1304

M
ost individuals with atrial brillation (AF) are at suf-
cient risk of thromboembolic ischemic stroke to war-
rant prophylactic oral anticoagulation therapy.
1
The most
feared complication of anticoagulation is intracranial hemor-
rhage (ICH) because it is responsible for most of the death
and disability attributable to anticoagulant-associated bleed-
ing.
2
A burning clinical question is how to predict reliably
which patients with AF are at high (and low) risk of ICH if
anticoagulated, and which factors reliably discriminate risk
of ICH (which may be caused by anticoagulation) from risk
Background and PurposeIntracranial hemorrhage (ICH) is a life-threatening complication of anticoagulation.
MethodsWe investigated the rate, outcomes, and predictors of ICH in 14 264 patients with atrial brillation from
Rivaroxaban Once Daily, Oral, Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of
Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF). Cox proportional hazards modeling was used.
ResultsDuring 1.94 years (median) of follow-up, 172 patients (1.2%) experienced 175 ICH events at a rate of 0.67% per
year. The signicant, independent predictors of ICH were race (Asian: hazard ratio, 2.02; 95% CI, 1.392.94; black:
hazard ratio, 3.25; 95% CI, 1.437.41), age (1.35; 1.131.63 per 10-year increase), reduced serum albumin (1.39; 1.12
1.73 per 0.5 g/dL decrease), reduced platelet count below 21010
9
/L (1.08; 1.021.13 per 1010
9
/L decrease), previous
stroke or transient ischemic attack (1.42; 1.021.96), and increased diastolic blood pressure (1.17; 1.011.36 per 10
mm Hg increase). Predictors of a reduced risk of ICH were randomization to rivaroxaban (0.60; 0.440.82) and history
of congestive heart failure (0.65; 0.470.89). The ability of the model to discriminate individuals with and without ICH
was good (C-index, 0.69; 95% CI, 0.640.73).
ConclusionsAmong patients with atrial brillation treated with anticoagulation, the risk of ICH was higher among Asians,
blacks, the elderly, and in those with previous stroke or transient ischemic attack, increased diastolic blood pressure, and
reduced platelet count or serum albumin at baseline. The risk of ICH was signicantly lower in patients with heart failure
and in those who were randomized to rivaroxaban instead of warfarin. The external validity of these ndings requires
testing in other atrial brillation populations. (Stroke. 2014;45:1304-1312.)
Key Words: anticoagulation

atrial brillation

intracranial hemorrhage

risk prediction
Intracranial Hemorrhage Among Patients With Atrial
Fibrillation Anticoagulated With Warfarin or Rivaroxaban
The Rivaroxaban Once Daily, Oral, Direct Factor Xa Inhibition Compared
With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial
in Atrial Fibrillation
Graeme J. Hankey, MD; Susanna R. Stevens, MS; Jonathan P. Piccini, MD;
Yuliya Lokhnygina, PhD; Kenneth W. Mahaffey, MD; Jonathan L. Halperin, MD;
Manesh R. Patel, MD; Gnter Breithardt, MD; Daniel E. Singer, MD; Richard C. Becker, MD;
Scott D. Berkowitz, MD; John F. Paolini, MD, PhD; Christopher C. Nessel, MD;
Werner Hacke, MD, PhD; Keith A.A. Fox, MB, ChB; Robert M. Califf, MD;
on behalf of the ROCKET AF Steering Committee and Investigators
Received December 12, 2013; nal revision received March 10, 2014; accepted March 11, 2014.
From the School of Medicine and Pharmacology, The University of Western Australia, Perth, Australia (G.J.H.); Department of Neurology, Sir Charles Gairdner
Hospital, Perth, Australia (G.J.H.); Duke Clinical Research Institute (S.R.S., J.P.P., Y.L., M.R.P.) and Duke Translational Medicine Institute (R.M.C.), Duke University
Medical Center, Durham, NC; Department of Medicine, Stanford University, CA (K.W.M.); Cardiovascular Institute, Mount Sinai Medical Center, New York
(J.L.H.); Department of Cardiovascular Medicine, Hospital of the University of Mnster, Mnster, Germany (G.B.); Massachusetts General Hospital and Harvard
Medical School, Boston (D.E.S.); University of Cincinnati College of Medicine, OH (R.C.B.); Department of Global Clinical Development, Bayer HealthCare
Pharmaceuticals, Whippany, NJ (S.D.B.); Cerenis Therapeutics, Labege, France (J.F.P.); Janssen Research and Development, Raritan, NJ (C.C.N.); Ruprecht-
Karls-University, Heidelberg, Germany (W.H.); and University of Edinburgh and Royal Inrmary of Edinburgh, Edinburgh, United Kingdom (K.A.A.F.).
Guest Editor for this article was Kazunori Toyoda, MD.
Presented in part at the International Stroke Conference of the American Heart Association, New Orleans, LA, January 31February 3, 2012.
The online-only Data Supplement is available with this article at http://stroke.ahajournals.org/lookup/suppl/doi:10.1161/STROKEAHA.
113.004506/-/DC1.
Correspondence to Graeme J. Hankey, MD, School of Medicine and Pharmacology, The University of Western Australia, Room 222, Harry Perkins
Institute of Medical Research, QQ Block, QEII Medical Centre, 6 Verdun St, Nedlands, Perth 6009, Australia. E-mail graeme.hankey@uwa.edu.au
2014 American Heart Association, Inc.
Stroke is available at http://stroke.ahajournals.org DOI: 10.1161/STROKEAHA.113.004506
Hankey et al Predictors of ICH in ROCKET AF 1305
of thromboembolic ischemic stroke (which may be prevented
by anticoagulation).
All-cause ICH in the general population has been linked to
Asian and black ethnicity; the presence of an apolipoprotein
E2 or E4 allele; decreased low-density lipoprotein cholesterol
and triglycerides; and increasing age, blood pressure, and
alcohol consumption.
