Download Relationships between Anticoagulation, Risk Scores and Adverse

ORIGINAL ARTICLE
Heart, Lung and Circulation (2016) 25, 243–249
1443-9506/04/$36.00
http://dx.doi.org/10.1016/j.hlc.2015.08.012
Relationships between Anticoagulation,
Risk Scores and Adverse Outcomes in
Dialysis Patients with Atrial Fibrillation
Tom Kai Ming Wang, MBChB a,b*, Janarthanan Sathananthan, MBChB a,b,
Mark Marshall, FRACP c, Andrew Kerr, FRACP b, Chris Hood, FRACP c
a
Green Lane Cardiovascular Service, Auckland City Hospital, Auckland, New Zealand
Department of Cardiology, Middlemore Hospital, Auckland, New Zealand
Department of Renal Medicine, Middlemore Hospital, Auckland, New Zealand
b
c
Received 7 June 2015; received in revised form 17 August 2015; accepted 20 August 2015; online published-ahead-of-print 25 September 2015
Background
Atrial fibrillation (AF) is the commonest cardiac arrhythmia including in end-stage renal failure patients,
but controversy remains whether these patients benefit from anticoagulation. We reviewed the characteristics, management and outcomes of end-stage renal failure patients on dialysis with AF.
Methods
All patients started on dialysis at Middlemore Hospital between January 2000 and December 2008 who had
AF were studied. Data regarding demographics, co-morbidities, renal disease, AF and embolic, bleeding
and/or mortality events were recorded.
Results
There were 141 out of 774(18.2%) dialysis patients with AF followed-up for 4.4+/-2.5 years, and 41.8%(59)
were on warfarin. Incidence of all embolic events, ischaemic stroke, all bleeding and intracranial bleed were
4.1, 3.1, 9.6 and 0.82/100 person years respectively. Warfarin anticoagulation was associated with increased
risk of intracranial bleed (hazards ratio=11.1, P=0.038), but not total embolic, bleeding events or mortality
during follow-up (P=0.317-0.980). All three scores (CHADS2, CHA2DS2-VASc and HAS-BLED) could
detect all embolic events (c=0.808-0.838), but not bleeding events (c=0.459-0.498).
Conclusions
Anticoagulation with warfarin didn’t significantly reduce embolism or mortality in dialysis patients with
AF, but increased the risk of intracranial bleeds. Convention risk scores predict embolic but not bleeding
events in these patients.
Keywords
Atrial fibrillation Dialysis Chronic kidney failure Warfarin Stroke
Introduction
Atrial fibrillation (AF) is the commonest form of cardiac
arrhythmia estimated at 1-2% in the general population in
developed countries [1]. The prevalence is even higher in
those with end-stage renal failure (ESRF) on dialysis at over
10-27% [2–5]. Anticoagulation is recommended for the prevention of ischaemic stroke in high-risk patients with AF
[1,6,7]. The role of anticoagulation remains controversial for
patients with ESRF and AF due to heterogeneous results
from observational studies that suggest minimal if not harmful effects on both embolic and bleeding events and absence
of randomised trials [5,8–14]. We reviewed the characteristics, management and outcomes of ESRF patients with
AF on dialysis at our centre, with a focus on anticoagulation
and risk scores.
*Corresponding author at: Auckland City Hospital, 2 Grafton Road, Grafton, Auckland 1023, New Zealand. Tel.: +64 9 367 0000; fax: +64 9 307 4950,
Email: [email protected]
© 2015 Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ). Published by Elsevier
Inc. All rights reserved.
244
Material and Methods
All patients with end-stage renal disease who started dialysis
during January 2000 to December 2008 were obtained from
the Department of Renal Medicine database at Middlemore
Hospital, Auckland, New Zealand. Those who had pre-existing AF or developed AF confirmed on electrocardiogram
while on dialysis were retrospectively studied, with the start
date of each patient being the first day they had AF and were
on dialysis. The end date was the date of death, renal transplantation or June 30, 2014 whichever was the earliest. Baseline demographics, co-morbidities and characteristics of the
end-stage renal disease recorded in the database were all
recollected to ensure accuracy using standard definitions.
