Myocardial Revascularization with Cardiologic Interventional Devices

	INTRODUCTION

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The decision to perform a revascularization procedure is based on careful evaluation of several factors, including the patient's history, the extent of vascular involvement, anatomical considerations, and risks involved with the procedure itself. It is important for the interventionalist to have a broad knowledge of the literature and to understand the trends in interventional therapy—how techniques are developing, how they are best utilized, and how they compare with other strategies. In the following pages, a summary of current and alternative approaches used in interventional cardiology for the patient with coronary artery disease will be discussed.

	THROMBOLYSIS FOR ACUTE MYOCARDIAL INFARCTION

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Thrombolytic therapy for acute MI evolved from early attempts in the 1970s to treat patients with MI on an emergent surgical basis.⁶ Because cardiac catheterization was required to delineate the coronary anatomy before undertaking coronary bypass, it soon became apparent that thrombotic coronary occlusion was present in most of these patients. Still, many investigators remained unconvinced that total thrombotic occlusion was a significant factor in acute MI. Although thrombolytic therapy was widely tested in Europe throughout the 1970s, it was not uniformly accepted. Interventional studies during that period provided further evidence that thrombotic occlusion was the cause of acute MI and opened the way for the study of both intracoronary and intravenous thrombolytic therapy.

The modern era of thrombolytic therapy began in the late 1970s with the observation by Rentrop⁷ that intracoronary streptokinase provided effective thrombolysis for the infarct-related coronary artery and when, in the early and mid-1980s, intravenous streptokinase therapy was shown to reduce mortality in patients with myocardial infarction in the Gruppo Italiano per lo Studio della Streptochinasi nell'Infarcto Miocardio (GISSI) clinical trial.⁸ Since that time, numerous clinical trials have been undertaken to test the efficacy of various thrombolytic agents in the treatment of acute myocardial infarction. The results have shown definitively that timely administration of thrombolytic agents reduces infarct size, preserves left ventricular function, and improves short- and long-term survival in patients with acute MI. Despite the irrefutable evidence that thrombolytic therapy is beneficial, controversial issues regarding this therapy remain, such as the choices of the specific drug to be used and the need for adjunctive therapy, including platelet glycoprotein IIb/IIIa receptor antagonists or other platelet antagonists in addition to heparin or low molecular weight heparin.

Thrombolytic Agents

Complete thrombotic coronary occlusion usually results from ulceration or fissuring of vascular endothelium at the site of an atherosclerotic plaque. As a response to vessel injury, platelets adhere to the damaged endothelium and release and/or activate factors that promote thrombosis, vasoconstriction, and fibroproliferation. This results in fibrin formation and thrombotic coronary occlusion. Thrombolytic drugs work by activation of plasminogen to the active enzyme plasmin, which digests the fibrin component of the clot.

Thrombolytic agents may be divided into two general groups—the relatively fibrin-specific and non–fibrin-specific activators. The relatively specific group consists of tissue-type plasminogen activator (t-PA) and its mutants (r-PA and others) and, to a lesser extent, single-chain urokinase plasminogen activator (scu-PA); the relatively nonspecific proteases include streptokinase (SK), urokinase (UK), and anistreplase (APSAC).⁹ Four of these drugs, SK, t-PA, urokinase, and APSAC, are commercially available, and two (t-PA and its mutants and SK) are widely used in the treatment of acute MI. The drugs vary according to their clearance, fibrin selectivity, and plasminogen binding, in their potential to induce allergic reactions, and in costs.^10,11

STREPTOKINASE

Streptokinase was the first thrombolytic protein discovered, and it has been studied more extensively than any other thrombolytic agent. It works by joining to plasminogen in a complex that converts neighboring plasminogen to plasmin.¹² As a product of beta-hemolytic streptococci, streptokinase is antigenic and may produce allergic reactions in patients with recent streptococcal infections. The recommended dose of streptokinase (1.5 million units) is usually sufficient to overcome the neutralizing effect of antibodies; therefore, most patients will develop systemic fibrinolysis. The pharmacologic half-life of streptokinase is 30 minutes; depletion of fibrinogen usually lasts for 24 hours. Antibodies develop approximately 4 days after streptokinase therapy and persist for 6 months to 1 year; therefore, it is recommended that patients not be retreated with streptokinase (or APSAC) during that time.

Streptokinase has been tested in thousands of patients and has shown the ability to improve left ventricular function and save lives. It is less costly than other agents, but it does have the potential for allergic reactions¹³ and hypotension.¹⁴

TISSUE PLASMINOGEN ACTIVATOR

Tissue plasminogen activator (t-PA) is a naturally occurring serine protease that is nonantigenic and may be readministered immediately in the event of reinfarction.¹² Unlike SK and APSAC, t-PA is relatively fibrin-specific and clot-selective, producing more local thrombolysis. One disadvantage of t-PA is that its short half-life (5 minutes) may contribute to infarct vessel reocclusion. This limitation has led to the development of t-PA mutants with glycosylation and other defects that delay the clearance of t-PA and, in experimental animal models, result in more rapid thrombolysis and reduction in the risk of reocclusion.^15–17 Originally, the recommended dose of t-PA was 100 mg over a 3-hour period (60, 20, and 20 mg over hours 1, 2, and 3, respectively). In 1989, Neuhaus et al^18,19 initiated front-loaded or accelerated t-PA dosing by demonstrating that higher patency could be achieved with a regimen of a 15-mg bolus, another 50 mg given in the first 30 minutes, and the remainder (35 mg) infused over the next 60 minutes. More recently, an initial 20-mg bolus is administered, with the remainder of the t-PA being given over 1 hour. With the doses at which t-PA is usually given, the decline in fibrinogen is approximately 50%; therefore, there is less generation of fibrinogen split products.

