Online Appendix for the following JACC article
TITLE: Major Bleeding During HeartMate II Support
AUTHORS: Matthew C. Bunte, MD, Eugene H. Blackstone, MD, Lucy Thuita, MS, Jeff
Fowler, DO, Lee Joseph, MD, Aska Ozaki, DO, Randall C. Starling, MD, MPH, Nicholas G.
Smedira, MD, Maria M. Mountis, DO
APPENDIX
Section 1: Baseline demographics and clinical variables
Patient characteristics are presented in table 1. Mean  standard deviation and median (15th, 85th
percentiles) are given for continuous data. Frequencies and percentages provide a description for
categorical data. Uncertainty is expressed by 68% confidence limits, comparable to +/- 1
standard error. Methodological analysis used SAS software (SAS Institute Inc. Cary, NC)
Table 1: Patient Characteristics at implant (N=139)
No. (%)
15 50 85
Characteristic
n
or
Percentile
Mean ± SD
Demography
Age (Years)
139
54 ± 13.5
Female
139
31 (22)
37.8/57.1/66.6
Race
139
Caucasian
108 (78)
African-American
27 (19)
Other
4 (2.9)
Height (cm)
139
174 ± 10.7
163/175/185
Weight (kg)
139
85.1 ± 22.4
62.2/84.4/105
Weight Height Ratio
139
0.49 ± 0.11
0.36/0.48/0.58
Body Mass Index
139
27.8 ± 6.18
21/27.2/33
Body Surface Area(m2)
139
2.04 ± 0.31
1.72/2.04/2.31
Coronary Artery Disease
139
65 (47)
Dilated Cardiomyopathy
139
59 (42)
Hypertrophic cardiomyopathy
139
11 (7.9)
Valvular heart disease
139
4 (2.9)
Smoking
139
80 (58)
Smoking 6mths before surgery
139
4 (2.9)
Alcohol
139
33 (24)
Cocaine/Marijuana
139
13 (9.4)
Atrial Fibrillation
139
53 (38)
Stroke/CVA
139
15 (11)
DVT
139
8 (5.8)
Primary Diagnosis
Psychosocial Issues
Cardiac comorbidity history
MI
139
61 (44)
MI within 6weeks before surgery
118
15 (13)
Thoracic surgery
139
2 (1.4)
Hypertension
139
73 (53)
GI Bleed
139
4 (2.9)
Malignancy
139
11 (7.9)
Albumin (g/dL)
133
3.45 ± 0.64
Hyperlipidemia
139
71 (51)
Glucose
98
115 ± 44.8
Diabetes
139
56 (40)
Preop Hemoglobin A1C
58
6.46 ± 1
5.6/6.25/7.12
BUN (mg∙dL-1)
138
34.3 ± 19.7
16.9/30/53.2
Serum creatinine (mg∙dL-1)
138
1.4 ± 0.53
0.9/1.32/2
Creatinine clearance (Cockcroft-Gault)
138
85.4 ± 82.5
40/71.9/119
Glomerular filtration rate (MDRD)
138
72.1 ± 91.7
36.1/59.8/89.1
Chronic Renal Disease, No Dialysis
139
19 (14)
Dialysis
139
29 (21)
Non-cardiac comorbidity/History
Nutrition
2.7/3.5/4.1
84/103/143
Renal function
Sodium
115 133 ± 5.35
127/134/138
Liver function
Serum total bilirubin (mg∙dL-1)
138
1.47 ± 1.26
0.6/1.05/2.4
Serum Glut. Oxalo Trans. SGOT
109
62.4 ± 88.9
20.5/34/90.5
Serum Glut. Pynevic Trans. SGPT
109
72.2 ± 153
14/34/97
Hematocrit (%)
138
33.7 ± 5.91
27.5/33.5/40.6
Hemoglobin
135
10.9 ± 2.08
8.7/10.8/13.2
Transfusions
139
15 (11)
Diastolic BP
132
59.8 ± 10.1
50/60/70
Systolic BP
132
96.4 ± 14.6
82/95.5/109
Mean BP
132
72 ± 10.5
62/71.5/82.7
PAP-Diastolic
136
24.2 ± 7.72
16/24/32
PAP-Systolic
136
47.9 ± 14.9
30.6/48/64
PAP-Mean
136
32.1 ± 9.28
22/32/42
Heart Rate
127
90.6 ± 17.8
73.2/90/111
Cardiac index
117
2.24 ± 0.63
1.6/2.2/2.83
INR
112
1.22 ± 0.34
1/1.1/1.4
Prothrombin Time (Secs)
111
13.3 ± 3.5
11.2/12.2/15
Partial Thromboplastin Time (Secs)
109
42.7 ± 23.3
28.5/32.9/61.6
Aspirin
139
74(53)
Thienopyridine (i.e., clopidogrel,
139
15 (11)
Serology
Blood Pressure
Hemodynamics
Clotting
Preop Medications
ticlopidine)
Warfarin
139
Strategies
139
52 (37)
Bridge to transplant
55 (40)
Bridge to decision
53 (38)
Destination therapy
31 (22)
INTERMACs Level
139
INTERMACs Enrolled
139
74 (53)
INTERMACs level 1
46 (33)
INTERMACs level 2
30 (22)
INTERMACs level 3
28 (20)
INTERMACs level 4
33 (24)
INTERMACs level 5
2 (1.4)
Life Support
139
ECMO life support
14 (10)
IABP life support
44 (32)
Inotrope life support
85 (61)
VENT life support
19 (14)
Preoperative ICU
139
91 (65)
139
96.1 ± 36
63/92/124
133
14.9 ± 4.72
10/15/20
Intraoperatives
CPB- minutes
ECHO
Ejection fraction
Left atrial diameter
122
4.91 ± 0.91
4/5/5.7
Unscaled LA volume
122
68.6 ± 42.5
33.5/65.5/97
Calc LV mass (ASE-cube mass)
126
336 ± 125
232/323/440
LV end diastolic volume
126
251 ± 90
167/239/326
LV end systolic volume
125
192 ± 84.7
111/187/281
Calc LV eject fraction (echo est)
125
24.7 ± 13.9
13.2/21.6/36.8
AV stenosis degree
35
0.74 ± 1.63
0/ 0/2.8
AV mean gradient
12
14.7 ± 7.09
5.95/12.5/23.1
Initial VAD flow
115
4.9 ± 0.91
4/4.7/5.92
Initial VAD Pulsatility Index
122
4.94 ± 0.97
3.85/5/6
Initial VAD speed
137
8720 ± 471
8200/8800/9200
Days: Admission to implant
139
13 ± 13.8
3/10/23
Interval: 1/1/2004 to HeartMate II
139
5.02 ± 1.04
4.29/5.22/6.03
VAD settings
Time intervals
Postoperative Events
n
Overall transplant
45
Overall death
44
Causes of death
Anoxia
1
Cardiac arrest
1
Hemorrhage non stroke
7
Infections
9
Liver failure
1
Multiple organ failure
14
Other cerebral/HF
6
Stroke
2
Unknown
3
Section 2:
Bleeding event definitions based on INTERMACS adverse event criteria.