36
All-cause ICH in the anticoagulated
population occurs at a rate of 0.2% to 1.0% per year
79
and
has likewise been associated not only with increasing age and
blood pressure but also with previous ischemic stroke, chronic
kidney disease, the early period of anticoagulation use, higher
intensity (ie, poorly controlled) anticoagulation, antiplatelet
use in addition to anticoagulation, and brain imaging evidence
of cerebral leukoaraiosis and microbleeds.
926
Difculty arises
in clinical practice, because the risk factors for ICH with anti-
coagulation are also risk factors for ischemic stroke that could
be prevented with anticoagulation. A recent study suggests
that increasing age and previous stroke are more often associ-
ated with ischemic stroke than with ICH, whereas a history of
hypertension, diabetes mellitus, renal impairment, and alcohol
intake are equally associated.
26
In the Rivaroxaban Once Daily,
Oral, Direct Factor Xa Inhibition Compared with Vitamin K
Antagonism for Prevention of Stroke and Embolism Trial in
Atrial Fibrillation (ROCKET AF) cohort of 14 264 patients
with nonvalvular AF and creatinine clearance 30 mL/min who
were randomized to rivaroxaban or dose-adjusted warfarin, the
factors at randomization that were independently associated
with the occurrence of all stroke (ischemic and hemorrhagic)
or noncentral nervous system embolism among 575 patients
(4.0%) over a median follow-up of 1.94 years were reduced
creatinine clearance, previous stroke or transient ischemic
attack (TIA), elevated diastolic blood pressure and heart rate,
as well as vascular disease of the heart and limbs.
27
However,
the predictors of hemorrhagic and ischemic stroke subtypes in
the ROCKET AF cohort have not been reported.
We aimed to determine the rate, outcomes, and indepen-
dent, signicant predictors of ICH in the large, international
cohort of 14 264 patients with AF who were enrolled in the
ROCKET AF trial and followed-up prospectively for the
occurrence of ICH.
28,29
We also aimed to determine whether
there are any predictors of ICH that are not also predictors
of ischemic stroke and thereby may help identify patients for
whom anticoagulants may be more hazardous than helpful.
Methods
The design, methods, and primary results of the ROCKET AF trial
have been described.
28,29
Briey, this was a multinational, random-
ized, double-blind, double-dummy clinical trial comparing xed-dose
rivaroxaban (20 mg daily; 15 mg daily in patients with creatinine
clearance, 3049 mL/min) with dose-adjusted warfarin (target inter-
national normalized ratio, 2.5; range, 2.03.0) in participants with
nonvalvular AF to prevent all stroke (ischemic or hemorrhagic) or
systemic embolism.
28,29
The trial protocol was approved by appropri-
ate national regulatory authorities and ethics committees at the partici-
pating centers, and all participants provided written informed consent.
Participants
Eligible participants had electrocardiographically documented AF
and increased risk of stroke as determined by a history of stroke,
TIA, or systemic embolism or 2 of the following risk factors: heart
failure or left ventricular ejection fraction 35%, hypertension, age
75 years, or diabetes mellitus. Participants were excluded if they
had any condition associated with increased bleeding risk.
29
Follow-Up
Patients were evaluated prospectively at 1, 2, and 4 weeks and month-
ly thereafter for the duration of the study for study drug management
and surveillance for primary end point events. A standardized ques-
tionnaire and examination were used to screen for stroke symptoms
and potential clinical events during follow-up.
Outcomes and Their Denitions
The primary outcome for this analysis was ICH, which was ascer-
tained by local investigators and reported for central adjudication by
an independent clinical events committee. The committee adjudicat-
ed all suspected ICHs, masked to baseline characteristics and treat-
ment allocation of all participants, and applied the protocol denition
and classication of ICH.
ICH was dened as any primary bleed into the cranial cavity that
was clinically overt (ie, caused symptoms or signs) and was con-
rmed by brain imaging (computed tomography or MRI brain scan)
or autopsy. If the hemorrhage was intraparenchymal and caused focal
neurological symptoms or signs, it was classied as a hemorrhagic
stroke. If the intraparenchymal hemorrhage was secondary hemor-
rhagic transformation of a focal brain infarct (ie, primary ischemic
stroke), it was not considered an ICH.
ICH was categorized as a major bleed and classied according to
the site of hemorrhage as any bleed into the brain parenchyma or
ventricular system (intracerebral hemorrhage), subarachnoid space
(subarachnoid hemorrhage), subdural space (subdural hemorrhage),
or extradural space (extradural hemorrhage) in the skull.
ICH was classied as spontaneous or not spontaneous.
Intraparenchymal (intracerebral) hemorrhage was classied as trau-
matic or nontraumatic, but extracerebral (subdural, subarachnoid, and
extradural) hemorrhage was not classied as traumatic or nontrau-
matic. Deaths after ICH were adjudicated as secondary to trauma if
trauma clearly precipitated the ICH and death (eg, assault and motor
vehicle accident).
Outcome after ICH because of hemorrhagic stroke (ie, intraparen-
chymal or subarachnoid) was classied according to the modied
Rankin Scale score (06) and residence (home, rehabilitation center,
and long-term care) at 3 months after ICH (and 1 month after ICH if
the ICH occurred at the end of the study). The modied Rankin Scale
score was not measured if the ICH did not cause a clinical stroke
syndrome of sudden onset of focal neurological dysfunction (eg, sub-
dural hematoma and extradural hematoma).
Statistical Analysis
All patients were included in the analysis regardless of study drug
exposure (ie, intention-to-treat population). Data were analyzed using
SAS version 9.2 (SAS Institute; Cary, NC).
