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Circulation. 1995;91:476-485

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(Circulation. 1995;91:476-485.)
© 1995 American Heart Association, Inc.

Articles

Does PTCA in Acute Myocardial Infarction Affect Mortality and Reinfarction Rates?

A Quantitative Overview (Meta-Analysis) of the Randomized Clinical Trials

Karin B. Michels, MS, MPH; Salim Yusuf, FRCP, DPhil

From the Department of Epidemiology, Harvard School of Public Health, Boston, Mass (K.B.M.), and the Division of Cardiology and Program of Preventive Cardiology and Therapeutics, Hamilton General Hospital, McMaster University, Hamilton, Ontario, Canada (S.Y.).


*    Abstract
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 *Abstract
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down arrowResults
down arrowDiscussion
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Background Percutaneous transluminal coronary angioplasty (PTCA) is often performed after acute myocardial infarction (AMI) either as an adjuvant to thrombolytic therapy or instead of thrombolysis. The effect of PTCA in AMI on mortality and reinfarction has remained unclear, with the available randomized trials indicating inconsistent results.

Methods and Results A systematic overview (meta-analysis) of the randomized trials was conducted to assess the effect of PTCA in AMI on mortality and reinfarction rates. Data from 7 trials in which primary PTCA was evaluated and 16 trials in which PTCA after thrombolysis was studied were included in this overview, comprising a total of 8496 patients. The trials represented different approaches to the timing of PTCA after AMI. The trials of PTCA after thrombolytic therapy were also categorized according to the different protocols with respect to the routine or elective character of PTCA in the invasive group. A reduction in short-term (6 week) mortality (odds ratio, 0.56; 95% CI, 0.33, 0.94) and in the combined outcome of short-term mortality and nonfatal reinfarction (odds ratio, 0.53; 95% CI, 0.35, 0.80) was observed in the trials comparing primary PTCA with thrombolytic therapy. In contrast, in trials in which an approach of thrombolysis and PTCA was compared with thrombolytic therapy alone, there was no important difference in early mortality, with an apparent reduction in mortality between 6 and 52 weeks. The lower mortality between 6 and 52 weeks among 6-week survivors seemed to be restricted to the subgroup of trials in which PTCA was used as a routine strategy (odds ratio, 0.58; 95% CI, 0.39, 0.87).

Conclusions Although the analyses of the various categories of trials suggest that primary PTCA may be more beneficial than thrombolytic therapy in AMI, these data should be interpreted cautiously unless confirmed by larger studies. In contrast, the addition of various other strategies of PTCA to thrombolytic therapy does not convincingly indicate a clinically different outcome than if a more conservative strategy is followed, in which PTCA is used only if clinically indicated. Some specific strategies, however, such as rescue PTCA in high-risk patients with occluded arteries, may be of benefit.


Key Words: meta-analysis • angioplasty • thrombolysis • myocardial infarction


*    Introduction
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 up arrowAbstract
 *Introduction
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down arrowDiscussion
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Reperfusion therapy with a thrombolytic agent reduces mortality and improves left ventricular function in acute myocardial infarction (AMI).1 After thrombolytic therapy, about 50% of patients still have some residual stenosis of the infarct-related artery. This predisposes to recurrent ischemia and recurrent coronary occlusion, which may worsen ventricular function or lead to impaired quality of life or catastrophic events such as sudden death or reinfarction. Percutaneous transluminal coronary angioplasty (PTCA) of the stenotic infarct artery reduces the degree of stenosis, but the procedure itself sometimes produces reocclusion, which may lead to an extension of the infarct. In other cases, despite persistent occlusion or stenosis of the infarct-related artery, flow to the ischemic myocardium may be restored by collateral flow. Therefore, the balance of benefits versus risks with PTCA in an individual patient cannot be generally predicted, especially if there is no evidence of ongoing ischemia or hemodynamic instability.

Attempting PTCA instead of thrombolytic therapy in patients presenting very early after myocardial infarction (primary PTCA) has the theoretical advantage of early and complete coronary patency in the vast majority of patients in addition to decreasing residual stenosis. Therefore, compared with PTCA as an adjuvant to thrombolytic therapy, primary PTCA has the potential of decreasing the extent of myocardial necrosis. Such a strategy could lead to greater preservation of ventricular function and hence better short-term and long-term survival. On the other hand, primary PTCA requires rapid access to a catheterization laboratory 24 hours per day. Therefore, it may not be widely feasible; moreover, it may be associated with greater perioperative risks.

