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J Thorac Cardiovasc Surg 2002;123:517-524
© 2002 The American Association for Thoracic Surgery

Surgery for Acquired Cardiovascular Disease (ACD)

Effect of perioperative complications on excess mortality among women after coronary artery bypass: The Israeli Coronary Artery Bypass Graft study (ISCAB)

From the Department of Health Services Research, Ministry of Health,^a Jerusalem, the School of Public Health, Hebrew University and Hadassah Medical Organization,^b Jerusalem, and the Department of Epidemiology, Ben-Gurion University of the Negev,^c Beer-Sheva, Israel, and all the cardiac departments in Israel.^dThe ISCAB consortium^*The ISCAB Consortium: Azay Appelbaum, Nima Amit, Yaron Barel, Yitzhak Berlovitz, Dani Biteran, Amram Cohen, Elieser Kaplinsky, Jacob Lavee, Gideon Merin, Simcha Milo, Benjamin Mozes, Gideon Oretzki, Gideon Sahar, Arie Schachner, Aram Smolenski, Bernardo Vidne, and Vladimir Yakirevitch.

Source of funding: Ministry of Health, Israel.

Received for publication May 30, 2001; revisions requested July 31, 2001; revisions received Aug 16, 2001; accepted for publication Aug 30, 2001. Address for reprints: E. Simchen, MD, MPH, School of Public Health, Hadassah Medical Center, Ein Kerem, Jerusalem 91120, Israel (E-mail: sara.sachs{at}moh.health.gov.il).

	Abstract

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Background: Widely observed excess mortality among women after coronary artery bypass grafting is still largely unexplained, although case-mix factors have been identified. We evaluated the contribution of perioperative complications to the risk of 180-day mortality among women while adjusting for case-mix factors.
Methods: This is part of a prospective, 1-year nationwide Israeli coronary artery bypass graft study of 1029 female and 3806 male patients. Deaths within 180 days were independently ascertained. Case-mix risk strata were obtained from a pooled Cox survival model (including all subjects and study variables) by using the adjusted coefficients corresponding to the case-mix factors within the model. Sex-specific mortality associated with perioperative complications was evaluated within the strata. In addition, sex-specific Cox models were constructed.
Results: Higher mortality among women compared with that among men was significant within the pooled model (hazard ratio, 1.4; P = .038) and was evident early in the postoperative period. Women tended to cluster in the highest risk quartile compared with men (39.8% vs 20.9%, P < .001). However, although the incidence of perioperative complications was similar for the 2 sexes, the associated mortality for a given perioperative complication was higher among women. Sex-specific Cox models confirmed the above findings. For example, the hazard ratio for women with low postoperative hemoglobin was 6.9, whereas for men, the hazard ratio was 3.9.
Conclusions: The role of perioperative factors in the excess mortality among women after coronary artery bypass grafting shifts the focus of attention from the selection of women for the operation to the in-hospital experience. Improving the outcome for women will entail efforts to prevent complications in the perioperative period.

	Introduction

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Outcome studies in patients undergoing coronary artery bypass grafting (CABG) have shown consistently that women are at higher risk for postoperative mortality. ^1-11 Several factors associated with the excess mortality in women are discussed in the literature, suggesting a greater severity of illness before the operation. Higher prevalence of known risk factors, such as older age, ^1-9 diabetes mellitus, ^1-6 obesity, ^5-7 hypertension, ^5-8 renal dysfunction, ⁵ and advanced coronary artery disease, ^6,12 were found in women. Delayed referral of women for surgical intervention was also cited as a possible explanation for sex differences in mortality. ¹³ Smaller coronary vessels in women were thought to predispose them to technical difficulties during the operation, resulting in incomplete revascularization ¹⁴ and reduced use of arterial grafts. ^2,10 However, few reports have focused on sex differences in perioperative complications. Utley and colleagues ³ compared the incidence of postoperative complications without adjustment for case-mix factors.

The present study is part of a nationwide study of patients undergoing CABG in 1994, with complete follow-up of patients from admission to discharge and mortality up to 180 days after surgical intervention. The analysis attempts to evaluate the independent contribution of perioperative complications to mortality among women adjusting for on-admission risk.

	Methods

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This report is a part of the National Israeli CABG Study, which was carried out in all 14 cardiac surgery departments in Israel in 1994. All the patients undergoing isolated CABG during the period from January 1, 1994, to December 31, 1994, were included. The present report was based on 4835 patients (3806 men and 1029 women), representing 95% of the total target population. The 265 patients who had not completed the baseline interview because of staff vacations were excluded from the analysis. A detailed description of the study is given elsewhere. ¹⁵

In brief, information was collected prospectively by a team of specially trained nurses. The information included patient's demographic characteristics and health practices, which were obtained from a personal interview before the operation. The clinical history was obtained both from personal interview and medical records, and the severity of coronary disease was verified with catheterization reports. Information on the operative variables was extracted from the operation reports filled out by the surgeons. Information on the postoperative variables was obtained by means of daily follow-up of the patients until discharge or death, whichever was earlier. Data collection was standardized and supervised throughout the year. The study was monitored by a steering committee consisting of the heads of all cardiac surgery departments in the country.

Six-month mortality was chosen as the outcome of interest, assuming that within this time frame, death could be reasonably attributed to the surgical procedure.

Deaths were verified by linkage to the national death records, regardless of hospitalization status.

