Although restoration of blood flow to ischemic regions is essential, the accompanying reperfusion injury initially can worsen rather than improve myocardial dysfunction. The area at risk is affected not only by reperfusion but also by the conditions of reperfusion and the composition of the reperfusate.32 Thus controlling reperfusion itself may aid in reducing myocardial infarct size and ventricular injury.
At the cellular level, myocardial ischemia results in a change in energy production from aerobic to anaerobic metabolism. The consequences of ischemia vary from decreased adenosine triphosphate production and increased intracellular calcium to decreased amino acid precursors such as aspartate and glutamate. These changes can be reversed only by reperfusion.
However, as oxygen is reintroduced into a region, oxygen free radical generation ensues with resulting cellular damage. Cellular swelling and/or contracture leads to a "no-reflow phenomenon" that limits the recovery of some myocytes and possibly adds to irreversible injury of others. The production of oxygen free radicals during ischemia and at the time of reperfusion is the leading mechanism proposed to explain cellular injury. Four basic types of reperfusion injury have been described: lethal cell death, microvascular injury, stunned myocardium, and reperfusion arrhythmias (Table 24-4).
Buckberg and coworkers33–38 conducted studies of controlled reperfusion after ischemia and produced a clinical application for controlled reperfusion. The surgical strategy of controlled reperfusion, especially as espoused by Buckberg and associates, includes several elements. First, extracorporeal circulation is established as expeditiously as possible with venting of the left ventricle as required. Initially, antegrade cardioplegia is delivered using either a warm Buckberg solution to rebuild adenosine triphosphate stores or cold high-potassium cardioplegia to achieve rapid diastolic arrest. We routinely add retrograde cardioplegia to ensure global cooling, even in areas of active ischemia. The temperatures of the anterior and inferior walls of the ventricle are measured to ensure adequate cooling. After each distal anastomosis, cold cardioplegia is infused into each graft and the aorta at 200 mL/min over 1 minute. This is followed by retrograde infusion through the coronary sinus for 1 minute. After completion of the final distal anastomosis, warm substrate-enriched blood cardioplegia is given at 150 mL/min for 2 minutes into each anastomosis and the aorta. After removal of the aortic cross-clamp, regional blood cardioplegia is given at 50 mL/min into the graft supplying the region at risk for 18 minutes. This controlled rate of reperfusion minimizes cellular edema and myocyte damage. The proximal vein grafts are then completed, followed by reestablishment of normal blood flow. To decrease oxygen demand, the heart is allowed to beat in the empty state for 30 minutes. After this time, the patient is weaned off bypass.
Application of the Buckberg solution and technique has been shown to be effective in improving mortality rates and myocardial function after acute coronary occlusion. With ischemic times averaging 6 hours, a prevalence of multivessel disease, and cardiogenic shock, the overall mortality in patients with acute coronary arterial occlusions who underwent surgical revascularization applying this method of reperfusion was 3.9%. Postoperative ejection fractions averaged 50%.39 Surgical revascularization in this series using controlled reperfusion compared favorably with PTCA in several large series. The superior results of this method for the treatment of cardiogenic shock, a 9% mortality, have brought this method to the forefront in the treatment of cardiogenic shock.
Role of Thrombolytic Therapy
Because myocardial salvage depends on reperfusion of occluded coronary arteries, rapid dissolution of an occluding thrombus with thrombolytic therapy is an appealing intervention. Intracoronary streptokinase in patients with acute myocardial infarction demonstrates that thrombolytic therapy is a safe and efficient way to achieve the desired early reperfusion.40 Following this study, a number of multi-institutional megatrials showed the effectiveness of thrombolytic therapy in treating acute myocardial infarctions.
The trial of the Italian Group for the Study of Streptokinase in Myocardial Infarction (Gruppo Italiano per lo Studio della Streptochinasi nell'Infarto Miocardio, [GISSI])41 and the Second International Study of Infarct Survival [ISIS-2])42 found a reduced hospital mortality in patients treated with streptokinase. The effectiveness of tissue-type t-PA also has been evaluated in randomized studies. The Thrombolysis in Myocardial Infarction (TIMI) study43 and the European Cooperative Study Group (ECSG)44 demonstrated the effectiveness of t-PA for the treatment of acute myocardial infarction.
