Search for evidence to improve symptom management and prevent complications in atrial fibrillation

Joshua Rose-Hansen Feinberg

Research output: ThesisPh.D. thesis

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Atrial fibrillation is the most common arrhythmia of the heart in the world. Complications include stroke,heart failure, and death. Symptoms include shortness of breath, heart palpations, fatigue, and chest pain.Atrial fibrillation may be paroxysmal or non-paroxysmal. Depending on whether sinus rhythm is pursued ornot, non-paroxysmal atrial fibrillation may be divided into persistent or permanent atrial fibrillation.In the latest European guidelines for atrial fibrillation, treatment follows an A, B, C approach. The ‘A’represents Anticoagulation/Avoid stroke, the ‘B’ represents Better symptom control, and the ‘C’ representsComorbidity and includes optimizing of Cardiovascular risk factors and lifestyle.Anticoagulation can be achieved using a new oral anticoagulant or a vitamin K antagonist. The risk of strokeand the indication for starting anticoagulation in atrial fibrillation is in clinical practice usually assessedusing the CHA2DS2VASc score. Women who develop atrial fibrillation appear to have a higher risk of strokecompared with men. However, sex, is seen as an effect modifier, and not an independent risk factor. Themechanism behind this differential risk is unknown – theoretically, it could be related to residualconfounding or biological sex.Rate control is the main treatment for controlling symptoms in patients with permanent atrial fibrillation.Drugs include beta-blockers, calcium channel blockers, and digoxin. The optimal heart rate is currently notknown for atrial fibrillation, neither is the best drug to achieve this heart rate control.To prevent development of atrial fibrillation and prevent cardiovascular complications in patients withatrial fibrillation, physical activity is recommended. However, it seems the benefits of physical activitydepend on if it is occupational physical activity (OPA) or leisure time physical activity (LTPA). This is calledthe physical activity paradox.

The objective of this PhD thesis was to search for evidence to improve symptom management and preventcomplications in atrial fibrillation by looking at different aspects of the A, B, C guideline recommendedapproach where there are unanswered questions related to management of atrial fibrillation.

First and foremost, we designed, planned, initiated, and are currently conducting DanAF, a randomizedclinical trial. 350 patients with persistent or permanent atrial fibrillation prior to inclusion are beingrandomized to either a lenient heart rate target (80-110 beats per minute (bpm)) or a strict heart rate target (
Study 1 – Protocol for a randomized clinical trial, DanAF
At the time of writing, 75 out of 350 participants have been randomized, 20 participants have reached oneyear follow-up. Three sites have recruited participants, with at least one more expected to startrecruitment in May 2023.

Study 2 – Systematic review of rate controlling drugs
We included 51 trials. There was very limited data on all-cause mortality and serious adverse events for allcomparisons. Likewise, there was very limited data for quality of life, non-serious adverse events andsymptom scores for all comparisons.Beta-blockers and calcium channel blockers appeared superior to digoxin in reducing maximal exertionalheart rate but there was no difference in exercise capacity. There seemed to be no overall differencebetween beta-blockers and calcium channel blockers for resting heart rate or maximal exertional heart rate control, but subgroup analysis suggest some beta-blockers may reduce maximal exertional heart rate morethan calcium channel blockers and some less.Beta-blockers may reduce exercise capacity compared with calcium channel blockers.

Study 3 – Retrospective cohort study on sex, atrial fibrillation and risk of stroke
Both the prevalence of a history with atrial fibrillation upon inclusion and the incidence of new-onset atrialfibrillation during the study was higher among men than women. The difference decreased with older age.In patients with new-onset atrial fibrillation, the overall point estimate for the risk of stroke associated withfemale sex was higher but not statistically significant (Hazard ratios (HR) 1.52, CI 95% 0.95 – 2.43). Incontrast, the point estimate for the risk of stroke associated with female sex in patients with a history ofatrial fibrillation was insignificantly lower (HR 0.88, CI 95% 0.5 – 1.6).In new-onset atrial fibrillation, the risk of stroke increased with older age in females whereas it fell inmales. In patients with a history of atrial fibrillation, the risk of stroke increased with age for both femalesand males.

Study 4 – Cross-sectional study on the physical activity paradox
A total of 5304 participants were included in the analysis. Compared to low OPA, high OPA was associatedwith increased levels of hsCRP (6% increase, CI 95% 0% - 12%). In contrast, compared to high LTPA, lowLTPA was also associated with a higher hsCRP (12% increase, CI 95% 6% - 18%).

Conclusion and perspectives
Study 1, the DanAF trial is ongoing comparing lenient rate control to strict rate control on quality of lifemeasured using SF-36 physical component score. So far, 75 patients from three sites have been recruited.
In study 2, we found that there is very limited data on the best rate controlling drug to prevent all-causemortality, serious adverse events, or improve quality of life. Beta-blockers and calcium channel blockersappeared superior to digoxin in reducing maximal exertional heart rate. It is uncertain if this translates tohigher or lower exercise capacity. There seems to be no overall difference between beta-blockers andcalcium channel blockers for heart rate control, but subgroup analysis suggest some beta-blockers mayreduce maximal exertional heart rate more than calcium channel blockers and some beta-blockers less.Beta-blockers may reduce exercise capacity compared with calcium channel blockers.In study 3 with participants with hypertension and left ventricular hypertrophy on ECG, only participantswith new-onset atrial fibrillation had higher risk of stroke in women than in men, primarily in older women.The same relationship was not seen in patients with a history of atrial fibrillation. Study 4 showed that hsCRP seems to depend on the context of the physical activity, and hence, a differencein systemic inflammation could be the mechanism behind the physical activity paradox.
Original languageDanish
Awarding Institution
  • University of Southern Denmark
  • Jakobsen, Janus Christian, Principal supervisor
  • Olsen, Michael Hecht, Co-supervisor
  • Brandes, Axel, Co-supervisor
  • Raymond, Ilan, Co-supervisor, External person
Date of defence14. Sept 2023
Publication statusPublished - 19. Jun 2023

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