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The effect of metoprolol on perioperative outcome in coronary patients undergoing nonvascular abdominal surgery
Journal of Clinical Anesthesia (2008) 20, 284–289
Original contribution
The effect of metoprolol on perioperative outcome in coronary patients undergoing nonvascular abdominal surgery Vesna Miodrag Karapandzic MD (Cardiologist)a,⁎, Bosiljka D. Vujisic-Tesic MD, PhD (Professor)b , Predrag M. Pesko MD, PhD, FACS (Professor)c , Brankica M. Nenadic MD (Anesthesiologist)d , Dragan D. Babic MD, PhD (Assistant Professor)e a
Intensive Care Unit, Department of Surgery, Institute for Digestive System Diseases, Clinical Center of Serbia, 11000 Belgrade, Serbia b Department of Echocardiography, Institute of Cardiovascular Diseases, Clinical Center of Serbia, 11000 Belgrade, Serbia c Department of Surgery, Institute of Digestive System Diseases, Clinical Center of Serbia, 11000 Belgrade, Serbia d Department of Anaesthesia, Institute of Digestive System Diseases, Clinical Center of Serbia, 11000 Belgrade, Serbia e Institute for Statistics and Informatics, School of Medicine, 11000 Belgrade, Serbia Received 14 December 2006; revised 30 November 2007; accepted 22 December 2007
Keywords:
β-Blockers; Metoprolol; Noncardiac surgery; Perioperative cardiac complications; complications; Perioperative cardioprotection cardioprotection
Abstract Study Objective: To analyze the clinical effectiveness of the β-1-aderenergic blocker, metoprolol. Design: Prospective, observational, clinical study. Setting: Operating room and intensive care unit of a tertiary-care teaching hospital. Patients: 111 ASA physical status II, III, and IV consecutive patients who were scheduled for open abdominal nonvascular surgery. Interventions: Patients were divided into two stratification groups: 83 (74.8%) of 111 received metoprolol, and 28 (25.2%) of 111 were controls. Within 24 to 96 hours, the drug was used parenterally in a dose of 5, 10, and 15 mg per 24 hours. Metoprolol cardioprotection was applied during the whole perioperative period, in the form of tablets in a dose of 25, 50, and 100 mg per 24 hours until the 30th postoperative day. Measurements: During surgery, and in the first 72 postoperative hours, patients were monitored by continuous ST-T segment monitoring. A 12-lead electrocardiogram was attached immediately after surgery; on postoperative days 1, 2, and 7; and one day before discharge from the hospital. Serum troponin-T level was controlled 6, 24, and 96 hours after surgery. Main Results: Postoperative mortality of cardiac etiology after 30 days of surgery was 1.2% (1/83) in the metoprolol group versus 7.1% (2/28) in the nonmetoprolol group (P b 0.05). The causes of death in these three patients were acute myocardial infarction, congestive heart failure, and malignant arrhythmias.
⁎ Corresponding author. Tel.: +381 11 246 7838. E-mail address: [email protected] (V.M. Karapandzic). 0952-8180/$ – see front matter © 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.jclinane.2007.12.014
Metoprolol in coronary surgical patients
285
Conclusions: Perioperative cardioprotection significantly reduced mortality until postoperative day 30 in patients having open abdominal nonvascular surgery with general anesthesia. © 2008 Elsevier Inc. All rights reserved.
1. Introduction Many studies have analyzed the prophylactic use of βblockers as part of a strategy of cardiac risk reduction in patients undergoing noncardiac surgery [1-26]. Guidelines support β-blocker treatment in high-risk cardiac patients undergoing major noncardiac surgery [27-30]. The goal of our prospective, observational clinical study was to analyze the clinical effectiveness of our original cardioprotective protocol using the cardioselective β-1aderenergic blocker, metoprolol, applied for the first time in our patients with angiographically verified coronary artery disease (CAD), having undergone open abdominal nonvascular surgery during general anesthesia.
