This page contains a Flash digital edition of a book.

While not completely understood, potential explanations could be the higher mean age and thereby higher prevalence of intestinal angiodysplasias of AF patients (mean age 70–73 years in the Phase III trials) compared with VTE patients (mean age 54–58 years) and chronic versus timely defined treatment duration in VTE.

bleeding by 39% (RR 0.61; 95%CI 0.45–0.83). In line with the AF trials, NOACs sharply reduce the risk of ICH (RR 0.37; 95%CI 0.21–0.68) and fatal bleeding (RR 0.36; 95%CI 0.15–0.84). The increased risk of gastrointestinal bleeding, however, was not observed in the VTE trial (RR 0.78; 95%CI 0.47– 1.31).20

Risk factors for bleeding

Numerous observational and intervention studies have evaluated risk factors of bleeding in patients treated with VKA or NOACs. Increasing age and concomitant use of antiplatelet drugs are among the most consistent independent predictors of major bleeding in patients using VKA therapy.21

However, many more risk

factors have been associated with increased bleeding risk, including hypertension, diabetes mellitus, prior stroke or prior major bleeding (especially ICH), liver disease, alcoholism, malignancy, and renal insufficiency.21 Most of these risk factors for major bleeding with VKA are also risk factors for bleeding with NOACs.


Age is a risk factor for bleeding as well as for thromboembolism.22,23

In AF, patients

≥75 years have a twofold increased risk of stroke or systemic embolism compared with patients <65 years (RR 2.04; 95% CI 1.59–2.61). The risk of major bleeding increases even more with increasing age: RR 3.13 (95% CI 2.56–3.83) for patients ≥75 years vs < 65 years.22

However, the

relative risks of NOACs versus VKAs are similar in elderly patients compared with younger patients.24

This implies that the

relative risk reduction of major bleeding leads to a larger absolute risk reduction in elderly than in younger patients. The exception is dabigatran. The risk of major bleeding in patients treated with dabigatran rises more sharply with increasing age than in patients treated with VKA.25,26

Compared with VKAs,

dabigatran 150mg BID in patients aged >75–80 years increases the risk of major bleeding, and dabigatran 110mg BID has a similar risk of major bleeding. The

therefore unknown if the risk–benefit ratio of NOACs observed in the trials is maintained in patients with CKD IV or higher. However, based on population pharmacokinetic modelling, apixaban, edoxaban and rivaroxaban and also, in the US, dabigatran 75mg BID was approved for patients with eGFR 15–30ml/min. Ongoing Phase IV post-marketing registries will establish the true risk–benefit profile in these patients.

European Medicines Agency (EMA) therefore advises using 110mg BID for patients >80 years of age, and to consider 110mg BID for patients >75 years of age with additional bleeding risk factors.27 The incidence of a first VTE rises from 0.4 per 1000 patient-years in patients aged 20–49 years to 5.7 per 1000 patient-years in patients 75 years or over.23

However, it

is uncertain whether age is a risk factor for recurrent VTE in those that discontinue oral anticoagulation after a first event.28

Renal insufficiency

All NOACs are, in part, renally cleared. Approximately 80% of dabigatran is renally cleared, and corresponding proportions are 25% for apixaban, 35% for rivaroxaban, and 50% for edoxaban.18 Intuitively, NOACs would lead to higher bleeding risks in patients with renal impairment than VKAs, which are not renally cleared. This was not confirmed in the Phase III trials for patients with AF that included patients with an estimated glomerular filtration rate (eGFR) ≥30ml/ min.7–10

In the trial comparing dabigatran with VKA in AF patients, the risks of both stroke and bleeding increased with decreasing renal function, but there was no significant interaction between eGFR and allocated treatment.7,26

This implies

that eGFR 30–50ml/min is probably more important as a marker of frail patients at high risk of bleeding than as a pharmacokinetic parameter, even in a drug with 80% renal clearance such as dabigatran. For apixaban versus warfarin, a significant interaction between eGFR and allocated treatment was observed for major bleeding, with a larger risk reduction in patients with eGFR 25– 50ml/min (RR 0.50; 95% CI 0.38– 0.66).29 All Phase III trials excluded patients with stage IV chronic kidney disease (CKD; eGFR <30ml/min). It is

Concomitant use of antiplatelet drugs Acetylsalicylic acid (ASA) is regularly used in AF patients as primary or secondary prevention for arterial cardiovascular disease. For example, in the RE-LY trial, approximately 40% of patients used ASA at study entry and half of those continued ASA throughout the study period.26

As may be expected from

adding an antiplatelet drug to oral anticoagulation, the risk of bleeding increased by approximately 40%.26 Because ASA is the cornerstone of secondary prevention in patients with coronary artery disease (CAD), continuing ASA in patients who develop an indication for oral anticoagulation might seem plausible. However, in a meta- analysis of randomised trials comparing combined ASA/VKA with VKA alone, the addition of ASA did not reduce the risk of thromboembolism in patients with AF or with stable CAD.30

The increased bleeding

risk of combined ASA/VKA therapy compared with VKA alone was again confirmed (RR 1.43; 95% CI 1.00–2.02).30 The same most likely also applies to combined NOAC/ASA therapy compared with NOAC alone, as there was no significant interaction between allocated treatment and ASA use at baseline in any of the NOAC AF trials.7–10

Providing the optimal benefit–risk profile

Even though patients with AF and recurrent VTE have an indication for long-term anticoagulation, the indication could be subject to change. Periodic re-evaluation, for example, every one to two years, of patient preferences and newly acquired risk factors for bleeding should be performed, and could contribute to better adherence by our patients. For NOACs, periodic evaluation of renal function should be part of this re-evaluation. Concomitant antiplatelet drugs should probably be discontinued in most patients with the exception of


Page 1  |  Page 2  |  Page 3  |  Page 4  |  Page 5  |  Page 6  |  Page 7  |  Page 8  |  Page 9  |  Page 10  |  Page 11  |  Page 12  |  Page 13  |  Page 14  |  Page 15  |  Page 16  |  Page 17  |  Page 18  |  Page 19  |  Page 20  |  Page 21  |  Page 22  |  Page 23  |  Page 24  |  Page 25  |  Page 26  |  Page 27  |  Page 28  |  Page 29  |  Page 30  |  Page 31  |  Page 32  |  Page 33  |  Page 34  |  Page 35  |  Page 36