Indications for angiography subsequent to coronary artery bypass grafting

Indications for angiography subsequent to coronary artery bypass grafting Peter Alter, MD,a Sebastian Vogt, MD,b Matthias Herzum, MD,a Marc Irqsusi,b Heinz Rupp, PhD,a Bernhard Maisch, PhD,a and Rainer Moosdorf, MD b Marburg, Germany

Background Postoperative myocardial infarction is a rare, but potentially severe complication after coronary artery bypass grafting (CABG). Early markers for coronary bypass graft failure or native vessel occlusion are required, because immediate intervention could prevent major myocardial damage. Methods

One thousand patients with coronary artery disease consecutively underwent CABG. Postoperative coronary angiography was performed in 40 patients with suspected myocardial ischemia. Creatine kinase (CK), CK-MB, leukocyte count, C-reactive protein (CRP), lactate dehydrogenase (LDH), and glutamate-oxalacetate transaminase (GOT) were assessed at 0, 6, 12, 24, 48, and 72 hours after CABG as well as 12-lead standard electrocardiography (ECG).

Results Postoperative angiography of 40 patients with suspected myocardial infarction revealed graft failure or occluded native vessels in 13 (32.5%) individuals. Patients with graft or vessel occlusion presented elevated ( P b .005) leukocyte counts (17 215 F 6632 vs 10 773 F 3902 G/L) immediately after CABG. CK-MB concentrations differed ( P b .05) at 6 hours after CABG (54 F 48 vs 30 F 18 U/L). CK, CRP, LDH, and GOT did not show any differences between both groups. Frequency of ECG ST-segment elevation was increased ( P b .05) in ischemic patients (69.2% vs 29.6%). Conclusions Common signs of myocardial ischemia usually allow to diagnose unstable angina or myocardial infarction under native conditions. In contrast, these criteria frequently fail after CABG. Combined diagnostic criteria of elevated leukocytes (N14 000 G/L, at hour 0) and either ST elevation or CK-MB concentrations N35 U/L (at hour 6) at least seem to be very useful in detecting myocardial infarction after bypass grafting. In parallel, CK-MB elevation (N70 U/L, at hour 6) alone seems to predict ischemia. Both criteria should indicate angiography and potential revascularization. If these conditions were not fulfilled, the risk of perioperative myocardial infarction appears to be moderate. (Am Heart J 2005;149:1082- 90.) Coronary artery bypass grafting (CABG) is a frequently performed method to treat multivessel or left main coronary artery disease. Postoperative myocardial infarction is a rare but potentially severe complication after CABG. Reports on its incidence vary widely (2% -13%), because of poor data based on a few postoperative control coronary angiographies and not standardized noninvasive criteria.1,2 Despite the procedural risk is b1%,3 coronary angiography is not recommended routinely after CABG.4 Usual diagnostic tools for assessing myocardial infarction, including chest pain, electrocardiographic (ECG) ST-segment alteration, occurrence

From the aDepartment of Internal Medicine — Cardiology and Cardiovascular Surgery, Philipps University of Marburg/Lahn, Marburg, Germany. Submitted January 18, 2004; accepted August 11, 2004. Reprint requests: Peter Alter, MD, Department of Internal Medicine — Cardiology, Philipps University of Marburg/Lahn, Baldingerstrasse, D-35033 Marburg, Germany. E-mail: [email protected] 0002-8703/$ - see front matter n 2005, Elsevier Inc. All rights reserved. doi:10.1016/j.ahj.2004.08.016

