Supplemental Digital Content
Angiotensin –Converting Enzyme Inhibition or Mineralocorticoid Receptor Blockade Do
Not Affect Incidence of Atrial Fibrillation in Patients Undergoing Cardiac Surgery
Mias Pretorius MBChB, MSCI; Katherine T. Murray, MD; Chang Yu, PhD; John G. Byrne, MD;
Frederic T. Billings, IV, MD, MSCI; Michael R. Petracek, MD; James P. Greelish, MD; Steven
J. Hoff, MD; Stephen K. Ball, MD; Vineet Mishra, MD; Simon C. Body MBChB, MPH; Nancy
J. Brown, MD
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Standardized Patient Treatment
Anesthetic and surgical management were conducted according to institutional protocols.
Briefly, patients received general endotracheal anesthesia, consisting of induction with a
combination of propofol, midazolam, fentanyl, or etomidate and maintenance with isoflurane,
vecuronium, and fentanyl. Monitoring included standard modalities [ECG, temperature, invasive
blood pressure, pulse oximetry, and gas monitoring], plus central venous pressure or pulmonary
artery catheter monitoring, and transesophageal echocardiography. Aprotinin was used for repeat
sternotomy procedures and those involving more than one valve procedure, but its use was
discontinued following release of study results by Mangano et al.(1) showing increased mortality
in patients treated with aprotinin. -Aminocaproic acid (-ACA) was used for all other on-pump
operations in patients without a history of venous thrombosis or unstable coronary syndromes.
Anticoagulation for cardiopulmonary bypass (CPB) consisted of 400 U/kg unfractionated
porcine heparin with supplementation to achieve an activated clotting time (ACT) >400 seconds.
Temperature management involved cooling to 28° to 30°C, temperature uncorrected blood gas
management (alpha stat), and cold anterograde and retrograde cardioplegia techniques when a
cross-clamp was applied. At the conclusion of CPB, anticoagulation was reversed with 250 mg
protamine, with an additional 50 mg administered in the following 10 minutes in the presence of
ongoing microvascular bleeding. Off-pump cardiac surgery patients were anticoagulated with
150 U/kg unfractionated heparin before revascularization and supplemented with 3000 U every
30 minutes if necessary to maintain an ACT of 300 seconds. Anticoagulation was reversed with
100 mg protamine following revascularization.
Vasopressors were used at separation from CPB for a mean arterial blood pressure less
than 60 mmHg. Inotropes were used for separation from CPB for the following criteria: left
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ventricular ejection fraction less than 40 per cent, CPB time longer than 120 minutes, a cardiac
index less than 2L/min/M2 or evidence of new onset left ventricular dysfunction by
transesophageal echocardiogram. Use of inotropes and/or vasopressor in the postoperative period
was at the discretion of the intensive care physicians. Milrinone was preferentially used if the
post-bypass left ventricular ejection fraction was less than 30 per cent, for evidence of right
ventricular dysfunction, or for pulmonary hypertension. Milrinone was started as a continuous
infusion at a dose of 0.5 μg/kg/min and adjusted at the discretion of the supervising physician.
Norepinephrine was used to offset milrinone-induced vasodilation. Metoprolol 12.5mg twice a
day was given if heart rate was greater than 60 and systolic blood pressure greater than 100
mmHg starting on postoperative day one. Furosemide was given at a dose of 20 mg twice a day
beginning on postoperative day 1, unless the patient required vasopressors or was hypovolemic.
Reference
1.
Mangano DT, Miao Y, Vuylsteke A, et al. Mortality associated with aprotinin during 5
years following coronary artery bypass graft surgery. JAMA 2007;297:471-479.
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Study patient enrollment
Six hundred ten patients were consented to participate in the study. One hundred and
fourteen of these did not meet inclusion and exclusion criteria. An additional thirty-eight subjects
withdrew prior to randomization. Four hundred fifty-eight patients who met inclusion criteria
were randomized. Thirteen patients changed their mind and withdrew after randomization but
prior to taking study medication. An additional 14 patients withdrew or were excluded after
taking at least one dose of study medication. These 14 patients were included in the intention-totreat analysis. There were 17 protocol violations in which a subject was given a single dose (3 in
the placebo arm, 6 in the ramipril arm, and 3 in the spironolactone arm), two doses (2 in placebo
arm, 1 in ramipril arm, 1 in spironolactone arm) or 4 doses (a subject in the placebo arm) of an
ACE inhibitor, angiotensin receptor blocker or spironolactone during the postoperative period.
