Strategies for Optimizing Outcomes in the NSTE-ACS Patient: The CATH (Cardiac Catheterization and Antithrombotic Therapy
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Target Audience: Clinical Cardiologists, Interventional Cardiologists and Nurses. Release Date: 12-01-06 Expiration Date: 11-30-07 Learning Objectives: Upon completion of this educational activity, participants should be able to: Educate clinicians about the latest pharmacological treatment options for ACS patients; Review proper utilization of thrombolytic and antiplatelet drugs; Discuss the risks and benefits of device treatment versus pharmacologic treatment. Method of Participation: Read the journal supplement and complete the Post-Test and Evaluation form and send to: North American Center for CME, 83 General Warren Blvd. #100, Malvern, PA 19355. Fax: (610) 560-0501 Successful Completion: Successful completion entails participants obtaining a score of at least 70% on the Post-Test. A certificate of completion will be mailed to the address listed on your Post-Test/Evaluation form within 6 weeks of receipt of the documents. 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Please refer to the official prescribing information for each product for discussion of approved indications, contraindications and warnings. Faculty Disclosures: All faculty participating in Continuing Education programs sponsored by the North American Center for Continuing Medical Education are expected to disclose to the meeting audience any real or apparent conflict(s) of interest related to the content of their presentation. It is not assumed that these financial interests or affiliations will have an adverse impact on faculty presentations; they are simply noted here to fully inform participants. Doctor Cohen has disclosed that he has received grant/research support from Sanofi-Aventis. He is a consultant to Datascope. He is a member of the speakers’ bureau for Sanofi Aventis, Merck, Schering and BMS. Doctor Fry has disclosed that he has no significant financial relationship with any organization that could be perceived as a real or apparent conflict of interest in the context of the subject of his presentation. Doctor Levine has disclosed that he is a consultant and member of the speakers’ bureau for Millenium, Sanofi-Aventis, BMS and The Medicines Company. Doctor Diez has disclosed that he has received grant/research support from Sanofi-Aventis. Doctor Ferguson has disclosed that he has the following relationships: — ¹Research Grants, ²Consulting, ³Speaker’s Bureau: Abbott^1,2 Accumetrics¹ Astra-Zeneca² Aventis^1,2,3 Biogen¹ Bristol Myers-Squibb^1,2,3 Centocor^1,2,3 COR/Millenium^1,2 Datascope^1,2 Eli Lilly & Company^1,2,3 ESP Pharma² Genentech^1,2 Guidant Coporation^1,2 Guilford Pharmaceuticals² Medical Simulator Corporation² Medtronic, Inc.¹ Merck^1,2 Procter & Gamble^1,2 Pharmacia^1,2 Roche² Sanofi-Synthelabo^1,2,3 St. Jude Medical¹ Searle/Monsanto^1,2 Texas Biotechnology^1,2 The Medicines Company.^1,2 Doctor Zidar has disclosed that he has no significant financial relationship with any organization that could be perceived as a real or apparent conflict of interest in the context of the subject of his presentation. Doctor Shani has disclosed that he has no significant financial relationship with any organization that could be perceived as a real or apparent conflict of interest in the context of the subject of his presentation. Doctor Rao has disclosed that he is a consultant and member of the speakers’ bureau for Sanofi-Aventis, The Medicines Company and Cordis Corporation. Commercial Supporter: This activity is supported by an educational grant from Sanofi-Aventis. Conflict of Interest Resolution/Content Validation: In compliance with ACCME Standards for Commercial Support and NACCME’s policy and procedure for resolving conflicts of interest, this continuing medical education activity was reviewed by a member of the NACCME Cardiology Advisory Board in October, 2006 for clinical content validity to insure that the activity’s materials are fair, balanced and free of bias toward the commercial supporter(s) of the activity, and that activity materials represent a standard of practice within the profession in the U.S. and that any studies cited in the materials upon which recommendations are made are scientifically objective and conform to research principles generally accepted by the scientific community. Sponsor: North American Center for Continuing Medical Education. Introduction Every year, close to 1.5 million patients are admitted to the hospital with a diagnosis of unstable angina or non-ST-elevation myocardial infarction (UA/NSTEMI).1 Both of these conditions fall under the umbrella term “acute coronary syndromes” (ACS). Relative to acute ST-elevation myocardial infarction (STEMI), patients with UA/NSTEMI have a slightly higher 1-year mortality,² and constitute a significantly larger proportion of patients with ACS.³ During the course of their hospitalization, these patients will interact with many different health care professionals, be bombarded by several different drugs and procedures and be moved through several different hospital units before being discharged on multiple different medications. The 2002 American College of Cardiology/American Heart Association Guidelines (ACC/AHA) provided a foundation for management of patients with UA/NSTEMI based on the available scientific knowledge at the time, integrating the patient’s acuity, the use of potent antithrombotic agents and a strategy of early catheterization and revascularization (Figure 1).