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SA JOURNAL OF DIABETES & VASCULAR DISEASE
REVIEW
VOLUME 9 NUMBER 1 • MARCH 2012
7
Correspondence to: Dr PF Wessels
Consultant: Ampath Laboratories
Part-time consultant: Department of Medical Oncology,
University of Pretoria
Private practice: clinical hematologist, LCM Hospital, Pretoria
e-mail: wesselspf@mweb.co.za
S Afr J Diabetes Vasc Dis
2012;
9
: 6–7
Anticoagulation therapy in diabetic patients
PF WESSELS
Introduction
Diabetic patients have a high risk of developing
arterial disease (coronary artery, cerebrovascular and
peripheral arterial disease) and are therefore often
given antiplatelet therapy.
Although only retrospective studies
1,2
suggest that
diabetic patients are also prone to venous thrombo-
embolism, many comorbid factors in the diabetic
patient, such as heart failure, physical inactivity
and atrial fibrillation increase the risk of venous
thrombosis. A recent sub-analysis of the RECORD
study
3
examined the risk of hyperglycaemia during
hip replacement, as a risk factor for postoperative
venous thrombo-embolism. For these reasons, diabetic patients are
also often given anticoagulant therapy.
Pathophysiology of vascular disease in diabetic
patients
Endothelial cell dysfunction, smooth muscle cell migration and
platelet hyper-reactivity play an important role in arterial disease.
Virchow’s triad of endothelial injury, endothelial dysfunction and
hypercoagulability (hyper-reactive platelets and increased clotting
factors) are important factors in venous thrombosis.
Endothelial cells produce important active substances that lead
to decreased vascular tone and blood flow, increased fibrinolysis,
activation of endogenous anticoagulants, decreased leucocyte
diapedesis and decreased platelet activation. The nitric oxide
(NO) produced by endothelial cells also prevents vascular smooth
muscle proliferation and migration (thus protecting the cell from
atherosclerosis).
Endothelial dysfunction in diabetic patients is due to metabolic
abnormalities such as hyperglycaemia, insulin resistance and
increased serum free fatty acid levels.
Platelet function in the diabetic patient is also abnormal due
to increased GPIb receptors (increased platelet interaction with
the ‘glue’ von Willebrand factor) and increased GPIIb/IIIa receptors
(increased platelet interaction with fibrin and fibrinogen). Calcium
homeostasis is abnormal and NO production decreased in the
platelets.
Increased levels of procoagulants (clotting factors) such as FIII
(tissue factor), FVII and FII, and a decrease in naturally occurring
anticoagulants (thrombomodulin on the endothelial surface
activates some of the anticoagulants) lead to hypercoagulability. The
fibrinolytic pathway is also abnormal, with decreased fibrinolysis due
to the increased production of plasminogen activator
inhibitor-1 (PAI-1).
Atrial fibrillation and diabetes mellitus
Atrial fibrillation (AF) is the most common cardiac
arrhythmia, and is more prevalent in older patients and
men. Risk factors include coronary artery disease and
hypertensive heart disease. Since atrial fibrillation is an
important risk for stroke and thrombo-embolism, many
of these patients are given anticoagulant therapy.
It is important to realise that stroke risk in
asymptomatic or paroxysmal AF patients is comparable
with that seen in patients with permanent AF.
Management of these patients also includes control of heart rate
or rhythm.
The decision to give anticoagulation must be weighed against
the risk of bleeding. Either aspirin (antiplatelet effect) or warfarin
(anticoagulant) has been used. A risk-scoring system, the CHADS
2
score,
4
considers congestive heart failure, hypertension, age over
75 years, diabetes mellitus and previous stroke/TIA. A new scoring
system (CHA
2
DS
2
VASc)
5
adds vascular disease (myocardial infarction,
peripheral arterial disease or aortic plaque), female gender and an
altered age stratification. The HASBLED
6
score has been developed
to evaluate the risk of bleeding in AF patients.
Taking this latest CHA
2
DS
2
VASc scoring system into consideration,
the 2010 European Society of Cardiology (ESC) guidelines
7
recommend that any patient with AF and diabetes (without any
other added risk) should receive either anticoagulation therapy or
aspirin (and preferably anticoagulation). If any one other risk factor
(e.g. female, 65 years and older, hypertension) is present, oral
anticoagulation is definitely recommended. The reason for this is
the superiority of warfarin and the newer oral anticoagulants over
aspirin. It is also suggested that patients with a CHA
2
DS
2
VASc score
of 0 receive no antithrombotic therapy.
Warfarin has been used successfully for many years, but most
strokes occur inAF patients onwarfarin during under-anticoagulated
periods. Due to the narrow therapeutic index (INR between 2 and
3), control of oral anticoagulation can be challenging, especially
due to the wide variety of drug–drug and drug–food interactions.
Newer oral drugs, the anti-FII drug (acting against clotting factor
II) dabigatran (Pradaxa) and the anti-FX drug (acting against clotting
factor FX) rivaroxaban (Xarelto) have been extensively tested for
stroke prevention in atrial fibrillation patients. In the RE-LY study,
8
dabigatran was shown to be more effective than warfarin, with a
similar risk of bleeding in dosages of 150 mg twice a day. The 110
mg bd dose of dabigatran showed significantly less bleeding than
warfarin, with a similar efficacy. In 2010 the USA Food and Drug
Administration (FDA) approved the use of the 220-mg bd dose of
dabigatran for atrial fibrillation.
Rivaroxaban (the ROCKET-AF study
9
) has also been shown to
be non-inferior to warfarin, with comparable rates of bleeding
but significantly lower rates of intracranial bleeding compared to
warfarin. In 2011 the FDA approved rivaroxaban 20 mg once daily
for use in patients with AF in the USA. Recently, the results of a
PF Wessels