Baseline characteristics were presented separately for participants
with ICH, ischemic stroke, stroke of unknown pathological type, and
no ICH or stroke. Baseline characteristics were summarized as num-
bers (percentages) for categorical variables and medians (25th, 75th
percentiles) for continuous variables.
Survival free of ICH was calculated, and survival curves were gen-
erated by means of the KaplanMeier product limit technique.
Multivariable Cox proportional hazards models were developed
using stepwise selection of predened candidate variables that have
previously been shown to predict ICH in other studies.
926
Entry and
exit criteria of the stepwise selection was <0.05. All variables in
Table 1 were candidate variables for the models. The models were de-
rived from the intention-to-treat population (ie, all patients random-
ized), of whom 13 832 patients had complete data for the covariates
selected for the nal model.
The candidate variables for the primary model for ICH were all vari-
ables in Table 1 except for geographical region and medications at base-
line, before randomization. A nomogram was created from this model.
1306 Stroke May 2014
Table 1. Baseline Characteristics of the 14 264 Patients Enrolled in Rivaroxaban Once Daily, Oral, Direct
Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial
Fibrillation (ROCKET AF)
29
Characteristic ICH (n=172)
Ischemic Stroke,
No ICH (n=382)
Unknown Stroke,
No ICH (n=32)
No ICH or Stroke
(n=13 678)
Age, y 75 (66.5, 80) 74 (68, 79) 71 (66, 76) 73 (65, 78)
Men 105 (61.0) 199 (52.1) 17 (53.1) 8283 (60.6)
Race
White 122 (70.9) 313 (81.9) 29 (90.6) 11 415 (83.5)
Asian 39 (22.7) 53 (13.9) 3 (9.4) 1691 (12.4)
Black 6 (3.5) 6 (1.6) 0 (0) 168 (1.2)
Other 5 (2.9) 10 (2.6) 0 (0) 404 (3.0)
Hispanic or Latino 31 (18.0) 61 (16.0) 2 (6.3) 2240 (16.4)
Region
Asia/Pacic Islands 46 (26.7) 60 (15.7) 3 (9.4) 2000 (14.6)
Eastern Europe 33 (19.2) 153 (40.1) 23 (71.9) 5291 (38.7)
Latin America 29 (16.9) 51 (13.4) 1 (3.1) 1797 (13.1)
North America 41 (23.8) 52 (13.6) 4 (12.5) 2584 (18.9)
Western Europe 23 (13.4) 66 (17.3) 1 (3.1) 2006 (14.7)
Randomized to rivaroxaban 64 (37.2) 194 (50.8) 16 (50.0) 6857 (50.1)
Baseline CHADS
2
score 3 (3, 4) 4 (3, 4) 4 (3, 4) 3 (3, 4)
CHADS
2
score >3 (ie, 46), median 73 (42.4) 220 (57.6) 20 (62.5) 5873 (42.9)
Baseline BMI, kg/m
2
26.9 (24.5, 30.6) 27.5 (24.8, 31.0) 26.6 (24.3, 31.6) 28.2 (25.1, 32.0)
BMI >28.17 kg/m
2
, median 69 (40.1) 171 (44.9) 12 (37.5) 6876 (50.3)
Baseline heart rate, bpm 76.5 (67.5, 85) 76 (68, 86) 80.5 (72, 90) 76 (67, 86)
Baseline SBP, mm Hg 131 (121, 144) 132 (124, 141) 135 (126, 145) 130 (120, 140)
Baseline DBP, mm Hg 80 (70, 89) 80 (71, 86) 82.5 (80, 88.5) 80 (70, 85)
DBP >80 mm Hg, median 67 (39.0) 152 (39.8) 18 (56.3) 4630 (33.9)
History of AF
Persistent 145 (84.3) 314 (82.2) 29 (90.6) 11 060 (80.9)
Paroxysmal 23 (13.4) 61 (16.0) 3 (9.4) 2427 (17.7)
New 4 (2.3) 7 (1.8) 0 (0) 191 (1.4)
Left bundle branch block 6 (3.5) 26 (7.0) 3 (9.4) 942 (6.9)
History of stroke or TIA 100 (58.1) 251 (65.7) 19 (59.4) 7098 (51.9)
History of hypertension 153 (89.0) 349 (91.4) 31 (96.9) 12 377 (90.5)
History of CHF 81 (47.1) 230 (60.2) 26 (81.3) 8571 (62.7)
History of diabetes mellitus 68 (39.5) 137 (35.9) 12 (37.5) 5478 (40.0)
History of COPD 22 (12.8) 43 (11.3) 4 (12.5) 1428 (10.4)
History of GI bleed 11 (6.4) 13 (3.4) 1 (3.1) 474 (3.5)
History of liver disease 5 (2.9) 19 (5.0) 1 (3.1) 722 (5.3)
Vascular disease variable for
CHA
2
DS
2
-VASc
37 (21.5) 100 (26.2) 9 (28.1) 3181 (23.3)
History of sleep apnea 11 (6.4) 17 (4.5) 0 (0) 617 (4.5)
History of cigarette smoking 64 (37.4) 115 (30.2) 7 (21.9) 4606 (33.7)
Alcohol consumption in last 12 mo
None 114 (66.7) 259 (67.8) 26 (81.3) 8812 (64.4)
Light 49 (28.7) 102 (26.7) 5 (15.6) 4180 (30.6)
Moderate 7 (4.1) 17 (4.5) 1 (3.1) 587 (4.3)
Heavy 1 (0.6) 4 (1.0) 0 (0) 98 (0.7)
Aspirin 61 (35.5) 110 (28.8) 11 (34.4) 3920 (28.7)
Thienopyridine 9 (5.2) 6 (1.6) 0 (0) 224 (1.6)
(Continued )
Hankey et al Predictors of ICH in ROCKET AF 1307
Associations are reported as hazards ratios (HRs) with 95% con-
dence intervals (CIs) and P values. The linearity assumption of Cox
proportional hazards regression modeling was tested for continuous
variables. When deviations were found, linear splines or variable
truncations were used.
