Angiographically Documented Late Reocclusion After Successful Coronary Angioplasty of an Infarct-Related Lesion Is a Powerful Predictor of Long-Term Mortality
Background—Late reocclusion of an infarct-related artery (IRA) that was patent in the early days after acute myocardial infarction (MI) is a frequent event; the reocclusion rate may be as high as 30%. Few studies have been designed to analyze the impact of late reocclusion of the IRA on late survival.
Methods and Results—We studied 528 patients who all had a patent IRA after a successful PTCA procedure 10±6 days after MI and who underwent systematic 6-month angiographic follow-up to assess late patency of the IRA. We compared long-term survival of patients with and without late reocclusion. Based on the results of 6-month follow-up angiography, 2 groups of patients were defined: (1) 90 patients (17%) with reocclusion (Thrombolysis In Myocardial Infarction [TIMI] flow 0 or 1) and (2) 438 patients (83%) without reocclusion. Long-term clinical follow-up was obtained for all 528 patients at a median of 5.7 years after follow-up angiography (6.4 years after PTCA). The overall actuarial 8-year total mortality rate was 13%. At the end of follow-up, there were 35 deaths (8%) among the 438 patients without reocclusion and 18 deaths (20%) among the 90 patients with reocclusion (P=0.002). The actuarial 8-year total mortality rate was 10% in patients without reocclusion and 28% in patients with reocclusion (P=0.0003). The actuarial cardiovascular mortality rate was 7% in patients without reocclusion and 25% in patients with reocclusion (P<0.0001). The impact of reocclusion on long-term mortality was greater in patients with anterior MI.
Conclusions—Late IRA patency is strongly associated with long-term survival after MI. These observations should encourage prospective studies to evaluate the impact of strategies designed to prevent late reocclusion in postinfarction patients.
It is well established that early myocardial reperfusion leads to better short- and long-term survival in patients with acute myocardial infarction (MI).1 2 Although this is explained in part by a beneficial effect on left ventricular function, some experimental and clinical studies suggest that reestablishing patency of the infarct-related artery (IRA) may have beneficial effects that are independent of myocardial salvage.3 4 5 6 7 Possible mechanisms include reduction of ventricular remodeling, improvement in electrical stability, and provision of collaterals in the event of occlusion of a contralateral coronary artery.3 4 8 9
Patency of the IRA, however, is a dynamic process. Angiographic studies have demonstrated frequent reocclusion of patent IRAs. Reocclusion of an initially patent IRA may occur in the initial hours, days, weeks, or months after acute MI. Three months after successful thrombolytic therapy, the reocclusion rate may be as high as 30%.10 11 High reocclusion rates have also been documented 6 months after PTCA of an IRA.12 13
Few studies have been designed to analyze the impact of late reocclusion of the IRA on long-term prognosis. We studied 528 patients who all had a patent IRA after a successful PTCA procedure 10±6 days after MI and who underwent systematic 6-month angiographic follow-up to assess late patency of the IRA. We compared the long-term survival of patients who had a patent IRA at follow-up angiography with that of patients in whom the IRA was occluded at 6-month angiography.
From the records of our catheterization laboratory, we identified 677 consecutive patients who, between January 1988 and December 1992, underwent delayed PTCA at the infarct-related lesion after an MI treated with thrombolytic therapy. PTCA was successful in 625 patients (92%). During the time period of this study, the strategy in our institution for patients undergoing coronary angiography after thrombolysis for MI was to perform immediate angioplasty of the infarct-related lesion, provided that the diameter stenosis was >50% and that the overall anatomy of the coronary vessels did not preclude angioplasty, eg, left main disease and lesions judged nonamenable for angioplasty at the discretion of the operator. Patients who had PTCA within 3 days of MI or who had stent implantation were excluded.
PTCA was performed as previously described.14 15 The procedure was considered successful when the residual luminal narrowing immediately after PTCA was <50% and when no major complication (ECG or enzymatic evidence of MI, the need for bypass surgery during hospitalization, or in-hospital death) occurred.
Six-Month Angiographic Follow-Up
During the study period, we routinely attempted to obtain a follow-up angiogram 6 months after successful PTCA, regardless of symptomatic status; angiography was performed earlier if there was a clinical indication.
Patency of the IRA was graded according to the Thrombolysis In Myocardial Infarction (TIMI) Study Group classification.16 An occluded IRA was defined as the presence of TIMI 0 or 1 flow. The myocardial score was defined as the amount of myocardium supplied by the IRA on a scale of 0 to 15.17
Ventricular function was evaluated on single-plane left ventricular angiograms obtained before PTCA and at follow-up.18 The ventriculogram was performed in a 30° right anterior oblique projection.
