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J Thorac Cardiovasc Surg 2009;137:840-845
© 2009 The American Association for Thoracic Surgery

Acquired Cardiovascular Disease

Impact of prior percutaneous coronary intervention on the outcome of coronary artery bypass surgery: A multicenter analysis

^a Department of Thoracic and Cardiovascular Surgery, West-German Heart Center Essen, Germany
^b Institute for Medical Informatics, Biometry and Epidemiology, University Hospital Essen, Essen, Germany
^c Department of Thoracic and Cardiovascular Surgery, The Heart and Diabetes Center North Rhine-Westphalia, Bad Oeynhausen, Ruhr University of Bochum, Bochum, Germany
^d Department of Thoracic and Cardiovascular Surgery, Heart Center Duisburg, Duisburg, Germany
^e Department of Thoracic and Cardiovascular Surgery, Heinrich Heine-University, Düsseldorf, Germany
^f Department of Thoracic and Cardiovascular Surgery, University Hospital Münster, Münster, Germany
^g Department of Cardiac Surgery, University Hospital Bonn, Bonn, Germany
^h Department of Thoracic and Cardiovascular Surgery, University Hospital Aachen, Aachen, Germany
ⁱ Department of Cardiothoracic Surgery, Cologne University Hospital, Cologne, Germany
^j Department of Mathematics and Technique, Rhein Ahr Campus Remagen, Koblenz University of Applied Science for the NRW (North Rhine-Westphalia) CABG Study group, Koblenz, Germany

Received for publication June 24, 2008; revisions received August 20, 2008; accepted for publication September 3, 2008.

^_* Address for reprints: Parwis Massoudy, MD, Department of Thoracic and Cardiovascular Surgery, West German Heart Center Essen, Hufelandstr. 55, 45147 Essen, Germany. (Email: parwis.massoudy{at}uk-essen.de).

	Abstract

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Objectives: Do prior percutaneous coronary interventions adversely affect the outcome of subsequent coronary artery bypass grafting? We investigated this effect on a multicenter basis.

Methods: Eight cardiac surgical centers provided outcome data of 37,140 consecutive patients who underwent isolated first-time coronary bypass grafting between January 2000 and December 2005. Twenty-two patient characteristics and outcome variables were retrieved. Three groups of patients were analysed for in-hospital mortality and in-hospital major adverse cardiac events: patients without a previous percutaneous coronary intervention, with 1 previous intervention, and with 2 or more previous percutaneous coronary interventions before bypass grafting. A total of 29,928 patients with complete information for prior percutaneous coronary intervention underwent final analysis. Unadjusted univariate and risk-adjusted multivariate logistic regression analysis as well as computed propensity score matching were performed, based on 14 major risk factors to correct for and minimize selection bias.

Results: A total of 10.3% of patients had 1 previous percutaneous coronary intervention, and 3.7% of patients had 2 or more previous interventions. Risk-adjusted multivariate logistic regression analysis revealed a significant association of 2 or more previous percutaneous coronary interventions with in-hospital mortality (odds ratio [OR], 2.0; confidence interval [CI], 1.4–3.0; P = .0005) and major adverse cardiac events (OR, 1.5; CI, 1.2–1.9; P = .0013). After propensity score matching, conditional logistic regression analysis confirmed the results of adjusted analysis. A history of 2 or more previous percutaneous coronary interventions was significantly associated with in-hospital mortality (OR, 1.9; CI, 1.3–2.7; P = .0016) and major adverse cardiac events (OR, 1.5; CI, 1.2–1.9; P = .0019).

Conclusions: Multicenter analysis confirms that a history of multiple previous percutaneous coronary interventions increases in-hospital mortality and the incidence of major adverse cardiac events after subsequent coronary artery bypass grafting. Critical discussion of the treatment strategy in these patients is warranted.

	Introduction

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Earn CME credits at http://cme.ctsnetjournals.org

 

Worldwide, the number of coronary artery bypass grafting (CABG) procedures performed per year reached a maximum in the late 1990s and has declined since then by 20%.¹ In contrast, the number of percutaneous coronary interventions (PCIs) performed per year keeps on growing exponentially worldwide.² Accordingly, the number of patients requiring CABG who have a history of previous PCI procedures rises.