Even though t-PA is clot-selective, it does not cause fewer bleeding complications than the other drugs. Increased bleeding complications have been noted particularly in patients of smaller body size (less than 165 kg). Therefore, in these patients, the recommended dosage is lowered to 1.25 mg/kg over 3 hours, with 10% as a bolus, 50% for the first hour, and 40% for the last 2 hours. Although acute reperfusion rates have been shown to be higher with t-PA than with streptokinase (Tables 20-1 and 20-2),²⁰ reocclusion also may be higher. In addition, because of its higher fibrinolytic potency, t-PA may induce hemorrhagic stroke at a higher rate than streptokinase. It is also more costly than other thrombolytic drugs—about 5 to 10 times more costly than streptokinase.^21,22

Anisoylated plasminogen streptokinase activator complex (APSAC) is a new second-generation thrombolytic agent that was developed to overcome some of the limitations of streptokinase therapy.¹² With APSAC, the active enzymatic site of the plasminogen streptokinase complex is temporarily protected by acylation, therefore allowing rapid intravenous injection of the drug. This results in prolonged fibrinolytic action. Compared with streptokinase, APSAC has greater fibrin binding and a longer duration of action (half-life of 90 minutes). This simplifies intravenous administration of the drug, with improved coronary reperfusion and reduced reocclusion rates. The entire bolus of the drug can be administered over a period of 2 to 5 minutes, and its expense is moderate compared with the other fibrinolytic agents. APSAC is not superior to other drugs, however, in improving ventricular function or reducing mortality.

UROKINASE

Another thrombolytic agent, urokinase, has been approved by the FDA for intravenous administration but is not available for intracoronary use. Urokinase is a proteolytic enzyme produced from human fetal kidney tissue cultures.¹² The usual dosage is 3 million units, which usually is sufficient for depletion of fibrinogen. The dosage consists of 1.5 million units as a bolus, with 1.5 million additional units given over a 1-hour period.

Clinical trials have shown that after intravenous urokinase, the rate of coronary patency is approximately 50% to 70%; reocclusion is 5% to 10%.^23–25 Compared with streptokinase, urokinase has much less antigenicity, can be given in a bolus dose, and has a relatively low rate of reocclusion. There are fewer allergic reactions and less hypotension associated with this drug. The disadvantages include its relative expense compared with other agents and the relative lack of experience with it in the United States. It has been more widely used in Europe.

Indications

The current consensus is that thrombolytic therapy is underutilized in patients with acute MI, despite a broader application of the therapy.²⁶ The criteria for appropriate patient selection for thrombolytic intervention have evolved as more knowledge is gained through clinical trials. All patients presenting with MI should be considered candidates for intravenous thrombolytic therapy if they are seen less than 6 hours after the onset of symptoms and have no potential bleeding problems. Patients with systemic arterial hypertension are not candidates for thrombolytic therapy as they have an increased risk of intracranial hemorrhage. Because the extent of myocardial damage occurring during acute MI is time-dependent, mortality reduction is greatest in those patients treated early with thrombolytic agents, although beneficial effects have been shown with treatment initiated up to 12 hours after the onset of symptoms.^27–29 It is agreed generally that patients presenting with symptoms of acute myocardial infarction and ST-segment elevation or left bundle-branch block will benefit by thrombolytic therapy. Those with only ST depression should be excluded because thrombolytic therapy is not helpful in these patients and may actually be harmful.

Contraindications

Late presentation after symptom onset, systemic arterial hypertension, and older patient age are the most common contraindications to thrombolytic therapy. Within the past several years, elderly patients with MI have been treated more routinely, however.³⁰ In a meta-analysis of eight large clinical trials, with regard to older patients, thrombolytic therapy was shown to have the greatest margin of benefit in patients aged 65 to 74 years.³¹ In patients older than 75 years, only 18 lives were saved per 1,000 patients; this is owing, in part, to an increase in bleeding complications in this patient subset.

In 1990, Muller and Topol³² critically reviewed the recommendations regarding patient eligibility for thrombolytic therapy after acute MI by examining studies published during a 10-year period. They examined only randomized, controlled trials of intravenous thrombolysis in acute MI and unstable angina. This study revealed that relatively few patients with MI were considered eligible for the therapy. Those excluded from thrombolysis, however, had a high early mortality. The findings suggested that selected, high-risk subgroups might benefit from thrombolytic therapy. Such groups would include otherwise healthy elderly patients, certain patients presenting more than 6 hours after the onset of symptoms, and those with a history of controlled systolic hypertension or brief nontraumatic cardiopulmonary resuscitation. Their data did not support the use of fibrinolytic therapy as the primary treatment for patients with unstable angina or suspected myocardial infarction in the absence of confirmatory electrocardiographic changes.

Investigators from the Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries (GUSTO-I) trial developed a multivariable statistical model for risk assessment in candidates for thrombolytic therapy.³³ They used criteria from the large population of 41,021 patients in this trial to analyze the relationship between baseline clinical data and 30-day mortality. They concluded that multiple characteristics of the patient must be considered for an accurate prognosis to be determined. These characteristics include age, medical history, physiological significance of the infarction, and medical treatment.

Specifically, multivariable analysis identified age as the most significant factor influencing 30-day mortality, with rates of 1.1% in the youngest decile (younger than 45 years) and 20.5% in patients older than 75 years. Other factors most significantly associated with increased mortality were lower systolic blood pressure, higher Killip class, elevated heart rate, and anterior infarction. These five factors comprised 90% of the prognostic information in the baseline clinical data. Other less significant factors included previous myocardial infarction, height, time to treatment, diabetes, weight, smoking status, type of thrombolytic, previous bypass surgery, hypertension, and prior cerebrovascular disease.

Choice of Thrombolytic Agent

Information regarding drug selection has become available from three large-scale randomized trials directly comparing the risks and benefits of various thrombolytic agents in acute MI.^34–36 These include the Gruppo Italiano per lo Studio della Sopravvivenze nell'Infarcto Miocardico (GISSI-2) trial and its international extension, the Third International Study of Infarct Survival (ISIS-3), and the GUSTO-I trial (mentioned earlier). In the interpretation of results from these trials, it is agreed generally that the agents most commonly used in the United States—t-PA, SK, and APSAC—all reduce mortality when given to patients with acute evolving MI.

In addition, when the therapy is given to patients presenting up to 12 hours after onset of symptoms, the mortality rate is reduced by approximately 20%. When aspirin therapy is used in patients presenting up to 24 hours after symptoms begin, there is a 23% reduction in mortality. The combination with aspirin enhances the thrombolytic efficacy of streptokinase and, probably, of all thrombolytic interventions. Heparin (or another thrombin inhibitor) given intravenously in adequate dosage is required to allow t-PA to exert a maximal thrombolytic effect. Aspirin is a cyclooxygenase inhibitor and reduces the availability of thromboxane A₂, a potent promoter of platelet aggregation. Thrombin is formed at sites of vascular injury and constriction and promotes platelet aggregation and vasoconstriction. Thrombolytic therapy activates platelets and the addition of aspirin and thrombin inhibitors counteracts the platelet activation and local effects of thrombin.