2. Materials and methods We conducted a prospective study of 111 consecutive patients, who were operated on at the Department of Digestive Surgery, Institute of Digestive System Diseases, University Clinical Center of Serbia in Belgrade, Serbia, from July 2002 to December 2003. Enrollment criterion was angiographically verified CAD. All patients from the selected group underwent coronary angiography in the preoperative, prehospital period, independent of noncardiac surgery along with cardiosurgical consultation. The group of consecutive patients without coronary angiography was excluded from the study because their CAD was diagnosed only by medical history, without any former diagnostic tests. Risk assessment, preoperative preparation, postoperative follow-up as well as perioperative drug therapy were completed according to American College of Cardiology/ American Heart Association (ACC/AHA) guidelines published in 2002 [27]. All patients had complete physical, medical, and cardiological examinations. They also underwent preoperative 12-lead electrocardiogram (ECG), chest and heart radiography (Shimadzu RS-50A, Shimadzu Corp, Kyoto, Japan), transthoracic echocardiography (Siemens Sequoia 256, Siemens Corp, Mountain View, CA), and complete laboratory analyses (Olympus 400, Olympus, Tokyo, Japan). The patients were monitored by continuous ECG during surgery as well as in the immediate postoperative 72-hour period in the intensive care unit. Electrocardiography (12lead) was performed immediately after surgery; on postoperative days 1, 2, and 7; and one day before discharge from
hospital. Cardiac biomarkers (creatine kinase–MB and troponin) were evaluated at 6, 24, and 96 hours after surgery according to ACC/AHA 2002 recommendations [27]. Clinical characteristics of selected patients are shown in Table 1. The ASA physical status II group included 28 (25.2%) of 111 patients; ASA physical status III group included 53 (47.7%) of 111; and the ASA physical status IV group included 30 (27.0%) of 111 patients.
2.1. Study protocol Coronary patients having undergone open abdominal nonvascular surgery were divided into two stratification groups: group 1 consisted of patients receiving β-blockers (83/111, 74.8%), and group 2 patients received no β-blocker therapy (28/111, 25.2%). The β-1-adrenergic blocker, metoprolol, was used in the form of 100-mg tablets applied orally, or 5 mg ampule for intravenous use. All patients from the selected group had indications for perioperative β-blocker application according to type and number of risk factors. One group consisting of 72 patients was covered by longterm chronic metoprolol therapy in the preoperative period, and the second group, consisting of 39 patients, had no such therapy. In the therapy group, metoprolol was discontinued in 9 patients because of sudden development of contraindications. In the second group, who received no metoprolol therapy in the preoperative period, metoprolol was given to 20 patients. Group 1 was given metoprolol in the form of tablets taken orally, in doses of 25, 50, and 100 mg per 24 hours divided into two individual doses, including the day of operation. The drug use was continued postoperatively in intravenous form, in doses of 5, 10, and 15 mg per 24 hours during the following 24 to 96 hours. Metoprolol tablets were applied in equal doses as in the preoperative period until postoperative day 30. Dosage of drugs was determined by blood pressure (BP) and heart rate (HR) values, which were controlled twice a day, before each administration of drug. The target BP was 110/70 to 120/ 80 mmHg, and target HR was 55 to 60 bpm. Group 2 patients received standard-of-care without β-blockers. The following perioperative cardiac complications were recorded: (1) hypertension (BP N160/100 mmHg, Class II JNC 7); (2) newly developed arrhythmias and conduction disturbances; (3) transient myocardial ischemia with or without chest pain (transient and/or repeating ST ↑ ≥ two mm in leads V1, V2, and V3; ≥ one mm in the other leads; ST ↓ ≥ one mm in at least two adjoining leads; and/or symmetric
286 Table 1
V.M. Karapandzic et al. Clinical characteristics of selected patients
Clinical characteristics of selected patients
With metoprolol therapy Without metoprolol therapy Total number of patients
History of CAD (angiographically verified) History of heart failure chronic/acute History of arrhythmias and conduction disturbances History of renal failure chronic/acute History of cerebrovascular accident History of peripheral arterial disease Chronic obstructive pulmonary disease Risk factors for coronary disease Hypertension Diabetes mellitus Dyslipidemia Active smokers Family history of coronary disease Age N70 yrs Men Echocardiographic parameters End-diastolic diameter of left ventricle N5.7 cm Left ventricular ejection fraction b35% Segmental wall motion abnormalities Type of surgery Emergent/Urgent surgery Elective surgery Nature of digestive illness Malignant disease of digestive system Benign disease of digestive system Esophageal surgery Hepatobiliary surgery Colorectal surgery Incisional hernia repair
83 10 35 3 9 5 0
(74.8) (9) (31.5) (2.7) (8.1) (4.5) (0.0)
28 7 13 2 8 3 11
(25.2) (6.3) (11.7) (1.8) (7.2) (2.7) (9.9)
111 (100) 17 (15.3) 48 (43.2) 5 (4.5) 17 (15.3) 8 (7.2) 11 (9.9)
48 22 17 17 13 37 71
(43.2) (19.8) (15.3) (15.3) (11.7) (33.3) (64.0)
22 6 12 11 8 8 21
(19.8) (5.4) (10.8) (9.9) (7.2) (7.2) (18.9)
70 (63.1) 28 (25.2) 29 (26.1) 28 (25.2) 21 (18.9) 45 (40.5) 92 (82.9)
31 (27.9) 11 (9.9) 47 (42.3)
14 (12.6) 4 (3.6) 13 (11.7)
45 (40.5) 15 (13.5) 60 (54.0)
24 (21.6) 59 (53.1)
7 (6.3) 21 (18.9)
31 (27.9) 80 (72.1)
40 43 9 30 31 13
12 16 3 18 5 2
52 (46.8) 59 (53.1) 12 (10.8) 48 (43.2) 36 (32.4) 15 (13.5)
(36.0) (38.7) (8.1) (27.0) (27.9) (11.7)
(10.8) (14.4) (2.7) (16.2) (4.5) (1.8)
Values are expressed as numbers (percentages). CAD = coronary artery disease.
