Compliance of atrial fibrillation treatment with the ABC pathway in patients with concomitant diabetes mellitus in the Middle East based on the Gulf SAFE registry

Atrial fibrillation (AF) and diabetes mellitus (DM) constitute a heavy burden on healthcare expenditure due to their negative impact on clinical outcomes in the Middle East. The Atrial fibrillation Better Care (ABC) pathway provides a simple strategy of integrated approach of AF management: A—Avoid stroke; B—Better symptom control; C—Cardiovascular comorbidity risk management.


| INTRODUCTION
Atrial Fibrillation (AF) is a leading cause of cardiovascular death as well as disability and impaired quality of life by exacerbating other underlying comorbidities such as heart failure, stroke or dementia. [1][2][3][4][5] Furthermore, AF is a growing epidemic is associated with high costs of treatment and hospitalisations, thus having significant implications for healthcare costs. 4,6,7 Similarly, for diabetes mellitus (DM), the latest estimates show a steadily increasing trend in the numbers of such patients. By the end of 2045, the number of DM patients is expected to reach 700 million, which represents an increase by around 40%. 8 Indeed, the Middle East is one of the world's regions where the growth of people with diabetes is predicted to be the largest over the next few years, and the prevalence is increasing 8 This is even more important given that DM is a well-established risk factor for many cardiovascular diseases, including AF. 9,10 Many studies report the common coexistence of AF and DM, and their associated cardiovascular risks. 7,[11][12][13][14][15] Hence, patients with DM are not only more likely to develop AF during their life, but they also have a significantly higher overall risk of cardiovascular complications. 16,17 Given the multifactorial background of AF, a more integrated and holistic approach to AF management with optimised drug therapies may improve clinical outcomes. [18][19][20] The Atrial fibrillation Better Care (ABC) pathway for integrated care of AF patients is a simple strategy showing stepby-step how to approach AF management in a comprehensive and sensible way. 5 The ABC pathway refers to the following steps: Avoid stroke with Anticoagulation (A); Better symptom management with patient-centred symptom-directed decisions on rate or rhythm control (B); Cardiovascular and comorbidity risk optimisation (C). The 'A' criterion refers to optimisation of stroke prevention, which involves initial identification of low-risk patients, who are not recommended any antithrombotic therapy. Following this, patients with ≥1 stroke risk factors are considered for OAC and would require assessment of bleeding risk and decision-making on OAC type. 5 The 'B' criterion refers to symptom assessment of the patient with AF and deciding the initial treatment strategy to be established with rate control drugs or rhythm control with antiarrhythmic drugs or electrophysiological procedures. The 'C' criterion refers to effective management of comorbidities as well as patient involvement with lifestyle changes, dietary habits or physical activity. 5 The above-mentioned holistic care approach facilitates risk reduction through effective treatment of accompanying diseases, whereby DM is one of the most prominent examples. 5 In this study, we evaluated whether the management of AF patients with concomitant DM in the Middle East region was generally compliant with the ABC regimen, based on a 'real-world' dataset enrolled in the Gulf Survey of Atrial Fibrillation Events (Gulf SAFE registry). Second, the impact of ABC pathway compliant management on adverse clinical outcomes. The adherence to the ABC pathway and its impact on clinical outcomes has never been previously evaluated in this Middle Eastern population.

| METHODS
The Gulf SAFE dataset is a multi-centre, observational, prospective cohort study recording subsequent AF patients from 6 countries in the Gulf region of the Middle East. Details on the methods have been described in the previously published papers. 21  consent for their participation after being informed about the details of the study. The study received approval from the ethics committees of each institution/country and conforms to recognised standards. For the purposes of this study, we included only patients with AF and DM, and this cohort of 603 patients was analysed. We analysed compliance in line with the ABC pathway components, which were defined on the basis of ESC Guidelines 22 as follows: • 'A' -avoid stroke: All AF patients with DM have a high risk of stroke (CHA 2 DS 2 -VASc score of ≥1 in men or ≥2 in women), and therefore, we assessed whether subjects were treated with OAC ('A compliant'). Those who did not receive OACs were considered as 'A noncompliant'. The vast majority of patients receiving OAC in the current study were administered with vitamin K antagonists (VKA eg warfarin). • 'B-better symptoms control': We evaluated the occurrence of symptoms and classified them according to the European Heart Rhythm Association (EHRA) symptom scale. We assumed that patients with EHRA I or II had well-controlled AF symptoms ('B compliant') in comparison to those with EHRA III or IV, who were more symptomatic and treated insufficiently ('B noncompliant'). • 'C-Cardiovascular and other comorbidities': To reduce cardiovascular risk, we evaluated appropriate treatment(s) of the following comorbidities based on available data: hypertension (HT), coronary artery disease (CAD), peripheral artery disease (PAD), stroke/TIA. HT assessment was based on an average of blood pressure values at hospital admission that should be <140/90 mm Hg in order to be considered as well controlled. For other comorbidities, optimal pharmacologic management was evaluated in accordance with the current European guidelines and recommendations ( Figure 1). 'C compliant' means that all comorbidities were either well-controlled or treated with appropriate prevention drugs or both. Finally, patients who met all criteria were defined as the 'ABC group', and those who did not meet all criteria were the 'Non-ABC' group.

