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J Am Coll Cardiol, 2007; 49:1763-1769, doi:10.1016/j.jacc.2006.11.052
(Published online 13 April 2007). © 2007 by the American College of Cardiology Foundation |
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* Department of Anesthesiology, Erasmus Medical Center, Rotterdam, the Netherlands
Department of Vascular Surgery, Erasmus Medical Center, Rotterdam, the Netherlands
Department of Cardiology, Erasmus Medical Center, Rotterdam, the Netherlands
¶ Department of Cardiothoracic Surgery, Erasmus Medical Center, Rotterdam, the Netherlands
Department of Cardiology, Leiden University Medical Center, Leiden, the Netherlands
|| Department of Anesthesiology, University of Alberta, Winnipeg, Manitoba, Canada.
Manuscript received July 19, 2006; revised manuscript received October 31, 2006, accepted November 2, 2006.
* Reprint requests and correspondence: Dr. Don Poldermans, Room H921, Department of Anesthesiology, Erasmus Medical Center, 3015 GD Rotterdam, the Netherlands. (Email: d.poldermans{at}erasmusmc.nl).
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Abstract |
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Background: Prophylactic coronary revascularization in vascular surgery patients with coronary artery disease does not improve postoperative outcome. If a beneficial effect is to be expected, then at least those with extensive coronary artery disease should benefit from this strategy.
Methods: One thousand eight hundred eighty patients were screened, and those with 
3 risk factors underwent cardiac testing using dobutamine echocardiography (17-segment model) or stress nuclear imaging (6-wall model). Those with extensive stress-induced ischemia (5 segments or 3 walls) were randomly assigned for additional revascularization. All received beta-blockers aiming at a heart rate of 60 to 65 beats/min, and antiplatelet therapy was continued during surgery. The end points were the composite of all-cause death or myocardial infarction at 30 days and during 1-year follow-up.
Results: Of 430 high-risk patients, 101 (23%) showed extensive ischemia and were randomly assigned to revascularization (n = 49) or no revascularization. Coronary angiography showed 2-vessel disease in 12 (24%), 3-vessel disease in 33 (67%), and left main in 4 (8%). Two patients died after revascularization, but before operation, because of a ruptured aneurysm. Revascularization did not improve 30-day outcome; the incidence of the composite end point was 43% versus 33% (odds ratio 1.4, 95% confidence interval 0.7 to 2.8; p = 0.30). Also, no benefit during 1-year follow-up was observed after coronary revascularization (49% vs. 44%, odds ratio 1.2, 95% confidence interval 0.7 to 2.3; p = 0.48).
Conclusions: In this randomized pilot study, designed to obtain efficacy and safety estimates, preoperative coronary revascularization in high-risk patients was not associated with an improved outcome.
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However, noninvasive testing may delay surgery and run the risk of aortic aneurismal rupture or exacerbation of critical limb ischemia. Furthermore, coronary revascularization is commonly performed by percutaneous coronary intervention (PCI) with stent placement instead of bypass surgery (CABG). Although this approach prevents further delay of the index surgical procedure, it necessitates the prolonged use of extensive antiplatelet therapy, which may aggravate the risk of perioperative bleeding complications. But temporary discontinuation of antiplatelet therapy is potentially harmful, as it may lead to in-stent thrombosis (2,3).
The current ACC/AHA recommendations are based on small observational, noncontrolled studies and expert opinion (4,5). The usefulness of the strategy of prophylactic revascularization was not confirmed by the recently completed CARP (Coronary Artery Revascularization Prophylaxis) randomized trial (6). In this trial, the incidence of perioperative myocardial infarction was similar in patients allocated to prophylactic revascularization versus those allocated to optimal medical therapy (12% vs. 14% events). There was also no beneficial effect observed during long-term follow-up. However, it should be realized that the vast majority of patients included in the CARP trial had single- or 2-vessel disease with a preserved left ventricular function. Indeed, based on previous research from our group, sufficient cardioprotection by medical therapy can be expected in these patients, which may explain the CARP trial findings (7). In contrast, patients with multiple cardiac risk factors and extensive stress-induced myocardial ischemia are insufficiently protected (7).