inversion T waves ≥ one mm) [31]; (4) newly developed heart failure according to the Framingham Criteria for Heart Failure [32]; (5) nonfatal myocardial infarction (MI), according to criteria of the European Society of Cardiology/American College of Cardiology 2000 [31]; (6) nonfatal cardiac arrest; and (7) cardiac death to the 30th postoperative day. The following side effects were analyzed: hypotension, bradycardia, newly developed atrioventricular node block, newly developed heart failure, and acute bronchospasm.
2.2. Statistical analysis Pearson χ2 test in the form of contingence tables was used for statistical analysis, considering that features were attributive categorical type and significance level was at the limit of 0.05.
3. Results Two stratification groups of coronary patients were compared: 83 (74.8%) of 111 covered by metoprolol, and 28 (25.2%) of 111 without metoprolol. The group of patients
with metoprolol therapy had a lower percentage of all expected cardiac complications compared with the group without metoprolol. Postoperative mortality of cardiac etiology to the 30th postoperative day was 1.2% (1/83) in the metoprolol group versus 7.1% (2/28) in the nonmetoprolol group (P b 0.05). The study also found a statistically significant difference in relation to frequency of perioperative hypertension (P b 0.05), newly developed perioperative arrhythmias and conduction disturbances (P b 0.05), perioperative transient myocardial ischemia (P b 0.05), newly developed perioperative heart failure (P b 0.05), and a total number of patients with all types of perioperative cardiac complications (P b 0.05) in favor of metoprolol therapy. However, the study failed to prove statistically significant differences in relation to frequency of perioperative MI (P N 0.05), but MI percentage was lower in patients treated with metoprolol. In both stratification groups, the proportion of coronary patients with perioperative cardiac complications was 59.5% (66/111), whereas 40.5% (45/111) had no cardiac complications. A total of 132 major, minor, and fatal perioperative cardiac complications were recorded in the study patients. The
Metoprolol in coronary surgical patients
287
most common perioperative cardiac complication was hypertension (47/111, 42.3%), followed by transient myocardial ischemia (25/111, 22.5%), newly developed arrhythmias and conduction disturbances (19/111, 17.1%), and newly developed heart failure (6/111, 5.4%). The least-frequent cardiac complication was acute MI (5/111, 4.5%). The percentage of cardiac death 30 days after surgery was 2.7% (3/111) (Table 2). Side effects of the β-blocker were manifested in one patient only, in the form of transient episodes of hypotension and complete heart block.
4. Discussion Our prospective, observational, clinical study included 111 consecutive patients with angiographically verified CAD, undergoing open abdominal nonvascular surgery during general anesthesia. The clinical effectiveness of the cardioselective β-1adrenergic blocker, metoprolol, in the frequency of perioperative cardiac complications was analyzed, and its positive cardioprotective effect was confirmed. Perioperative cardiac complications were monitored at all times in both study groups. It was verified that the frequency of expected perioperative cardiac complications was lower in patients treated with metoprolol, although no statistical significance was established. Side effects of the β-blocker was manifested in one patient only as transient episode of hypotension and complete heart block. Our study showed that the frequency of perioperative transient myocardial ischemia was 16.7% (metoprolol group) versus 39.3% (nonmetoprolol group), perioperative MI was 3.6% (metoprolol) versus 7.1% (nonmetoprolol group), and perioperative cardiac death up to postoperative day 30 was 1.2% (metoprolol) versus 7.1% (nonmetoprolol group). Immediate causes of death in all three patients were acute MI, congestive heart failure, and malignant arrhythmias. One patient died on postoperative day 2, and the other two died on
postoperative day 3. Cardiac cause of death was confirmed by postmortem examination. The patients who died had several risk factors and associated diseases that are known predictors of higher perioperative morbidity and mortality. The following risk factors were found in all three patients: non–ST-segment elevation MI with postinfarction angina pectoris, considerable coronary artery stenosis as verified by angiography, chronic heart failure with occasional acute decompensations, and malignant arrhythmias as documented by ECG and/or Holter echocardiography. One patient had dilating ischemic cardiomyopathy with low ejection fraction, two patients manifested chronic nonregulated hypertension greater than 180/110 mmHg, one