MEDSCAPE
Author: L Grunberg
Patient History and Introduction
SJ is a 59-year-old white woman, 5′5″, 165 pounds, and a smoker, who presents to the emergency department (ED) complaining of recurrent episodes of chest pain. She reports that 4 weeks ago she started experiencing “slight pressure” in her chest when going up the stairs at home. Over the past 2 days, these episodes have worsened; they occur when she is eating breakfast or doing basic housework and last 5-10 minutes.
Patient history reveals prior myocardial infarction (MI) 5 years earlier, but with no angina. Six months ago, the patient presented to the ED with an acute coronary syndrome (ACS). The electrocardiogram (ECG) demonstrated nonspecific ST-segment depression and laboratory results showed a borderline creatine kinase (CK)-MB level. Cardiac troponin I was 0.5 ng/mL. Coronary angiography revealed a 90% stenosis of the left circumflex artery (LCx) and a 50% stenosis of the mid-portion of the right coronary artery (RCA). SJ underwent percutaneous coronary intervention (PCI) with a drug-eluting stent deployed in the mid LCx. She was administered clopidogrel (300 mg loading dose) prior to the procedure and unfractionated heparin (UFH; 60 U/kg + 12 U/kg/hr) during the procedure. She was discharged on maintenance therapy of aspirin 162 mg/day, clopidogrel 75 mg/day, simvastatin 40 mg/day, lisinopril 10 mg/day, and atenolol 50 mg/day.
With her most recent presentation, physical examination was unremarkable with the exception of a left carotid bruit. ECG revealed a normal sinus rhythm with a 0.5 mm ST-segment depression in the inferior leads. Cardiac troponin I level on admission was 1.3 ng/mL. CK-MB was 7 (upper limit of normal: 5). Patient maintains that she has been compliant with her medical regimen.
Presentation of ACS
As most clinicians know, when a patient presents for medical attention with “chest pain” or “pressure,” the immediate question is whether the pain is of cardiovascular origin (as opposed to indigestion or other reasons). The history remains crucial and the patient should be asked to describe the quality, location, duration, radiation, precipitating and aggravating factors and accompanying symptoms that will help the physician distinguish among the many possible causes of chest discomfort.
Once it is determined that the chest pain is of cardiovascular origin, the next step is to define the type of presentation. The term “acute coronary syndrome” (ACS) to describe the various presentations of this condition, ranging from UA and non-ST-segment elevation MI (NSTEMI) to ST-segment elevation MI (STEMI), a condition which in 2005 the American Heart Association (AHA) reports led to hospitalization for over 1.5 million patients.[1] Distinguishing among these diagnoses is important for planning appropriate therapeutic strategies.
In simple terms, the various presentations of ACS depend on the degree of severity of the disruption of built-up lipid-rich atherosclerotic plaque, which leads to thrombus formation and interruption of the blood supply to the myocardium.[2] In the case of partial blockage, the diagnosis can be either UA or NSTEMI, which are closely related conditions with similar pathogenesis and clinical presentations, but of differing severity.
In UA, the blockage is less severe than that for NSTEMI, and there are not necessarily ECG changes. By definition, there is no elevation in cardiac biomarkers, and the condition has at least 1 of the following features: crescendo angina (more prolonged, severe, or frequent) episodes, new-onset angina, and/or angina at rest.
Unlike UA, in NSTEMI, the blockage tends to be more severe, and the limited blood flow to the myocardium is maintained. Differentiating NSTEMI from UA is dependent upon documented evidence of myocardial necrosis, represented by elevations in cardiac biomarkers.[1]
STEMI, on the other hand, is associated with complete thrombotic occlusion; chest pain is typically refractory and there is evidence of ST-segment elevation on ECG. STEMI is treated as a medical emergency and timing of intervention (with intervention or fibrinolysis) is critical to ensure favorable outcomes.