Study drug was discontinued in one subject in the spironolactone arm on postoperative day 3 due
to presumed AF, which was later adjudicated to be a junctional rhythm with premature atrial
contractions. These 18 subjects were excluded from the per-protocol analysis.
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Perioperative course of patients who developed acute renal failure
61 year-old male with hypertension and myxomatous mitral regurgitation randomized to placebo.
Patient initially underwent mitral valve repair. Patient required vasoactive medications and
inotropes due to a low cardiac index. His course was complicated by intermittent rapid atrial
fibrillation and bradycardia, hemolytic anemia, acute pancreatitis, jaundice, hematuria and acute
renal failure. The patient’s creatinine increased from 1.42 to 4.16 on postoperative day 12.
Patient underwent mitral valve replacement twelve days after the initial surgery. The patient then
improved and was discharged to home twenty days after admission.
56 year-old male with an atrialseptal defect, pulmonary hypertension, and right ventricular
failure randomized to placebo. Patient underwent closure of his atrial septal defect and coronary
artery bypass to the left anterior descending artery and obtuse marginal. Postoperative course
was complicated by respiratory insufficiency, rapid atrial fibrillation, gastrointestinal bleeding
and acute renal failure requiring dialysis. The patient was discharged to a rehabilitation facility
and eventually weaned from dialysis.
52 year-old male with hypertrophic obstructive cardiomyopathy and mitral regurgitation
randomized to placebo. The patient underwent a minimally invasive mitral valve replacement.
The patient developed acute renal failure with a peak creatinine of 3.1 on postoperative day 3.
He also developed complete heart block requiring pacemaker placement. The patient was
discharged home on postoperative day 9 with a creatinine of 1.0.
62 year-old male with severe myxomatous mitral insufficiency randomized to placebo. He
underwent a minimally invasive mitral valve replacement. The hospital course was complicated
by pneumonia and respiratory failure, atrial fibrillation, and acute renal failure. The patient died
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with multi-organ system failure on postoperative day 15.
49 year-old male with aortic stenosis, morbid obesity, and type 2 diabetes randomized to
placebo. The patient underwent an aortic valve replacement. The serum creatinine increased
from 1.44 prior to surgery to 2.98 on postoperative day 3. The patient was discharged one week
following surgery with a creatinine of 1.60.
66 year-old female with severe mitral regurgitation and moderate aortic insufficiency,
hypertension and pulmonary hypertension. She underwent a mitral valve repair. The
postoperative course was complicated by profound biventricular failure and cardiogenic shock
requiring vasopressor support and balloon pump during the early postoperative period,
respiratory failure, and atrial fibrillation. The creatinine increased from 1.43 to 2.56 on
postoperative day five. The patient recovered as her ejection fraction returned to normal. The
patient was discharged on the eighteenth postoperative day with a creatinine of 0.84.
35 year-old male with a history of aortic valve replacement sixteen years earlier who presented
with a fusiform aneurysm of the ascending aorta and was randomized to ramipril. The patient
underwent a Bentall procedure with reimplantation of the left and right coronary arteries and
resection of the ascending aortic aneurism, and a single vein coronary artery bypass to the right
coronary artery. The postoperative course was complicated by pulmonary hypertension, right
heart failure, coagulopathy, heparin-induced thrombocytopenia, pneumonia with respiratory
failure, and acute renal failure requiring dialysis. The patient died on the 15th post-operative day.
80 year-old male with hypertension and coronary artery disease randomized to placebo. The
patient underwent coronary artery bypass grafting times four. Coronary angiography was done in
the operating room. The patient developed acute renal failure and respiratory distress. The acute
renal failure was attributed to cholesterol emboli, ischemia and contrast exposure. He became
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hypertensive and had two bleeding episodes requiring reoperation. He ultimately developed
multi-organ failure with a creatinine of 5.8 and died eleven days after surgery.
79 year-old man with a history of coronary artery disease and prior bypass, presented with severe
mitral regurgitation, randomized to placebo. The patient underwent a minimally invasive mitral
valve leaflet repair and mitral annuloplasty. The patient’s creatinine increased from 1.57 prior to
surgery to 3.87 on postoperative day four. The patient was discharged eight days following
discharge with a creatinine of 2.7. The following week his creatinine was 1.6.
