Stenting in Acute Myocardial Infarction

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1 Home SVCC Area: English - Español - Português Stenting in Acute Myocardial Infarction David Antoniucci, MD; Renato Valenti, MD Division of Cardiology and Interventional Cardiovascular Catheterization Laboratory, Careggi Hospital, Florence, Italy BACKGROUND For a long time coronary stenting was believed to be absolutely contraindicated in the setting of acute myocardial infarction (AMI), because the implantation of a metallic device within a thrombotic environment like one of a plaque disruption resulting in myocardial infarction, would be very likely to precipitate stent thrombosis, with resultant vessel reocclusion. The first report of stenting in AMI was published in 1991 by Cannon and Roubin (1). This is a case report of a patient with inferior AMI complicated by cardiogenic shock who had successful bailout right coronary stenting. Three years after this report, Wong and Wong published 3 cases of successful bailout stenting and intracoronary fibrinolysis (2), but the first studies showing the feasibility and efficacy of provisional or bailout stenting in patients with AMI appeared only in 1996 in 4 small series of patients, for a total of 128 patients (3-6). At that time, stent thrombosis, whose rate could be as high as 20% in the early stent experience, had been dramatically reduced (to less than 2%) by the improvement in deployment techniques (ie, use of high pressure for stent expansion) and advances in antiplatelet therapy, allowing a prompt reassessment of the role of stenting in AMI. In fact, after the very encouraging results of these preliminary observational studies, stent implantation in patients with AMI grew enormously, and in 1997 the results of over 30 observational studies in more than 2,000 patients appeared. At the same time, 6 randomized trials comparing primary stenting with primary PTCA started. THE EXPECTED BENEFIT OF CORONARY INFARCT-RELATED ARTERY (IRA) STENTING The mechanisms of the potential benefit of stent in AMI may be summarized as follows. First, the major pitfall of a primary PTCA strategy is the high incidence of early and late restenosis or reocclusion of the infarct vessel. As a consequence of early restenosis or reocclusion, patients with successful primary PTCA have a very high incidence of early recurrent ischemia (the early recurrent ischemia rate after successful primary PTCA was 10% in the PAMI trial) (7), while late restenosis or reocclusion may occur in more than 50% of patients (8). Regarding early recurrent ischemia, a suboptimal angiographic result after successful primary PTCA is a strong predictor of early adverse events, while, with regarding late recurrent ischemia, an initial optimal angiographic result (that is the largest IRA diameter achievable) is assumed to be inversely related to late restenosis or reocclusion ("bigger is better"). Thus, the postulated mechanisms of the benefit of stent in AMI are the achievement of an initial optimal angiographic result and the correction of any residual dissection by stenting in order to decrease the incidence of recurrent ischemia, and the clinical events related to recurrent ischemia, such as fatal and nonfatal reinfarction, and angina. Thus, the primary clinical end point of a trial of stenting in AMI should be target vessel failure, that is a composite end point of the events related to restenosis or reocclusion of the IRA: fatal and nonfatal reinfarction, and repeat target vessel revascularization (TVR). It is important to point out that most patients with recurrent ischemia due to target vessel failure experience only angina or nonfatal reinfarction, while death as a consequence of recurrent ischemia accounts for only a minority of deaths (10% in the PAMI trial cohort), since the large majority of deaths after successful PTCA are due to refractory cardiogenic shock despite a patent IRA. As a consequence, the expected benefit of stent in terms of reduction of mortality is limited only to patients with a large area at risk or severe left ventricular dysfunction; in these patients reocclusion of the IRA may result in fatal reinfarction. For patients "not at high risk" the benefit of stent may result only in a significant reduction of