To evaluate the possibility that the factors associated with the oc-
currence of ICH may have differed according to the randomized treat-
ment assignment (dose-adjusted warfarin versus rivaroxaban), we
conducted interaction tests across all candidate variables.
The models were validated by 2 methods. One was by means of
bootstrapping to obtain the optimism-corrected C-index. The second
was summarizing how often each variable was selected in stepwise
models t with 1000 bootstrap samples of the data set. Bootstrap
samples of the same size as the original were taken from the original
by means of random sampling with replacement. A table showing
the number of times each variable was chosen in the 1000 models
was produced.
A sensitivity analysis was undertaken by deriving models based
on: (1) the population of patients who adhered to their randomized
treatment allocation (the safety and on-treatment population); (2)
allowing geographical region to enter the model; and (3) including
medication recorded at baseline, taken before randomization. We also
developed models for secondary outcomes of intracerebral hemor-
rhage, ischemic stroke, and hemorrhagic stroke.
Results
Participant Characteristics
A total of 14 264 participants were randomized between
December 18, 2006, and June 17, 2009. Overall, the median
age was 73 years, the median congestive heart failure, hyper-
tension, age >75 years, diabetes mellitus, prior stroke or TIA
(CHADS
2
) score was 3.0, and 52% had a history of previous
stroke or TIA.
27
The median (25th, 75th) duration of follow-up
was 1.94 years (1.42, 2.41) and was 99.8% complete (n=32
[0.2%] lost to follow-up).
Number of ICHs
A total of 172 (1.2%) participants (intracerebral hemorrhage
[n=128], subarachnoid hemorrhage [n=5], subdural hemor-
rhage [n=38], and extradural hemorrhage [n=1]) experienced 1
(n=175) ICH events. Hence, 3 of the participants experienced
>1 ICH event. The characteristics of all patients according to
the occurrence of ICH, ischemic stroke, unknown pathological
type of stroke, and no ICH or stroke are shown in Table 1.
Rate of ICH
The average rate of ICH for the duration of follow-up was
0.67% per 100 patient-years. Table I in the online-only Data
Supplement shows the rates of ICH in different regions of the
world, highest in Asia Pacic (1.21 per 100 patient-years)
and lowest in Eastern Europe (0.33 per 100 patient-years). A
KaplanMeier plot is presented showing the rates by random-
ized treatment (Figure I in the online-only Data Supplement).
Causes and Treatment of ICH
Trauma caused 9 (7%) intracerebral hemorrhages. Among 135
ICHs for which treatments were reported, medical or surgical
intervention was undertaken in 92 (68%) cases, and transfu-
sion of fresh, frozen plasma in 27 (20%) cases.
Outcome of ICH
Among the 172 participants with ICH, 75 (43%) died within
30 days (all attributed to the ICH), 90 were still alive at
30 days, and 7 had <30 days of follow-up. At 90 days, 87
(51%) had died (84 attributed to ICH and 3 to other causes),
70 were alive, and 15 had <90 days of follow-up. Table 2
shows that there was no signicant difference in case fatality
Previous VKA use 97 (56.4) 245 (64.1) 9 (28.1) 8553 (62.5)
Anemia (Hb <13 in men and
Hb <12 in women)
26 (15.4) 38 (10.1) 2 (6.3) 1916 (14.3)
Platelets, 10
9
/L 206 (168, 261) 234 (192, 284) 252 (208, 280) 221 (184, 265)
Platelets, <21010
9
/L 87 (51.5) 128 (34.4) 9 (28.1) 5649 (42.5)
Creatinine clearance, mL/min* 59.5 (48.5, 76.5) 62 (48, 78) 64 (50, 78) 68 (52, 87)
cGFR <67 mL/min, median 107 (62.2) 219 (57.5) 18 (56.3) 6570 (48.1)
Albumin, g/dL 3.9 (3.7, 4.2) 4.0 (3.7, 4.1) 3.9 (3.75, 4.2) 4.0 (3.8, 4.2)
Albumin <4 g/dL, median 94 (54.7) 187 (49.2) 17 (53.1) 6048 (44.4)
SGOT/AST, U/L 23 (19, 28) 23 (19, 28) 23 (21, 30) 23 (19, 28)
SGPT/ALT, U/L 19 (15, 28) 20 (15, 27) 18 (15, 25.5) 21 (16, 28)
Total bilirubin, mg/dL 0.6 (0.4, 0.8) 0.6 (0.4, 0.8) 0.6 (0.5, 0.8) 0.6 (0.4, 0.8)
Serum glucose, mg/dL 111 (94, 139) 106 (94, 140) 108 (96, 157) 108 (95, 135)
Values presented as number (%) or median (25th, 75th percentile). AF indicates atrial brillation; ALT (formerly SGPT), alanine transaminase
(formerly serum glutamic pyruvic transaminase); AST (formerly SGOT), aspartate transamine (formerly serum glutamic oxaloacetic transaminase);
BMI, body mass index; cGFR, calculated glomerular ltration rate; CHADS
2
, congestive heart failure, hypertension, age >75 years, diabetes
mellitus, prior stroke or TIA; CHA
2
DS
2
-VASc, congestive heart failure, hypertension, age >75 years, diabetes mellitus, prior stroke or TIA or
systemic embolism, vascular disease, age 65-75 years, sex-female; CHF, congestive heart failure; COPD, chronic obstructive pulmonary disease;
DBP, diastolic blood pressure; GI, gastrointestinal; Hb, hemoglobin; ICH, intracranial hemorrhage; SBP, systolic blood pressure; TIA, transient
ischemic attack; and VKA, vitamin K antagonist.
