What's New in the Treatment of Acute Coronary Syndromes

The best approach to each patient with unstable angina or MI is not always clear as therapies continue to evolve. The authors discuss recent research findings about the various chemical and mechanical tools available to enhance and stabilize the coronary circulation.

By Debabrata Mukherjee, MD, and Kim A. Eagle, MD

The term acute coronary syndrome (ACS) refers to a spectrum of acute and severe cardiac disorders characterized by a myocardial oxygen demand-and-supply mismatch. Patients with ACS represent a major medical problem, accounting for 2.5 million hospitalizations and 500,000 deaths annually in the United States. About 1.5 million of those hospitalized patients have a final diagnosis of unstable angina; the remaining 1 million are diagnosed with myocardial infarction (MI) (with and without ST-segment elevation). Management of ACS presents a challenge to the physician because treatment strategies continue to evolve. A number of trials have now assessed the safety and efficacy of early revascularization strategies in the treatment of patients with ACS, whereas others have focused on pharmacologic adjunctive therapy. An optimal single strategy encompassing most patients' needs is not clear. This review focuses on significant advances in the management of patients presenting with a spectrum of ACS, including unstable angina (UA), non-ST-segment elevation MI (NSTEMI) and ST-segment elevation MI (STEMI).
 

NONINVASIVE AND INVASIVE STRATEGIES
FOR UNSTABLE ANGINA AND NSTEMI

Two treatment strategies—noninvasive and invasive—have evolved for patients with unstable angina and NSTEMI. With the noninvasive strategy, coronary angiography is reserved for patients with evidence of recurrent ischemia, dynamic ECG changes, or a strongly positive stress test, despite optimal medical therapy. With the invasive strategy, patients routinely undergo coronary angiography and revascularization, if feasible. In patients with unstable angina and NSTEMI without recurrent ischemia in the first 24 hours, use of early angiography provides several advantages for risk stratification. It can identify the 10% to 15% of patients with no significant coronary stenoses and the 15% to 20% with three-vessel disease with left ventricular dysfunction or left main stenoses. This latter group may derive a survival benefit from coronary artery bypass graft (CABG) surgery.

In addition, early percutaneous revascularization of the culprit lesion may reduce the risk of subsequent hospitalization and the need for multiple antianginal drugs compared with the early conservative strategy, as demonstrated in the TIMI IIIB trial. The use of improved antithrombotic therapy with low-molecular-weight heparin (LMWH) and/or a platelet glycoprotein IIb/IIIa receptor blocker has improved outcomes in patients managed noninvasively, as well as patients managed with the invasive approach. Pharmacologic and technologic advances, high success rates, and low complication rates have made the invasive strategy an increasingly attractive option in hospitals with catheterization facilities.

The noninvasive and invasive strategies have been evaluated in four major trials—TIMI IIIB, VANQWISH, FRISC II, and TACTICS-TIMI 18. Although similar in scope, they differed in design and level of patient acuity. No difference in death or MI was seen in the initial studies (TIMI IIIB and VANQWISH). However, there was a large crossover rate from the conservative arms to the invasive arms, and the VANQWISH trial had an excessive CABG mortality rate. Moreover, contemporary techniques and pharmacologic adjunctive therapy such as coronary stents and glycoprotein IIb/IIIa antagonists were not used.

FRISC-II and TACTICS-TIMI-18 are more appropriate comparisons of invasive versus noninvasive management of patients with unstable angina and NSTEMI in the current clinical environment. In both, an early invasive strategy was preceded by modern anti-ischemic and antithrombotic medications, and both studies demonstrated a reduced risk of the combined end point of death, MI, and rehospitalization with the invasive strategy.

The American College of Cardiology recommends the invasive strategy as a class I recommendation in patients with any of the following high-risk indicators: recurrent angina/ischemia at rest or with low-level activities despite intensive anti-ischemic therapy; elevated troponin levels; new or presumably new ST-segment depression; recurrent angina/ischemia with symptoms of congestive heart failure (CHF), an S₃ gallop, pulmonary edema, worsening rales, or new or worsening mitral regurgitation; high-risk findings on noninvasive stress testing; depressed left ventricular systolic function (for example, ejection fraction less than 0.40); hemodynamic instability; sustained ventricular tachycardia; percutaneous coronary intervention (PCI) within the previous six months; and prior CABG surgery.
 