⁴ In just 4 years since the 2002 guidelines were published, no less than 50,000 patients have been enrolled in new, prospective, randomized, clinical therapeutic trials of some already-approved antithrombotics as well as newer agents. This huge body of “evidence” is intimidating in its breadth for clinicians and healthcare providers. However, despite all of this new information, many patients do not receive therapies that are identified as beneficial in the guidelines. As shown in Figure 2, antiplatelet agents in particular are underused.5 In addition, substantial challenges remain in identifying the optimal combination of therapeutic agents that will maximize benefits while minimizing drug-related adverse events in patients with NSTEMI [e.g., low-molecular-weight heparins (LMWHs), unfractionated heparin (UFH), direct antithrombins (DTI), direct factor-Xa inhibitors, P2Y12- adenosine diphosphate (ADP) receptor blockers and glycoprotein (GP) IIb/IIIa inhibitors]. The decision-making process regarding choosing among the spectrum of pharmacologic options and the optimal timing for invasive catheterization and percutaneous interventional (PCI) approaches is confounded by the large number of “stakeholders”: emergency physicians, medical cardiologists, interventionalists, cardiac surgeons, nurse practitioners and nurses (Figure 3). Not infrequently, the choices appealing to emergency department (ED) providers may be different from the choices interventional cardiologists may make. For example, the quick and simple administration of aspirin, a loading dose of clopidogrel and subcutaneous LMWH that does not need monitoring is a strategy that could be very appealing to the “stressed” ED staff. However, this same strategy could be disturbing to the cardiac catheterization staff who are used to measuring activated clotting times and worried that the patient may have multivessel disease and may need early coronary artery bypass grafting (CABG). The evolution of clinical practice as well as the results of the clinical trials published since the 2002 ACC/AHA guidelines have changed the landscape for managing patients with NSTE-ACS in a number of important ways. First, increased emphasis has been placed on the concept that pharmacological and interventional strategies should be risk-directed. In this model, specific clinical, electrocardiographic (ECG) and/or laboratory features modulate aggressiveness of both the medical therapy and the propensity to perform PCI in patients with NSTE-ACS. Second, catheterization is being performed sooner and far more frequently. Third, more attention has recently been focused on the bleeding risks associated with the antithrombotics.^6–9 Cardiac Catheterization and Antithrombotic Therapy in the Hospital Clinical Consensus Panel The second Cardiac Catheterization and Antithrombotic Therapy in the Hospital (CATH) Clinical Consensus Panel & Scientific Roundtable assembled on September 9, 2006. With the above-mentioned clinical controversies and treatment options as targets, the purpose of the Panel was to critically evaluate recent clinical trial data; elaborate a rational and evidence-based approach to integrating the new thrombin inhibitors and new antiplatelet agents; develop a strategy for invasive care; and outline a site-, specialty-, and spectrum-of-care–specific evidence-based strategy that distinguishes among pharmacological and/or invasive interventions based on risk-group stratification for maximizing outcomes in patients with NSTE-ACS. The CATH Panel focused on those therapeutic areas in which the most important changes related to pharmacological management in the setting of PCI are occurring: (1) the expanding array of “anticoagulation cascade” agents such as the LMWH enoxaparin, the indirect, selective Xa inhibitor fondaparinux, the direct selective thrombin inhibitor bivalirudin, including combination with aspirin, oral antiplatelet drugs and/or GP IIb/IIIa inhibitors; (2) identification of high-risk features and treatment trigger points that support either more intensive medical therapy or the need for PCI; and (3) recognition that management must be tailored to the capabilities and specialty services offered at individual institutions. A significant percentage of patients in the United States do not have immediate access to facilities where cardiac catheterization, PCI and/or CABG services are available. As a result, risk-directed care must also take into account site-specific features as well as the availability of clinical subspecialists. Acknowledging these realities will yield management protocols and treatment guidelines that are customized for individual institutions and practice settings. To account for the full site-, specialty- and spectrum-of-care issues in NSTE-ACS management in its recommendations, the CATH Panel issued specific therapeutic guidelines for each of the three major clinical zones (emergency department, cardiac catheterization laboratory and postcatheterization stepdown unit) in which patients with NSTE-ACS are managed (see Appendix). Risk Stratification in NSTE-ACS High-risk criteria that support more aggressive medical therapy (i.e., addition of a small-molecule GP IIb/IIIa inhibitor to a core regimen of aspirin, enoxaparin and, in some cases, clopidogrel) or direct clinicians toward early catheterization and revascularization as the dominant modality for patients with ACS are outlined in Table 1A. Additional factors that may suggest the need for a more intensive approach include the presence of such comorbid conditions as heart failure, prior myocardial infarction (MI), previous CABG and left ventricular (LV) dysfunction. Patients with advanced renal disease, clearly a group at higher risk for recurrent ischemic events, must be approached cautiously given the risks of contrast-induced nephropathy and bleeding. When serum creatinine levels are greater than 4.0 mg/dL, alternative strategies may need to be considered. Perhaps one of the most important aspects of managing patients with NSTE-ACS is the ability to risk-stratify patients into those individuals who will benefit most from either pharmacological or an early invasive strategy. Although a number of risk stratification tools have been suggested by clinical experts and associations, the Thrombolysis in Myocardial Infarction (TIMI) Risk Factor Score has emerged as one of the most widely accepted approaches to date for identifying patients who are most likely to benefit from specific strategies (Table 1B).¹⁰ The TIMI Risk Score is derived from the sum of the following clinical parameters, each assigned a value of one point: (1) diagnostic elevation of cardiac markers; (2) history of three or more conventional cardiac risk factors (e.g., diabetes, smoking, elevated low-density lipoprotein cholesterol, hypertension, family history of premature coronary artery disease [CAD]); (3) age 65 years or older; (4) known CAD, defined as documented 50% or greater stenosis in at least one major coronary artery; (5) aspirin use within one week of presentation; (6) two or more episodes of resting angina during the previous 24 hours prior to presentation; and (7) new ST-segment deviation (persistent depression or transient elevation not meeting fibrinolytic criteria) of 0.5 mm or greater in limb and/or precordial leads.