The most important finding in the analysis of randomized trials is that earlier administration, as well as more widespread use of thrombolytic therapy and aspirin, would save more lives. In several studies, patients who received streptokinase had slightly fewer strokes than those who received t-PA or APSAC, but the biological difference is very small.

One important contribution of the GUSTO trial, according to Habib,¹¹ is that it provided compelling evidence for the open artery theory.³⁷ Regardless of which thrombolytic drug was used, 30-day mortality was substantially higher (8.9% vs. 4.4%, p = .009) in patients with a nonperfused infarct-related artery. According to the theory, rapid and complete coronary reperfusion is associated with improved clinical outcome (improved survival and improved ventricular function).³⁷

Thrombolysis with Other Treatment Strategies

Thrombolytic therapy has been compared with other treatment strategies in recent years in several clinical trials. The Thrombolysis in Myocardial Ischemia (TIMI)-IIIB clinical trial, which included 1,473 patients, was designed to compare the efficacy of t-PA with early invasive versus early conservative strategies in patients with unstable angina and non–Q-wave myocardial infarction.³⁸ In this large study of patients with unstable angina and non–Q-wave MI, the incidence of death and nonfatal infarction or reinfarction was low but not trivial after 1 year (4.3% mortality, 8.8% nonfatal infarction). An early invasive management strategy was associated with slightly more coronary angioplasty procedures but equivalent numbers of bypass surgery procedures than was a more conservative early strategy of catheterization, in which revascularization was performed only when there were signs of recurrent ischemia. No difference was seen in death or nonfatal infarction, or both, after 1 year, according to strategy assignment, but fewer patients in the early invasive strategy group underwent later repeat hospital admission (26% vs. 33%, p = .001). According to these results, either strategy appears to be acceptable for treatment of patients with unstable angina and non–Q-wave MI; in this regard, physicians have latitude in individualizing care for such patients. In the patients with unstable angina and non–Q-wave infarction, thrombolytic therapy did not reduce mortality or morbidity.

Very recently, however, the Treat Angina with Aggrastat and Determine Cost of Therapy with an Invasive or Conservative Strategy (TACTICS) trial done in a very similar patient population has provided different conclusions.³⁹ In this trial in patients with unstable angina and non–Q-wave myocardial infarcts, invasive strategy proved superior to conservative therapy in patients with elevations in their serum troponin I or T or C-reactive protein.³⁹ In patients without elevations in their serum C-reactive protein or troponin I or T, the results were similar between invasive and conservative therapies. This suggests the ability to select patients at highest risk for more aggressive therapy.³⁹

Angioplasty and Thrombolytic Therapy

Percutaneous transluminal coronary angioplasty (PTCA) often is performed in patients with acute ST-segment elevation (Q-wave) MIs after thrombolytic therapy or in lieu of thrombolysis. An early trial by Ribeiro et al⁴⁰ compared the benefit of thrombolytic therapy utilizing streptokinase with that of direct coronary angioplasty in 100 patients who presented with acute MI at a single interventional center. They excluded patients who were older than 75 years or had prior bypass surgery, Q-wave infarction in the region of ischemia, or excessive risk of bleeding. There were no major differences in the baseline characteristics of the two treatment groups in this study. Results showed no difference in 48-hour infarct-related artery patency or LV-ejection fraction. Also, there were no major bleeding events, and mortality was similar. The investigators concluded that intravenous therapy might be preferred over coronary angioplasty because of the shorter time to treatment.

Several prospective clinical trials in the United States and Europe have been undertaken to test the role and timing of angioplasty after intravenous thrombolytic therapy—the Thrombolysis and Angioplasty in Myocardial Infarction (TAMI) study,⁴¹ the European Co-operative Study,⁴² and the Thrombolysis in Myocardial Infarction (TIMI) II-B study.^43,44 These early trials revealed some detrimental effects of aggressive treatment for MI patients. Invasive therapy after intravenous thrombolytic therapy with recombinant tissue-type plasminogen activator (rt-PA) resulted in no additional preservation of ventricular function and no improvement in survival probability. Furthermore, this aggressive approach was associated with greater morbidity and a trend toward higher mortality.

A meta-analysis of randomized clinical trials examining the benefits of PTCA alone and PTCA after thrombolysis revealed less convincing evidence for the superiority of one therapy over another for treatment of acute ST-segment elevation MI.⁴⁵ The analyses of the various categories of trials have suggested, however, that primary PTCA may be more beneficial than thrombolytic therapy in the treatment of these acute MIs.¹⁰ According to Ross, the current overall impression is that direct PTCA for acute infarction is an effective method of reperfusion so long as it can be accomplished in the same time frame as can pharmacologic reperfusion.¹⁰ Based on several large-scale trials, however, there has been failure to confirm a lower reocclusion rate for PTCA as compared with plasminogen activator therapy.¹⁰

Very recently, Stone et al have shown that, at experienced centers, stent implantation with or without the platelet glycoprotein inhibitor abciximab appears to be superior to PTCA in the treatment of acute ST-segment elevation myocardial infarctions.⁴⁶ They randomly assigned 2,082 patients with acute ST-segment elevation myocardial infarcts to undergo PTCA (518 patients), PTCA plus abciximab therapy (528 patients), stenting alone with the Multi-Link stent (512 patients), or stenting plus abciximab therapy (524 patients). At 6 months, the primary end point—a composite of death, reinfarction, disabling stroke, and ischemic-driven revascularization of the target vessel—had occurred in 20% of patients after PTCA, 16.5% after PTCA and abciximab, 11.5% after stenting, and 10% after stenting and abciximab (p < .001). Rates of angiographically established restenosis were 40.8% after PTCA and 22% after stenting (p < .001).

EFFECTS OF GENDER

Stone et al⁴⁷ compared in-hospital outcomes in men versus women who were treated by either thrombolytic therapy or primary coronary angioplasty for acute MI. Their study comprised 395 patients (288 men, 107 women) in 12 centers who were prospectively randomized to treatment with t-PA or primary PTCA. The in-hospital mortality in women was 3.3-fold higher than in men (9.3% vs. 2.8%, p = .005). Women were older, more often had diabetes mellitus, systemic hypertension, or prior congestive heart failure, and presented later after symptom onset. In contrast, after primary PTCA, women and men had similar in-hospital mortality (4.0% vs. 2.1%, respectively, p = .46). Multiple logistic regression analysis of 15 clinical variables showed that treatment with PTCA, as well as younger age, was independently predictive of in-hospital survival in women.