LOW-MOLECULAR-WEIGHT HEPARIN VERSUS UFH

Despite extensive use in clinical practice over several decades, unfractionated heparin (UFH) has important limitations. It has an inconsistent anticoagulant effect, needs frequent monitoring, and is inactivated by plasma proteins and platelet factor 4. Other potential problems include a rebound increase in thrombogenicity after an infusion is stopped, activation of platelets, and the risk of heparin-induced thrombocytopenia. The unpredictable inhibition of thrombin by UFH is attributable to a relatively low bioavailability, due to extensive nonspecific binding to serum proteins, macrophages, and endothelial cells.

Low-molecular-weight heparin has a more predictable anticoagulant effect than UFH, is easier to administer, and may not require monitoring. Additional beneficial effects of LMWH include less sensitivity to the effects of platelet factor 4, a lower propensity to promote activation and aggregation of platelets, and potential antiplatelet effects via suppression of von Willebrand factor.

In the management of ACS, adjunctive heparin therapy has been shown to be beneficial. Although the combination of heparin and aspirin is effective for short-term treatment of unstable angina, between 6% and 15% of patients progress to MI or death within one month despite continuing aspirin therapy. The recent success of LMWH in the treatment of venous thromboembolism and the feasibility and safety of out-of-hospital use have led to the evaluation of these drugs administered subcutaneously, without laboratory monitoring, for ACS. To date, five randomized trials have compared LMWH with UFH in patients with ACS. The figure below shows the results of individual and pooled analyses comparing LMWH and UFH in these studies.

Pooled analysis of short-term trials comparing low-molecular-weight heparins (LMWH) and unfractionated heparin (UFH) in the management of unstable angina. The specific LMWH used is in parentheses. When all trials that compared LMWH with UFH were pooled (n=12,171), an odds ratio of 0.85 (95% CI 0.70-1.04) was derived, which suggests a 15% reduction in outcomes of death or MI with LMWH over UFH. Source: Hirsh et al, Circulation 103:2994, 2001

The reason for the discrepancies in the trial results is not clear. One possible explanation is therapeutic differences between the LMWHs. However, there were also significant differences in trial design, end points, administration of UFH, and patient populations. A meta-analysis of all the LMWH trials, including studies with dalteparin, nadroparin, and enoxaparin compared with UFH, showed no effect on death and MI at 30 days. However, a meta-analysis performed by Eikelboom has several important limitations, including the choice of end points and the combination of different LMWHs, despite guidelines indicating that all LMWHs should be considered pharmacologically distinct entities.

A separate meta-analysis of the two trials of enoxaparin (ESSENCE and TIMI-11B) showed that compared with UFH, enoxaparin produced a 20% relative reduction in rates of death and MI during the first 7 to 14 days of treatment. Based on available evidence, enoxaparin should be considered the antithrombotic agent of choice in patients with ACS. In clinical trials only enoxaparin has been shown to consistently reduce the risk of adverse cardiac events and reduce the need for revascularization when compared with UFH.
 

GLYCOPROTEIN IIB/IIIA INHIBITORS

The binding of fibrinogen to glycoprotein IIb/IIIa receptors on platelets is the final step in platelet aggregation. Glycoprotein IIb/IIIa antagonists occupy these receptors, preventing fibrinogen from crosslinking platelets, thereby preventing platelet aggregation.