¹⁰ As the number of risk factors increases from 0/1 to 5/7, the risk of death, MI or urgent revascularization within 14 days increases from 4.7% to 40.9% in a stepwise fashion. The TIMI Risk Score was derived from data available from the TIMI-11B trial¹¹ and its predictive value has been validated in at least three additional trials: Efficacy and Safety of Subcutaneous Enoxaparin in Non-Q-Wave Coronary Events (ESSENCE);¹² Treat Angina with Aggrastat + determine Cost of Therapy with an Invasive or Conservative Strategy (TACTICS)-TIMI 18¹³ and Platelet Receptor Inhibition in Ischemic Syndrome Management in Patients Limited by Unstable Signs and Symptoms (PRISM-PLUS).¹⁴ From a clinical, risk-directed management perspective, patients with NSTE-ACS appear to derive progressively greater benefit from pharmacologic therapies such as enoxaparin^11,12 and platelet GP IIb/IIIa inhibitors,¹⁵ as well as an interventional strategy¹³ with increasing TIMI risk score.¹⁰ The CATH Panel evaluated the usefulness of the TIMI Risk Score and also considered other high-risk features that help guide pharmacoinvasive therapy in NSTE-ACS. It was concluded that no single model or risk factor is 100% predictive of adverse outcomes nor the degree of incremental benefit from early PCI in any individual patient. Cardiac biomarkers such as cardiac troponin (Tn), C-reactive protein (CRP) and b-type natriuretic peptide (BNP) have been shown to provide unique prognostic information in patients with ACS.^16,17 Sabatine and colleagues found that Tn-1, CRP and BNP each provided independent and incremental prognostic information. Simultaneous evaluation of these three markers at the time of presentation allowed powerful prediction of risk of death, MI and congestive heart failure (CHF) both at 30 days and at 6 or more months.¹⁷ In one study, the combination of N-terminal proBNP (a substrate of BNP) and creatinine clearance provided the best prediction of 1-year mortality.¹⁶ There is some controversy surrounding these newer markers. Any elevation of Tn above 0.01 ng/mL is considered abnormal.¹⁸ Because Tn is a very sensitive marker, elevations are common in patients with a variety of acute and chronic cardiovascular diseases, including CHF, aortic valve disease and hypertension. Similarly, elevated CRP levels are frequently associated with a number of other clinical issues, including obesity, diabetes, estrogen therapy and hypertension. Thus, the clinician must determine whether or not the presentation is one of acute ischemia and should consider the biomarker in the context of the clinical presentation.¹⁸ In patients with ACS, BNP and NT-proBNP are prognostic for mortality but less consistently for recurrent MI.¹⁸ At present, there is no consensus on proper cutoff values and routine use of BNP and NT-proBNP cannot be recommended. Safety and Drug-Related Events While the combination of antithrombotic treatments and an early invasive strategy has improved the outcomes of patients with NSTE-ACS, the risk of bleeding and blood transfusion remains an important issue. Not infrequently, patients receive excess doses of antithrombotic therapy.⁶ Dosing errors occur more frequently in vulnerable populations and predict an increased risk of major bleeding. Alexander and colleagues found that excessive dosing occurs most commonly in elderly patients (Figure 4).⁶ Rates of major bleeding and transfusion reported from NSTE-ACS trials range from 1% to 9%.^19–22 Long considered an inevitable consequence of anticoagulant and invasive therapies, it is now clear that bleeding is independently associated with an increased risk for short- and longer-term mortality among patients with NSTE-ACS as well as those undergoing PCI.^7,23,24 There is a stepwise increase in the risk of mortality as bleeding severity worsens,^7,24 such that even “mild” bleeding portends a worse prognosis compared with no bleeding (Table 2). There are two definitions that have been used extensively to classify the severity of bleeding events among ACS patients: TIMI or the Global Use of Strategies to Open Occluded Arteries (GUSTO) classifications.⁸ In studies in which both systems have been used, there are often disparities in the reported incidence of bleeding events. For example, in the Platelet Glycoprotein IIb/IIIa in Unstable Angina Receptor Suppression Using Integrilin Therapy (PURSUIT) trial, the rate of TIMI major bleeding among eptifibatide-treated patients was 3.0% compared with a rate of severe bleeding of 1.1% when the GUSTO system was used.¹⁵ The TIMI system is predominantly a laboratory-based scale, whereas the GUSTO system is clinically based.^25,26 In a study comparing the prognostic impact of bleeding events classified by the two systems, Rao and colleagues found that both identify patients at increased risk for adverse clinical events and that each scale identifies patients with bleeding events missed by the other scale. However, after adjustment for blood transfusion, the stepwise increase in risk with worsening GUSTO bleeding persisted, whereas the risk with TIMI bleeding was no longer significantly correlated with poorer outcomes.⁸ These data are corroborated by the randomized Superior Yield of the New Strategy of Enoxaparin, Revascularization and Glycoprotein IIb/IIIa inhibitors (SYNERGY) trial that compared enoxaparin with unfractionated heparin in 10,000 patients with NSTE-ACS undergoing early invasive risk stratification.²⁷ There were no significant differences in the incidence of in-hospital GUSTO severe bleeding or transfusion between patients randomized to enoxaparin or unfractionated heparin, but there was a significantly higher incidence of TIMI major bleeding among patients assigned to enoxaparin. Despite this increase in TIMI major bleeding, there were no differences in the rates of 30-day death or recurrent MI between the two arms. This underscores the concept that for determining prognosis, clinically manifest bleeding (e.g., that measured by the GUSTO bleeding scale) is more important than laboratory-based indices of bleeding such as decreases in hemoglobin or hematocrit. Mechanisms underlying this increased risk are likely related to cessation or reversal of anti-ischemic therapy (e.g., aspirin, clopidogrel antithrombin therapy), hypotension, anemia and blood transfusion (Table 2). Data from the Can Rapid Risk Stratification of Unstable Angina Patients Suppress Adverse Outcomes With Early Implementation of the American College of Cardiology/American Heart Association Guidelines (CRUSADE) project demonstrate that 14.9% of the overall and 10.3% of the non-CABG population underwent transfusion during hospitalization for NSTE-ACS.