Evidence from randomized trials^3,4 and from large registries^5-7 has proven that, concerning 3-vessel disease, CABG is a more effective treatment than PCI, not only in terms of freedom from recurrent angina and reintervention, but also in terms of survival and freedom from major adverse cardiac events (MACEs).

Just as important as the choice of therapy for patients with coronary artery disease is the question of how one of the respective therapies (CABG or PCI) may be influenced by the other. CABG after prior PCI might not achieve the same excellent results. Patients with initial percutaneous transluminal coronary angioplasty, who subsequently underwent CABG, had a poorer long-term survival than those without angioplasty.⁸ There is also evidence that PCI itself adversely affects the outcome after repeated PCI.⁹ Recent single center study data indicated that patients with 2 or more prior PCIs have a significantly higher in-hospital mortality and MACE rate when they subsequently undergo CABG.¹⁰ In the subgroup of patients with multivessel disease and diabetes mellitus, 1 previous PCI procedure before subsequent CABG was associated with an increase in-hospital mortality and MACE rate.¹¹ Moreover, recent data indicate that long-term outcomes and quality of life are impaired after CABG with prior PCI¹² and that the rates of unstable angina requiring hospitalization and the rates of repeated coronary revascularization during follow-up are increased in CABG patients with prior PCI.¹³

The present study was performed to compare early outcome after CABG with and without prior PCI on a multicenter basis.

	Methods

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Study Design
The study was a retrospective, multicenter, cohort study. Eight cardiac surgical centers in North Rhine–Westphalia, the largest federal state in Germany, participated. A total of 37,140 consecutive patients undergoing first time isolated CABG between January 2000 and December 2005 were included and assigned to groups as follows: group 1, no previous PCI; group 2, one single previous PCI; or group 3, multiple repeated (2) PCIs before CABG. Single or multiple PCIs applies to episodes or sessions. This implies that, in one session, more than one vessel may have been subjected to intervention. Reoperative and concomitant cardiac surgical procedures were excluded. The study was approved by the institutional review boards of the participating centers. All patients gave permission for the use of their medical records for research purposes.

Data Collection
For each patient, 22 parameters were retrieved. Among them, 18 patients and surgery characteristics (age, sex, obesity with a body mass index > 30, left main stem disease, left ventricular ejection fraction [LVEF], peripheral vascular disease , chronic obstructive pulmonary disease [COPD], diabetes mellitus, hypertension, ever smoking, hyperlipidemia, previous myocardial infarction (MI), emergency, elective surgery, number of grafts, history of PCI, number of prior PCI procedures, year of surgery), and four major event categories (in-hospital death and in-hospital MACEs, the latter being defined as perioperative MI, low cardiac output syndrome, or cardiac death). In most cases, PCI consisted of a combination of coronary stenting and coronary balloon angioplasty. In a not further defined small number of cases, percutaneous transluminal coronary angioplasty may have been the only procedure preformed. In addition, other procedures such as coronary atherectomy, coronary ablation therapy, and coronary brachytherapy may have been performed. The dates of PCI procedures were not defined.

Outcome Measures and Definitions
The primary end point was in-hospital mortality after CABG. The secondary end point was the rate of MACEs. Previous MI was considered to have occurred when one of the following criteria were present: (1) new persistent ST-segment or T-wave changes, (2) the development of new Q waves, (3) a creatine kinase level more than 3 times above the upper reference level, or (4) a cardiac troponin I level greater than 10.5 ng/mL. Low cardiac output syndrome was assumed to exist in patients who had a cardiac index less than 2.0 L · min^–1 · m^–2 or a systolic arterial pressure less than 90 mm Hg, despite high-dose inotropic support (intravenous dopamine 8 µg · kg^–1 · min^–1, dobutamine 6 µg · kg^–1 · min^–1, epinephrine > 0.1 µg · kg^–1 · min^–1, or norepinephrine > 0.1 µg · kg^–1 · min^–1). Death was considered cardiac in origin if it was caused by previous MI, significant cardiac arrhythmias, refractory low cardiac output syndrome, or if it was otherwise unexplained.