When streptokinase and t-PA were compared, two studies failed to demonstrate any difference in mortality.45,46 A third study, however, the Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries (GUSTO) trial, supported the use of t-PA by demonstrating a more rapid and complete restoration of coronary flow that resulted in improved ventricular performance and reduced mortality.47,48
Although thrombolysis improves survival and ventricular function, the patency of infarct-related arteries is reported to be between 50 and 85%.41–48 Normal flow should be achieved in 60% of patients by today's standards. Thrombolytic therapy works well but is not without complications, including bleeding and intracranial hemorrhage.49 Bleeding is usually minor and occurs mostly at the sites of vascular puncture. Intracranial hemorrhage and stroke rates are around 1% and are an "acceptable" risk. The relative benefits of thrombolytic therapy appear to decrease as patient age increases, and a higher risk of intracranial hemorrhage in the elderly may partially account for these findings.47,50,51 Careful selection of patients suitable for fibrinolytic therapy is warranted, especially in an increasingly older population.
Thrombolytic therapy for patients presenting in cardiogenic shock or heart failure does not appear to improve survival in this population but may decrease the incidence of patients developing heart failure after myocardial infarction.52
Thrombolytic agents for the treatment of myocardial infarction have demonstrated several important points. Survival is improved by decreasing time to reperfusion. The GUSTO trial showed that patients treated within the first hour had the greatest improvement in survival, with a 1% reduction in mortality for each hour of time saved.47,48 Thrombolytic therapy is easy to administer in the community by trained personnel, although a significant risk of bleeding exists in certain patients. Because the time to reperfusion is a critical element in preserving myocardium, thrombolytic therapy is ideal for most communities without percutaneous interventional capabilities. In this setting, thrombolytics may be used for treatment of patients with acute myocardial infarction.
Role of Percutaneous Transluminal Coronary Angioplasty
Since the first reported use of PTCA by Gruntzig and associates74 in 1979, the efficacy of this procedure in the treatment of coronary artery disease has been well recognized. A number of studies have evaluated the efficacy of primary PTCA in the treatment of acute myocardial infarction. Overall, PTCA hospital mortality rates range from 6 to 9%.53–56
Several different strategies employing PTCA for acute myocardial infarction have been developed and examined through clinical trials. Primary, rescue, immediate, delayed, and elective PTCA are options for the treatment of acute myocardial infarction. Primary PTCA uses angioplasty as the method of reperfusion in patients presenting with acute myocardial infarction. Rescue, immediate, delayed, and elective PTCA all are done in conjunction with or following thrombolytic therapy. Rescue PTCA is done after recurrent angina or hemodynamic instability after thrombolytic therapy. Immediate PTCA is performed in conjunction with thrombolytic therapy, and delayed PTCA occurs during the intervening hospitalization. Finally, elective PTCA is done following thrombolytic therapy and medical management when a positive stress test is obtained during the same hospitalization or soon thereafter.
Primary PTCA functions in several roles for the treatment of acute myocardial infarctions. Because there are some absolute and relative contraindications to thrombolytics, PTCA is the one of best methods of reperfusion in patients with acute myocardial infarction, according to studies that evaluated PTCA as first-line therapy. Several studies evaluated the role of PTCA compared with thrombolytic therapy. The first study, the Primary Angioplasty in Myocardial Infarction Study Group trial in 1993, concluded that immediate PTCA without thrombolytics reduced occurrence of reinfarction and death and was associated with a lower rate of intracranial hemorrhage.53 Since then, more than 20 studies have compared PTCA to thrombolysis. The results from these studies have consistently and conclusively demonstrated the superiority of PTCA to thrombolysis, regardless of the thrombolytic agent used. The findings include a lower short-term mortality rate, lower rates of reinfarction, reduced stroke and intracranial hemorrhage rates, and a decreased composite end point of death, reinfarction, and stroke.57 These findings have been reconfirmed on long-term follow-up. A higher overall rate of bleeding was observed, likely because of vascular access complications. Myocardial salvage is similar for PTCA and thrombolytic therapy. However, primary PTCA may be slightly less costly than thrombolytic therapy.54
There are limits to the use of primary PTCA. Logistic and economic constraints apply to invasive modes of therapy. Catheterization laboratories and personnel must be ready at all times. This is not practical in most communities, and transportation to tertiary care centers raises costs considerably.