There are currently three intravenous glycoprotein IIb/IIIa inhibitors approved for clinical use: abciximab, a monoclonal antibody; eptifibatide, a cyclic heptapeptide; and tirofiban, a nonpeptide agent. Boersma and colleagues performed a meta-analysis of all large randomized trials designed to study the clinical efficacy and safety of glycoprotein IIb/IIIa inhibitors in patients with ACS. Six trials, enrolling 31,402 patients, were included in the analysis. At 30 days, a 9% reduction in the odds of death or MI was seen with glycoprotein IIb/IIIa inhibitors compared with placebo or control (10.8% vs 11.8% events). In patients with positive troponins (troponin T or I concentration greater than 0.1 g/L), glycoprotein IIb/IIIa inhibitors were associated with a 15% reduction in the odds of 30-day death or MI compared with placebo or control (10.3% vs 12.0% events). In patients with negative troponins, no risk reduction was seen.

Glycoprotein IIb/IIIa inhibitors were also associated with a significant reduction in death or MI in patients undergoing PCI within five days of receiving these agents, compared with patients who did not undergo PCI. Major bleeding complications were increased by glycoprotein IIb/IIIa inhibitors (2.4% vs 1.4%), but intracranial bleeding was not (0.09% vs 0.06%). Overall, glycoprotein IIb/IIIa inhibitors reduce the occurrence of death or MI in patients with ACS, with the greatest benefit seen in patients with positive troponins and those undergoing PCI.
 

DIRECT THROMBIN INHIBITORS VERSUS HEPARIN

Direct thrombin inhibitors have the theoretical advantage over heparin of inhibiting clot-bound thrombin and not being inhibited by circulating plasma proteins and platelet factor 4. A pooled analysis of several trials comparing hirudin to heparin demonstrated a 22% relative risk reduction in cardiovascular death or MI at 72 hours, with minimal loss of this early benefit at 7 and 35 days. Major bleeding episodes, however, were more common in the hirudin group than in the heparin group (59% vs 34%). These trials suggested that hirudin was more effective than heparin in preventing new ischemic events, revascularization procedures, and new MI, but with a higher bleeding risk.

Bivalirudin is a synthetic analogue of hirudin and a specific and reversible inhibitor of thrombin, which binds directly with fluid-phase and clot-bound thrombin. The HERO-1 trial (n=412) indicated that bivalirudin recipients were significantly more likely to have TIMI grade 3 flow at 90 to 120 minutes than heparin recipients. The HERO-2 trial (n=17,073) showed bivalirudin was significantly more effective than heparin in reducing 96-hour reinfarction and 30-day death/reinfarction than heparin. Data from a meta-analysis of four randomized trials involving patients undergoing PTCA for treatment of ACS indicate that at 30 to 50 days follow-up, bivalirudin was significantly more effective than heparin in reducing the incidence of nonfatal MI and the combined end point of death or nonfatal MI. In individual trials, bivalirudin was as well tolerated as heparin and had a reduced incidence of bleeding complications. Its major advantages are improved efficacy and safety (in terms of fewer bleeding episodes).

The TIMI 8 trial was undertaken to compare the efficacy and safety of bivalirudin versus UFH in a double-blind phase III trial of patients with ACS. At 14 days, the incidence of death or nonfatal MI was 9.2% in the 65 patients in the UFH group and 2.9% in the 68 patients in the bivalirudin group. Major bleeding occurred in three patients in the UFH group (4.6%) but in none of the patients in the bivalirudin group. The consistent trend toward a lower rate of death or nonfatal MI in the bivalirudin group without an increased risk of bleeding appears clinically attractive.

These small preliminary studies appear promising but more definitive evidence is required before thrombin inhibitors can be incorporated in the routine management of ACS. These agents are also indicated in place of heparin in patients with heparin-induced thrombocytopenia.
 

USE OF DRUG-COATED STENTS

A number of pharmacologic agents—including antiplatelet agents, anticoagulants, ACE inhibitors, lipid-lowering agents, vitamin supplements, antioxidants, and cytotoxic agents—have failed to significantly reduce restenosis after PCI. Arterial injury resulting from PCI is associated with smooth muscle cell activation and proliferation. Attention has recently been focused on the use of rapamycin to prevent stent restenosis. Rapamycin, a macrolide antibiotic, is a natural fermentation product of Streptomyces hygroscopicus.

