Blog entry by Meguid El Nahas
In this wek's NEJM, an article by Olesen and colleagues from Denmark shows that CKD is associated with increased risk of stroke and thromboembolism in patients withatrial fibrillation (AF); hazard ration in CKD ~2, and HR in ESRD ~3 (compared to general, non CKD, population).The data was derived from Danish National Registries and from an observational cohort of around 4,000 patients with CKD (3587 non-ESRD CKD) and 901 with ESRD. http://www.ncbi.nlm.nih.gov/pubmed/22894575
They also show that warfarin therapy is associated with significantly decreased risk. But there was a 33% increased risk of bleeding with warfarin therapy in CKD patients compared to those without CKD. Aspirin was not associated with decreased risk.
This analysis supports a recently published meta-analysis showing the beneficial effect of warfarin anticoagulation in incident AF patients: http://www.ncbi.nlm.nih.gov/pubmed/22450212. In this anlysis, there was a significant increase in the annual incidence of stroke with progressively increasing CHADS(2) (congestive heart failure, hypertension, age, diabetes, and prior stroke) scores.
The implications of the Olesen et al study would be to recommend warfarin therapy in patients with AF with CKD/ESRD. This would be all the more justified in view of the fact that most of the ESRD patients would have a CHADS score>2; old, hypertensive, diabetic with underlying CVD!
What the authors dont mention is the risks associated with warfarin therapy in ESRD.
There is growing evidence and concern that warfarin therapy is potentially harmful in this population due to the impact of warfarin on vascular calcifications as well as calciphylaxis. There is also evidence to link warfarin use and increased mortality in this population. The impact of warfarin on vascular calcifications has been l;inked to its inhibitory effect on vitamin K synthesis as well as that of other proteins. Apart from clotting factors, vitamin K-dependent proteins include regulatory proteins like protein C, protein S, protein Z, osteocalcin, growth arrest-specific gene 6 protein, and matrix Gla protein (MGP). MGP is a known natural inhibitor of vascular calcifications present in vascular walls and strongly inhibited by treatment with warfarin.
In addition to bleeding and vascular calcifications, other risks have been associated with the use of warfarin, including an increased susceptibility to fractures caused by a reduction in the levels of vitamin K dependent carboxylated enzymes, matrix Gla-protein (MGP) and bone Gla-protein or osteocalcin (BGP).
Consequently, anticoagulant therapy in patients with with CKD/ESRD and AF requires careful evaluation because its benefits i.e. prevention of thromboembolism, must be greater than the risk of bleeding. Patients at higher risk of thrombosis are evaluated through specific scores, such as the CHADS(2), coupled with scoring systems for assessing bleeding risks, such as the HAS-BLED score.
Caution should therefore be exerted in using Warfarin in patients with AF and advanced CKD.
Alternate therapies may have to be considered with a more favourable RISK:BENEFIT profile. Newer anticoagulants such as dabigatran and rivaroxaban offer promise as future therapeutic options in such cases.
Drugs including statins and vitamin K are currently under study as therapies to prevent or treat warfarin-associated calcification. A large EU study of the effect of vitamin K1 (precursor of K2) in HD patients is underway.