The use of intracoronary stents after myocardial infarction has expanded as PTCA has become more prevalent. Benefits of stenting include lowered rates of restenosis and abrupt closure, and a reduced need for target revascularization after PTCA. Although the STENT-PAMI trial in 1999 using first-generation stents showed lower restenosis rates compared with thrombolysis, a trend toward higher mortality was seen, and its effectiveness as first-line therapy was questioned.58 Composite end points of death, reinfarction, and urgent target vessel revascularization at 30 days have now been shown to be lower in subsequent studies, such as the CADILLAC, ISAR-2, and ADMIRAL trials, which employed newer-generation stents.59–61 In these trials, abciximab, a glycoprotein IIb/IIIa inhibitor, was added to primary stenting. A striking reduction in restenosis rates with stenting plus abciximab versus PTCA alone was evident at 12-month follow-up in the CADILLAC study (41 versus 22%).59 Current data suggest that stenting combined with antiplatelet therapy provides superior benefit to PTCA alone. Drug-eluting stents offer the potential to lower restenosis even further through the use of anti-inflammatory medication delivered via the stent. Most recently, patients in the STRATEGY trial treated with drug-eluting stents after acute ST-elevation myocardial infarction (STEMI) had a significantly lower composite end point of death, reinfarction, stroke, and angiographic evidence of restenosis at 8-month follow-up compared with bare-metal stenting plus abciximab (50 versus 19%).62 Using propensity score matching, retrospective analysis of patients post acute myocardial infarction in Massachusetts has shown a slight 2-year mortality benefit for drug-eluting stents when compared with bare-metal stents (10.7 versus 12.8%), as well as a lower need for repeat revascularization.63 Further prospective studies are under way to determine if long-term data confirm these findings.
Antithrombotic agents continued for 12 to 18 hours after PTCA and stenting are an important adjunctive therapy to prevent further ischemic complications. Traditional agents, such as heparin, have been replaced by glycoprotein IIb/IIIa inhibitors, which may have survival benefit when used after PTCA.64 Newer agents, such as direct thrombin inhibitors, have been introduced with the hope of reducing bleeding and/or heparin-associated complications. The Harmonizing Outcomes with Revascularization and Stents in Acute Myocardial Infarction (HORIZONS-AMI)65,66 trial investigated bivalirudin, a direct thrombin inhibitor, versus heparin plus a glycoprotein IIb/IIIa inihibitor for use after primary PTCA with or without stenting. Both 30-day and 1-year outcomes revealed decreased hemorrhagic events, and 1-year cardiac mortality was lower in patients treated with bivalirudin, despite a higher 24-hour risk of stent thrombosis in the bivalirudin cohort. Concerns regarding increased thrombogenicity with drug-eluting stents persist; further research is warranted to ensure that late in-stent thrombosis does not preclude use in this setting. Intracoronary stenting with adjunctive antiplatlelet medications has been embraced by the medical community for off-label use after acute myocardial infarction since its recent introduction.
Primary PTCA may play a greater role in patients presenting in cardiogenic shock, and percutaneous interventions have become more common over the past 10 years (Fig. 24-4). The GISSI-1 and GISSI-2 trials demonstrated no benefit from intravenous thrombolysis, with mortality rates of 70%.41,45 In patients presenting in or developing cardiogenic shock after acute myocardial infarction, PTCA improved survival to 40 and 60%.67 This improvement was even greater when angioplasty was successful; in-hospital survival rates increased to 70%. In most of these series an IABP was used in conjunction with PTCA. The SHOCK trial showed that revascularization by PTCA or CABG within 12 hours of the onset of cardiogenic shock results in improved 1- and 6-year survival rates versus medical stabilization followed by delayed revascularization (32.8 for PTCA/CABG versus 19.6% for initial medical stablization, 6-year follow-up) in this high-risk group, particularly for those under the age of 75 years (Fig. 24-5).12,30,31 Subgroup analysis in patients undergoing successful PTCA or with TIMI Grade 3 coronary flow after PTCA in the SHOCK trial revealed that 1-year survival was even higher, at 61%.68 Independent predictors of mortality include age, hypotension, lower TIMI flow, and multivessel PTCA.
