Introduction
Randomized trials and observational studies have demonstrated survival benefits conferred by coronary-artery bypass grafting (CABG) [
1]. The intervention has been shown to improve long-term survival in stable symptomatic patients with left main coronary disease, triple-vessel disease, or two-vessel disease with significant stenosis of the proximal left anterior descending coronary artery [
2]. In practice, however, personal reasons, scheduling procedures, or surgical wait lists can delay CABG after decision to operate has been made [
3]. Hannan et al. argued that estimates of survival benefits conferred by CABG should account for the total number of deaths including deaths resulting from delays for required revascularization [
4]. We anticipate that such estimates can show the difference in the risk of death between patients who actually undergo required CABG and those who remain untreated after the decision to treat has been made. The purpose of this analysis was to compare survival after the treatment decision between patients who underwent CABG and those who remained untreated. We used observational data from a population-based registry of patients with established coronary artery disease for whom surgical revascularization was indicated and planned. That registry collects information about adverse events on wait lists during the pre-operative period. Therefore it allows us to compare prognosis for both alternatives: if CABG is performed or if the patient remains untreated. In our view, such estimates introduce a methodological innovation, whereby deaths among untreated patients are used to estimate the risk of death for the treated group if they had remained untreated.
Results
Access to surgery
Table
2 shows the baseline characteristics of the study cohort by access to surgery. Of the 8,220 patients registered for first-time isolated CABG, 7,316 (89.0 percent) underwent surgery, and 904 (11.0 percent) remained untreated because they died while awaiting CABG (80 or 1.0 percent), withdrew from treatment because they reconsidered the decision to undergo surgery, their condition deteriorated such that surgery was no longer possible or for other reasons
( 716 or 8.7 percent), or were lost to follow-up before the operation (108 or 1.3 percent). The median time from registration to surgery was 12 weeks (interquartile range, 6 to 23 weeks). Of patients in the semi-urgent group, 1,986 (31.4 percent) underwent elective CABG within the recommended time, 3,599 (56.8 percent) underwent elective CABG but after the recommended time, and 207 (3.3 percent) underwent the procedure via unplanned emergency admission. Among those in the non-urgent group, 538 (28.5 percent) underwent elective CABG within the recommended time, 927 (49.1 percent) underwent elective CABG but after the recommended time, and 59 (3.1 percent) underwent the procedure via unplanned emergency admission.
Survival after treatment decision
One in 10 patients died during the first five years after the treatment decision: 80 while awaiting surgery, 141 after withdrawal from surgical treatment, 97 post-operatively during the admission for CABG, and 551 after hospital discharge (Table
3). The mean follow-up time after the treatment decision was 4.3 (standard error 0.02) years in the semi-urgent group and 4.3 (0.03) years in the non-urgent group.
Table 3
Characteristics of patients in the study cohort by death after registration for CABG *(as number and percentages within each category for each characteristic)
Age | | | | |
< 50 yr | 5 (6.3) | 5 (3.5) | 2 (2.1) | 15 (2.7) |
50–59 yr | 17 (21.3) | 20 (14.2) | 17 (17.5) | 73 (13.2) |
60–69 yr | 29 (36.3) | 38 (27.0) | 35 (36.1) | 196 (35.6) |
70–79 yr | 28 (35.0) | 64 (45.4) | 41 (42.3) | 244 (44.3) |
≥ 80 yr | 1 (1.3) | 14 (9.9) | 2 (2.1) | 23 (4.2) |
Sex | | | | |
Female | 7 (8.8) | 35 (24.8) | 25 (25.8) | 95 (17.2) |