Despite the widespread use of early postinfarction PTCA after AMI in the United States,2 the benefit of this intervention in AMI has remained unproven.3 4 5 6 7 8 Although a few randomized trials have suggested some benefit to performing PTCA after thrombolysis,9 10 11 12 13 14 15 16 other trials have shown no advantage or an adverse trend compared with more conservative management.17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 Large properly randomized controlled trials of PTCA in AMI are difficult to organize, since only a limited number of centers can offer PTCA. Further, there are additional reasons that make it difficult to achieve a sufficient difference in the proportion of patients receiving PTCA in the intervention and control groups. First, the procedure may prove impracticable among a high proportion of patients, or the stenosis of the culprit lesion may have spontaneously decreased in severity so that PTCA might not be considered to be indicated. Second, PTCA cannot be withheld from patients randomized to the control arm of these trials when specific indications, such as ischemia, arise. Third, in some trials, in an attempt to resemble clinical decision making, PTCA is attempted in the invasive group only if certain clinical situations arise or if a considerable degree of residual stenosis remains. Although all the above problems decrease statistical power, such trials potentially shed some light on two contrasting generic strategies (more invasive versus less invasive).

To the extent that inconsistencies among the available studies reflect inadequate sample size, a quantitative overview, or "meta-analysis," of results of all randomized trials conducted may be helpful, and this is the main purpose of the present report.

The trials of PTCA in AMI can be divided into two main categories: (1) primary PTCA (direct PTCA) versus thrombolytic therapy and (2) PTCA after thrombolytic therapy versus thrombolytic therapy alone. The second category can be further subdivided into (2a) immediate PTCA (to be performed as soon as possible after thrombolytic therapy) versus no routine PTCA, (2b) early PTCA (to be performed several hours or within a few days after thrombolysis) versus no routine PTCA, (2c) delayed PTCA (to be performed 4 or more days after thrombolysis) versus no routine PTCA, (2d) immediate PTCA versus delayed PTCA, and (2e) rescue PTCA for persistent occlusion of the infarct-related artery after thrombolytic therapy versus no routine PTCA.

Furthermore, the latter category of trials can be subdivided according to another aspect of the study design, ie, whether PTCA was performed as a routine strategy (systematic PTCA) in the invasive group (2A) or only as an elective procedure (2B). Therefore, a variety of analyses of the data are required to help determine the most appropriate strategy regarding the use of PTCA in patients with AMI.


*    Methods
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 *Methods
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Identification of Trials
The goal was to identify all randomized trials, published or unpublished, of PTCA in the treatment of AMI. This review includes trials of primary PTCA and those in which PTCA was performed after thrombolysis. Published studies were identified through a literature search using MEDLINE and Index Medicus, extensive hand research using cross-references from original articles and reviews, and screening of abstracts of the major cardiology meetings between 1984 and 1994 (Scientific Sessions of the American Heart Association, the American College of Cardiology, and the European Society of Cardiology). In addition, we corresponded with the principal author of each study identified to inquire about studies that might have been unpublished or overlooked. This strategy was essential to discovering trials with unpromising results that might remain unreported.32 33 Our search did not reveal any trial that had not been published, either in full or at least in abstract form.

In most trials included in this analysis, the comparison of PTCA with a control treatment strategy was the main randomization of the study. However, in some studies, this was a secondary randomization arm. For the purpose of this meta-analysis, we have included data only from the treatment arms in which patients were randomized to receive PTCA or alternative therapy.

End Points of Interest
The primary end point of interest was short-term mortality within 6 weeks after myocardial infarction. When mortality at 6 weeks was not available even from correspondence with the principal investigator, deaths that occurred at the closest available time during short-term follow-up were used instead, ie, mortality at any time up to 6 weeks or in-hospital mortality (which may be only 1 to 3 weeks but usually includes the majority of deaths). In the majority of trials of primary PTCA versus thrombolytic therapy, only in-hospital mortality was available.

Other end points studied were mortality at 1 year after myocardial infarction (or the closest available time), nonfatal reinfarction within 6 weeks, and nonfatal reinfarction up to 1 year. Data on nonfatal infarction were combined with mortality to avoid the problem of competing risks.34 Information was also sought on the adherence to the protocol in regard to the actual number of patients receiving PTCA in the intervention group and in the control group.