of new Q waves, and molecular parameters (eg, creatine kinase [CK] and troponin), are frequently not assessable in analgetic, sedated, and, often, pacemaker-stimulated patients, or could conceal false-positive results in postoperative conditions. Thus, there is yet no consensus on the indication of angiography subsequent to CABG. CK-MB as well as troponin are sensitive parameters for cardiomyocyte injury.2,5 - 7 Therefore, increase of serum concentrations could also result from surgical injury during CABG procedure itself. Presence of circumscribed myocardial infarction is not obligatory for this pattern.8,9 However, use and therapeutic significance of increase of CK-MB serum concentrations to indicate revascularization is limited because of its delayed occurrence (4 - 6 hours) after ischemia. Recent studies regarding the diagnostic and prognostic value of CK-MB or troponin in postoperative myocardial infarction are not based on coronary angiographies.5,6,8,10,11 ST-segment alteration is not specific for ischemia, it could also result from pericardial trauma, potential electrolyte imbalance, intracoronary air, and transient hypoxia in the early postoperative phase.12-14 Q waves are also suitable

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Table I. Baseline characteristics

Variable Age (y) Male sex Body mass index (kg/m2) Diabetes Type 1 Type 2, oral therapy Type II, requires insulin Lipids Triglycerides (mg/dL) Cholesterol (mg/dL) HDL (mg/dL) LDL (mg/dL) Smoking Never Past or current Prior infarction Prior PTCA Prior CABG Angiographic data LVEF (%) EDP (mm Hg) 1-Vessel disease 2-Vessel disease 3-Vessel disease

Table II. Baseline characteristics

Patients with patent grafts (n = 27)

Patients with occlusion of graft or native vessel (n = 13)

68.0 F 9.1 21 (77.8) 27.2 F 3.2

64.2 F 8.7 10 (76.9) 29.0 F 2.7

Distribution of CABGs

P NS NS NS

0 2 (7.4)

0 2 (15.4)

NS NS

1 (3.7)

3 (23.1)

NS

154.7 F 47.0

188.1 F 105.5

NS

175.8 F 36.4

179.2 F 39.9

NS

37.5 F 12.7 104.1 F 28.9

33.0 F 12.7 109.0 F 29.8

NS NS

11 16 14 7 3

(40.7) (59.3) (51.9) (25.9) (11.1)

64.8 F 15.8 18.1 F 6.6 1 (3.7) 3 (11.1) 23 (85.5)

7 (53.8) 6 (46.2) 2 (15.3) 3 (23.1) 0 69.7 F 10.1 14.7 F 6.5 2 (15.3) 0 11 (84.6)

NS NS 0.04 NS NS NS NS NS NS NS

Distribution of demographic features in accordance to the angiographically proven vessel status. Data are presented as mean F SD or n (%). HDL, High-density lipoproteins; LDL, low-density lipoproteins; LVEF, left ventricular ejection fraction assessed by angiography; EDP, end-diastolic left ventricular pressure.

(not always specific) markers of ischemia, but they occur not until transmural necrosis is present.15,16 Obviously, early assessable markers for bypass graft failure or native vessel occlusion after CABG are required, because immediate percutaneous transluminal coronary angioplasty (PTCA) or Re-CABG could prevent major myocardial damage.8,17-20

Methods Patients One thousand patients undergoing CABG at the Marburg Heart Center were enrolled in the study during 2 years. Combined surgical procedures (eg, CABG with valve replacement or reconstruction) were not included. Age, sex, body weight, and length, status of smoking (never, past, or current), serum lipids (triglycerides, high-density lipoproteins cholesterol, or lowdensity lipoprotein cholesterol), medical history including presence or absence of hypertension, diabetes mellitus (oral therapy or insulin requiring), prior PTCA, previous CABG, or myocardial infarction were assessed from each patient.