Male | 73 (91.3) | 106 (75.2) | 72 (74.2) | 456 (82.8) |
Urgency group | | | | |
Semi-urgent | 54 (67.5) | 98 (69.5) | 86 (88.7) | 456 (82.8) |
Non-urgent | 26 (32.5) | 43 (30.5) | 11 (11.3) | 95 (17.2) |
Comorbidity | | | | |
Major conditions§
| 26 (32.5) | 53 (37.6) | 32 (33.0) | 176 (31.9) |
Other conditions||
| 20 (25.0) | 36 (25.5) | 23 (23.7) | 130 (23.6) |
None | 34 (42.5) | 52 (36.9) | 42 (43.3) | 245 (44.5) |
Coronary anatomy | | | | |
Left main | 6 (7.5) | 13 (9.2) | 12 (12.4) | 75 (13.6) |
Multi-vessel¶
| 66 (82.5) | 112 (79.4) | 81 (83.5) | 447 (81.1) |
Limited** | 8 (10.0) | 16 (11.3) | 4 (4.1) | 29 (5.3) |
Period | | | | |
1991–1992 | 13 (16.3) | 22 (15.6) | 26 (26.8) | 145 (26.3) |
1993–1994 | 23 (28.8) | 27 (19.1) | 14 (14.4) | 114 (20.7) |
1995–1996 | 18 (22.5) | 39 (27.7) | 22 (22.7) | 131 (23.8) |
1997–1998 | 17 (21.3) | 33 (23.4) | 21 (21.6) | 113 (20.5) |
1999–2000 | 9 (11.3) | 20 (14.2) | 14 (14.4) | 48 (8.7) |
Hospital | | | | |
1 | 11 (13.8) | 46 (32.6) | 8 (8.2) | 108 (19.6) |
2 | 26 (32.5) | 38 (27.0) | 51 (52.6) | 188 (34.1) |
3 | 35 (43.8) | 43 (30.5) | 15 (15.5) | 121 (22.0) |
4 | 8 (10.0) | 14 (9.9) | 23 (23.7) | 134 (24.3) |
Surgical revascularization significantly reduced mortality in the study cohort. The observed mortality rate was 1.7 deaths per 1000 patient-months in the treated patients and 4.0 deaths per 1000 patient-months in the untreated patients. The mortality rate was 1.5 and 1.8 deaths per 1000 patient-months for early (within the recommended time) and late (longer than the recommended time) treatment, respectively.
Among those who underwent CABG, the hazard of death was 51 percent of that in the untreated group, the adjusted hazard ratio 0.51 (95 percent confidence interval, 0.43 to 0.61) (Table
4). The effect was stronger when CABG was performed within the recommended time: the adjusted hazard ratios were 0.43 (95 percent confidence interval, 0.35 to 0.53) and 0.58 (95 percent confidence interval, 0.48 to 0.70) for early and late treatment, respectively (Wald chi-square = 12.2, df = 1, P < 0.001). The effect sizes for early and late treatment and the difference between them remained unchanged when an additional variable for undergoing CABG through unplanned emergency admission was entered into the regression model. In all models listed in Table
4, patients in the semi-urgent group were at a higher hazard of death than those in the non-urgent group, the adjusted hazard ratio ranging from 1.25 (95 percent confidence interval, 1.04 to 1.50) to 1.27 (95 percent confidence interval, 1.05 to 1.53). The full model was consistent with the data (likelihood ratio test = 148.9, df = 10, P < 0.001).
Table 4
Hazard ratios (HRs) for death at any time after registration for CABG for treated patients relative to untreated patients and for patients who had surgery within target times relative to those who had surgery after target times
Model I, Treatment indicator | | |
Treated vs Untreated | 0.53 (0.45–0.63) | 0.51 (0.43–0.61) |
Model II, Treatment indicators by target time | | |
Early Surgery vs Untreated | 0.46 (0.38–0.57) | 0.43 (0.35–0.53)‡
|
Late Surgery vs Untreated | 0.59 (0.49–0.71) | 0.58 (0.48–0.70)‡
|
Model III, Treatment indicators by target time and admission type | | |
Early Surgery vs Untreated | 0.46 (0.37–0.57) | 0.42 (0.34–0.52)§
|
Late Surgery vs Untreated | 0.58 (0.48–0.71) | 0.58 (0.48–0.70)§
|
Unplanned Emergency vs Untreated | 0.59 (0.39–0.90) | 0.56 (0.37–0.86) |
The survival benefit differed between urgency groups. For semi-urgent patients the mortality rates in the treated and untreated groups (1.8 and 4.6 per 1000 patient-months) were higher than those for non-urgent patients (1.3 and 3.1 per 1000 patient-months). The rates were 1.6 and 1.9 deaths per 1000 patient-months in early and late treatment groups of semi-urgent patients, and 1.1 and 1.4 deaths per 1000 patient-months respectively of non-urgent patients.