COST

As greater numbers of clinical trials have been undertaken to compare the efficacy of thrombolysis versus primary angioplasty for acute MI, comparisons regarding cost-effectiveness of these separate strategies have been made by several investigators.

According to a study by Goldman,²¹ the incremental cost for thrombolysis with streptokinase in patients with acute myocardial infarction ranges from approximately $3,500 to approximately $21,000 per year of life saved. The incremental cost-effectiveness of tissue-type plasminogen activator (t-PA) compared with streptokinase ranges from approximately $16,000 to $60,000 per year of life saved. Combined data from three randomized trials suggest that primary angioplasty can reduce mortality by as much as 63% without any increase in cost. This reduction is much greater than that shown by early administration of thrombolytic therapy or by accelerated t-PA versus streptokinase. The recent study by Stone et al has now established the clinical superiority of stenting over PTCA alone in the treatment of patients with acute ST elevation myocardial infarcts at experienced centers where these patients can be treated relatively acutely.⁴⁶

	PERCUTANEOUS TRANSLUMINAL CORONARY ANGIOPLASTY

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Indications

The role of PTCA and now stenting in the treatment of coronary artery disease continues to evolve.⁴⁸ The original indication for PTCA was the presence of angina pectoris with failure of maximal medical therapy in a patient with an anatomically appropriate lesion (de novo, type A) of a single diseased coronary artery.⁴⁹

Today, PTCA is used in selected patients with multivessel disease, calcified and/or eccentric lesions, distal coronary stenosis, complex or multiple lesions within the same vessel, or saphenous or internal mammary bypass grafts.⁵⁰ PTCA also is used as primary therapy for patients with acute ST-segment elevation myocardial infarction (Fig. 20-1),^10,51 and as reviewed above, is even better with stenting.⁴⁶ In patients with stable angina and single-vessel disease, PTCA alleviates symptoms more completely than medical therapy alone. It may also reduce the development of unstable angina and result in fewer hospitalizations.

View larger version (76K): [in this window] [in a new window]   FIGURE 20-1 Acute inferior myocardial infarction, with demonstration of total mid right coronary artery occlusion (left). Angiographic result after direct PTCA (right).

Deciding to utilize PTCA/stenting is dependent on several criteria: lesion classification, the number of lesions or diseased vessels involved, and the patient's history and clinical status. The American College of Cardiology (ACC) and the American Heart Association (AHA) have developed a classification system for patients undergoing PTCA, based on the likelihood of a successful procedure (Table 20-3), and this has been recently updated.⁵²

The Task Force also has outlined contraindications to coronary angioplasty (Tables 20-4 and 20-5).

Early trials showed that angioplasty during the first hours after onset of MI is associated with a lower incidence of reinfarction, intracranial hemorrhage, and death than thrombolysis.⁵³ For this reason, the procedure has been approved in hospitals that do not have coronary bypass backup programs. However, according to the current Task Force guidelines, the national standard of accepted medical practice for coronary angioplasty requires that an experienced cardiovascular surgical team be available within the institution to perform emergency coronary bypass surgery should the clinical need arise.⁵² Surgical consultation is advisable in cases in which the extent of disease indicates that surgery may be a more effective means of therapy than angioplasty.⁵⁴

Single-Vessel Coronary Artery Disease

Patients with single-vessel coronary artery disease with significant symptoms are still one of the largest groups undergoing angioplasty. In this group of patients, a 90% to 95% success rate can be expected.^55,56

Several studies have been undertaken in recent years to compare the outcome of PTCA with other therapeutic measures in patients with single-vessel disease. The Department of Veterans Affairs Angioplasty Compared with Medical Therapy (ACME) Study addressed 212 patients who had single-vessel lesions of 70% to 99% diameter stenosis and myocardial ischemia by treadmill testing for whom continued medical therapy was still an option.⁵⁷ This study showed that PTCA offers earlier and more complete relief of angina than medical therapy and is associated with better performance on the exercise test. The drawbacks of PTCA are its initial higher costs and an association with a higher frequency of need for a second procedure. The addition of stenting has further improved the efficacy of angioplasty, reducing the occurrence of restenosis problems requiring a second intervention to the 15% to 20% range. Even more recently, the use of "coated" stents, specifically with rapamycin (Sirolimus), appears to reduce the risk of restenosis to less than 5%.⁵⁸

Angioplasty vs. Surgery

The role of angioplasty in the treatment for multivessel disease has become increasingly common, yet the benefits of this approach versus bypass surgery have not been determined. Coronary bypass surgery offers the advantage of more complete revascularization regardless of the coronary anatomy at the time of the procedure, yet it carries the risks of general anesthesia, mechanical ventilation, midline sternotomy, extracorporeal circulation, and a prolonged recovery time. Coronary angioplasty carries the risks of abrupt vessel closure and early restenosis, and it does not guarantee complete revascularization at the time of the procedure.⁵¹ As noted above, the use of stents, and most likely "coated" stents in the future (most especially rapamycin-coated stents), should make interventional therapy even more attractive. Randomized trials of surgical therapy have shown that the benefits of surgical revascularization are proportional to the amount of myocardium affected by, or at risk for, ischemic injury. Comparisons between angioplasty and bypass surgery in select populations with single- and multivessel coronary artery disease have shown that PTCA is not as effective as surgery for long-term symptomatic control, and that it often requires repeat PTCA or crossover to bypass surgery; however, long-term outcomes (i.e., death and myocardial infarction) are similar.⁵⁹ The best "coated" stent may further enhance the effectiveness of PTCA, allowing it to be used successfully and with better long-term results in more patients with two- and three-vessel coronary heart disease. The critical outcome measures of these procedures will be functional status, quality of life, employment, and health care costs.⁶⁰

The Coronary Artery Surgery Study (CASS) showed no survival benefits for revascularization among patients who received PTCA without having failed medical therapy. The advantages of PTCA are measured by symptom relief, functional improvement, or reduced cost in this patient subset.⁶¹

The Emory Angioplasty versus Surgery Trial (EAST)⁶² recently assessed the 5-year outcome in 392 patients randomized to coronary surgery (n = 194) or coronary angioplasty (n = 198). Each group had an in-hospital mortality of 1%. Survival was 91% in the CABG group versus 87.9% in the PTCA group (p = .29). Whereas there was no difference in mortality at 3 years, by 5 years there was a slight but not significant separation of the curves favoring surgery. Most of the additional revascularization procedures occurred in the first year, and there were more additional revascularization procedures in the PTCA group.

