Primary Coronary Angioplasty in Acute Myocardial Infarction

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1 REVIEW ARTICLE Primary Coronary Angioplasty in Acute Myocardial Infarction Chih-Wei Chen, Chin-Lon Lin Division of Cardiology, Department of Internal Medicine, Buddhist Dalin Tzu Chi General Hospital, Chiayi, Taiwan ABSTRACT Acute myocardial infarction is a disease caused by sudden occlusion of the coronary arteries resulting in myocardial ischemia and necrosis. The mortality and morbidity rates are high. The most direct and effective treatment to reduce mortality and morbidity is early recannalization of the occluded coronary artery and reperfusion of the ischemic myocardium. Thrombolytic therapy used to be the treatment of choice for this disease and was documented to be effective in reperfusion. However, in recent years, primary percutaneous transluminal coronary angioplasty has been shown to have better results in reducing mortality, stroke (especially hemorrhagic stroke), reinfarction, recurrent ischemia, hospital stay and total costs in comparison with thrombolytic therapy. Routine stenting is recommended in all cases to lower rates of target vessel revasculization, restenosis and even death. Furthermore, for patients with acute ST elevation myocardial infarction presenting to hospitals without available catheterization laboratories or experienced staff, transfer to a primary angioplasty center has been shown to be superior to on-site thrombolytic therapy, especially for patients presenting more than 3 hours after symptom onset. (Tzu Chi Med J 2006; 18:1-7) Key words: primary, coronary, angioplasty, myocardial infarction, stenting PATHOGENESIS OF ACUTE MYOCARDIAL INFARCTION Acute ST-segment elevation myocardial infarction (STEMI) is a disease caused by rupture or fissure of a previously stable atherosclerotic plaque superimposed platelet aggregation and thrombus formation, resulting in coronary occlusion and full-thickness myocardial necrosis [1,2]. Most STEMI evolve from mild to moderate coronary stenosis [3]. Plaque rupture or fissure results in exudation of its lipid core into the coronary lumen as well as platelet aggregation [4]. The release of tissue factors from the lipid-rich core results in activation of the coagulation cascade and generation of thrombin [5]. These result in thrombus formation, which can interrupt the coronary blood flow and cause transmural infarction of the myocardium. THE IMPORTANCE OF REPERFUSION The cornerstone of treatment is recannulization of the occluded coronary artery and reperfusion of the ischemic myocardium. The relationship between the restoration of normal coronary artery flow and mortality after myocardial infarction is well documented. A metaanalysis of angiographic infarct trials showed a mortality rate of 3.7% in patients demonstrating normal flow compared with 6.6% (p=0.0001) in patients with impaired flow and 9.2% (p=0.0003) in patients with occluded or nearly occluded infarct related arteries [6]. Early restoration of normal myocardial blood flow is the therapeutic goal in the management of acute myocardial infarction. Thrombolytic therapy for acute myocardial infarction was first illustrated in 1958 [7] and the benefits in mortality and morbility were documented in many studies [8-10]. Based on the GISSI [8] and Received: April 19, 2005, Revised: May 13, 2005, Accepted: May 16, 2005 Address reprint requests and correspondence to: Dr. Chin-Lon Lin, Division of Cardiology, Department of Internal Medicine, Buddhist Dalin Tzu Chi General Hospital, 2, Min Sheng Road, Dalin, Chiayi, Taiwan N

2 C.W. Chen, C. L. Lin GUSTO [9] studies, thrombolytic therapy was considered the standard reperfusion therapy for acute myocardial infarction. It has been documented that treatment within one hour after onset of symptoms results in a 6.5% absolute reduction in mortality compared with placebo, and this benefit falls with time to 3.7% at 1-2 hours, 2.6% at 2-3 hours, 2.9% at 3-6 hours and1.8% at 6-12 hours [11]. Thus we see that the earlier the reperfusion to the ischemic myocardium, the lower the rate of mortality. WHY PRIMARY PERCUTANEOUS TRANSLUMINAL CORONARY ANGIOPLASTY (PTCA) INSTEAD OF THROMBOLYTIC THERAPY Although thrombolytic therapy significantly reduced mortality in acute myocardial infarction in comparison with placebo, many disadvantages and limitations were found. Hemorrhagic complications and low rates of patency of infarct related arteries caused the most concern. Intracranial hemorrhage occurred in about 0.5% to 1 % of patients in most studies [10,12-16] and was as high as 0.9% to 3.4% with more aggressive regimens [17-19]. The mortality rate was high in patients with this condition. Other hemorrhagic complications such as gastrointestinal and genitourinary bleeding, hemoptysis and access-site bleeding occurred frequently. These complications were life-threatening and hindered further anticoagulation and anti-platelet therapy, resulting in higher rates of coronary reocclusion after successful thrombolytic therapy. The GUSTO study demonstrated that only the presence of TIMI (thrombolysis in myocardial