Data Extraction and Verification
Information was sought on the exact study design, on the numbers actually undergoing PTCA in each group, and on the 6-week and 52-week outcomes (survival and recurrence-free survival, ie, survival without reinfarction). The relevant results were extracted from each of the published articles into a standard format. These standard tables were then mailed to the principal investigators, who were requested to review the extracted data, to verify their accuracy, and when necessary, to provide additional data.

Statistical Methods
The statistical methods used to combine data have been described in detail and used extensively.35 36 37 The underlying principle is the comparison of patients allocated to intervention in one trial only with those allocated to control treatment in the same trial, avoiding direct comparisons of patients across different trials. These are basically the standard methods for the combination of information from multiple "2x2" tables, as reviewed by Mantel and Haenszel.38


*    Results
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*Results
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Description of Trials
The value of PTCA in AMI has been assessed in many nonrandomized studies but only a few randomized ones. A total of 26 relevant trials were identified.9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 39 40 41 42 43 44 45 46 47 48 In 7 of these trials, primary PTCA41 42 43 44 45 46 47 48 was evaluated, and in 19 trials, PTCA after thrombolytic therapy9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 39 40 was studied. Investigators responsible for each of these 26 studies were contacted. Nineteen responded to the request to verify the data extracted and to provide additional unpublished information. Investigators of the LIFT study40 (Late Intervention Following Thrombolysis) had not analyzed the data with respect to the outcomes of interest for this meta-analysis at the time of submission of this article. Two other studies of PTCA after thrombolytic therapy12 39 had to be excluded from this overview because the published data were insufficient for the purposes of the overview. These trials represent less than 3% of the total of 8496 patients in the remaining 23 trials. For four trials, published or publicly presented data were used.41 43 44 45 46 Therefore, a total of 7 trials in which primary PTCA and thrombolysis were compared and 16 trials in which PTCA in addition to a thrombolytic regimen was studied, with 1 trial providing two15 31 and another three contrasts,26 27 were included in this meta-analysis.

In the primary PTCA trials,41 42 43 44 45 46 47 48 angioplasty was performed as soon as the patient presented to the hospital. Patients in the comparison group received thrombolytic therapy as quickly as possible.

In four of the trials of PTCA after thrombolytic therapy, immediate PTCA was compared with no PTCA9 10 11 17 18 28 (2a). In five trials, early PTCA versus no PTCA were compared13 19 20 22 23 24 25 (2b). In three trials, delayed PTCA was compared with no planned PTCA16 21 30 (2c). In two trials, immediate PTCA was compared with delayed PTCA29 31 (2d). In two trials, rescue PTCA was studied14 15 (2e). In one trial, a three-way comparison of immediate PTCA versus early PTCA versus no PTCA was used.26 27 In one trial, two comparisons were made, one between immediate PTCA and delayed PTCA31 (2c) and another between rescue PTCA for occluded vessels and no rescue PTCA15 (2e).

In three trials of the first category (immediate versus no PTCA, 2a), PTCA was planned immediately and routinely in the invasive group, whereas the conservatively treated group was not to receive PTCA unless clinically indicated.9 10 11 17 18 In the fourth trial of this category, patients were treated with PTCA soon after thrombolysis if the infarct-related artery was not patent.28 If TIMI grade 0 or 1 flow was present at acute cardiac catheterization, rescue angioplasty was attempted.

In the second category (early PTCA versus no PTCA, 2b), the strategies used were more diverse. In two trials, TAMI 623 24 (Thrombolysis and Angioplasty in Myocardial Infarction) and the trial conducted by Guerci et al,13 randomization was restricted to candidates who were suitable for PTCA only, and the trials contrasted PTCA performed between 6 and 24 hours13 or 3 days23 24 after thrombolysis with no PTCA. In the largest of all the trials, TIMI II19 20 (Thrombolysis In Myocardial Infarction), patients were randomized to undergo PTCA 18 to 48 hours after thrombolysis if anatomically suitable or an approach in which PTCA was used only if patients had ischemia. In the other two trials in category 2b, angioplasty was offered for specific reasons. In the SIAM trial22 (Streptokinase in Acute Myocardial Infarction), patients were randomized to undergo PTCA in the invasive group if angiography demonstrated its "necessity" 14 to 48 hours after thrombolysis. In the conservatively treated group, an angiographic evaluation of the necessity for PTCA was again conducted only if evidence for myocardial ischemia existed. In the SWIFT study25 (Should We Intervene Following Thrombolysis), the decision whether to perform angioplasty in patients randomized to the invasive group after thrombolysis was left up to the operator's discretion. Patients with occluded vessels were included in this trial. No PTCA was planned for the conservative group unless clinically indicated.