| Outcomes
In our analysis, we assessed all-cause mortality and a composite outcome, which consists of the following events that occurred during follow-up: stroke or systemic embolism, allcause death and cardiovascular hospitalisation. The primary analysis was a comparison of the above-mentioned outcomes between patients with integrated care management in accordance with the ABC pathway (ABC group), compared to those without ABC pathway compliance (non-ABC group).

| Statistical analysis
Continuous variables were reported as mean ± standard deviation and evaluated by Student's t test or Mann-Whitney, as necessary. Categorical variables were expressed as percentages and counts and compared using Pearson's chi-square test or Fisher's exact test, as appropriate. All the patients included a further assessment to have AF and DM. The major analyses were based on the comparison of the clinical outcomes between two study groups: ABC group vs the non-ABC group, whereby the former reflects compliance with the ABC pathway in AF management while the latter does not. The secondary analysis evaluated the impact of the total number of ABC steps fulfilled, the partial compliance with ABC regimen (0 or 1 ABC fulfilled criteria vs 2 of 3 fulfilled ABC criteria) and particular criteria met (A, B or C) on the major clinical outcomes, that is, allcause mortality and composite outcome. Odds ratios (ORs) were analysed using multivariable logistic regression model and were used according to the outcomes considered. All multivariable regression models were adjusted for AF type, renal dysfunction, dyslipidemia, use of aspirin and major bleeding, which are well-known risk factors for all-cause mortality and the composite outcome components.
All tests were 2-sided and P value <.05 was considered as statistically significant. Analyses were performed with the SPSS version 24 software package (SPSS Inc).

| RESULTS
From 2043 patients with AF enrolled in the Gulf SAFE registry, there were 603 (30%) patients with concomitant DM, who were included in the analysis. Overall, 86 (14.3%) patients were treated optimally according to ABC pathway. Baseline characteristics of the study cohort are presented in Table 1. Patients from the ABC group and the non-ABC group did not significantly differ in terms of gender, age and BMI.
Compared to the non-ABC group, patients in ABC group had lower mean systolic and diastolic blood pressure (both P < .001), suffered more frequent due to chronic kidney disease (P = .021). Patients from ABC compliant group were also administered a larger number of medications (Table. 1).

| 'A' compliance and anticoagulation management
All 603 patients included in the analysis were at high stroke risk (CHA 2 DS 2 -VASc score ≥2 for women or ≥1 for men) therefore required anticoagulant therapy. There were 349 (57.9%) patients in the study cohort treated in line with 'A' ( Table 2). Of these, 151 (25.1%) were treated with an OAC monotherapy, 142 (23.5%) received dual antithrombotic therapy and 25 (4.2%) received triple antithrombotic therapy, while 34 (5.6%) had no anticoagulant/antiplatelet therapy at all. A detailed description of OAC management is presented in Table S1.

| 'C' compliance and comorbidities risk optimisation
Of the whole cohort, 183 (30.3%) were optimally treated for comorbidities. HT was the most prevalent associated disease (78.1%). Treatment regimens and the prevalence of concomitant diseases are summarised in Table S2.

| ABC compliance and clinical outcomes
After adjusting for clinical variables, we analysed the risk of all-cause mortality and the composite outcome after 6 months and 1 year of follow-up (Table 3). In this time period, 207 composite outcome events occurred, and 87 individuals died.
The mortality rate was significantly lower in ABC group comparing to noncompliant ABC patients (5.8% vs 15.9%, P = .014, respectively). A nonsignificant trend was observed in the comparison of the composite outcome rates between ABC and non-ABC groups (25.6% vs 36.8%, P = .065, respectively).
Considering the components of partially fulfilled ABC criteria, there was no statistically significant impact on allcause mortality and composite outcome after 1 year of follow-up, when only 2 of 3 criteria were met (AB or BC or AC) except for BC compliance, which was associated with lower risk of composite outcome (OR 0.58, 95% Cl, 0.37-0.91) after 1 year (Table 4).