infarction) grade 3 flow in infarct-related arteries on the 90-minute angiogram was correlated with improved survival [9]. The 30-day mortality rate was 4.0% if TIMI grade 3 flow was restored, 7.9% if TIMI grade 2 flow was restored and 8.6% if TIMI grade 0 or 1 flow was restored. Yet, many studies showed a low patency rate following thrombolytic therapy. The angiographic substudy of the GUSTO trial showed that the 90-minute patency rate (TIMI grade 2 and 3) of the infarct related-artery was only 60% after treatment with streptokinase plus intravenous heparin, and 81% after accelerated t-pa (tissue plasminogen activator) plus intravenous heparin [20]. In addition to a low rate of coronary patency, there were no reliable markers to access the success of thrombolytic therapy except coronary angiography. A high risk of reinfarction and recurrent ischemia were additional disadvantages of thrombolytic therapy [21,22]. It was demonstrated that reinfarction was the most important determinant of late mortality after thrombolytic therapy for a first myocardial infarction [23]. For high-risk patients, such as those in cardiogenic shock, thrombolytic therapy seemed ineffective [24,25]. This may have been due to a low rate of coronary reperfusion in shock status. Primary percutaneous transluminal coronary angioplasty (primary PTCA), also called direct coronary angioplasty, is emergency coronary angiography followed by mechanical recanalization of the occluded coronary artery with a balloon catheter in cases of acute myocardial infarction. It was first performed by a group at the Mid America Heart Institute in November 1980 [26] and was first described by Hartzier et al in 1983 [27]. They demonstrated the safety and efficacy of direct percutaneous transluminal coronary angioplasty for infarct-related arteries in patients with acute myocardial infarction without thrombolytic therapy. Primary PTCA was demonstrated as an alternative reperfusion strategy for patients with acute myocardial infarction in addition to thrombolytic therapy. It has been recently recommended as the first choice for treatment. Primary PTCA offers many advantages over thrombolytic therapy, which we will discuss below. EVOLUTION OF PRIMARY PTCA In 1986 and 1987, the results of primary coronary angioplasty were reported from 6 single-center experiences [28-33]. These observational studies showed a patency rate of 87% to 95%, an in-hospital mortality rate of around 1.5% to 9%, and some increase in the left ventricular ejection fraction from admission to discharge. Although these were not randomized, controlled studies, the results were better than those of thrombolytic therapy. O'Keefe and coworkers reported 1000 consecutive patients undergoing primary coronary angioplasty at the Mid America Heart Institute [26]. The recanalization rate in infarct-related arteries was 94% and the mortality rate 7.8%. The independent risk factors for in-hospital mortality were cardiogenic shock, failure of reperfusion, age over 70 years, a left ventricular ejection fraction of 40% or less, and anterior myocardial infarction. The results encouraged further studies to test the superiority of primary coronary angioplasty. Some small randomized trials between 1990 and 1997 showed good results in mortality, nonfatal reinfarction and stroke rates. Three large-scale, randomized trials compared the outcomes of and major adverse cardiac events in primary coronary angioplasty and thrombolytic therapy. O

3 The first study was the PAMI (Primary Angioplasty in Myocardial Infarction) trial published in 1993[34-36]. A total of 395 patients with acute myocardial infarction seen within 12 hours of onset of chest pain were assigned randomly to undergo primary PTCA or receive intravenous t-pa infusion (100 mg over 3 hours). The trial successfully demonstrated a reduction in in-hospital deaths, nonfatal reinfarction, recurrent ischemia and intracranial hemorrhage. Fewer hospital days for primary PTCA were also evident. At two years after reperfusion, patients treated with primary PTCA had fewer deaths, repeat myocardial infarctions, repeat PTCAs, recurrent ischemias and hospital readmissions than patients who had t-pa. Zwolle published another trial in 1993 [37-41]. A total of 301 patients with acute myocardial infarction presenting within 6 hours of chest pain onset were randomly assigned to undergo primary PTCA or to receive intravenous streptokinase (1.5 MU over 1 hour). The trial showed lower rate of recurrent ischemia and fewer inhospital deaths, unplanned revasculization procedures required after PTCA and hospital stays. After a mean follow-up time of 2.6 years, patients treated with primary PTCA showed a higher rate of survival, a lower rate of reinfarction and less need for revasculization procedures, including PTCA or coronary artery bypass graft (CABG). In the substudy, patients treated with primary PTCA rather than thrombolytic therapy had a greater minimal luminal diameter in infarct-related arteries(1.99 ±0.83 mm versus 0.69±0.60 mm, p < 0.001), lower residual stenosis (35%±22% versus 77%±20%, p < 0.001), and less frequent reocclusion