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High-risk patients with atrial fibrillation: Spotlight on diabetes

Patients with AF and concomitant diabetes may need special attention. Do you understand the risks?

Understanding the risk of stroke in patients with diabetes and AF

SPAF diab diagram


The vast majority of patients with type 2 diabetes will die of a cardiovascular (CV) event such as stroke; therefore, it is crucial that physicians look for opportunities to reduce the risks of these events.


One such opportunity is stroke prevention in patients with atrial fibrillation (AF). The ORBIT-AF registry found that AF and diabetes often occur concomitantly, with diabetes present in 29.5% of patients with AF in US clinical practice. Furthermore, in patients with AF, diabetes was associated with a significantly higher 2-year risk of all-cause and CV mortality. Of particular concern is that patients with AF aged <70 years old were more than twice as likely to die from CV causes if they had diabetes.


The ORBIT-AF registry did not find an association between diabetes and stroke risk; however, a meta-analysis of seven studies found that the risk of stroke in patients with AF is almost doubled if they have concomitant diabetes. There is also evidence to suggest that diabetes worsens prognosis after a stroke. A prospective Swedish study found that in patients who had suffered a stroke, mortality in those with diabetes was 4.4-fold higher for men and 5.1-fold higher for women compared with those without diabetes.


Taken together, these data highlight the importance of preventing stroke when diabetes and AF coincide, but how should these patients be managed?


What did we learn from clinical trials?

Patients with diabetes were enrolled in all four of the phase III trials of NOACs for stroke prevention in patients with AF; however, the exact proportions varied between trials. The highest proportion of patients with diabetes was enrolled in the ROCKET AF trial of rivaroxaban, where 40% of patients had this co-morbidity. The high proportion of patients with diabetes in ROCKET AF is consistent with the high-risk population enrolled in this trial (see “High-risk patients with AF in phase III trials”).

SPAF diab diagram

Proportions of patients with diabetes in phase III NOAC trials of patients with AF

The NOACs had a consistent efficacy and safety profile vs warfarin in patients with and without diabetes in a meta-analysis of the four phase III NOAC trials.


Some trials included a sub-analysis in patients with diabetes. A pre-specified sub-analysis of ROCKET AF found that rivaroxaban was associated with a significant 20% relative risk reduction in the risk of cardiovascular death compared with warfarin, with no difference in the risk of major bleeding. In a sub-analysis of patients with diabetes in the ARISTOTLE trial of apixaban, there were no significant differences in the risk of CV death, stroke or major bleeding. Furthermore, in a sub-analysis of patients with diabetes in RE-LY, neither dabigatran 150 mg bid nor dabigatran 110 mg bid was associated with a significant difference in CV death or major bleeding compared with warfarin, although there was a significant decrease in the risk of stroke for the dabigatran 150 mg bid dose only.


However, because the phase 3 NOAC trials had different trial designs and recruited different patient populations, it is not possible to make direct comparisons regarding the safety and efficacy of each NOAC.


There has not yet been a sub-analysis published of patients with diabetes receiving edoxaban in the ENGAGE AF-TIMI 48 trial.

SPAF diab diagram

Outcomes in the diabetes subgroups of ROCKET AF, ARISTOTLE and RE-LY (Results are not intended for direct comparison between NOACs)

Patients with AF and diabetes in the real world

The safety and efficacy of rivaroxaban was also evaluated in XANTUS – a prospective, real-world, phase IV study with sufficiently robust methodology that it was included on the EMA label of rivaroxaban. The XANTUS study enrolled 6784 patients with AF – 19.6% of whom had co-morbid diabetes – and the results supported the conclusions of the ROCKET AF trial.


The most recent real-world analysis to look specifically at patients with diabetes and AF is an analysis of a US administrative claims database, which looked at outcomes in 11,034 patients with AF and diabetes in routine clinical practice. The results demonstrated that the effectiveness and safety of rivaroxaban is at least as good as that of warfarin in this high-risk patient population.

These data from daily clinical practice complement the data collected in the phase III trials and provide reassurance that the efficacy and safety profiles observed in randomized controlled trials are applicable to patients with diabetes in clinical practice.



Overall, the high risk of stroke in patients with AF and diabetes means that careful management is essential. The phase III NOAC trials provided a large amount of relevant data by enrolling a substantial number of patients with diabetes, although the exact proportions varied between individual trials. Data from randomized trials has been complemented by real-world evidence, which provides an additional perspective. When making treatment decisions, an appreciation of the stroke risk associated with diabetes, together with evaluation of your patients’ individual risk profile, will help you to make the most appropriate anticoagulant choice.


High-risk patients (HAS-BLED ≥3) with AF in phase III trials

Although the designs of the phase III NOAC trials are superficially similar, the populations enrolled were quite different. Notably, ROCKET AF included the highest proportion of patients at high risk of bleeding (based on HAS-BLED score ≥3). Furthermore, according to mean CHADS2 score, the patients in ROCKET AF also had the highest risk of stroke (ROCKET AF, 3.5; ENGAGE AF, 2.8; ARISTOTLE, 2.1; RE-LY, 2.1)


Updated ACC/AHA/HRS guidelines

Approximately 1 in 3 patients with type 2 diabetes have clinically significant chronic kidney disease (estimated glomerular filtration rate <60 ml/min/1.73 m2) based on UK medical records. A diagnosis of renal impairment alongside diabetes makes effective management of stroke risk even more important because, like diabetes, renal impairment increases the risk of stroke in patients with AF. Therefore, it is important to preserve renal function in patients with diabetes and consider management approaches that reduce the risk of renal decline.


With this in mind, the 2019 update to the ACC/AHA/HRS guidelines notes that the NOACs, in particular rivaroxaban and dabigatran, may be associated with lower risks of adverse renal outcomes than warfarin in patients with AF.

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