⁹ There was significant variation in transfusion rates across sites, which may be partly explained by the controversy surrounding the role of blood transfusion in the management of anemia and bleeding among patients. There are no randomized clinical trials of transfusion strategies specifically in patients with ischemic heart disease; however, there are observational studies that suggest a strong association between transfusion and a higher risk of recurrent MI as well as death in this patient population.^9,20 Although patients undergoing transfusion have a higher baseline risk and experience worse unadjusted outcomes (e.g., 30-day mortality) compared with those not undergoing transfusion,⁹ transfusion increases this risk by two- to four-fold after adjustment for these differences.^9,20 Thus, clinicians should make every effort to minimize the risk of bleeding and blood transfusion through careful dosing of adjustable anticoagulants and management of patients during invasive procedures. Invasive versus Conservative Therapy in NSTE-ACS Initial studies evaluating the benefits of an early invasive or “anatomic” strategy as compared to a conservative or “ischemia-driven” strategy suggested that outcomes are not improved with routine catheterization and early revascularization in the absence of recurrent or provoked ischemia.^28,29 These trials were conducted before the routine use of stents, which drastically improved safety and durability of PCI, as well as prior to improved antithrombotic therapies such as thienopyridines, GP IIb/IIIa inhibitors, and LMWH. Recent studies in the past 4 years have readdressed the merits of an early invasive strategy in the setting of improved PCI techniques, optimal pharmacotherapy in both medically managed and revascularized patients, and longer clinical follow up. The importance of an invasive strategy is supported by the consistent findings across three trials, each of which employed different antithrombin and GP IIb/IIIa inhibitor strategies.^13,30,31 The second Fragmin During Instability in Coronary Artery Disease (FRISC-II) trial compared 3 months of the LMWH dalteparin versus placebo and compared the use of early catheterization and revascularization with a conservative strategy in a second randomization in a 2 x 2 design.³⁰ At 6 months, the composite of death or MI was decreased by early catheterization and revascularization from 12.1% to 9.4% (p = 0.031) compared with those managed conservatively, despite a high rate of early crossover (38%) from the noninvasive to the invasive strategy.³⁰ The benefit of an invasive strategy at 6 months was due primarily to a reduction in MI (7.8% versus 10.1%) and was greatest in those at highest risk as evidenced by ST-depression or positive biomarkers at presentation.³⁰ At 2 years, superior outcomes were seen in the invasive group not only with respect to the composite endpoint of death, MI and readmission (12.1% vs. 16.3%; p = 0.003; RR = 0.74), but also for mortality (3.7% vs. 5.4%; p = 0.038; RR = 0.68).³² The greatest reduction in mortality occurred in the first 12 months of follow-up and was primarily seen in men. TACTICS TIMI-18 enrolled 2,220 patients with UA and NSTEMI who had ischemic ST-segment or T-wave changes, elevated levels of cardiac markers, a history of CAD or all three findings.¹³ All patients were treated with aspirin, heparin and the GP IIb/IIIa inhibitor, tirofiban. Patients were randomly assigned to an early invasive strategy, in which routine catheterization was performed as early as 4 hours and no later than 48 hours after presentation or to a more conservative (selectively invasive) strategy, in which catheterization was performed only if patients had objective evidence of recurrent ischemia or abnormal stress testing. The primary endpoint was a composite of death, nonfatal MI and rehospitalization for ACS at 6 months.¹³ At 6 months, the primary endpoint was reached in 15.9% with the use of the early invasive strategy, and in 19.4% with the use of the conservative strategy [OR = 0.78; 95% confidence interval (CI) 0.62–0.97; p = 0.025]. The rate of death or nonfatal MI at 6 months was similarly reduced (7.3% vs. 9.5%; OR = 0.74; 95% CI 0.54–1.00; p 13 However, mortality at 6 months was not significantly improved by the invasive strategy (3.3% vs. 3.5%, invasive vs. conservative, RR = 0.93; p = 0.74).¹³ Benefit of an early invasive approach was predicted by the presence of elevated cardiac biomarkers at presentation.³³ The risk of death, MI or readmission was reduced by 46% in patients with positive troponins managed with an invasive strategy (15.3% vs. 25.0%, RR = 0.54; p p = 0.16), possibly due to periprocedural MIs in the early-revascularization patients.³³ The relative benefit of an early-invasive strategy was also greatest in those patients at highest risk, as reflected by a TIMI risk score > 5 (RR = 0.55).¹⁰ Unlike FRISC-II, benefits of an invasive strategy were seen in both men and women (RR = 0.72 vs. 0.64, respectively; p = 0.88).³⁴ Additionally, the benefits of an invasive strategy were independent of age. Patients over the age of 65 years had a similar reduction in the primary endpoint with an invasive strategy as compared with younger patients.³⁵ Economic analysis suggested that although initial hospital costs for an invasive strategy were higher (average $1,667), the difference in total cost was markedly attenuated by 6 months ($586 more for the invasive group).³⁶ The British Heart Foundation-sponsored third Randomized Interventional Treatment of Angina (RITA-3) trial tested the hypothesis that routine early angiography and revascularization was superior to a conservative strategy in patients with NSTE-ACS.³¹ Eligible patients were randomized within 48 hours of their index episode of rest angina to an early invasive strategy (n = 895) with planned catheterization less than 72 hours after enrollment or to a conservative strategy (n = 915). An important exclusion criterion was the presence of elevated total CK or CK-MB two times the upper limits of normal prior to randomization.