The Year in Non-ST-Segment Elevation Acute Coronary Syndromes

Journal of the American College of Cardiology © 2005 by the American College of Cardiology Foundation Published by Elsevier Inc.

Vol. 46, No. 5, 2005 ISSN 0735-1097/05/$30.00 doi:10.1016/j.jacc.2005.06.051

YEAR IN CARDIOLOGY SERIES

The Year in Non–ST-Segment Elevation Acute Coronary Syndromes Robert P. Giugliano, MD, SM, FACC,*† Eugene Braunwald, MD, MACC*† Boston, Massachusetts Non–ST-segment elevation acute coronary syndrome (NSTE-ACS), which comprises unstable angina and non– ST-segment elevation myocardial infarction (NSTE-MI), accounted for approximately 1.7 million discharges (primary or secondary diagnoses) from U.S. hospitals in 2002, with NSTE-ACS accounting for approximately 1.2 million of these discharges (1). The year 2004 marked the tenth anniversary of the publication of a guideline for management of patients with NSTE-ACS—the first such evidence-based guideline to establish clearly detailed diagnostic criteria, to provide a scheme for risk stratification, and to recommend diagnostic procedures and treatment for patients with this condition (2). In the subsequent decade, a large body of literature and many clinical trials (Table 1) have further refined and improved the approach to these patients. Given the broad nature of this topic and extensive number of publications in the past year, we have elected to focus on important observations in the following areas: 1) risk assessment and risk scores, 2) biomarkers, 3) platelet P2Y12 receptor blockers, 4) glycoprotein (GP) IIb/IIIa blockers, 5) anticoagulants, 6) early invasive treatment strategy, and 7) lipid therapy.

RISK ASSESSMENT AND RISK SCORES A number of scores derived from clinical trials (3,4) and registries (5–7) have been developed to assess the risk of patients with NSTE-ACS and to help identify patients most likely to benefit from aggressive therapy (Table 2). An analysis comparing three risk scores (the TIMI, PURSUIT, and GRACE scores) (8) concluded that all three demonstrated good predictive accuracy for death or MI at one year, thus identifying patients who might be likely to benefit from aggressive therapy, including early myocardial revascularization. A second comparison of risk scores (9) demonstrated better clinical outcomes among patients whose treatment From the *TIMI Study Group, Cardiovascular Division, Brigham and Women’s Hospital and the †Department of Medicine, Harvard Medical School, Boston, Massachusetts. Dr. Giugliano reports the following potential conflicts and financial disclosures: Millennium, research grant support, Speaker’s Bureau; Schering-Plough, research grant support, Speaker’s Bureau; Nuvelo, research grant support; Merck/ Schering-Plough, research grant support; Sanofi-Aventis, Speaker’s Bureau; Bristol Myers Squibb, Speaker’s Bureau; Pfizer, Speaker’s Bureau. Dr. Braunwald reports the following potential conflicts and financial disclosures: research grant support from: Millennium, Aventis, Nuvelo, Astra-Zeneca, Eli Lilly, and Merck/Schering-Plough. Manuscript received May 2, 2005; revised manuscript received May 23, 2005, accepted June 1, 2005.

was compliant with current guideline recommendations, regardless of the risk group. The TIMI unstable angina risk score also was found to be useful in the prediction of angiographic severity and extent of coronary artery disease (10), including greater intracoronary thrombus burden and impaired flow (11). Analyses of the TIMI risk index (12), which uses only age, systolic blood pressure, and heart rate, demonstrated that this simple risk index not only predicted short-term mortality in ST-segment elevation myocardial infarction (STEMI) ACS but also was a useful tool for predicting 30-day and 1-year mortality across the spectrum of patients with ACS, including patients with NSTE-ACS (13). Although initially applied to patients with STEMI, the concept of a “risk score profile” (14), a novel approach to characterize the risk of a population, was also shown to be applicable in patients with NSTE-ACS (15). Analyses of subgroups of patients at high-risk, including women (16), the elderly (17), nonwhites (18,19), as well as those with positive troponin or ST-segment depressions (20), heart failure (21), or renal failure (22), showed that paradoxically, these patients, who stand to benefit the most from proven therapies recommended in existing treatment guidelines, are less likely to receive them than are patients at lower risk. Underuse of cardiac catheterization, particularly in patients with elevated troponin, was observed, with only 45% of such patients undergoing an early invasive strategy with catheterization within 48 h (23). Patients who underwent early catheterization within 48 h were more likely to receive guidelinerecommended treatments and had a significantly lower risk of adjusted in-hospital mortality (2.5% vs. 3.7%) (24). These observations present a major opportunity for improving the care of patients with NSTE-ACS.

BIOMARKERS Considerable research on five groups of biomarkers that had been shown previously to be useful in prognostication of patients with ACS (markers of necrosis, inflammation, natriuretic factors, renal dysfunction, and glucose tolerance), and multimarker approaches were reported during the past year (Fig. 1) (25). Troponin. Elevation of troponin, an accurate marker of cardiac necrosis, even if only marginal (26), is correlated with worse clinical outcomes in NSTE-ACS. An elevation of troponin correlated strongly with intracoronary thrombus

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Table 1. Acronyms of Clinical Trials and Registries A to Z ACUITY ALBION ANTHEM-TIMI-32 CLEAR PLATELETS CREDO DISPERSE 2-TIMI-33 GRACE GUSTO-IV ACS ICTUS IMPROVE IT ISAR-COOL JUMBO OASIS PEACE PROTECT-TIMI-30 PROVE IT-TIMI-22 PURSUIT REPLACE-2 REVERSAL SYNERGY TACTICS-TIMI-18 TIMI TRITON-TIMI-38

Aggrastat to Zocor Acute Catheterization and Urgent Intervention Triage strategY Assessment of the best Loading dose of clopidogrel to Blunt platelet activation, Inflammation, and Ongoing Necrosis Anticoagulation with rNAPc2 To Help Eliminate MACE-TIMI 32 Clopidogrel Loading with Eptifibatide to Arrest the Reactivity of Platelets Clopidogrel for the Reduction of Events During Observation Does greater Inhibition of platelet aggregation lead to Superior Prevention of thrombotic Events afteR Non-ST Elevation? 2-TIMI-33 Global Registry of Acute Coronary Events Global Use of Strategies To improve Outcomes-IV ACS Invasive Versus Conservative Treatment in Unstable Coronary Syndromes IMProved Reduction of Outcomes: Vytorin Efficacy International Trial Intracoronary Stenting with Antithrombotic Regimen COOLing-off Joint Utilization of Medications to Block platelets Optimally Organisation to Assess Strategies for Ischemic Syndromes Platelet Activity Extinction in non–Q-wave Myocardial Infarction with Aspirin, Clopidogrel, and Eptifibatide A randomized trial to evaluate the relative PROTECTion against post-PCI microvascular dysfunction and post-PCI ischemia among anti-platelet and anti-thrombotic agents-TIMI-30 Pravastatin or Atorvastatin Evaluation and Infection Therapy-TIMI-22 Platelet glycoprotein IIb/IIIa in Unstable angina: Receptor Suppression Using InTegrilin Randomized Evaluation in PCI Linking Angiomax to Reduced Clinical Events-2 Reversal of Atherosclerosis with Aggressive Lipid Lowering Superior Yield of the New Strategy of Enoxaparin, Revascularization, and Glycoprotein IIb/IIIa Inhibitors Treat angina with Aggrastat ⫹ determine Cost of Therapy with an Invasive or Conservative Strategy-TIMI-18 Thrombolysis In Myocardial Infarction TRial to assess Improvement in Therapeutic outcomes by Optimizing platelet inhibitioN with prasugrel-TIMI-38

as visualized by angioscopy (27). This finding may explain the particular benefit of GP IIb/IIIa receptor blockers in such patients (see “Glycoprotein IIb/IIIa Blockers”). Elevated troponin levels after percutaneous coronary intervention (PCI) were associated with short-term complications (28) and mortality at two years (29). Mechanistic insight into the relationship between elevation of post-PCI troponin and worse clinical outcomes were provided by demonstration of impaired myocardial contrast enhancement and myocardial tissue perfusion (30), as well as new irreversible myocardial injury on delayed-enhancement magnetic resonance imaging (31). Markers of inflammation. High-sensitivity C-reactive protein (hs-CRP) is a measure of inflammation that predicts cardiovascular risk above and beyond traditional risk factors and adds independent prognostic information to long-term risk assessment in normal subjects as well as in those with coronary artery disease (32). Patients with NSTE-ACS had higher levels of hs-CRP and more complex angiographic stenoses than did patients with chronic stable angina (33). The hs-CRP ordinarily rises after the implantation of both

bare metal and sirolimus-eluting stents (34), but these elevations can be attenuated by two-thirds with clopidogrel pretreatment (35). Myeloperoxidase is an enzyme secreted during leukocyte activation that possesses proinflammatory properties and predicts an increased risk for cardiovascular events independently of other biomarkers (36). A close link between myeloperoxidase-mediated endothelial dysfunction, oxidation, inflammation, and cardiovascular disease has been demonstrated (37), and a common myeloperoxidase-promoter polymorphism present in two-thirds of the Western population, which is associated with higher myeloperoxidase levels, has been identified (38). At present, both hs-CRP and myeloperoxidase appear to be of clinical value in risk stratification. Ongoing research is being conducted to clarify the value of the broad array of these and other inflammatory markers in understanding the pathobiology of NSTE-ACS and in determining whether they add to hs-CRP and myeloperoxidase in clinical assessment and risk stratification.

Table 2. Comparison of Risk Scores Name (Ref. No.)

