Clinical and angiographic outcomes in patients with previous coronary artery bypass graft surgery treated with primary balloon angioplasty for acute myocardial infarction

The PAMI-2 trial

As previously described (8,9), 1,100 consecutive patients with AMI <12 h in duration who were not treated with antecedent thrombolytic therapy were enrolled into the prospective, randomized PAMI-2 trial and underwent primary PTCA with a mechanical reperfusion strategy. Study criteria were deliberately nonrestrictive, allowing entry of patients of any age, with any electrocardiographic pattern of AMI. Major exclusion criteria consisted of cardiogenic shock, absolute contraindications to aspirin or heparin, previous use of thrombolytic therapy during the same hospital period and refusal or inability to provide written, informed consent. After arteriography and left ventriculography, PTCA was performed, if appropriate, using standard equipment and techniques (8–10). However, per protocol, PTCA was deferred in selected patients for either medical therapy or bypass surgery, on the basis of anatomic and clinical considerations (8–10).

Patients were also risk stratified after PTCA into high and low risk groups, as previously described (5,6). High risk patients were subrandomized to standard care versus a 36- to 48-h course of intraaortic balloon counterpulsation (8), and low risk patients were subrandomized to standard care versus an accelerated hospital discharge strategy (10). As reported, the primary clinical end points of death, reinfarction, infarct-related artery reocclusion or postadmission new-onset congestive heart failure or sustained hypotension were not affected by the randomization strategies (8,9), permitting analysis of the combined study group. Of the 1,100 enrolled patients, 192 (17%) were ineligible for randomization and were followed in a parallel registry. The study cohort of the present analysis includes all 1,100 enrolled patients (randomized plus registry).

Definitions

“Reinfarction” was defined as recurrent clinical symptoms in association with any increase in creatine kinase, MB fraction (CK-MB) above its previous nadir. “Recurrent ischemia” was defined as clinical symptoms associated with either new electrocardiographic ST segment or T wave changes, hypotension, new murmur, CK-MB elevation or necessity for urgent repeat PTCA or CABG. “Target vessel revascularization” (TVR) was defined as the performance of CABG or a repeat percutaneous intervention of the infarct-related vessel after the index procedure.

Data collection and statistical analysis

Clinical data were collected prospectively and independently verified at each site by study monitors. Follow-up was performed by physician office visits and study nurse interviews. All adverse events were adjudicated at the data coordinating center after review of original source documentation. Independent core laboratory angiographic analysis was performed by a technician who had no knowledge of the randomization scheme. Diameter stenosis was determined by electronic calipers and TIMI flow grades by visual assessment (11). Flow grade 3 (TIMI) was defined as complete filling of the distal vessel by the third cardiac cycle. Global left ventricular ejection fraction was calculated by the area–length method (12).

Categoric variables were compared by using chi-square analysis or the Fisher exact test. Continuous variables are presented as the mean value ± SD and were compared by using the Student ttest or Mann-Whitney Utest. All p values are two-tailed. The independent correlates of in-hospital events were examined using forward, stepwise logistic regression analysis. Follow-up clinical events were analyzed with actuarial methods, and Kaplan-Meier curves were constructed. The influence of baseline demographic and angiographic variables on late clinical events during the follow-up period was evaluated with the log-rank test. Cox proportional hazard regression was then used to determine the independent predictors of late adverse events.

Baseline features

Of 1,100 patients with AMI, 58 (5.3%) had previous CABG. Compared with patients without previous CABG, patients with previous CABG were older, more frequently had hyperlipidemia, previous myocardial infarction and triple-vessel disease and were less likely to be current cigarette smokers (Table 1). Other baseline clinical and angiographic characteristics were similar between the two groups.

Cardiac catheterization and primary PTCA

Of the 58 patients with previous CABG, the infarct-related vessel was a bypass graft conduit in 32 (55%) (including 31 saphenous vein grafts and one left internal mammary artery) and a native coronary artery in 26 (45%). The early cardiac catheterization laboratory findings and results appear in Tables 2 and 3. ⇓Coronary angioplasty was performed in 89% of patients with a native coronary artery infarct-related vessel and in only 72% of patients in whom the infarct vessel was a bypass graft (p = 0.001). Coronary angioplasty was not attempted in nine patients in whom a saphenous vein graft was the infarct vessel, because of unfavorable anatomy (n = 7: three treated with intragraft urokinase, two treated conservatively and two referred for nonemergent repeat surgery) or spontaneous reperfusion with TIMI flow grade 3 (n = 2, treated medically). Compared with primary PTCA of native coronary arteries, PTCA of bypass graft infarct vessels resulted in significantly lower rates of TIMI flow grade 3 with greater postprocedural thrombus noted (Table 3). Considering all patients, including those achieving patency by either primary PTCA, emergent CABG or spontaneous reperfusion, TIMI flow grade 3 was restored in 70.8% of bypass graft conduits versus 93.2% of native coronary vessels (p < 0.0001) and in 81.8% of patients with previous CABG versus 93.1% of those without previous CABG (p = 0.005).