2 the incidence on nonfatal reinfarction, and mainly of repeat TVR. Obviously, TVR is a "soft" end point as compared to death. Nevertheless, this soft end point has very important economic and clinical implications when considering the adjunctive costs of a repeat revascularization procedure, the longer hospital stay, and the quality of life of the patients. Moreover, repeat TVR may be performed on an emergency basis and result, by a twist of fate, in bailout stenting in many patients. THE RESULTS OF RANDOMIZED STUDIES COMPARING PRIMARY PTCA AND PRIMARY IRA STENTING. The results of randomized studies comparing primary stenting with primary PTCA are summarized in Table 1. THE GIANTURCO-ROUBIN STENT IN ACUTE MYOCARDIAL INFARCTION (GRAMI) TRIAL This south American trial was the first concluded trial. It is a multicenter trial with a small sample size, 104 patients. The population is heterogeneous and include also patients at high risk, patients with AMI and ST-segment depression, failed fibrinolytic treatment, previous coronary surgery. Randomization was allowed only after coronary wire crossing. The six-month event-free survival rate was 83% in the stent group and 65% in the PTCA group (p = ) (9). THE FLORENCE RANDOMIZED ELECTIVE STENTING IN ACUTE CORONARY OCCLUSIONS (FRESCO) The FRESCO trial design includes some unique features and overcomes many limitations of the other trial designs. First, unlike the other trials that randomized patients to stent or nonstent before PTCA, patients were randomized only after an optimal angiographic result had been achieved with PTCA. In this way, the comparison was between elective stenting and optimal PTCA, since it was taken for granted the benefit of stenting due to IRA dissection or to a suboptimal result after PTCA. As a consequence, no crossover could occur from PTCA arm to stent, rendering the analysis based on intention to treat very similar to the one based on the treatment itself. Second, to correctly assess the feasibility and efficacy of stenting, the study protocol did not include any exclusion criterion, except for a reference vessel diameter less than 2.5 mm. There were no restrictions based on age, clinical status on presentation, or complexity of coronary anatomy. Third, for patients who were not randomized due to an initial non optimal angiographic result, stenting was recommended; these patients were studied in a separate parallel registry with complete follow-data. Patients who could not be randomized due to an initial non-optimal PTCA were older, and had a greater incidence of anterior AMI, severe left ventricular dysfunction, and multivessel disease. The study showed a benefit of provisional or elective stenting in terms of reduction of clinical events related to recurrent ischemia (death, myocardial infarction, repeat TVR) on both randomized stent patients, and in nonrandomized patients. At 6 months, the recurrent ischemia rate was 9% in the randomized stent group, 11% in the nonrandomized group, and 28% in the optimal PTCA group (10). As expected, because of the higher risk of nonrandomized patients, the overall mortality in the nonrandomized group was higher as compared to randomized groups. However, these results were

3 obtained from a single high-volume center and involved a limited number of patients, and should be reproduced in a larger, multicenter trial. The FRESCO investigators performed also a cost-effectiveness analysis of primary IRA stenting and optimal primary PTCA. In the FRESCO trial cohort, primary stenting was more cost-effective as compared to optimal PTCA. At 1-year, the total costs per patient were similar in both arms, but the average cost per event-free survivor was lower for primary stenting than for optimal PTCA: 12,026 $ vs. 15,638 $, and the incremental cost per event-free survival was only 962 $ (11). The Zwolle trial. In this study 227 patients were randomized to primary stenting (n = 112) or PTCA (n = 115). The 6-month cardiac event-free survival rate was 95% in the stent group and 80% in the PTCA group (p = ) (12). Nonfatal reinfarction and repeat TVR accounted for the difference in the composite end point, since mortality rate was very low in both groups (2%). The major limitation of this study is that only a minority of patients with AMI were considered eligible for randomization, and randomized patients could be considered at very low risk. Out of the series of 498 patients with AMI admitted during the study period, 25 patients were treated conservatively, 21 were referred for immediate bypass surgery, and 225 were excluded for "high risk" anatomy (small IRA, diffuse IRA disease, target lesion involving a major side branch, no-reflow or extensive thrombus through the IRA, left main or severe 3-vessel disease, excessive IRA tortuosity). THE STENT-PRIMARY ANGIOPLASTY IN ACUTE MYOCARDIAL INFARCTION (PAMI) TRIAL This multicenter trial randomized 900 patients to primary stenting or primary PTCA. The 6-month incidence of the combined end point of death, reinfarction, disabling stroke or