Variables Included

Advantages

Disadvantages

Externally Validated

Useful to Select Tx

GRACE (7) PREDICT (5) PURSUIT (4) RUSH (6) TIMI risk score (3) TIMI risk index (12)

8 clinical variables 6 clinical, 1 detailed ECG 5 clinical variables 6 clinical variables 7 clinical variables Age, SBP, HR

Accuracy Accuracy Weighting used Accuracy Simple Very simple

Very complex Very complex Mod complexity Logistic regression Equal weighting Need chart

No No No No Yes Yes

Unknown Unknown Unknown Unknown Yes Unknown

ECG ⫽ electrocardiogram; HR ⫽ heart rate; PREDICT ⫽ Predicting Risk of Death in Cardiac Disease Tool; SBP ⫽ systolic blood pressure; Tx ⫽ therapy.

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Figure 1. Multimarker approach for risk stratification in acute coronary syndromes, adapted from Morrow and Braunwald (25). *Glucose metabolism ⫽ hyperglycemia or elevated hemoglobin (HB) A1C. BNP ⫽ B-type natriuretic peptide; CrCl ⫽ creatine clearance; CRP ⫽ C-reactive protein; hs-CRP ⫽ high sensitivity C-reactive protein.

Natriuretic peptides. Plasma B-type natriuretic peptide (BNP) has been shown to be an independent predictor of mortality in patients with NSTE-ACS (39), and recent analyses extended these findings by demonstrating the utility of plasma BNP even among patients without the presence of markers of necrosis (40) and in an apparently asymptomatic community population (41). The N-terminal fragment of its prohormone, N-terminal-pro-BNP (NtproBNP), was found to be the strongest independent biochemical predictor of in-hospital and 180-day mortality, adding substantial information after adjustment for baseline risk (42). Dynamic changes of Nt-proBNP were associated with marked increases in adverse outcome (43). Levels of Nt-proBNP were shown to parallel the severity of angiographic disease (44) and to correlate independently with death or nonfatal MI during the year after PCI in patients with NSTE-ACS (45). Nt-pro-atrial natriuretic peptide is an independent predictor of mortality at two years in patients with NSTE-ACS with normal levels of NtproBNP (46). The elevation of circulating concentrations of natriuretic peptides is associated with increased ventricular wall stress. Although such elevations clearly identify high-risk patients, they have not yet been shown to be useful in identifying patients in whom revascularization, intensive anti-ischemic therapy, or other therapeutic maneuvers improve outcome. Nonetheless, it appears logical to treat such patients with agents such as angiotensin-converting enzyme inhibitors to reduce ventricular wall stress in an effort to reduce the concentration of natriuretic peptide levels. Impaired glucose tolerance. Although it has been clear that upwards of 75% of patients with diabetes die of cardiovascular complications, the reverse, i.e., the high prevalence of impaired glucose tolerance in patients presenting with ACS has been underappreciated until recently. In

the Euro Heart Survey, 58% of patients with acute coronary artery disease had an abnormal oral glucose tolerance test (22% new diabetes, 36% pre-existing impaired glucose regulation) (47). Among diabetics with ACS, both hyperglycemia and hypoglycemia were associated with significant higher all-cause mortality (48). Thus, careful assessments of glucose concentration, glucose tolerance, and the presence of the metabolic syndrome among patients with NSTEACS should be obtained, and these conditions should be treated vigorously. Renal dysfunction. Impaired renal function is an independent predictor of poor short-term outcomes (in-hospital death, bleeding, and contrast-induced nephropathy) (49) as well as mid-term outcomes (death at 30 days and 6 months, stroke and recurrent ischemia at 30 days) (50). Increased levels of cystatin C, a more accurate marker of renal function than serum creatinine, are associated with a graded increase in the risk of death (51). Renal dysfunction is a marker of vascular damage; patients with NSTE-ACS having this common and serious risk factor require close follow up. Multimarker approach. With the proliferation of biomarkers, combinations of two (52) or more (53) individual markers, or classes of markers (e.g., necrosis, inflammation, coagulation) (54) are being pursued. The importance of various marker combinations should now be assessed in various key subgroups of patients, particularly in light of the observation that women with ACS have a different pattern of biomarker expression (higher hs-CRP and BNP, but lower troponin) than do men (55). Genetic markers. Genetic markers have the potential to be even more powerful risk markers than the classical phenotypic markers described previously. For example, polymorphisms of the cytochrome P450 epoxygenase CYP2J2 gene (56) were associated with a doubling of the risk of coronary artery disease. Identification of genetic polymorphisms also

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may allow the tailoring of drug therapies according to individual genotype. For example, patients with one of two common polymorphisms in the 3-hydroxy-3-methylutarylCoA reductase gene demonstrated reduced efficacy of cholesterol lowering with pravastatin (57).

PLATELET P2Y12 RECEPTOR BLOCKERS Clopidogrel. The stimulation of the platelet P2Y12 receptor leads to sustained platelet aggregation. Thienopyridines, such as ticlopidine and now clopidogrel, irreversibly block these receptors. Although the clinical value of the P2Y12 receptor blocker clopidogrel in patients with NSTE-ACS has been well-established, determination of the appropriate loading dose (58) and the variability of responsiveness (59) recently have received considerable attention. Inhibition of platelet aggregation with 75 mg of clopidogrel daily in healthy volunteers achieves a steady state in five days, and it is not until day 8 that the fluctuation between peak and trough platelet inhibition becomes negligible (60). Administration of a 300-mg loading dose shortens the time to peak effect to 12 h (61), which is consistent with a clinical treatment effect at approximately 15 h in the CREDO trial, which compared a 300-mg pretreatment loading dose with no clopidogrel load before PCI (62). Increasing the loading dose to 600 mg achieves the full antiplatelet effect of clopidogrel by 2 h (63), whereas 300 mg, the dose approved by the Food and Drug Administration, fails to enhance platelet inhibition in 40% of patients at 2.5 h (64). A loading dose of 600 mg also reduces the incidence of clopidogrel nonresponsiveness to onequarter the rate observed with 300 mg of clopidogrel (65). Furthermore, loading with 600 mg compared with 300 mg of clopidogrel 4 to 8 h before PCI was safe and reduced the primary composite of death, MI, or target vessel revascularization significantly from 12% to 4%, with all of the difference attributed to a reduction in post-PCI myonecrosis (66). Finally, a 600 mg reload in patients on maintenance (75 mg/day) clopidogrel achieved additional inhibition of adenosine diphosphate-induced expression of GP IIb/IIIa and P-selectin receptors, even among patients who were chronically taking 75 mg of clopidogrel daily (67). An even higher loading dose (900 mg) of clopidogrel is being compared with 300 and 600 mg in a French trial known as ALBION that is due to report initial results in May 2005 at the EUROPCR scientific sessions (G. Montalescot, personal communication, 2005.). Although the loading dose of clopidogrel approved by the Food and Drug Administration is 300 mg, the recently released guidelines for PCI, released by the European Society of Cardiology (68), recommend 600 mg in patients with NSTE-ACS undergoing immediate (⬍6 h) PCI. Because there appears to be little extra risk to the higher loading dose, it is likely that it will be used increasingly widely before PCI in patients with NSTEACS. The first extensive report exploring the interindividual

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response to clopidogrel demonstrated marked variability in the degree of inhibition of platelet aggregation, with 31% and 15% of patients at 5 and 30 days exhibiting “resistance” (69), which was defined as ⬍10% reduction in platelet aggregation compared with baseline using light transmission aggregometry in response to platelet stimulation with 5 ␮mol/l adenosine diphosphate. Emerging data link clopidogrel hyporesponsiveness in patients undergoing primary PCI with recurrent cardiovascular events (70), and in a broader group of patients undergoing stenting to a higher risk of stent thrombosis (71) and postdischarge ischemic events (72). Assays measuring the phosphorylation of vasodilator-stimulated phosphoprotein, an inhibitor protein that is predominantly expressed in platelets, may be useful in the identification of patients at risk for subacute stent thrombosis. Thus, patients who are hyporesponsive to clopidogrel as determined by flow cytometric measurement of vasodilator-stimulated phosphoprotein phosphorylation were shown to be at very high risk for subacute stent thrombosis (73). Increased bleeding at the time of cardiac surgery after the recent use of clopidogrel remains a challenging clinical issue because preoperative clopidogrel use is associated with increased odds of reoperation for bleeding and for transfusion (74). However, the risk of perioperative bleeding must be weighed against the benefits of beginning clopidogrel early in patients presenting with NSTE-ACS, as one analysis revealed a 44% reduction in cardiovascular death, MI, or stroke in patients treated with clopidogrel preoperatively (75). One approach to deal with this issue is to hold clopidogrel on admission if patients are scheduled for coronary angiography within 24 h but to pretreat patients in whom cardiac catheterization is likely to be deferred. Combination treatment with a thienopyridine and a GP IIb/IIIa blocker has received considerable attention. The possible additional benefits of abciximab in patients undergoing elective PCI pretreated with 600 mg of clopidogrel were evaluated in three trials (76 –78) and included one-year follow-up in one of the studies (79). In each of these three trials, there was no benefit of adding abciximab to clopidogrel. However, these results should be interpreted with caution in light of the lower than anticipated event rates in patients undergoing elective PCI. Furthermore, it is unclear if these findings apply to other GP IIb/IIIa blockers which, in fact, did demonstrate a benefit when added to clopidogrel in other studies (see “Glycoprotein IIb/IIIa Blockers”). Other P2Y12 receptor blockers. Prasugrel is a thienopyridine under development that has several potential advantages over clopidogrel, including 1) a more rapid and efficient generation of an active metabolite, leading to a faster onset of action (80); 2) a 10-fold greater potency in the inhibition of adenosine-induced platelet aggregation; and 3) a more consistent antiplatelet response without the unresponsiveness or hyporesponsiveness to clopidogrel noted previously. In a phase II dose-ranging trial of patients with stable atherosclerosis, prasugrel added to aspirin

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Table 3. New Antiplatelet Agents Targeting the P2Y12 Receptor Name (Ref. No.)