Atrial fibrillation was defined as paroxysmal or permanent
as per international guidelines [1]. Demographic, renal, comorbidities and treatment data were recorded. Anticoagulation regimens with or without aspirin and/or warfarin were
recorded – no patients were on novel oral anticoagulants. We
pre-specified the main comparative analyses to be between
those anticoagulated with warfarin to those without, regardless of whether they were on aspirin. The embolic risk scores
CHADS2 [15] and CHA2DS2-VASc [16] as well as bleeding
risk score HAS-BLED [17] were calculated for all patients.
In terms of outcomes, embolic events encompasses ischaemic stroke (focal neurological deficit lasting >24 hours with
radiological evidence on computed tomography or magnetic
resonance imaging of the brain) and other arterial embolism.
Bleeding events include intracranial bleed, gastrointestinal
bleed, dialysis site bleed (fistula or catheter-related) and
other (non-intracranial, gastrointestinal or dialysis site)
bleed. Intracranial bleed required radiological confirmation,
while gastrointestinal, dialysis site and other bleeds required
having a blood transfusion to be counted.
Mean+/-standard deviation and percentage (frequency)
were used to present continuous and categorical variables,
and univariate analyses for these were performed with the
Mann-Whitney U test and Fisher’s exact test respectively.
Variables with P<0.10 in univariate analyses were incorporated into multivariate models using logistic regression to
calculate odds ratios (OR) or Cox proportional hazards regression used to calculate hazards ratios (HR) for cross-sectional
and longitudinal outcomes respectively, with 95% confidence
intervals (95%CI). Receiver-operative characteristics analysis
was used to calculate the c-statistic (area under the curve) for
the risk scores at detecting adverse outcomes. Statistical analyses were conducted with SPSS (Version 17.0, SPSS Inc.,
Chicago, IL, USA) and Prism (Version 5, GraphPad Software,
San Diego, CA, USA), and P<0.05 deemed statistically significant. Ethical approval was obtained from our institution’s
research office prior to the commencement of the study.
Results
During January 2000 to December 2008, 774 end-stage renal
disease patients were commenced on long-term dialysis at
T.K.M. Wang et al.
Middlemore Hospital, 141 (18.2%) of which had preexisting or developed AF. Baseline characteristics are listed
in Table 1. Mean age was 61.2+/-11.3 years and 38.3% (54)
were female. Diabetes was the commonest pathology for
end-stage renal failure at 44.7% (63). The majority of
patients were on haemodialysis at 68.8% (97). Warfarin
was used for anticoagulation in 41.8% (59), and compared
to those not on warfarin was associated with lower prevalence of paroxysmal AF (45.8% vs 63.4%, P=0.041) and
higher prevalence of hypertension (98.3% vs 89.0%,
P=0.045).
Table 2 shows the characteristics and management of
atrial fibrillation in our cohort. There were 75 (53.2%) with
pre-existing AF and 66 (46.8%) who developed AF after
starting dialysis. Paroxysmal AF was present in 56.0%
(79) and less commonly in those who were on warfarin
(45.8% vs 63.4%, P=0.041). Only 2.4% (4) of the cohort had
clopidogrel for three to six months while on dialysis. Mean
CHADS2, CHA2DS2-VASc and HAS-BLED scores were
2.4+/-1.2, 3.8+/-1.6 and 3.3+/-1.0 respectively. CHADS2
(2.6 vs 2.2, P=0.159) and CHA2DS2-VASc (3.9 vs 3.7,
P=0.676) were not significantly higher in patients on warfarin. Beta-blocker was the most commonly used rate-control
medication at 59.6% (84).