Compared with untreated patients, the hazard of death for those who underwent CABG was 46 percent lower in the semi-urgent group and 55 percent lower in the non-urgent group, and the adjusted hazard ratios were 0.54 (95 percent confidence interval, 0.44 to 0.66) and 0.45 (95 percent confidence interval, 0.32 to 0.63), respectively (Table
5). In each group, patients waiting longer than the recommended time were less likely than those with a shorter delay to benefit from the treatment. However, when CABG was performed after the recommended time, the survival benefit appeared to be smaller in the semi-urgent than the non-urgent group (adjusted hazard ratios 0.61 [95 percent confidence interval, 0.49 to 0.76] and 0.51 [95 percent confidence interval, 0.35 to 0.74], respectively). Among patients in the non-urgent group, treatment delay resulting in unplanned emergency admission reduced the survival effect to a non-significant level (adjusted hazard ratio 0.73 [95 percent confidence interval, 0.33 to 1.63]). The regression models were consistent with the data in both the semi-urgent group (likelihood ratio test = 103.5, df = 9, P < 0.001) and the non-urgent group (likelihood ratio test = 53.8, df = 9, P < 0.001).
Table 5
Hazard Ratios for death at any time after registration for CABG for treated patients relative to untreated patients and for post-operative death for patients who had surgery within target times relative to those who had surgery after target times (figures in brackets are 95-percent confidence interval)
Overall survival, time-dependent treatment effect* | | |
No. of deaths/no. of patients | | |
Treated patients | 517/5,792 | 95/1,524 |
Untreated patients | 152/541 | 69/363 |
Model I, Treatment indicator | | |
Treated vs Untreated | | |
Unadjusted hazard ratio | 0.53 (0.43–0.65) | 0.42 (0.30–0.59) |
Adjusted hazard ratio | 0.54 (0.44–0.66) | 0.45 (0.32–0.63) |
Model II, Treatment by target time | | |
Early Surgery vs Untreated | | |
Unadjusted hazard ratio | 0.47 (0.37–0.59) | 0.35 (0.23–0.55) |
Adjusted hazard ratio | 0.45 (0.36–0.58) | 0.36 (0.23–0.56) |
Late Surgery vs Untreated | | |
Unadjusted hazard ratio | 0.58 (0.47–0.73) | 0.47 (0.32–0.68) |
Adjusted hazard ratio | 0.61 (0.49–0.76) | 0.51 (0.35–0.74) |
Model III, Treatment by target time and admission type | | |
Early Surgery vs Untreated | | |
Unadjusted hazard ratio | 0.47 (0.37–0.60) | 0.32 (0.20–0.51) |
Adjusted hazard ratio | 0.45 (0.36–0.58) | 0.33 (0.20–0.53) |
Late Surgery vs Untreated | | |
Unadjusted hazard ratio | 0.58 (0.46–0.73) | 0.46 (0.32–0.67) |
Adjusted hazard ratio | 0.61 (0.48–0.76) | 0.51 (0.35–0.74) |
Unplanned Emergency vs Untreated | | |
Unadjusted hazard ratio | 0.51 (0.31–0.84) | 0.80 (0.37–1.76) |
Adjusted hazard ratio | 0.52 (0.32–0.87) | 0.73 (0.33–1.63) |
Long-term post-operative survival†
| | |
No. of deaths/follow-up yrs | | |
Early Surgery | 153/8,409 | 31/2,121 |
Late Surgery | 303/13,883 | 64/3,648 |
Unadjusted hazard ratio | 0.85 (0.70–1.03) | 0.84 (0.55–1.29) |
Adjusted hazard ratio | 0.79 (0.65–0.96) | 0.86 (0.55–1.33) |
Long-term post-operative survival
Among the 7,316 patients who underwent CABG, 97 (1.3 percent) died post-operatively during the same hospital admission and 7,219 (98.7 percent) survived surgery. Of those who was discharged alive 551 (7.6 percent) died within five years. The observed death rate was 1.7 deaths per 100 patient-years for those who underwent surgery within the recommended time (184 deaths over 10,530 patient-years) and 2.1 deaths per 100 patient-years for those whose surgery was delayed (367 deaths over 17,531 patient-years). After adjustment, those who underwent CABG within the recommended time showed a 20 percent lower hazard of post-operative death than patients whose surgery was delayed (hazard ratio 0.80 [95 percent confidence interval, 0.67 to 0.95]).