patient had insulin-dependent diabetes mellitus, and two patients had hyperlipoproteinemia and positive heredity. The results of our study are compatible with other studies' results. Both our study and formerly published studies obtained lower percentages of minor, major, and fatal perioperative cardiac complications in the β-blocker–treated groups. Meta-analysis of 11 randomized studies (6 medications, 866 patients) proved significantly lower incidence of intraoperative myocardial ischemia (7.6% vs 20.2%), postoperative myocardial ischemia (15.2% vs 27.9%), MI (0.9% vs 5.2%), and cardiac death (0.8% vs 3.9%) [14]. A retrospective cohort study involving 782,969 patients from 329 hospitals found a significant reduction in incidence of intrahospital cardiac death in high-risk cardiac patients treated with β-blockers who underwent major noncardiac surgery [15]. Meta-analysis of 6 randomized studies, which included 632 patients, confirmed significantly lower frequency of myocardial ischemia (33% vs 15%) and long-term cardiac mortality (12% vs 2%) in favor of β-blockers [16]. Meta-analysis of all 15 randomized controlled studies, which involved 1,077 patients, established a significant reduction of incidence of perioperative myocardial ischemia, 65% (11.0% vs 25.6%); MI, 56% (0.5% vs 3.9%); and cardiac death, 67% (1.1% vs 6.1%) in favor of β-blockers [17]. Finally, a meta-analysis of 69 randomized controlled trials concluded that β-blockers significantly reduce arrhythmias and myocardial ischemia in noncardiac surgery [18].
Table 2 Classification of patients who were administered and were not administered metoprolol therapy according to incidence of minor, major, and fatal perioperative cardiac complications Perioperative cardiac complications
With metoprolol therapy (n = 83, 74.8%)
Without metoprolol therapy (n = 28, 25.2%)
Total number of cardiac complications (n = 111)
P
Hypertension BP N160/100 mmHg Arrhythmias and conduction disturbances Transient myocardial ischemia MI Heart failure Cardiac death up to the 30th postoperative day Total number of patients with cardiac complications
31 11 14 3 2 1 45
16 8 11 2 4 2 21
47 19 25 5 6 3 66
b0.05 b0.05 b0.05 N0.05 b0.05 b0.05 b0.05
Values are expressed as numbers (percentages). BP = blood pressure; MI = myocardial infarction.
(37.3) (13.3) (16.9) (3.6) (2.4) (1.2) (54.2)
(57.1) (28.6) (39.3) (7.1) (14.3) (7.1) (75.0)
(42.3) (17.1) (22.5) (4.5) (5.4) (2.7) (59.5)
288 Three randomized, controlled studies, which analyzed the effect of perioperative metoprolol cardioprotection, the noncardiac Diabetic Postoperative Mortality and Morbidity trial [19], the Perioperative Beta-Blockade study (vascular) [20], and the Metoprolol after Vascular Surgery study (vascular) [21], failed to prove the significance of cardiac risk reduction in noncardiac surgery. Three earlier, smaller studies, which also analyzed the effect of metoprolol, found significant differences in incidence of perioperative myocardial ischemia [22-24] and MI [22]. Two ongoing large, randomized, controlled, international trials, PeriOperative ISchemic Evaluation trial (metoprolol) [25] with 10,000 patients and the DECREASE IV trial (bisoprolol) [26] involving 6,000 patients, will provide a reliable assessment of the effects of β-blocker therapy in patients undergoing noncardiac surgery. We believe our study obtained a significantly lower percentage of side effects in comparison to other studies because of our original protocol for perioperative metoprolol application. Our protocol differed from previously used ones because β-blocker therapy was not discontinued during the whole perioperative period until postoperative day 30. Continuous administration of β-blockers during the whole perioperative period, in low doses equally divided in 24 hours, succeeded in maintaining BP and frequency within normal limits, without any large variations. Abrupt discontinuation of chronic β-blocker therapy, as well as intermittent short-term breaks and reintroduction, results in significantly varying BP and HR values, which may lead to ischemia and MI. Our 5-year clinical experience supports perioperative βblocker administration because we have obtained significantly lower frequencies of major, minor, and fatal perioperative cardiac complications in relation to patients who received no β-blocker therapy.
5. Conclusion Postoperative mortality of cardiac etiology up to postoperative day 30 was 1.2% (1/83) in the metoprolol group versus 7.1% (2/28) in the nonmetoprolol group. Perioperative cardioprotection by our therapeutical protocol with the cardioselective β-1-adrenergic blocker, metoprolol, significantly reduced mortality up to postoperative day 30 in coronary patients having undergone open abdominal nonvascular surgery during general anesthesia.