*Calculated using CockcroftGault formula.
Table 1. Continued
Characteristic ICH (n=172)
Ischemic Stroke,
No ICH (n=382)
Unknown Stroke,
No ICH (n=32)
No ICH or Stroke
(n=13 678)
1308 Stroke May 2014
from ICH among participants assigned warfarin (50%) and
rivaroxaban (48%).
Among 90 participants who experienced an ICH because of
hemorrhagic stroke, and in whom the modied Rankin Scale
score was measured at 3 months after stroke or 1 month after
stroke if the stroke occurred at the end of the study, the median
time from hemorrhagic stroke to modied Rankin Scale score
measurement in surviving patients was 92.5 days (89, 107). A
total of 15 (17%) survived free of disability, 13 (14%) were
disabled, and 62 (69%) were dead at 3 months after hemor-
rhagic stroke.
Among the remaining 82 participants with ICHs that were
not hemorrhagic stroke, 59 (72%) survived (followed up for
a median of 328 [101, 528] days after hemorrhage) and 23
(28%) died (followed up for a median of 5 [2, 18] days after
hemorrhage).
Predictors of ICH
Table 3 shows that the signicant, independent baseline pre-
dictors of an increased risk of ICH were race (Asian HR,
2.02; 95% CI, 1.392.94; black HR, 3.25; 95% CI, 1.43
7.41), age (1.35; 1.131.63 per 10-year increase), reduced
serum albumin (1.39; 1.121.73 per 0.5 g/dL decrease),
reduced platelet count below 21010
9
/L (1.08; 1.021.13 per
1010
9
/L decrease), previous stroke or TIA (1.42; 1.021.96),
and increased diastolic blood pressure (1.17; 1.011.36 per
10 mm Hg increase). The predictors of a reduced risk of ICH
were randomization to rivaroxaban (0.60; 0.440.82) and his-
tory of congestive heart failure (CHF; 0.65; 0.470.89). The
ability of the model to discriminate individuals with and with-
out ICH was good (C-index, 0.69; 95% CI, 0.640.73).
30,31
The results of interaction tests for all candidate variables
are shown in Table II in the online-only Data Supplement.
There was no signicant interaction between treatment allo-
cation (rivaroxaban or warfarin) and any of the variables listed
in Table 1 and, therefore, no evidence that different factors
would be selected for the model depending on whether the
subject was taking rivaroxaban or warfarin.
Table III in the online-only Data Supplement shows the
results of internal validation by means of taking 1000 boot-
strap samples from the data and summarizing the percentage
of bootstrap samples in which each variable was selected in
the 1000 stepwise models. In the case of highly correlated
variables, the validation was run, including only 1 of these
variables and was repeated with the other. These variables are
shown as the contribution in a model that does not include the
correlated variable. Interval validation by means of bootstrap-
ping realized the optimism-corrected C-index as 0.669.
Table 4 shows the platelets, albumin, no CHF, warfarin, age,
race, diastolic blood pressure, stroke (PANWARDS) nomo-
gram for predicting absolute risk of ICH in this cohort, which
is based on the independent, signicant prognostic factors for
ICH and the strength of their association with risk of ICH.
Table 5 and the Figure show the predicted probabilities of ICH
at 2.5 years according to the score derived from the variables
within the PANWARDS nomogram. There was evidence of
good calibration between predicted and observed ICH rates
(Figure II in the online-only Data Supplement).
Sensitivity analyses showed that the primary model in the
intention-to-treat population (Table 3) was internally consis-
tent in the safety, on-treatment population (Table IV in the
online-only Data Supplement), except diastolic blood pres-
sure and history of CHF did not enter.
The multivariate analysis of the effect of geographical
region on the risk of ICH revealed that the adjusted HRs for
ICH among residents of Asia Pacic (HR, 3.27; 95% CI,
2.065.21), Latin America (2.74; 1.644.56), North America
(2.76; 1.704.47), and Western Europe (1.99; 1.163.41) were
similar. Consequently, these regions were combined (versus
Eastern Europe) in a second model (Table V in the online-only
Data Supplement). In the second model, with geographical
region entered into the model, residence in Eastern Europe
(0.37; 0.250.55) and reduced creatinine clearance (1.11;
1.041.19 per 10 mL/min decrease) emerged as additional
signicant, independent predictors of ICH, whereas race, age,
and history of CHF did not.
A third model, in which baseline use of antithrombotic
agents (aspirin, vitamin K antagonism, and thienopyridines)
was allowed to enter the model (Table VI in the online-only
Data Supplement), showed that the baseline use of a thieno-
pyridine signicantly increased the hazard of ICH (HR, 2.57;
Table 2. Case Fatality of ICH According to Location and
Treatment Allocation
Site of ICH n
Fatal, n (%)
P
Value Total Rivaroxaban Warfarin
Intracerebral 128 73 (57) 25 (53) 48 (59) 0.504
Hemorrhagic stroke 90 62 (69) 22 (67) 40 (70) 0.729
Subdural hemorrhage 38 11 (29) 5 (38) 6 (24) 0.457
Subarachnoid hemorrhage 5 1 (20) 1 (25) 0 (0) 1.000
Extradural hemorrhage 1 0 (0) 0 (0) 0 (0) ...
Total ICH 172 85 (49) 31 (48) 54 (50) 0.843
Hemorrhagic stroke is a subcomponent of intracerebral hemorrhage. The
percentages are those of patients with ICH whose ICH was fatal. ICH indicates
intracranial hemorrhage.