Long-term clinical follow-up, beginning at the time of hospital discharge, was accomplished through a questionnaire completed by the patient, a telephone interview, or a chart review. Municipal registries and telephone contact with relatives or with the referring doctor enabled us to complete missing information.
The present study focuses on the effect of IRA patency on total or all-cause mortality and cardiovascular mortality.
Data are presented as mean±SD. Comparisons between groups for continuous data were made with paired or unpaired Student t tests. Differences between proportions were assessed by χ2 analysis. Late survival was estimated with the Kaplan-Meier method; differences were tested with a log rank test. Multivariate analysis was performed with SAS software (version 6.10; SAS Institute). A logistic regression analysis was used to determine the variables that were independently associated with long-term mortality. These variables were entered into a Cox proportional hazards model to calculate the hazard ratios for death for closed compared with open arteries. Values of P<0.05 were considered significant.
Patient Characteristics and Follow-Up
Of the 625 patients with successful PTCA, 10 had died at 6 months and 2 underwent coronary artery bypass surgery. Of the remaining 613 patients, 528 (86%) underwent repeat angiography at a mean of 6.4±1.6 months after PTCA. Eighty-three patients declined angiography; 2 were lost to follow-up. There were no differences in baseline characteristics of patients who were and who were not restudied (data not shown).
On the basis of the results of the 6-month follow-up angiography, 2 groups of patients were defined: (1) 90 (17%) with reocclusion of the IRA and (2) 438 (83%) without reocclusion of the IRA. Most of the patients (61%) with reocclusion were asymptomatic between PTCA and 6-month angiographic follow-up; 27% had stable angina; 9% had unstable angina; and 3% had a recurrent MI. Table 1⇓ compares the baseline characteristics of patients with and without reocclusion; the sole factor associated with reocclusion was a low TIMI grade before PTCA.
At the time of the 6-month follow-up, repeat revascularization was performed in 182 (34%) of the 528 patients. In patients with multivessel disease, repeat revascularization was performed in a similar proportion in patients with reocclusion versus no reocclusion (38% and 42%, respectively; P=0.71). By contrast, in patients with single-vessel disease, repeat revascularization was less frequently performed in patients with reocclusion versus no reocclusion (16% and 34%, respectively; P=0.003). Among the 90 patients with late reocclusion, 14 (16%) had repeat revascularization of the IRA at the time of angiographic follow-up.
Changes in Left Ventricular Function
Table 2⇓ shows the relationship between left ventricular function and IRA patency at 6-month follow-up. A small but significant improvement in ejection fraction was observed in patients without reocclusion; patients with reocclusion had no change in ejection fraction. End-diastolic volumes before PTCA and at follow-up did not differ significantly between the 2 groups. Reocclusion at follow-up had a similar deleterious effect on ejection fraction in patients with patent IRA before PTCA versus patients with occluded IRA before PTCA (data not shown).
Long-Term Clinical Follow-Up
Long-term clinical follow-up was obtained for all 528 patients at a median of 5.7 years after follow-up angiography (6.4 years after PTCA). Fifty-three patients (10%) died during the follow-up period; this rate was similar to that of the 83 patients who declined follow-up angiography (6 deaths; 7%). Figure 1⇓ shows the Kaplan-Meier survival curves as a function of late vessel patency. At the end of follow-up, there were 35 deaths (8%) among the 438 patients without reocclusion and 18 deaths (20%) among the 90 patients with reocclusion (P=0.002). Actuarial 8-year total mortality rates were 10% and 28%, respectively (P=0.0003). Actuarial cardiovascular mortality rates were 7% in patients without reocclusion and 25% in patients with reocclusion (P<0.0001). Among the 14 patients with late reocclusion who had repeat revascularization of the IRA at the time of angiographic follow-up, 12 (86%) underwent repeat angiographic follow-up 6 months later: 9 had a patent IRA, and 3 had recurrent reocclusion. At long-term clinical follow-up, 1 patient had died among the 3 patients with recurrent reocclusion; no patient died among the 9 patients with patent IRAs.
Univariate predictors of long-term mortality are listed in Table 3⇓. By logistic regression, 2 variables were independently associated with total mortality: a low ejection fraction at angiographic follow-up (P=0.02) and reocclusion (P=0.01). Three variables were independently associated with cardiovascular mortality: previous MI (P=0.04), low ejection fraction at angiographic follow-up (P=0.01), and reocclusion (P=0.003). When other covariates were controlled for by the Cox model, the hazard ratios for death for reocclusion versus no reocclusion were 2.01 (95% CI, 1.16 to 3.75) for total mortality and 2.78 (95% CI, 1.40 to 5.55) for cardiovascular mortality.