Survival patterns among men and women until the 180th postoperative day were evaluated by using the Kaplan-Meier estimate.

A pooled Cox model including both sexes and all study variables (case-mix factors and perioperative complications) was constructed in the usual manner to estimate the independent effect of perioperative factors on mortality. Similarly, 2 sex-specific models were developed. The models' performance was evaluated with the Harrel c statistics. ¹⁶

The pooled model was used for comparison with the sex-specific models and to form on-admission risk strata by using the partial score corresponding to the ß-coefficients of the case-mix factors within the model, excluding the sex variable. This partial score reflected the net effect of case-mix factors because they were already adjusted for the later complications. The sex-specific incidence and effect of perioperative factors were then evaluated within quartiles of risk. Finally, 2 sex-specific Cox models were constructed, including variables significant in either model.

	Results

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Of the 4835 CABG operations in Israel in 1994, only 1029 (21.3%) were performed in women. The mortality rate for the total population within 180 days after CABG was 5.1%, which is similar to that of other published reports. ^17,18 The corresponding mortality rates in women and men were 7.8% and 4.4%, respectively (relative risk, 1.8; P < .01). The Kaplan-Meier survival curves for women and men are presented inFigure 1, demonstrating that the divergence of the survival curve for women occurred early in the perioperative period. Later, the 2 survival curves run parallel.

View larger version (12K): [in this window] [in a new window]   Fig. 1. Observed 180-day survival after CABG: women versus men.

The relative effect of various factors on mortality within the sexes was strongly affected by the high mortality in the reference group among women. For example, although the absolute mortality rate in women with 3-vessel disease and left main involvement was 15.7% versus 7.4% in men, the relative risks for the 2 sex groups were similar (2.9 and 2.6, respectively) because of the high mortality rate in the reference group among women (Appendix 1).

A pooled multivariate Cox model was constructed to evaluate the independent effect of all study variables on 180-day mortality. Generally, it demonstrated stronger effects for perioperative complications compared with case-mix factors. The relative risk associated with female sex after controlling for all significant factors within the model was 1.35 (P = .038, Table 1).

View larger version (21K): [in this window] [in a new window]   Fig. 2. Mortality at 180 days for perioperative complications among women versus men in the highest quartile of on-admission risk.

	Discussion

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We examined the hypothesis that perioperative factors were especially important when attempting to explore sex differences in mortality because significant sex differences were found in the operative technique: incomplete revascularization in women ¹⁴ and diminished use of internal thoracic artery grafts, ² as well as differences in mortality related to the prevalent use of exclusive venous grafting in women. ¹⁰

Proposed explanations in the literature for sex differences in mortality after CABG usually center on a more severe patient profile among women. ⁷ It is assumed that residual variability in mortality after adjusting for case-mix is usually a result of patient care, but surgical technique is hard to quantify, and meaningful data on the operation and the postoperative period are hard to get. However, there is evidence from published reports that patient experience in the hospital is important. Duration of the operation, type of grafting used, reexploration for bleeding, intraoperative complications, inability to wean patients off respirators, need for inotropic drugs and blood transfusions, and development of wound infections have all been shown to be associated with mortality after CABG. ^19-23 In a previous report we suggested that not all complications during the operation and the perioperative period could be attributed to patient inherent risk at the time of the operation. ¹⁵ Furthermore, the sequential addition of the operative and postoperative factors to the case-mix characteristics suggested an independent effect of these factors on mortality.

Using detailed information on inherent patient characteristics at entry to the hospital and during the operation and the postoperative period enabled us to isolate the effect of perioperative factors while adjusting for patients' on-admission risk within a Cox model.

Our study confirmed previous reports demonstrating that risk factors are more prevalent in women than in men before the operation. ^1-11 However, in contrast to other studies, ³ we found no significant sex differences in the incidence of postoperative complications.

The main finding in the present study was that perioperative complications tended to be more lethal for women. For example, women with postoperative myocardial infarction had a 3-fold risk of dying relative to men with the same complication, and those with low postoperative hemoglobin or multiple transfusions had twice the probability of dying relative to men(Table 1). Although our study sample included 1029 women, it is possible that with a larger sample size some additional risk factors would have entered the female model.

The differential effect on mortality for perioperative factors was especially prominent among patients in the upper quartile of on-admission risk. Although the overall sex-specific crude 180-day mortality rates were relatively low (7.8% vs 4.4% for women and men, respectively), the rates associated with perioperative complications in the upper risk quartile were of a different order of magnitude, especially for women: with additional surgery, 63% mortality; with prolonged mechanical ventilation, 51%; with multiple transfusions, 48%; and with low hemoglobin, 40%(Figure 2). The fact that perioperative complications were less well tolerated by female patients may be due in part to the inherent risk of female patients undergoing an operation. However, the possibility that surgeons experienced more difficulties in managing complications in high-risk female patients should also be considered.

Recently, publications have shifted the attention concerning mortality among women undergoing CABG from a biased selection of female patients for surgical intervention to the actual surgical event. O'Connor and colleagues ²⁴ found that interventions by reviewing operative technique resulted in reducing mortality after CABG. Petro and coworkers ²⁵ reported encouraging results from minimally invasive procedures among women. However, although the standard CABG is a common procedure, our findings lend support to the continuing efforts to manage female patients with extra care to avoid perioperative complications.

	Appendix 1

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	References

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