Stent Trials in Acute Myocardial Infarction

IAGS 1998 Proceedings Stent Trials in Acute Myocardial Infarction Alfredo Rodríguez MD, PhD Primary angioplasty in the early phase of acute myocardial infarction has been demonstrated to reduce in-hospital major adverse events. PTCA has been shown to result in lower rates of mortality, recurrent myocardial infarction and stroke than t h r o m b o l y s i s. 1 3 Furthermore, this result was also demonstrated in the GUSTO IIB 4 trial, the largest randomized comparison between PTCA and thrombolysis. However, recurrent ischemia, early reocclusion of the infarct-related vessel (between 10 15%), suboptimal PTCA results, and less than TIMI 3 flow (15 20%) were also described with conventional balloon technique. 5 In the PAMI registry, suboptimal PTCA results are associated with higher in-hospital adverse events. 5 7 Also, angiographic restenosis or late reocclusion may occur in 50% of patients. 7 Preliminary non-randomized data indicate that unplanned stenting for suboptimal or poor angiographic results after primary PTCA may be safety performed with a high success rate. 8 10 In these early studies, inhospital mortality and recurrent ischemia were low despite the high-risk profile of the patients treated. Throughout 1996, several randomized trials comparing conventional balloon angioplasty with stents during the acute phase of myocardial infarction were started (Table 1). Four of these were published during this year and are the subject of this revision (Table 2). 11 14 From the Otamendi Hospital, Cardiac Unit, Buenos Aires, Argentina. Presented at the Fifth Biennial International Andreas Gruentzig Society Meeting, Punta del Este, Uruguay. Address reprint requests to: Centro de Estudios en Cardiologia Intervencionista (CECI), Anchorena 1858 1er Piso, (1425) Capital Federal, Buenos Aires, Argentina. The GRAMI Trial. 11 This multicenter study randomized 104 patients with less than 24 hours since symptom onset. It was limited to patients less than 75 years old. Patients with cardiogenic shock and Killip IIIwereincluded(16%),aswerethosewithfailed thrombolysis (8%). The Gianturco Roubin II stent (Cook, Inc., Bloomington, Indiana) was used. Randomization was begun after the guide wire crossed the culprit lesion. In this study of intention to treat analysis, procedural success was similar between the PTCA and stent groups. However, device success was better in the stent arm (98% vs. 75%). Due to acute complications or suboptimal PTCA results (defined as > 30% residual stenosis by on-line QCA), 25% of the balloon arm were stented during the initial procedure. Hospital mortality was not significantly different in the PTCA group (7.6%; 2.1% in patients without cardiogenic shock) versus 3.8% in the stent group. Major adverse cardiac events (defined as death, recurrent ischemia and reinfarction) were 19.3% in the PTCA group and 3.8% in the stent group (p = 0.03). After initial catheterization, 83% of the patients in the coronary angioplasty group and 96% in the stent grouphadatimiflowofgrade3(p <0.02).A m u l t ivariate predictors analysis of TIMI grade flow identified patients assigned in coronary angioplasty group and with Killip III IV independently associated with higher risk of less than TIMI 3 grade flow before hospital discharge. At late follow up, target lesion revascularization was not significantly different between the PTCA and stent arms (20.8% vs. 14%, respectively; p = 0.8). However, 56 The Journal of Invasive Cardiology

Stent Trials in Acute Myocardial Infarction Table 1. Study design in stent versus balloon angioplasty in acute myocardial infarction trials. Trial Name Principle Investigator Patient Number Device Final Results GRAMI A. Rodriguez 104 Gianturco-Roubin II Published (1998) FRESCO D. Antoniucci 150 Gianturco-Roubin II Published (1998) ESCOBAR H. Syprayanata 227 Palmaz-Schatz Published (1998) PAMI Pilot G. Stone 312 Palmaz-Schatz Published (1998) PASTA S. Saito 136 Palmaz-Schatz Abstract (1997) STENTIM-II L. Maillord 211 Wiktor Pending PAMI Randomized C. Grines 900 Palmaz-Schatz Abstract (1998) CADILLAC G. Stone 1720 Multi-Link Pending it must be noted that 25% of the patients in the PTCA group were stented during the initial procedure. Event-free survival, including in-hospital and followup, was better in the stent group than in the coronary angioplasty group (83% vs. 65%, respectively; p = 0.002). The FRESCO Trial. 