Rates of adverse outcomes during the mean follow-up
period of 3.4+/-2.5 years are listed in Table 3. Incidence
of ischaemic stroke and intracranial bleed were 10.6%
(3.1/100 person years) and 2.8% (0.82/100 per years) respectively, and all embolic events and bleeding events were
13.8% (4.1/100 person years) and 32.6% (9.6/100 person
years) respectively. The majority of patients died during
the follow-up period at 76.6% (108). Patients on warfarin
had a significantly higher incidence of intracranial bleed
(6.8% vs 0.0%, P=0.029).
In multivariate analyses, permanent, rather than paroxysmal, AF was the only independent predictor of warfarin use
(OR 2.07, 95%CI 1.02-4.21, P=0.044). Table 4 displays results of
the multivariate analyses of outcomes. Warfarin anticoagulation was independently associated with intracranial bleed
(HR 11.1, P=0.038) and other bleed (HR 3.26, P=0.028), but
was not associated with change in all embolic events (HR 1.01,
P=0.980), ischaemic stroke (HR 0.667, P=0.482), all bleeding
events (HR 1.44, P=0.317) or mortality during follow-up
(HR 0.825, P=0.631). History of cerebrovascular disease predicted all embolic events (HR 9.92, P<0.001), ischaemic stroke
(HR 12.6, P<0.001) and mortality during follow-up (HR 1.95,
P=0.007).
Results of the receiver-operative characteristics
analyses are shown in Table 5. All three scores (CHADS2,
CHA2DS2-VASc and HAS-BLED) were able to detect
all embolic events (c=0.808-0.838), ischaemic stroke
(c=0.825-0.880) and other arterial embolism (c=0.673-0.833).
None of the scores could detect all bleeding events and individual bleeding outcomes, except that the HAS-BLED score
detected dialysis site bleed (c=0.718). The CHA2DS2-VASc
and HAS-BLED scores were also able to detect mortality
during follow-up (c=0.638 and 0.627 respectively).
245
Dialysis and atrial fibrillation
Table 1 Baseline characteristics
All
No warfarin
Warfarin
141
82
59
Age (years)
61.2+/-11.3
62.1+/-11.8
59.8+/-10.5
0.120
Female
38.3% (54)
37.8% (31)
39.0% (23)
1.000
Caucasian
37.6% (53)
43.9% (36)
28.8% (17)
Maori
31.9% (45)
26.8% (22)
39.0% (23)
Pacific Island
27.0% (38)
26.8% (22)
27.1% (16)
3.5% (5)
32.1+/-8.2
2.4% (2)
31.2+/-8.1
5.1% (3)
33.2+/-8.2
Diabetes
44.7% (63)
42.7% (35)
47.5% (28)
Hypertension/renovascular
17.7% (25)
15.9% (13)
20.3% (12)
Glomerulonephritis
20.6% (29)
24.4% (20)
15.3% (9)
Other
17.0% (24)
17.1% (14)
16.9% (10)
68.8% (97)
72.0% (59)
64.4% (38)
31.2% (44)
28.0% (23)
35.6% (21)
Diabetes
59.6% (84)
54.9% (45)
66.1% (39)
0.224
Hypertension
92.9% (131)
89.0% (73)
98.3% (58)
0.045
Smoking
14.9% (21)
15.9% (13)
13.6% (8)
0.813
Ischaemic heart disease
71.6% (101)
72.0% (59)
71.2% (42)
1.000
6.4% (9)
9.9% (14)
7.3% (6)
11.0% (9)
5.1% (3)
8.5% (5)
0.735
0.778
Congestive heart failure
30.5% (43)
32.9% (27)
27.1% (16)
0.578
Cerebrovascular disease
20.6% (141)
15.9% (13)
27.1% (16)
0.139
Peripheral vascular disease
42.6% (60)
45.1% (37)
39.0% (23)
0.494
Chronic respiratory disease
31.2% (44)
30.5% (25)
32.2% (19)
0.855
All bleeding events
19.1% (27)
20.7% (17)
16.9% (10)
0.667
Gastrointestinal bleeding
11.3% (16)
15.9% (13)
5.1% (3)
0.060
Intracranial haemorrhage
Other bleeding
0.7% (1)
7.1% (10)
1.2% (1)
3.7% (3)
0.0% (0)
11.9% (7)
1.000
0.094
N
P-value
Demographics
0.227
Ethnicity
Asian
Body mass index (kg/m^2)
0.220
Renal failure
0.581
Pathology
Mode of dialysis
Haemodialysis
Peritoneal dialysis
0.362
Co-morbidities
Percutaneous coronary intervention
Coronary artery bypass grafting
Discussion
Our study has several important findings. Rates of embolic
(mainly ischaemic strokes) and bleeding (over half of which
are gastrointestinal) are significantly higher than the general
population in dialysis patients with AF. Anticoagulation
with warfarin does not reduce rates of embolic events but
increases the risk of intracranial bleed and other non-intracranial or gastrointestinal bleed. We have also identified
several important predictors of embolic, bleeding and mortality events in these high risk patients. The CHADS2,
CHA2DS2-VASc and HAS-BLED scores are able to predict
embolic events but not bleeding events for our cohort.