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Original contribution
The effect of metoprolol on perioperative outcome in coronary patients undergoing nonvascular abdominal surgery Vesna Miodrag Karapandzic MD (Cardiologist)a,⁎, Bosiljka D. Vujisic-Tesic MD, PhD (Professor)b , Predrag M. Pesko MD, PhD, FACS (Professor)c , Brankica M. Nenadic MD (Anesthesiologist)d , Dragan D. Babic MD, PhD (Assistant Professor)e a
Intensive Care Unit, Department of Surgery, Institute for Digestive System Diseases, Clinical Center of Serbia, 11000 Belgrade, Serbia b Department of Echocardiography, Institute of Cardiovascular Diseases, Clinical Center of Serbia, 11000 Belgrade, Serbia c Department of Surgery, Institute of Digestive System Diseases, Clinical Center of Serbia, 11000 Belgrade, Serbia d Department of Anaesthesia, Institute of Digestive System Diseases, Clinical Center of Serbia, 11000 Belgrade, Serbia e Institute for Statistics and Informatics, School of Medicine, 11000 Belgrade, Serbia Received 14 December 2006; revised 30 November 2007; accepted 22 December 2007
Keywords:
β-Blockers; Metoprolol; Noncardiac surgery; Perioperative cardiac complications; complications; Perioperative cardioprotection cardioprotection
Abstract Study Objective: To analyze the clinical effectiveness of the β-1-aderenergic blocker, metoprolol. Design: Prospective, observational, clinical study. Setting: Operating room and intensive care unit of a tertiary-care teaching hospital. Patients: 111 ASA physical status II, III, and IV consecutive patients who were scheduled for open abdominal nonvascular surgery. Interventions: Patients were divided into two stratification groups: 83 (74.8%) of 111 received metoprolol, and 28 (25.2%) of 111 were controls. Within 24 to 96 hours, the drug was used parenterally in a dose of 5, 10, and 15 mg per 24 hours. Metoprolol cardioprotection was applied during the whole perioperative period, in the form of tablets in a dose of 25, 50, and 100 mg per 24 hours until the 30th postoperative day. Measurements: During surgery, and in the first 72 postoperative hours, patients were monitored by continuous ST-T segment monitoring. A 12-lead electrocardiogram was attached immediately after surgery; on postoperative days 1, 2, and 7; and one day before discharge from the hospital. Serum troponin-T level was controlled 6, 24, and 96 hours after surgery. Main Results: Postoperative mortality of cardiac etiology after 30 days of surgery was 1.2% (1/83) in the metoprolol group versus 7.1% (2/28) in the nonmetoprolol group (P b 0.05). The causes of death in these three patients were acute myocardial infarction, congestive heart failure, and malignant arrhythmias.
⁎ Corresponding author. Tel.: +381 11 246 7838. E-mail address: [email protected] (V.M. Karapandzic). 0952-8180/$ – see front matter © 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.jclinane.2007.12.014
Metoprolol in coronary surgical patients
285
Conclusions: Perioperative cardioprotection significantly reduced mortality until postoperative day 30 in patients having open abdominal nonvascular surgery with general anesthesia. © 2008 Elsevier Inc. All rights reserved.
1. Introduction Many studies have analyzed the prophylactic use of βblockers as part of a strategy of cardiac risk reduction in patients undergoing noncardiac surgery [1-26]. Guidelines support β-blocker treatment in high-risk cardiac patients undergoing major noncardiac surgery [27-30]. The goal of our prospective, observational clinical study was to analyze the clinical effectiveness of our original cardioprotective protocol using the cardioselective β-1aderenergic blocker, metoprolol, applied for the first time in our patients with angiographically verified coronary artery disease (CAD), having undergone open abdominal nonvascular surgery during general anesthesia.