Modifications made to INTERMACS-defined adverse events included reclassification of
hemorrhagic stroke as a major bleeding event and an additional category of anemia of
undetermined source (AUS). AUS events were used to account for clinically significant anemia
requiring transfusion when a conspicuous source of blood loss was absent.
Major bleeding:

A confirmed source of bleeding resulting in:
1. Death;
2. Reoperation;
3. Rehospitalization;
4. Hemorrhagic stroke;
5. Transfusion;
a. ≥4 units PRBCs within 7 days of surgery
b. Any transfusion beyond 7 days from surgery
Anemia of undetermined source:

A clinically significant non-hemolytic anemia meeting above INTERMACS
transfusion requirements, plus indeterminate primary source of bleeding
despite noninvasive or invasive testing
Section 3: Assessment of INR profile and modeling risk of INR on bleeding.
a) Trend: General postoperative INR description
The table below indicates the number of INR records beyond 1day, 7days, 1month, 3, 6, 9, 12,
15, 18, and 24 months. For analyses, INR measurements were considered through 15 months.
The median time from last INR to subsequent bleeding complication was 1 day (1 - 8 days, 15th
and 85th percentile). The mean time (and standard deviation) from last INR to bleeding was
4.6±7.9 days.
Table 3a: Available INR data over 24 months follow-up. Number (#) at risk indicates patients
at risk for bleeding at the listed time interval. One patient did not have an available postoperative INR record. # INR records indicates the total number of cumulative INR records
available for all patients beyond the listed time point.
1
1
1
3
6
9
12
15
18
24
day
week
mo
mo
mo
mo
mo
mo
mo
mo
138
138
132
121
99
74
56
41
24
13
5
8145
8027
7309
4939 2930 1894 1252
784
470
261
37
Total
# at risk
# INR
records
#: number; mo: month
When INR was considered in the multivariable model, early implant year and prolonged bypass
time remained significant risk factors for combined bleeding,. Although elevated INR was a
significant risk factor for bleeding events in univariable analysis, this effect disappeared in the
multivariable model.
Table 3b: Incremental risk factors for ALL bleeding combined. Multiphase hazard
regression was used in a multivariable model to isolate risk factors for all bleeding. Because
INR was the focus of this section of subanalysis, exceptions were made for bootstrapped INR
value and bootstrapped time to INR measurement: these variables were forced into each phase of
the multivariable model, irrespective of reaching the prespecified 50% reliability or alpha ≤ 0.07
significance levels. Parametric estimates were obtained from a multiphase hazard function model
of time-related events. Early HeartMate II implant year and prolonged bypass time were
predictors of bleeding in the early hazard phase. Earlier implant year remained a significant
predictor of bleeding into the late hazard phase. INR was not a significant risk factor in either
early or late hazard phases.
Factors
Coefficient + SE
p-value
R*
INR
0.17 + 0.11
0.1
87
HeartMate II implant year
-7.13 + 2.96
0.02
69
Cardiopulmonary bypass time
0.66 + 0.19
0.0005
74
INR
-0.038 + 0.13
0.8
35
HeartMate II implant year
-0.56 + 0.087
<0.0001
56
Early Hazard Phase
Late Hazard Phase
* Reliability: % of occurrence of factors in the 500-bootstrapped model
Section 4: Hazard function for death among the overall cohort (excluding destination
therapy). The hazard curve illustrates the instantaneous risk of death after HeartMate II implant,
excluding those implanted as destination therapy. Solid lines are parametric estimates enclosed
within 68% confidence limits. Hazard of death rose steeply immediately after implant, reaching
its peak at 7 days, followed by a steep fall and leveling off at 2 weeks.
Section 5: Bleeding incidence by preoperative INTERMACS score. HMII recipients with the
highest acuity INTERMACS score of 1 experienced the greatest rates of early and long-term
incident bleeding complications. Overall, INTERMACS score trended poorly with incident
bleeding events. HMII recipients with an INTERMACS score of 4 and 5 were combined due to
a small number of patients.