In-hospital outcomes

As seen in Table 4, patients with previous CABG undergoing a primary PTCA strategy had significantly greater in-hospital mortality than did patients without previous CABG, especially if the infarct-related vessel was a bypass conduit. However, by logistic regression analysis of 18 baseline clinical and angiographic variables, only advanced age (p = 0.004), triple-vessel disease (p = 0.004) and Killip class ≥2 (p = 0.02) were independent predictors of in-hospital mortality; infarct vessel type (bypass graft vs. native artery) was not independently related to mortality (odds ratio 1.4 [95% confidence interval 0.6 to 4.8], p = 0.44). Other than mortality, major adverse in-hospital events occurred with similar frequency in the two groups (Table 4), except for a greater frequency of congestive heart failure in patients with bypass graft occlusion.

Considering only those 58 patients with previous CABG, TIMI flow grade 3 was restored in 70.2% of patients with vein graft occlusion versus 95% of patients with native vessel disease (p = 0.03), which was associated with a trend toward increased in-hospital mortality (9.4% vs. 3.8%, p = NS).

Late clinical events

Of 1,069 patients surviving the initial hospital period, late follow-up was available in 1,030 (96.4%) at a mean time of 8.4 ± 4.8 months. As seen in Figures 1 and 2, cumulative late survival ⇓⇓(including in-hospital events) was significantly reduced after primary PTCA for AMI in patients with previous CABG, especially if the infarct-related vessel was a bypass graft. By Cox regression analysis, the independent predictors of cumulative late mortality were advanced age (p < 0.0001), triple-vessel disease (p = 0.005) and Killip class ≥2 (p = 0.04); infarct vessel type (bypass graft vs. native artery) was not independently related to mortality (odds ratio 1.3 [95% confidence interval 0.5 to 6.2], p = 0.49). When the model was run for only those patients undergoing primary PTCA, establishment of TIMI flow grade 3 was also predictive of late survival (p < 0.05).

• Download figure
• Open in new tab
• Download powerpoint

Figure 1

Survival curves (Kaplan-Meier estimates) for 1,100 patients with AMI treated with primary PTCA, stratified by whether or not the patient had undergone CABG before the index hospital admission. Event rates are cumulative (including in-hospital and postdischarge outcomes). Bold linesrepresent patients with previous CABG; standard linesrepresent patients without previous CABG. reMI = repeat myocardial infarction.

• Download figure
• Open in new tab
• Download powerpoint

Figure 2

Survival curves, stratified by whether or not the infarct-related vessel was a bypass graft conduit or native coronary artery. Event rates are cumulative (including in-hospital and postdischarge outcomes). Bold linesrepresent bypass graft infarct vessels; standard linesrepresent native coronary artery infarct vessels. reMI = repeat myocardial infarction.

Acute myocardial infarction in patients with previous CABG

In the present trial, 58 (5.3%) of 1,100 patients with AMI had previously undergone CABG, similar to the 5% to 15% incidence found in previous series (3,13,14). Patients with previous CABG and AMI represent a high risk subset, with greater mortality, as compared with patients without previous CABG (15–17). Patients with previous CABG, however, have been excluded from many previous thrombolytic trials because of a perceived lack of efficacy (2,17,18). In the Global Utilization of Streptokinase and TPA for Occluded Arteries (GUSTO-I) angiographic substudy, 48 patients (2.5%) had saphenous vein graft occlusion (19). Flow grade 2 or 3 (TIMI) was established in 48% of patients with vein graft AMI (including only 34% with TIMI flow grade 3), versus 69% of patients with native coronary occlusion (p < 0.01). Saphenous vein graft occlusion was an independent determinant of thrombolytic failure (19). Similarly, thrombolytic therapy resulted in TIMI flow grade 2 or 3 in only 47% of patients with previous CABG, versus 65% of patients without previous CABG in the Duke University experience. Thus, reperfusion rates of occluded saphenous vein grafts after thrombolytic therapy are lower than those rates in native vessels, and mortality has remained high (3).

Primary PTCA in patients with previous CABG

Before the PAMI-2 trial, scant data existed to judge the efficacy of primary PTCA in patients with previous CABG. With 58 patients with previous CABG undergoing a primary PTCA strategy, PAMI-2 represents the largest multicenter study to date in which the utility of this therapy can be evaluated in this important subset, and it is the only study to employ an independent angiographic core laboratory. Similar to thrombolytic therapy, PTCA success in PAMI-2 was also found to be notably lower in patients in whom the infarct-related vessel was a bypass graft rather than a native coronary artery. At least two reasons underlie this finding. First, given the frequent presence of unfavorable anatomy and extensive thrombus burden, PTCA was only attempted in 72% of patients with a bypass graft infarct vessel, as compared with 89% of patients with native coronary artery occlusions (p = 0.001). Second, when PTCA was attempted, TIMI flow grade 3 was restored in only 70% of bypass grafts, as compared with 94% of native coronary arteries (p < 0.0001), which may be related to extensive thrombus and atherosclerosis burden with limited runoff, graft ectasia and increased rates of distal embolization (3). Local infusion of urokinase was also more likely to be used with vein graft disease as compared with native coronary artery occlusion, either for primary reperfusion or as an adjunct to angioplasty, although its utility in this setting is speculative (20). In the only other published experience of primary PTCA in >15 patients with previous CABG, O’Keefe et al. (13)reported an 86% rate of TIMI flow grade 2 or 3 in patients with previous CABG, as compared with 94% in native coronary artery occlusion (p < 0.0001).