Class

Formulation

Reversibility

Prasugrel (81,82)

Thienopyridine

Oral

No

AZD6140 (84) Cangrelor (83)

Cyclolpentyltriazolopyrimidine ATP derivative

Oral Intravenous

Yes Yes

achieved higher platelet inhibition than clopidogrel (81). In a phase II dose-ranging study of prasugrel in PCI (JUMBO-TIMI-26), prasugrel was associated with rates of bleeding similar to clopidogrel while resulting in lower rates of target vessel thrombosis and recurrent ischemia (82). Prasugrel currently is being compared with clopidogrel in a phase III trial of patients with ACS undergoing PCI (TRITON-TIMI-38). Two reversible blockers of the P2Y12 receptor in development include cangrelor (AR-C69931MX) and AZD6140 (Table 3) (80). Cangrelor is an intravenous ATP derivative with a plasma half-life of 5 min that achieves 90% inhibition of platelet aggregation, with recovery of platelet function 20 min after termination of infusion. In a pilot, dose-ranging study of patients with STEMI, cangrelor and half-dose alteplase achieved similar rates of epicardial and myocardial reperfusion, ST-segment resolution, and bleeding compared to a full dose of alteplase (83). Cangrelor is being compared with abciximab in a phase II trial of patients undergoing PCI. AZD6140 is an orally active, directly acting, cyclopentyltriazolopyrimidine that also reversibly blocks the P2Y12 receptor and can achieve high levels of platelet inhibition (84). A phase II dose-ranging clinical trial (DISPERSE 2-TIMI-33) is compared AZD6140 to clopidogrel in NSTE-ACS and results are anticipated late in 2005.

GLYCOPROTEIN IIb/IIIa BLOCKERS Although GP IIb/IIIa blockers have been available clinically for more than a decade, several pharmacodynamic studies

Comparison With Clopidogrel Higher-level inhibition Fewer hypo/non-responders Higher-level inhibition Shorter half life (3 to 5.5 min) Higher-level platelet inhibition

during the past year have helped to shed additional light on their mechanism of action and their incremental effects in combination with other antiplatelet drugs. Tirofiban blunts the rise in hs-CRP after presentation with NSTE-MI (85) and after PCI (86) and reverses the endothelial dysfunction induced by PCI (87). The PEACE study (88) compared platelet activation by a panel of agonists with three combinations of antithrombotic agents: 1) aspirin and enoxaparin; 2) aspirin, enoxaparin, and clopidogrel; and 3) aspirin, enoxaparin, clopidogrel, and eptifibatide. Relative reductions in activated GP IIb/IIIa receptor expression of 33% to 48% (depending upon the type of agonist) were observed after the addition of clopidogrel, whereas additional reductions of 72% to 80% were observed after eptifibatide (Fig. 2). The CLEAR PLATELETS study (89) was a 2 ⫻ 2 factorial study (300 mg or 600 mg clopidogrel with or without eptifibatide) of patients undergoing elective stenting, assessed platelet reactivity, and release of cardiac markers. Eptifibatide more than doubled platelet inhibition when added to 600 mg of clopidogrel whereas the latter dose achieved significantly higher levels of platelet inhibition than did 300 mg (Fig. 3). Compared with clopidogrel alone, eptifibatide was associated with lower rates of release of CK-MB, troponin, and myoglobin after PCI. Clearly, GP IIb/IIIa blockers are more powerful inhibitors of platelet aggregation than are thienopyridines, but the clinical relevance of these findings remains controversial because some analyses have demonstrated incremental benefit of eptifibatide when added to clopidogrel (90 –

Figure 2. Measures of platelet (PLT) activation and aggregation in the platelet activity extinction in non–Q-wave myocardial infarction with aspirin (ASA), clopidogrel (Clopid), and eptifibatide (PEACE) study (88) demonstrated the incremental benefit of adding clopidogrel to ASA and enoxaparin (Enox) and then the further incremental benefit of eptifibatide (Ept). ADP ⫽ adenosine diphosphate; GP ⫽ glycoprotein; PAC ⫽ activated GP IIb/IIIa.

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Figure 3. In the Clopidogrel Loading With Eptifibatide to Arrest the Reactivity of Platelets (CLEAR PLATELETS) study (90) (2 ⫻ 2 randomization to clopidogrel [clop] 300 vs. 600 mg and no eptifibatide vs. eptifibatide [ept]), the use of 600 mg of clopidogrel achieved a higher level of platelet inhibition than 300 mg of clopidogrel using standard light transmission platelet aggregometry with 5 ␮mol/l adenosine diphosphate as the stimulus. *p ⱕ 0.001. The release of troponin and myoglobin after PCI among the four treatment groups from highest to lowest were as follows: clopidogrel 300 mg without eptifibatide, clopidogrel 600 mg without eptifibatide, clopidogrel 300 mg with eptifibatide, clopidogrel 600 mg with eptifibatide. ADP ⫽ adenosine diphosphate; CK-MB ⫽ creatine kinase-myocardial band; ULN ⫽ upper limit of normal.

92), whereas the three aforementioned trials with abciximab (76 –78) failed to do so. Several studies have explored the clinical efficacy of GP IIb/IIIa blockers in patients undergoing PCI. Longer durations of infusion (⬎16 h) both before (93) and after (94) PCI were associated with better clinical outcomes than shorter infusions. A meta-analysis of five studies involving 6,766 patients with NSTE-ACS that were assigned randomly to routine invasive versus conservative therapy demonstrated improved survival with an early invasive approach that includes stenting with adjunctive GP IIb/IIIa blockade in men and in patients of both genders who present with an elevated troponin (95). A comparison of two trials (TIMI-3B and TACTICS-TIMI-18) comparing an early invasive to an early conservative strategy demonstrated better outcomes with the early invasive strategy only in the trial that mandated use of an upstream GP IIb/IIIa blocker (TACTICS-TIMI-18), suggesting a potential positive interaction between these two therapies (15). Several articles have reported new information regarding the safety of GP IIb/IIIa blockers. In patients in the GUSTO IV ACS trial using abciximab in whom early revascularization was not planned, major bleeding was rare (1.2%), and when it did occur, it was associated with a longer duration of abciximab infusion, performance of

nonplanned revascularization, and older age (96). One approach to minimize the incremental increased risk of bleeding with the addition of a GP IIb/IIIa blocker to aspirin and clopidogrel (so-called “triple antiplatelet therapy”) may be to utilize vascular closure devices (97). Despite the wealth of new information about the use of GP IIb/IIIa blockers, the recommendations provided in the updated American College of Cardiology/American Heart Association guidelines (98) remain pertinent (Table 4).

ANTICOAGULANTS Interest in lowering the dose or even eliminating the use of unfractionated heparin (UFH) in an attempt to minimize bleeding is of great interest, given the increasing tendency to administer triple antiplatelet therapy (aspirin, clopidogrel, and a GP IIb/IIIa blocker) to many patients with ACS. A consecutive case series of 500 patients undergoing elective PCI received aspirin, clopidogrel, eptifibatide, and no routine heparin resulted in 100% technical success of PCI, with no major adverse events in the first 24 h, and low rates of non–Q-wave MI (1.6%), thrombocytopenia (0.6%), and major (0.2%) and minor (0.6%) bleeding complications (99). Data from larger randomized trials are needed to establish

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Table 4. American College of Cardiology/American Heart Association Guidelines (98) Regarding GP IIb/IIIa Blockers Class I A platelet GP IIb/IIIa antagonist should be administered, in addition to aspirin and heparin, to patients in whom catheterization and PCI are planned. The GP IIb/IIIa antagonist may also be administered just prior to PCI (Level of Evidence: A) Class IIa Eptifibatide or tirofiban should be administered, in addition to aspirin and low molecular weight heparin or unfractionated heparin, to patients with continuing ischemia, an elevated troponin or with other high-risk features in whom an invasive m anagement is not planned. (Level of Evidence: A) Class IIa A platelet GP IIb/IIIa antagonist should be administered to patients already receiving heparin, aspirin, and clopidogrel in whom catheterization and PCI are planned. The GP IIb/IIIa antagonist may also be administered just prior to PCI. (Level of Evidence: B) GP ⫽ glycoprotein; PCI ⫽ percutaneous coronary intervention.

the safety and efficacy of reducing or eliminating adjunctive heparin in patients with ACS undergoing PCI. Low molecular weight heparin. Two large-scale openlabel clinical trials, A to Z (100) and SYNERGY (101) compared the low-molecular weight heparin, enoxaparin, with UFH in patients with NSTE-ACS and concluded that enoxaparin is not inferior to UFH and is, in fact, a safe, effective alternative. Petersen et al. (102) provided a systematic evaluation of the outcomes in 21,946 patients in six randomized controlled clinical trials that compared enoxaparin and UFH in patients with NSTE-ACS (Table 5). There was a 9% significant reduction in the composite of death or nonfatal MI after 30 days with enoxaparin and no differences in major bleeding or blood transfusions. Patients who received an antithrombin before randomization appeared to experience higher absolute rates of bleeding. Thus, the practice of switching between antithrombins in the same patient in the course of a single hospitalization should be avoided whenever possible. Since current practice has resulted in shorter intervals between presentation and PCI, the question of whether an adequate level of anticoagulation is achieved with fewer than three doses of enoxaparin (without an initial bolus) is important, particularly because lower anti-Xa activity on enoxaparin is independently associated with higher rates of 30-day mortality (103). However, a retrospective analysis of patients who went rapidly to PCI (after only two injections of enoxaparin with a 12-h interval) demonstrated a level of anti-Xa activity similar to those referred later to PCI (104).

