Impact of BMI on clinical outcomes of NOAC therapy in daily care - Results of the prospective Dresden NOAC Registry (NCT01588119)
Introduction
Direct acting non-Vitamin K antagonist oral anticoagulants (NOAC) are more and more replacing vitamin K antagonists (VKA) as anticoagulant treatments for stroke prevention in atrial fibrillation (SPAF) or venous thromboembolism (VTE) [[1], [2], [3], [4]]. The class of NOAC is characterized by a fixed dosing regimen and dose adjustment for overweight patients is not recommended [[5], [6], [7], [8]]. Theoretically, the distribution volume of drugs can increase with increasing body weight or body mass index (BMI), which would result in a hypothetical risk for relative underdosing. The overall effect of BMI on NOAC exposure seems to be small but measurable, as suggested by PK/PD studies with dabigatran, edoxaban and apixaban [[9], [10], [11]], and even less so for rivaroxaban [12,13]. However, the clinical relevance with regard to NOAC effectiveness and safety is currently unclear. Although obese patients (BMI ≥ 30 kg/m2) were not excluded from the phase III NOAC trials, their proportions as well as the applied weight classifications were highly variable in the phase III NOAC SPAF trials: 40% in ARISTOTLE [14] and 35% in ENGAGE-AF [15] had a BMI of ≥30 kg/m2; 10% in RE-LY [16] a BMI of ≥36 kg/m2 and, in ROCKET-AF 37% had a BMI ≥ 30 kg/m2 [17] and 13.6% had a BMI > 35 kg/m2 [18]. Similarly, proportions of obese patients were highly variable across the respective VTE trials AMPLIFY (13% with BMI > 35 kg/m2), EINSTEIN DVT and PE (14% had a body weight > 100 kg); HOKUSAI (14% had a body weight > 100 kg), RECOVER I (12% had a BMI > 35 kg/m2) and RECOVER II (23.6% had a BMI > 35 kg/m2) [[19], [20], [21], [22], [23], [24]].
Recently, post-hoc analyses of some of these trials [14,17,25] as well as two meta-analyses [26,27] indicated that NOACs provide consistent efficacy and safety also for obese patients but, obviously, conclusions from these studies are limited by varying weight cut-offs and BMI stratifications. A guidance statement of the Standardization Subcommittee (SSC) of the International Society of Thrombosis and Haemostasis concluded from the data that appropriate standard dosing of the NOACs in patients with a BMI less than or equal to 40 kg/m2 and weight less than or equal to 120 kg for VTE treatment, VTE prevention, and prevention of ischemic stroke and systemic arterial embolism in non-valvular AF can be recommended. On the other hand, the SSC suggested not to use NOACs in patients with a BMI of >40 kg/m2 or a weight of >120 kg, because of the limited availability of clinical data for patients at the extreme of weight and because the available PK/PD evidence suggests that decreased drug exposures, reduced peak concentrations and shorter half-lives occur with increasing weight [18].
All of this suggests a need to evaluate the impact of BMI on cardiovascular and bleeding outcomes in unselected patients treated with NOAC under real-world conditions.
Using prospectively collected data of patients from a non-interventional registry we aimed to evaluate the impact of BMI on cardiovascular (CV) events, major bleeding (MB) and all-cause mortality in daily care NOAC recipients to evaluate if extremes of body weight affect the rate of outcomes during fixed-dose NOAC therapy without dose-adjustments for higher BMI.
Section snippets
Patients and outcomes
The Dresden NOAC Registry (NCT01588119) is a large, prospective registry in the administrative district of Dresden (Saxony), Germany. In this ongoing project, a network of >230 physicians from private practices and hospitals are enrolling consecutive NOAC patients, who are prospectively followed up by the central registry office. The design and methodology of the Dresden NOAC Registry has been published previously [[28], [29], [30]]. All patients with an intended NOAC treatment duration for at
Cohort characteristics
Between November 1st 2011 and December 31st 2016, 3432 patients were enrolled into the registry (2104 received rivaroxaban [61.3%]; 685 apixaban [20.0%]; 348 dabigatran [10.1%], 295 edoxaban [8.6%]). Indication for anticoagulation was VTE in 1055 (30.7%) patients, SPAF in 2334 (68%) patients or off-label use in 43 (1.3%) patients. Overall, mean age was 70.4 years and 1814 patients (52.9%) were male (Table 1).