In a similar trial, the Bypass Angioplasty Revascularization Investigation (BARI), 1,800 patients from 16 centers across the United States were enrolled for a 5-year study period.^63,64 This trial was designed to evaluate whether the strategy of PTCA is as safe (regarding mortality) as the strategy of starting with bypass surgery. The surgical cohort of this trial represents the largest group of patients with multivessel coronary artery disease who have been randomly assigned to surgical treatment. Patients were eligible for BARI if they had multivessel coronary artery disease, had a clinical indication for revascularization, and were suitable for both coronary angioplasty and bypass surgery. The results from this study were very similar to those from the EAST trial. One problem patient group that has emerged from these studies are the patients with diabetes, especially insulin-dependent diabetes. They do not have as favorable results from PTCA/stenting as do the nondiabetics. They have higher restenosis rates and greater morbidity, and current data favor surgical revascularization in this group of patients, especially those with two- and three-vessel disease. It has been shown, however, that the combined use of PTCA/stenting with a platelet IIb/IIIa receptor inhibitor, such as Reopro, enhances the effectiveness of PTCA/stenting in the diabetic patient.^65,66

The Randomized Intervention Treatment of Angina (RITA) trial was established to compare angioplasty with surgical therapy in stable and unstable angina.⁶⁷ This trial differed from BARI and EAST in that the lesions in each patient had to be suitable for both angioplasty and surgery. The goal for both strategies is to achieve complete revascularization. At the second year follow-up in RITA, there was no difference between PTCA and bypass surgery for survival following myocardial infarction.⁶⁷ Additional revascularization procedures, myocardial infarction, and death were more common among PTCA patients (38%) than among bypass surgery patients (11%) within 2 years of randomization. Repeat coronary angiography was four times more common among PTCA patients (31% vs. 7%).

Other clinical trials that are in progress will include angiography and myocardial perfusion stress testing in their follow-up evaluations.^68,69 In the German Angioplasty Bypass Surgery Investigation (GABI),⁶⁸ PTCA and CABG showed equivalent improvement in angina at the end of one year. The patients treated with PTCA were more likely to require further interventions and antianginal drugs, whereas the patients treated with bypass surgery were more likely to sustain an acute MI at the time of the procedure.

In the Coronary Artery Bypass Revascularization Investigation (CABRI), 183 Dutch patients with multivessel disease were randomized to treatment with PTCA or coronary artery bypass surgery between 1988 and 1992.⁶⁹ The CABG group consisted of 88 patients with a total of 255 vascular obstructions; the PTCA group comprised 95 patients with 294 vascular lesions. Within 30 days after intervention, the clinical results of the two treatments were the same. The differences in death rate and myocardial infarctions were not significant, in contrast to the difference in the numbers of reinterventions. The death rates were 1.1% and 2.1% for CABG and PTCA, respectively. The proportion of transmural, nonfatal myocardial infarctions was 2.3% in the CABG group versus 3.1% in the PTCA group. The proportion of reinterventions was higher in the PTCA group, 11.4% versus 1.1%. Early results with CABRI indicate that PTCA is a reasonable alternative to coronary surgery in patients with multiple-vessel coronary disease.

In a review of surgery versus angioplasty for coronary artery disease, Wilson and Ferguson⁵⁹ concluded that surgical bypass remains the mainstay of therapy for patients with severe disease and a poor prognosis for survival, and it is warranted in patients in whom PTCA/stenting has failed repeatedly. Revascularization should be offered on the basis of symptom severity (in the presence of medical therapy) in accordance with the prognosis for survival, as judged by the extent and severity of disease.

Complications of Angioplasty

Procedural success in angioplasty relates to certain patient characteristics, such as younger age and male gender, and to clinical variables, such as diabetes, prior myocardial infarction, prior bypass surgery, and impairment of left ventricular function.⁵¹ Of major importance in predicting the success of the procedure are the angiographic characteristics of the lesion (or lesions) to be dilated.⁷⁰ Long, calcified, or ostial lesions; tortuosity of the vessels; and degenerative vein grafts are particularly challenging for the interventionalist. The risk of abrupt vessel closure and early restenosis must be carefully weighed when determining which patients will most benefit from angioplasty. Other risks associated with the procedure include stroke, myocardial infarction, arrhythmias, and vascular complications at the catheter entry site.

ABRUPT VESSEL CLOSURE

It is estimated that an acute ischemic complication will develop in approximately 7% of patients undergoing coronary angioplasty.⁷¹ In more than half of these patients, thrombus, dissection, or both can be identified angiographically as the underlying cause of abrupt closure.⁷¹ Predictors of dissection-mediated closure include degenerated vein graft, de novo stenosis, proximal tortuosity, high lesion grade, eccentricity, longer lesion length, and angulation.⁷¹ Yellow plaque identified by angioscopy confers a heightened risk of major complications. Lesions containing areas of calcium adjacent to areas of soft plaque have been identified by ultrasound as a powerful predictor of major dissection. The presence of thrombus in the artery to be dilated is associated with a higher risk of postprocedural thrombotic occlusion.

Tan et al⁷² examined the determinants of coronary angioplasty success and complications by evaluating the American College of Cardiology/American Heart Association ABC lesions classification scheme and its modifications. They assessed the lesion morphologic determinants of immediate angioplasty outcome in 729 consecutive patients who underwent coronary angioplasty of 994 vessels and 1248 lesions. Angioplasty success was achieved in 91% of lesions, and abrupt closure occurred in 3%. They found that longer lesions, calcified lesions, diameter stenosis of 80% to 99%, and presence of thrombus were predictive of a lower success rate. Longer lesions, angulated lesions, diameter stenosis of 80% to 99%, and calcified lesions were predictive of an abrupt closure.