Hence, if a beneficial effect of the invasive strategy of prophylactic revascularization is to be expected, then at least patients with extensive coronary artery disease should benefit from this strategy. We therefore undertook the DECREASE (Dutch Echocardiographic Cardiac Risk Evaluation Applying Stress Echo)-V pilot study to assess the feasibility and to obtain initial efficacy and safety estimates for the design of an adequately powered randomized controlled clinical trial in these patients.
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Methods |
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Cardiac testing.
Left ventricular ejection fraction (LVEF) was measured from resting echocardiographic images using the biplane Simpson’s rule. Cardiac stress testing was performed by dobutamine echocardiography or dobutamine or dipyridamole perfusion scintigraphy, as previously described (8,9). Test results were scored by the extent of stress-induced ischemia using a 17-segment model in dobutamine echocardiography and a 6-wall model in stress perfusion scintigraphy. Limited ischemia was defined by the presence of 1 to 4 ischemic segments or 1 to 2 ischemic walls, whereas extensive ischemia was defined by 5 ischemic segments or 3 ischemic walls.
Allocated treatment. Perioperative beta-blocker therapy was installed in all patients at the screening visit, regardless of test results. A computer algorithm was used at each center to assign patients with extensive stress-induced ischemia randomly, in a 1:1 ratio, to 1 of the 2 strategies. The sealed envelope method was used to conceal treatment allocation, and it was assured that envelopes were opened in consecutive order. Patients were randomized to either an invasive approach followed by revascularization or a noninvasive approach. Quantitative analysis of all coronary angiographies was reviewed centrally at Erasmus Medical Center, Rotterdam, the Netherlands, by 2 experienced cardiologists. They assessed independently the number of affected vessels. The mode of revascularization, CABG or PCI with stenting, was decided by the treating physicians, based on coronary anatomy and the possible delay of the index surgical procedure. Patients allocated to the medical-only strategy were referred for surgery without further delay.
Beta-blocker therapy. Patients on chronic beta-blocker therapy continued their medication. Patients without beta-blockers started with bisoprolol 2.5 mg once a day at the screening visit. Beta-blocker dose was adjusted in all patients at admission to the hospital and on the day before surgery to achieve a resting heart frequency of 60 to 65 beats/min. The same dose of beta-blockers was continued postoperatively except in patients who were unable to take medication orally or by nasogastric tube postoperatively. In these patients, the heart rate was monitored continuously at the intensive care unit or hourly at the ward, and intravenous metoprolol was administered at a dose sufficient to keep the heart rate between 60 to 65 beats/min. The heart rate and blood pressure were measured immediately before each scheduled dose of beta-blockers. Beta-blockers were withheld if the heart rate was <50 beats/min or the systolic blood pressure was <100 mm Hg. After discharge, patients continued beta-blocker therapy, and dose adjustments were carried out during outpatient visits to achieve a resting heart frequency of 60 to 65 beats/min.
Perioperative management. Anesthetic management, monitoring, and other aspects of perioperative management were at the discretion of the attending physician. Results of preoperative testing and coronary revascularization were discussed with the attending physicians, and hemodynamic management was implemented accordingly. Anticoagulant and antiplatelet therapy was continued after PCI and during the index surgical procedure. Intraoperative ischemia was treated at the discretion of attending physicians, and additional beta-blockers were permitted.