| DISCUSSION
This is the first study analysing the compliance of AF management in accordance with the ABC pathway among patients with AF and concomitant DM, based on a real-world observational trial in the Middle East which has a high prevalence of DM. Our study shows that the vast majority of these patients were not managed optimally despite having a high risk of stroke. Second, optimal integrated treatment fulfilling all criteria in the ABC pathway regimen significantly reduced the risk of all-cause mortality and the composite outcome in comparison to the non-ABC compliant group. Third, the lower risk of mortality and composite outcome in ABC group was independent of either of the duration of follow up and other adjusted covariables.
Our findings indicate that a low percentage of patients received comprehensive AF treatment, compliant with ABC pathway (14.3%) are consistent with other studies on the subject. [23][24][25] Stroke prevention and proper AF management are even more important among AF patients with concomitant DM as it increases the risk of death from unfavourable thrombotic events. 26,27 Moreover, AF patients with DM have a high risk of stroke (CHA 2 DS 2 -VASc ≥ 1), and the age threshold for initiating OAC in an AF patient with DM as his/her only stroke risk factor is 50 years. 28 Hence, anticoagulation should have been implemented to all patients in the DM cohort group, while slightly <50% of them were not prescribed OAC at all. Despite the high risk of stroke associated with AF, only 7%-10% die from stroke. 29,30 The vast majority of deaths are related to cardiovascular complications, especially from heart failure. The ABC pathway underlines the need of proper and holistic symptom control of concomitant diseases and their associated symptoms. This means that not only appropriate anticoagulation, but also optimal management and control of other symptoms and comorbidities lead to reductions in allcause death and the composite outcome. 29 indeed, AF can be associated with a high mortality despite high overall rates of anticoagulation. 18 Our study revealed that only holistic AF management in accordance with all ABC components is related to a reduction in either all-cause mortality or occurrence of the composite outcome. Similarly, Pastori et al 31 showed that the risk of adverse cardiovascular events raised with the number of uncontrolled risk factors. In a clinical trial cohort with adjudicated outcomes, Proietti et al reported progressively lower total risk for allcause death and composite outcome across the groups with the increasing number of fulfilled ABC components. 23   trend was presented in a nationwide cohort study based on an Asian population. 25 The above evidence indicates the value of compliance with the ABC pathway for reducing the risk of death and composite adverse outcomes and highlights the importance of integrated, complex care in AF management. 5 The above findings are essential for any healthcare system as either DM or AF treatment is associated with high healthcare costs. Moreover, DM is, and an independent risk factor for AF development 9,10,32 and their coexistence worsens the outcome among patients. [33][34][35] Hence, the awareness of the risk factors, early detection of disease and finally, adequate medical care is crucial to reduce cardiovascular mortality in such patients.

| Strengths and limitations
This is the first study in the Middle East population assessing the compliance of holistic AF management among patients with concomitant DM and the impact on relevant clinical outcomes. The database is based on a large number of consecutive patients from various medical centres who met precisely defined criteria, which enhances the reliability of the analysis results. Nevertheless, there are also some limitations, which should be considered.
This was an observational study with relatively limited of diabetic participants that fulfilled our inclusion criteria for the study, therefore some bias and deficiencies of assessment may have occurred. The compared groups were not homogeneous in terms of concomitant diseases, and some diseases (eg. sleep apnoea) may be undiagnosed. In addition, ABC noncompliant patients were in majority, in keeping with other series. 36 As for DM, its diagnosis, duration and specific type were unknown, which preclude an appropriate evaluation of the impact of DM on the overall cardiovascular risk. In addition, we did not have information about haemoglobin A1c values, which is an indicator of diabetes control in patients with DM. Undeniably, such information would enrich the content of the study and strengthen the credibility of the results. Furthermore, because of the retrospective nature of the study, we were not able to intervene in the treatment regimen that has changed over time, nor do we have data on compliance with drug treatments or therapy cessation, which may have implications for outcomes. 37,37 Although, our registry was conducted in a broad spectrum of clinical settings, in 6 Gulf region countries -but we would be underpowered to perform our analysis by individual country. Due to the retrospective nature of the study, the authors were not able to interfere in the treatment regimen that has changed over time. Finally, the data from the Gulf SAFE registry was collected in 2009-2010, which may affect the reliability of our results in relation to current standards. Nevertheless, although the ABC pathway was not promoted at that time, the general recommendations in accordance with the guidelines for the treatment of AF did not differ from those used in prior treatment approaches.

| CONCLUSIONS
Integrated AF care, according to the ABC pathway, was independently associated with a lower risk of all-cause death and the composite outcome, in DM patients with AF. This highlights the importance of a comprehensive and holistic approach to AF management.