(Circulation. 1999;99:2243-2250.)
© 1999 American Heart Association, Inc.
Clinical Investigation and Reports |
Angiographically Documented Late Reocclusion After Successful Coronary Angioplasty of an Infarct-Related Lesion Is a Powerful Predictor of Long-Term Mortality
From the Service de Cardiologie B, Hôpital Cardiologique, Lille, France.
Correspondence to Michel E Bertrand, Service de Cardiologie B, Hôpital Cardiologique, Blvd du Professeur J Leclercq, 59037 Lille, France. E-mail bertrandme{at}aol.com
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Abstract |
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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.
Key Words: angioplasty • myocardial infarction • prognosis
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Introduction |
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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.
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Methods |
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Study Population
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.
Angioplasty Procedure
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.
Angiographic Analyses
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.
Clinical Follow-Up
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.
Statistical Analysis
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
2 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.
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Results |
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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.
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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).
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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.
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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.
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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.
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Discussion |
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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.
Study Limitations
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.
Clinical Implications
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.
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