Update from Cardiology Literature: Antithrombotic therapy in Atrial Fibrillation and CKD

In 2015 I hope to blog on articles from non-renal journals that are of interest to nephrologists. First up is cardiology and a topic that has been covered in previous RFN posts (here, here, here). 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 well established in reducing the risk of stroke in patients with atrial fibrillation but the trials excluded patients with a creatinine clearance of < 30ml/min. Thus we have had to rely on, often contradictory, observational studies to guide us in this area.

A study in the Journal of the American College of Cardiology in December is the latest to investigate the net clinical benefit (or harm) of antithrombotic therapy in these patients. It was 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. Out of the 154,259 patients identified; 11,128 (7.2%) had non-end stage CKD and 1,728 (1.1%) were receiving dialysis. They used the CHA2DS2-VASC score to stratify the patients into high and low/intermediate risk of stroke groups. Briefly the score is calculated by adding one point for heart failure, hypertension, diabetes, vascular disease, age 65-74 and female sex and 2 points for age over 75 and a previous stroke. A score of ≥ 2 is considered high risk.
They found that among high risk patients on dialysis, warfarin was 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. There was no benefit of warfarin in low-intermediate risk dialysis patients; indeed there was a trend toward higher all-cause mortality (HR 1.36, CI 0.96-1.94). 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. Warfarin was 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 with non-end stage CKD. One caveat, highlighted in the journal’s editorial, is that certain components of the CHA2DS2-VASC score (diabetes, hypertension and heart failure) were identified based on filled prescription data, meaning the frequency of these risk factors may have been underestimated and therefore overestimating the number of patients classified as low-intermediate risk. We should therefore interpret the mortality benefit for this group with caution.

The most recent NICE guidelines in the UK, published in June 2014, do not recommend aspirin as monotherapy for the prevention of stroke in patients with AF. This study suggests the same should apply to patients on dialysis as aspirin was not associated with a lower risk of any outcome.
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 cleared via the kidneys and drugs levels can accumulate and precipitate bleeding though their use in this setting has increased nonetheless. A study from the U.S. out this month in Circulation 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.

Balancing the risks and benefits of anticoagulation in patients with AF and ESRD remains complex. The current evidence suggests that warfarin remains the best anti-thrombotic available but it also has a significant potential for harm and the decision of whether or not to start treatment needs to be an individualized patient choice.

Authored by David Baird
Royal Infirmary of Edinburgh

Warfarin for Atrial Fibrillation in Dialysis Patients: Where’s the data?

ESRD patients have an increased incidence of atrial fibrillation (AF) and a higher risk of stroke compared to patients with normal renal function. However they also have an increased bleeding tendency due in part to uremia and the associated platelet dysfunction. Anticoagulation with warfarin for AF is widespread in the general population, where the sense of risk and benefit are better understood. Like many other conditions, ESRD patients are routinely excluded from clinical trials in AF and therefore we lack hard data on how to manage our ESRD patients with AF. We must rely on observational data, which is often contradictory. Firstly, increased INR variability has been demonstrated in dialysis patients treated with warfarin and they spend much time outside of target INR range. Some registry data supports warfarin use with a suggestion of improved survival in dialysis patients with AF while other studies demonstrate an increased risk of stroke with warfarin [here, here, here]. Overall, the majority of studies do not support a protective effect for warfarin in ESRD patients with AF.

A current study from Canada in Circulation weighs in on the issue. The authors conducted a retrospective cohort study of patients > 65 years admitted with a diagnosis of AF from 1998 to 2007. There were 1,626 dialysis patients (46% received warfarin) and >200,000 non-dialysis patients. In a multivariate analysis, warfarin use in the dialysis patients was associated with similar risk of non-hemorrhagic stroke but a significantly higher risk of bleeding (defined as intra-cerebral, intra-ocular, GI, unspecified hemorrhage & hematuria; HR 1.44). The non-dialysis patients did see a lower incidence of ischemic stroke with warfarin use.