Table 3. Primary Model Showing the Factors Independently
and Signicantly Associated With ICH
Factors
2
HR 95% CI P Value
Race (vs white or other) 19.18 <0.001
Asian 2.02 (1.392.94)
Black 3.25 (1.437.41)
Randomized to rivaroxaban
(vs warfarin)
10.39 0.60 (0.440.82) 0.001
Age (HR for 10-year increase) 10.35 1.35 (1.131.63) 0.001
Albumin (HR for 0.5 g/dL decrease) 8.89 1.39 (1.121.73) 0.003
Platelets <21010
9
/L (HR for each
1010
9
/L below 21010
9
/L)
8.43 1.08 (1.021.13) 0.004
History of CHF 7.27 0.65 (0.470.89) 0.007
Previous stroke or TIA 4.41 1.42 (1.021.96) 0.036
Diastolic BP (HR for 10 mm Hg
increase)
4.13 1.17 (1.011.36) 0.042
C-index, 0.69 (0.64, 0.73). BP indicates blood pressure; CHF, congestive heart
failure; CI, condence interval; HR, hazard ratio; ICH, intracranial hemorrhage;
and TIA, transient ischemic attack.
Hankey et al Predictors of ICH in ROCKET AF 1309
95% CI, 1.305.07; P=0.006), and previous experience with a
vitamin K antagonist was associated with a signicantly lower
risk of ICH (0.68; 0.500.94; P=0.018).
Predictors of Intracerebral Hemorrhage and
Hemorrhagic Stroke
The independent, signicant predictors of intracerebral hem-
orrhage (ie, intraparenchymal hemorrhage only [n=128];
excluding subarachnoid, subdural, and extradural hemor-
rhage) were the same as those for all ICH (Table 3), except for
the inclusion of creatinine clearance rather than age (HR, 1.09;
95% CI, 1.011.17 per 10 mL/min decrease) and the absence
of stroke history in the model (Table VII in the online-only
Data Supplement).
The independent, signicant predictors of hemorrhagic
stroke (ie, intraparenchymal hemorrhage causing focal
neurological symptoms or signs [n=90]) were the same as
those for all ICH (Table 3), except for the exclusion of previ-
ous stroke as a signicant, independent predictor of hemor-
rhagic stroke (Table VIII in the online-only Data Supplement).
Predictors of Ischemic Stroke
Table IX in the online-only Data Supplement shows the inde-
pendent, signicant predictors of ischemic stroke. Three of
these 6 factors were also predictors of ICH (ie, previous stroke
or TIA, reduced albumin, and increased diastolic blood pres-
sure), whereas 3 were not predictors of ICH (reduced creati-
nine clearance [HR, 1.14; 95% CI, 1.091.19 per 10 mL/min
decrease], increasing blood glucose [1.03; 1.011.05 per 10
mg/dL increase], and increasing platelet count [1.02; 1.011.04
Table 5. Predicted Probabilities of ICH at 2.5 Years According
to Total Score on PANWARDS Nomogram
Total Score on Nomogram n Probability of ICH at 2.5 y
10 20 0.002
15 161 0.003
20 679 0.004
25 1465 0.006
30 2185 0.008
35 3001 0.012
40 2788 0.017
45 1889 0.025
50 994 0.035
55 406 0.049
60 166 0.070
65 62 0.098
70 12 0.137
75 4 0.190
ICH indicates intracranial hemorrhage; n, number of patients in the
Rivaroxaban Once Daily, Oral, Direct Factor Xa Inhibition Compared With Vitamin
K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation
(ROCKET AF) cohort with PANWARDS score; and PANWARDS, platelets, albumin,
no congestive heart failure, warfarin, age, race, diastolic blood pressure, stroke.
Figure. Predicted probabilities of intracranial hemorrhage (ICH) at
2.5 years according to total score on platelets, albumin, no con-
gestive heart failure, warfarin, age, race, diastolic blood pressure,
stroke (PANWARDS) nomogram.
Table 4. PANWARDS Nomogram for Predicting Risk of
Intracranial Hemorrhage
Points
Platelets, 10
9
/L
<125 11
125149 8
150174 5
175199 3
200 0
Albumin, g/dL
<3.0 18
3.03.49 14
3.53.99 9
4.04.49 5
4.5 0
No history of CHF 6
Warfarin instead of rivaroxaban 7
Age, y
<55 0
5564 4
6574 8
7584 13
85 17
Race
Black 18
Asian 9
White or other 0
Diastolic blood pressure, mm Hg
<50 0
5069 4
7089 9
90109 13
110 17
Previous stroke or TIA 5
CHF indicates congestive heart failure; PANWARDS, platelets, albumin, no
CHF, warfarin, age, race, diastolic blood pressure, stroke; and TIA, transient
ischemic attack.
1310 Stroke May 2014
per 1010
9
/L increase]). Indeed, a decreasing platelet count
below 21010
9
/L was associated with an increased hazard of
ICH (Table 3; Figure III in the online-only Data Supplement),
and an increasing platelet count above 21010
9
/L was associ-
ated with an increased hazard of ischemic stroke (Table IX
and Figure IV in the online-only Data Supplement).
The predictors of a reduced risk of ICH that were not pre-
dictors of ischemic stroke were history of CHF (HR, 0.65;
95% CI, 0.470.89) and randomization to rivaroxaban (0.60;
0.440.82). Predictors of an increased risk of ICH that were
not predictors of ischemic stroke were age (1.35; 1.131.63
per 10-year increase) and Asian (2.02; 1.392.94) or black
race (3.25; 1.437.41; Table 3).
Discussion
Principal Findings
In an international cohort of 14 264 patients with AF at moder-
ate to high risk of stroke who were treated with anticoagula-
tion, the overall rate of ICH was 0.67% per 100 patient-years,
and the overall case fatality rate was 49%. There was no dif-
ference in case fatality from ICH among participants assigned
warfarin or rivaroxaban. The risk of ICH was signicantly
higher in Asians, blacks, the elderly, those with a history of
stroke or TIA, those with increased diastolic blood pressure,
and those with reduced platelet count and serum albumin at
baseline. The risk of ICH was signicantly lower among those
who had a history of heart failure and who were randomized
to rivaroxaban instead of warfarin. Internal validation by boot-
strapping revealed that race and region were highly correlated,
as were diastolic and systolic blood pressure. The discrimina-
tive capacity of the model was good (C-index, 0.69; 95% CI,
0.640.73).