12 This single-center study randomized 150 patients with acute myocardial infarction until 24 hours of symptom onset. Patients in Killip III and cardiogenic shock were included; no upper age limit was used. Patients with previous thrombolysis were excluded. Randomization started after optimal balloon angioplasty was achieved (residual stenosis < 30%). The Gianturco-Roubin II stent design was used. In both groups, 32% of the patients had a Killip of greater than II and 9% had cardiogenic shock. At 30 days, recurrent ischemia (defined as death, reinfarction or need for repeat revascularization) was 3% in the stent group versus 15% in the PTCA group (p = 0.009). At long-term follow up, recurrent ischemia was found in 28% of the PTCA group and 9% in the stent group (p = 0.003); target lesion revascularization was also better in the stent group than in the PTCA group (7% versus 25%, respectively; p =0.002).At6 months, freedom from survival events was 87% in stent group versus 68% for the PTCA group (p = 0.002). Multivariate analysis showed that the only Table 2. Study design: Stent versus balloon angioplasty in acute myocardial infarction. PAMI Trial GRAMI FRESCO ESCOBAR Pilot Killip III-IV 16% 16% Few Few Cardiogenic shock 8% 9% No No Age limit Yes No Yes No Mechanical ventilation Included Included Excluded Excluded Previous thrombolysis Included Excluded Excluded Excluded TIMI counter Yes No No Yes independent predictor of freedom from recurrent ischemia was stenting of the IRA. A follow-up angiogram was performed in 95% of the study group. Angiographic restenosis was significantly lower in the stent group (15% vs. 30% in the PTCA group; p = 0.036). Including early outcomes, angiographic restenosis or reocclusion occurred in 47% of the PTCA group and in 17% of the stent group (p = 0.001). Even though this study randomized patients only after an optimal balloon angioplasty, it is still evident that primary stenting achieved better acute and long-term results. The ESCOBAR Trial. 13 This single-center study included patients with acute myocardial infarction during the first 6 hours and also from 6 24 hours after exhibiting persistent ischemia symptoms. Patients requiring mechanical ventilation, in cardiogenic shock, or those with previous thrombolytic therapy were excluded. Randomization started after the guide wire crossed the target lesion. The bare Palmaz-Schatz stent design (Cordis Corporation, Miami, Florida) was used. Multiple angiographic and technical exclusions (i.e., unprotected left main, severe multivessel disease, bifurcation lesion, excessive vessel tortuosity, etc.) related to stent design were used. Two hundred and twenty-seven patients were randomized to either the PTCA (n = 115) or stent group (n = 112). Procedural success was similar in both study groups; however, 13% of the patients in the PTCA group were crossed over to the stent group during the initial procedure (p = 0.0016). In-hospital death and recurrent infarction were similar in both groups (3% in stented patients versus 7% in PTCA patients; p = NS). At six months follow-up, recurrent infarction was higher in the PTCA patients (7%versus1%instentedpatients;p = 0.036). Repeat revascularization procedures were lower in stented patients than in PTCA patients (4% vs. 17%, respectively; p = 0.0016). Consequently, event-free survival was significantly higher in the stented patients (95%) than in the balloon angioplasty group (80%; p = 0.0012). Vol 11 No 1 January 1999 57

RODRIGUEZ Table 3. In-hospital and late outcome Trial GRAMI FRESCO ESCOBAR PAMI Pilot Hospital Events Major adverse cardiac events Reduced * Reduced * Similar TIMI grade 3 Improved Not available Not available Improved Late Events Target lesion revascularization Similar Lower ** Lower ** Event free Improved Improved Improved Restenosis Similar Lower ** Not available Results expressed outcome of stents over PTCA arm. p=0.036; * p=0.03; ** p=0.002 Multivariate analysis of the predictors of major cardiac events identified the following factors associated with adverse outcomes: male; Killip > 2; and treatment with balloon angioplasty. The PAMI Stent Pilot. 14 This trial was a nonrandomized multi-center pilot study of the safety and feasibility of primary stenting in acute myocardial infarction. Only the highly-qualified centers of the PAMI investigators were involved in this trial (7 in North America, 1 in Europe and 1 in South America). Patients with less than 12 hours of AMI were included. Those patients with cardiogenic shock or previous thrombolysis were excluded. PTCA was first performed to restore patency; a Palmaz-Schatz stent was then deployed. There were several anatomical and technical exclusions (i.e., ostial LAD or LCX, bifurcation lesion, excessive lesion tortuosity or lesion calcification, etc.) many of them related to the stent design. Upon admission, only 12.5% of the patients were in Killip II or more (basal ejection fraction of 48% in the stent arm). Stenting was attempted in 240 patients and PTCA in only 72 patients (stenting was not to be considered feasible in this group). In-hospital rates of death and reinfarction were low in the stent group (0.8% and 1.7%, respectively). The need for repeat revascularization during hospitalization and at 30 days was significantly lower with the stent group. TIMI grade 3 flow was achieved at the end of the procedure in 94.4% of the stented patients versus 87.3% of PTCA patients; p = 0.04 (central core laboratory analysis). CONCLUSION The results of these early trials, in which coronary stenting was used electively as a primary device in the infarct-related artery during acute myocardial infarction, are summarized in Table 3. Although rates of target lesion revascularization and angiographic restenosis are not reduced with stents in the GRAMI trial, they are significantly lower than those previously reported with conventional balloon angioplasty during acute myocardial infarction. 