Implantation of rapamycin-coated stents in de novo lesions has been shown to be safe and effective in inhibiting neointimal hyperplasia in patients with stable and unstable angina. No patient who underwent this procedure approached more than 50% vessel narrowing, as confirmed by intravascular ultrasound (IVUS) or quantitative coronary angiography, and only three patients had more than 15% intimal hyperplasia by IVUS when followed up after four months. Although the significance of the trial results is limited by the small number of patients, no edge restenosis or stent thrombosis was observed, both of which have been reported in studies of patients undergoing radiation therapy during coronary intervention. At longer follow-up, the reduction in IVUS-measured intimal hyperplasia in patients treated with rapamycin-coated stents persisted. The double-blinded RAVEL trial of patients with de novo native coronary artery lesions found a zero restenosis rate in patients treated with a rapamycin-coated stent.

In aggregate, these data suggest that rapamycin may significantly reduce restenosis after stent implantation in coronary arteries without the complications seen with other modalities that reduce the incidence of restenosis. Thus, drug-coated stents may treat both mechanisms of restenosis—namely, geometric remodeling and neointimal hyperplasia. Other agents such as paclitaxel and taxol have shown promise in animal and initial human studies and are being evaluated in clinical trials. The U.S.-based SIRIUS trial of rapamycin-coated stents reported an in-stent restenosis rate of 3.2% at eight months compared with 35.4% with noncoated stents.

Overall, drug-coated stents appear very promising in patients undergoing elective PCI, but they have not been studied in patients with ACS. Future dedicated trials may be needed to confirm the benefit of the coated stents in the ACS cohort.
 

ASPIRIN AND ANTICOAGULATION

Aspirin at doses ranging from 75 to 325 mg daily irreversibly inhibits cyclo-oxygenase-1, blocking the formation of thromboxane A2, thus reducing platelet aggregation. When used in ACS, it has consistently reduced the risk of cardiac death and nonfatal MI by approximately 50%. Consequently, it is recommended for all patients with ACS and should be continued indefinitely, unless the patient experiences side effects. Contraindications to its use are allergy and active bleeding.

Meta-analysis of the few small trials comparing moderate-to-high-intensity anticoagulation with aspirin did not demonstrate improved efficacy. Moreover, the incidence of bleeding was lower with aspirin. However, the ASPECT-2 (target INR, 3 to 4) and WARIS-2 (target INR, 2.8 to 4.2) trials both reported that full-intensity anticoagulation as monotherapy was superior to aspirin alone in the secondary prevention of death, MI, and stroke. Higher-intensity oral anticoagulation with frequent INR monitoring seems to be an effective alternative to aspirin.

Four trials with a target INR above 2 have been completed, three involving patients with MI (APRICOT-2, ASPECR-2, and WARIS-2) and one that included primarily patients with unstable angina (OASIS-2). Overall, the data suggest that oral anticoagulation with a target INR above 2 may have incremental benefit over aspirin alone. However, the need for frequent monitoring of anticoagulation activity has limited the widespread adoption of this strategy.
 

COMBINATION ANTIPLATELET THERAPY

The Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) trial randomized 12,562 ACS patients to either aspirin alone or aspirin plus clopidogrel. There was a 20% reduction in the composite end point of cardiovascular death, MI, or stroke, with only a slight increase in the risk of bleeding, in the group receiving combination antiplatelet therapy. The incidence of the primary end point of cardiac death, nonfatal MI, and/or stroke was 9.3% in the aspirin plus clopidogrel group and 11.4% in the aspirin alone group. The incidence of the prespecified second primary end point (cardiac death, MI, stroke, and/or refractory ischemia) was 16.5% in the aspirin plus clopidogrel group and 18.8% in the aspirin alone group.

The percentage of patients with in-hospital refractory or severe ischemia, heart failure, and revascularization procedures was significantly lower with combination antiplatelet therapy using aspirin plus clopidogrel. However, there were more patients with major bleeding in the aspirin plus clopidrogel group than in the aspirin alone group (3.7% vs 2.7%), but there was no significant increase in life-threatening bleeding (2.1% vs 1.8%) or hemorrhagic strokes (0.1% vs 0.1%).