74 year-old male with aortic stenosis and ascending aortic aneurysm randomized to placebo. The
patient underwent aortic valve replacement and repair of the ascending aortic aneurysm. His
creatinine climbed to a peak of 3.39 on postoperative day. He was discharged on postoperative
day with a creatinine of 1.5.
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Supplemental Table 1: Additional intra-operative and immediate postoperative
characteristics among treatment groups
Variable
Placebo
Ramipril
Spironolactone
(N=147)
(N=151)
(N=147)
Procedure (%)
P value
0.60
Valve Surgery
59.9
57.0
54.4
CABG
32.0
29.1
29.9
Both
6.8
10.6
11.6
Other
1.4
3.3
4.1
2.4±1.3 (n=63)
2.4±1.2 (n=61)
2.4±1.1 (n=63)
0.98
16.3
12.6
17.7
0.45
Bypass time (min)
109.9±78.2
108.5±70.5
101.8±60.5
0.96
Cross-clamp time (min)
56.8±63.2
56.7±54.6
54.6±53.7
0.94
Chest tube output (mL)
620.4±498.1
660.9±543.9
586.7±382.7
0.67
Red blood cells
1.17±2.69
1.07±2.82
0.82±1.60
0.81
Fresh frozen plasma
0.50±1.77
0.69±3.66
0.27±0.91
0.62
Platelets
0.45±1.81
0.22±1.16
0.18±0.95
0.19
Cryoprecipitate
0.54±2.27
0.19±1.26
0.14±1.18
0.08
4.8
2.0
6.1
0.16
Loop Diuretics
99.3
97.4
96.6
0.30
Thiazide Diuretics
22.5
31.1
29.9
0.20
β-blocker
81.6
84.8
87.1
0.43
Calcium Channel Blocker
27.2
23.8
28.6
0.63
Statins
56.5
50.0
51.7
0.49
Non-steroidal anti-
47.6
46.4
52.4
0.55
Number of grafts (N)
Off-pump (%)
Blood products (U)
Medications (%)
Aprotinin
inflammatory drugs
CABG indicates coronary artery bypass grafting.
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Supplemental Table 2
Without
Atrial Fibrillation
Postoperative
Atrial Fibrillation
P value
Wilcoxon
rank sum
test
Initiation of surgery
41.8±22.6 (293)
40.6±19.8 (110)
0.89
30 minutes intraop
60.2±56.6 (231)
59.8±30.4 (100)
0.50
60 minutes intraop
62.8±63.8 (226)
61.1±32.8 (98)
0.51
Postop
44.8±27.6 (289)
47.8±27.6 (109)
0.37
Initiation of surgery
5.0±7.2 (297)
6.3±10.5 (115)
0.29
30 minutes intraop
15.9±53.5 (242)
11.8±13.9 (103)
0.20
60 minutes intraop
22.0±73.4 (232)
18.0±25.7 (104)
0.18
Postop
162.9±528.7 (296)
150.5±299.2 (114)
0.01
Postoperative day 1
145.6±195.2 (286)
166.8±163.2 (109)
0.029
Postoperative day 2
95.7±106.0 (259)
119.0±101.9 (92)
0.008
Initiation of surgery
17.6±13.6 (292)
17.9±14.0 (112)
0.82
30 minutes intraop
19.2±12.1 (237)
17.7±9.7 (106)
0.62
60 minutes intraop
21.2±12.7 (228)
20.7±10.9 (103)
0.95
Postop
35.0±25.2 (290)
40.1±24.3 (114)
0.008
Postoperative day 1
47.3±36.5 (279)
59.4±37.8 (109)
0.0008
Postoperative day 2
27.0±20.8 (255)
31.8±30.2 (91)
0.60
Initiation of surgery
4.2±8.9 (279)
3.7±7.3 (103)
0.81
Postoperative day 1
57.9±83.4 (269)
47.9±35.4 (103)
0.15
Postoperative day 2
136.9±209.2 (246)
114.4±79.8 (84)
0.62
Postoperative day 3
162.5±407.5 (214)
153.2±136.5 (58)
0.13
Postoperative day 4
101.9±84.5 (159)
135.3±99.1 (31)
0.04
F2-isoprostanes (pg/mL)
Interleukin-6 (pg/mL)
Plasminogen activator inhibitor-1
(ng/mL)
C-reactive protein (µg/mL)
9
Plus-minus values are means ± SD. The number of patients assayed appears in the parentheses.