The correlation between reocclusion and mortality was studied in the following patient subgroups: (1) MI location (anterior versus nonanterior); (2) baseline ejection fraction (<50% versus >50%); (3) IRA myocardial score (<5 versus >5); and (4) IRA patency before PTCA (occluded versus patent) (Tables 4⇓ and 5⇓). The impact of reocclusion on long-term mortality was greater in patients with anterior MI. Figure 2⇓ shows the Kaplan-Meier survival curves as a function of late vessel patency in patients with anterior versus nonanterior MI. Figure 3⇓ shows the Kaplan-Meier survival curves as a function of late vessel patency in patients with occluded IRA before PTCA versus patent IRA before PTCA; the impact of reocclusion on total or cardiovascular mortality was similar in the 2 groups of patients.
The major finding of the present study was that reocclusion of an IRA that had been successfully dilated early after an MI was strongly associated with long-term mortality.
Late Reocclusion of the IRA
In the present study, the 6-month reocclusion rate of IRAs that were patent after a successful PTCA procedure 10±6 days after MI was 17%. This rate does not differ significantly from those previously reported in similar study populations (13% and 14%).12 19 High reocclusion rates have also been documented in IRAs reopened by thrombolysis and not treated by PTCA. In the APRICOT study (AsPiRIn vs COumadin Trial),10 248 patients with a patent IRA within 48 hours after thrombolysis underwent angiographic follow-up at 3-months; late reocclusion occurred in 29% of patients. In a study by White et al,11 154 patients with a patent IRA 4 weeks after MI underwent angiographic follow-up at 1 year; late reocclusion occurred in 25% of patients. Similarly, after primary PTCA for acute MI, a 13% 6-month reocclusion rate has been reported.13 Late reocclusion is thus a frequent event in patients with an initially open IRA irrespective of the technique used to achieve initial patency.
As previously shown,12 20 the majority of late reocclusions are clinically silent; systematic angiographic follow-up is thus needed to assess late vessel patency. In the present study, 86% of eligible patients underwent 6-month angiographic follow-up, irrespective of recurrent symptoms; thus, our results reflect, with reasonable accuracy, the angiographic probability of late reocclusion in our patient population.
The mechanisms of late reocclusion after PTCA of IRAs are not entirely clear but probably relate to rethrombosis. An alternative explanation would be that progressive renarrowing may lead to severe restenosis and eventually to reocclusion; however, the fact that IRAs not treated by PTCA are also at high risk of late reocclusion does not support this hypothesis. Angioscopic studies have shown that markers of instability such as thrombus or complex yellow plaque may persist at the infarct-related lesion site for ≥1 month after MI21 and that a large thrombus at the lesion site is associated with a higher risk of late reocclusion.22 These in vivo data are concordant with postmortem studies that have shown complex plaque and intramural thrombus in patients who developed reocclusion after thrombolysis.23
Late Reocclusion and Left Ventricular Function
We observed an improvement in ejection fraction at 6-month follow-up in patients without reocclusion; in contrast, in patients with reocclusion, no such improvement was seen. These results are concordant with those of prior studies that have emphasized the importance of a patent IRA 3 to 6 months after MI for the recovery of left ventricular function. The deleterious impact of late reocclusion of the IRA on the recovery of left ventricular function has been demonstrated previously 6 months after PTCA12 13 and 3 months after thrombolysis.10
In the present study, late reocclusion was not associated with significant changes in end-diastolic volume at 6-month follow-up. We cannot, however, exclude that a later follow-up would have given different results. Indeed, in a recent analysis of a subset of the patients enrolled in the APRICOT study, Nijland et al24 have shown that late reocclusion of the IRA is associated with left ventricular dilatation 5 years after first MI.
Late Reocclusion and Long-Term Survival
Previous studies have demonstrated the importance of IRA patency for late cardiac survival.6 7 25 26 Moreover, it has been suggested that IRA patency may have a beneficial effect on long-term survival, independent of myocardial salvage.6 7 In these studies, however, IRA patency was assessed in the early days or weeks after MI. As previously discussed, owing to late reocclusion, a patent vessel relatively early after MI is not a guarantee of long-term vessel patency. Our study hypothesis was that late reocclusion of a vessel that was patent 10 days after MI may still interfere with long-term survival.
