YEAR IN CARDIOLOGY SERIES
The Year in Non—ST-Segment Elevation Acute Coronary Syndromes
Robert P. Giugliano, MD, SM, FACC*, and
Eugene Braunwald, MD, MACC*,,*
* TIMI Study Group, Cardiovascular Division, Brigham and Women’s Hospital
Department of Medicine, Harvard Medical School, Boston, Massachusetts
Manuscript received May 2, 2005;
revised manuscript received May 23, 2005,
accepted June 1, 2005.
* Reprint requests and correspondence: Dr. Eugene Braunwald, TIMI Study Group, Brigham and Women’s Hospital, 350 Longwood Avenue, 1st Floor Offices, Boston, Massachusetts 02115. (Email: ebraunwald{at}partners.org).
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.
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Risk assessment and risk scores
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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 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 guideline-recommended 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.
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Biomarkers
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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).
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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.
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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 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.
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 (Nt-proBNP), 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 Nt-proBNP (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 NSTE-ACS 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 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-methylutaryl-CoA reductase gene demonstrated reduced efficacy of cholesterol lowering with pravastatin (57).
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Platelet P2Y12 receptor blockers
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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 one-quarter 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 NSTE-ACS.
The first extensive report exploring the interindividual 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 µmol/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 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.
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Glycoprotein IIb/IIIa blockers
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Although GP IIb/IIIa blockers have been available clinically for more than a decade, several pharmacodynamic studies 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 x 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 (90–92), whereas the three aforementioned trials with abciximab (76–78) failed to do so.
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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 x 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 µmol/l adenosine diphosphate as the stimulus. *p  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.
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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).
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Anticoagulants
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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 the safety and efficacy of reducing or eliminating adjunctive heparin in patients with ACS undergoing PCI.
Low molecular weight heparin.
Two large-scale open-label 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 NSTE-ACS and a similar safety profile (Table 5). Given the greater convenience (twice-daily subcutaneous injections), absence of the need for routine monitoring, and simple weight-based dosing that does not require subsequent dose-adjustment 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 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 NSTE-ACS (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 dose-dependent 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
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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 NSTE-ACS 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 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.
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Lipid-lowering therapy after ACS
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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).
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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 IT-TIMI-22 trial (123).
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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 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).
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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."
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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 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).
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Conclusions
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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, Angiotensin-converting enzyme inhibition
- B Beta-adrenergic receptor blocker, Blood pressure control
- C Cholesterol lowering, Cigarette smoking cessation
- D Diet, Diabetes management
- E Exercise
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Footnotes
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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.
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