Delays in treatment had a different effect in each group (Table
5). Among patients in the semi-urgent group (456 deaths over 22,292 patient-years), those who waited longer than the recommended time were less likely than those with a shorter delay to survive beyond five years. The observed rate of post-operative death was 1.8 deaths (95 percent confidence interval, 1.5 to 2.1) per 100 patient-years for those who underwent CABG within the recommended time and 2.2 deaths (95 percent confidence interval, 1.9 to 2.4) per 100 patient-years for those whose surgery was delayed. After adjustment, those who underwent CABG within the recommended time had a 21 percent lower hazard of late post-operative death than those with delayed surgeries (hazard ratio 0.79 [95 percent confidence interval, 0.65 to 0.96]). Among patients in the non-urgent group (95 deaths over 5,769 patient-years), the observed death rate was 1.5 deaths (95 percent confidence interval, 0.9 to 2.0) per 100 patient-years in those who underwent CABG during the recommended time and 1.8 deaths (95 percent confidence interval, 1.3 to 2.2) per 100 patient-years in those whose surgery was delayed. After adjustment, the effect of early surgery was not significant (hazard ratio 0.86 [95 percent confidence interval, 0.55 to 1.33]).
Discussion
In this cohort of 8,220 patients with angiographically-proven coronary artery disease and planned surgical revascularization, we compared survival between patients who underwent CABG and those who remained untreated after the decision to treat was made. We found that the hazard of death among patients who underwent CABG was 51 percent of that in the untreated group (adjusted hazard ratio 0.51 [95 percent confidence interval, 0.43 to 0.61]). The effect was stronger when patients underwent surgery shortly after the treatment decision (adjusted hazard ratios 0.43 [95 percent confidence interval, 0.35 to 0.53] and 0.58 [95 percent confidence interval, 0.48 to 0.70] for early and late intervention, respectively). Relative to untreated patients, the hazard of death for those who underwent CABG was 46 percent lower in the semi-urgent group and 55 percent lower in the non-urgent group (adjusted hazard ratios 0.54 [95 percent confidence interval, 0.44 to 0.66] and 0.45 [95 percent confidence interval, 0.32 to 0.63], respectively).
CABG is indicated to alleviate symptoms and to reduce the risk of death among patients who have limiting angina that persists despite optimal medical treatment and suitable coronary anatomy [
1]. To fully evaluate the survival benefit of CABG, the hazard of death for patients who have undergone CABG should be compared with the hazard of death for those who have not undergone the procedure, considering the intervention as an intermediate event in the course of disease. Because the group membership (treated vs. untreated) cannot be defined at the beginning of follow-up, we accomplished this by using the Cox regression with a time-dependent indicator variable for CABG occurrences during the follow-up period after registration for the treatment. The hazard ratio for that variable gives the estimated survival benefit, which a patient for whom surgical revascularization is indicated can interpret as the reduction in the risk of death offered by undergoing CABG relative to remaining untreated. Contrasting post-operative and pre-operative mortality had two premises. The first was that excluding pre-operative deaths and losses to follow-up relating to a longer wait for treatment would imply that survival time begins at the time of the procedure, rather than at the time of the decision to treat [
3]. The second was that measuring mortality reduction afforded by undergoing CABG requires an allowance for the possibility that the patient undergoes treatment and dies anyway.
