The impact of timing and order of disease development on the risk of mortality in atrial fibrillation and heart failure patients

Atrial fibrillation (AF) and heart failure (HF) frequently co-exist and have emerged as epidemics in 21st century. The presence of both AF and HF increases the risk of morbidity and mortality, further exacerbating the burden on healthcare systems. Although many studies have described the augmented risk associated with the diagnosis of both diseases, the prognostic impact of the temporal relationship between the timing and order of disease development for these two diseases has yet to be elucidated.

To compare the risk of mortality between AF patients who developed HF ("AF First") and HF patients who developed AF ("HF First"). We also determined the long-term risk of developing HF in AF patients and vice versa, as well as identified phenotypes associated with the development of both diseases.

Patients with new-onset AF or HF in the UK Biobank (2006-2022) were included in the present study (N=31,374). To compare mortality risk, patients were categorized as AF first or HF first and followed from the date both diseases were diagnosed until death in a time-dependent multivariable Cox regression model. For the secondary aims, two cohorts were created based on the first disease diagnosis (i.e. AF or HF). A multivariable Cox model was created following patients from the date of first disease diagnosis (e.g. AF) until death, with the second disease (e.g. incident HF) as a time-dependent variable.

The crude incidence rates of incident HF in AF patients and incident AF in HF patients were 25.3 and 45.1 per 1000 person-years, respectively. HF first patients had a longer median time to develop AF (2.91 vs. 1.44 years), were younger at diagnosis (71 vs. 69 years) and had multi-morbidities (P<0.05 for all), compared to AF first (Figure 2). Patients with HF had a 31% increased risk of developing AF, compared to patients with AF who developed HF (aHR 1.31 (95% CI 1.22-1.40) (Figure 1). Regardless of which disease developed first, there was no statistically significant difference in mortality risk after multivariable adjustments (HF first vs. AF first; aHR 0.95 (95% CI 0.85-1.07)). Compared to AF patients without HF, mortality risk was elevated in AF patients who developed new-onset HF (aHR 3.82 (95% CI 3.45-4.24)). Similarly, HF patients who developed incident AF had higher mortality risk, compared to HF patients without AF (aHR 2.31 (95% CI 2.09- 2.55)).

Although the order of disease development did not impact the risk of death, the presence of both diseases conferred a higher mortality risk compared to either disease alone. Early intervention with a targeted approach to treat comorbidities is needed to prevent the development of subsequent disease potentially reducing mortality, particularly in patients with AF.