End point definition. All patients were monitored for cardiac events after screening. Twelve-lead electrocardiogram (ECG) and serum troponin-T level were systematically determined 1, 3, 7, and 30 days after surgery. Outpatient follow-up was performed at 30 days if a patient had been discharged from the hospital. At the outpatient clinic, all patients were screened at 3-month intervals for cardiac events by clinical history and 12-lead ECG. All data were collected by the participating centers and evaluated in a blinded fashion by members of the adverse-events committee. The primary end point was the composite of all-cause death and nonfatal myocardial infarction that occurred between screening and 30-days after the index surgical procedure. Patients were followed-up during at least 1 year after surgery, and the composite of all-cause death and nonfatal myocardial infarction during this period was considered as secondary end point. Myocardial infarction within 48 h after CABG was defined as a creatine kinase (CK)-MB rise above 5x the local upper limit of normal. Myocardial infarction within 48 h after PCI was defined as a CK-MB rise above 3x the upper limit of normal. Myocardial infarction within 30 days after the index surgical procedure was defined as a positive troponin-T level in combination with new Q waves on the ECG lasting more than 0.03 s. In all other situations, myocardial infarctions were defined by new Q waves lasting more than 0.03 s.
Sample size. The purpose of this pilot study was to assess the feasibility of prophylactic revascularization in high-risk patients scheduled for major vascular surgery, and to obtain initial efficacy and safety estimates needed for the design of an adequately powered randomized controlled clinical trial. We aimed for the enrollment of 100 patients, 50 in each strategy. Based on the DECREASE-I study (7), an incidence of 33% of the primary end point was expected in the patients allocated to optimal medical therapy only. It was recognized a priori that a modest, but clinically relevant, risk reduction by prophylactic revascularization would not be detectable given this sample size. However, if the beneficial effect of revascularization was similar to the observations in the CASS (Coronary Artery Surgery Study) registry (85% risk reduction associated with prior CABG in vascular surgery), then our study has 93% power (type II error of 7%), based on a 2-sided test with a type I error of 5%.
Statistical analysis. All analyses were based on the intention-to-treat principle. Continuous data are presented as median values and corresponding 25th and 75th percentiles, whereas dichotomous data are presented as percentages. Differences in clinical and surgical characteristics between patients allocated to revascularization or no revascularization were evaluated by Wilcoxon nonparametric tests, chi-square tests, or Fisher exact tests, as appropriate. Differences in the incidence of the end points were evaluated by a chi-square test. The incidence of events over time was further examined by the Kaplan-Meier method, whereas a log-rank test was applied to evaluate differences between the allocated treatment strategies. Analyses were performed according to the intention-to-treat principle. All statistical tests were 2-sided, and a p value <0.05 was considered significant.
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Results |
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Perioperative cardiac events. Two patients died before vascular surgery because of a ruptured aneurysm after successful bypass surgery. Their aortic diameters were, respectively, 62 and 73 mm. In 1 patient, a myocardial infarction occurred after an incomplete coronary revascularization. This precluded the proceeding of the scheduled vascular surgery. Revascularization did not improve 30-day outcome after vascular surgery. Troponin elevation was found in 38.8% in the noninvasive group versus 34.7% in the invasive group. The incidence of all-cause death or nonfatal myocardial infarction for patients with preoperative revascularization or medical treatment only was 43% versus 33%, respectively (odds ratio [OR] 1.4, 95% confidence interval [CI] 0.7 to 2.8; p = 0.30) (Table 2). Also, no difference was observed in the incidence of perioperative cardiac events between patients treated by prophylactic bypass surgery or percutaneous intervention (41.1% vs. 43.8%, respectively).