In observational studies, death before CABG has been reported to occur in 0.4 to 1.3 percent of patients for whom it was felt that surgery could be safely delayed [
16‐
18]. Expressed in terms of group phenomena [
19], these percentages may be less relevant to the patient who is more concerned with the fact that treatment delay may result in otherwise avoidable deaths. The analysis presented in our paper, which concludes that undergoing CABG rather than remaining untreated will reduce the risk of death by half, is more relevant to patients because it compares the 5-year prognosis for both alternatives: if CABG is performed or if the patient remains untreated.
A meta-analysis of trials comparing CABG and medical therapy showed that five-year mortality was 39 percent lower among patients who underwent CABG [
2], which is similar to our findings for the semi-urgent group. The more profound effect in the non-urgent group was due to a 25 percent higher mortality rate for the semi-urgent group independent of the intervention. However, the fact that we considered all deaths among patients who had never undergone CABG, including patients who became not healthy enough to withstand the procedure or who reconsidered the surgery for other reasons, might have affected our estimates.
Our study was observational and therefore required risk adjustment for potential differences between treated and untreated patients. The existing literature suggests that elderly patients are more likely to undergo revascularization as an urgent procedure [
20], that a smaller coronary vessel diameter may account for the higher risk of adverse cardiovascular events among women [
21], that co-existing medical conditions may delay open heart surgery [
22], that post-operative survival depends on institutional constraints and individual care providers [
3], and that changes in practice or supplementary funds may reduce time until surgery [
9]. All of these factors were entered into multivariate regressions in our study. Still, we were unable to adjust for upgrades in urgency during the pre-operative period. Because increasing urgency reduced the time to surgery, those who underwent CABG after an urgency upgrade might have been more ill, which might have resulted in a downward bias in the survival effect. On the other hand, several studies have shown that, when compared with medical charts, comorbid conditions are underreported in administrative databases among persons discharged after cardiovascular procedures [
7,
23,
24]. Thus delayed surgery may be attributable to other unmeasured factors, which might have resulted in a upward bias in the survival effect for those unfit the operation. The quality of information about decision and withdrawal dates is a concern in this analysis. Although we considered the date of the booking request as the date of the decision for surgery, no audit was conducted to verify the accuracy of the coding dates in the BCCR records. Also, because we used only the British Columbia Linked Health Database Deaths File, we did not have information about patients who died or underwent CABG in other provinces.
This study has provided estimates of mortality reduction afforded by surgical revascularization, taking account of patients who died before they could undergo a required CABG. In particular, we found a significant survival benefit for patients registered to undergo coronary revascularization on the non-urgent basis. The survival benefit of CABG was greater when patients underwent the operation within the recommended time, suggesting that some of the benefit was lost by the delay beyond the recommended time.
Acknowledgements
This research was supported by the Canada Research Chairs Program (BS), the Canada Foundation for Innovation (BS, AL), the Michael Smith Foundation for Health Research (AL, MF), the Vancouver Coastal Health Research Institute (BS, LK, MF), and the St. Paul's Hospital Foundation (AL). BCCR is operated by the Provincial Health Services Authority. None of the sponsors had a role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the paper for publication. We are indebted to nurses, cardiac surgeons and cardiologists in the participating hospitals for their efforts to ensure the completeness and accuracy of the registry data. We gratefully acknowledge the support from the following members of the Surgical Research Committee: James Abel, Richard Brownlee, Larry Burr, Anson Cheung, James Dutton, Virginia Gudas, Eric Jamieson, Michael Janusz, Shahzad Karim, Tim Latham, Jacques LeBlanc, Sam Lichtenstein, Hilton Ling, John Ofiesh, Michael Perchinsky, Peter Skarsgard and Frank Tyers; and the able assistance of Peggy Robinson in preparing the manuscript.
Authors' contributions
BS conceived the study concept and design, participated in analysis and interpretation, and drafted the manuscript. GF participated in data acquisition and critically revised the manuscript. RH participated in data acquisition. LK performed statistical analysis and drafted the manuscript. AL participated in data acquisition. MF critically revised the manuscript and has been involved in drafting the manuscript. All authors read and approved the final manuscript.