Two studies have previously analyzed the impact of late reocclusion on long-term survival. In the study by Brouwer et al,20 248 (87%) of 284 patients with a patent IRA within 48 hours after thrombolysis for acute MI underwent systematic 3-month angiographic follow-up; late reocclusion was observed in 71 patients (29%). Clinical follow-up was obtained at a median of 2.6 years. A significant reduction in event-free survival (defined as a clinical course without death, reinfarction, or revascularization) was observed in patients with late reocclusion. The difference in mortality, however, was not significant: 9% in patients with reocclusion versus 3% in patients without reocclusion. This may be explained by the relatively low number of patients included and by the relatively short clinical follow-up period. The study by Brodie et al27 included a large number (576) of hospital survivors after primary PTCA for acute MI. However, 6-month angiographic follow-up was not systematic and was performed in only 374 patients (65%). Clinical follow-up was obtained at a median of 5.3 years. Reocclusion was associated with an increased late mortality in patients with acute ejection fraction <45%; this was primarily due to the effect of patency on recovery of left ventricular function. Reocclusion was independently associated with late mortality only in patients with a large anterior MI.
The present study combines the strengths of the 2 previous studies: (1) a large number (625) of patients included, (2) a systematic (86%) 6-month angiographic follow-up, and (3) a long (5.7 years) clinical follow-up period. Our results show that late reocclusion is significantly associated with an adverse long-term prognosis. Although this was probably related in part to the effect of patency on recovery of left ventricular function, the results of the multivariate analyses also show that late reocclusion is an independent predictor of late mortality. The mechanisms by which late reocclusion may independently affect long-term prognosis are not known specifically; as previously discussed, late reocclusion may interfere with left ventricular remodeling, electrical stability, and the availability of collaterals in the event of occlusion of a contralateral artery.3 4 8 9 Nevertheless, despite similar baseline characteristics in patients with and without reocclusion, the design of our study does not allow us to exclude the hypothesis that late reocclusion may be a marker rather than the actual cause of late mortality.
Our results also suggest that the adverse effect of late reocclusion is more important in patients with an anterior MI. Whereas in nonanterior MI, late reocclusion was only of marginal importance in term of late mortality, it was of major importance in anterior MI (Figure 2⇑). These results, which are concordant with those of previous studies that have suggested that IRA patency may be especially important in the case of “large” MI,6 25 27 may be particularly important for the selection of patients for therapeutic strategies designed to prevent late reocclusion.
In the present study, long-term survival was similar in patients with an occluded or a patent IRA 10 days after MI providing that the IRA could be reopened by PTCA. Moreover, although the number of patients with an occluded IRA before PTCA was too low to draw definite conclusions, the impact of late reocclusion on mortality appeared similar in the 2 groups of patients. This demonstrates the major importance of long-term patency regardless of the status of the IRA (ie, patent versus occluded) in the early days or weeks after MI.
This was a retrospective study. However, 6-month angiographic follow-up was obtained in 86% of eligible patients irrespective of recurrent symptoms, and long-term clinical follow-up was obtained in 100% of the patients who had 6-month angiographic follow-up. Our results are thus likely to reflect the true reocclusion rate and clinical outcome in our study population. In addition, as stated above, the design of this study does not allow us to state that late reocclusion is causally related to late mortality but only that late reocclusion is associated with late mortality. Finally, the large number of possible correlates of death and the relatively small number of deaths in this study make it possible that some variables predictive of mortality either with univariate or multivariate statistics may not have been shown to be significant.
These results may have at least 2 potential clinical implications. First, the knowledge of the status (patent/occluded) of an IRA relatively late after the acute phase may allow a better assessment of the long-term prognosis after MI. Second, these observations should encourage prospective studies to evaluate strategies designed to prevent late reocclusion. We19 have recently demonstrated the beneficial effect of coronary stenting on late IRA patency; the effect of new potent antithrombotic drugs such as glycoprotein IIb/IIIa antagonists on late reocclusion is unknown but warrants further investigation. Whether a therapeutic strategy leading to a decrease in late IRA occlusion improves late cardiac survival will also require prospective investigation. Such a study might usefully target patients with an anterior MI in whom late reocclusion is associated with a very significant increase in late mortality.
- Received October 23, 1998.
- Revision received January 23, 1999.
- Accepted February 4, 1999.
- Copyright © 1999 by American Heart Association
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Brodie BR, Stuckey TD, Kissling G, Hansen CJ, Weintraub RA, Kelly TA. Importance of infarct-related artery patency for recovery of left ventricular function and late survival after primary angioplasty for acute myocardial infarction. J Am Coll Cardiol. 1996;28:319–325.This study was designed to analyze the impact of late reocclusion of the infarct-related artery on long-term survival after myocardial infarction. Late reocclusion occurred in 17% of 528 patients who underwent 6-month follow-up angiography. The actuarial 8-year total mortality rate was 10% in patients without reocclusion and 28% in patients with reocclusion (P=0.0003); the actuarial cardiovascular mortality rates were 7% and 25%, respectively (P<0.0001). Late reocclusion of the infarct-related artery is strongly associated with long-term mortality.