Our ESRD patients comprise a unique cohort with labile, often high blood pressure, repetitive AV access puncture, proven variability in INR and usually anticoagulation use during dialysis. They are certainly high risk for bleeding. Moreover, warfarin use is associated with accelerated vascular calcification in CKD patients and calciphylaxis, an admittedly uncommon but devastating condition. Unfortunately we suffer from a lack of alternatives to warfarin. Accumulation of low-molecular weight heparin in ESRD precludes its use and there is no experience with newer agents such as direct thrombin and Factor Xa inhibitors.
Many authors, including those at UpToDate, recommend warfarin use with AF and an eGFR<15mls/min. They are equivocal when CHADS2=0, but this is rare in a dialysis patient. Remember CHADS2 includes congestive heart failure, hypertension, age ≥75, diabetes and previous stroke/TIA. Despite older age being part of the CHADS2 score suggesting treatment efficacy, age >75 has been associated with a particularly high risk of bleeding in dialysis patients treated with warfarin. Also, CKD is part of the HAS-BLEED score which predicts high risk of hemorrhagic complications to warfarin when the score is ≥3. Many dialysis patients would fall into this category based on hypertension, older age and concomitant meds (85% in the current study in Circulation). I often feel uncomfortable using warfarin in ESRD and certainly feel it should be an individualized patient choice. With the current evidence (or lack of it) to guide us and the significant potential for harm, withholding warfarin for many of our older dialysis patients would not seem unreasonable.

Warfarin-induced AKI

We have recently posted about problems using warfarin in renal patients. On a similar note, I was recently involved in the care of a 58-year-old African-American patient who presented with oliguric AKI and a supratherapeutic INR level of 14.9 while on warfarin therapy for pulmonary embolism. Although AKI was probably secondary to ischemic ATN from massive bleeding (requiring 11 units of PRBCs), this patient made me wonder whether warfarin could itself cause AKI in the absence of significant hemodynamic changes.

It has been suggested that warfarin may induce AKI by causing glomerular hemorrhage and renal tubular obstruction by RBC casts. The first report by Abt, et al observed glomerular hematuria in a patient with excessive warfarin anticoagulation with underlying structural abnormality of glomerular basement membrane, suspected warfarin-induced glomerular hematuria. This finding was also noted by Kabir et al and Brodsky et al. subsequently reviewed renal biopsies from 9 patients with elevated serum creatinine level (mean, 4.3±0.8 mg/dL) and abnormal INR (mean, 4.4±0.7 IU) after excluding acute/active glomerulonephritis. INR was normalized before the kidney biopsy. The biopsy specimens revealed RBCs in both Bowman spaces and tubules. The occlusive RBC casts were mostly localized to distal nephron segments. The presence of RBCs was unlikely related to the biopsy procedure as the distribution of RBCs was within the nephron, non-uniform, and not in the interstitium or around the edges of the biopsy specimens. Moreover, the presence of occlusive RBC casts compressing tubular epithelium suggested glomerular hematuria. All of these patients had underlying kidney disease. Recovery was incomplete in six of nine patients. Based on this review, it seems that warfarin is unlikely to cause AKI in patients with normal renal parenchyma. However, elderly patients with underlying kidney diseases may be at risk for developing warfarin-associated AKI by this mechanism.

In addition to this potential renal complication of warfarin therapy, there were 2 case reports of warfarin-induced AIN by Volpi et al. and Kapoor et al. The latter case reports a patient on warfarin for 2 months for DVT who presented with AKI, supratherapeutic INR and skin rash. Renal biopsy revealed AIN and punch skin biopsy showed LCV with high eosinophil count, highly suggestive of drug-induced reaction after a negative comprehensive work-up and the absence of other recent medication changes. Warfarin was withdrawn and the patient’s renal function began to resolve upon discharge. Spontaneous cholesterol embolization is also widely reported in patients with diffuse atherosclerosis on anticoagulation.

In summary, it appears that in patients with pre-exiting CKD, warfarin may precipitate AKI via either glomerular hemorrhage and intra-tubular obstruction, AIN, spontaneous cholesterol embolization, in addition to hemodynamic change secondary to massive blood loss. This should be borne in mind in cases of AKI in patients taking warfarin, when diagnosis is unclear.

Boonsong Kiangkitiwan, M.D.