Despite the various interventions used to prevent abrupt closure, it remains a highly unpredictable occurrence, with a substantial incidence of myocardial infarction and angioplasty-related morbidity and mortality.⁷³ Intracoronary visualization by intravascular ultrasound can help to identify important characteristics that identify lesions at risk for abrupt closure.⁷³ Repeat dilatation is often successful in the treatment of abrupt closure.⁷⁴

In one study examining the impact of new devices on the incidence and reversal rate of abrupt closure,⁷⁵ abrupt closure occurred in 80 (4.2%) of 1919 consecutive coronary angioplasty procedures; 389 procedures (20%) were performed with the use of stents, coronary atherectomy, or laser balloon angioplasty. Abrupt closure was less frequent following newer coronary interventions (1.8%) compared with standard balloon angioplasty (4.9%, p = .01). Although this may have reflected case selection, the results indicated that new interventional devices were associated with a lower incidence of abrupt closure. Most catheterization laboratories administer heparin for 12 to 24 hours after angioplasty to reduce the risk of abrupt closure,⁷⁶ and in some cases, such as diabetics and others deemed to be at increased risk, an inhibitor of the platelet glycoprotein IIb/IIIa receptors may be used.

RESTENOSIS

Restenosis has been deemed the Achilles' heel of angioplasty.⁷⁷ Despite many innovations in interventional techniques for coronary disease in recent years, restenosis remains the most common complication following PTCA. Restenosis may be described simply as the chronic renarrowing of the dilated vessel in response to the balloon (or other interventional device) injury that typically occurs over 3 to 6 months after the procedure. In other words, coronary arteries that have been subjected to balloon angioplasty or other interventions will be traumatized and undergo wound healing, which culminates in the formation of stenotic lesions.

In 1992, the average restenosis rate reported in the literature was 30%,^77,78 but recent reports have estimated a range of 20% to 55% occurrence of restenosis in arteries subjected to percutaneous interventions.^79,80 Studies of serial longitudinal angiographic evaluations⁸¹ after successful PTCA have shown that 11% of patients will have restenosis within the first month; 39% will have restenosis at the end of the first 3 months; and an additional 6% will have restenosis 3 to 6 months after PTCA. A small number of patients will have angiographic evidence of restenosis at the end of 1 year.

Renarrowing within the first few days after an angioplasty procedure usually represents abrupt closure rather than restenosis. This is often caused by thrombosis superimposed on a vessel wall dissection or intimal flap. Asymptomatic angiographic renarrowing (50% or greater diameter stenosis) has been shown to occur in as many as 7.8% of lesions treated.⁸² Some researchers⁸³ have noted that although anginal symptom recurrence is the hallmark of restenosis, approximately 25% of patients are asymptomatic. Also noteworthy is the fact that among those with recurring angina, up to 44% are not found to have restenosis.^83,84 After the first several days, further renarrowing probably reflects chronic recoil, vessel remodeling, and neointimal proliferation.⁸⁰

Although restenosis does not result in increased mortality (because patients with restenosis develop angina rather than myocardial infarction or sudden death), restenosis does lead to repeat PTCA or coronary artery bypass grafting; thus, it increases morbidity and costs.⁸⁵ There is, however, considerable enthusiasm for the use of coated stents, especially rapamycin-coated stents, as a means to reduce the restenosis risk. Stents have reduced the risk of restenosis from 30% to 50% with PTCA alone to 15% to 20% with stents following PTCA. The use of rapamycin-coated stents has reduced the risk of restenosis to less than 5% in the first several hundred patients that have been treated.⁵⁸

Mechanisms of Restenosis Findings from angioscopic, intravascular ultrasound, atherectomy, and autopsy studies have supported the hypothesis that early restenosis is a local vascular manifestation of the general response to injury and wound healing. Restenosis early after angioplasty usually consists of immediate elastic recoil, platelet deposition, and thrombus formation, followed by smooth muscle cell proliferation and matrix formation.^86,87

The time course of restenosis can be determined from studies of injury in animal models and autopsy studies.^88–95 Within seconds of injury, endothelial removal and endothelial death, as well as some smooth muscle death, smooth muscle separation, and smooth muscle stretch, occur. For the next several minutes, there is platelet attachment, release, aggregation, and coagulation. Within a few days after injury, endothelial and smooth cells and macrophages proliferate and migrate. Over several weeks, synthesis, maturation, and contraction of the extracellular matrix occur, in addition to the remodeling process, during which the vessel may enlarge or decrease in size.

Prevention of Restenosis Angiographic results have shown that arteries undergoing any type of intervention—balloon angioplasty, atherectomy, or laser balloon angioplasty— show a similar extent of restenosis at 6 months.⁹⁶ Use of angiography to predict the long-term success or failure of PTCA is of limited value, however, because these images provide only a circumscribed view of the arterial lumen and offer little insight into the morphologic characteristics of the underlying plaque.⁹⁷ Intravascular ultrasound has been used with more success to identify patients in whom restenosis is likely to develop, because it provides information about the morphologic features of the atheroma and its composition.^98,99 With ultrasound, the interventional strategy may be modified to optimize lumen size and possibly reduce the risk of restenosis.⁹⁹ Restenosis after stent placement is a somewhat different process and one that reflects primarily the proliferative process of smooth muscle cells without vessel recoil.

The process of wound healing after balloon angioplasty begins within minutes or up to 2 hours after the procedure and may continue for weeks or months. This process is dependent not only on the release and complex interaction of thrombosis, cytokines, and growth factors, but also on the extent of healing and the type of injury.⁹⁷ Therefore, therapies have to be targeted at processes that occur early after balloon injury to combat the early release of growth factors and cytokines and for processes that occur late (2 to 4 weeks) when factors that induce substance deposition are at their peak.⁹⁷ Although a variety of agents designed to reduce the risk of restenosis have been successful in animal studies, no pharmacologic agent has clearly proved to be successful in reducing restenosis in humans, even after more than 50 published major clinical trials randomizing greater than 20,000 patients with the goal of limiting restenosis by pharmacologic means.¹⁰⁰ In addition, few risk factors for restenosis have stood the test of time, and their predictive power is relatively weak,¹⁰¹ including such factors as lipoprotein (a), low high-density lipoprotein (HDL), prior restenosis, total occlusion, diabetes, or location of the left anterior descending coronary artery.^85,102–109