30,31
The PANWARDS nomogram has been derived
from the model for predicting the probability of ICH at 2.5
years for any individual patient.
Our Results in Context With Other Studies
The rate and outcomes of ICH observed in ROCKET AF were
similar to those observed among anticoagulated participants
in large cohorts
32,33
and in the Randomized Evaluation of
Long-Term Anticoagulant Therapy (RE-LY) trial.
9
The simi-
larly high case fatality rates from ICH among patients taking
warfarin or rivaroxaban in ROCKET AF and warfarin or dabi-
gatran in RE-LY are consistent with other studies that report a
poor prognosis in anticoagulant-associated ICH.
34
Our ndings of a higher risk of anticoagulant-associated
ICH in Asians, blacks, the elderly, and patients with a history
of stroke and elevated blood pressure are consistent with other
observational studies and schema for predicting an increased
risk of major (intracranial and extracranial) hemorrhage
among anticoagulated individuals in other populations, sup-
porting the external validity of our results.
926,3537
The more
novel ndings from this study are the association of declining
platelet count and albumin with an increased risk of ICH and
the association of a history of heart failure and taking rivar-
oxaban (instead of warfarin) with a reduced risk of ICH.
Declining platelet count has also been reported as a com-
ponent of the hepatic or renal disease, ethanol abuse, malig-
nancy, older age, rebleeding, reduced platelet count or function,
hypertension, anemia, genetic factors (CYP2C9), excessive fall
risk, and stroke (HEMORRHAGES) scheme for predicting all
major bleeding, but it was not reported whether reduced platelet
count actually added independent, signicant predictive power
for major bleeding.
38
Furthermore, a low platelet count, particu-
larly a low-normal platelet count, has not been reported previ-
ously as an independent, signicant predictor of ICH.
The higher risk of ICH with declining serum albumin may
reect that both warfarin and rivaroxaban are highly protein
bound. The lower risk of ICH in patients with a history of
CHF may reect a hypercoagulable state in heart failure.
39
The signicantly lower risk of ICH in patients with rivarox-
aban when compared with those with warfarin, irrespective of
age, is consistent with the lower risk of ICH with dabigatran
when compared with warfarin.
9
This may reect the possibil-
ity that warfarin compromises a normal hemostatic mecha-
nism in the brain. In the event of injury to a vessel wall in the
brain, tissue factor, which is found in high concentrations in
the brain, interacts with activated factor VII (VIIa) to initiate
coagulation and provide hemostatic protection.
40,41
Warfarin
blocks vitamin Kdependent -carboxylation of coagulation
factors II, VII, IX, and X; suppresses the production of fac-
tor VIIa; and compromises the formation of tissue factorVIIa
complexes. In contrast, rivaroxaban selectively inhibits factor
Xa, and dabigatran inhibits thrombin. Both agents do not com-
promise the formation of tissue factorVIIa complexes, which
are primary cellular initiators of coagulation. Our study did
not have the statistical power to identify or exclude reliably
a difference in rates of subdural hemorrhage between partici-
pants assigned rivaroxaban and warfarin, which, if real, would
invalidate the theory proposed above. Other mechanisms, such
as the fact that rivaroxaban does not substantially penetrate the
bloodbrain barrier, may also be important.
42
The nding in our second model of a consistently lower rate
of ICH among residents of Eastern Europe, when compared
with other parts of the world, most likely reects ascertain-
ment or diagnostic bias for several reasons. First, the valid-
ity of the diagnosis of ICH in Eastern Europe is less robust
because the pathological diagnosis of stroke (ischemic versus
hemorrhagic) was based on denitive brain imaging less often
in Eastern Europe (computed tomography brain scan, 65% and
MRI brain scan, 11%) when compared with other regions of
the world (computed tomography brain scan range, 77%84%
and MRI brain scan range, 12%26%). Second, the preva-
lence of hypertension and mean level of diastolic blood pres-
sure (major causal risk factors for hemorrhagic stroke) were
highest among residents of Eastern Europe when compared
with other regions of the world. Third, the magnitude of the
effect of residence in Eastern Europe on ICH, as the strongest
predictor (
2
, 24.3; HR, 0.37; 95% CI, 0.250.55), is extraor-
dinary, not previously reported, and unlikely to be plausible.
Fourth, there was no signicant association between residence
in Eastern Europe and risk of ischemic stroke.
One of the challenges in selecting patients with AF for anti-
coagulant therapy is that the predictors of harm (ie, high risk of
ICH) are frequently the same predictors of benet (ie, high risk
of ischemic stroke).
26
Our prediction models for ICH and isch-
emic stroke reinforce this impression to some extent. Previous
stroke or TIA, increased diastolic blood pressure, and reduced
Hankey et al Predictors of ICH in ROCKET AF 1311
serum albumin were independent, signicant predictors of
both ICH and ischemic stroke. However, the independent
predictors of an increased risk of ICH that were not predic-
tors of an increased risk of ischemic stroke were race (Asian,
black), increased age, and reduced platelet count. The indepen-
dent predictors of a reduced risk of ICH that were not predic-
tors of an increased risk of ischemic stroke were a history of
CHF and randomization to rivaroxaban instead of warfarin. A
reduced platelet count below 21010
9
/L was associated with
an increased hazard of ICH, and an elevated platelet count was
associated with an increased hazard of ischemic stroke.