Risk Stratification
According to the American College of Cardiology (ACC)/AHA 2007 guidelines for the Management of Patients With Unstable Angina/Non ST-elevation MI,[1] treatment decisions for UA/NSTEMI must be based on assessment of the patient’s risk. The physician should integrate patient history and findings from physical examination, 12-lead ECG, and initial cardiac biomarker tests to develop an estimation of a patient’s risk for mortality and cardiac events.[1] Specifically, risk-stratification tools, such as the TIMI[3] and GRACE[4] scores and the Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy (PURSUIT) risk model,[5] have been developed to facilitate prediction of short- and long-term outcomes in patients with UA/NSTEMI, as well as to guide treatment decisions. For instance, patients with higher risk scores have been shown to derive greater benefit from more aggressive pharmacologic therapies and an early invasive strategy.
TIMI
The Thrombolysis in Myocardial Infarction (TIMI) risk score for UA/NSTEMI has been found to be a reliable tool to predict 30-day and 1-year mortality.[1] The risk model integrates 7 independent predictors, including historical factors, frequency of symptoms, electrocardiographic findings, and cardiac biomarker levels.[3] One point is assigned for the presence of each risk factor (Table 1). Higher scores suggest higher risk, with risk for all-cause mortality, MI, and severe recurrent ischemia prompting urgent revascularization through 14 days ranging from about 5% for patients with a TIMI risk score of 0-1 to approximately 41% in patients with TIMI scores of 6-7 (Table 2).[3]
Table 1. TIMI Risk Score: 7 Independent Predictors
| Predictor Variables |
Points |
Table 2. TIMI Risk Score for UA/NSTEMI: Risk for Events by 14 Days in TIMI 11B Trial[2]
| Total Score |
All-Cause Mortality/Nonfatal MI (%) |
Death/MI/Urgent Revascularization (%) |
SJ presents with multiple cardiovascular risk factors, prior stenosis, ST deviation 0.5 mm, recent anginal events, elevated cardiac biomarkers, and recent aspirin use. Thus, her total TIMI score is 6, suggesting her risk for all-cause death/nonfatal MI/urgent revascularization is more than 40%.
GRACE
The Global Registry of Acute Coronary Events (GRACE) hospital discharge risk score has also been validated in patients with UA/NSTEMI.[4] This model includes 9 variables, including age, history of congestive heart failure, history of MI, resting heart rate, systolic blood pressure, ST-segment depression, initial serum creatinine, elevated cardiac enzymes, and no in-hospital PCI. Each parameter is scored, and the total GRACE risk score corresponds to an estimated probability of all-cause mortality from hospital discharge to 6 months.
Cardiac biomarkers should be measured in all patients who present with chest discomfort consistent with ACS. The traditional biomarker in routine clinical use to detect MI has been CK-MB; however, because of their high specificity and sensitivity for predicting myocardial necrosis, the 2007 ACC/AHA guidelines have identified cardiac-specific troponins as the preferred biomarker in these patients.[1] Levels of troponin are correlated in a nearly linear manner with risk for adverse outcomes among patients with ACS (Table 3).[6]
Table 3. Risk for Mortality in ACS Patients by Cardiac Troponin I Level[6]
| Cardiac Troponin I (ng/mL) |
Mortality at 42 days (%) |
Detectable levels of troponin can be delayed for up to 8-12 hours after myocardial injury. Therefore, troponin measurement at baseline and at 8 and 16 hours is recommended to adequately differentiate UA from NSTEMI.
[7]
Although cardiac troponins remain the preferred biomarker to detect myocardial necrosis, CK-MB remains a useful measurement for the diagnosis of early reinfarction and periprocedural MI, since its short half-life permits better detection of secondary increases in marker levels.[1]
The presence of multiple risk criteria and biomarkers should be considered when diagnosing UA/NSTEMI. For example, patients with elevations in both troponin and CK-MB are known to be at the highest short-term risk, patients with elevated levels of troponin only are at intermediate risk, and patients with elevations in CK-MB only are considered at lowest risk.[1] Other markers of cellular inflammation, plaque rupture, or thrombosis are also used and/or are under investigation to determine risk in ACS, including B-type natriuretic peptide, CRP, and myeloperoxidase.