Graft LIMA graft LAD Diagonal branch Venous graft LAD Diagonal branch Intermediate branch LCX Marginal branch RCA RPD RPL Sum of all grafts Sum of LIMA grafts Sum of venous grafts

Patients with patent grafts (n = 27)

Patients with occlusion of graft or native vessel (n = 13)

15 (55.5) 3 (11.1)

10 (76.9) 1 (7.7)

10 9 3 8 12 9 5 3 77 18 59

2 5 1 5 7 2 3 2 38 11 27

(37.0) (33.3) (11.1) (29.6) (44.4) (33.3) (18.5) (11.1) (2.85) (66.7) (2.19)

(15.4) (38.5) (7.7) (38.5) (53.8) (15.4) (23.1) (15.4) (2.92) (84.6) (2.08)

P

NS NS NS

Distribution of grafts in patients with and without angiographically proven graft or native vessel occlusion. There was no difference in the frequency of arterial LIMA grafts between both groups. No patient received N1 arterial graft. Data are presented as n (%). The number of venous grafts per patient is given in brackets. LAD, Left anterior descending coronary artery; LCX, left circumflex coronary artery; RCA, right coronary artery; RPD, right posterior descending coronary artery; RPL, right posterolateral coronary artery.

Coronary artery bypass grafting The surgical CABG procedure followed current standard techniques in cold cardioplegic arrest, systemic hypothermia, and topical cooling. The left internal mammary artery was the preferred graft for the left anterior descending coronary artery (LAD) or the first diagonal branch. Saphenous vein conduits were grafted to further coronary arteries. Time of ischemia, duration on-pump, duration of reperfusion, postoperative ventilation, blood loss, and the quantity of transfused erythrocyte packages were assessed.

Molecular and ECG markers Molecular markers were evaluated in the following manner: total CK (1552147), CK-MB (1127608), lactate dehydrogenase (LDH; 3002209), glutamate-oxalacetate transaminase (GOT; 1730533), C-reactive protein (CRP; 1346016) (all from Roche Diagnostics, Mannheim, Germany), and leukocyte count (white blood cell count) were assessed immediately after CABG (within the first 30 minutes, mentioned in the following as hour 0) as well as 6, 12, 24, 48, and 72 hours later. Normal values are defined within the following ranges: CK 10 to 80 U/L, CK-MB b5 U/L, LDH 120 to 240 U/L, GOT 5 to 17 U/L, leukocytes 4.3 to 10.0 G/L, and CRP b5 mg/dL. Simultaneously, 12-lead standard ECGs were assessed. ST-segment elevation z2 mV was judged as potential transmural ischemia and ST depression z2 mV as potential subendocardial ischemia; however, perioperative pericarditis could conceal false-positive ECG signs.

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Figure Figure 1 1

Leukocyte count. P values within 2 adjacent columns indicate significant differences between patent and occluded grafts.

Criteria indicating postoperative angiography Postoperative coronary angiography was performed within 6 to 8 hours after completion of CABG, when at least 1 criterion was fulfilled: CK-MB elevation N35 U/L at 6 hours after CABG or ST-segment alteration in 12-lead standard ECG at 0 or 6 hours after CABG. CK-MB elevation was observed in 17 patients (42.5%), ST-segment elevation occurred in 17 (42.5%), and ST depression in 11 (27.5%). Thus, angiography was performed in 40 patients. Every recent angiography was compared with the previous heart catheter examination that had indicated CABG procedure. All other patients not undergoing coronary control angiography did not exhibit postoperative CK-MB elevation N35 U/L within 72 hours of observation that excludes relevant myocardial infarction.

End point Patients were classified into 2 groups in accordance to the study end point. The latter was defined as angiographically proven bypass graft occlusion or new occlusion (when compared with the prior angiography) of the native vessel that was not fully compensated by perfusion from patent grafts. Total occlusion of a previously subtotal occluded native vessel that is sufficiently supplied by a distally connected patent graft without angiographic evidence for ischemia or side branch ischemia was not rated as perfusion failure. In case of ischemia, depending on the location or morphology of vessel occlusion, PTCA or reoperation was subsequently performed for myocardial revascularization.

Statistical analysis Contingency tables were analyzed using Fisher exact test. Gaussian distribution was checked by the method from Kolmogorov and Smirnov. For comparison of means with equal variances, the unpaired t test was performed; otherwise, Welch correction was applied. For comparisons of repeated meas-

urements within single groups, multiple comparisons were made by on-way analysis of variance and Tukey post test. All values were expressed as means F SD. Statistical significance was assumed at P b .05.