In a subgroup analysis of the patients enrolled in the A to Z trial managed with a conservative strategy, those randomized to enoxaparin experienced a significant 28% reduction in the primary triple composite end point of death, new MI, or documented refractory ischemia within seven days compared with patients randomized to UFH, with no difference in safety (105). In conclusion, enoxaparin appears to result in similar or slightly better efficacy than UFH in patients with NSTEACS and a similar safety profile (Table 5). Given the greater convenience (twice-daily subcutaneous injections), absence of the need for routine monitoring, and simple weightbased dosing that does not require subsequent doseadjustment with enoxaparin, we believe that enoxaparin generally should be preferred over UFH in most patients with NSTE-ACS. Bivalirudin. The REPLACE-2 trial demonstrated that the direct antithrombin bivalirudin (with provisional use of a GP IIb/IIIa blocker) achieved comparable results to the combination of UFH and a GP IIb/IIIa blocker, as assessed by the quadruple composite end point of death, MI, urgent target vessel revascularization, and major bleeding in 6,010 patients undergoing urgent or elective PCI (106). A major feature of bivalirudin with provisional GP IIb/IIIa blocker in this trial was reduced bleeding. No differences emerged in long-term efficacy (death, MI, or repeat revascularization) (106). A subgroup analysis (107) revealed that clopidogrel pretreatment was associated with a trend toward lower adverse events in both treatment arms, but no significant

Table 5. Systematic Overview of Six Randomized Trials Comparing Enoxaparin With Unfractionated Heparin in NSTE-ACS (102) End Point All-cause mortality at 30 days All patients No pre-randomization antithrombin Death or MI at 30 days All patients No pre-randomization antithrombin Transfusions up to 7 days All patients No pre-randomization antithrombin Major bleeding up to 7 days All patients No pre-randomization antithrombin

N

Enoxaparin (%)

UFH (%)

Odds Ratio (95% CI)

21,945 9,833

3.0 2.8

3.0 3.2

1.00 (0.85–1.17) 0.88 (0.69–1.11)

21,946 9,835

10.1 8.0

11.0 9.4

0.91 (0.83–0.99) 0.81 (0.70–0.94)

16,650 8,401

7.2 5.0

7.5 5.5

1.01 (0.89–1.14) 0.94 (0.77–1.16)

16,650 8,401

4.7 3.8

4.5 3.4

1.04 (0.89–1.30) 1.15 (0.86–1.55)

CI ⫽ confidence interval; MI ⫽ myocardial infarction; NSTE-ACS ⫽ non–ST-segment elevation acute coronary syndrome; UFH ⫽ unfractionated heparin.

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treatment interaction was observed. A registry of 6,996 consecutive patients undergoing PCI at a single tertiary care center during a four-year period confirmed that the results of REPLACE 2, i.e., fewer bleeding events and no evident increase in the incidence of ischemic complications with bivalirudin compared with heparin with or without a GP IIb/IIIa blocker (108). Among moderate- and high-risk patients with ACS undergoing PCI in the PROTECT-TIMI-30 trial (109) that compared bivalirudin with the combination of the GP IIb/IIIa blocker with UFH or enoxaparin, bivalirudin was associated with a lower rate of normal myocardial perfusion, a longer duration of ischemia on Holter monitoring among patients with ischemia, and a trend toward a higher composite rate of death, MI, or ischemia but no difference in coronary flow reserve. Again, there were fewer episodes of transfusion or serious bleeding with bivalirudin. Taken together, the available results indicate that bivalirudin appears to be a safer and equally or perhaps slightly less effective alternative to the combination of heparin with a GP IIb/IIIa blocker. The ACUITY trial is randomizing 13,800 patients with NSTE-ACS undergoing an invasive strategy randomly to 1) UFH or enoxaparin with a GP IIb/IIIa blocker versus 2) bivalirudin with a GP IIb/IIIa blocker versus 3) bivalirudin with provisional use of a GP IIb/IIIa blocker (110). This large trial should provide important guidance regarding the necessity for and timing of heparin, bivalirudin, and GP IIb/IIIa blockade. Other anticoagulants. The synthetic factor Xa inhibitor fondaparinux was comparable with UFH in a pilot study of 350 patients undergoing PCI as a potential replacement for heparin (111). Ongoing large phase III trials are evaluating fondaparinux versus enoxaparin in patients with NSTEACS (OASIS-5) and fondaparinux versus UFH (if indicated) in patients with STE-MI treated with either fibrinolytic therapy or primary PCI (OASIS-6). The first clinical study of a monoclonal antibody to tissue factor (Sunol-cH36), blocking the most proximal step in the extrinsic coagulation pathway, demonstrated dosedependent anticoagulant effects, although mucosal bleeding was observed at higher doses (112). An inhibitor of the tissue factor-factor VIIa complex, recombinant nematode anticoagulant protein c2 (113), is being evaluated in patients with NSTE-ACS in the phase II ANTHEM-TIMI-32 trial with preliminary results expected in late 2005. Aptamers, single-stranded three-dimensional nucleic acids bind to target molecules (analogous to antibodies), directed at thrombin represent another promising class of anticoagulants. The RNA aptamer Ch-9.3t (114) and ARC183, a DNA-based direct thrombin inhibitor, are two such aptamers currently in early clinical trials. Given the great importance of interfering safely with the clotting system in patients with NSTE-ACS, further exploration of these novel anticoagulants is welcome.

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EARLY INVASIVE TREATMENT STRATEGY A comprehensive summary of the year in interventional cardiology was published in the Journal earlier this year (115). Here, we focus on new findings with respect to the early invasive management of patients with NSTE-ACS. Each of three meta-analyses (95,116,117) concluded that an early routine invasive strategy is superior to a selectively invasive approach. Mehta et al. (116) analyzed data from seven trials involving 9,212 patients and concluded that a routine invasive strategy was associated with a significant 18% relative reduction in death or MI, a nonsignificant trend toward fewer deaths, and a significant 25% relative reduction in MI alone through the end of follow-up. Although an early invasive strategy was associated with excess mortality during the inhospital phase (1.8% vs. 1.1%), this was more than offset by a significant reduction in mortality between discharge and the end of follow-up (3.8% vs. 4.9%). A routine invasive strategy also was associated with relative reduction in angina and rehospitalizations of 33% and 34%, respectively. A meta-regression analysis (117) showed that the most significant predictors of the benefits of an early invasive strategy on survival free of infarction were the use of an aggressive antiplatelet treatment (defined as use of a GP IIb/IIIa blocker or thienopyridine in addition to aspirin) and intracoronary stenting in the early invasive group which was associated with a substantial improvement in health-related quality of life. These meta-analyses have strengthened further the case for a routine early invasive strategy. Additional support for an early invasive strategy in patients with NSTE-ACS came from ISAR-COOL (118), a trial comparing prolonged antithrombotic pretreatment (median 86 h) with aspirin, heparin, clopidogrel, and tirofiban before intervention with early intervention (median 2.4 h after presentation) with the same background antithrombotic therapies. Patients randomized to the “cooling-off” strategy had a significantly increased risk of death or large nonfatal MI at 30 days. This difference in outcome was attributed to events occurring before catheterization in the group receiving prolonged antithrombotic pretreatment. Furthermore, patients undergoing an early invasive management have improved functional status and quality of life, including greater treatment satisfaction and lower disease perception (119). Subgroup analyses from elderly patients with NSTEACS enrolled in the TACTICS-TIMI-18 trial demonstrated that a routine early invasive strategy was associated with relative reductions of 39% (patients age ⬎65 years) and 56% (patients age ⬎75 years) in the rates of death or MI at six months (120). Men appear to benefit more than women from an early invasive strategy (121), although much of this difference may be related to a lower incidence of positive baseline markers of myonecrosis in women compared with men (55). In contrast to these studies and analyses favoring an early

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invasive strategy, in the ICTUS trial of 1,200 patients with NSTE-ACS, an elevated troponin T, and either ischemic electrocardiographic changes or a documented history of coronary artery disease, randomization to an early invasive versus a selective invasive strategy demonstrated no difference in the composite end point of death, MI, or rehospitalization for ACS at one year (122). One potential explanation for the lack of benefit with an early invasive approach was the high rate of catheterization (67%) and revascularization (47%) in the “selective” invasive strategy, thereby markedly reducing the differences between the treatment arms.

LIPID-LOWERING THERAPY AFTER ACS Two large, double-blind, randomized controlled trials have compared early intensive lipid lowering statin regimens with more standard statin regimens in patients after NSTE-ACS or STEMI. In the PROVE IT-TIMI-22 trial, 4,162 patients hospitalized with ACS within 10 days were randomized to either 40 mg of pravastatin or 80 mg of atorvastatin daily and followed for a mean of 24 months (123). The median low-density lipoprotein (LDL) achieved during treatment was significantly lower in patients randomly assigned to high-dose atorvastatin (62 mg/dl vs. 95 mg/dl, p ⬍ 0.001), which translated into a 16% significant relative reduction in the primary composite end point of all-cause mortality or major cardiovascular events with the more intensive lipid-lowering regimen (Fig. 4). Consistent reductions were observed across a variety of cardiac events except stroke. Furthermore, the reduction in clinical events became apparent quite early, with event curves diverging within 30 days after the initiation of therapy (124). These findings led to a modification of the recommendations of the Adult Treatment Panel III guidelines of the Cholesterol Education Program in very high-risk patients, providing an optional LDL cholesterol goal of ⬍70 mg/dl (125). In the Z phase of the A to Z trial, 4,487 post-ACS patients were randomized to an early initiation of intensive statin (simvastatin 40 mg/day for one month followed by 80 mg/day thereafter) or a delayed conservative statin regimen consisting of diet with placebo for four months followed by 20 mg/day thereafter for an average of two years (126). At one month, the mean LDL cholesterol levels were reduced to 68 mg/dl in the simvastatin 40 mg group compared with 122 mg/dl in the group randomly assigned to placebo, whereas at eight months the mean LDL cholesterols were 77 versus 63 mg/dl in the simvastatin 20- and 80-mg groups, respectively. A favorable trend toward a lower rate of the primary composite end point of cardiovascular death, nonfatal MI, readmission for ACS, and stroke was observed with more intensive statin arm (14.4% vs. 16.7% in the delayed conservative arm). No difference between these arms was evident during the first four months after randomization. However, from four months through the end of the