Stents have markedly reduced the risk of restenosis, except in diabetic patients as noted earlier, and that may be improved in the diabetic patient by using the platelet glycoprotein IIb/IIIa receptor inhibitor, Reopro, before, during, and following stent placement so the results look similar to those in nondiabetics.⁶⁵ Early studies have found that the rapamycin-coated stents may reduce the risk of restenosis to less than 5%, and if this is confirmed in future studies, this will have a major effect on interventional procedures generally. Inhibitors of platelet glycoprotein IIb/IIIa receptors and new therapies are still being sought based on the role of smooth muscle cell proliferation, inflammatory cells, and humoral factors in the restenotic process.^109–117

Arterial Remodeling One avenue of research in prevention of restenosis involves arterial remodeling. According to Currier and Faxon,⁸⁶ restenosis can be thought of not merely as neointimal formation in response to balloon injury, but as arterial remodeling in response to balloon injury and neointimal formation. This remodeling may consist of actual constriction of the artery, as has been described in some animal models and in preliminary fashion in humans, or of compensatory enlargement, as has been described in de novo atherosclerosis and in the hypercholesterolemic rabbit iliac artery model. Compensatory enlargement and chronic constriction may represent two ends of the spectrum of arterial remodeling in response to balloon angioplasty. Thus, therapeutic strategies to alter arterial remodeling in conjunction with altering neointimal formation may be required to reduce restenosis after coronary interventions.

Lipid-lowering Agents Omega-3 fatty acids, in addition to lowering triglyceride level, also affect platelet aggregation and coagulation, which are important in restenosis. Conflicting results have been found in five clinical trials addressing the effect of omega-3 fatty acid supplementation on the risk of restenosis.^118–123 The weight of the evidence suggests, however, that they do not generally reduce the risk of restenosis after PTCA. In one early trial, a beneficial effect on restenosis was shown with the lipid-lowering agent lovastatin¹²⁴; however, subsequent trials were unable to confirm this observation.^125,126 The Lovastatin Restenosis Trial after PTCA¹²⁷ also failed to show the efficacy of hypocholesterolemic therapy for reducing the risk of restenosis.

Platelet Inhibitors After coronary angioplasty, patients usually are treated with aspirin, nitrates, calcium channel antagonists, and heparin. Such medications are given specifically to interfere with coronary artery vasoreactivity and platelet function. These drugs are useful in treating coronary vasospasm and preventing abrupt closure. Platelet inhibitors have shown promise for prevention of restenosis in recent clinical studies. One large-scale trial, Evaluation of c7E3 for the Prevention of Ischemia Complications (EPIC), was designed to examine the role of thrombosis, angiotensin II, and oxidation in restenosis. The platelet glycoprotein IIb/IIIa integrin is the receptor that mediates the final common pathway of platelet aggregation. According to the EPIC investigators, agents that block this platelet receptor represent a promising new approach to preventing cardiovascular ischemic complications and late restenosis after PTCA.^128,129 In the trial, which included high-risk patients undergoing coronary intervention procedures, a monoclonal antibody Fab fragment (c7E3) directed against glycoprotein IIb/IIIa integrin was administered as a bolus dose and through infusion (Fig. 20-2). In early results of the trial, c7E3 significantly reduced the 30-day incidence of major ischemic events relative to aspirin and heparin, as well as decreased the need for repeat revascularization during the 6-month follow-up period. However, this finding was not confirmed in later studies by these same investigators, and so it is difficult to use this finding from the EPIC trial in the treatment of patients at the current time. The major complication in the EPIC trial was bleeding,¹³⁰ the risk of which appeared to be inversely related to body weight.¹³¹

View larger version (85K): [in this window] [in a new window]   FIGURE 20-2 Acute lateral myocardial infarction (left). Final result after direct PTCA and tandem stenting, with use of c7E3 (Reopro) platelet inhibitor (right).

	ALTERNATIVE APPROACHES TO CONVENTIONAL BALLOON ANGIOPLASTY

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Since balloon angioplasty was developed, improvements in the procedure have kept it the primary interventional therapy for patients with ischemic heart disease.¹³⁵ However, research has indicated that certain lesion types and patient populations may be treated more effectively with other newer technologies, such as intracoronary stents as already discussed, coronary atherectomy and ablation, and cutting devices. These devices appear to be more effective than conventional angioplasty in treating calcified, eccentric, or ulcerated lesions; ostial stenosis or stenosis of the left anterior descending (LAD) artery; disease in older saphenous vein grafts; restenotic lesions after prior interventions; and dissected vessels with actual or threatened abrupt closure.¹³⁶ The challenge for the clinician is deciding the optimal application for these technologies in specific clinical settings.

Stents

The use of vascular endoprostheses or stents developed as a result of complications seen in percutaneous transluminal angioplasty. Appropriate indications for stent placement include restenosis, dissection, abrupt closure, residual stenosis, or reopened total occlusion (Fig. 20-3). Intracoronary stenting has proved to be a successful method of circumventing emergency bypass surgery after acute vessel closure in angioplasty procedures.

View larger version (74K): [in this window] [in a new window]   FIGURE 20-3 Severe spiral dissection of the right coronary artery following routine angioplasty (left). Excellent angiographic result after repair of dissection with tandem stenting (right).

Though it is a rare occurrence, loss of the stent from its delivery system into the peripheral circulation is another possible complication of the stent procedure. In such cases, magnetic resonance imaging may be useful for locating the misplaced device.¹⁴²

There are now reports of stent implantation after myocardial infarction.^143–146 Recent evidence suggests that PTCA/stenting may be the preferred therapy for acute ST-segment elevation MI,⁴⁶ and perhaps the preferred therapy for patients with unstable angina/non–ST-segment elevation MIs with elevated serum CRP or troponin I or T concentrations (unstable angina, as reviewed earlier in this chapter).³⁹

One disadvantage of coronary stenting is cost. Elective coronary stenting, as performed in the randomized Stent Re-Stenosis Study (STRESS) trial, increased total 1-year medical care costs by approximately $800 per patient, compared with conventional angioplasty. Ongoing refinements in stent design, implantation techniques, and anticoagulation regimens may narrow this cost difference by reducing stent-related vascular complications or length of stay.

Directional Coronary Atherectomy

Directional coronary atherectomy (DCA) has been proposed as an alternative to balloon dilatation for treatment of coronary artery disease, but the long-term efficacy of this procedure is not known. DCA was introduced in 1986 and approved by the FDA for clinical use in 1990. The goal of DCA is for debulking rather than dilating a coronary artery lesion (Fig. 20-4).