Ischaemic stroke incidence was 4.1/100 person years
in our cohort, comparable to the 2.8-11.8/100 person years
reported in other studies [10,12,18–23]. The physiology of
hypercoagulable states, accentuated atherosclerosis and
recurrent immobility from dialysis puts renal failure patients
at higher risk of embolism [24], alongside the higher than
general population prevalence of other cerebrovascular risk
factors particularly previous stroke, hypertension, diabetes
and heart failure [18,21]. Notably, these factors also constitute
the majority of conventional embolic risk scores for AF
[15,16].
Incidence of intracranial haemorrhage is less at 0.82/100
person years in our cohort than ischaemic strokes, but similar
to the 0.5-1.7/100 person years reported in other studies
[12,13,21]. Despite this, all bleeding events at 9.1/100 person
years was significantly higher than all embolic events at
4.6/100 person years, also seen in other studies
[9,12,19,20,22]. Reasons for the higher bleeding risk in ESRF
patients than the general population irrespective of AF
246
T.K.M. Wang et al.
Table 2 Characteristics of atrial fibrillation and management
All
No warfarin
Warfarin
141
82
59
Pre-existing before dialysis
53.2% (75)
51.2% (42)
55.9% (33)
New after dialysis
46.8% (66)
48.8% (40)
44.1% (26)
Permanent
44.0% (62)
36.6% (30)
54.2% (32)
Paroxysmal
56.0% (79)
63.4% (52)
45.8% (27)
CHADS2
CHA2DS2-VASc
2.4+/-1.2
3.8+/-1.6
2.2+/-1.1
3.7+/-1.6
2.6+/-1.2
3.9+/-1.7
0.159
0.676
HAS-BLED
3.4+/-1.1
3.5+/-1.1
3.3+/-1.0
0.310
2.8% (4)
2.4% (2)
3.4% (2)
1.00
N
Onset
P-value
0.611
0.041
Type
Risk scores
Anticoagulation
None
14.2% (20)
Aspirin alone
44.0% (62)
Warfarin alone
22.7% (32)
Aspirin and warfarin
19.1% (27)
Clopidogrel
Rate/rhythm control
Beta-blocker
59.6% (84)
61.0% (50)
57.6% (34)
0.730
Calcium-channel blocker
40.4% (57)
34.1% (28)
49.2% (29)
0.084
Digoxin
16.3% (23)
13.4% (11)
20.3% (12)
0.356
Amiodarone
22.0% (31)
26.8% (22)
15.3% (9)
0.148
2.1% (3)
1.2% (1)
3.4% (2)
0.572
Direct current cardioversion
Table 3 Adverse outcomes during follow-up
Outcomes
All
No warfarin
Warfarin
N
141
82
59
All embolic events
Ischaemic stroke
13.8% (19)
10.6% (15)
13.4% (11)
12.2% (10)
13.6% (8)
8.5% (5)
1.000
0.586
Other arterial embolism
5.0% (7)
4.9% (4)
5.1% (3)
1.000
Dialysis site thrombosis
7.1% (10)
7.3% (6)
6.8% (4)
1.000
32.6% (41)
29.3% (24)
37.3% (22)
0.364
2.8% (4)
0.0% (0)
6.8% (4)
0.029
19.1% (27)
19.5% (16)
18.6% (11)
1.000
4.3% (6)
6.1% (5)
1.7% (1)
0.401
11.3% (16)
76.6% (108)
6.1% (5)
78.0% (64)
18.6% (11)
74.6% (44)
0.030
0.689
All bleeding events
Intracranial bleed
Gastrointestinal bleed
Dialysis site bleed
Other bleed
Mortality during follow-up
include platelet dysfunction and accelerated turnover,
altered interaction between platelets and vessel wall and
levels of coagulation proteins, gastrointestinal co-morbidities, and additional anticoagulant use and frequent skin
puncture of arterial vessels during haemodialysis [25–27].