Figure 4. The composite of death or major cardiovascular events were reduced by 16% in patients after acute coronary syndromes who were randomized to high-intensity statin (atorvastatin 80 mg/day) compared with standard-dose statin (pravastatin 40 mg/day) in the PROVE ITTIMI-22 trial (123).

study, the primary composite was reduced significantly by 25% in the high-dose simvastatin group. The findings of the PROVE IT-TIMI-22 and A to Z trials were supported by an intracoronary ultrasound study, REVERSAL, that demonstrated slower progression of atherosclerosis in 502 patients with chronic coronary artery disease undergoing coronary angiography with intensive lipid lowering with atorvastatin 80 mg/day compared to pravastatin 40 mg/day (127). A second smaller study demonstrated a reduction in plaque volume of nonculprit lesions by serial volumetric intravascular ultrasound assessments six months after an admission for ACS in patients who were managed with PCI and treated with atorvastatin 20 mg/day versus placebo (128). Similar findings of plaque regression and reverse remodeling were observed by serial magnetic resonance imaging of the aorta; plaque regression correlated strongly with the degree of LDL reduction in patients treated with simvastatin at doses of 20 to 80 mg/day (129). An important additional lesson learned from the studies of early intensive statin therapy is the achievement of an acute anti-inflammatory effect and its association with better clinical outcomes. In the PROVE IT-TIMI-22 trial, patients who achieved hs-CRP levels ⬍2 mg/l had lower event rates than those who had higher hs-CRP levels regardless of the LDL achieved (Fig. 5) (130). The dual goals of LDL ⬍70 mg/dl and hs-CRP ⬍2 mg/l were more likely to be achieved with atorvastatin 80 mg/day than with pravastatin 40 mg/day (131). A second randomized trial comparing atorvastatin 40 mg/day with placebo in patients with ACS also showed the rapid reduction in hs-CRP seen in PROVE IT-TIMI-22 (132). In the REVERSAL trial, hs-CRP levels were independently and significantly correlated with the rate of progression of atherosclerosis (133). The data now available support the use of an intensive statin regimen, such as atorvastatin 80 mg/day in patients after ACS, preferably commencing in the hospital. The reduction of CRP appears to be an equally useful goal. The IMPROVE IT trial is comparing Vytorin (MSP Singapore LLC, Merck/Schering-Plough Pharmaceuticals, North

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Figure 5. An analysis (130) from the PROVE IT-TIMI-22 trial of achieved low-density lipoprotein (LDL) and achieved high-sensitivity C-reactive protein (hs-CRP), stratified at cutpoints of 70 mg/dl and 2 mg/l respectively, identified four groups of patients. Event rates were highest in the group with “high” LDL and “high” hs-CRP, and lowest in the group with “low” LDL and “low hs-CRP.”

Wales, Pennsylvania) the combination of simvastatin with ezetimibe, an inhibitor of cholesterol absorption, with simvastatin alone in patients early after ACS. In addition, more potent therapies to raise HDL, such as combinations of existing therapies (134), inhibitors of cholesterol ester transfer protein (135), and infusions of apoA-1 Milano and phospholipids (136) are also on the horizon. The pharmaceutical industry is now focusing appropriate attention on anti-inflammatory drug development as well. Interestingly, long-term treatment with gatifloxacin, an antibiotic that is bactericidal against Chylamydia pneumoniae, did not reduce the rate of cardiovascular events compared with placebo in the PROVE IT-TIMI-22 trial, even among patients with elevated titers to C. pneumoniae or hs-CRP (137).

CONCLUSIONS Because analyses of combinations of proven therapies demonstrate that each additional treatment provides incremental benefit (138,139), we end this Year in Review with a simplified “ABCDE” mnemonic approach to the management of NSTE-ACS recently proposed by Gluckman et al. (140). This can be used as a checklist of proven therapies. A: Antiplatelet therapy, Anticoagulation, Angiotensinconverting enzyme inhibition B: Beta-adrenergic receptor blocker, Blood pressure control C: Cholesterol lowering, Cigarette smoking cessation D: Diet, Diabetes management E: Exercise Reprint requests and correspondence: Dr. Eugene Braunwald, TIMI Study Group, Brigham and Women’s Hospital, 350 Longwood Avenue, 1st Floor Offices, Boston, Massachusetts 02115. E-mail: [email protected].

REFERENCES 1. American Heart Association. Heart Disease and Stroke Statistics— 2005 Update. Dallas, TX: American Heart Association, 2005. 2. Braunwald E, Mark DB, Jones RH, et al. Unstable angina: diagnosis and management. Agency for Health Care Policy and Research, Clinical Practice Guideline No. 10. Bethesda, MD: Public Health Service, National Heart, Lung, and Blood Institute, 1994. 3. Antman EM, Cohen M, Bernink PJ, et al. The TIMI risk score for unstable angina/non-ST elevation MI: a method for prognostication and therapeutic decision making. JAMA 2000;284:835– 42. 4. Boersma E, Pieper KS, Steyerberg EW, et al. Predictors of outcome in patients with acute coronary syndromes without persistent ST-segment elevation. Results from an international trial of 9461 patients. The PURSUIT Investigators. Circulation 2000;101:2557– 67. 5. Jacobs DR Jr., Kroenke C, Crow R, et al. PREDICT: A simple risk score for clinical severity and long-term prognosis after hospitalization for acute myocardial infarction or unstable angina: the Minnesota heart survey. Circulation 1999;100:599 – 607. 6. Calvin JE, Klein LW, VandenBerg EJ, et al. Validated risk stratification model accurately predicts low risk in patients with unstable angina. J Am Coll Cardiol 2000;36:1803– 8. 7. Eagle KA, Lim MJ, Dabbous OH, for the GRACE Investigators. A validated prediction model for all forms of acute coronary syndrome. JAMA 2004;291:2727–33. 8. de Araujo Goncalves P, Ferreira J, Aguiar C, Seabra-Gomes R. TIMI, PURSUIT, and GRACE risk scores: sustained prognostic value and interaction with revascularization in NSTEACS. Eur Heart J 2005;865–72. 9. Gulati M, Patel S, Jaffe AS, et al. Impact of contemporary guideline compliance on risk stratification models for acute coronary syndromes in the Registry of Acute Coronary Syndromes. Am J Cardiol 2004;94:873– 8. 10. Garcia S, Canoniero M, Peter A, et al. Correlation of TIMI risk score with angiographic severity and extent of coronary artery disease in patients with non-ST-elevation acute coronary syndromes. Am J Cardiol 2004;93:813– 6. 11. Mega JL, Morrow DA, Sabatine MS, et al. Correlation between the TIMI risk score and high-risk angiographic findings in non-STelevation acute coronary syndromes. Am Heart J 2005;149:846 –50. 12. Morrow DA, Antman EM, Giugliano RP, et al. A simple risk index for rapid initial triage of patients with ST-elevation myocardial infarction: an InTIME II substudy. Lancet 2001;358:1571–5.

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13. Ilkhanoff L, O’Donnell CJ, Camargo CA Jr., et al. The TIMI risk index predicts short and long-term mortality across the spectrum of acute coronary syndromes. Am J Cardiol 2005. In Press. 14. Morrow DA, Antman EM, Murphy SA, et al. The Risk Score Profile: a novel approach to characterising the risk of populations enrolled in clinical studies. Eur Heart J 2004;25:1139 – 45. 15. Sabatine MS, Morrow DA, Giugliano RP, et al. Implications of upstream glycoprotein IIb/IIIa inhibition and coronary artery stenting in the invasive management of unstable angina/non-ST-elevation myocardial infarction: a comparison of the Thrombolysis In Myocardial Infarction (TIMI) IIIB trial and the Treat angina with Aggrastat and determine Cost of Therapy with Invasive or Conservative Strategy (TACTICS)-TIMI 18 trial. Circulation 2004;109:874 – 80. 16. Blomkalns AL, Chen AY, Hochman JS, et al. Gender disparities in the diagnosis and treatment of non-ST-segment elevation acute coronary syndromes: large-scale observations from the CRUSADE (Can Rapid Risk Stratification of Unstable Angina Patients Suppress Adverse Outcomes With Early Implementation of the American College of Cardiology/American Heart Association Guidelines) National Quality Improvement Initiative. J Am Coll Cardiol 2005;45: 832–7. 17. Halon DA, Adawi S, Dobrecky-Mery I, et al. Importance of increasing age on the presentation and outcome of acute coronary syndromes in elderly patients. J Am Coll Cardiol 2004;43:346 –52. 18. Sabatine MS, Blake GJ, Drazner MH, et al. Influence of race on death and ischemic complications in patients with non-ST-elevation acute coronary syndromes despite modern, protocol-guided treatment. Circulation 2005;111:1217–24. 19. Sonel AF, Good CB, Mulgund J, et al. Racial variations in treatment and outcomes of black and white patients with high-risk non-STelevation acute coronary syndromes: insights from CRUSADE (Can Rapid Risk Stratification of Unstable Angina Patients Suppress Adverse Outcomes With Early Implementation of the ACC/AHA Guidelines?). Circulation 2005;111:1225–32. 20. Roe MT, Boden WE, Chen A, et al. Is the “Hub and Spoke” model working? Patterns of transfer for high-risk acute coronary syndromes patients from community hospitals without revascularization capacity (abstr). J Am Coll Cardiol 2004;43 Suppl A:1A. 21. Steg PG, Dabbous OH, Feldman LJ, et al. Determinants and prognostic impact of heart failure complicating acute coronary syndromes: observations from the Global Registry of Acute Coronary Events (GRACE). Circulation 2004;109:494 –9. 22. Masoudi FA, Plomondon ME, Magid DJ, et al. Renal insufficiency and mortality from acute coronary syndromes. Am Heart J 2004;147: 623–9. 23. Ohman EM, Roe MT, Smith SC Jr., et al. Care of non-ST-segment elevation patients: insights from the CRUSADE national quality improvement initiative. Am Heart J 2004;148:S34 –9. 24. Bhatt DL, Roe MT, Peterson ED, et al. Utilization of early invasive management strategies for high-risk patients with non-ST-segment elevation acute coronary syndromes: results from the CRUSADE Quality Improvement Initiative. JAMA 2004;292:2096 –104. 25. Morrow DA, Braunwald E. Future of biomarkers in acute coronary syndromes: moving toward a multimarker strategy. Circulation 2003; 108:250 –2. 26. Henrikson CA, Howell EE, Bush DE, et al. Prognostic usefulness of marginal troponin T elevation. Am J Cardiol 2004;93:275–9. 27. Okamatsu K, Takano M, Sakai S, et al. Elevated troponin T levels and lesion characteristics in non-ST-elevation acute coronary syndromes. Circulation 2004;109:465–70. 28. Mandadi VR, DeVoe MC, Ambrose JA, et al. Predictors of troponin elevation after percutaneous coronary intervention. Am J Cardiol 2004;93:747–50. 29. Cavallini C, Savonitto S, Violini R, et al. Impact of the elevation of biochemical markers of myocardial damage on long-term mortality after percutaneous coronary intervention: results of the CK-MB and PCI study. Eur Heart J 2005;26:1494 – 8. 30. Bolognese L, Ducci K, Angioli P, et al. Elevations in troponin I after percutaneous coronary interventions are associated with abnormal tissue-level perfusion in high-risk patients with non-ST-segmentelevation acute coronary syndromes. Circulation 2004;110:1592–7. 31. Selvanayagam JB, Porto I, Channon K, et al. Troponin elevation after percutaneous coronary intervention directly represents the extent of