A Grey Area: warfarin for atrial fibrillation in dialysis patients

I recently wrote a short post detailing safety concerns surrounding warfarin use for atrial fibrillation (AF) in dialysis patients. I focussed mostly on the emerging evidence that it may promote vascular and valvular calcification by the inhibition of vitamin-K dependent gamma-carboxylation, as well as recent observational data linking warfarin use to higher mortality rates in ESRD. I finished the piece with this line: "adopting a restrictive policy towards warfarin use in ESRD seems wise, such as reserving it for patients with a CHADS score greater than 2". The use of the CHADS score to stratify dialysis patients with AF has been addressed in a study in this month's Kidney International, and the results suggest that even this restrictive approach may not be safe.
Briefly, CHADS2 is a risk score that stratifies members of the general population with AF by stroke risk, in order to permit informed clinical decision-making regarding the risks/benefits of warfarin anticoagulation. Its name is an acronym derived from the component independent stroke risk factors, namely Congestive heart failure, Hypertension, Age over 75 years, Diabetic status, and history of Stroke (or TIA). This study highlights several caveats regarding the use of CHADS2 (and warfarin use in general) in the dialysis population, information you’ll need next time you’re thrashing out this thorny issue with your Cardiology colleagues.
The authors examined 17,500 dialysis patients from the international DOPPS study, among whom the prevalence of AF was 12% and the incidence of new-onset AF was 1 case per 100 patient years.

1. CHADS2 divides this representative sample of dialysis patients 50:50 into high ( greater than 4 per 100 pt-yrs) and low (less than 2) risk for stroke. 
2. In the low-risk group, the risk of stroke equals the rate below which anticoagulation is not recommended for AF in the general population and, as such, would support a decision not to anticoagulate a dialysis patient with AF and a low CHADS2 score. 
3. Two key components of the CHADS2 score, HTN and heart failure, did not independently predict stroke in this study. As a result, CHADS2 may overcall stroke risk in some low-risk HD patients, and caution should be exercised when calling a patient high risk based on these 2 conditions. A dialysis-specific CHADS score that drops hypertension and heart failure would likely improve its discriminatory power, but requires further study. 
4. Warfarin anticoagulation did not reduce stroke risk in this study. In fact, there was a strong tendency to more frequent cerebrovascular events, particularly in the elderly. Whether this surprising finding was caused by a direct effect of warfarin on the rate of hemorrhagic stroke, or that patients who were prescribed warfarin were already an inherently high-risk group, the fact remains that one needs to be very cautious when prescribing anticoagulation to these patients. It would appear that in some patients identifyed as being at higher stroke risk (particularly older patients), the risks of anticoagulation still outweigh the benefits. 

The upshot of this study is that CHADS2 appears to function adequately in identifying patients at low-risk for stroke, and provides support to a clinical decision to withhold warfarin in that context. However, its ability to identify high-risk patients suitable for anticoagulation is highly questionable, as 3 of its 5 component factors (HTN, heart failure and possibly age) perform poorly in the dialysis population. How to approach the issue of anticoagulation in such patients remains a gray area.

Warfarin and Vascular Calcification

Warfarin has recently been associated with an increased risk of stroke in ESRD patients with atrial fibrillation. This makes the decision whether to initiate warfarin therapy in dialysis patients with atrial fibrilltion anything but clear cut. Add to this the emerging evidence that it also promotes vascular calcification, and you have a real dilemma.

This latter side effect hinges on Matrix Gla protein, or MGP. In ESRD, vascular smooth muscle cells (VSMCs) undergo a phenotypic switch to take on the appearance of osteoblasts, in a well-described process thought to be driven by hyperphosphatemia. Once this has occurred, VSMCs lay down a protein matrix which can undergo calcification, similar to normal bone. MGP is an essential endogenous inhibitor of this process, mediated in part by it’s ability to bind calcium. This ability to bind calcium is a Vitamin K dependant process, explaining how warfarin may increase the risk of vascular calcification.

Warfarin has been linked to aortic valve calcification in both the general population and in ESRD, as well as calcific uremic arteriopathy in the latter. In fact, the odds ratio for severity of aortic valve calcification after 18 months of warfarin in ESRD was almost 4. Prospective trials are clearly needed, but for now, adopting a restrictive policy towards warfarin use in ESRD seems wise, such as reserving it for patients with a CHADS score > 2.