TVR was 12.6% in the stent group and 20.1% in the PTCA group (p = 0.01), and the difference was due entirely to the different rates of TVR in the 2 groups (13). Similarly to the Zwolle trial, in this study many patients with unfavorable characteristics were excluded (out of 1,458 patients with AMI, 558 were excluded from randomization mainly for a small IRA, IRA tortuosity, or a perceived need for stenting). Despite the adoption of these exclusion criteria, a substantial percentage of patients randomized to PTCA (15%) crossed over to stent because of suboptimal angiographic result. Thus, the trial, more exactly, compared a strategy of routine IRA stent implantation with a strategy of provisional IRA stenting. Differently from previously published trials, this study showed a trend toward increased mortality in the stent arm at 1 year (5.8% vs. 3.1%, p = 0.07). The increase in mortality in the stent arm was associated with a slight decrease in TIMI 3 flow rate compared to the PTCA arm, and this findings have raised questions regarding the benefit of routine stenting for AMI. Finally, no benefit of IRA stenting could be demonstrated in women (14). THE PRIMARY ANGIOPLASTY VERSUS STENT IMPLANTATION IN ACUTE MYOCARDIAL INFARCTION (PASTA) TRIAL This japanese multicenter study randomized 136 patients with AMI to primary stenting or primary PTCA. The 1 year incidence of major cardiac events was 21% in the stent group and 46% in the PTCA group (p = ) (15). THE STENTING IN ACUTE MYOCARDIAL INFARCTION (STENTIM) TRIAL This french multicenter trial randomized 211 patients with AMI to primary stenting or PTCA. At 1 year, the event-free survival rates (80.2% vs. 71.8%, p = 016), and the TVR rates (17.8% vs. 28.2%, p = 010) were similar in both groups, while the 6-month angiographic restenosis rate was lower in the stent group as compared to the one of the PTCA group (25.3% vs. 39.6%, p = 0.04) (16). The major limitation of this study is the very high cross-over rate to provisional stenting in the PTCA arm (36.4%). Overall, a total of 1,720 patients with AMI were randomized to primary stenting or no further intervention after PTCA. All studies showed a benefit of primary stenting in terms of decreased incidence of early and late repeat TVR, while as expected, no benefit of stenting in terms of decreased mortality could be demonstrated. At first sight, the results of these trials seem very similar. However several major differences in study designs should be emphasized to put these results into proper perspective. The 2 largest trials, the Zwolle and the Stent-PAMI trials, with a total of 1,127 patients, adopted inclusion criteria that resulted in the exclusion of a high percentage of high risk patients from randomization, and raised the

4 important question of the applicability of the results to the generality of patients with AMI, and not only to the low-risk patient subset. Furthermore, in all but 1 study, patients were randomized before PTCA. This study design feature resulted in a comparison of planned stenting with optimal as well as non-optimal PTCA, and also resulted in the cross-over of a substantial percentage of patients from PTCA arm to the stent arm. Thus, the pooled data from trials are not sufficiently evident to answer the major question of whether stents should be used as primary treatment in all cases, or as a provisional therapy for suboptimal or a poor angiographic results after balloon angioplasty. Observational prospective studies in nonselected patients with AMI may help to overcome the limitations of most randomized trial designs, resulting in an unnatural selection of patients with AMI and the enrollment of mainly low-risk patients. The Florence investigators have shown in 2 series of 190 and 201 consecutive patients with AMI that a policy of routine IRA stent implantation is highly feasible and may actually improve the outcome of patients with AMI (17,18). These population series reflect the "real world" of AMI, and included many patients who are poorly represented or excluded from randomized trials, such as elderly patients or patients with cardiogenic shock or severe left ventricular dysfunction. In the first series the incidence of patients over 75 was 22%, and of patients with cardiogenic shock 10%. In the second series, the incidence of elderly patients (over 75) was 16%, and of cardiogenic shock 9%. Primary IRA stenting was performed in most patients (85% in the first series, and 88% in the second series), and only a minority of patients, just those with a IRA diameter less than 2.5 mm did not have stenting attempt. The 6-month mortality rates were 5% and 9%, respectively, while the 