32. 33. 34. 35. 36. 37. 38. 39. 40.

41. 42.

43. 44.

45.

46.

47.

48. 49.

50.

51. 52.

JACC Vol. 46, No. 5, 2005 September 6, 2005:906–19 irreversible myocardial injury: insights from cardiovascular magnetic resonance imaging. Circulation 2005;111:1027–32. Ridker PM. High-sensitivity C-reactive protein, inflammation, and cardiovascular risk: from concept to clinical practice to clinical benefit. Am Heart J 2004;148:S19 –26. Arroyo-Espliguero R, Avanzas P, Cosin-Sales J, et al. C-reactive protein elevation and disease activity in patients with coronary artery disease. Eur Heart J 2004;25:401– 8. de la Torre-Hernandez JM, Sainz-Laso F, Burgos V, et al. Comparison of C-reactive protein levels after coronary stenting with bare metal versus sirolimus-eluting stents. Am J Cardiol 2005;95:748 –51. Vivekananthan DP, Bhatt DL, Chew DP, et al. Effect of clopidogrel pretreatment on periprocedural rise in C-reactive protein after percutaneous coronary intervention. Am J Cardiol 2004;94:358 – 60. Baldus S, Heeschen C, Meinertz T, et al. Myeloperoxidase serum levels predict risk in patients with acute coronary syndromes. Circulation 2003;108:1440 –5. Vita JA, Brennan ML, Gokce N, et al. Serum myeloperoxidase levels independently predict endothelial dysfunction in humans. Circulation 2004;110:1134 –9. Asselbergs FW, Tervaert JW, Tio RA. Prognostic value of myeloperoxidase in patients with chest pain (letter and reply). N Engl J Med 2004;350:516 – 8. de Lemos JA, Morrow DA, Bentley JH, et al. The prognostic value of B-type natriuretic peptide in patients with acute coronary syndromes. N Engl J Med 2001;345:1014 –21. Bassan R, Potsch A, Maisel A, et al. B-type natriuretic peptide: a novel early blood marker of acute myocardial infarction in patients with chest pain and no ST-segment elevation. Eur Heart J 2005;26: 234 – 40. Wang TJ, Larson MG, Levy D, et al. Plasma natriuretic peptide levels and the risk of cardiovascular events and death. N Engl J Med 2004;350:655– 63. Bazzino O, Fuselli JJ, Botto F, et al. Relative value of N-terminal probrain natriuretic peptide, TIMI risk score, ACC/AHA prognostic classification and other risk markers in patients with non-STelevation acute coronary syndromes. Eur Heart J 2004;25:859 – 66. Heeschen C, Hamm CW, Mitrovic V, et al. N-terminal pro-B-type natriuretic peptide levels for dynamic risk stratification of patients with acute coronary syndromes. Circulation 2004;110:3206 –12. Ndrepepa G, Braun S, Mehilli J, et al. Plasma levels of N-terminal pro-brain natriuretic peptide in patients with coronary artery disease and relation to clinical presentation, angiographic severity, and left ventricular ejection fraction. Am J Cardiol 2005;95:553–7. de Winter RJ, Stroobants A, Koch KT, et al. Plasma N-terminal pro-B-type natriuretic peptide for prediction of death or nonfatal myocardial infarction following percutaneous coronary intervention. Am J Cardiol 2004;94:1481–5. Jarai R, Iordanova N, Raffetseder A, et al. Risk assessment in patients with unstable angina/non-ST-elevation myocardial infarction and normal N-terminal pro-brain natriuretic peptide levels by N-terminal pro-atrial natriuretic peptide. Eur Heart J 2005;26:250 – 6. Bartnik M, Ryden L, Ferrari R, et al. The prevalence of abnormal glucose regulation in patients with coronary artery disease across Europe. The Euro Heart Survey on diabetes and the heart. Eur Heart J 2004;25:1880 –90. Bartnik M, Malmberg K, Norhammar A, et al. Newly detected abnormal glucose tolerance: an important predictor of long-term outcome after myocardial infarction. Eur Heart J 2004;25:1990 –7. Dumaine R, Collet JP, Tanguy ML, et al. Prognostic significance of renal insufficiency in patients presenting with acute coronary syndrome (the Prospective Multicenter SYCOMORE study). Am J Cardiol 2004;94:1543–7. Gibson CM, Dumaine RL, Gelfand EV, et al. Association of glomerular filtration rate on presentation with subsequent mortality in non-ST-segment elevation acute coronary syndrome; observations in 13,307 patients in five TIMI trials. Eur Heart J 2004;25:1998 – 2005. Jernberg T, Lindahl B, James S, et al. Cystatin C: a novel predictor of outcome in suspected or confirmed non-ST-elevation acute coronary syndrome. Circulation 2004;110:2342– 8. Zahid M, Sonel AF, Kelley ME, et al. Effect of both elevated troponin-I and peripheral white blood cell count on prognosis in

JACC Vol. 46, No. 5, 2005 September 6, 2005:906–19

53. 54.

55.

56. 57. 58. 59. 60.

61.

62.

63.

64.

65.

66.

67. 68.

69. 70.

71.

Giugliano and Braunwald The Year in Non–ST-Segment Elevation Acute Coronary Syndromes

patients with suspected myocardial injury. Am J Cardiol 2005; 95:970 –2. Bodi V, Sanchis J, Llacer A, et al. Multimarker risk strategy for predicting 1-month and 1-year major events in non-ST-elevation acute coronary syndromes. Am Heart J 2005;149:268 –74. James SK, Siegbahn A, Armstrong P, et al. Activation of the inflammation, coagulation, and fibrinolysis systems, without influence of abciximab infusion in patients with non-ST-elevation acute coronary syndromes treated with dalteparin: a GUSTO IV substudy. Am Heart J 2004;147:267–74. Wiviott SD, Cannon CP, Morrow DA, et al. Differential expression of cardiac biomarkers by gender in patients with unstable angina/ non-ST-elevation myocardial infarction: a TACTICS-TIMI 18 (Treat Angina with Aggrastat and determine Cost of Therapy with an Invasive or Conservative Strategy-Thrombolysis In Myocardial Infarction 18) substudy. Circulation 2004;109:580 – 6. Spiecker M, Darius H, Hankeln T, et al. Risk of coronary artery disease associated with polymorphism of the cytochrome P450 epoxygenase CYP2J2. Circulation 2004;110:2132– 6. Chasman DI, Posada D, Subrahmanyan L, et al. Pharmacogenetic study of statin therapy and cholesterol reduction. JAMA 2004;291: 2821–7. Williams DO. Clopidogrel pretreatment for percutaneous coronary intervention. Circulation 2005;111:2019 –21. Nguyen TA, Diodati JG, Pharand C. Resistance to clopidogrel: a review of the evidence. J Am Coll Cardiol 2005;45:1157– 64. Bal dit Sollier C, Mahe I, Berge N, et al. Reduced thrombus cohesion in an ex vivo human model of arterial thrombosis induced by clopidogrel treatment: kinetics of the effect and influence of single and double loading-dose regimens. Thromb Res 2003;111:19 –27. Gurbel PA, Cummings CC, Bell CR, et al. Onset and extent of platelet inhibition by clopidogrel loading in patients undergoing elective coronary stenting: the Plavix Reduction Of New Thrombus Occurrence (PRONTO) trial. Am Heart J 2003;145:239 – 47. Steinhubl SR, Berger PB, Brennan D, et al., for the CREDO Investigators. Optimal timing for the initiation of pretreatment with 300 mg of clopidogrel prior to percutaneous coronary intervention. J Am Coll Cardiol 2005. In press. Hochholzer W, Trenk D, Frundi D, et al. Time dependence of platelet inhibition after a 600-mg loading dose of clopidogrel in a large, unselected cohort of candidates for percutaneous coronary intervention. Circulation 2005;111:2560 – 4. Lepantalo A, Virtanen KS, Heikkila J, et al. Limited early antiplatelet effect of 300 mg clopidogrel in patients with aspirin therapy undergoing percutaneous coronary interventions. Eur Heart J 2004;25: 476 – 83. Gurbel PA, Bliden KP, Hayes KM, et al. The relation of dosing to clopidogrel responsiveness and the incidence of high post-treatment platelet aggregation in patients undergoing coronary stenting. J Am Coll Cardiol 2005;45:1392– 6. Patti G, Colonna G, Pasceri V, et al. Randomized trial of high loading dose of clopidogrel for reduction of periprocedural myocardial infarction in patients undergoing coronary intervention. Results from the ARMYDA-2 (Antiplatelet therapy for Reduction of MYocardial Damage during Angioplasty) Study. Circulation 2005;111: 2099 –106. Kastrati A, von Beckerath N, Joost A, et al. Loading with 600 mg clopidogrel in patients with coronary artery disease with and without chronic clopidogrel therapy. Circulation 2004;110:1916 –9. Silber S, Albertsson P, Aviles FF, et al. Guidelines for percutaneous coronary interventions: the task force for percutaneous coronary interventions of the European society of cardiology. Eur Heart J 2005;26:804 – 47. Gurbel PA, Bliden KP, Hiatt BL, et al. Clopidogrel for coronary stenting: response variability, drug resistance, and the effect of pretreatment platelet reactivity. Circulation 2003;107:2908 –13. Matetzky S, Shenkman B, Guetta V, et al. Clopidogrel resistance is associated with increased risk of recurrent atherothrombotic events in patients with acute myocardial infarction. Circulation 2004;109: 3171–5. Gurbel PA, Bliden KP, Samara W. The clopidogrel resistance and stent thrombosis (CREST) study (abstr). J Am Coll Cardiol 2005. In press.