In the category of trials comparing delayed with no PTCA (2c), three studies with somewhat different protocols were included. In a trial conducted in Israel,21 patients were randomized to an invasive group that underwent routine coronary arteriography at least 72 hours after thrombolysis (average, 5±2 days) or to a conservatively treated group, in which arteriography was performed only if myocardial ischemia persisted after this time period. In both groups, PTCA was performed if the residual stenosis led to a >50% obstruction in diameter of the infarct-related artery. In the TOPS trial30 (Treatment of Post-thrombolytic Stenoses), patients treated with thrombolytic therapy within 6 hours of chest pain onset, without evidence of ischemia on stress testing, with a residual stenosis of >50% in the infarct-related artery, and with anatomy suitable for PTCA were randomized between PTCA to be performed 4 to 14 days after MI versus no PTCA. In a subset of the European Cooperative Study Group heparin trials,16 patients were randomly assigned to angioplasty or conservative management 48 to 120 hours after infusion of recombinant tissue-type plasminogen activator (rTPA).

The fourth category (2d) consisted of two trials, TAMI I29 and one comparison of the trial conducted by Belenkie et al.31 In TAMI I, immediate PTCA was routinely performed and compared with delayed elective PTCA if, on day 7 to 10, a residual stenosis obstructed the vessel lumen by >50%. In the Canadian study, patients with a patent infarct-related artery and a residual lumen diameter stenosis of >=70% that was amenable to angioplasty were randomized to undergo either immediate or delayed (18 to 48 hours) angioplasty.

The fifth category (2e) contained two trials. The RESCUE trial14 included patients with anterior infarction who received thrombolytic therapy. Patients with TIMI grade 0 to 1 after failed thrombolysis were randomized to undergo rescue PTCA or continued conservative management. In the study conducted by Belenkie et al,15 patients in one arm were randomized to either rescue PTCA or a conservative strategy if the infarct-related artery was occluded more than 3 hours after the onset of infarction despite thrombolytic therapy. The patients in this arm of Belenkie's study did not overlap with the patients from the contrast group included in the fourth category described above. It should be noted that some trials from the other categories, namely TAMI 5, also included patients with occluded arteries, but in those trials this was not the primary comparison.

In TIMI IIA,26 27 three different treatment strategies were compared: immediate PTCA versus early PTCA versus no PTCA. The immediate invasive arm provided for PTCA if the residual stenosis was >60%. In the early invasive arm, in contrast, PTCA was performed 18 to 48 hours after thrombolysis only if the infarct-related arteries were patent with a residual stenosis. Among conservatively treated patients, PTCA was performed only if medically necessary.

Table 1Down summarizes the treatment protocols.


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  		Table 1. Key Design Features of the Trials Included in the Meta-Analysis

Patient Crossover
In the seven trials of primary PTCA versus thrombolytic therapy, there was a high rate of intervention in those allocated to the PTCA group (93%) compared with about 29% in the control group who underwent PTCA at some time during hospitalization (mostly in subsequent days) or within the first 6 weeks after infarction. Therefore, the contrast in the proportions of patients receiving any PTCA versus patients receiving no PTCA was substantial (64%). Moreover, the contrast in the proportions of patients who were treated with PTCA within the first few hours after onset of symptoms compared with patients who were not treated with PTCA within the first few hours was likely to be even larger.

The trials of PTCA after thrombolytic therapy were also categorized according to the different protocols with respect to the routine or elective character of PTCA administered in the invasive group, since the contrast in the proportions of patients receiving PTCA varied in the different trials. Two groups were formed: group A summarizing the trials comparing a routine approach to PTCA (ie, irrespective of the presence or absence of ischemia) versus no planned PTCA and group B comparing PTCA performed when medically indicated (ie, for ischemia) versus no planned PTCA. The two comparisons of immediate versus delayed PTCA were not included in this analysis. From TIMI IIA, only the contrast between immediate versus no PTCA was included.

