Tuesday March 17, St Patrick's Day we were tipping back green beers while we met for the NephJC #23:

Net clinical benefit of antithrombotic therapy in patients with atrial fibrillation and chronic kidney disease: a nationwide observational cohort study.

Bonde AN, Lip GY, Kamper AL, Hansen PR, Lamberts M, Hommel K, Hansen ML, Gislason GH, Torp-Pedersen C, Olesen JB

PMID: 25500231

Storify 1: American chat

Storify 2: EU chat

Initial Summary, prepared by Paul Phelan and David Baird follows:

Background

The optimal management of atrial fibrillation in patients with CKD is controversial as they are at both a higher risk of stroke and higher risk of bleeding than the non-CKD population; this is particularly true of patents on dialysis. Warfarin is the standard of care for reducing the risk of stroke in patients with atrial fibrillation (AF), however these trials excluded patients with a creatinine clearance of < 30ml/min (CKD). This week's NephJC article examines the efficacy and risk of of warfarin and aspirin in patients with AF and CKD.

Methods

The investigators conducted a retrospective cohort study using nationwide Danish registries to identify all patients discharged from hospital with a diagnosis of non-valvular AF between 1997 to 2011. Of the 154,259 patients identified; 11,128 (7.2%) had non-end stage CKD and 1,728 (1.1%) were receiving dialysis. Patients on antiplatelet drugs other than aspirin were excluded.

Analysis of a sample of the non-end stage CKD patients found 19.1% were CKD stage 1-2, 20% were CKD 3, 36.4% were CKD 4 and 24.5% were CKD 5.

They used the CHA2DS2-VASC score to stratify the patients into high or low/intermediate risk of stroke.

Outcomes

  1.  Composite endpoint of death/hospitalisation from stroke/bleeding
  2. Composite of fatal stroke/fatal bleeding
  3.  Cardiovascular death
  4. Death from any cause

Statistical analysis:

Cox proportional-hazards survival models with patients able to change renal status and anti-thrombotic treatment during follow-up.

Results

Risk of stroke in patients not on warfarin:

  • Patients on dialysis were at higher risk of stroke compared to non-CKD patients (5.5-fold higher for patients with a CHA2DS2-VASC score of 0 and 1.6-fold higher with CHA2DS2-VASC ≥ 2)
  • Non-end-stage CKD patients also at higher risk of stroke compared to non-CKD patients (HR 1.31, CI 1.22-1.41) 

Warfarin treatment:

Lots of figures on the table but I’ve highlighted the key results in color codes below.

  • High risk patients on dialysis - warfarin associated with a significantly lower risk of all-cause mortality (HR 0.85, CI 0.72-0.99) and there was a non-significant trend toward a reduction in cardiovascular death and a composite end point of hospitalization or death from all stroke/all bleeding. (RED)
  • Intermediate/low risk patients on dialysis - no benefit of warfarin; indeed there was a trend toward higher all-cause mortality! (HR 1.36, CI 0.96-1.94) (BLUE)
  • Non-end-stage CKD patients - warfarin associated with significantly lower risk of all-cause mortality in both high risk (HR 0.64) and low-intermediate risk groups (HR 0.62) in patients. (GREEN)
  • High risk non-end-stage CKD patients - Aspirin treatment showed a small benefit in all-cause mortality (HR 0.93, CI 0.88-0.98). This was not reproduced in low risk of any other outcome.

Limitations

  • Observational study
  • Risk factors used to calculate CHA2DS2-VASC score identified based on filled prescription data, leading to a potential for under-reporting risk in the low/intermediate risk non end-stage CKD patients.
  • Warfarin treatment is often discontinued in terminal patients; to account for this patients were analysed as being in the treatment group until 30 days after treatment was discontinued and the net clinical benefit of warfarin in high risk dialysis patients was still significant. However, when treatment periods where prolonged to 90 days it was no longer significant suggesting that some of the positive effect of warfarin could be related to its cessation in terminal patients
  • Did not stratify the non-end stage CKD patients based on the degree of renal impairment. 