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72. Gurbel PA, Bliden KP, Hayes KM, et al. The relation of dosing to clopidogrel responsiveness and the incidence of high posttreatment platelet aggregation in patients undergoing coronary stenting. J Am Coll Cardiol 2005;45:392– 6. 73. Barragan P, Bouvier JL, Roquebert PO, et al. Resistance to thienopyridines: clinical detection of coronary stent thrombosis by monitoring of vasodilator-stimulated phosphoprotein phosphorylation. Catheter Cardiovasc Interv 2003;59:295–302. 74. Kapetanakis EI, Medlam DA, Boyce SW, et al. Clopidogrel administration prior to coronary artery bypass grafting surgery: the cardiologist’s panacea or the surgeon’s headache? Eur Heart J 2005;26: 576 – 83. 75. Fox KA, Mehta SR, Peters R, et al. Benefits and risks of the combination of clopidogrel and aspirin in patients undergoing surgical revascularization for non-ST-elevation acute coronary syndrome: the Clopidogrel in Unstable angina to prevent Recurrent ischemic Events (CURE) Trial. Circulation 2004;110:1202– 8. 76. Kastrati A, Mehilli J, Schuhlen H, et al. A clinical trial of abciximab in elective percutaneous coronary intervention after pretreatment with clopidogrel. N Engl J Med 2004;350:232– 8. 77. Mehilli J, Kastrati A, Schuhlen H, et al. Randomized clinical trial of abciximab in diabetic patients undergoing elective percutaneous coronary interventions after treatment with a high loading dose of clopidogrel. Circulation 2004;110:3627–35. 78. Claeys MJ, Van der Planken MG, Bosmans JM, et al. Does pre-treatment with aspirin and loading dose clopidogrel obviate the need for glycoprotein IIb/IIIa antagonists during elective coronary stenting? A focus on peri-procedural myonecrosis. Eur Heart J 2005;26:567–75. 79. Schomig A, Schmitt C, Dibra A, et al. One year outcomes with abciximab vs. placebo during percutaneous coronary intervention after pre-treatment with clopidogrel. Eur Heart J 2005;26:1379 – 84. 80. Boeynaems JM, van Giezen H, Savi P, et al. P2Y receptor antagonists in thrombosis. Curr Opin Invest Drugs 2005;6:275– 82. 81. Wallentin L, Jernberg T, Leese PT, et al. Inhibition of platelet aggregation with prasugrel (CS-747, LY640315), a novel thienopyridine P2Y12 receptor antagonist, compared with clopidogrel in aspirin-treated patients with atherosclerotic vascular disease (abstr). J Am Coll Cardiol 2005;45 Suppl A:416A. 82. Wiviott SD, Antman EM, Winters KJ, et al. A randomized comparison of prasugrel (CS-747, LY640315), a novel thienopyridine P2Y12 antagonist, to clopidogrel in percutaneous coronary intervention; results of the Joint Utilization of Medications to Block Platelets Optimally (JUMBO)-TIMI 26 trial. Circulation 2005;111: 3366 –73. 83. Greenbaum AB, Ohman EM, Gibson CM, et al. Preliminary experience with intravenous P2Y12 platelet receptor inhibition as an adjunct to reduced-dose alteplase during acute myocardial infarction: results of the Safety, Tolerability and Effect on Patency in Acute Myocardial Infarction (STEP-AMI) angiographic trial. Am Heart J 2005. In Press. 84. Peters G, Robbie G. Single dose pharmacokinetics and pharmacodynamics of AZD6140 — an oral reversible ADP receptor antagonist (abstr). Haematologica 2004;89 Suppl 7:14 –15. 85. Ercan E, Tengiz I, Duman C, et al. Effect of tirofiban on C-reactive protein in non-ST-elevation myocardial infarction. Am Heart J 2004;147:e1– 4. 86. Azar RR, Badaoui G, Sarkis A, et al. Effects of tirofiban and statins on high-sensitivity C-reactive protein, interleukin-6, and soluble CD40 ligand following percutaneous coronary interventions in patients with stable coronary artery disease. Am J Cardiol 2005;95:236 – 40. 87. Warnholtz A, Ostad MA, Heitzer T, et al. Effect of tirofiban on percutaneous coronary intervention-induced endothelial dysfunction in patients with stable coronary artery disease. Am J Cardiol 2005; 95:20 –3. 88. Dalby M, Montalescot G, Bal dit Sollier C, et al. Eptifibatide provides additional platelet inhibition in non-ST-elevation myocardial infarction patients already treated with aspirin and clopidogrel. Results of the platelet activity extinction in non-Q-wave myocardial infarction with aspirin, clopidogrel, and eptifibatide (PEACE) study. J Am Coll Cardiol 2004;43:162– 8. 89. Gurbel PA, Bliden KP, Zaman KA, et al. Clopidogrel loading with eptifibatide to arrest the reactivity of platelets: results of the Clopi-

918

90.

91.

92.

93.

94. 95.

96. 97. 98.

99.

100.

101.

102.

103. 104. 105.

Giugliano and Braunwald The Year in Non–ST-Segment Elevation Acute Coronary Syndromes dogrel Loading With Eptifibatide to Arrest the Reactivity of Platelets (CLEAR PLATELETS) study. Circulation 2005;111:1153–9. Bonz AW, Lengenfelder B, Strotmann J, et al. Effect of additional temporary glycoprotein IIb/IIIa receptor inhibition on troponin release in elective percutaneous coronary interventions after pretreatment with aspirin and clopidogrel (TOPSTAR trial). J Am Coll Cardiol 2002;40:662– 8. Chan AW, Moliterno DJ, Berger PB, et al. Triple antiplatelet therapy during percutaneous coronary intervention is associated with improved outcomes including one-year survival: results from the Do Tirofiban and ReoProGive Similar Efficacy Outcome Trial (TARGET). J Am Coll Cardiol 2003;42:1188 –95. Dery J-P, Campbell ME, O’Shea C. Administration of a loading dose amplifies the beneficial effect of thienopyridine pretreatment and complements the use of GP IIb/IIIa inhibitor therapy in patients undergoing percutaneous coronary intervention with stenting. Circulation 2003;108 Suppl:IV374. Gibson CM, Singh KP, Murphy SA, et al. Association between duration of tirofiban therapy before percutaneous intervention and tissue level perfusion (a TACTICS-TIMI 18 substudy). Am J Cardiol 2004;94:492– 4. Rebeiz AG, Dery JP, Tsiatis AA, et al. Optimal duration of eptifibatide infusion in percutaneous coronary intervention (an ESPRIT substudy). Am J Cardiol 2004;94:926 –9. Bavry AA, Kumbhani DJ, Quiroz R, et al. Invasive therapy along with glycoprotein IIb/IIIa inhibitors and intracoronary stents improves survival in non-ST-segment elevation acute coronary syndromes: a meta-analysis and review of the literature. Am J Cardiol 2004;93:830 –5. Lenderink T, Boersma E, Ruzyllo W, et al. Bleeding events with abciximab in acute coronary syndromes without early revascularization: an analysis of GUSTO IV-ACS. Am Heart J 2004;147:865–73. Exaire JE, Dauerman HL, Topol EJ, et al. Triple antiplatelet therapy does not increase femoral access bleeding with vascular closure devices. Am Heart J 2004;147:31– 4. Braunwald E, Antman EM, Beasley JW, et al. ACC/AHA 2002 Guideline Update for the Management of Patients With Unstable Angina and Non-ST-Segment Elevation Myocardial Infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on the Management of Patients With Unstable Angina). 2002. Available at: http://www.acc.org/clinical/guidelines/unstable/unstable/pdf. Accessed July 6, 2005. Denardo SJ, Davis KE, Tcheng JE. Elective percutaneous coronary intervention using broad-spectrum antiplatelet therapy (eptifibatide, clopidogrel, and aspirin) alone, without scheduled unfractionated heparin or other antithrombin therapy. Am Heart J 2005;149:138 – 44. Blazing MA, de Lemos JA, White HD, et al. Safety and efficacy of enoxaparin vs unfractionated heparin in patients with non-STsegment elevation acute coronary syndromes who receive tirofiban and aspirin: a randomized controlled trial. JAMA 2004;292:55– 64. Ferguson JJ, Califf RM, Antman EM, et al. Enoxaparin vs unfractionated heparin in high-risk patients with non-ST-segment elevation acute coronary syndromes managed with an intended early invasive strategy: primary results of the SYNERGY randomized trial. JAMA 2004;292:45–54. Petersen JL, Mahaffey KW, Hasselblad V, et al. Efficacy and bleeding complications among patients randomized to enoxaparin or unfractionated heparin for antithrombin therapy in non-ST-segment elevation acute coronary syndromes: a systematic overview. JAMA 2004;292:89 –96. Montalescot G, Collet JP, Tanguy ML, et al. Anti-Xa activity relates to survival and efficacy in unselected acute coronary syndrome patients treated with enoxaparin. Circulation 2004;110:392– 8. Collet JP, Montalescot G, Golmard JL, et al. Subcutaneous enoxaparin with early invasive strategy in patients with acute coronary syndromes. Am Heart J 2004;147:655– 61. de Lemos JA, Blazing MA, Wiviott SD, et al. Enoxaparin versus unfractionated heparin in patients treated with tirofiban, aspirin and an early conservative initial management strategy: results from the A phase of the A-to-Z trial. Eur Heart J 2004;25:1688 –94.