In all trials of group A, a higher proportion of patients (63%) allocated to receive PTCA underwent PTCA, with few patients in the control group receiving PTCA (15%), thereby achieving a contrast of 48%. In the TIMI II trial,19 20 only patients with suitable anatomy underwent PTCA in the invasive group (54%). Further, 17% of the control patients in this trial underwent PTCA by 6 weeks, so that the contrast between the active and control groups was moderate (37%).

In group B, roughly half of the patients randomized to the invasive group actually received PTCA, as well as 18% of patients in the conservative treatment group (contrast, 35%).

The randomization and the actual treatment in both groups are listed in Table 2Down.


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  		Table 2. Treatment Allocation and Rates of PTCA Performed Within the First 6 Weeks After Acute Myocardial Infarction

Mortality and Reinfarction
Data on the events in the population reviewed are listed in Table 3Down. The results of the comparisons are summarized in Tables 4Down and 5Down.


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  		Table 3. Events


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  		Table 4. Summary Odds Ratios and 95% CIs for Aggressive vs Less Aggressive Treatment


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  		Table 5. Summary Odds Ratios and 95% CIs for Routine PTCA vs No PTCA and Elective PTCA vs No PTCA

Trials of Primary PTCA Versus Thrombolytic Therapy
Data on in-hospital or 6-week mortality were available for all 7 trials. A considerable reduction in mortality was found in the combined data (odds ratio, 0.56; 95% CI, 0.33, 0.94) (Table 4Up). No important statistical heterogeneity was observed between the trials ({chi}2, 7.3; P=.29). When deaths and nonfatal MI were combined, the reduction in risk was similar and the estimate somewhat more stable (odds ratio, 0.53; 95% CI, 0.35, 0.80). Long-term data are not yet available from a sufficiently large number of patients to provide reliable estimates beyond 6 weeks.

Trials of PTCA After Thrombolytic Therapy
For 13 of the studies, data were available for mortality at 6 weeks after MI. In the three trials in which 6-week data per se were not available, these have been substituted by in-hospital mortality data in SWIFT,25 by 2-week mortality data in ECSG,17 18 and by mortality at 13 weeks in the study conducted by van den Brand et al.16 From TIMI IIA, all three contrasts were used for the appropriate categories. No significant difference was observed in either of the three categories accounting for the different timing of PTCA (Table 4Up) or in one of the two groups considering the routine or elective character of the intervention (Table 5Up). No important heterogeneity was observed between the trials within the different categories or groups (immediate PTCA: {chi}2=5.2, P=.27; early PTCA: {chi}2=4.8, P=.44; delayed PTCA: {chi}2=1.1, P=.3; immediate versus late PTCA: {chi}2=0.6, P=.74; rescue PTCA: {chi}2=1.0, P=.33; routine PTCA: {chi}2=12.3, P=.14; elective PTCA: {chi}2=1.6, P=.82). The results of the rescue PTCA trials differed considerably from those of the other categories. The combined estimate of the odds of dying within 6 weeks after MI was compatible with a reduction in risk if rescue PTCA was performed (OR=0.38; 95% CI, 0.13, 1.06). The number of outcome events in this category of trials, however, was sparse (Table 3Up).

Data from the five categories were also combined. Four categories were combined to compare PTCA versus no planned PTCA. All these approaches taken together could also be viewed as addressing the more global question of whether an aggressive policy of mechanical intervention might be superior to a more conservative approach to invasive intervention in the treatment of AMI. For all combinations of categories, data from the only three-arm trial, TIMI IIA,26 27 were included only from category one (immediate versus no PTCA). None of the combinations revealed a significant result (Table 4Up).