Early Hospital Management
According to the ACC/AHA 2007 guidelines, patients with definite or probable UA/NSTEMI should be admitted to an inpatient unit, where they should undergo continuous monitoring for arrhythmias and recurrent ischemia.[1] High-risk patients, including those with recurrent pain or hemodynamic instability, should be admitted to a coronary care unit and observed for at least 24 hours without any major complications.
Optimal management of UA/NSTEMI should focus on the immediate relief of ischemia and the prevention of serious adverse outcomes. This can be achieved with an approach that includes anti-ischemic and antithrombotic therapy, while ongoing risk stratification is undertaken to assess the possible need for invasive procedures.[1] Patients with diabetes should be treated with aggressive glucose control while hospitalized.
The ACC/AHA guidelines recommend bed/chair rest with continuous ECG monitoring during the early hospital phase.[1] Supplemental oxygen should be given to patients with an arterial saturation less than 90%, respiratory distress, or other high-risk features for hypoxemia.
Patients with UA/NSTEMI should receive aspirin (initial dose: 162-325 mg) as soon as possible after hospital presentation, unless contraindicated. In addition to antiplatelet therapy, anticoagulation agents should be added as soon as the patient’s course of therapy has been decided. Additional early hospital care should include nitroglycerin and oral beta-blockers.[1]
Patients with ongoing ischemic discomfort should receive sublingual nitroglycerin (0.4 mg) every 5 minutes for a total of 3 doses. Intravenous nitroglycerin is indicated in the first 48 hours for treatment of persistent ischemic heart failure or hypertension.
Oral beta-blockers should be initiated within the first 24 hours for patients who do not have signs of heart failure; evidence of a low-output state, increased risk for cardiogenic shock, or other relative contraindications to beta-blockade.[1] In the absence of clinically significant left ventricular (LV) dysfunction or other contraindications, a non-dihydropyridine calcium-channel blocker (eg, verapamil, diltiazem) can be given to patients with continuing or frequently recurring ischemia in whom beta-blockers are contraindicated.
Patients with pulmonary congestion or LV ejection fraction (LVEF) ≤ 40% should receive an angiotensin converting enzyme (ACE) inhibitor as long as they do not have hypotension (systolic blood pressure < 100 mm Hg or < 30 mm Hg below baseline) or known contraindications to this class of medications. Patients who have either clinical or radiological signs of heart failure or LVEF ≤ 40% who cannot tolerate ACE inhibitors should receive an angiotensin receptor blocker.
Nonsteroidal anti-inflammatory drugs (COX-1 or COX-2 inhibitors) other than aspirin should be discontinued on admission to the hospital due to increased risk for mortality, reinfarction, hypertension, heart failure, and myocardial rupture.[1] The 2007 guidelines have also downgraded the use of morphine as an analgesic from a Class I to a Class IIa recommendation, since it has been associated with a worse outcome in observational studies.
Initial Treatment Strategies: Conservative vs Invasive
The primary objective in selecting a treatment strategy for UA/NSTEMI patients is to yield the best long-term clinical outcome.[1] The potential risks for adverse outcomes must be considered when selecting a treatment strategy for an individual patient.
Treatment of the UA/NSTEMI patient should be directed at stabilizing the hemodynamics, relieving ischemic pain, using antithrombotic therapy to minimize myocardial damage, and reducing the risk for recurrent ischemia. Subsequently, risk stratification should be utilized to assess the likelihood of failure of medical therapy and the need for revascularization.
Two treatment pathways have emerged: an initial “conservative strategy” and an early “invasive strategy.”