View larger version (71K): [in this window] [in a new window]   FIGURE 20-4 Stenosis of the proximal left anterior descending coronary artery (left). Angiogram showing result of directional coronary atherectomy procedure following suboptimal balloon angioplasty (right).

In a study of the clinical and angiographic outcome after directional coronary atherectomy, the procedure was associated with a high procedural success rate (94.8%) and infrequent complications in selected lesion subsets.¹⁴⁸ Late clinical events (death, Q-wave myocardial infarction, coronary bypass surgery, coronary angioplasty) occurred in 69 patients (28%). Independent predictors of late clinical events included diabetes mellitus, unstable angina, and a prior history of restenosis.

DCA for saphenous vein graft lesions was performed at 21 centers during a 2-year period; 318 procedures were performed in 363 vein graft lesions.¹⁴⁹ Angiographic success was achieved in 86% of lesions and clinical success was achieved in 85%. Restenosis was significantly lower in primary vein graft lesions than in vein grafts with prior intervention. This initial multicenter investigation indicates that DCA is safe and effective in selected cases of degenerative vein grafts.

Several studies have been undertaken to compare the results of angioplasty with DCA for treatment of coronary lesions. One recent study involving complex lesions showed that DCA is limited by a modest degree of lumen enlargement, frequent need for adjunctive angioplasty, and a high restenosis rate, and appears to offer no advantage over conventional balloon angioplasty for such lesions.¹⁵⁰

Investigators in the Coronary Angioplasty Versus Excisional Atherectomy Trial (CAVEAT I) examined the efficacy of DCA for ostial coronary lesions.¹⁵¹ For ostial left anterior descending (LAD) coronary artery stenosis, procedures yielded similar rates of initial success and restenosis, but atherectomy was associated with a higher incidence of non–Q-wave-MI. The predominant angiographic benefit in this study was shown in proximal nonostial lesions of the LAD. At 1-year follow-up in CAVEAT I, of 1012 patients randomized to either angioplasty or DCA, a statistically significant excess of deaths after DCA was revealed that was not evident at 6-month follow-up.¹⁵²

A review of acute and long-term results of coronary stenting and atherectomy in women and the elderly has shown that both techniques can be performed safely and effectively in these patient subsets, despite a somewhat lower success rate and higher rates of acute complications.¹⁵³

Rotablator

The Rotablator, which encompasses an olive-shaped high-speed burr coated with diamond chips, is used primarily for debulking lesions (Fig. 20-5). When introduced into the stenosed area of the vessel, the Rotablator attacks preferentially hard resistant material and is thus indicated for calcified lesions. Its fine elliptoid tip rotates at 180,000 rpm, grinding atheroma into millions of tiny fragments. Whereas DCA is used to physically remove plaque from the vessels, the Rotablator is used to ablate the plaque in situ. Its use is contraindicated in irregular or thrombus-containing stenoses, highly angulated stenoses (and possibly right coronary artery stenoses), or in those associated with impaired distal runoff caused by a recent MI or manifest by a fixed thallium defect.¹⁵⁴ The primary success rate with this device is 95%.¹⁵⁵ In most Rotablator procedures, concomitant balloon angioplasty is necessary, however, for creation of a suitable lumen.

View larger version (44K): [in this window] [in a new window]   FIGURE 20-5 Rotablator system (left). Artist's depiction of ablation of atherosclerotic plaque using the Rotablator (right). (Courtesy of Heart Technology, Inc., Redmond, WA.)

	THE FUTURE IN ALTERNATIVE CORONARY INTERVENTIONS

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Other new technologies undergoing evaluation for treatment of coronary artery disease include various types of stents, low-speed rotators, and transluminal extraction catheters. Although laser angioplasty initially was greeted with enthusiasm, the current consensus is that its use will be limited.

The adjunctive therapies in use today have made it possible for interventionalists to treat long, calcified, ulcerated, and distal lesions that would not have been possible to treat with balloon angioplasty alone. A lesion-specific approach is commonplace now. The restenosis rate has not been significantly reduced with these adjunctive strategies, although refinements in stent placement are promising.

Coronary angioplasty, now along with stenting, remains the cornerstone of interventional cardiology, currently accounting for more than 90% of all coronary interventions. If selected stent coatings prove as successful as they appear presently, especially rapamycin-coated stents, the future impact of interventional cardiology in patient care will be even greater. It is likely to remain the primary procedure for coronary interventions and the standard against which we measure new therapies in the future. The impact of any new device will depend to a great extent on the technical experience and clinical judgment of the cardiology team. To aid in evaluating the safety and efficacy of new percutaneous transluminal interventional devices, the New Approaches to Coronary Intervention (NACI) voluntary registry was founded in the early 1990s.¹⁵⁷ Reports from this registry should be useful to all physicians interested in keeping abreast of evolving technologies.

Brachytherapy

Local radiotherapy with both beta and gamma emitters has been shown to markedly reduce the risk of restenosis following stent placement in human coronary arteries.¹⁵⁹ This form of therapy has already had a major beneficial impact in preventing restenosis when it has occurred with the original stent placement. General estimates of the risk of restenosis following brachytherapy suggest that in the first year, the incidence is approximately 5% to 15%.¹⁵⁸ Iridium 192 and strontium 90/yttrium 90 have been used for gamma and beta radiation, respectively. Longer term follow-up problems have been identified, including edge restenosis at the distal ends of the radiated segment, the later development of thrombosis, occasional coronary aneurysms, and a rare pseudoaneurysm.¹⁵⁸ Thus, longer term antiplatelet therapy has been recommended in the treatment of these patients, including aspirin and clopidogrel given for at least 1 year following radiation therapy; some physicians give this therapy for even longer periods of time. Clearly, the local radiotherapy has reduced the restenosis rate in patients with in-stent restenosis when a second procedure is needed. Whether this form of therapy will continue to be used if the drug-coated stents, such as rapamycin-coated stents, prove to be as successful in the future as they appear to be presently is uncertain. However, it is the author's belief that localized radiotherapy will be a useful adjunct therapy even in an era where coated stents are the preferred therapy.

	ACKNOWLEDGMENTS

 
The excellent and dedicated assistance of Rebecca Teaff and Linda Spangler in preparing this manuscript is gratefully acknowledged. Case illustrations were generously provided by Emerson Perin, M.D.