Non-embolic outcomes in patients with cardiovascular disease and atrial fibrillation treated with rivaroxaban

The design and methods of the EMIR study have been described elsewhere [12,13]. Briefly, EMIR was a prospective and observational study that included adult patients with a diagnosis of AF treated with rivaroxaban for at least 6 months before enrollment. All patients had to give their written informed consent before being included in the study and were followed up for 2.5 years according to routine clinical practice. The exclusion criteria were prosthetic heart valves, severe valvopathy, chronic infections, systemic autoimmune diseases, active cancer, severe liver or renal insufficiency and severe cognitive impairment. The study was approved by the local ethics committees. For the purpose of this study, we performed a retrospective analysis of the EMIR database, although all the end points were prospectively collected.

Baseline data, including biodemographic parameters, scales (CHA₂DS₂-VASc, HAS-BLED, 2MACE), cardiovascular risk factors and history of vascular disease were collected from the patients’ clinical history and via interview and recorded on a specific electronic case report form. Data were analyzed in the overall study population and according to the presence of vascular disease, which was defined as the presence of baseline CAD, cerebrovascular disease or peripheral artery disease. The presence of coronary heart disease, vascular disease and aortic plaque were recorded from the electronic clinical history of patients, according to physicians’ criteria. Chronic kidney disease was defined as an estimated glomerular filtration rate <60 ml/min/1.73 m² according to the MDRD-4 formula [14].

Outcomes (MACE, thromboembolic events, major bleeding, myocardial infarction, revascularization, cardiovascular death and all-cause mortality) during the study were evaluated by an independent scientific committee. MACE included a combination of non-fatal myocardial infarction, revascularization and cardiovascular death (ischemic heart disease, progressive heart failure and sudden cardiac death). Thromboembolic events included a combination of stroke, systemic embolism and/or transient ischemic attack, together with myocardial infarction. Major bleeding was defined according to definition of the International Society of Thrombosis and Hemostasis [15]. Events were analyzed in the overall study population and according to the presence of previous CAD, peripheral artery disease/aortic plaque and vascular disease. In addition, predictors of MACE, thromboembolic events and major bleeding in patients with previous CAD or vascular disease were determined.

The initial study population comprised 1503 patients from 83 Spanish centers (hospitals and private clinics). After the exclusion of 70 patients, 1433 (93.7%) patients from 79 Spanish centers, were included in the final analysis. At baseline, 235 (16.4%) had CAD, 96 (6.7%) peripheral artery disease/aortic plaque and 406 (28.3%) vascular disease (Figure 1).

Table 1 presents the baseline clinical characteristics overall and according to the presence of previous CAD, peripheral artery disease/aortic plaque and vascular disease. Mean age was 74.2 ± 9.7 years, 55.5% of patients were male, 37.5% had permanent AF, mean CHA₂DS₂-VASc was 3.5 ± 1.5, mean HAS-BLED was 1.6 ± 1.0, and 26.9% had a 2MACE score ≥3. Compared with patients without CAD, those with ischemic heart disease were more commonly men, had higher CHA₂DS₂-VASc and HAS-BLED scores, and more frequently had diabetes, heart failure and peripheral artery disease. In addition, a greater proportion of patients presented with 2MACE ≥3. Compared with patients without peripheral artery disease/aortic plaque, those with peripheral artery disease/aortic plaque were older, had higher CHA₂DS₂-VASc and HAS-BLED scores and more frequently had hypertension, diabetes, heart failure and chronic kidney disease. In addition, a greater proportion of patients had 2MACE ≥3. Compared with patients without vascular disease, those with vascular disease were older and more commonly men and had more permanent AF, higher CHA₂DS₂-VASc and HAS-BLED scores, as well as more frequent diabetes and heart failure. In addition, more patients had 2MACE ≥3.

The mean follow-up was 2.2 ± 0.6 years (median: 2.5 years; interquartile range: 2.2–2.6 years). The incident rates of relevant events were calculated based on 1425 patients (Table 2). Overall, annual percentages of stroke + systemic embolism + transient ischemic attack, MACE, cardiovascular death, death from any cause and major bleeding were 0.72, 1.07, 0.63, 2.73 and 1.04%, respectively. Compared with patients with no previous CAD at baseline, those with ischemic heart disease had a greater annual frequency of MACE, coronary revascularization, cardiovascular death and death from any cause, with a trend toward more thromboembolic outcomes and major bleeding. Compared with patients without previous vascular disease at baseline, those with vascular disease had higher incidence rates of stroke + systemic embolism + transient ischemic attack, MACE, coronary revascularization, cardiovascular death, death from any cause and major bleeding. By contrast, no significant differences were found regarding outcomes according to the presence of peripheral artery disease/aortic plaque.