Perioperative Management
Surgical revascularization was performed either on cardiopulmonary bypass or off-pump. In all centers, the percentage of off-pump procedures was less than 10%. For surgery with cardiopulmonary bypass, three centers used intermittent crossclamping and five centers used the crossclamp technique with cardioplegic arrest. The use of aprotinin was not uniform. Four centers did not routinely use aprotinin. Four centers routinely used aprotinin, two with 4.5 million KIU and two with half this dose in each patient. Aspirin was continued until the day before surgery and resumed either on the day of surgery or on postoperative day 1. If the patient did not have unstable angina, preoperative medication with clopidogrel was discontinued at least 24 hours before surgery and resumed within 48 hours after surgery.

Statistical Analysis
Associations between PCI groups and prognostic factors were evaluated by ² or Kruskal–Wallis tests. Association between outcome (death and MACE) and PCI was evaluated with the Cochran–Armitage test for trend.

Logistic regression analysis was performed to identify independent predictors for in-hospital death and MACE. Variables identified by univariate regression analysis to have a probability value of .1 or less for association with at least one study end point were added to the multivariate logistic regression model. To control for selection bias as a result of nonrandom assignment to the three groups, we performed propensity score matching.¹⁴ The propensity scores were calculated separately by comparing between group 1 versus group 2 and group 1 versus group 3, using logistic regression with 14 risk factors (age, sex, obesity, left main stem disease, LVEF, peripheral vascular disease, COPD, diabetes, hypertension, ever smoking, hyperlipidemia, previous MI, emergency, and number of grafts) and year of surgery. For both comparisons, patients with similar propensity scores were matched into 20 sets of equal size and conditional logistic regression was used.¹⁵ Multiple adjusted odds ratios for group 3 versus group 1 concerning in-hospital death and MACE were also calculated in subgroups defined by certain risk factors. All statistical analyses were performed with the SAS system, version 9.1 (SAS Institute Inc, Cary, NC).

	Results

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The present analysis comprised 37,140 patients, and the parameter no previous PCI/1 previous PCI procedure/2 previous procedures was documented in 29,928 (81%) of these patients. Otherwise, the data sets were not complete for peripheral arterial disease in 17.3% of patients and for LVEF in 23.6% of patients. All other parameters were missing in less than 3%.

Preoperative characteristics of the patients are presented in Table 1 . Significant differences were present between groups.

Tables 2 and 3 show the results for univariate and multivariate logistic regression analysis. Besides other parameters, a history of multiple prior PCIs was an independent predictor for in-hospital death and for MACE.

Adjusted ORs were also calculated in subgroups defined by (1) with or without previous MI, (2) emergency yes/no, (3) LVEF <50%/>50%, and (4) with or without COPD (Table 4 ). The subgroups of LVEF <30% and LVEF 30%–50% were merged, because there were too few events in the LVEF <30% subgroup to conduct a fully adjusted analysis. In the subgroups of patients with or without previous MI, with or without COPD, with normal left ventricular function (>50%), and in the subgroup of patients undergoing nonemergency surgery, 2 or more previous PCIs were significantly associated with in-hospital death and with MACE. In contrast, no association with either in-hospital death or MACE was observed in the subgroup of patients undergoing emergency surgery. In the subgroup of patients with reduced LVEF (50%), 2 or more previous PCI procedures were associated with in-hospital death but not with MACE (Table 4).

View this table: [in this window] [in a new window]   Table 4 Adjusted odds ratios for in-hospital death and MACEs in patients with CABG after 2 previous PCIs versus CABG without previous PCI from multiple logistic regression in subgroups

	Discussion

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Why do multiple prior PCI procedures lead to a worse outcome after subsequent CABG? PCI procedures initiate a sequence of inflammatory reactions,¹⁶ of poststenting endothelial dysfunction,¹⁷ of periprocedural myocardial injury,¹⁸ and of late poststenting structural changes.¹⁹ The late structural changes may affect not only the stented area itself but also the coronary artery section distal to the stent, which would be the target area of a subsequent bypass graft anastomosis.²⁰ In fact, in a coronary artery that is covered with stents, only distal sites remain for bypass graft anastomosis, which may not offer adequate runoff so that a bypass graft will have a poor prognosis.²¹ The assumption that CABG can safely be performed in patients with coronary stenting failure may not hold true and graft patency may be adversely affected by prior coronary stenting. Coronary side-branch obstruction or occlusion resulting from multiple and overlapping stents may lead to compromised collateral flow,²² inducing release of cardiac ischemic markers and causing focal infarctions. Release of cardiac troponin I after PCI has been reported for roughly 50% of patients with stents.²³ In these patients, the magnitude of irreversible myocardial injury represented, on average, 5% of total left ventricular mass.²⁴ A possible reduction in left ventricular function, associated herewith, could change the patient's risk profile, transferring him or her to a higher risk patient subgroup, which may, by itself, explain the higher mortality in CABG patients with a history of multiple previous PCI procedures. This effect, however, did not apply to our 1098 patients with 2 or more PCIs before CABG, whose preoperative left ventricular function was not different from that of the patients without prior PCI. Further investigation on the number of PCIs and subsequent loss of left ventricular function may clarify a possible correlation.