2. Materials and methods We conducted a prospective study of 111 consecutive patients, who were operated on at the Department of Digestive Surgery, Institute of Digestive System Diseases, University Clinical Center of Serbia in Belgrade, Serbia, from July 2002 to December 2003. Enrollment criterion was angiographically verified CAD. All patients from the selected group underwent coronary angiography in the preoperative, prehospital period, independent of noncardiac surgery along with cardiosurgical consultation. The group of consecutive patients without coronary angiography was excluded from the study because their CAD was diagnosed only by medical history, without any former diagnostic tests. Risk assessment, preoperative preparation, postoperative follow-up as well as perioperative drug therapy were completed according to American College of Cardiology/ American Heart Association (ACC/AHA) guidelines published in 2002 [27]. All patients had complete physical, medical, and cardiological examinations. They also underwent preoperative 12-lead electrocardiogram (ECG), chest and heart radiography (Shimadzu RS-50A, Shimadzu Corp, Kyoto, Japan), transthoracic echocardiography (Siemens Sequoia 256, Siemens Corp, Mountain View, CA), and complete laboratory analyses (Olympus 400, Olympus, Tokyo, Japan). The patients were monitored by continuous ECG during surgery as well as in the immediate postoperative 72-hour period in the intensive care unit. Electrocardiography (12lead) was performed immediately after surgery; on postoperative days 1, 2, and 7; and one day before discharge from
hospital. Cardiac biomarkers (creatine kinase–MB and troponin) were evaluated at 6, 24, and 96 hours after surgery according to ACC/AHA 2002 recommendations [27]. Clinical characteristics of selected patients are shown in Table 1. The ASA physical status II group included 28 (25.2%) of 111 patients; ASA physical status III group included 53 (47.7%) of 111; and the ASA physical status IV group included 30 (27.0%) of 111 patients.
2.1. Study protocol Coronary patients having undergone open abdominal nonvascular surgery were divided into two stratification groups: group 1 consisted of patients receiving β-blockers (83/111, 74.8%), and group 2 patients received no β-blocker therapy (28/111, 25.2%). The β-1-adrenergic blocker, metoprolol, was used in the form of 100-mg tablets applied orally, or 5 mg ampule for intravenous use. All patients from the selected group had indications for perioperative β-blocker application according to type and number of risk factors. One group consisting of 72 patients was covered by longterm chronic metoprolol therapy in the preoperative period, and the second group, consisting of 39 patients, had no such therapy. In the therapy group, metoprolol was discontinued in 9 patients because of sudden development of contraindications. In the second group, who received no metoprolol therapy in the preoperative period, metoprolol was given to 20 patients. Group 1 was given metoprolol in the form of tablets taken orally, in doses of 25, 50, and 100 mg per 24 hours divided into two individual doses, including the day of operation. The drug use was continued postoperatively in intravenous form, in doses of 5, 10, and 15 mg per 24 hours during the following 24 to 96 hours. Metoprolol tablets were applied in equal doses as in the preoperative period until postoperative day 30. Dosage of drugs was determined by blood pressure (BP) and heart rate (HR) values, which were controlled twice a day, before each administration of drug. The target BP was 110/70 to 120/ 80 mmHg, and target HR was 55 to 60 bpm. Group 2 patients received standard-of-care without β-blockers. The following perioperative cardiac complications were recorded: (1) hypertension (BP N160/100 mmHg, Class II JNC 7); (2) newly developed arrhythmias and conduction disturbances; (3) transient myocardial ischemia with or without chest pain (transient and/or repeating ST ↑ ≥ two mm in leads V1, V2, and V3; ≥ one mm in the other leads; ST ↓ ≥ one mm in at least two adjoining leads; and/or symmetric
286 Table 1
V.M. Karapandzic et al. Clinical characteristics of selected patients
Clinical characteristics of selected patients
With metoprolol therapy Without metoprolol therapy Total number of patients
History of CAD (angiographically verified) History of heart failure chronic/acute History of arrhythmias and conduction disturbances History of renal failure chronic/acute History of cerebrovascular accident History of peripheral arterial disease Chronic obstructive pulmonary disease Risk factors for coronary disease Hypertension Diabetes mellitus Dyslipidemia Active smokers Family history of coronary disease Age N70 yrs Men Echocardiographic parameters End-diastolic diameter of left ventricle N5.7 cm Left ventricular ejection fraction b35% Segmental wall motion abnormalities Type of surgery Emergent/Urgent surgery Elective surgery Nature of digestive illness Malignant disease of digestive system Benign disease of digestive system Esophageal surgery Hepatobiliary surgery Colorectal surgery Incisional hernia repair
83 10 35 3 9 5 0
(74.8) (9) (31.5) (2.7) (8.1) (4.5) (0.0)
28 7 13 2 8 3 11
(25.2) (6.3) (11.7) (1.8) (7.2) (2.7) (9.9)
111 (100) 17 (15.3) 48 (43.2) 5 (4.5) 17 (15.3) 8 (7.2) 11 (9.9)
48 22 17 17 13 37 71
(43.2) (19.8) (15.3) (15.3) (11.7) (33.3) (64.0)
22 6 12 11 8 8 21
(19.8) (5.4) (10.8) (9.9) (7.2) (7.2) (18.9)
70 (63.1) 28 (25.2) 29 (26.1) 28 (25.2) 21 (18.9) 45 (40.5) 92 (82.9)
31 (27.9) 11 (9.9) 47 (42.3)
14 (12.6) 4 (3.6) 13 (11.7)
45 (40.5) 15 (13.5) 60 (54.0)
24 (21.6) 59 (53.1)
7 (6.3) 21 (18.9)
31 (27.9) 80 (72.1)
40 43 9 30 31 13
12 16 3 18 5 2
52 (46.8) 59 (53.1) 12 (10.8) 48 (43.2) 36 (32.4) 15 (13.5)
(36.0) (38.7) (8.1) (27.0) (27.9) (11.7)
(10.8) (14.4) (2.7) (16.2) (4.5) (1.8)
Values are expressed as numbers (percentages). CAD = coronary artery disease.