6-month TVR rates were 12% and 14%, respectively. The results of these observational studies are consistent with those of the FRESCO trial, and strongly support the use of routine stent implantation in patients undergoing primary mechanical intervention. STENTING SMALL INFARCT RELATED ARTERIES Elective stenting of small coronary arteries is not a generally accepted practice, and retrospective analysis as well as randomized studies based on patients with angina did not find any advantage of elective stenting over PTCA (19-21). A lack of data exists about the efficacy of stent in small infarct arteries since 3 out of 5 randomized trials (GRAMI, Zwolle, Stent-PAMI) excluded patients with a vessel reference diameter < 3.O mm, while in the 2 trials that included patients with small arteries (PASTA, FRESCO) a separate analysis comparing elective stenting with PTCA in this subset of patients is not available. Further studies are needed to address this issue. STENTING LONG LESIONS Just like in other clinical settings, in patients with AMI the restenosis rate increases according to the stented length, and the placement of multiple or long stents increases the risk of restenosis and repeat TVR (22,23). POTENTIAL ADVANTAGES OF DIRECT IRA STENTING WITHOUT PREDILATION In the Stent-PAMI trial, IRA stenting was associated with a trend toward a lower incidence of TIMI grade 3 flow at the end of the procedure and an increased mortality as compared to angioplasty alone (14). On the other hand, an acute reduction of a normal angiographic flow after balloon angioplasty may be observed after stent deployment and expansion, suggesting that the negative effect on distal flow may be the consequence of increased atherosclerotic and thrombotic material embolization in the microvasculature. The rate of arterial embolization in the microvasculature after percutaneous coronary interventions is unexpectedly high (24). In patients with angina, the rate of arterial embolization complicated by myocardial infarction induced by stenting using a conventional technique appears to be greater than that occurring with balloon angioplasty (25). It is likely that the pathological substrate of AMI, including an already disrupted atherosclerotic plaque with superimposed thrombosis, may potentiate the bulk atherosclerotic-platelet embolization promoted by catheter based reperfusion therapy. Direct stenting without predilation could be expected to reduce embolization of plaque constituents and the incidence of the no-reflow phenomenon, thereby increasing perfusion and myocardial salvage in patients with AMI. It has been hypothesized that with the conventional stenting technique, the single or multiple high pressure balloon inflations after stent deployment, associated with a bulky effect of the expanding stent, may promote the embolization of atherosclerotic debris and thrombotic material extruded through the struts

5 during initial stent expansion (13). Moreover, in animal models it has been shown that stent deployment and expansion with a single balloon inflation is associated with less vessel wall injury (26), and as a consequence, one may infer, less disruption to distal flow produced by embolic material. Finally, coronary angioscopy performed after direct stent implantation in patients with AMI, has shown that the stent exerts a "jailing" effect on thrombotic material (Guagliumi G., personal communication, Endovascular Therapies Course, Paris, May 2000). Potential disadvantages of the direct stenting technique are embolization promoted during target lesion crossing attempt, stent loss, and incomplete balloon and stent expansion in a "hard" calcified lesion. Enhanced designs of second generation stents and delivery systems, as well as the enhanced crimping techniques, seem to overcome these potential limitations, while the risk of an undilatable lesion in the setting of AMI may be considered remote. Direct stenting was associated with a decreased incidence of no-reflow phenomenon as compared to conventional stenting in a series of 310 consecutive patients with AMI (27). THE ADDITIONAL BENEFIT OF MORE POTENT ANTIPLATELET THERAPY Additional benefit of IIb/IIIa inhibitors in terms of reduction of restenosis or reocclusion is suggested by the results of the RAPPORT trial and the RESTORE trial (28,29). In these studies stenting was strongly discouraged, and only a small cohort of patients had provisional stenting. Nevertheless, among patients with provisional stenting, a trend toward a reduction of the incidence of adverse events was revealed in patients treated with IIb/IIIa inhibitors. Most importantly, abciximab could have a benefit in