Survival estimates for early revascularization (n = 152) and initial medical stabilization (n = 150) groups in the SHOCK trial. Log-rank test, p = .03. ERV = early revascularization groups; IMS = initial medical stabilization group. (Reproduced with permission from Hochman JS, Sleeper LA, White HD, et al: One-year survival following early revascularization for cardiogenic shock. JAMA 2001; 285:190.)
Revascularization rates in patients with cardiogenic shock at presentation (n = 7356). (Reproduced with permission from Babaev A, Frederick PD, Pasta DJ, et al: Trends in management and outcomes of patients with acute myocardial infarction complicated by cardiogenic shock. JAMA 2005; 294:448.)
Primary PTCA or intracoronary stenting should be performed as first-line therapy in patients with acute myocardial infarction and those with contraindications to thrombolytic therapy. Patients with established or developing cardiogenic shock should be revascularized early by PTCA or stenting rather than initial medical stabilization by thrombolytic therapy. Specialized centers that have 24-hour catheterization facilities can provide primary PTCA or stenting as a first-line therapy. Rescue PTCA after failed thrombolytic therapy for patients with ongoing ischemia or clinical compromise is also recommended. Finally, elective PTCA should be performed on patients who have recurrent or provokable angina before hospital discharge.
Role of Coronary Artery Bypass Grafting
The role of surgical revascularization in the treatment of acute myocardial infarction has changed considerably over the past 30 years. Improvements in intraoperative management and myocardial preservation techniques have strengthened the surgeon's armamentarium. However, the development and use of thrombolytic therapy and PTCA offer effective alternatives to surgery.
During the 1980s, reports appeared recommending surgical revascularization in preference to medical therapy for acute myocardial infarction.69,70 Mortality rates under 5% were reported. Critics argued that these studies lacked randomization or consecutive entry of patients, preoperative stratification was absent, and enzyme levels were not included. Inherent bias that favored surgery in low-risk patients was believed to be the reason for the excellent outcomes.71
At the time these reports surfaced, thrombolytic therapy and interventional cardiology were emerging as alternative options for acute infarction. With the availability of thrombolytics and PTCA, large multicenter trials began looking at the efficacy and usefulness of these two techniques. Randomized trials using CABG were not done, and thus this option was never established as an alternative for acute myocardial infarction.
However, several centers continued to use surgical revascularization to treat acute myocardial infarction. Excellent results were achieved by coordinated community and hospital systems. However, practical, logistic, and economic constraints relegate surgical revascularization to a third option behind thrombolytics and PTCA for the primary treatment of acute myocardial infarction.
There continue to be several scenarios that require emergent or urgent surgical revascularization. Failure of thrombolytics, PTCA, or intracoronary stenting with acute occlusion may require surgical intervention. Additionally, CABG for postinfarction angina has become a critical step in the pathway of treating acute myocardial infarction. Finally, surgical revascularization may be indicated in patients with multivessel disease or left main coronary artery disease developing cardiogenic shock after myocardial infarction.
If surgical revascularization within 6 hours after the onset of symptoms is feasible, the mortality rate is improved over that of medically treated, nonrevascularized patients.69,70 Although these early studies were not controlled and were criticized for selection bias, they did demonstrate that surgical revascularization may be performed with an acceptable mortality in the presence of acute myocardial infarction with improved myocardial protection, anesthesia, and surgical techniques. However, with the advent of thrombolytic therapy, PTCA, and an aging population, the surgical patient we encounter today bears little resemblance to the patient population represented in these early data.