The numbers of patients who suffered a subsequent nonfatal myocardial infarction during the short-term follow-up were available from 13 of the 16 stu-dies.9 10 11 15 17 18 19 20 21 22 23 24 25 26 27 28 30 31 Ten of the study investigators provided data on reinfarction at 6 weeks after MI. In three studies, the closest time during short-term follow-up at which reinfarction data were available was substituted (in-hospital reinfarction in SWIFT,25 reinfarction at 2 weeks in ECSG,17 18 and reinfarction at 13 weeks in the study by van den Brand et al16 ). Since nonfatal reinfarction is not an independent end point as described above, nonfatal reinfarction and mortality were used as a combined outcome in the analysis. If data on nonfatal reinfarction were not available, only data on mortality were used. The odds of suffering either death or a reported nonfatal myocardial infarction were not altered significantly by PTCA in all but one category. An increase in the odds of death or nonfatal reinfarction was apparent in patients who received PTCA in a delayed fashion (several days after AMI) compared with patients who were not randomized to undergo PTCA at all (odds ratio=1.78; 95% CI, 0.99, 3.19). The lack of difference was consistent for the individual categories and the combination of categories as well as the two groups of trials (A and B).

Longer-term mortality data were available from 12 of the 16 trials.9 10 16 17 18 19 20 21 23 24 25 26 27 28 29 30 Again, PTCA did not alter the outcome after a 1-year follow-up (Tables 4Up and 5Up).

The risk of suffering death or reported nonfatal reinfarction during long-term follow-up was evaluated from the data available at 1 year. The resulting odds ratios for the five categories and for the combinations as well as for the groups did not show a significant association (Tables 4Up and 5Up). Delayed PTCA, however, was found to be associated with a significantly increased risk of death at 1 year (odds ratio=6.79; 95% CI, 1.32, 35.03) and the combined end point of mortality or nonfatal reinfarction at 1 year (odds ratio=2.24; 95% CI, 1.19, 4.19). These results, however, were based on the data obtained from only one21 and two21 30 trials, respectively, and the high variability is reflected in the relatively wide CIs of the estimates.

It is possible that with interventional procedures, an excess of early perioperative events may be offset by delayed and sustained benefit (as has been observed in trials of coronary artery bypass graft surgery. To explore this possibility, deaths that occurred between 6 weeks and 52 weeks were analyzed separately. Data were combined for patients who were alive at 6 weeks and for whom a 1-year follow-up was available. Among the various categories, the trials comparing early versus no PTCA showed a nearly 40% reduction in risk (OR=0.61; 95% CI, 0.42, 0.88), suggesting the possibility of a long-term beneficial effect of PTCA when performed during the first days after AMI (Table 4Up). When the four categories comparing PTCA versus no PTCA were combined, nearly 30% lower odds of death were found for the patients receiving PTCA (OR=0.71; 95% CI, 0.51, 0.99). A combination of all five categories indicated an odds ratio of 0.74 (95% CI, 0.53, 1.02).

When trials were grouped into groups A and B, routine PTCA appeared protective in the interval between 6 and 52 weeks among 6-week survivors (OR=0.58; 95% CI, 0.39, 0.87) (Table 5Up).


*    Discussion
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 up arrowIntroduction
 up arrowMethods
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*Discussion
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The analyses of the various categories of trials suggest but do not conclusively prove that primary PTCA may be more beneficial than thrombolytic therapy in AMI, whereas the addition of various strategies of PTCA to thrombolytic therapy may not result in an outcome clinically superior to a more conservative strategy when PTCA is used only if clinically indicated.

Primary PTCA
The trials of primary PTCA compared with thrombolytic therapy suggest lower mortality and reinfarction rates with PTCA. Myocardial infarction is considered to result from acute coronary occlusion. In animal experiments, very early mechanical reperfusion leads to a substantial limitation of infarct size. In humans, the most common approach to reperfusion has been the use of pharmacological agents such as streptokinase, TPA, or anistreplase. However, even with the most aggressive of these regimens (accelerated front-loaded TPA), within 90 minutes after the initiation of thrombolytic therapy, complete (TIMI grade 3) reperfusion is achieved in only about 50% of all patients treated within 6 hours after onset of pain.49 This suggests that even with the best currently available thrombolytic regimen, in approximately half the patients adequate coronary blood flow is not achieved rapidly. Therefore, approaches to reestablish more complete and earlier coronary blood flow are warranted. Innovative thrombolytic approaches such as the use of double-bolus rTPA, adjunctive therapies with antiplatelet antibodies, RheothRx, and substituting hirudin for heparin may enhance the rates of more complete 90-minute patency. Alternatively, primary PTCA results in recanalization of the infarct-related artery in more than 95% of patients (the rate of TIMI grade 3 flow with primary PTCA is not well defined; however, it is likely that a high proportion of patients would have TIMI grade 3 flow). Moreover, in the patients in whom the artery was opened, the increase in lumen after direct PTCA is greater than that achieved with thrombolytic therapy. Therefore, as long as direct PTCA can be applied rapidly and with minimal procedural risks, it might lead to greater reductions in myocardial infarct size, improved ventricular function, and lower mortality.