Clinical outcomes after primary PTCA in patients with previous CABG

In the present study, patients with previous CABG undergoing primary PTCA had significantly greater in-hospital and late mortality than did patients without previous CABG, consistent with earlier studies (14–16). In these studies, the increased mortality in patients with previous CABG and AMI was noted, despite the fact that infarct size tended to be smaller, an observation attributed to the more frequent presence of high risk features such as multivessel disease and previous myocardial infarction in patients with previous CABG (3,14–16). In PAMI-2, multivariate analysis of 1,100 patients with AMI identified three major factors independently related to short-term and late mortality: advanced age, triple-vessel disease and Killip class ≥2 on hospital admission, features that were more frequently present in patients with previous CABG. Patients with previous CABG were also much more likely to have had a myocardial infarction before, contributing to the propensity for congestive heart failure. Thus, much of the poor prognosis in patients with previous CABG may be explained by the coexistence of adverse high risk characteristics, although the relatively low TIMI flow grade 3 rates achieved after primary PTCA, when the infarct-related vessel is a bypass graft, is contributory (21).

In contrast to mortality, the overall rates of death, reinfarction and TVR at a mean 8.0 months of follow-up were nearly identical between patients with and those without previous CABG after primary PTCA, with the excess mortality in patients with bypass graft infarction counterbalanced by a trend toward less late TVR.

No randomized trial has directly compared the outcomes of primary PTCA and thrombolytic therapy in patients with previous CABG. In the PAMI-1 trial (22), PTCA was successful in five of five patients with previous CABG, none of whom developed recurrent ischemia or reinfarction or died. In contrast, three (42%) of seven patients treated with tissue-type plasminogen activator (t-PA) had recurrent ischemia in the study (p = 0.09 vs. PTCA), two of whom died or developed reinfarction (23).

Study limitations

The major limitation of this study is that newer treatment modalities, including glycoprotein IIb/IIIa inhibitors and coronary stents, were not used in PAMI-2. However, there is no present evidence that glycoprotein IIb/IIIa antagonists improve TIMI flow or reduce mortality in patients with AMI undergoing primary PTCA (24), and recent studies suggest they are relatively ineffective in saphenous vein graft intervention (25). Compared with PTCA, stent implantation may improve long-term graft patency (26). However, in the recently completed PAMI stent randomized trial, although coronary stents, as compared with balloon angioplasty, reduced late restenosis in native vessel AMI, early stent implantation resulted in lower TIMI flow grade 3 rates, with concordant trends toward increased early and late mortality (27), an effect that may be exacerbated in heavily diseased saphenous vein grafts. Future studies will therefore be required to determine whether stents or glycoprotein IIb/IIIa inhibitors, or both, can indeed improve on the benchmark results of balloon angioplasty in patients with previous CABG and AMI, as reported in this study.

Although this report is the largest multicenter experience with primary PTCA in patients with previous CABG to date, the relatively modest sample size of patients with previous CABG and saphenous vein graft occlusion constitutes a second limitation. Nonetheless, the event rates were sufficiently high in these patients so that the point estimates for TIMI flow and mortality were statistically significant and highly different from those of patients without previous CABG and native coronary occlusion. The present analysis may have limited power, however, to detect other secondary end point differences between the groups, as well as any possible benefits of intraaortic balloon counterpulsation in patients with vein graft occlusion.

Clinical implications

Patients with previous CABG and AMI remain at high risk for early and late mortality, despite the contemporary practice of primary PTCA, in large part because of their late age at presentation, the presence of diffuse coronary artery disease and left ventricular dysfunction. Although the 71% TIMI grade 3 flow rate found in the present trial with the early catheterization approach (achieving reperfusion by primary PTCA, operation or with conservative medical care) is approximately double that reported for accelerated t-PA (19), it is strikingly lower than the ≥90% TIMI grade 3 flow rates achieved with primary PTCA of native coronary arteries (27). Thus, although the present study supports withholding thrombolysis for the preferential triage of patients with previous CABG to early cardiac catheterization, followed by primary PTCA when appropriate, more effective strategies are required for acute saphenous vein graft occlusion. Favorable results of pilot studies in small numbers of patients with AMI and vein graft occlusion treated with either extraction atherectomy (Transluminal Extraction Catheter, InterVentional Technologies, Inc., San Diego, California) or rheolytic thrombectomy (Angiojet, Possis Medical, Inc., Minneapolis, Minnesota) suggest that mechanical thrombolysis may have a role before definitive angioplasty (28–30). Randomized trials will be required to establish the clinical utility of these approaches, as well as stents, distal protection devices and adjunctive pharmacologic agents, in patients with vein graft occlusion undergoing mechanical reperfusion therapy for AMI.