Results Postoperative angiography revealed graft failure or occluded native vessels in 13 of 40 individuals who had fulfilled the criteria for cardiac catheterization of 1000 post-CABG patients. The other 27 had no evidence for perfusion deficiency. Baseline characteristics of all 40 patients did not differ significantly when classified into 2 groups: group A, patent grafts; group B, graft failure or occluded native vessel. Except an elevated ( P b .05) rate of prior infarction in patients with angiographically patent vessels, both groups were equally distributed regarding age, sex, medical history, body mass index, presence of diabetes mellitus, blood lipids, the status of smoking, and hemodynamic parameters (Table I). The frequency of LIMA grafts (group A 66.7%, group B 84.6%) and venous grafts (group A 2.19 per patient, group B 2.08 per patient) in both groups were similar (Table II). Procedure-associated technical data showed no differences between both groups (patent vs occluded grafts: ischemia 49.2 F 16.2 vs 60.1 F 17.0 minutes, cardiopulmonary bypass time 97.0 F 36.4 vs 104.3 F 31.2 minutes, reperfusion 38.0 F 19.7 vs 38.6 F 19.1 minutes, perioperative blood loss 1397 F 1109 vs 1324 F 509 mL, and erythrocyte packages 3.1 F 2.8 vs 2.9 F 3.5). Preoperative leukocyte count was not elevated in both groups, because patients with evidence for systemic infection have not been chosen for elective CABG

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Figure 2

C-reactive protein.

Figure 3

Creatine kinase.

procedure. Determination of leukocytes immediately after completion of CABG procedure (hour 0) revealed markedly elevated ( P b .005) counts in the group with angiographically proven graft failure or occlusion of the native vessel: group A 10 773 F 3902, group B 17 215 F 6632 G/L (Figure 1). Differences remained significant within the next 6 hours; subsequently, no differences between both groups were found within the first 24 hours postoperatively. Afterward, a mild increase occurred in patients with patent grafts. CRP did not differ

between groups at any time. An increase of leukocyte in both groups was observed within 3 days after CABG (Figure 2). Total CK concentration increased after bypass grafting to a maximum at 24 hours. Differences between patients with occluded grafts or vessels and patients with patent grafts were not observed at any time (Figure 3). In contrast, CK-MB concentrations differed at 6 hours after CABG (Figure 4). Patient with graft or vessel occlusion showed significantly ( P b .05) elevated concentrations (group B 54 F 48 U/L) when compared with the other

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Figure 4

CK-MB. P values within 2 adjacent columns indicate significant differences between patent and occluded grafts.

Table III. Postoperative (hours subsequent to CABG procedure) concentrations of LDH and GOT (U/L) LDH

Hour 0 6 12 24 48 72

Patent grafts 203 377 376 544 492 454

F F F F F F

70 159 141 339 313 260

Table IV. ECG ST-segment characteristics immediately after completion of CABG Patients with patent grafts (n = 27)

Patients with occlusion of graft or native vessel (n = 13)

3 (11.1) 4 (14.8)

5 (38.5) 2 (15.4)

5 (18.5) 1 (3.7)

1 (7.7) 1 (7.7)

3 (11.1) 2 (7.4)

3 (23.1) 1 (7.7)

8 (29.6)

9 (69.2)

b.05

7 (25.9)

4 (30.1)

NS

GOT Occluded grafts

Patent grafts

Occluded grafts

238 502 538 756 531 489

20 35 58 91 68 32

17 49 92 128 82 42

F F F F F F

65 136 310 433 310 176

F F F F F F

12 25 43 78 72 20

F F F F F F

4 26 66 77 84 31

There are no significant differences between comparable couples with patent and occluded grafts. Data are presented as mean F SD.