7 REFERENCES 1. Grines CL, Browne KR, Marco J, et al. Comparison of primary angioplasty with thrombolytic therapy for acute myocardial infarction. N Engl J Med 1993;328:673 679. 2. Zijlstra F, DeBoer MJ, Hoorntje JCA, et al. A comparison of immediate coronary angioplasty with intravenous streptokinase in acute myocardial infarction. N Engl J Med 1 9 9 3 ; 3 2 8 : 6 8 0 6 8 4. 3. Gibbons RJ, Holmes DR, Reeder GS, et al. Immediate angioplasty compared with the administration of a thrombolytic agent followed by conservative treatment for myocardial infarction. N Engl J Med 1993;328:6985 6991. 4. The global use of strategies to occluded coronary arteries in acute coronary syndromes (GUSTO IIb) angioplasty study investigators. A clinical trial comparing primary coronary angioplasty with tissue plasminogen activator for acute myocardial infarction. N Engl Med 1997;336:1621 1628. 5. O Neill WW, Brodie BR, Ivanhoe R, et al. Primary coronary angioplasty for acute myocardial infarction (the primary Angioplasty Registry). Am J Cardiol 1994;73:627 634 6. Stone GW, Grines CL, Browne KF, et al. Implications of recurrent ischemia after reperfusion therapy in acute myocardial infarction: A comparison of thrombolytic therapy and primary coronary angioplasty. J Am Coll Cardiol 1995;26:66 72. 7. Stone GW, Grines CL, Browne et al. Predictors of in-hospital and 6-month outcome after acute myocardial infarction in the reperfusion era: The Primary Angioplasty in Myocardial Infarction (PAMI) trial. J Am Coll Cardiol 1995;25:370 377. 8. Rodriguez AE, Fernandez M, Santera O, et al. Coronary stenting in patients undergoing percutaneous transluminal coronary angioplasty during acute myocardial infarction. Am J Cardiol 1996;77:685 689. 9. Antoniucci D, Valenti R, Buonamici P, et al. Direct angioplasty and stenting of the infarct-related artery in acute myocardial infarction. Am J Cardiol 1996;78:568 571. 10. Saito S, Hosokawa G, Kunikane K, et al. Primary stent implantation without coumadin in acute myocardial infarction. JAm Coll Cardiol 1996;28:74 81. 11. Rodriguez A, Bernardi V, Fernández M, et al. In-hospital and late results of coronary stents versus conventional balloon angioplasty in acute myocardial infarction (GRAMI trial). Am J Cardiol 1998;81:1286 1291. 1 2. Antoniucci D, Santoro GM, Bolognese L. A clinical trial comparing primary stenting of the infarct-related artery with optimal pri- 58 The Journal of Invasive Cardiology

Stent Trials in Acute Myocardial Infarction mary angioplasty for acute myocardial infarction. Results from the Florence Randomized Elective Stenting in Acute Coronary Occlusions (FRESCO) Trial. J Am Coll Cardiol1 9 9 8 ; 3 1 : 1 2 3 4 1 2 3 9. 1 3. Suryapranata H, Van t Hof AWJ, Hoorntje JCA, et al. Randomized comparison of coronary stenting with balloon angioplasty in selected patients with acute myocardial infarction. C i r c u l a t i o n 1 9 9 8 ; 9 7 : 2 5 0 2 2 5 0 5. 14. Stone GW, Brodie BR, Griffin JJ, et al. Prospective, multicenter study of the safety and feasibility of primary stenting in acute myocardial infarction: In-hospital and 30 day results of the PAMI stent pilot trial. J Am Coll Cardiol 1998;31:23 30. PANEL DISCUSSION STEPHEN RAMEE: That was a very nice study, Dr. Rodriguez. First, I have a comment regarding the choice of the Gianturco-Roubin II stent for treating an acute myocardial infarction: how do you think that compares with other stents that are available? Second, what was the role of IIb/IIIa inhibitors in this patient population? Lastly, I just want to make a comment. In 100 consecutive patients that we treated with stenting, a higher incidence of acute occlusion during the first 30 days was found in diabetic patients; this was almost non-existent in the non-diabetic patients. I wonder if you have any thoughts on that. ALFREDO RODRIGUEZ: Regarding your first question: I think it is important to use a flexible stent when treating an acute myocardial infarction; we may be dealing with a total occlusion, and a flexible stent may prove to be more advantageous in this case. The incidenceofsidebranchpressureinthisstudywas almost 7% in 10 groups because of the use of stents. Add in the restenosis rate in the first group and our result is favorable we have only 16% restenosis. Regarding the question about the role of IIb/IIIa in this trial: we did not use IIb/IIIa inhibitors, but I think they could play a role in some thrombotic lesions or in a bypass surgery. The interventional cardiology community routinely uses IIb/IIIa agents, which may result in acute myocardial infarction or compromise the saphenous vein graft. Regarding your last question: in our experience, there is no difference in the occlusion rate between diabetic and non-diabetic patients. LUIS DE LA FUENTE: I think that Dr. Rodriguez s presentation is important because it demonstrates