The conservative strategy entails prescribing an intensive medication regimen that includes antiplatelet agents, anticoagulants, beta-blockers, statins, as well as agents (eg, ACE inhibitors) normally prescribed for patients with coronary artery disease. When an initial conservative approach is selected, clopidogrel (loading dose followed by maintenance dose) should be added to aspirin and anticoagulant therapy as soon as possible after admission and continued for at least 1 month, and ideally up to 1 year.[1] Anticoagulant therapies, including enoxaparin and UFH, as well as fondaparinux (which is preferable in patients who are at increased risk for bleeding) are also Class I recommendations.
An early invasive therapy for UA/NSTEMI patients refers to the routine use of coronary angiography within 48 hours of admission. Patients undergoing invasive therapy can be categorized into 2 groups:
- Early invasive: those who are designated by patient/physician discretionary choice or after risk assessment to benefit from early, but nonurgent, angiography/intervention; and
- Immediate invasive: those who require urgent angiography/revascularization due to ongoing ischemic symptoms or hemodynamic or rhythm instability.[1]
Once a decision has been made to manage the patient invasively and the coronary anatomy has been delineated, the interventionalist must decide whether percutaneous or surgical revascularization would be more beneficial for the patient. In recent years, stenting and the use of improved antiplatelet and anticoagulant agents have improved the safety and durability of PCI in UA/NSTEMI. Coronary artery bypass graft surgery (CABG) is usually reserved for patients with left main artery stenosis or 3-vessel disease and treated diabetes mellitus or LV dysfunction. Stenting has reduced the risks of both acute vessel closure and late restenosis, and the advent of drug-eluting stents has significantly reduced the risk for restenosis but modestly increase the risk for late coronary thrombotic events.
When an initial invasive strategy is selected for a patient, aspirin and an anticoagulant (with 1 of 4 choices: UFH, enoxaparin, bivalirudin, and fondaparinux) should be added to antiplatelet therapy as soon as possible after presentation in patients for whom an invasive strategy is selected.[1] In addition, the guidelines recommend administering at least 1 of the 2 other antiplatelet therapies: clopidogrel (loading dose followed by maintenance dosing) or an intravenous glycoprotein (GP) IIb/IIIa inhibitor (tirofiban, eptifibatide) before diagnostic angiography in selected patients.[1] The guidelines note that it is reasonable (a Class IIa recommendation) to administer both, especially if the patient has high-risk features, has a delay to angiography, or has recurrent ischemia. Table 4 provides guideline-recommended dosing for initial medical treatment with select antiplatelet and anticoagulant therapy in UA/NSTEMI patients.
Table 4. Guideline-Recommended Antiplatelet and Anticoagulant Dosing for Initial Medical Treatment in UA/NSTEMI[1]
| Drug |
Dosing Recommendation |
aPTT = activated partial thromboplastin time; IV = intravenous; LD = loading dose; MD = maintenance dose; SC = subcutaneous
According to the ACC/AHA guidelines, initial treatment with an invasive strategy is indicated in patients with recurrent angina, elevated biomarkers, ST-segment depression, prior revascularization, high risk scores, and signs or symptoms of heart failure or reduced LV function.[1] A conservative strategy may be considered for patients who are stabilized and who have mildly elevated risks, including patients who are troponin positive (Table 5).
Table 5. Patient Characteristics to Consider When Selecting Conservative vs Invasive Strategy[1]
GRACE = Global Registry of Acute Coronary Events; HF = heart failure; LVEF = left ventricular ejection fraction; PCI = percutaneous coronary intervention; TIMI = thrombolysis in myocardial infarction; TnI = cardiac troponin I; TnT = cardiac troponin T
The updated ACC/AHA 2007 treatment algorithms for an initial conservative and an initial invasive strategy in patients with UA/NSTEMI are shown in Figures 1 and 2, respectively.
Figure 1. Treatment algorithm for patients with UA/NSTEMI managed with a conservative strategy.