³¹ The exclusion of these higher-risk patients may have influenced the short- and intermediate-term results. All patients received enoxaparin 1 mg/kg every 12 hours, aspirin, beta-blockers and nitrates. The use of GP IIb/IIIa antagonists or thienopyridines prior to PCI was at the discretion of the treating physicians. At 4 months, the primary endpoint of death, nonfatal MI and refractory angina was met in 9.6% of the invasive group and in 14.5% of the conservatively managed patients (RR = 0.66, 95% CI 0.51–0.85; p = 0.001).³¹ The difference in outcomes was due to a 50% reduction in recurrent refractory angina. At 1 year, the coprimary endpoint of death and nonfatal MI was not significantly different between the two strategies (invasive vs. conservative: 7.6% vs. 8.3%, RR = 0.91, 95% CI 0.67–1.25; p = 0.58).³¹ More patients in the invasive group had procedure-related MIs (15 vs. 4), but fewer subsequent spontaneous MIs (30 vs. 52; p = 0.019) during 1-year follow up. Non-CABG bleeding was more frequent in the invasive arm (8% vs. 4%), although overall need for transfusion, excluding CABG patients, was low (0.9% for both).³¹ As in FRISC-II, men benefited from the invasive strategy but women did not. At 1 year, death or nonfatal MI occurred in 5.1% of women in the conservative group and in 8.6% in the invasive group, whereas 10.1% of men in the conservative group and 7.0% in the invasive arm experienced death or nonfatal MI (interaction test; p = 0.011).³¹ The early and intermediate results of RITA-3 were similar to TACTICS-TIMI-18 where the primary benefit of the invasive strategy was to reduce recurrent symptoms without clearcut evidence of a reduction in mortality or MI. Unlike other trials, patients in RITA-3 were followed long-term.³⁷ At 5-year follow up, a significant benefit of the invasive strategy was seen with a reduction in death and nonfatal MI from 20.0% in the conservatively managed patients down to 16.6% in the patients in the invasive group (RR = 0.78, 95% CI 0.61–0.99; p = 0.044). There was a trend toward reduced mortality in the invasive group, although it did not quite reach statistical significance (12% vs. 15%, RR = 0.76, 95% CI 0.58–1.00; p = 0.054).³⁷ At 5 years, 61% of patients originally randomized to the invasive group had undergone revascularization (60% PCI, 40% CABG), predominantly in the first month, whereas 40% of patients in the original conservative-strategy group had been revascularized (52% PCI, 48% CABG) over the first 2 years of follow up. The late benefit of the invasive strategy and its higher rate of revascularization is reminiscent of the late benefits of CABG seen in the Coronary Artery Bypass Graft Surgery Trialists Collaboration (CASS trial),³⁸ suggesting that trials with shorter follow up may underestimate the potential long-term value of an early invasive strategy. The most recent randomized trial comparing a strategy of early catheterization and revascularization to a conservative approach is the Invasive versus Conservative Treatment in Unstable Coronary Syndromes (ICTUS) study.³⁹ In this trial, conducted in the Netherlands, 1,200 ACS patients presenting less than 24 hours after onset of symptoms and who all had positive troponins were randomized to early angiography within 24 to 48 hours of enrollment with 60% undergoing PCI and 16% undergoing CABG during their initial hospitalization versus a conservative strategy of initial medical therapy and angiography ± revascularization in those patients with recurrent or provoked ischemia.³⁹ The primary endpoint was death, recurrent MI or rehospitalization for angina within 1 year. CK-MB was measured every 6 hours in the first 24 hours. MI was defined as any increase in CK-MB above the upper limit of normal. At 1 year, there was a high rate of revascularization in both groups: 79% in the invasive group (78% PCI, 22% CABG) and 54% in the conservative group (74% PCI, 26% CABG).³⁹ All patients received aspirin and subcutaneous enoxaparin 1 mg/kg every 12 hours (maximum dose 80 mg every 12 hours). All patients undergoing PCI during the initial hospitalization were treated with abciximab. Early use of clopidogrel and high-dose atorvastatin was recommended. At 1-year follow up, there were no significant differences between the groups with respect to the primary endpoint (22.7% in the invasive group versus 21.2% in the conservative group, RR = 1.07, 95% CI 0.87–1.33; p = 0.33). Mortality was very low in both groups (2.5%). The incidence of MI was significantly higher in the early invasive group (15% vs. 19%; p = 0.005), which was driven by the incidence of PCI-related CK-MB elevations (invasive group = 11.3%, conservative group = 5.4%; p = 0.001).39 Rehospitalization for recurrent angina was less frequent in the invasive group (7.4% vs. 10.9%; p = 0.04). The rate of non-CABG bleeding was low in both groups (3.1% in the invasive group and 1.7% in the conservative group).³⁹ The absence of a reduction in the primary endpoint in the invasive group, in contrast to FRISC-II, TACTICS-TIMI 18 and RITA-3, may have been due to the definition of recurrent MI, the high rate of revascularization in the conservative group, aggressive medical therapy in both groups and the relatively short duration of follow up. In trials of patients with NSTE-ACS undergoing early catheterization and revascularization, the term “early” has been relative. Mean time to catheterization in TACTICS-TIMI 18 was 23 hours, but was 6 days in FRISC-II. Two additional smaller studies investigated the use of a very early invasive strategy.^40,41 The Value of First Day Angiography/Angioplasty In the Evolving Non-ST Segment Elevation Myocardial Infarction (VINO) study evaluated a cohort of 131 patients from 10 participating hospitals in the Czech Republic with confirmed NSTEMI, randomized within 24 hours of symptom onset to either first-day angiography or early-conservative treatment (angiography only after recurrent or stress-induced myocardial ischemia).⁴¹ The mean time to catheterization in the invasive group was 6.2 hours (8.6 hours to PCI). On the first day, in the angiography group, PCI of the infarct-related artery was performed in 47% while 35% were referred for CABG. In the conservative group, 55% underwent angiography (mean time = 61 days), 10% PCI (mean time = 55 days) and 30% bypass surgery within 6 months.