clinical outcome, that is not related only to the reduction of target vessel failure, but also to a protective effect in the prevention and reduction of reperfusion injury by inhibition of activated alphambeta 2 receptors and as a consequence of neutrophil activation. In the ISAR (Intracoronary Stenting and Antithrombotic Regimen)-2 trial, 200 patients with AMI were randomized to IRA stenting alone, and 201 to IRA stenting plus abciximab (30). At 1-month, the incidence of the composite of death, nonfatal reinfarction, and target vessel revascularization was lower in the abciximab group as compared to the stent alone group (5.0% and 10.5%, respectively, p = 0.038). However, at 1 month, there were no differences between the 2 groups in the incidence of the individual components of the composite clinical end point, including mortality (2.0 in the abciximab group, and 4.5% in the stent alone group, p = 0.16). In the ADMIRAL (Abciximab before Direct angioplasty and stenting in Myocardial Infarction Regarding Acute and Long-term follow-up) trial, 150 patients with AMI were randomized to abciximab plus IRA stenting, and 150 to IRA stenting alone (31). The 1-month mortality rate was 3.3% in the abciximab group, and 7.3 % in the stent alone group. This difference did not reach significance (p = 0.33), and this was due mainly to the relative low-risk profile of patients enrolled. Nearly 90% of patients were in Killip class 1, the majority of them had nonanterior myocardial infarction, and the study design excluded patients with cardiogenic shock. The largest randomized trial comparing primary coronary angioplasty and primary coronary stenting with and without abciximab administration, is the CADILLAC (Controlled Abciximab and Device Investigation to Lower Late Angioplasty Complications) trial (32). This trial involved 2,082 patients who were randomized to 4 arms: conventional angioplasty and provisional stenting with and without adjunct abciximab treatment, and primary IRA stenting with and without adjunct abciximab treatment. The primary end point of the study was the 6-month composite incidence of death, reinfarction, disabling stroke, and ischemic target vessel revascularization. The comparison between the 2 groups of stent alone (516 patients), and stent plus abciximab (529 patients) did not show any clinical benefit of abciximab in patients undergoing routine IRA stent implantation. The incidence of the primary end point was 10.8% in the abciximab treated patients, and 10.9% in the stent alone group, and no differences were revealed for each individual component of the composite end point. The low risk of the enrolled population may explain these results.

6 The 6-month mortality rate was very low for all 4 arms (4.3% in the angioplasty alone arm, 2.3% in the angioplasty plus abciximab arm, 2.8% in the stent alone arm, and 3.8% in the stent plus abciximab arm), as was the median age of the 4 groups (60, 61, 60, and 61 years, respectively). Furthermore, patients with cardiogenic shock were excluded, and the baseline left ventricular function of the enrolled patients was nearly normal (the left ventricular ejection fraction, as assessed by the operator, was 50%). Finally, only in a minority of patients the left anterior descending artery was the infarct vessel (38.7%). In a mechanicistic randomized trial from the Munich investigators involving 200 patients with AMI, abiciximab plus IRA stenting was compared with stenting alone (33). Patients in the abciximab arm showed a better microvascular function recovery (assessed by intracoronary Doppler flow measurements) and left ventricular function recovery (assessed by angiographic left ventricular ejection fraction measurements). The results of this study suggest that the benefit of abciximab in patients with AMI who undergo routine IRA stent implantation is related to its effects on the microvessel network, resulting in a ultimate more effective reperfusion and myocardial salvage. The results of this study strongly support the use of abciximab in patients with AMI undergoing routine IRA stent implantation. Obviously, the improvement on coronary microvascular function and ventricular function might not be expected to be associated with an improvement in early survival in patients at low-risk while the expected impact on mortality could be easily revealed only in nonselected populations which include a relatively high percentage of patients with severe ventricular failure and large area at risk. Thus, the postulated mechanism of benefit may explain the lack of effect of abciximab on survival in concluded randomized studies that enrolled mainly low risk patients, while