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106. Lincoff AM, Kleiman NS, Kereiakes DJ, et al. Long-term efficacy of bivalirudin and provisional glycoprotein IIb/IIIa blockade vs heparin and planned glycoprotein IIb/IIIa blockade during percutaneous coronary revascularization: REPLACE-2 randomized trial. JAMA 2004;292:696 –703. 107. Saw J, Lincoff AM, DeSmet W, et al. Lack of clopidogrel pretreatment effect on the relative efficacy of bivalirudin with provisional glycoprotein IIb/IIIa blockade compared to heparin with routine glycoprotein IIb/IIIa blockade: a REPLACE-2 substudy. J Am Coll Cardiol 2004;44:1194 –9. 108. Gurm HS, Rajagopal V, Fathi R, et al. Effectiveness and safety of bivalirudin during percutaneous coronary intervention in a single medical center. Am J Cardiol 2005;95:716 –21. 109. Gibson CM. Late-breaking clinical trials: PROTECT-TIMI 30. Advancing the Standard of Care. New Orleans, LA: Texas Heart Institute, 2004. 110. Stone GW, Bertrand M, Colombo A, et al. Acute Catheterization and Urgent Intervention Triage strategY (ACUITY) trial: study design and rationale. Am Heart J 2004;148:764 –75. 111. Mehta SR, Steg PG, Granger CB, et al. Randomized, blinded trial comparing fondaparinux with unfractionated heparin in patients undergoing contemporary percutaneous coronary intervention: Arixtra Study in Percutaneous Coronary Intervention: a Randomized Evaluation (ASPIRE) Pilot Trial. Circulation 2005;111:1390 –7. 112. Morrow DA, Murphy SA, McCabe CH, et al. Potent inhibition of thrombin with a monoclonal antibody against tissue factor (SunolcH36): results of the PROXIMATE-TIMI 27 trial. Eur Heart J 2005;26:682– 8. 113. Moons AH, Peters RJ, Bijsterveld NR, et al. Recombinant nematode anticoagulant protein c2, an inhibitor of the tissue factor/factor VIIa complex, in patients undergoing elective coronary angioplasty. J Am Coll Cardiol 2003;41:2147–53. 114. Rusconi CP, Roberts JD, Pitoc GA, et al. Antidote-mediated control of an anticoagulant aptamer in vivo. Nat Biotechnol 2004;22:1423– 8. 115. O’Neill WW, Dixon SR, Grines CL. The year in interventional cardiology. J Am Coll Cardiol 2005;45:1117–34. 116. Mehta SR, Cannon CP, Fox KAA, et al. Routine versus selective invasive strategies in patients with acute coronary syndromes: a collaborative meta-analysis of the randomized trials. JAMA 2005; 293:2908 –17. 117. Biondi-Zoccai GGL, Abbate A, Agostoni P, et al. Long-term benefits of an early invasive management in acute coronary syndromes depend on intracoronary stenting and aggressive antiplatelet treatment: a metaregression. Am Heart J 2005;149:504 –11. 118. Neumann FJ, Kastrati A, Pogatsa-Murray G, et al. Evaluation of prolonged antithrombotic pretreatment (“cooling-off ” strategy) before intervention in patients with unstable coronary syndromes: a randomized controlled trial. JAMA 2003;290:1593–9. 119. Eisenberg MJ, Teng FF, Chaudhry MR, et al. Impact of invasive management versus noninvasive management on functional status and quality of life following non-Q-wave myocardial infarction: a randomized clinical trial. Am Heart J 2005;149:813–9. 120. Bach RG, Cannon CP, Weintraub WS, et al. The effect of routine, early invasive management on outcome for elderly patients with non-ST-segment elevation acute coronary syndromes. Ann Intern Med 2004;141:186 –95. 121. Clayton TC, Pocock SJ, Henderson RA, et al. Do men benefit more than women from an interventional strategy in patients with unstable angina or non-ST-elevation myocardial infarction? The impact of gender in the RITA 3 trial. Eur Heart J 2004;25:1641–50. 122. Schellekens S, Verheugt FW. Hotline sessions of the 26th European Congress of Cardiology. Eur Heart J 2004;25:2164 – 6. 123. Cannon CP, Braunwald E, McCabe CH, et al. Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med 2004;350:1495–504. 124. Ray KK, Cannon CP, Cairns R, et al. The timing of benefits of intensive statin therapy in ACS: a PROVE IT-TIMI 22 substudy. J Am Coll Cardiol 2005. In Press. 125. Grundy SM, Cleeman JI, Merz CN, et al. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines. Circulation 2004;110:227–39.

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Giugliano and Braunwald The Year in Non–ST-Segment Elevation Acute Coronary Syndromes

126. de Lemos JA, Blazing MA, Wiviott SD, et al. Early intensive vs a delayed conservative simvastatin strategy in patients with acute coronary syndromes: phase Z of the A to Z trial. JAMA 2004;292:1307–16. 127. Nissen SE, Tuzcu EM, Schoenhagen P, et al. Effect of intensive compared with moderate lipid-lowering therapy on progression of coronary atherosclerosis: a randomized controlled trial. JAMA 2004; 291:1071– 80. 128. Okazaki S, Yokoyama T, Miyauchi K, et al. Early statin treatment in patients with acute coronary syndrome: demonstration of the beneficial effect on atherosclerotic lesions by serial volumetric intravascular ultrasound analysis during half a year after coronary event: the ESTABLISH Study. Circulation 2004;110:1061– 8. 129. Lima JA, Desai MY, Steen H, et al. Statin-induced cholesterol lowering and plaque regression after 6 months of magnetic resonance imaging-monitored therapy. Circulation 2004;110:2336 – 41. 130. Ridker PM, Cannon CP, Morrow D, et al. C-reactive protein levels and outcomes after statin therapy. N Engl J Med 2005;352:20 – 8. 131. Ridker PM, Morrow DA, Rose LM, et al. Relative efficacy of atorvastatin 80 mg and pravastatin 40 mg in achieving the dual goals of low-density lipoprotein cholesterol ⬍70 mg/dl and C-reactive protein ⬍2 mg/l: an analysis of the PROVE-IT TIMI-22 trial. J Am Coll Cardiol 2005;45:1644 – 8. 132. Macin SM, Perna ER, Farias EF, et al. Atorvastatin has an important acute anti-inflammatory effect in patients with acute coronary syndrome: results of a randomized, double-blind, placebo-controlled study. Am Heart J 2005;149:451– 457.

919

133. Nissen SE, Tuzcu EM, Schoenhagen P, et al. Statin therapy, LDL cholesterol, C-reactive protein, and coronary artery disease. N Engl J Med 2005;352:29 –38. 134. Whitney EJ, Krasuski RA, Personius BE, et al. A randomized trial of a strategy for increasing high-density lipoprotein cholesterol levels: effects on progression of coronary heart disease and clinical events. Ann Intern Med 2005;142:95–104. 135. Brousseau ME, Schaefer EJ, Wolfe ML, et al. Effects of an inhibitor of cholesteryl ester transfer protein on HDL cholesterol. N Engl J Med 2004;350:1505–15. 136. Brewer HB Jr. Increasing HDL cholesterol levels. N Engl J Med 2004;350:1491– 4. 137. Cannon CP, Braunwald E, McCabe CH, et al. Antibiotic treatment of Chlamydia pneumoniae after acute coronary syndrome. N Engl J Med 2005;352:1646 –54. 138. Mukherjee D, Fang J, Chetcuti S, et al. Impact of combination evidence-based medical therapy on mortality in patients with acute coronary syndromes. Circulation 2004;109:745–9. 139. Schwammenthal E, Sandach A, Klempfner R, et al. Predicting mortality in survivors of acute coronary syndrome using the 4 drug (4 D) score: risk stratification by discharge medication (abstr). Circulation 2004;110 Suppl III:III500. 140. Gluckman TJ, Sachdev M, Schulman SP, et al. A simplified approach to the management of non-ST-segment elevation acute coronary syndromes. JAMA 2005;293:349 –57.