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Making connections: Stroke risk in patients with multiple co-morbidities

AF and co-morbidities – worsening renal function – a patient case study

 

Learn how co-morbid diabetes and renal impairment influence stroke risk in patients with NVAF

Co-morbidities are prevalent in patients with atrial fibrillation

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Co-morbid conditions in the GARFIELD-AF registry

Co-morbidities occur frequently in patients with atrial fibrillation (AF) and can further increase the risk of stroke and/or bleeding in this already at-risk population. In one retrospective, observational study of patients with AF in the US (N=1297), 98% had at least one additional co-morbidity and 20.5% had a Charlson Comorbidity Index score of ≥3, indicating that they had a high risk of mortality due to serious concomitant disease.

 

Of 51,270 patients in the prospective GARFIELD-AF registry, over three-quarters had hypertension, nearly one-quarter had diabetes, approximately one-fifth had chronic heart failure and a similar proportion had coronary artery disease. In patients enrolled between 2013 and 2016, for whom chronic kidney disease (CKD) status was available (n=33,024), 10.9% had moderate-to-severe CKD and 16.9% had mild CKD, as defined in the National Kidney Foundation’s Kidney Disease Outcomes Quality Initiative guidelines.

 

Why are co-morbid diabetes and renal impairment of particular concern in patients with NVAF?

Diabetes, renal function and cardiovascular (CV) risk are closely interlinked. Diabetes is one of the leading causes of CKD, with moderate to severe kidney disease estimated to be found in 15–27% of patients with diabetes. Diabetes has also been identified as a strong and independent risk factor for stroke in patients with AF and is independently associated with a risk of developing AF itself. Renal dysfunction is prevalent in patients with AF and increases progressively with age.

 

In patients with renal impairment and non-valvular AF (NVAF), the risk of stroke, bleeding events and mortality is substantially increased compared with patients without renal impairment; the risk of mortality, as well as stroke, is also increased in patients with NVAF and diabetes. When patients have both kidney disease and type II diabetes, their mortality and CV mortality risks are even higher than when either condition occurs alone.

 

This highlights the need to be particularly cognisant of the elevated stroke and mortality risks in patients with NVAF and co-morbid diabetes and renal impairment, so that anticoagulation management can be optimized to reduce these risks as much as possible. In addition, optimizing anticoagulation therapy is essential to preserving renal function as overanticoagulation can lead anticoagulation-related nephropathy, a newly recognized form of acute kidney injury in which causes profuse glomerular haemorrhage.

 

What do the available data with the Factor Xa inhibitors in patients with diabetes and renal impairment tell us?

Patients with diabetes and patients with moderate renal impairment were included in all three of the Factor Xa inhibitor phase III randomized trials. The proportions of patients with these co-morbidities varied between studies, but the rivaroxaban trial, ROCKET AF, included the highest proportion of both. In this trial 40% of patients had diabetes (range 31–40% across trials) and 21% had creatinine clearance (CrCl) <50 ml/min (range 17–21% across trials).

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The proportions of patients with diabetes or moderate renal impairment in the phase III Factor Xa inhibitor trials

In subanalyses of patients with diabetes in the ROCKET AF and ARISTOTLE trials, the risk of stroke and vascular death was higher in diabetic versus non-diabetic patients (adjusted outcomes in ROCKET AF). The subanalyses indicated that these NOACs were at least as effective as warfarin and offered a similar safety profile in patients with diabetes and that NOACs may even provide a benefit over warfarin with respect to mortality.

 

Similar findings were seen in the subanalyses of patients with moderate renal impairment. Patients with moderate renal impairment were at increased risk of stroke and bleeding compared with those without renal impairment, but the relative efficacy and safety of the NOACs versus warfarin was maintained in this high-risk group.

 

Summary

Effectively managing stroke prevention in patients with NVAF and co-morbidities has always been challenging. With an ageing population and rising prevalence of co-morbidities, such as diabetes, this challenge will increasingly become part of everyday clinical practice. Therefore, it is vital to understand the elevated stroke risk in patients with AF and multiple co-morbidities. This will help you, as clinicians, to determine an anticoagulation strategy that will not only minimize your patient’s stroke risk but could also help improve their future outlook by reducing impact on renal function. Of note, the 2019 focussed update to the 2014 American Heart Association/American College of Cardiology/Heart Rhythm Society (AHA/ACC/HRS) guidelines for the management of patients with AF state that “Over time, NOACs (particularly dabigatran and rivaroxaban) may be associated with lower risks of adverse renal outcomes than warfarin in patients with AF”.

 

VKA exposure significantly accelerates progression of kidney disease in patients with AF and CKD

A study of 14,432 patients with AF and CKD stage 3/4 in a primary care setting showed that patients exposed to a vitamin K antagonist (VKA) had significantly faster CKD progression than those who were not exposed to a VKA.

“Patient case: How does co-morbid renal impairment influence stroke prevention in the diabetic patient with NVAF?”

Think about how you would treat the following patient:

  • Graham is a 72-year-old man who has been taking metformin for type II diabetes since he was 62 years old; he was diagnosed with NVAF 4 years ago
  • Graham has been receiving anticoagulation therapy with warfarin for stroke prevention and has not had any obvious issues with the medication. However, he recently went to his GP for a regular check-up and was found to have mildly swollen ankles. Upon further discussion Graham mentioned that he had been urinating less frequently than normal
  • A urine function test revealed he had a CrCl of 45 ml/min

 

Graham has moderate renal impairment. Based on recent data suggesting that VKA exposure may accelerate the progression of kidney disease in patients with AF and CKD, should Graham’s anticoagulation be changed?

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