Figure 2. Treatment algorithm for patients with UA/NSTEMI managed with an invasive strategy.
Conservative vs Invasive Strategy
Early studies in UA/NSTEMI patients — such as the TIMI IIIB[8] and Veterans Affairs Non-Q-Wave Infarction Strategies in Hospital (VANQWISH)[9] trials — did not show a clear benefit for the early invasive strategy over a conservative strategy, but more recent studies — such as the Fragmin and Fast Revascularisation During Instability in Coronary Artery Disease (FRISC II),[10] Treat Angina with Aggrastat and Determine Cost of Therapy with an Invasive or Conservative Strategy (TACTICS)-TIMI 18,[11] and Third Randomized Intervention Treatment of Angina (RITA 3)[12] trials — have suggested a clear benefit for the early intervention approach in these patients. However, the most recently published Invasive Versus Conservative Treatment in Unstable Coronary Syndromes (ICTUS) study[13] favored a selective invasive strategy in UA/NSTEMI patients.
It has been noted that the differences between the results of TACTICS-TIMI 18 and the ICTUS study may have resulted from the definition of MI in the latter study, where a post-PCI troponin elevation was considered an equivalent to MI. This definition may account for the perceived higher rate of MI among the patients undergoing early invasive management in the ICTUS study.
The long-term benefit of an early invasive strategy was supported by the results of a contemporary meta-analysis of 7 randomized trials of management strategies in UA/NSTEMI, including ICTUS.[14] This meta-analysis of 8375 patients showed that an early invasive strategy was associated with a significantly decreased risk in the rate of all-cause mortality and nonfatal MI at 2 years (P = .001 and P = .012, respectively).
Dual Antiplatelet Therapy
Dual antiplatelet therapy with aspirin and clopidogrel has been endorsed as “standard of care” for all patients undergoing PCI. Many trials have shown the benefit of aspirin. Clinical trials comparing aspirin with placebo in UA/NSTEMI patients have yielded consistent results documenting the benefit of aspirin therapy in these patients. Aspirin’s primary mechanism of action is to irreversibly inhibit cyclooxygenase-1 (COX-1). Despite the proven efficacy in clinical studies, there is growing concern regarding patients who continue to experience vascular thrombotic events despite receiving aspirin therapy.
Research to augment the benefits of antiplatelet therapy with aspirin led to discovery of the thienopyridines, a class of molecules that block platelet aggregation via the ADP pathway. The initial agent was ticlopidine followed by clopidogrel. The use of ticlopidine is limited due to adverse effects, such as neutropenia, making clopidogrel the current agent of choice.[1] Since the mechanism of action of thienopyridines differs from that of aspirin, it was thought that “dual antiplatelet therapy” with both classes of antiplatelet agents should improve outcomes in patients with UA/NSTEMI over use of either agent alone.
The first 2 major trials to support the use of dual antiplatelet therapy in this patient population were the Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) trial in UA/NSTEMI patients,[15] followed a year later by the Clopidogrel for the Reduction of Events During Observation (CREDO) trial.[16]
CURE randomized 12,562 UA/NSTEMI patients to either a 300-mg loading dose of clopidogrel followed by a maintenance dose of 75 mg once daily (for a mean of 9 months) or to placebo. All patients received daily aspirin (75 to 325 mg). At follow-up, the use of dual-antiplatelet therapy was associated with a 20% relative risk reduction in the combined endpoint of cardiovascular death/MI/stroke compared with aspirin alone. A subsequent substudy of the patients in this trial who underwent PCI (PCI-CURE)[17] found that clopidogrel therapy was associated with a 30% relative risk reduction in the combined endpoint of cardiovascular death/MI/target vessel revascularization at 30 days (P = .03). The findings from PCI-CURE support the guidelines’ recommendation to use clopidogrel in patients who undergo PCI.[1]
CREDO tested 2 different aspects of dual-antiplatelet regimens in patients undergoing PCI: (1) the benefit of initiating clopidogrel 3-24 hours prior to PCI; and (2) the safety and efficacy of long-term (12-month) clopidogrel treatment after PCI as compared with 1 month of therapy. All patients were maintained on aspirin throughout the course of the study. At 28 days, compared with patients who did not receive a preloading dose, those treated with a 300-mg preloading dose of clopidogrel had a nonsignificant reduction in the risk for the combined endpoint of death/MI/urgent target vessel revascularization. Overall, the use of long-term clopidogrel therapy (75 mg/day) was associated with a significant 27% relative risk reduction in the composite endpoint at 1 year compared with patients who were only treated with clopidogrel following PCI for 28 days (P = .02).