According to the WHO classification, 17 patients were underweight (BMI < 18.5 kg/m2;
Discussion
In a large set of real-life NOAC recipients treated for SPAF or VTE, which included >30% with obesity and 98 patients with a BMI > 40 kg/m2, we found no indication that elevated BMI is associated with a lack of NOAC effectiveness or safety. This is a reassuring observation since the perception of a risk of relative underexposure to drug and a resulting lack of antithrombotic effectiveness with increasing body weight still is a major concern [18,33,34]. This concern was already addressed in the
Conclusion
In a large set of real-life NOAC recipients we found no indication that elevated BMI is associated with a lack of NOAC effectiveness or safety. Consistent with epidemiological data, increased BMI seems to be associated with a better survival also in NOAC recipients, if compared to underweight patients.
Funding
The NOAC registry is supported by the Gesellschaft für Technologie- und Wissenstransfer der Technischen Universität Dresden (GWT-TUD GmbH), Germany (sponsor); by research funds of the University Hospital “Carl Gustav Carus”, Dresden, and by grants from Bayer AG, Boehringer Ingelheim, Daiichi Sankyo and Pfizer. All authors declare that these companies and institutions had no influence on the study design, conduct, data collection, statistical analysis, or preparation of the presented manuscript.
Acknowledgements
We are grateful to all participating patients and physicians, who continue to be maximally supportive in helping to follow patients and provide detailed information/documentation on suspected outcome events.
Conflict of interest
J.B.-W. has received honoraria and research support from Bayer AG, Boehringer Ingelheim, Daichii Sankyo, Pfizer and Portola. S.M. has received honoraria from Bayer AG and Daiichi Sankyo.
None of the other authors declared a conflict of interest with regard to the NOAC registry or this manuscript.
References (47)
- et al.
The effect of dabigatran plasma concentrations and patient characteristics on the frequency of ischemic stroke and major bleeding in atrial fibrillation patients: the RE-LY trial (randomized evaluation of long-term anticoagulation therapy)
J. Am. Coll. Cardiol.
(2014) - et al.
Relation of risk of stroke in patients with atrial fibrillation to body mass index (from patients treated with rivaroxaban and warfarin in the rivaroxaban once daily oral direct factor Xa inhibition compared with vitamin K antagonism for prevention of stroke and embolism trial in atrial fibrillation trial)
Am. J. Cardiol.
(2017) - et al.
Use of the direct oral anticoagulants in obese patients: guidance from the SSC of the ISTH
J. Thromb. Haemost.
(2016) - et al.
Direct oral anticoagulants compared with vitamin K antagonists for acute venous thromboembolism: evidence from phase 3 trials
Blood
(2014) - et al.
Rates, management, and outcome of rivaroxaban bleeding in daily care: results from the Dresden NOAC Registry
Blood
(2014) - et al.
Definition of major bleeding in clinical investigations of antihemostatic medicinal products in non-surgical patients
J. Thromb. Haemost.
(2005) - et al.
The long- and short-term impact of elevated body mass index on the risk of new atrial fibrillation the WHS (women's health study)
J. Am. Coll. Cardiol.
(2010) - et al.
Association of body weight with efficacy and safety outcomes in phase III randomized controlled trials of direct oral anticoagulants: a systematic review and meta-analysis
J. Thromb. Haemost.
(2017) - et al.
Influence of obesity on outcomes in atrial fibrillation: yet another obesity paradox
Am. J. Med.
(2010) - et al.
Obesity paradox in patients with atrial fibrillation and heart failure
Int. J. Cardiol.
(2014)