Although the currently available data on primary PTCA appear promising, they should be interpreted cautiously. First, only in two41 44 of the trials in which left ventricular function was measured was PTCA found to be superior to thrombolysis in improving left ventricular function. Second, these trials were conducted in a few highly specialized centers, and it may be that the outcome of PTCA is less impressive when performed in community hospitals by low-volume operators.50 Therefore, the present data should be viewed as a strong impetus for the conduct of larger trials in a more diverse range of hospitals, with clinical outcomes being the primary end points of interest. In the design of such trials, it may be prudent to expect differences that are more moderate than those currently observed. The need for such trials is further highlighted by the observations from a recent community registry that suggested similar survival and reinfarction rates up to 1 year in patients treated with PTCA (n=441) or thrombolysis (n=653) for AMI.51 Patients treated with angioplasty, however, tended to have fewer strokes, shorter hospital stays, and less recurrent ischemia.

PTCA as an Adjunct Treatment
In the trials in which PTCA was used as an adjunct to thrombolytic therapy, the results were less impressive. When mortality at 6 weeks was analyzed, four of the five different approaches to angioplasty (immediate PTCA compared with no PTCA, early PTCA compared with no PTCA, delayed PTCA versus no PTCA, and immediate PTCA compared with delayed PTCA) showed trends toward increased risk in the more aggressively treated group. In none of these categories nor when the categories were combined were these differences significant. It should be noted, however, that one trial, the ECSG trial, was stopped by the Monitoring Committee because of excess mortality in the PTCA group.17 Similar findings hold in differentiating between routine PTCA versus no PTCA and elective PTCA versus no PTCA. Routine mechanical intervention in addition to thrombolysis therefore appears to offer no immediate advantage in short-term mortality over the more conservative approach. However, this situation may be analogous to the trials of coronary artery bypass graft surgery, in which patients in the surgical group have a higher initial operative mortality.52 Only with subsequent 5-year follow-up was lower mortality observed in the surgical group compared with the medical group. Such long-term data are not yet available for most trials of PTCA. When the data on 1-year mortality and reinfarction were combined, results appeared somewhat more favorable for PTCA than in the short term. Six-year follow-up data from the trial conducted by Spiecker et al,53 however, do not show any long-term survival benefit from immediate PTCA. The reduction in mortality observed after 6 weeks and, to some extent, at 1 year did not persist after 6 years of follow-up. In the ECSG trial, the excess mortality observed during hospital stay persisted throughout the 5-year follow-up period.54 Also, no reduction in late recurrent infarction was observed.

It is possible that in the trials of adjunctive PTCA there was little effective myocardial reperfusion, or if it did occur, this was achieved relatively late. Late reperfusion beyond 12 hours has been associated with increased early mortality55 , and it is possible that these early hazards may also have been accentuated in these trials, in which PTCA was used relatively late compared with the trials of primary PTCA.55

Furthermore, a benefit from PTCA after thrombolysis was not apparent if the combined end point of mortality and nonfatal reinfarction at 6 weeks was considered. Reocclusion and reinfarction have been held responsible for the lack of benefit of immediate coronary angioplasty after thrombolytic therapy for AMI. It has been suggested, therefore, that immediate PTCA may be beneficial in selected patients, provided that these complications can be prevented.56 In the present overview, immediate PTCA seemed slightly favorable compared with no PTCA, whereas data on an early or delayed PTCA approach compared with no mechanical intervention or data on immediate PTCA compared with delayed PTCA were compatible with an increased risk of experiencing an event. The apparent difference in direction of the odds ratios for these categories could be due to random variation or to differences in design and conduct of the trials.