Multivariate logistic regression analyses were performed to determine the potential predictors of MACE events, thromboembolic events and major bleeding (Table 3). The concomitant use of antiplatelet agents and older age were independent predictive factors associated with MACE in patients with previous CAD, whereas antiplatelet agents and heart failure were independent predictive factors associated with MACE in patients with vascular disease. On the other hand, permanent AF and previous stroke were independently associated with the development of thromboembolic events in patients with previous CAD, and permanent AF was associated with the development of thromboembolic events in patients with vascular disease. Finally, chronic kidney disease was an independent predictor for major bleeding in patients with previous CAD and vascular disease.

Although, it is known that the presence of comorbidities may have a negative impact on the prognosis of AF patients, it has not been well established how cardiovascular disease may impact on AF patients. This is even more relevant among patients taking direct oral anticoagulants. Our study of a wide sample of real-life patients with AF anticoagulated with rivaroxaban showed that patients with atherosclerotic vascular disease have a worse clinical profile and a much higher risk of MACE (cardiac mortality, coronary revascularization, non-fatal myocardial infarction), thromboembolic events and cardiovascular mortality than patients without vascular disease.

In the EMIR study, rivaroxaban was prescribed in high-risk patients, as in the pivotal clinical trial and in other real-life registries [11,16]. In addition, our study showed, in line with the ROCKET-AF substudies [17–19], that patients with CAD, peripheral artery disease/aortic plaque and vascular disease had a worse clinical profile, with more comorbidities and a higher thromboembolic and bleeding risk than patents without these conditions. As a result, our data are representative of this population. Therefore, the management of these patients is more challenging and requires a comprehensive, holistic approach addressing all aspects of prevention of cardiovascular disease [7].

In the EMIR study, patients with ischemic heart disease had greater incidence rates of MACE, coronary revascularization, cardiovascular death and death from any cause. In the ROCKET-AF trial, rates of cardiovascular death and myocardial infarction were higher in patients who had previously had myocardial infarction than in those who had not. Of note, among patients with previous myocardial infarction, the risk of ischemic cardiac events fell by 14% in those treated with rivaroxaban than in those treated with warfarin, although the difference was not significant [17]. A meta-analysis of nine trials from various clinical scenarios (AF, acute coronary syndrome, prophylaxis and treatment of deep venous thrombosis/pulmonary embolism), showed that compared with the control groups, rivaroxaban was associated with an 18% reduction in the risk of myocardial infarction [20]. As a result, although the risk of outcomes is higher in patients with CAD, this risk remains low among real-world AF patients taking rivaroxaban, likely owing to its beneficial effects on these outcomes [21]. A trend toward more major bleeding was observed; however, and is probably associated with the more frequent use of antiplatelet agents in this population [22]. Of note, the AFIRE trial showed that in patients with AF and stable CAD, rivaroxaban in monotherapy had a similar efficacy but better safety profile than the combination of rivaroxaban and a single antiplatelet agent [23].

In our study, similar outcomes were observed regardless of the presence of peripheral artery disease/aortic plaque. Although this could be explained by the low number of patients included in this subgroup, in the pivotal ROCKET AF clinical trial, patients with peripheral artery disease did not have a higher risk of stroke or systemic embolism [18]. However, in the EMIR study, patients with vascular disease had a higher risk of thromboembolic events, MACE and death. Therefore, it is necessary to consider not only the risk of stroke, but also that of other cardiovascular outcomes. In ROCKET AF, compared with warfarin, rivaroxaban exhibited a favorable net clinical benefit in terms of death, stroke, systemic embolism, myocardial infarction and major bleeding [24]. Our data would confirm the effectiveness and safety of rivaroxaban in clinical practice among patients with vascular disease.

Despite bleeding risk or cancer could be associated with more events [25,26], the multivariate analysis showed that concomitant use of antiplatelet agents was associated with a higher risk of MACE, both in patients with previous CAD and in those with vascular disease. This observation was also reported by other authors [27] and could have been associated with the possibility that these patients may have had recent acute coronary syndrome or undergone a myocardial revascularization procedure. It is well known that such patients are at particularly high risk for heart failure, repeated urgent revascularization and cardiovascular death [28]. Another explanation for the adverse outcomes affecting patients taking concomitant antiplatelet and anticoagulation medication is the possible increasing risk of embolic or atherosclerotic complications immediately after bleeding events. Accordingly, patients in the AFIRE trial who experienced major bleeding also had a higher risk of thrombotic complications, especially during the first 30 days after the bleeding event, likely associated with withdrawal of antithrombotic therapy [29]. Remarkably, in real-life patients, the combination of antiplatelet agents and oral anticoagulants among patients with AF does not prevent ischemic events, but rather significantly increases the frequency of major bleeding [30]. As a result, except for the first 12 months after an acute event coronary syndrome or coronary revascularization, antiplatelets agents should be withdrawn and anticoagulation should be considered the only antithrombotic therapy in AF patients with stable CAD (7).