Novel Antiplatelet Agents
Despite the proven efficacy of clopidogrel in patients with UA/NSTEMI and in patients undergoing PCI, significant limitations still exist.[19] The drug has a delayed onset of action and requires activation to an active metabolite in the liver. In addition, approximately 15% to 30% of patients treated with clopidogrel do not achieve adequate levels of platelet inhibition, and some studies suggest that these patients may be at increased risk for adverse events.[20]
Some clinicians elect to reload patients on chronic clopidogrel therapy who undergo subsequent PCI based on studies demonstrating that higher oral loading doses more rapidly inhibit platelet aggregation.[1] However, the results of the Antiplatelet Therapy for Reduction of Myocardial Damage During Angioplasty (ARMYDA-4),[18] which evaluated a pre-PCI loading dose of clopidogrel 600 mg in UA/NSTEMI patients already on chronic maintenance therapy (clopidogrel 75 mg/day), found that the reloading dose did not confer any additional clinical benefit, but also did not increase the rate of bleeding events compared with placebo. Therefore, our patient, SJ, who was already on chronic clopidogrel therapy, did not receive further reload of clopidogrel therapy.
Recent attention has focused on the development and evaluation of novel antiplatelet agents, such as prasugrel, cangrelor, and AZD6140, which are currently under study for the treatment of ACS and/or as adjunctive therapy to PCI.[21]
Prasugrel
Prasugrel is a third-generation thienopyridine that can achieve high levels of platelet activity inhibition, even in patients previously considered to be resistant to clopidogrel. Like clopidogrel, it requires conversion to an active metabolite before binding to the platelet P2Y12 receptor to confer antiplatelet activity.[20] However, prasugrel has been described as being more efficient with a single-step rather than a multiple-step process for platelet activation.[19]
Initial studies have demonstrated that prasugrel is associated with a more consistent and more intense inhibition of platelet activity compared with standard and higher-than-standard doses of clopidogrel (300 mg and 600 mg, respectively).[22] Even with the higher dose of clopidogrel, recent studies have demonstrated that 60 mg of prasugrel yields greater inhibition of platelet aggregation than the use of 600 mg of clopidogrel in patients with chronic coronary artery disease. Similar findings were noted in the Prasugrel in Comparison to Clopidogrel for Inhibition of Platelet Activation and Aggregation-Thrombolysis in Myocardial Infarction 44 (PRINCIPLE-TIMI 44) trial,[18] in which a loading dose of prasugrel 60 mg showed a markedly superior inhibition of platelet aggregation than a 600-mg loading dose of clopidogrel in patients who had undergone elective PCI. In addition, maintenance therapy with 10 mg/day prasugrel resulted in a greater antiplatelet effect compared with 150 mg/day of clopidogrel.
The Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial Infarction (TRITON-TIMI) 38 trial[20] demonstrated that a regimen that provides more potent inhibition of platelet aggregation is associated with fewer ischemic events compared with standard-dose clopidogrel therapy. TRITON-TIMI 38 was a phase 3 trial that randomized 13,608 moderate- to high-risk ACS patients scheduled for PCI to prasugrel (60-mg loading dose and then 10-mg/day maintenance dose) or clopidogrel (300-mg loading dose with maintenance therapy of 75 mg/day) for 6 to 15 months.[20] At 15-month follow-up, the risk for the primary efficacy endpoint of cardiovascular death/MI/stroke was significantly reduced by 19% in patients treated with prasugrel relative to patients treated with clopidogrel (P = .0004); the finding was mainly driven by a significant reduction in the rate of MI. Prasugrel was also associated with a significant 52% reduction in the rate of stent thrombosis compared with clopidogrel. The rate of major bleeding complications (using TIMI criteria), however, was 32% higher in patients treated with prasugrel (2.4% vs 1.8%; P = .03). The overall “net clinical benefit” of the rate of death, MI, stroke, or major (non-CABG associated) bleeding still favored the intensive antiplatelet therapy regimen (with a 13% risk reduction [P = .0004]). Post hoc analyses, however, found that patients with a history of stroke or transient ischemic attack had increased intracranial hemorrhage and a negative overall net clinical benefit, and in the elderly (≥ 75 years) and those with a body weight ≤ 60 kg, the use of prasugrel was associated with higher bleeding rates and a neutral net clinical benefit.
AZD6140
AZD6140 is an oral, reversible, non-thienopyridine ADP receptor antagonist with a rapid onset of activity.[23] As with clopidogrel and prasugrel, this agent also inhibits platelet aggregation by selective blockade of the P2Y12 receptor, but unlike the other 2 drugs, AZD6140 does not require conversion to an active metabolite.
AZD6140 was studied in the Dose Confirmation Study Assessing AntiPlatelet Effects of AZD6140 vs Clopidogrel in UA/NSTEMI (DISPERSE)-2,[24] which randomized 990 UA/NSTEMI patients treated with aspirin and standard ACS therapy to receive either twice-daily AZD6140 90 mg, twice-daily AZD6140 180 mg, or clopidogrel 300-mg loading dose plus 75 mg/day for up to 12 weeks. The results demonstrated that the incidence of major bleeding was similar between the AZD6140 and clopidogrel groups (7.1% vs 5.1% vs 6.9%; P = .91 and P = .35, respectively, vs clopidogrel). A substudy of DISPERSE-2 found that AZD6140 inhibited platelet aggregation in a dose-dependent fashion and that both doses of AZD6140 achieved greater levels of platelet inhibition than clopidogrel.[25] AZD6140 also produced further suppression of platelet aggregation in patients previously treated with clopidogrel. A head-to-head outcomes study of AZD6140 vs clopidogrel (A Study of Platelet Inhibition and Patient Outcomes [PLATO]) in 18,000 patients with ACS is currently under way.
Cangrelor
Cangrelor is another potent P2Y12 receptor antagonist and causes almost immediate, full inhibition of platelet aggregation when administered intravenously. Clinical studies with cangrelor in patients with UA/NSTEMI and in those undergoing PCI have confirmed potent platelet anti-aggregatory effects with a clinical half-life of < 5 minutes with 90% of patients achieving steady-state concentrations at < 9 minutes.[26] This drug is currently being investigated in a series of studies (CHAMPION).
Other Adjunctive Therapies
Anticoagulant therapies are an essential part of the treatment strategy for UA/NSTEMI patients. The ACC/AHA guidelines assigned Class I recommendations to the use of anticoagulation, and there are 4 options that one can use, including UFH, low-molecular-weight heparin (LMWH), bivalirudin, and fondaparinux.[1] In addition, GP IIb/IIIa inhibitors have a prominent role in UA/NSTEMI patients who undergo diagnostic angiography and PCI, as well as for those who are initially treated with a medical management strategy. Recommended dosing for each of these agents during PCI is shown in Table 6.