Based on the results of the CURE study, the American College of Cardiology now recommends that clopidogrel should be added to aspirin as soon as possible after admission of a patient with ACS and administered for at least one month and in some cases for as long as nine months. Gaspoz and colleagues demonstrated that each additional quality-adjusted year of life comes at a cost of approximately $130,000 for combination clopidogrel/aspirin therapy compared with aspirin alone.
 

ACUTE LIPID LOWERING

The Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) study assessed the role of statins in patients presenting with ACS. The study randomized 3086 patients with ACS to receive atorvastatin (80 mg/day) or placebo between 24 and 96 hours after hospital admission. This study found that atorvastatin was safe and reduced the incidence of the composite end point of death, nonfatal MI, resuscitated sudden cardiac death, and/or emergent rehospitalization for recurrent ischemia at 16 weeks compared with placebo (14.8% vs 17.4%). These and other observational data suggest that there are significant benefits to starting statin therapy when patients present with ACS.
 

PCI VERSUS FIBRINOLYSIS FOR STEMI

Several studies have now compared PCI and fibrinolysis as the initial reperfusion modality for STEMI. In the GUSTO-IIb trial, 1138 patients with STEMI within 12 hours of onset of chest pain were randomly assigned to receive PTCA (n=565) or fibrinolysis with accelerated tissue plasminogen activator (tPA) (n=573). Thirty days after enrollment, the incidence of death, recurrent MI, or disabling stroke was 9.6% in those who underwent PTCA and 13.6% in those who received tPA. However, at six months, there was no significant difference in the incidence of the composite outcome, which was 13.3% in the PTCA group and 15.7% in the tPA group.

Weaver and colleagues performed a meta-analysis of the treatment effects of primary angioplasty vs fibrinolysis for STEMI from 10 randomized trials. The pooled mortality rate at 30 days was 4.4% for the 1290 patients treated with primary angioplasty, compared with 6.5% for the 1316 patients treated with fibrinolysis. The pooled rate of death or nonfatal reinfarction was also lower in patients treated with primary angioplasty than in those treated with fibrinolysis (11.9% vs 7.2%). Angioplasty was also associated with a significant reduction in total stroke (0.7% vs 2%) and hemorrhagic strokes (0.1% vs 1.1%). This analysis concluded that primary PTCA appeared to be superior to fibrinolytic therapy for treatment of patients with STEMI. The graph shows lower mortality rates with primary PCI compared with fibrinolysis in several trials.

In-hospital or 30-day mortality in trials comparing primary angioplasty with fibrinolytic therapy. PTCA = percutaneous transluminal coronary angioplasty Source: Herrmann et al, Am J Cardiol 85(8 suppl):10, 2000

Suryapranata and colleagues investigated the long-term clinical outcome and cost-effectiveness of stenting compared with balloon angioplasty in patients with acute MI. The primary end point was the cumulative first-event rate of death, nonfatal reinfarction, or target vessel revascularization. After 24 months, the combined clinical end point of death/reinfarction was 4% after stenting and 11% after balloon angioplasty. The cumulative cardiac event-free survival rate was higher after stenting (84% vs 62%). Despite the higher initial costs of stenting, the cumulative costs at 24 months were comparable to those of balloon angioplasty. The authors concluded that compared with balloon angioplasty, primary stenting for acute MI results in a better long-term clinical outcome without increased cost.

The CADILLAC investigators demonstrated that at six months, the primary end point of a composite of death, reinfarction, disabling stroke, and ischemia-driven revascularization of the target vessel occurred in 20.0% of patients after PTCA, 16.5% after PTCA plus abciximab, 11.5% after stenting, and 10.2% after stenting plus abciximab. Thus, PCI with stenting and adjunctive abciximab appears to be the mechanical reperfusion modality of choice in patients presenting with acute STEMI.
 