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Discussion |
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TopAbstractMethodsResultsDiscussionConclusionsAppendixReferences |
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The randomized CARP trial was the first study that addressed the strategy of prophylactic revascularization compared with optimal medical therapy in patients with clinically stable coronary artery disease who were scheduled for major vascular surgery (6). This trial showed that prophylactic revascularization was safe but did not improve perioperative or long-term outcome. The long-term mortality was 22% in patients allocated to prophylactic coronary revascularization, compared with 23% in the medical only strategy (p = 0.92). Also, the incidence of perioperative nonfatal myocardial infarction was similar, respectively, 12% and 14% (p = 0.37). In the present study, the effect of prophylactic revascularization was comparable to the effect reported by McFalls et al. (6), although the study population is different. The current study population consisted of 12% women, 43% of the patients had a reduced left ventricular function (LVEF <35%), and the vast majority of patients, 75%, had 3-vessel or left main disease compared with 33% in the CARP trial. In a subgroup of 37 comparable patients of the CARP trial (i.e., 3 or more cardiac risk factors and extensive stress-induced ischemia assessed by noninvasive testing), prophylactic coronary revascularization was associated with a favorable, nonsignificant trend for long-term survival (OR 4.0, 95% CI 0.8 to 19). If a beneficial effect of revascularization was to be expected, this should have occurred in the selected population with high-risk anatomy. However, this was not observed, although the current study was not powered to test this strategy. A study to establish the effect of coronary revascularization would require, based on the findings of this pilot study, a screening population of 9,000 patients, of which 2,000 would have 3 or more risk factors, and of these 600 would have extensive stress-induced ischemia during cardiac testing and be eligible for randomization to revascularization. Our findings support the current guidelines of the ACC/AHA on perioperative management in high-risk patients to reserve revascularization only for cardiac unstable patients. After successful vascular surgery, these patients should be regularly screened for the presence of ischemic complaints, and aggressive anti-ischemic therapy, both medical and invasive, should be considered. As shown in Figure 2, a trend was observed for a "catch up" of late cardiac events in patients treated medically. In these patients at high risk scheduled for major vascular surgery, prophylactic revascularization might be switched to late revascularization, preventing the delay of surgery.
The apparent lack of benefit of coronary revascularization of the present study is not fully understood. Most likely, patients with stress-induced ischemia not only suffer from a blood flow-limiting coronary lesion but also from (multiple) nonsignificant lesions that are vulnerable to rupture due to the stress of surgery (10). The perioperative stress response, which includes a cytokine response, catecholamine surge with associated hemodynamic stress, vasospasm, reduced fibrinolytic activity, platelet activation, and consequent hypercoagulability, triggers coronary plaque rupture, leading to thrombus formation and subsequent vessel occlusion (11,12). Autopsy results have shown that this mechanism is responsible for at least half of all perioperative infarctions (10,12). These findings are in line with dobutamine echocardiography results that show a correlation between the assessment of the preoperative culprit coronary lesion and the location of the perioperative myocardial infarction in only half of all cases (13). Surgical or percutaneous treatment of the culprit coronary lesion(s) apparently provides insufficient protection for rupture of these instable lesions.
The optimal perioperative evaluation and management of patients with multiple risk factors and extensive stress-induced ischemia remains controversial. Success will depend on careful collaboration between cardiologists, anesthesiologists, and surgeons. In patients with aortic aneurysms, a surgical repair is performed to reduce the chance of aneurysm-related death. It might be hypothesized that abdominal aortic aneurysm repair should not be performed in this high-risk group. As the current trial shows, open repair poses an unacceptable 30-day cardiac event rate of approximately 30%, whereas the chance of aneurysm rupture is around 9 per 100 person-years. Endovascular treatment modalities may be an alternative for these high-risk patients. Although the EVAR (Endovascular Aneurysm Repair)-2 trial showed no benefit of elective endovascular repair in patients deemed unfit for open repair because of comorbidities (14), these findings were not confirmed in the recently conducted study by the Society for Vascular Surgery Outcomes Committee. In a group of 565 high-risk patients, matched for the EVAR-2 inclusion criteria, undergoing endovascular repair, perioperative mortality was 2.9%. These promising results need to be confirmed in a large study population. Importantly, in all cases, an individualized strategy should be performed, weighing the chances of future aneurysms rupture or limb salvage instead of amputation and short-term perioperative events.
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Appendix |
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TopAbstractMethodsResultsDiscussionConclusionsAppendixReferences |
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Acknowledgments |
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Footnotes |
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