Long-term Results
In examination of short-term mortality, the risk of the interventional procedure itself must be taken into account. Coronary angioplasty is associated with operator-dependent mortality that varies with the skill and experience of the cardiologist. PTCA-related mortality is viewed as part of the price of this approach to treatment and should be factored into clinical decisions.52 There is no good way to take such differences into account. Nevertheless, analysis of late mortality conditional on survival beyond the first few weeks may provide some valuable insights that might be helpful in the design of future trials. Interestingly, a favorable result was obtained in the analysis of mortality for the time interval between 6 and 52 weeks among 6-week survivors. PTCA was associated with a considerably lower mortality between 6 and 52 weeks among 6-week survivors. This association was particularly strong among patients receiving PTCA during the first days after AMI and among patients receiving PTCA as a routine strategy.

It might be possible that the apparent late benefit of the aggressive mechanical intervention simply represents survival of patients with good prognosis, representing a shift in mortality from later to earlier stages. Patients at high risk might die within the first weeks after the stressful intervention, which might be reflected in the slightly increased risk of death for the PTCA patients in the first 6 weeks. Longer follow-up would be necessary to determine whether an overall survival difference between the groups is likely to emerge. Similar long-term data from the trials of primary PTCA would also be helpful in assessing whether the early benefits are sustained or increased beyond 6 weeks. Other interventions (eg, CABG surgery or additional PTCA) that may be unequally performed in the two groups, however, will affect such a comparison.

Rescue PTCA
In most trials included in this overview, PTCA was performed in patients with lesions that seemed "suitable." Only few trials included patients in whom PTCA was performed on occluded vessels. The limited short-term data indicate that rescue PTCA for patients with failed reperfusion after thrombolytic therapy might be beneficial, although the risk reduction observed was not significant. It is possible that in most trials, angioplasty is performed in patients in whom the benefit is likely to be small, whereas PTCA is avoided in those with occluded vessels for whom the benefit might be large (eg, primary PTCA and rescue angioplasty of occluded vessels). Therefore, rescue angioplasty should also be a subject of future clinical trials in AMI.

Crossover Rates
Analysis of the trials using an intention-to-treat analysis may underestimate the effects of PTCA if there is a high rate of "crossover." The modest contrasts of 48% and 35% observed in the two respective groups of adjunctive PTCA will make it more difficult to detect real differences. A real beneficial effect of adjunctive PTCA may therefore be masked by the modest contrast in PTCA rates in these trials. In calculation of the odds ratios for the trials in group A, excluding the trial with the highest crossover (TIMI II), however, did not change the interpretation of the estimates.

Limitations and Conclusions
The present meta-analysis has several limitations. Heterogeneity in the design of the various trials has posed methodological difficulties. We have tried to overcome this by combining trials of similar design in different categories and groups. Although this tends to produce more homogeneous (and interpretable) subgroups, it also tends to result in fewer events per category or group, thereby decreasing statistical power and, conversely, increasing the variability of the results. Furthermore, different thrombolytic agents were used in the studies combined in the overview. It is unclear whether the selection of the specific thrombolytic agent before PTCA might influence the outcome. Finally, the method of meta-analysis itself has its limitations57 ; its best use may be in assisting the design of larger and more definite clinical trials.

In conclusion, although early primary PTCA appears to reduce mortality and reinfarction, even the data combined in this overview do not convincingly indicate a beneficial or harmful effect of systematic PTCA after thrombolysis. The possible value of rescue PTCA in occluded coronary arteries has not yet been sufficiently studied. The information contained in this overview can aid in the design of future trials. It appears that very early primary PTCA, when feasible, could have the greatest potential for benefit and requires reliable assessment in much larger trials with a few thousand patients followed over the long term.


*    Acknowledgments
 
The authors would like to thank all collaborators who provided the data necessary for this meta-analysis: Gabriel I. Barbash, MD; Israel Belenkic, MD; David de Bono, MD; Marcel J. van der Brand, MD; Robert M. Califf, MD; Marcus A. DeWood, MD; Jaime Elizaga, MD; Stephen G. Ellis, MD; Raimund Erbel, MD; Alan D. Guerci, MD; Genell Knatterud, PhD; Cem Özbek, MD; Expedito E. Ribeiro da Silva, MD; Maarten L. Simoons, MD; and Eric Topol, MD. The authors are indebted to Richard Peto for helpful advice.


*    Footnotes
 
Reprint requests to Salim Yusuf, 252 McMaster-HGH Clinic, Hamilton General Hospital, 237 Barton St E, Hamilton, Ontario, Canada L8L 2X2.

Received February 28, 1994; accepted August 29, 1994.


*    References
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