that when dealing with acute myocardial infarction, the most important factor to consider is a good opening of the artery responsible for the infarction and to obtain a good coronary flow. We started doing selective coronary angiographies in patients with acute myocardial infarction in January 1970 28 years ago this month. In almost all cases of acute transmural myocardial infarction that were studied in the first 4 hours, we found that a complete obstruction of the artery was responsible for the infarction; this confirmed Herric s research in 1912, which stated that coronary thrombosis is the cause of an acute myocardial infarction in the majority of patients. However, the cardiology establishment of the 1970s accepted the opinion of pathologists like Roberts, who believed that many occluding thrombi develop as a terminal or secondary event in recent myocardial infarction. This misconception delayed the modern treatment of acute artery myocardial infarction for several years. Pathological studies indicate that the majority of coronary obstructions resulting in acute myocardial infarction are severe, and that the thrombi is superimposed on a disrupted atherosclerotic plaque. Now we find ourselves with another paradigm shift. Coronary angiographic studies before and after nonfatal myocardial infarction reveal that the pre-existing lesion is mild or moderate at the site of the total obstruction. At the present time, many cardiologists conclude that plaque rupture often occurs in mildly occlusive coronary artery atherosclerotic plaques, resulting in an acute occlusion as a consequence of a superimposed large thrombus. We do not agree with this concept. First of all, these studies consist of less than 350 patients. The interval between the two coronary angiograms pre and post-myocardial infarction varies from several weeks to over 55 months. Sometimes, a complicated atherosclerotic plaque can increase its size and configuration in a relatively short time; therefore, what kind of conclusion can we reach with angiograms performed weeks or months before the acute myocardial infarction? Pathological studies show that there are different types of atherosclerotic plaques in acute myocardial infarction depending upon the amount of its fibrous and/or lipidic content. If the plaque has a lot of fibrous tissue and is severe, there is usually not much of a thrombus. On the other hand, if the plaque is severe and soft when it ruptures, its lipidic content is eliminated; this leaves a mild or moderate residual obstruction with a variable amount of thrombus mixed with atherosclerotic material. Dr. O Neill showed in his lecture that 21% of patients with acute myocardial infarction have thrombi and atherosclerotic material with the ruptured plaque. The paper that Dr. O Neill presented earlier is very important because it not only changes our idea of how to treat AMI patients, but also allows us to better understand its pathophysiology. If it was true that a ruptured atherosclerotic plaque of a mild coronary obstruction could lead to a total occlusion, one would be unable to successfully perform coronary angioplasties in unstable patients and would be less able to do so in AMI patients; I have not Vol 11 No 1 January 1999 59

RODRIGUEZ found this to be the case. We do not believe that there is a severe obstruction with either a hard or soft plaque with a superimposed thrombus at the moment of the acute event; that is the reason why PTCA has better results than thrombolytic therapy in acute myocardial infarction. I would like to invite Dr. O Neill to comment. BILL O NEILL: I think we must not consider all acute infarctions to be heterogenous events. There are some clinical clues as to which patients have more atherosclerotic burden. There is actual literature here from Argentina that examines the adverse prognosis of de novo angina versus de novo s y m p- toms versus patients that have antecedent angina. The patients who have had antecedent angina and then acute infarction often have had an atherosclerotic plaque with very low thrombus; I think those patients are the ones where mechanical approaches are going to be superior. Young patients who are smokers tend to have thrombus and less atherosclerotic obstruction. Therefore, I think we do need to have some clinical tools for differentiating between patients, because we may want to have separate strategies for the different pathologies. LUIS D E L A FUENTE: I am not referring to the clinical ramifications; I am talking about the pathophysiology of AMI and the different types of atherosclerotic plaques that can be present. Perhaps the younger AMI patients that smoke have softer lipidic plaques. When you do coronary angioplasty in patients with AMI, the plaque is sometimes soft and able to be opened with one or two atm; other times the plaque is very hard and we need 10 or more atm to get a good angiographic result. One usually needs a slow flow rate by a severe obstruction in order to get a superimposed thrombus and a total occlusion. 60 The Journal of Invasive Cardiology