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Safety issues and limitations of long-term anticoagulation

Safety in anticoagulation management can be successfully achieved through familiarising healthcare professionals of the risks and benefits of anticoagulation therapy and through regular training and education

Michiel Coppens MD PhD Department of Vascular Medicine, Academic Medical Centre, Amsterdam, The Netherlands

Oral anticoagulation is one of the most effective therapies in cardiovascular disease and has therefore become the cornerstone of treatment and prevention of thromboembolism. In patients with venous thromboembolism (VTE), oral anticoagulation with either vitamin K antagonists (VKAs) or non-vitamin K antagonist oral anticoagulants (NOACs) reduces the risk of recurrence by 80–90% compared with no treatment/placebo.1–3 In patients with atrial fibrillation AF, VKAs reduce the risk of ischaemic stroke by 64%.4

Inhibition of the coagulation cascade also attenuates the normal haemostatic response to blood vessel injury and therefore, the most important adverse effect is the increased risk of bleeding. In Western Europe and North America, VKAs consistently top the list of drugs for which the adverse effects lead to hospital admission.5,6

For patients treated with

oral anticoagulation, the incidence of major bleeding is 2–3% per year.7–11


case-fatality of major bleeding is approximately 10% and almost half of the deceased die after intracranial bleeding.12 If it is considered that an estimated six million Europeans suffer from AF,13 stroke protection with oral


anticoagulation would lead to 120,000– 240,000 episodes of major bleeding and 12,000–24,000 deaths each year. This highlights the risks of oral anticoagulation and the need for strategies that can further reduce bleeding.

NOACs have been compared with VKAs in unprecedentedly large Phase III, randomised, controlled trials in patients with AF (n=71,683) and VTE (n=29,728).2,3,7–10,14–17

Taken together,

NOACs provide similar protection from ischaemic stroke (relative risk (RR) 0.92; 95% CI 0.83–1.02) and reduce the risk of major bleeding by 14% (RR 0.86; 95%CI 0.73–1.00).18

More importantly, the

pattern of bleeding is different between NOACs and VKAs. VKAs exert their anticoagulant effect by inhibiting liver synthesis of coagulation factors II, VII, IX and X. Therefore, VKAs do not have an anticoagulant effect inside the intestinal lumen after ingestion. By contrast, NOACs directly inhibit coagulation Factors IIa or Xa and do have an anticoagulant effect inside the intestinal lumen. As a consequence, NOACs are associated with a 25% increased risk of gastrointestinal bleeding in AF patients.18 Arguably, the most important benefit of

NOACs is the reduction of the most destructive of all bleeds, intracranial haemorrhage (ICH), by 52% compared with VKAs (RR 0.48; 95%CI 0.39–0.59).18 The mechanism by which NOACs reduce the risk of ICH is not clearly established. Most likely, the haemostatic response to (micro) vessel injury is less attenuated by NOACs than by VKAs in tissues with very high tissue factor concentration, such as the brain.19

Asymptomatic cerebral

micro-bleeds would thereby lead to overt and symptomatic ICH more often in patients treated with VKAs than in NOAC-treated patients.19

these differences is a consistent 10% reduction in all-cause mortality in AF patients treated with a NOAC compared with VKAs.18

A similar pattern is seen in the VTE Phase III trials.20

NOACs have similar

effectiveness as VKAs for prevention of recurrent VTE (RR 0.90; 95%CI 0.77– 1.21) and reduce the risk of major

The net effect of

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