of the infarctrelated artery. In 1997, in the GUSTO(the Global Ulitization of Streptokinase and Tissue Plasminogen Activator for Occluded Arteries)-IIb Angioplasty Substudy [42], a total of 1,138 patients with acute myocardial infarction from 57 centers in 9 countries, were randomly assigned to treatment with primary PTCA or accelerated or frontloaded t-pa which was the best thrombolytic regimen [9]. This large population study demonstrated that patients who had primary PTCA had a 30% reduction in the composite end point of death, reinfarction and disabling stroke in comparison with those who had frontloaded t-pa. No hemorrhage stroke was found in the primary PTCA group and a 1.4% hemorrhagic stroke rate was found in the t-pa group. These 3 studies showed the benefits of primary PTCA in in-hospital mortality, reinfarction, recurrent ischemia, hospital stays, intracranial hemorrhage, long- term survival and repeat revasculization. In a 1999 [43] study, a total of 395 patients with acute myocardial infarction were randomly assigned to direct angioplasty or intravenous streptokinase. After a mean 5-year follow-up, primary PTCA showed a better clinical outcome in mortality (13% versus 24%), nonfatal reinfarction (6% versus 22%) and the rate of readmission for heart failure and ischemia in comparison with thrombolytic therapy with streptokinase. THE ROLE OF PRIMARY CORONARY STENTING IN ACUTE MYOCARDIAL INFARCTION As mentioned above, primary PTCA was documented to be superior to thrombolytic therapy in the patency rate of the infarct-related artery, survival rates, and rates of reinfarction and stroke. The rates of recurrent ischemia after primary PTCA in acute myocardial infarction were reported to be 5.5% to 10.3%, which resulted in increased morbidity, mortality and costs [35, 37,42]. Coronary stenting was proved to be effective in reducing the rates of restenosis and acute closure and in increasing the acute gain in luminal diameter in comparison with balloon angioplasty [44,45]. A nonrandomized trial [46] comparing primary stenting with balloon angioplasty in acute myocardial infarction showed a better outcome in in-hospital restenosis (0% versus 13.2%, p=0.007) and the major clinical events of repeat angioplasty, bypass surgery and death (2.8% versus 18.6%, p=0.009), 90-day clinical event-free rates (98%±16.0% versus 79%±43.7%, p= ) and 180-day event-free rates ( 86.5%±38.4% versus 64.2%±49.7%, p=0.014). Between 1998 and 2000, five randomized trials compared the results of primary stenting and balloon angioplasty in acute myocardial infarction [47-51]. In comparison with balloon angioplasty, primary stenting resulted in better minimal lumen diameters at pre-discharge [49,50] and 6-month follow-up angiograms [50], lower 6-month restenosis rates[48-51], lower rates of major cardiac events, including cardiac deaths, reinfarctions, target vessel revasculizations, at 6- and 12-months [47-51], and higher event-free survivals [47, 51]. A large-scale study published in 2002 elucidated of the role of stenting and abciximab in acute myocardial infarction [52]. A total of 2,082 patients were randomly assigned to four groups (PTCA alone, PTCA plus abciximab therapy, stenting, or stenting plus abciximab therapy). The results showed stenting implantation (with or without abciximab therapy) had less target-vessel revasculization(15.7% versus 5.2%, p<0.001), a lower P

4 C.W. Chen, C. L. Lin rate of angiographically established restenosis (22.2% versus 40.8%, p<0.001) and a lower rate of reocclusion of the infarct-related artery (5.7% versus 11.3%, p= 0.01). The authors recommended that stent implantation in acute myocardial infarction should be considered the routine reperfusion strategy. COST EFFECTIVENESS FOR PRIMARY CORONARY ANGIOPLASTY In addition to the clinical benefits of primary coronary angioplasty, reducing total costs is also an issue. In the PAMI trial [53], the average in-hospital total charge for 358 patients was insignificantly lower for patients treated with PTCA than for those with t-pa ($ versus $ 18903, p=0.21). In the Mayo Clinic trial [54], patients treated with primary PTCA, compared those with t-pa, had lower in-hospital costs ($ versus $ 21400, p=0.09), lower costs during the 6-month period after discharge ($ 480 versus $ 2738, p=0.03) and lower total 6-month costs ($ versus $ 24129, p= 0.09). In the Zwolle trial [55], total in-hospital costs were higher in patients treated with primary PTCA than in those treated with streptokinase ($ versus $ 11010, p<0.05). This result was different from two previous studies because less expensive thrombolytic agent (streptokinase) was used. During the 12-month followup, total costs were similar in the 2 groups ($ for PTCA versus $ in streptokinase) due to a higher incidence of stroke, death, reinfarction and recurrent ischemia in the streptokinase group. The above data demonstrated that the cost-effectiveness of primary PTCA in acute myocardial infarction is better than, or at least as good as that of thrombolytic therapy. SHOULD PATIENTS WITH ACUTE MYOCARDIAL INFARCTION BE TRANSPORTED TO TERTIARY HOSPITALS FOR PRIMARY