Recent analyses of the New York State Cardiac Surgery Registry, which included every patient undergoing a cardiac operation in the last decade in the state of New York, resulted in valuable information regarding the optimal timing of CABG in acute myocardial infarction. In this large and contemporary patient population, there is a significant correlation between hospital mortality and time interval from acute myocardial infarction to time of operation, particularly if CABG was performed within 1 week of acute myocardial infarction. In addition, patients with transmural and nontransmural acute myocardial infarction have different trends in mortality when the time course is taken into consideration. Mortality for the nontransmural group peaked if the operation was performed within 6 hours of acute myocardial infarction, and then decreased precipitously (Table 24-5).72 On the other hand, mortality for the transmural group remained high during the first 3 days before returning to baseline.73 Multivariate analyses confirmed that CABG within 6 hours for the nontransmural group and 3 days for the transmural group were independently associated with in-hospital mortality.72,73 Optimal timing of CABG in patients with acute myocardial infarction is a controversial subject. Early surgical intervention has the advantage of limiting the infarct expansion and ventricular remodeling that may result in possible ventricular aneurysm and rupture.74 However, there is the theoretical risk of reperfusion injury, which may lead to hemorrhagic infarction resulting in extension of infarct size, poor infarct healing, and scar development.75 The data from these studies caution against early revascularization, particularly among patients with transmural acute myocardial infarction within 3 days of onset. Some have advocated the use of mechanical support to stabilize and allow elective rather than emergent surgery.76,77 Using mechanical support "prophylactically" instead of CABG to improve outcome, however, would require placement of such support in many unnecessary cases. If revascularization cannot be delayed, aggressive mechanical support (such as an LVAD) must be available because mortality is most likely a result of pump failure. Furthermore, mechanical circulatory support has been shown to be efficacious as a bridge to ventricular recovery or transplantation for this patient cohort.77 Although emergent cases such as structural complications and ongoing ischemia clearly cannot be delayed, nonemergent cases, particularly patients with transmural acute myocardial infarction, may benefit from delay of surgery. Early surgery after transmural acute myocardial infarction has a significantly higher risk and surgeons should be prepared to provide aggressive cardiac support including LVADs in this ailing population. Waiting in some cases may be warranted.
Table 24-5 Comparison of Hospital Mortality with Respect to Time of Surgery—Transmural versus Nontransmural Myocardial Infarction ||Download (.pdf)
Table 24-5 Comparison of Hospital Mortality with Respect to Time of Surgery—Transmural versus Nontransmural Myocardial Infarction
|Time between CABG and MI||Transmural MI (%)||Nontransmural MI (%)|
| <6 h||14||13|
| 6-23 h||14*|| 6*|
| 1-7 d|| 5|| 4|
| >7 d|| 3|| 3|
In addition to timing of surgery as discussed in the preceding, risk factors include urgency of the operation, increasing patient age, renal insufficiency, number of previous myocardial infarctions, hypertension,78 reoperation, cardiogenic shock, depressed left ventricular function, and the need for cardiopulmonary resuscitation, left main disease, female gender, left ventricular wall motion score, IABP, and transmural infarction.79 Characteristics associated with better outcome early after myocardial infarction include preservation of left ventricular ejection fraction, male gender, younger patients, and subendocardial versus transmural myocardial infarction.
Surgical revascularization in acute myocardial infarction complicated by cardiogenic shock has been shown to improve survival. Cardiogenic shock, as discussed earlier, is accompanied by 80 to 90% mortality rates; various mechanisms of cardiogenic shock are shown in Fig. 24-6. DeWood and colleagues80 were the first to demonstrate improved results with revascularization in patients with cardiogenic shock complicating acute myocardial infarction. Patients who were stabilized with an IABP and underwent emergent surgical revascularization had survival rates of 75%. Early surgical revascularization is associated with survival rates of 40 to 88% in patients in cardiogenic shock resulting from nonmechanical causes. Guyton and coworkers81 reported an 88% in-hospital survival and a 3-year survival of 88%, with no late deaths reported. Furthermore, the SHOCK trial demonstrated survival benefit in early revascularization by CABG or PTCA within 12 hours of the diagnosis of cardiogenic shock for patients of all ages.30,31 Patients comprising the CABG cohort in the SHOCK trial had more severe disease, with higher rates of three-vessel disease, left main coronary artery disease, diabetes, and elevated mean coronary jeopardy scores than the PTCA cohort.82 Despite this, 87.2% of these patients achieved successful and complete revascularization with CABG, compared with successful revascularizaton in 77.2% with PTCA and only 23.1% with complete revascularization with PTCA. Overall, mortality was no different between groups at 1 year (Fig. 24-7). On subgroup analysis, patients older than age 75, with left main coronary disease or three-vessel disease, or with diabetes had trends toward better survival at 30 days and 1 year after CABG compared to PTCA. Thus, for patients in cardiogenic shock, surgical revascularization has become an established and viable option for select patient groups.