Permanent AF was associated with a higher risk of thromboembolic events in affected patients. Although the type of AF is not included in the CHA₂DS₂-VASc score, it is important to remember that patients with a higher AF burden may have a higher risk of stroke [31]. Finally, chronic kidney disease was associated with a higher risk of major bleeding. Of note, as chronic kidney disease also markedly increases the risk of stroke, affected patients should be anticoagulated in most cases [32]. In addition, in a previous analysis of the EMIR study, renal function was preserved among patients chronically anticoagulated with rivaroxaban [13]. However, to obtain the maximum benefit, it is important that the dosage of all direct oral anticoagulants be adjusted according to renal function [8].

This study is subject to a series of limitations. Its observational design precluded the inclusion of a control group. Therefore, despite the high number of patients included, the consecutive recruitment, and the high quality of data recorded, confounding factors could be present. In addition, as the presence of coronary heart disease, vascular disease and aortic plaque were recorded from the electronic clinical history of patients, according to physicians’ criteria, some of these conditions could be underdiagnosed. On the other hand, patients with some of these conditions could be included in the other groups, limiting the analysis for each conditions separately. As a result, this was an exploratory analysis and the results should be confirmed in future studies. On the other hand, patients were recruited after at least 6 months of treatment with rivaroxaban in Spain. Consequently, the results of the EMIR study can only be applied to patients with similar clinical characteristics.

Among AF patients anticoagulated with rivaroxaban in clinical practice, approximately 16% have CAD and 28% vascular disease. Overall, rates of thromboembolic events, MACE, cardiovascular death and major bleeding are low. However, patients with atherosclerotic vascular disease exhibit a worse clinical profile and a higher risk of MACE, thromboembolic events and cardiovascular mortality than those without. The management of patients with AF and vascular disease requires a comprehensive approach, with the aim of reducing not only the risk of stroke, but also that of cardiovascular related complications. In this context, rivaroxaban should be considered for the treatment of affected patients in clinical practice.

F Marín has received consultancy/lecturing fees from Bayer, Boehringer Ingelheim, Pfizer, Bristol Myers Squibb, Daiichi Sankyo and AFNET. M Sanmartín Fernández has received speaker and advisory fees from the following companies in the past 3 years: Bayer, Boehringer Ingelheim, BMS and Pfizer. G Barón-Esquivas has received honoraria as advisor from Bayer, Daiichi-Sankyo, BMS-Pfizer and Rovi; and honoraria as speaker from Boehringer-Ingelheim, Bayer, Daiichi-Sankyo, BMS and Pfizer. V Barrios has received consultancy/lecture fees from Bayer, BMS/Pfizer, Boehringer Ingelheim and Daiichi Sankyo. I Lekuona has received honoraria for presentations from Bayer, Boehringer-Ingelheim, Daiichi Sankyo and Pfizer-BMS. AI Pérez-Cabeza has received personal fees for educational activities or participation in boards from Daiichi Sankyo, Bayer, Boehringer Ingelheim and Bristol Myers Squibb. J Masjuan has received consultancy/lecturing fees from Bayer, Boehringer Ingelheim, Pfizer, Bristol Myers Squibb y Daiichi Sankyo. JM Vázquez Rodríguez has received lecturing fees from Bayer, Pfizer and Daiichi Sankyo. R Freixa-Pamias has received honoraria for presentations from Bayer, Boehringer-Ingelheim, Daiichi Sankyo and Pfizer-BMS. V Roldán Schilling has received honoraria for presentations from Bayer, Boehringer-Ingelheim, Daiichi Sankyo and Pfizer-BMS. F Arribas has received personal fees for educational activities or participation in boards from Daiichi Sankyo, Bayer, Boehringer Ingelheim and Bristol Myers Squibb. C Rafols Priu is an employee Bayer Hispania SL. M Anguita Sánchez has received funding for consulting and conference services from Bayer, Daiichi-Sankyo and Pfizer. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Writing and editorial assistance was provided by Content Ed Net (Madrid, Spain) with funding from Bayer Hispania.

The study was approved by each Ethical Committee of the participating centers.