⁴¹ The primary endpoint (death/reinfarction) at 6 months occurred in 6.2% versus 22.3% in the invasive and conservative groups, respectively (p p 41 The Intracoronary Stenting and Antithrombotic Regimen Cool (ISAR-COOL) trial randomized 410 patients with NSTEMI scheduled to undergo PCI to either immediate intervention or a “cooling-off” period.⁴⁰ All patients in both groups were treated with aspirin, clopidogrel, tirofiban and heparin. The “cooling-off” group received “quadruple antithrombotic therapy” for 72 to 120 hours before the procedure was conducted (mean time to PCI = 86 hours).⁴⁰ The early (immediate) intervention group received the same initial medications, but underwent PCI within an average of 2.4 hours of randomization. The primary endpoint of death/MI at 30 days in the “cooling-off” group was 11.6% versus 5.9% in the immediate-intervention group (RR = 0.51; p = 0.04), driven by a reduction in nonfatal MI prior to PCI (10.1% versus 5.9%). Events occurring after PCI were the same in both groups (11 patients each), despite the longer time to “passivate” the culprit lesion in the “cooling-off” group. The authors concluded that delay of intervention in order to passivate the culprit vessel does not improve outcome but may increase ischemic events prior to PCI.⁴⁰ Because trials of invasive and conservative strategies in NSTE-ACS were conducted during an era of rapid change in cardiology practice characterized by the introduction of new antithrombotic drugs and interventional techniques, direct comparison of trials completed in different countries comprising heterogeneous patient populations with changing definitions of MI is challenging at best. To account for these inherent differences, two meta-analyses have been reported, focusing on the role of early angiography and revascularization in the management of a broad spectrum of patients.^42,43 Mehta and colleagues analyzed results from 9,212 patients randomized in TIMI-IIIb, Medicine versus Angiography in Thrombolytic Exclusion (MATE), Veterans Affairs Non–Q-wave Infarction Strategies in Hospital (VANQWISH), FRISC-II, TACTICS TIMI-18, VINO and RITA-3.⁴³ During a mean follow up of 17 months, the overall composite endpoint of death or MI was reduced from 14.4% in the conservative group to 12.2% in the invasive group (RR = 0.82, 95% CI 0.72–0.93; p = 0.001), driven primarily by a reduction in MI (9.4% vs. 7.3%, RR = 0.75, 95% CI 0.65–0.88; p p = 0.007). After the initial hospitalization, however, the risk of death was 24% less in the invasively managed patients (4.9% vs. 3.8%, RR = 0.76, 95% CI 0.62–0.94; p = 0.01).⁴³ The meta-analysis by Hoenig and coworkers of FRISC-II, TACTICS TIMI-18, VINO, RITA-3 and ICTUS (total patients = 7,818) reached similar conclusions.⁴² Early in-hospital mortality overall was low, but higher in the invasive group (1.3% vs. 0.8%, RR = 1.59, 95% CI 0.96–2.64; p = 0.007). The risk of a periprocedural MI in the early-invasive group was two-fold higher, and the risk of bleeding was 1.7 times higher as compared with the conservatively managed patients.⁴² After hospital discharge, the risk of death or MI was significantly reduced by an invasive strategy at various time points. Late mortality (2 to 5 years) was significantly lower in the invasive strategy arm (6.9% vs. 9.3%, RR = 0.75, 95% CI 0.62–0.92; p = 0.006).⁴² Both meta-analyses found that benefit of the invasive strategy was confined to the highest-risk patients (i.e., troponin-positive) and that early intervention in the lower-risk patients had either a neutral or detrimental effect on outcomes. Panel Recommendations: Early-Invasive Therapy Early catheterization and revascularization in high-risk patients reduces risks of recurrent angina and the need for rehospitalization as well as MI and possibly death in the long term at the expense of higher rates of early mortality, periprocedural MIs and bleeding. Conversely, identifying patients who are poor candidates for revascularization or who are at high risk for bleeding may help avoid adverse outcomes and in turn improve overall outcomes with an invasive strategy. Therapies that reduce the risk of periprocedural MIs such as pretreatment with clopidogrel and appropriate use of GP IIb/IIIa antagonists are also likely to improve results with an early-invasive approach. Anticoagulants A number of anticoagulant alternatives have emerged for the pharmacoinvasive management of NSTE-ACS. One consistent message across the trials is that even in invasively managed patients, we can do better than the older, traditional approach of aspirin and UFH. Using the LMWH enoxaparin has been recognized as a superior strategy for medical management, and has received more recent attention as management strategies have evolved to encompass more aggressive invasive approaches. The revised 2002 AHA/ACC Guidelines recommend that anticoagulation with subcutaneous LMWH or intravenous UFH be added to antiplatelet therapy with aspirin, clopidogrel or both (Class I, Level A).⁴ In addition, enoxaparin is categorized as preferable to UFH as an anticoagulant in patients with UA/NSTEMI, unless CABG is planned within 24 hours (Class IIa, Level A).⁴ Worldwide, there is increasing usage of LMWH for ACS patients. In the international Global Registry of Acute Coronary Events (GRACE) in 1999 to 2001, LMWH was used in almost half of all ACS patients (including acute MI).44 More recent data from the CRUSADE Registry documented that in 2002 to 2003, in U.S. participating institutions, approximately 40% of patients were treated with LMWH.⁴⁵ Also, despite the lower likelihood of being admitted to an inpatient cardiology service, LMWH-treated patients in CRUSADE still had a high rate of diagnostic catheterization (85.9%) and PCI (56.9%).