Mechanisms of cardiogenic shock. Apical four chamber echo view with relative incidence of the mechanisms responsible for cardiogenic shock in the SHOCK and MILIS 4 registries. LV = left ventricle; MR = mitral regurgitation; RV = right ventricle; VSD = ventricular septal defect. (Reproduced with permission from Davies CH: Revascularization for cardiogenic shock. Q J Med 2001; 94:57.)
Kaplan-Meier survival estimates at 96 hours (A), 30 days (B), and 1 year (C) in patients treated with emergency percutaneous coronary intervention (PCI) versus emergency coronary artery bypass graft (CABG) in the SHOCK trial. (Reproduced with permission from White HD, Assman SF, Sanborn TA, et al: Comparison of percutaneous coronary intervention and coronary artery bypass grafting after acute myocardial infarction complicated by cardiogenic shock. Circulation 2005; 112:1992.)
Advantages of Coronary Artery Bypass Grafting
Reported survival rates are similar for CABG and PTCA in the treatment of acute myocardial infarction. To date there have been no large randomized clinical trials comparing CABG with PTCA and thrombolytics after myocardial infarction. For patients with stable angina and elective revascularization for ischemic heart disease, a number of trials have been conducted comparing CABG with stenting.83–86 In these studies, trends favoring CABG for multivessel disease were seen after 2 years in composite cardiac event end points, rate of reinfarction, and mortality; revascularization rates were five times higher in the stenting groups.87 Most notably, survival after CABG for two or more diseased vessels was significantly higher than stenting with 2-year follow-up in a retrospective study of the New York State Cardiac Surgery Reporting System and Percutaneous Coronary Intervention Reporting System.88 These results must be interpreted with caution, however, as patients with acute infarctions less than 24 hours pretreatment were excluded. Because of the lack of prospective, randomized trials, recommendations must be based on retrospective and observational studies. CABG offers several potential advantages. First, surgical revascularization is the most definitive form of treatment of the occlusion. CABG offers the longest patency of revascularized stenotic and occluded arteries in elective cases; 90% of internal mammary artery grafts are patent at 10 years. Second, CABG also offers more complete revascularization, because all vessel lesions are treated. This concept becomes especially important in patients with multivesssel disease or those in cardiogenic shock, in whom remote myocardium may continue to be comprised with only "culprit vessel" revascularization and inadequate restoration of collateral flow.89 A complete revascularization returns global myocardial perfusion to normal levels and offers the best chance for myocardial salvage. Third, difficult distal obstructions can be reached. Fourth, there is controlled reperfusion to reverse ischemic injury and reduce reperfusion injury. Fifth, as with other forms of reperfusion, CABG interrupts the progression of ischemia and necrosis and limits infarct size.
Disadvantages of Coronary Artery Bypass Grafting
Disadvantages of immediate surgical revascularization include the high mortality associated with early CABG. Off-pump procedures may reduce perioperative complications in high-risk patients, but are not yet widely practiced and have limitations.90 Rapid availability of catheterization and operating room personnel for emergency procedures imposes logistic and economic constraints. Thus, CABG is not readily applicable to the vast majority of patients in the community, and to provide this would strain health care resources. Second, it is difficult to analyze published results of CABG for acute myocardial infarction because randomized trials have not been done. Comparisons thus far have used medically treated patients as controls. Patients in the surgical group may be at lower risk; this might explain their progression to operation rather than continuing medical treatment. Crossover of patients from medical to surgical treatment also may have skewed the data.
Surgical revascularization following acute myocardial infarction can be performed with excellent results when the timing and patient cohort are appropriate. Most patients do not need such measures and would not benefit from this aggressive form of therapy. However, patients with mechanical complications, those in cardiogenic shock, and those with postinfarction angina are likely to benefit from early CABG.