging as it is crucial for elderly patients. The overall aim of this thesis was to expand the knowledge of modern antithrombotic therapy (ATT) in elderly AF patients by an in-depth clinical characterization (study I) and by investigating the effectiveness and safety of ATT and switching of ATT (study II) as well as the impact of acute atherothrombotic disease (type 1 myocardial infarction [MI]) with the addition of antiplatelet therapy (APT) to OAC (study III), in a hospitalized elderly AF and atrial flutter (AFL) population aged >75 over a time period defined by the paradigm shift from warfarin to Direct Oral Anticoagulant (DOAC) use.

Methods and results

The Carrebean-elderly cohort, consisting of all consecutive elderly patients >75 years admitted to the Department of Cardiology, Danderyd university hospital, Stockholm, due to AF or AFL as main diagnosis between November 1st 2010 and December 31st 2018 (n=3686), constituted study base for all studies of this thesis.

In study I, we explored the study population as a whole and divided into three age groups (>75 -< 80, 280 -< 90 and >90 years), with a cross-sectional analysis and clinical characterization including ATT use at discharge. Further, we investigated clinical predictors of the probability to be prescribed DOAC compared to warfarin with a logistic regression analysis. In the total study population (n=2943; median age 82; women 58.4%), warfarin was the most commonly prescribed OAC (46.8%) before DOAC (27.5%) and acetylsalicylic acid (ASA) (15.7%). The prevalence of cardiovascular (CV) comorbidities increased with age being particularly high among patients aged 290. Severe renal failure was more common (40.9%) in the oldest age group compared to the younger (2.6% in the >75 -< 80 and 12.2% in the ≥80 -< 90 group). Influencing

factors favoring warfarin prescription were renal impairment and high thromboembolic- and bleeding risk.

In study II, we investigated the effectiveness and safety of ATT at discharge and switching of ATT during follow-up using Cox regression models to estimate the associated risks of thromboembolism, bleeding and cardiac death, with estimates presented in hazard ratio (HR) with a 95% confidence interval (CI). ATT at discharge included comparisons between DOAC and non-guideline- recommended therapy (NG) of ASA and low-molecular weight heparin (LMWH) to warfarin. Both warfarin and DOAC were considered guideline-recommended ATT (G). All-cause death was evaluated as a competing risk to the studied outcomes in a Competing risk regression analysis. Results showed no observed risk difference between DOAC and warfarin for the composite endpoint in neither the Cox regression-, nor the Competing risk regression analysis. Switching ATT was common (45.3%) in the study population (n=2943) and most common among warfarin users (65.7%). Switching from a non-guideline- to a guideline-recommended regimen yielded a significant decrease in the risk for thromboembolism (adjusted HR of 0.26; 95% CI 0.12-0.53) and cardiac death (adjusted HR of 0.53; 95% 0.32-0.87) with no risk difference for bleeding. Switching from warfarin to DOAC yielded a decrease for both the risk of thromboembolism and bleeding, however, no difference in risk for cardiac death.

In study III, we investigated the effect of a type 1 MI in elderly AF/AFL patients on short- and long-term risks of CV events (thromboembolism, bleeding, recurrent MI and cardiac death) in a Competing risk regression analysis, with death of non-CV cause as competing risk, with estimates presented as sub-hazard ratio (SHR) and 95% CI. To evaluate the impact of guideline- adherence of ATT on the risks of the outcomes, we analyzed AF/AFL patients with type 1 MI and guideline-directed ATT with both OAC and antiplatelet (APT), i.e. dual or triple antithrombotic therapy (DAT/TAT), in comparison to AF/AFL patients with OAC on the associated risks of CV events in a Competing risk regression analysis. Further, the cumulative incidence of CV events, also including heart failure, was investigated in both AF/AFL patients with and without MI. OAC and APT according to guidelines was dispensed to 55% of the 136 AF/AFL patients with MI and OAC to 69% of the AF/AFL patients. At 1 year, we observed an increased risk for the composite endpoint in AF/AFL patients with MI, likely driven by a tendency to increased risk for recurrent MI and cardiac death. In the long-term, both the risk for recurrent MI and cardiac death was significantly increased. In consideration of uniquely patients with guideline- directed ATT, we observed a persistent increase in risk for recurrent MI in the long-term for AF/AFL patients with MI compared to AF/AFL patients, however, no increase in risk for bleeding or cardiac death.

Conclusions

In this cohort of elderly hospitalized AF and AFL patients, we found significant heterogeneity in their clinical presentation of comorbidities and organ function with an especially high prevalence among the oldest patients aged ≥90. A shift from warfarin to DOAC use occurred gradually during the study period, yet, a preference of prescribing warfarin persisted throughout the period for patients with renal impairment and high risk of thromboembolism and bleeding. No difference in effectiveness or safety was observed when comparing DOAC to warfarin with associated risks of CV events, in an intention-to-treat approach. Switching of ATT was common with large impacts on the outcomes. Importantly, switching from non-guideline- to guideline-directed ATT decreased both the risk of thromboembolism and cardiac death with no increase in bleeding risk. In elderly AF/AFL patients with a type 1 MI, we observed a lifelong increased risk for recurrent MI despite the initial addition of APT to OAC, in comparison to AF/AFL patients receiving OAC. No increase in bleeding risk or cardiac death was shown. The long-term risk of developing heart failure was high in this elderly AF/AFL population and particularly high in patients with concomitant AF/AFL and MI.

List of scientific papers

This thesis is based on the following studies, which will be referred to by their Roman numerals:

I. Ehrlinder H, Orsini N, Modig K, Hofman-Bang C, Wallén H, Gigante B. Clinical characteristics and antithrombotic prescription in elderly hospitalized atrial fibrillation patients - A cross-sectional analysis of a Swedish single-center clinical cohort. Int J Cardiol Heart Vasc. 2020;27:100505. https://doi.org/10.1016/j.ijcha.2020.100505

II. Ehrlinder H, Orsini N, Modig K, Wallén H, Gigante B. Antithrombotic treatment switching in elderly patients with atrial fibrillation and the risk of thromboembolism, bleeding and cardiac death. Res Pract Thromb Haemost. 2022;6(7):e12823. https://doi.org/10.1002/rth2.12823

III. Ehrlinder H, Orsini N, Modig K, Wallén H, Gigante B. The impact of type 1 myocardial infarction and dual antithrombotic therapy on short- and long-term risks of cardiovascular events and mortality in elderly atrial fibrillation patients. [Manuscript]