The PANWARDS nomogram is derived from the indepen-
dent, signicant prognostic factors for ICH and the strength of
their association with risk of ICH. It is designed to enable cli-
nicians to predict the probability of ICH for the next 2.5 years
for any individual patient with AF who is anticoagulated. In
the ROCKET AF cohort, most patients scored between 20 and
50 on the nomogram, which corresponded to a probability of
ICH at 2.5 years ranging from 0.4% (score of 20) to 3.5%
(score of 50). The predicted risk of ICH correlated closely
with the observed rates of ICH, but the predictive ability of the
PANWARDS nomogram awaits external validation in other
cohorts of anticoagulated patients with AF.
Strengths
A strength of our study is that it complies with the Strengthening
the Reporting of Observational Studies in Epidemiology
guidelines for reporting an observational study.
43
The study
design was prospective and follow-up was prospective, regular,
and nearly complete (99.8%), thus optimizing ascertainment
of ICH events. ICH was diagnosed by means of standard-
ized diagnostic criteria, including brain imaging and autopsy,
and audited by a committee blinded to the study hypothesis
and treatment allocation. The number of outcome events was
reasonably large (n=175 ICH events in 172 patients), thus
enabling 17 prognostic variables to be examined reliably in
the prognostic model, and the effect of potential confounding
by associated variables that were recorded was adjusted for by
means of multiple regression analysis.
Limitations
A limitation of our study is that we were unable to adjust for
variables that may inuence ICH risk but were not measured
at baseline or at the time of ICH, such as the presence or
absence of the apolipoprotein E2 or E4 allele,
4
CYP2C9 poly-
morphism,
18
cerebral leukoaraiosis,
12
cerebral microbleeds,
21,22

cerebrovascular pathology such as amyloid angiopathy,
21,22

creatinine clearance <30 mL/min,
20,25
and international nor-
malized ratio at the time of ICH.
10
There is also the possibility
of systematic differences in the ascertainment and diagnosis
of cases of ICH among different centers and regions. We also
did not record specic details of how ICH was treated. Finally,
because our model was derived from a large but, nevertheless,
selected clinical trial population with specic inclusion crite-
ria (eg, 55% with previous stroke/TIA) and exclusion criteria
(eg, creatinine clearance, <30 mL/min), the results may not be
generalizable to patient populations dissimilar from the popu-
lation enrolled in ROCKET AF.
Conclusions
Among 14 264 patients with AF at moderate to high risk of
stroke who were treated with anticoagulation, the average
annual rate of ICH was 0.67% per 100 patient-years, and
the mortality rate from ICH was 49%. The risk of ICH was
signicantly higher among Asians and blacks, those with a
history of stroke or TIA, those with increased age and dia-
stolic blood pressure, and those with decreased platelet count
and serum albumin. The risk of ICH was signicantly lower
among those with a history of CHF and who were random-
ized to take rivaroxaban instead of warfarin. These data sug-
gest that ICH during anticoagulation may be reduced by
lowering blood pressure and using rivaroxaban instead of
warfarin. The external validity of these ndings requires test-
ing in other AF populations.
Sources of Funding
The trial was supported by research grants from Johnson & Johnson
Pharmaceutical Research & Development (Raritan, NJ) and Bayer
HealthCare AG (Leverkusen, Germany).
Disclosures
Dr Hankey has received honoraria for serving on executive commit-
tees for Johnson & Johnson and Bayer. Dr Piccini has received re-
search grants from ARCA Pharmaceuticals, Janssen, GE Healthcare,
and ResMed, and provides consulting to Forest Laboratories, Janssen,
Medtronic, and Spectranetics. Dr Mahaffeys disclosures prior to
August 1, 2013, can be found at http://www.dcri.org, and disclosures
after August 1, 2013, at http://med.stanford.edu/proles/kenneth_
mahaffey. Dr Halperin has received consulting fees/honoraria and
research grant support from AstraZeneca, Bayer AG HealthCare,
Boehringer Ingelheim, Daiichi Sankyo, Johnson & Johnson, Pzer,
and Sano-Aventis, Biotronik Inc. Dr Patel has received honoraria
from Johnson & Johnson and Bayer HealthCare for serving on the ex-
ecutive committee of the Rivaroxaban Once Daily, Oral, Direct Factor
Xa Inhibition Compared With Vitamin K Antagonism for Prevention
of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF) tri-
al; consulting fees from Ortho McNeil Janssen and Bayer HealthCare;
and advisory board fees from Genzyme. Dr Breithardt has received
honoraria from Johnson & Johnson and Bayer and advisory board fees
from Boehringer Ingelheim, Bristol-Myers Squibb, Pzer, and Sano-
Aventis. Dr Singer was supported in part by the Eliot B. and Edith C.
Shoolman fund of the Massachusetts General Hospital (Boston, MA);
has served as a consultant and member of a scientic advisory board
for Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi-
Sankyo, Johnson & Johnson, and Pzer; has an institutional research
support contract with Johnson & Johnson and Bristol-Myers Squibb;
and served as an unpaid ROCKET AF executive committee mem-
ber. Dr Becker received consulting fees/honoraria and research grant
support from Johnson & Johnson, Regado, Boehringer Ingelheim,
AstraZeneca, and Daiichi-Sankyo. Dr Berkowitz is an employee
of Bayer. Dr Paolini was an employee of Bayer with compensation
and stock options provided by the company at the time the work was
done. Dr Nessel is employee of Janssen (formerly Johnson & Johnson
PRD). Dr Hacke received consulting fees/honoraria and research grant
support from Bayer, Johnson & Johnson, and Boehringer Ingelheim.
K.A.A. Fox received grant funding and honoraria from Bayer and
Johnson & Johnson. Dr Califf's disclosures are available at https://
www.dcri.org/about-us/conict-of-interest/COI-Califf_Jan-Mar2013.
pdf. The other authors report no conicts.
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