⁴⁵ Thus, in addition to medical management and catheterization laboratory management, covering the full “spectrum” of clinical care in modern-day practice also means covering the transition to the catheterization laboratory. Recent clinical trials have helped shed light on how important this transition is, and how this can be accomplished in invasively managed patients who have received LMWH. Low-Molecular-Weight Heparins What makes LMWH attractive for modern-day clinical care is their simplicity of use: subcutaneous administration, simple weight-based dosing, no need for monitoring and applicability in a variety of clinical circumstances. As management algorithms become more complicated, the most effective strategies are the most flexible ones, i.e., ones that do not interfere with subsequent management options. LMWH are already the preferred treatment for medical management, and have come into increasing use in emergency rooms and in transfer patients because of their simplicity. Given the growing importance (and complexity) of invasive management strategies, a foundation therapy will have to be compatible with invasive options. Issues associated with LMWH. There are a number of issues specifically relating to the use of LMWH in ACS patients managed with a rapid-invasive management strategy. First, how does one manage patients who come forward very rapidly to catheterization (11 A number of the acute MI studies, such as the third Efficacy and Safety of Tenecteplase in Combination with Enoxaparin, Abciximab or Unfractionated Heparin (ASSENT 3) trial⁴⁶ and Enoxaparin and Thrombolysis Reperfusion for Acute Myocardial Infarction Treatment (EXTRACT)-TIMI-25 trial,⁴⁷ have utilized an intravenous bolus to provide a more rapid onset of action. Other studies have shown that the use of an intravenous bolus provides virtually instantaneous therapeutic levels.⁴⁸ In patients coming rapidly forward to the catheterization laboratory for intervention (within approximately 2 hours of the initial subcutaneous dose), intravenous supplementation is probably warranted. Conversely, in patients who are admitted with plans for prompt transfer to the catheterization laboratory, if LMWH is to be used, therapy ought to include an intravenous bolus in addition to the subcutaneous injection (as was done in TIMI-11B). Another issue is that subcutaneous LMWH is not monitored or titrated. Traditionally, the cardiac catheterization laboratory is an environment where a specific “therapeutic range” for UFH is targeted as reflected by the activated clotting time (ACT). While therapeutic ranges for anti-Xa activity (0.6–1.0 anti-Xa U/ml) have been clearly defined for active treatment of acute deep vein thrombosis,⁴⁹ there are no comparable, prospectively validated therapeutic targets on the arterial side, although a theoretical arterial anti-Xa target level of 0.6–1.2 U/ml, has at least been referred to by some authors.^50,51 Moreover, at present we do not know for certain what constitutes an “adequate” degree of Xa inhibition for coronary interventional procedures, although the recently published Safety and Efficacy of Enoxaparin in Percutaneous Coronary Intervention (STEEPLE) trial begins to narrow the focus.⁵² The ACT is viewed as much less useful for LMWH and, given these difficulties, how can interventionalists be confident that their patients coming forward to the catheterization laboratory on LMWH have an adequate level of anticoagulation? There are also concerns about the transition to bypass surgery if it becomes necessary. LMWH and medical management. Much of our data on medical management come from studies done before invasive strategies were so aggressively and rapidly pursued. Older studies such as ESSENCE¹2 and TIMI-11B¹¹ demonstrated the superiority of enoxaparin over UFH in the management of ACS patients in the mid-to-late 1990s, before invasive management was so frequently and rapidly employed. While patients in the two studies did come forward to the catheterization laboratory, it was generally not part of the early initial management strategy, but more often in response to persistent clinical symptoms. The fragmin in unstable coronary disease (FRIC)⁵³ and the fraxiparin in ischemic syndrome (FRAXIS)⁵⁴ studies were studies of subcutaneous dalteparin and nadroparin, respectively, in ACS patients during that same mid-to-late 1990s time period. Neither was superior to UFH. A meta-analysis by Eikelboom and colleagues examined 12 trials comparing UFH or LMWH versus placebo, or UFH versus LMWH in 17,157 patients with NSTE-ACS.⁵⁵ Overall, UFH and LMWH reduced the risk of death or MI by half in comparison with placebo, with no major differences in safety or efficacy noted between the two.⁵⁵ Longer-term LMWH therapy (beyond the first 7 days) was associated with a significant increase in bleeding complications and no clinical benefit. A second meta-analysis by Kaul and colleagues supported the view that LMWH was more effective than placebo, and at least as effective as UFH in terms of the harder endpoints of death and MI.⁵⁶ Initial benefits are sustained in the longer term, but again, there appears to be no benefit (and increased bleeding risk) associated with extended therapy. The authors also suggest that the primary advantages of LMWH were the ease of administration and no need for monitoring and titration during therapy.⁵⁵ However, both of these analyses, performed in the year 2000, did not include studies with more aggressive and rapid use of invasive management strategies. There are very few studies directly comparing different LMWH. In the Enoxaparin versus Tinzaparin in non-ST segment Elevation Acute Coronary Syndromes (EVET) study, 438 patients with NSTE-ACS were randomized to receive either subcutaneous injections of 1 mg/kg enoxaparin twice daily (n = 220) or 175 IU/kg tinzaparin once daily (n = 218) for 7 days.⁵⁷ The primary endpoint was a composite of death, MI, refractory angina and recurrence of UA. At 6 months the primary composite endpoint was significantly lower in enoxaparin-treated patients (25.5% vs. 44.0%, respectively; p p = 0.05). Bleeding complication were similar in the two groups.⁵⁷LMWH for PCI. Early studies of LMWH during balloon angioplasty in the context of preventing restenosis demonstrated no clear advantage or disadvantage of UFH.^58,59 The use of LMWH as an alternative to UFH for procedural anticoagulation was also investigated in a number of preliminary observational studies^60–62 as well as preliminary randomized studies.^63,64 Borentain and colleagues performed a meta-analysis of 8 randomized trials (2,015 patients) comparing UFH and intravenous LMWH as procedural anticoagulants for PCI.⁶⁵ Six studies used enoxaparin, one used revaparin and one used dalteparin. LMWH was comparable to UFH in terms of efficacy (death, MI or urgent repeat revascularization; 6.2% vs. 7.5%, respectively (RR = 0.90; CI 0.65–1.23; p = 0.50) and major bleeding (0.9% vs. 1.8%, respectively; RR = 0.63; CI 0.29–1.37; p = 0.25).