patients deemed trial ineligible could have had the major benefit from abciximab treatment. ADDITIONAL BENEFIT OF COATED STENTS AND NEW STENT DESIGNS The list of materials used to coat stents in an attempt to reduce thrombosis and restenosis is very long and ever increasing, but the only controlled experience of coated stents in AMI is the one of the PAMI investigators who used a heparin-coated stent (13). The potential advantages of heparin-coated stents are the reduction of stent platelet deposition and thrombotic occlusion, and very importantly, the elimination of the need for heparin infusion after stenting. The design of the study does not allow any conclusion about the role of the heparin-coated stent, since the potential benefit could be demonstrated by the comparison between the coated and the uncoated version of the stent. It should be noted that the incidence of the composite end point of death, myocardial infarction, repeat TVR in the Zwolle trial (12), where the uncoated version of the same stent was used, is almost identical to the one in the Stent-PAMI trial (12.5% vs. 12.4%). Nevertheless, in the Stent-PAMI trial only 37% of patients in the stent arm had postprocedural heparin infusion as compared to the 88% of the PTCA arm (p< 0.001). CONCLUSIONS Available data from randomized and non-randomized studies clearly support the extensive use of stents in patients with AMI. It is likely a synergistic effect of abciximab treatment in patients undergoing routine stent implantation. The efforts of the next years will be focused on further refinement of stent design and composition, and the evaluation of pharmacological agents effective in restoring myocardial perfusion to the fullest extent. REFERENCES 1. Cannon AD, Roubin GS, Macander PJ et al. Intracoronary stenting as an adjunct to angioplasty in acute myocardial infarction. J Invas Card 1991; 3: Wong PHC, Wong CM. Intracoronary stenting in acute myocardial infarction. Cathet Cardiovasc Diagn 1994; 33: Garcia-Cantu E, Spaulding C, Corcos T, et al. Stent implantation in acute myocardial infarction. Am J Cardiol 1996; 77: Rodriguez AE, Fernandez M, Santaera O, et al. Coronary stenting in patients undergoing percutaneous transluminal coronary angioplasty during acute myocardial infarction. Am J Cardiol 1996; 77:

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8 28. Brener SJ, Barr LA, Burchenal J, et al. Randomized, placebo-controlled trial of platelet glycoprotein IIb/IIIa blockade with primary angioplasty for acute myocardial infarction;: Reopro and Primary PTCA Organization and Randomized trial (RAPPORT) Investigators. Circulation 1998; 98: The RESTORE Investigators. Effect of platelet glycoprotein IIB/IIIa blockade with tirofiban and adverse cardiac events in patients with unstable angina or myocardial infarction undergoing coronary angioplasty. Circulation 1997; 96: Neumann F-J, Kastrati A, Schmitt C, et al. Effect of glycoprotein IIb/IIIa receptor blockade with abciximab on clinical and angiographic restenosis rate after the placement of coronary stents following acute myocardial infarction. J Am Coll cardiol 2000; 35: Montalescot G, Barragan P, Wittenberg O, et al. Abciximab associated with primary angioplasty and stenting in acute myocardial infarction: the ADMIRAL study, 30-day final result (abstr). Circulation 1999; 100 (suppl I): I Stone GW. CADILLAC: a 4-arms prospective multicenter randomized trial of PTCA vs. stenting with and without glycoprotein IIb/IIIa blockade in patients with acute myocardial infarction. 12th Transcatheter Cardiovascular Therapeutics Symposium, Washington DC, October Neumann FJ, Blasini R, Schmitt C et al. Effect of glycoprotein IIb/IIIa receptor blockade on recovery of coronary flow and left ventricular function after the placement of coronary-artery stents in acute myocardial infarction. Circulation 1998; 98: Top Your questions, contributions and commentaries will be answered by the lecturer or experts on the subject in the Interventional Cardiology list. Please fill in the form (in Spanish, Portuguese or English) and press the "Send" button. Question, contribution or commentary: Name and Surname: Country: address: Send Erase Top 2nd Virtual Congress of Cardiology Dr. Florencio Garófalo Steering Committee President fgaro@fac.org.ar fgaro@satlink.com Dr. Raúl Bretal Scientific Committee President rbretal@fac.org.ar rbretal@netverk.com.ar Dr. Armando Pacher Technical Committee - CETIFAC President apacher@fac.org.ar apacher@satlink.com Copyright Argentine Federation of Cardiology All rights reserved This company contributed to the Congress:

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