Intraoperative blood samples were not obtained in patients undergoing off-pump surgery. The
postoperative sample was obtained after separation from bypass. For each biomarker, data are
provided for one time point beyond time of maximum concentration.
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Supplemental Table 3
Placebo
Ramipril
Spironolactone
P value
KruskalWallis
F2-isoprostanes (pg/mL)
Initiation of surgery
40.3±24.0 (134)
42.7±22.2 (133)
41.4±19.3 (136)
0.28
30 minutes intraop
65.7±77.9 (109)
56.8±29.9 (113)
57.9±25.4 (109)
0.74
60 minutes intraop
70.4±88.1 (107)
57.5±29.2 (109)
59.1±29.9 (108)
0.54
Postop
49.8±35.7 (131)
43.2±24.7 (134)
44.0±20.0 (133)
0.11
Initiation of surgery
4.7±6.7 (136)
4.6±7.1 (136)
6.6±10.2 (140)
0.13
30 minutes intraop
12.0±18.4 (114)
20.5±72.6 (119)
11.3±20.2 (112)
0.43
60 minutes intraop
15.6±20.1 (108)
28.8±100.9 (115)
17.4±29.4 (113)
0.25
Postop
130.0±213.7 (133)
202.1±668.7 (137)
145.7±427.1(140)
0.36
Postoperative day 1
119.0±143.1 (133)†
171.0±208.6 (129)
164.9±200.2 (133)
0.13
Postoperative day 2
100.3±106.8 (119)
95.5±90.8 (115)
109.6±116.9 (117)
0.51
Initiation of surgery
19.6±16.6 (135)
16.2±11.9 (133)
17.3±12.0 (136)
0.25
30 minutes intraop
19.2±10.7 (114)
19.7±12.5 (117)
17.3±10.9 (112)
0.17
60 minutes intraop
21.0±10.9 (108)
22.0±13.7 (113)
20.1±11.7 (110)
0.51
Postop
36.4±24.6 (135)
38.9±28.0 (133)
34.0±22.3 (136)
0.45
Postoperative day 1
55.2±43.8 (133)
47.9±31.4 (126)
48.9±35.0 (129)
0.81
Postoperative day 2
28.1±20.4 (119)
25.7±17.9 (111)
31.0±30.5 (116)
0.76
Initiation of surgery
12.2±5.6 (135)
12.8±8.8 (133)
13.5±6.9 (139)
0.20
30 minutes intraop
27.2±24.8 (115)
31.4±28.5 (115)
28.4±29.5 (114)
0.15
60 minutes intraop
26.7±19.1 (108)
34.8±31.0 (112)†
27.3±20.7 (111)
0.004
Postop
31.8±16.7 (135)
35.6±19.4 (132)
34.7±24.2 (136)
0.17
Interleukin-6 (pg/mL)
Plasminogen activator
inhibitor-1 (ng/mL)
Tissue plasminogen
activator (ng/mL)
11
Postoperative day 1
21.7±15.1 (132)
19.3±8.5 (127)
20.2±10.2 (132)
0.77
Initiation of surgery
4.1±6.8 (127)
4.3±10.8 (129)
3.9±7.3 (126)
0.14
Postoperative day 1
51.4±40.0 (128)
49.9±38.5 (122)
64.3±115.0 (122)
0.16
Postoperative day 2
134.8±137.4 (111)
131.0±281.5 (107)
127.8±84.8 (112)*
0.04
Postoperative day 3
128.3±88.7 (92)
164.8±416.5 (91)
189.4±476.0 (89)
0.13
Postoperative day 4
94.1±67.3 (66)
105.2±96.6 (70)
126.5±95.4 (54)†
0.11
C-reactive protein
(µg/mL)
Plus-minus values are means ± SD. The number of patients assayed appears in the parentheses.
Intraoperative blood samples were not obtained in patients undergoing off-pump surgery. The
postoperative sample was obtained after separation from bypass. F2-isoprostanes were not
analyzed in every patient due to cost. For each biomarker, data are provided for one time point
beyond time of maximum concentration. *P<0.05 versus ramipril, †P<0.05 versus the other two
treatment groups
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