⁶⁵ The largest and most recent study of LMWH for procedural anticoagulation in patients undergoing PCI is the STEEPLE trial, in which 3,528 patients undergoing nonemergent PCI were prospectively randomized to procedural anticoagulation with intravenous enoxaparin (0.5 mg/kg or 0.75 mg/kg) versus intravenous UFH, with and without GP IIb/IIIa antagonists.⁵² The primary endpoint was the incidence of non-CABG-related major or minor bleeding at 48 hours. Only 14% of patients in the trial had UA or an MI within the week prior to randomization. Non CABG-related major plus minor bleeding occurred in 6.0%, 6.6% and 8.7% of the 0.5 mg/kg enoxaparin group, 0.75 mg/kg enoxaparin group and the UFH group, respectively (p = 0.014 for enoxaparin 0.5 mg/kg vs. UFH, and p = 0.052 for enoxaparin 0.75 mg/kg vs. UFH).⁵² This reduction was primarily seen in patients not receiving GP IIb/IIIa inhibitors (4.2% vs. 3.7% vs. 6.9%, respectively). By multivariate analysis, assignment to enoxaparin was an independent predictor of reduced major plus minor bleeding (p = 0.014).⁵² There were no statistical differences in terms of 30-day death, nonfatal MI or urgent target vessel revascularization, or in the quadruple endpoint of adverse ischemic events within 30 days or major bleeding within 48 hours. Transition to the catheterization laboratory (See Figure 5). Collet and colleagues examined 132 patients undergoing PCI within 8 hours of subcutaneous enoxaparin administration (1 mg/kg every 12 hours).⁵⁰ PCI was performed without any additional anticoagulation or monitoring. Anti-Xa activity was measured in all patients and was found to be adequate (> 0.5 IU/ml), regardless of the exact timing of the last dose of enoxaparin within the previous 8 hours. The Pharmacokinetic Study of Enoxaparin in Patients Undergoing Percutaneous Coronary Intervention (PEPCI) study examined the pharmacodynamics of supplemental intravenous enoxaparin doses on a background of subcutaneous medical management, and found that anti-Xa activity was within an acceptable range following 0.3 mg/kg IV boluses in the 8- to 12-hour window following subcutaneous enoxaparin injections of 1 mg/kg.⁵¹ In National Investigators Collaborating on Enoxaparin (NICE-3), patients who underwent angioplasty within 8 hours of their last subcutaneous dose of enoxaparin received no additional anticoagulation, and patients brought to the catheterization laboratory 8 to 12 hours after their last subcutaneous dose of enoxaparin received an additional 0.3 mg/kg intravenous enoxaparin at the time of PCI.⁶⁶ The overall incidence of nonsurgical-related major bleeding was 1.9%, and 1.4% in patients undergoing PCI, with acceptably low rates of death, MI and urgent revascularization.⁶⁶ The A Phase of the Aggrastat to Zocor (A to Z) study randomized 3,987 ACS patients to either weight-adjusted IV UFH or enoxaparin (1 mg/kg subcutaneously every 12 hours).⁶⁷ It was designed as a noninferiority study with a primary endpoint of the composite of death, recurrent MI or refractory ischemia at 7 days. All patients received tirofiban and aspirin; an early invasive strategy was declared for 55% of patients in the study; approximately 43% had undergone catheterization or PCI by 48 hours, and approximately 60% had undergone catheterization or PCI by 108 hours, although a clear transition strategy was not spelled out in the protocol.⁶⁷ Primary outcome events occurred in 8.4% of the enoxaparin-treated patients and 9.4% of the UFH-treated patients, meeting prespecified criteria for noninferiority. Overall, the rates of TIMI major and minor bleeding (and transfusion) were low, but bleeding events were only documented up to 24 hours after the end of the tirofiban infusion.⁶⁷ SYNERGY randomized high-risk NSTE-ACS patients destined for an early invasive management strategy to either enoxaparin (1 mg/kg subcutaneously every 12 hours) or intravenous aPTT-guided UFH.²⁷ Similar to NICE-3, if enoxaparin-treated patients came to the catheterization laboratory within 8 hours of the last subcutaneous dose, no additional enoxaparin was used for PCI; if they came to the catheterization laboratory more than 8 hours after the last subcutaneous dose, an additional 0.3 mg/kg was given intravenously in the catheterization laboratory prior to PCI. The primary endpoint (death or MI at 30 days) was not significantly different between groups (14.0% with enoxaparin, 14.5% with UFH).²⁷ This did meet prespecified statistical criteria for noninferiority (OR = 0.96; 95% CI 0.86–1.06). Patients on consistent therapy (who did not change therapy at randomization) did significantly better with enoxaparin.²⁷ The use of enoxaparin was not associated with higher rates of ischemic events during PCI (abrupt closure, threatened closure, unsuccessful PCI, emergency CABG). There was significantly more TIMI major bleeding with enoxaparin, (9.1% vs. 7.6% with UFH; p = 0.005) and nonsignificant trends in GUSTO severe bleeding (2.7% vs. 2.2% with UFH) and transfusion (17% vs. 16% with UFH).²⁷ Thus, enoxaparin, while not superior to UFH in the overall population, appears to be a reasonable alternative to UFH in high-risk NSTE-ACS patients managed with an early invasive management strategy. There has been a great deal of discussion regarding “switching” and “crossover” in the study, and one incorrect message that emerged from SYNERGY was the “don’t switch” admonishment. Physicians wanting to use UFH in the catheterization laboratory were concerned about “switching” because they felt that there was no reason to start enoxaparin if patients were going to be switched to UFH in the catheterization laboratory anyway. These concerns arose from the significantly increased rate of bleeding events and transfusions noted in patients who received off-protocol, post-randomization “crossover” therapy with nonstudy drug — frequently enoxaparin-treated patients coming to the catheterization laboratory or to surgery. Unfortunately, this was a post-randomization event, and highly confounded by the use of interventional procedures, and was, appropriately, not subjected to rigid statistical analysis. See continuation of this article in Part II

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