Important clinical predictors of bleeding include advanced
age, previous bleed or anaemia and history of stroke [9,20].
This elevated bleeding risk is the primary reason for caution
with anticoagulation in dialysis patients with AF.
P-value
Anticoagulation use in dialysis patients with AF varies
significantly in the literature. Warfarin was prescribed in
41.8% of our cohort, on the high side of the 6-47% reported
in other studies [5,8–14,19,20]. Similarly, aspirin was prescribed in 63.1% compared to 19-60% reported elsewhere
[8-11,19,10], although as noted above, embolic and bleeding
rates of our cohort was similar to other studies. In terms of
rate control, beta-blockers, amiodarone and digoxin were
prescribed similarly (58.6%, 22.0% and 16.3% in our cohort
247
Dialysis and atrial fibrillation
Table 4 Multivariate analyses of outcomes (all predictors with P<0.10 listed)
Outcome/predictor
Ratio
95% confidence interval
P-value
<0.001
All embolic events
Cerebrovascular disease
9.92
3.28-30.0
Congestive heart failure
6.25
0.826-47.3
0.076
Ischaemic stroke
Cerebrovascular disease
12.6
3.32-48.1
<0.001
Other embolism
Body mass index (per 1kg/m^2)
0.893
0.783-1.02
0.093
Chronic respiratory disease
5.34
1.03-27.8
0.047
1.02
1.00-1.05
0.073
1.84
0.941-3.58
0.075
1.15-107
0.038
0.485
0.215-1.09
0.080
Warfarin anticoagulation
Mortality during follow-up
3.26
1.13-9.40
0.028
All bleeds
Age (per year)
Warfarin and aspirin
Intracranial bleed
Warfarin anticoagulation
11.1
Gastrointestinal bleed
Beta-blocker
Other bleed
Ischaemic heart disease
1.57
0.963-2.55
0.070
Cerebrovascular disease
1.95
1.20-3.17
0.007
Peripheral vascular disease
1.62
1.03-2.57
0.038
Table 5 Receiver-operative characteristics analyses
Outcome
CHADS2
CHA2DS2-VASc
HAS-BLED
All embolic events
Ischaemic stroke
0.838 (0.733-0.942)
0.880 (0.797-0.964)
0.808 (0.717-0.899)
0.847 (0.768-0.926)
0.838 (0.747-0.929)
0.825 (0.716-0.934)
Other arterial embolism
0.721 (0.519-0.923)
0.673 (0.506-0.841)
0.833 (0.728-0.937)
Dialysis site thrombosis
0.474 (0.277-0.671)
0.381 (0.195-0.566)
0.471 (0.66-0.676)
All bleeding events
0.494 (0.393-0.596)
0.459 (0.357-0.562)
0.498 (0.393-0.603)
Intracranial bleed
0.380 (0.055-0.704)
0.393 (0.195-0.591)
0.317 (0.071-0.562)
Gastrointestinal bleed
0.511 (0.391-0.631)
0.492 (0.367-0.618)
0.492 (0.359-0.624)
Dialysis site bleed
0.652 (0.440-0.865)
0.611 (0.393-0.829)
0.718 (0.552-0.884)
0.453 (0.310-0.596)
0.579 (0.469-0.688)
0.442 (0.294-0.590)
0.638 (0.536-0.740)
0.474 (0.319-0.629)
0.627 (0.519-0.734)
Other bleed
Mortality during follow-up
respectively) to other studies (20-74%, 1-38%, 4-22% respectively) [8,11,20,28], while calcium-channel blockers were prescribed more commonly at 40.4% than other studies 11-13%
[8–11]. It remains uncertain whether aggressive rate-control
improves outcomes in dialysis patients as it does in the
general population with AF.