CORONARY ANGIOPLASTY? Although the mortality, morbility, and cost benefits of primary coronary angioplasty in acute myocardial infarction have been documented, thrombolytic therapy is still the prevailing treatment in most countries due to a lack of 24-hour facilities for cardiac catheterization and experienced staff in most hospitals. The value of transferring patients initially admitted to a hospital without cardiac catheterization laboratory to a tertiary hospital with 24-hour percutaneous coronary intervention (PCI) has been tested in many studies in recent years. PRAGUE-2 [56] was a multicentre trial which followed 850 patients with acute ST elevation MI who presented within 12 hours of symptoms to the nearest community hospital without a catheterization laboratory. The patients were randomized to thrombolysis in the community hospital or immediate transport for primary PCI. Five complications (1.2%) occurred during the transport, including 2 deaths and 3 ventricular fibrillations which were successfully treated with defibrillation in the emergency vehicle. The mean transportation time was 48 minutes, and the time between randomization to reperfusion was 97 minutes. The results showed a significant benefit in mortality (6.0% for transferring for PCI versus 10.4% for on-site thrombolysis, p<0.05) and hospital stays (11±5 days for the PCI group versus 13±5 days for the thrombolysis group, p<0.05). The results showed no mortality difference in patients randomized within 3 hours of symptoms onset. A combined endpoint which included 30-day mortality, reinfarction, and stroke occurred in 8.2% of the PCI group versus 15.2% ofthe thrombolysis group (p<0.003). DANAMI-2 [57], the largest randomized, multicentre, controlled trial, followed 1,572 patients with acute ST elevation myocardial infarction who were treated with alteplase or primary PCI. A total of 1,129 patients were enrolled at 24 referral hospitals, of which 562 patients were randomized to fibrinolysis groups and 567 patients to angioplasty groups (transferred for PCI). A total of 443 patients were enrolled at invasive-treatment centers, of which 220 patients were randomized to the fibrinolysis group and 223 patients to the angioplasty group. The primary end point was a combination of death/clinical reinfarction/disabling stroke by 30 days. Among patients who underwent randomization at referral centers, the primary end point was reached in 8.5% of the patients transferred for PCI compared with 14.2% of the patients treated with alteplase (p=0.002). The result was similar among patients who were enrolled at invasive-treatment centers in which the primary endpoint was reached in 6.7% of the patients in the angioplasty group compared with 12.3% in the fibrinolysis group (p=0.05). The most significant benefit in the angioplasty group was a reduction in the reinfarction rate, which was 1.6% in the angioplasty group versus 6.3% in the fibrinolysis group, p<0.001); no significant differences were found in the rate of death (6.6% versus 7.8%, p=0.35) or stroke (1.1% versus 2%, p=0.15). The medium transport distance was 50 km and medium transfer time was 67 minutes. There were no deaths during transportation. In a meta-analysis trial [58] published in 2003, data Q

5 were analyzed from six recent studies which included 3750 patients. The transfer time was always less than 3 hours. The combined end point of death, reinfarction, and stroke was significantly reduced by 42% (95% confidence interval [CI] 29% to 53%, p<0.001) in the group transferred for primary PCI, compared with the group receiving on-site thrombolysis. When looking at the end points separately, reinfarction was significantly reduced by 68% and stroke by 56%. There was a trend towards a reduction of all-cause mortality of 19% by 30 days (p= 0.08). In conclusion, transfer for primary angioplasty has been shown to be superior to on-site thrombolytic therapy, especially for patients presenting more than 3 hours after symptom onset. This was mainly due to reduction in reinfarction, and to a lesser extent to a reduction in death and stroke by 30 days. CONCLUSION For patients with acute ST elevation myocardial infarction, primary PTCA is a better choice for reperfusion than thrombolytic therapy. In comparison with thrombolytic therapy, primary PTCA shows a better outcome in mortality, recurrent ischemia or infarction, stroke, hospital stays and short and long term costs. Primary coronary stenting is recommended for patients with acute ST elevation myocardial infarction due to less target-vessel revasculization, a lower rate of angiographically established restenosis, and a lower rate of reocclusion of the infarct-related artery. Furthermore, evidence demonstrates that for patients with acute myocardial infarction, especially for patients presenting more than three hours after symptom onset, transfer for primary PCI is a better choice than on-site thrombolysis. REFERENCES 1. DeWood MA, Spores J, Notske R, et al: Prevalence of total coronary occlusion during the early hours of transmural myocardial infarction. 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