inversion T waves ≥ one mm) [31]; (4) newly developed heart failure according to the Framingham Criteria for Heart Failure [32]; (5) nonfatal myocardial infarction (MI), according to criteria of the European Society of Cardiology/American College of Cardiology 2000 [31]; (6) nonfatal cardiac arrest; and (7) cardiac death to the 30th postoperative day. The following side effects were analyzed: hypotension, bradycardia, newly developed atrioventricular node block, newly developed heart failure, and acute bronchospasm.
2.2. Statistical analysis Pearson χ2 test in the form of contingence tables was used for statistical analysis, considering that features were attributive categorical type and significance level was at the limit of 0.05.
3. Results Two stratification groups of coronary patients were compared: 83 (74.8%) of 111 covered by metoprolol, and 28 (25.2%) of 111 without metoprolol. The group of patients
with metoprolol therapy had a lower percentage of all expected cardiac complications compared with the group without metoprolol. Postoperative mortality of cardiac etiology to the 30th postoperative day was 1.2% (1/83) in the metoprolol group versus 7.1% (2/28) in the nonmetoprolol group (P b 0.05). The study also found a statistically significant difference in relation to frequency of perioperative hypertension (P b 0.05), newly developed perioperative arrhythmias and conduction disturbances (P b 0.05), perioperative transient myocardial ischemia (P b 0.05), newly developed perioperative heart failure (P b 0.05), and a total number of patients with all types of perioperative cardiac complications (P b 0.05) in favor of metoprolol therapy. However, the study failed to prove statistically significant differences in relation to frequency of perioperative MI (P N 0.05), but MI percentage was lower in patients treated with metoprolol. In both stratification groups, the proportion of coronary patients with perioperative cardiac complications was 59.5% (66/111), whereas 40.5% (45/111) had no cardiac complications. A total of 132 major, minor, and fatal perioperative cardiac complications were recorded in the study patients. The
Metoprolol in coronary surgical patients
287
most common perioperative cardiac complication was hypertension (47/111, 42.3%), followed by transient myocardial ischemia (25/111, 22.5%), newly developed arrhythmias and conduction disturbances (19/111, 17.1%), and newly developed heart failure (6/111, 5.4%). The least-frequent cardiac complication was acute MI (5/111, 4.5%). The percentage of cardiac death 30 days after surgery was 2.7% (3/111) (Table 2). Side effects of the β-blocker were manifested in one patient only, in the form of transient episodes of hypotension and complete heart block.
4. Discussion Our prospective, observational, clinical study included 111 consecutive patients with angiographically verified CAD, undergoing open abdominal nonvascular surgery during general anesthesia. The clinical effectiveness of the cardioselective β-1adrenergic blocker, metoprolol, in the frequency of perioperative cardiac complications was analyzed, and its positive cardioprotective effect was confirmed. Perioperative cardiac complications were monitored at all times in both study groups. It was verified that the frequency of expected perioperative cardiac complications was lower in patients treated with metoprolol, although no statistical significance was established. Side effects of the β-blocker was manifested in one patient only as transient episode of hypotension and complete heart block. Our study showed that the frequency of perioperative transient myocardial ischemia was 16.7% (metoprolol group) versus 39.3% (nonmetoprolol group), perioperative MI was 3.6% (metoprolol) versus 7.1% (nonmetoprolol group), and perioperative cardiac death up to postoperative day 30 was 1.2% (metoprolol) versus 7.1% (nonmetoprolol group). Immediate causes of death in all three patients were acute MI, congestive heart failure, and malignant arrhythmias. One patient died on postoperative day 2, and the other two died on
postoperative day 3. Cardiac cause of death was confirmed by postmortem examination. The patients who died had several risk factors and associated diseases that are known predictors of higher perioperative morbidity and mortality. The following risk factors were found in all three patients: non–ST-segment elevation MI with postinfarction angina pectoris, considerable coronary artery stenosis as verified by angiography, chronic heart failure with occasional acute decompensations, and malignant arrhythmias as documented by ECG and/or Holter echocardiography. One patient had dilating ischemic cardiomyopathy with low ejection fraction, two patients manifested chronic nonregulated hypertension greater than 180/110 mmHg, one patient had insulin-dependent