Discussion

Balancing the risks and benefits of anticoagulation in patients with AF and ESRD remains complex. This study found a definite benefit of warfarin in patients with non-end stage CKD and this is supported by other studies (Hart RG 2011). The real difficulty however is in patients on dialysis. Though this is not the first observational study to show a benefit of warfarin therapy in this group (Carrero JJ 2014, ), others have shown a higher risk of stroke and bleeding (Shah M 2014, Chan KE 2009), especially for patients over 75 (Wizemann V, 2010).

Another publication in the current issue of Nephrology Dialysis Transplantation on this topic (Genovesi 2015) is a prospective Italian study in patients with AF on hemodialysis. It reported warfarin increased the risk of bleeding whilst not lowering the risk of thromboembolic stroke. There was no statistically significant difference in survival. Interestingly, this study found that patients who maintained their INR in the therapeutic range where protected from the bleeding risk suggesting that the increased risk of haemorrhage in dialysis patients stems from the greater variability in their INR rather than from the warfarin per se. Increased INR variability is well recognised in dialysis patients (Phelan 2011) and a study cited above (Carrero 2014) which demonstrated benefit to warfarin was also performed in a Scandinavian population. This was a post –myocardial infarction cohort from Sweden who developed AF. This population has previously been reported to have excellent INR control (Wieloch 2011), which may contribute to the beneficial effects of warfarin in dialysis patients from this part of the world. Food for thought!

Analysis of the newer anticoagulants such as Dabigatran, Rivaroxaban and Apixaban, were not included in this study. They are contraindicated in patients with ESRD as they are renally cleared though their use in this setting has increased nonetheless. A recent study in Circulation (Chan 2015) found that 5.9% of anticoagulated patients with AF on dialysis are started on dabigatran or rivaroxaban and that these drugs were associated with a higher risk of hospitalisation or death from bleeding compared to warfarin. 

In summary, the optimal treatment for patients with AF and RRT is far from resolved. With the current crop of contradictory observational studies, a randomised controlled is needed to answer this question. Until then, the decision on whether or not to start treatment must be individualized with the patient.

Authored by Dr David Baird and Dr Paul Phelan

References

  1. Hart RG, Pearce LA, Asinger RW, Herzog CA. Warfarin in atrial fibrillation patients with moderate chronic kidney disease. Clin J Am Soc Nephrol. 2011;6(11):2599-604.
  2. Carrero JJ, Evans M, Szummer K, et al. Warfarin, kidney dysfunction, and outcomes following acute myocardial infarction in patients with atrial fibrillation. JAMA. 2014;311(9):919-28.
  3. Shah M, Avgil tsadok M, Jackevicius CA, et al. Warfarin use and the risk for stroke and bleeding in patients with atrial fibrillation undergoing dialysis. Circulation. 2014;129(11):1196-203.
  4. Chan KE, Lazarus JM, Thadhani R, Hakim RM. Warfarin use associates with increased risk for stroke in hemodialysis patients with atrial fibrillation. J Am Soc Nephrol. 2009;20(10):2223-33
  5. Wizemann V, Tong L, Satayathum S, et al. Atrial fibrillation in hemodialysis patients: clinical features and associations with anticoagulant therapy. Kidney Int. 2010;77(12):1098-106.
  6. Genovesi S, Rossi E, Gallieni M, et al. Warfarin use, mortality, bleeding and stroke in haemodialysis patients with atrial fibrillation. Nephrol Dial Transplant. 2015;30(3):491-8.
  7. Phelan PJ, O'kelly P, Holian J, et al. Warfarin use in hemodialysis patients: what is the risk? Clin Nephrol. 2011;75(3):204-11.
  8. Wieloch M, Själander A, Frykman V, Rosenqvist M, Eriksson N, Svensson PJ. Anticoagulation control in Sweden: reports of time in therapeutic range, major bleeding, and thrombo-embolic complications from the national quality registry AuriculA. Eur Heart J. 2011;32(18):2282-9.
  9. Chan KE, Edelman ER, Wenger JB, Thadhani RI, Maddux FW. Dabigatran and Rivaroxaban Use in Atrial Fibrillation Patients on Hemodialysis. Circulation. 2015.