We did not find warfarin, or aspirin, to significantly reduce
the risk of ischaemic stroke or all embolic events statistically
in univariate and multivariate analyses. Mixed results have
been reported in other studies, that warfarin also has no
effect [5,9,12,13,22] or even increases [10,11] the risk of ischaemic strokes in dialysis patients with AF. However, warfarin
also significantly increased the risk of intracranial
haemorrhage in our cohort and several others [10,12,22,28]
but not all [13] studies. This may be partially because warfarin was prescribed to those at higher baseline risk of stroke
and bleeding in these observational studies, and also that
therapeutic INR levels are harder to maintain in dialysis
patients prone to both outcomes, taking multiple other medications and getting sick more often. Randomised studies
are warranted to more accurately assess whether warfarin,
aspirin and novel oral anticoagulants reduce ischaemic
stroke in dialysis patients with AF with minimal and acceptable increases in bleeding risks, but prior to such evidence
being confirmed warfarin should not routinely be prescribed
in this setting.
248
Several studies found that the CHADS2 Score helps predict
those at higher risk of stroke [10,11,13,20,21], however only
one study has investigated the prognostic utility of the
CHA2DS2-VASc score and concluded that it is superior to
the CHADS2 score [23]. Our study found that the CHA2DS2VASc Score performed well at predicting ischaemic stroke
and other arterial embolism, but with similar and not
improved efficacy over the CHADS2 Score. Furthermore,
the HASBLED was also able to predict embolic events, not
unsurprisingly as over half of its parameters are common with
the CHA2DS2-VASC Score. All three scores however, particularly the HASBLED Score, were not able to predict composite
or individual types of bleeding. One other study suggested
that the mORBI Score could stratify patients into different
levels of bleeding risk [20]. Accurate risk stratification could
help the decision-making as to who receives anticoagulation,
however their use would be limited in the absence of evidence
that anticoagulation is effective in reducing stroke in dialysis
patients.
Our study had several limitations. It is a single-centre
retrospective observational study. Underpowering of statistical analysis due to the cohort size and therefore the number
of some adverse events was a major limitation of the study,
including, for example, not finding statistically significant
differences for embolic events. That time in therapeutic range
for warfarin during the study period could not be obtained
was another important limitation, since it has been shown to
be reduced in dialysis patients and is associated with
increased risk of embolism and bleeding. Some patients took
aspirin, and a small proportion took clopidogrel, which
could introduce further biases to the analyses although they
were adjusted for. There may also be minor inaccuracies with
the retrospective calculation of anticoagulation scores for
embolic and bleeding events. Large sufficiently powered
randomised trials are warranted to address the anticoagulation controversy in dialysis patients with AF.
Conclusion
Patients with ESRF on dialysis and AF have a high incidence
of embolic, bleeding and mortality events. Warfarin did not
significantly reduce the rates of embolic events but increased
the risk of intracranial bleeds in our cohort. Randomised
trials are required to definitively answer whether warfarin
should or shouldn’t be routinely recommended in this clinical setting. Anticoagulation risk scores are prognostic of
embolic but not bleeding events.
T.K.M. Wang et al.
[2]
[3]
[4]
[5]
[6]
[7]
[8]
[9]
[10]
[11]
[12]
[13]
[14]
[15]
[16]
[17]
[18]
[19]
Acknowledgements/Disclosures
No financial assistance and no conflicts of interest to declare
for this study
[20]
[21]
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