diabetes mellitus, and two patients had hyperlipoproteinemia and positive heredity. The results of our study are compatible with other studies' results. Both our study and formerly published studies obtained lower percentages of minor, major, and fatal perioperative cardiac complications in the β-blocker–treated groups. Meta-analysis of 11 randomized studies (6 medications, 866 patients) proved significantly lower incidence of intraoperative myocardial ischemia (7.6% vs 20.2%), postoperative myocardial ischemia (15.2% vs 27.9%), MI (0.9% vs 5.2%), and cardiac death (0.8% vs 3.9%) [14]. A retrospective cohort study involving 782,969 patients from 329 hospitals found a significant reduction in incidence of intrahospital cardiac death in high-risk cardiac patients treated with β-blockers who underwent major noncardiac surgery [15]. Meta-analysis of 6 randomized studies, which included 632 patients, confirmed significantly lower frequency of myocardial ischemia (33% vs 15%) and long-term cardiac mortality (12% vs 2%) in favor of β-blockers [16]. Meta-analysis of all 15 randomized controlled studies, which involved 1,077 patients, established a significant reduction of incidence of perioperative myocardial ischemia, 65% (11.0% vs 25.6%); MI, 56% (0.5% vs 3.9%); and cardiac death, 67% (1.1% vs 6.1%) in favor of β-blockers [17]. Finally, a meta-analysis of 69 randomized controlled trials concluded that β-blockers significantly reduce arrhythmias and myocardial ischemia in noncardiac surgery [18].
Table 2 Classification of patients who were administered and were not administered metoprolol therapy according to incidence of minor, major, and fatal perioperative cardiac complications Perioperative cardiac complications
With metoprolol therapy (n = 83, 74.8%)
Without metoprolol therapy (n = 28, 25.2%)
Total number of cardiac complications (n = 111)
P
Hypertension BP N160/100 mmHg Arrhythmias and conduction disturbances Transient myocardial ischemia MI Heart failure Cardiac death up to the 30th postoperative day Total number of patients with cardiac complications
31 11 14 3 2 1 45
16 8 11 2 4 2 21
47 19 25 5 6 3 66
b0.05 b0.05 b0.05 N0.05 b0.05 b0.05 b0.05
Values are expressed as numbers (percentages). BP = blood pressure; MI = myocardial infarction.
(37.3) (13.3) (16.9) (3.6) (2.4) (1.2) (54.2)
(57.1) (28.6) (39.3) (7.1) (14.3) (7.1) (75.0)
(42.3) (17.1) (22.5) (4.5) (5.4) (2.7) (59.5)
288 Three randomized, controlled studies, which analyzed the effect of perioperative metoprolol cardioprotection, the noncardiac Diabetic Postoperative Mortality and Morbidity trial [19], the Perioperative Beta-Blockade study (vascular) [20], and the Metoprolol after Vascular Surgery study (vascular) [21], failed to prove the significance of cardiac risk reduction in noncardiac surgery. Three earlier, smaller studies, which also analyzed the effect of metoprolol, found significant differences in incidence of perioperative myocardial ischemia [22-24] and MI [22]. Two ongoing large, randomized, controlled, international trials, PeriOperative ISchemic Evaluation trial (metoprolol) [25] with 10,000 patients and the DECREASE IV trial (bisoprolol) [26] involving 6,000 patients, will provide a reliable assessment of the effects of β-blocker therapy in patients undergoing noncardiac surgery. We believe our study obtained a significantly lower percentage of side effects in comparison to other studies because of our original protocol for perioperative metoprolol application. Our protocol differed from previously used ones because β-blocker therapy was not discontinued during the whole perioperative period until postoperative day 30. Continuous administration of β-blockers during the whole perioperative period, in low doses equally divided in 24 hours, succeeded in maintaining BP and frequency within normal limits, without any large variations. Abrupt discontinuation of chronic β-blocker therapy, as well as intermittent short-term breaks and reintroduction, results in significantly varying BP and HR values, which may lead to ischemia and MI. Our 5-year clinical experience supports perioperative βblocker administration because we have obtained significantly lower frequencies of major, minor, and fatal perioperative cardiac complications in relation to patients who received no β-blocker therapy.
5. Conclusion Postoperative mortality of cardiac etiology up to postoperative day 30 was 1.2% (1/83) in the metoprolol group versus 7.1% (2/28) in the nonmetoprolol group. Perioperative cardioprotection by our therapeutical protocol with the cardioselective β-1-adrenergic blocker, metoprolol, significantly reduced mortality up to postoperative day 30 in coronary patients having undergone open abdominal nonvascular surgery during general anesthesia.
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