STENTING PLUS IIB/IIIA INHIBITORS VERSUS FIBRINOLYSIS

The STOPAMI trial assessed whether coronary stenting combined with abciximab results in a greater degree of myocardial salvage than fibrinolysis. The primary end point was the degree of myocardial salvage, determined by means of serial scintigraphic studies with technetium 99m sestamibi. In the group that received a stent plus abciximab, the median size of the final infarct was 14.3% of the left ventricle versus 19.4% in the alteplase group. The cumulative incidence of death, reinfarction, or stroke at six months was lower in the stent group than in the alteplase group (8.5% vs 23.2%). This study demonstrated that coronary stenting plus abciximab leads to a greater degree of myocardial salvage and a better clinical outcome than does fibrinolysis with a tissue plasminogen activator.

The STOPAMI-2 trial compared stenting plus abciximab to enhanced fibrinolysis with alteplase plus abciximab. Technetium 99m sestamibi scintigraphy was performed at admission and after a median of 11 days to calculate initial perfusion defect, final infarct size, and degree of myocardial salvage. The primary end point was the salvage index, or the ratio of the degree of myocardial salvage to the initial perfusion defect. Major adverse clinical events within six months from randomization were also compared.

Stenting was associated with greater myocardial salvage than alteplase (13.6% vs 8.0% of the left ventricle). The six-month mortality rate was 5% in the stent group and 9% in the alteplase group. This small pilot study demonstrated that in patients with acute MI, stenting with abciximab produced more myocardial salvage than the combination of fibrinolysis plus abciximab.
 

PCI FOR AMI WITH CARDIOGENIC SHOCK

The SHOCK trial demonstrated significantly improved survival with early revascularization for patients with STEMI presenting with cardiogenic shock. The prospective, multicenter SHOCK registry demonstrated significant reduction in mortality rates with PCI compared to medical treatment in patients with cardiogenic shock (46.4% vs 78.0%). This reduction remained significant even after adjustment for patient differences and survival bias. Measures to promote early and rapid reperfusion are extremely important in improving the otherwise poor outcome in patients with cardiogenic shock. Treatment benefit with revascularization has been demonstrated primarily in patients younger than 75. Patients with acute MI and cardiogenic shock (particularly those younger than 75) should undergo early revascularization or be rapidly transferred to medical centers capable of early angiography and revascularization.
 

ENHANCED FIBRINOLYSIS

Several new pharmacologic regimens are being evaluated to optimize reperfusion therapy. The GUSTO V trial compared the effect of full-dose reteplase to the combination of half-dose reteplase plus abciximab. There was no significant difference in 30-day mortality between the treatment groups, but the combination therapy led to a reduction in ischemic complications, including reinfarction, and may facilitate PCI.

The ASSENT-3 study randomized patients to one of three strategies: full-dose tenecteplase and enoxaparin; half-dose tenecteplase, weight-adjusted low-dose UFH, and a 12-hour infusion of abciximab; or full-dose tenecteplase with weight-adjusted UFH. There was a lower rate of death, reinfarction, and refractory ischemia in the enoxaparin and abciximab groups than in the UFH group; the ease of administration may make tenecteplase plus enoxaparin the more attractive option.

The HERO-2 trial compared the thrombin-specific anticoagulant bivalirudin to heparin in patients undergoing fibrinolysis with streptokinase for acute MI. The results demonstrated a reduction in the rate of adjudicated reinfarction within 96 hours by 30% with bivalirudin. None of the combination therapies has shown a reduction in mortality, but they have shown consistent reduction in reinfarction, refractory ischemia, and other secondary end points. Longer-term follow-up studies are needed to determine whether this reduction in secondary end points will eventually translate to lower mortality.
 

LONG-TERM STANDARD CARE

Advances in pharmacologic and mechanical reperfusion therapies have significantly improved the prognosis for patients with ACS. After initial stabilization of these patients, the major objective is effective secondary prevention. The medications that should be considered for evidence-based disease management are listed in the table below. Aggressive lifestyle and risk factor modification should be undertaken in all patients. Goals include complete smoking cessation, statin therapy to keep low-density-lipoprotein cholesterol below 100 mg/dl, optimal control of blood pressure with a target goal of 130/85 mm Hg, optimal glycemic control with a target HbAIc of 7 gm/dl, regular exercise training program, low-fat diet, and appropriate medical follow-up.

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