group (group A 30 F 18 U/L). Differences remained for 24 hours. Subsequently, CK-MB concentrations decreased analogous to total CK development. LDH and GOT (Table III) did not show any differences between both groups. Both parameters increased within the first 24 hours after CABG followed by a decrease within the next 2 days. ECG ST-segment elevation (Table IV) in at least one section (inferior, anteroseptal, or anterolateral) was observed in 8 patients (29.6%) in group A) and in 9 (69.2%) in group B ( P b .05). Frequency of ST depression was not different between both groups. In addition to leukocyte count, using ECG assessment and CK-MB measurement (at 6 hours) together enhances the predictive value for diagnosing ischemia subsequent to CABG procedures. Patients with vessel occlusion

Section Anteroseptal ST elevation ST depression Anterolateral ST elevation ST depression Inferior ST elevation ST depression Overall At least 1 section with ST elevation At least 1 section with ST depression

P

Data are presented as n (%).

showed increased CK-MB concentrations (54 F 48 U/L, hour 6) when compared with patients with patent grafts (30 F 18 U/L, hour 6). Separate measurement of CK-MB at 6 hours after CABG using 35 U/L as cutoff value (sensitivity 0.46, specificity 0.62, positive predictive value 0.38, negative predictive value 0.71) and ECG ST elevation (sensitivity 0.69, specificity 0.70, positive predictive value 0.53, negative predictive value 0.83) is not appropriate for diagnosing ischemia.

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Combined criteria of elevated leukocytes (N14 000 G/L) and either ST elevation or CK-MB concentrations of at least N35 U/L are reliable diagnostic tools in detecting myocardial infarction after bypass grafting. In parallel, CK-MB elevation (N70 U/L) alone after CABG procedure predicts ischemia (combined criteria: sensitivity 0.85, specificity 0.85, positive predictive 0.73, negative predictive value 0.92).

Outcome Repeat CABG procedure was performed in 4 patients: 2 had an occluded LIMA graft to the LAD, 1 presented an anastomosis-associated stenosis of the LAD itself, and 1 patient had an occluded venous graft to the right coronary artery. PTCA was performed in 5 patients: 2 showed LIMA anastomoses-associated stenoses of the native LAD and 3 had occluded grafts of the left circumflex coronary artery. PTCA has been performed in the native vessels without complications. The remaining 4 patients were treated medically because the suspected area of infarction was limited in relation to the small size of the occluded vessels or side branch. One patient in the group without vessel occlusion died of intracerebral bleeding within the first month after CABG. All others recovered completely.

Discussion Leukocytosis subsequent to coronary artery bypass surgery is yet not an established parameter for detecting myocardial ischemia. Mildly elevated leukocyte counts and CRP concentrations are well known in myocardial infarction, but the diagnostic and therapeutic significance remained ill defined, because common signs of myocardial ischemia including chest pain, ECG ST-segment alteration, CK/CK-MB, and troponin usually allow to diagnose unstable angina or myocardial infarction under native conditions.21-23 In contrast, these criteria frequently fail in patients immediately after CABG. Because of analgesia and sedation, anamnestic data are not available. CK-MB elevation is associated with cardiomyocyte necrosis. Accordingly, increase in concentrations occurs 4 to 6 hours after ischemia, but an earlier assessment should be done so that immediate revascularization can be instituted and further myocardial damage can be prevented. Furthermore, there is no consensus on a cutoff value for CK-MB after CABG that discriminates between CABG procedure–associated injuries and myocardial infarction. Troponin is a sensitive (0.75 - 0.90) and cardiomyocyte-specific (0.75 - 0.82) parameter6 occurring 2 to 3 hours after ischemia; thus, measurement frequently leads to false-positive postprocedural values. The overlap of CK-MB and troponin I of patients with and without graft occlusion is substantial, and the patency status of the individual cannot be reliably predicted from these parameters.24