A history of multiple previous PCIs has now repeatedly been shown to be associated with reduced survival and increased MACE rate in CABG patients.^10,11 We therefore support critical reflection of the present referral policy, which was repeatedly suggested in the recent past.²⁵ However, from the current data we cannot exclude that, even after multiple prior PCIs, further stenting may be superior to CABG. For this high-risk patient subpopulation, further evidence from a prospective study is warranted. Among other aspects, inadequate perioperative inhibition of platelet aggregation may adversely influence the results. A discontinuation of clopidogrel has been described to be the major determinant of stent thrombosis within the first 6 months after stent implantation.²⁶

Limitations
The study has the widely known limitations of a retrospective and nonrandomized investigation. Even propensity analyses cannot account for selection bias related to unmeasured characteristics. Although most of the modern era PCI procedures are coronary stents in combination with balloon angioplasty, we cannot exclude that, in some cases, balloon angioplasty or other procedures such as coronary atherectomy were the only procedures performed. Because of data base limitations, we could report neither the vessel territories targeted with PCI nor the time intervals between PCI and CABG procedures. The primary and secondary end points of the present study were in-hospital mortality and in-hospital MACE. Again, the data bases did not allow us to report on perioperative neurologic complications and long-term outcomes. Furthermore, early mortality, better defined as 30-, 60-, or 90-day all-cause mortality,²⁷ could only be followed until discharge from the surgical department.

The specific value of the present study is its nature of a "real life" patient investigation. All first-time CABG patients, irrespective of comorbidities, were included in the study. Because of the multicenter orientation, the surgical strategies, perioperative anticoagulation therapy, and other factors were not uniform. This also applies to the use of aprotinin, which is suspected to be associated with increased complications in cardiac surgical patients.²⁸ On the other hand, the severe limitations of randomized studies comparing CABG and PCI were recently reported. Because of inclusion and exclusion criteria, only 5% of the total eligible patient population are generally included in such studies, omitting the sicker and more comorbid patients.²⁹

Another caveat of the present study is the rapid development of the state of the art treatment in both CABG and PCI. In CABG, the number of off-pump procedures and of total arterial revascularization increases. In PCI, new technology such as self-resorbing stents has lately been introduced into clinical practice.³⁰

	Conclusion

Top Abstract Introduction Methods Results Discussion Conclusion References

 
In this multicenter study, we observed a significantly higher in-hospital mortality and MACE rate in CABG patients with 2 or more prior PCIs compared with no prior PCIs. The mechanism is multifactorial and is possibly triggered by an inflammatory reaction, repetitive myocardial ischemia, and endothelial dysfunction. Single and multicenter studies investigating "real-life" patients have now generated strong evidence that multiple previous PCI procedures put patients at higher risk during subsequent CABG. A critical reflection of the revascularization strategy for this high-risk patient cohort is warranted.

	Footnotes

 
Drs Massoudy and Thielmann equally contributed to this work.

	References

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Personal Folders Download to citation manager Author home page(s): Parwis Massoudy Matthias Thielmann Georg Kleikamp Ariane Maleszka Reiner Körfer Arno Krian Emmeran Gams Hans Scheld Wolfgang Schiller Armin Welz Guido Dohmen Thorsten Wahlers Heinz Jakob Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Massoudy, P. Articles by Jakob, H. Search for Related Content PubMed PubMed Citation Articles by Massoudy, P. Articles by Jakob, H. Related Collections Coronary disease Related Article