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This study shows that occurrence of leukocytosis after CABG is a sensitive marker for ischemia that is assessable immediately after completion of surgery. Therefore, its diagnostic value is superior to other single parameters measured in this study. An enhancement of specificity could be achieved in combination with ECG ST elevation or CM-MB concentrations. In accordance, CRP concentrations were elevated markedly after bypass surgery. Thus, the extended inflammatory response resulting from acute coronary syndrome because of coronary artery occlusion or bypass graft failure provides systemically assessable diagnostic parameters. It is known from previous studies that increased leukocyte counts, increased CRP, and elevated concentrations of proinflammatory interleukin 6 (IL - 6) are associated with a worse outcome and increased mortality in patients with acute myocardial infarction, unstable angina pectoris, or advanced coronary artery disease.10,25-39 Elevated serum concentrations of proinflammatory parameters (eg, CRP, IL - 6, IL-7, and serum amyloid A protein) reflect cytokine-mediated hepatic production that is triggered by tissue injury, inflammation, and infection.40 - 42 Unstable angina or myocardial infarction due native vessel occlusion in coronary artery disease is frequently caused by rupture of an atheromatous plaque. The presence of inflammatory mononuclear cells with focal infiltration of monocytes, macrophages, and T lymphocytes in the arterial wall has been demonstrated histologically.43,44 The most common site of plaque rupture occurs in the shoulder region.29 The lesion results from an inflammatory-fibroproliferative response to various forms of insult to the endothelium and smooth muscle of the artery wall. Several growth factors, cytokines, and vasoregulatory molecules participate in this process.45 The balance of proinflammatory and antiinflammatory mediators seems to be important for the patients’ outcome in acute coronary syndromes.38 It remains unsettled if the increase of CRP in unstable angina reflects the inflammatory activity of coronary artery disease itself 45 - 52 or if it reflects effects of recurrent local injury or ischemia.35,53-55 Enhanced inflammatory response to PTCA is described for patients with unstable angina that leads to an increase of CRP, proinflammatory IL - 6, and serum amyloid A protein.50,57 Glycoprotein IIb/IIIa antagonists are reported to reduce proinflammatory mediators after PTCA.58 In contrast, there are yet no data regarding these inflammatory parameters subsequent to CABG. Myocardial ischemia after CABG procedure is usually caused by thombotic graft occlusion.59 Perfusion via sufficient grafts leads to decreasing blood flow in the native vessel proximal to the anastomosis that could rapidly cause total thrombotic occlusion of formerly high grade stenoses. It requires further investigation if the observed increase in leukocyte count and CRP concentration directly resulted from ischemia or if

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damage. If these conditions were not fulfilled, the risk of perioperative myocardial infarction appears to be moderate and angiography is not obligatory.

Figure 5

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Indications for coronary angiography.

the exacerbation of proinflammatory procedures analogous to that occurring in atherosclerotic plaques are responsible. The leukocyte count immediately after CABG procedure seems to be a suitable and early-occurring sensitive but nonspecific parameter in detecting myocardial ischemia. Analysis of our data suggest that 14 000 G/L is the useful cutoff value. Additional assessment of ECG and measurement of CK-MB (at 6 hours) enhances the predictive value for diagnosing postoperative ischemia, whereas using each of these parameters singly is not sufficient in these conditions. Measuring CK-MB at 6 hours after CABG and ECG ST elevation separately does not appear as appropriate diagnostic marker for ischemia. Change in LDH and GOT concentrations occurs N12 hours after ischemia; thus, they are not useful for early detection of ischemia. Therefore, well-established standard criteria to diagnose myocardial infarction are insufficient subsequent to CABG procedure. Coronary angiography is not recommended routinely for every patient. Nevertheless, early diagnoses and potential intervention are required. Therefore, combined diagnostic criteria of elevated leukocytes (N14 000 G/L) and either ST elevation or CK-MB concentrations N35 U/L seem to be very useful in detecting myocardial infarction after bypass grafting (Figure 5). In parallel, CK-MB elevation N70 U/L solely after CABG seems to predict ischemia. Both criteria should indicate immediate coronary angiography and potential revascularization to prevent major myocardial

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