Table 6. Guideline-Recommended Antiplatelet and Anticoagulant Dosing for Initial Medical Treatment in UA/NSTEMI[1]
| Drug |
Dosing Recommendation During PCI |
| Patient received initial medical treatment |
Patient did not receive initial medical treatment |
ACT = activated clotting time; GPI = glycoprotein IIb/IIIa inhibitor; IV = intravenous; LD = loading dose; MD = maintenance dose; SC = subcutaneous; UFH = unfractionated heparin
*Recommendation from OASIS-5 investigators
Unfractionated Heparin
The benefits of adding intravenous UFH to aspirin for the management of UA/NSTEMI has been well established, and the combination has been widely used in clinical practice.[27] However, UFH has significant disadvantages that limit its use. It has less predictable clearance and protein binding, which create significant dosing and monitoring challenges.[28] As a result, UFH has been associated with bleeding complications and frequent medication errors. In addition, UFH can cause immune-mediated heparin-induced thrombocytopenia (HIT). Standard duration of UFH studied in most trials has been 2-5 days; however, optimal duration of UFH therapy is uncertain and will likely vary according to treatment strategy.
Enoxaparin
The LMWH enoxaparin exhibits a more predictable dose-response relationship compared with UFH, reducing the need for dose adjustments or routine monitoring. In addition, due to a dose-independent clearance and extended half-lives, therapeutic anticoagulation with enoxaparin can be achieved with convenient dosing regimens.[29] The drug is also associated with a lower incidence of HIT than UFH.[29]
Multiple studies have documented the benefits of using adjunctive enoxaparin therapy compared with UFH across the entire spectrum of ACS presentations.[30] A recent meta-analysis that included data on 49,088 ACS patients from 12 randomized trials comparing UFH with enoxaparin found that compared with UFH, the use of enoxaparin reduced the composite endpoint of death, MI, or major bleeding at 30 days in all patients (OR 0.90, P =.051), but also significantly increased the risk for major bleeding (OR 1.25, P =.019).[30] When the findings were grouped by STEMI and NSTEMI trials, investigators found that the rate of the net clinical endpoint was significantly reduced in STEMI patients, but was offset by a significant increase in the rate of major bleeding. By contrast, when limiting the data to the 6 major randomized trials comparing UFH with enoxaparin in NSTEMI patients, there was a modest reduction in death or MI (OR 0.90, P = .043), with only a slight but nonsignificant increase in the rate of major bleeding events (OR 1.13, 95% CI 0.84-1.54, P = .419). Thus, there was no difference in the rate of the net clinical endpoint between the treatment strategies in UA/NSTEMI patients.
The consistent findings from trials evaluating enoxaparin in UA/NSTEMI demonstrate that enoxaparin is an acceptable anticoagulant agent in UA/NSTEMI patients in whom either an invasive or conservative strategy is selected. Careful attention is warranted given the risks of bleeding, however.
Fondaparinux
Fondaparinux is a synthetic pentasaccharide that selectively binds antithrombin and rapidly inhibits factor Xa without interfering with other clotting factors. The drug is administered once daily in a fixed dose (2.5 mg) and does not require monitoring. Currently approved by the United States Food and Drug Administration for the prevention of deep vein thrombosis in orthopaedic surgical procedures and abdominal surgery, fondaparinux has also shown promise in the management of ACS (FDA approval for the indication of ACS is pending, as of February 2008). The Fifth Organization to Assess Strategies in Acute Ischemic Syndrome (OASIS-5) trial,[31] for example, which randomized more than 20,000 UA/NSTEMI patients to either enoxaparin (1 mg/kg twice daily) or fondaparinux (2.5 mg daily), found that the rate of clinical events at Day 9 was similar between the 2 groups; however, at 30 days, the rate of mortality was significantly lower in the fondaparinux treatment group compared with the enoxaparin group (295 vs 352, P = .02), and the difference remained significant at 180 days (574 vs 638, P = .05). Use of the drug was also associated with lower rates of major bleeding complications at Day 9 (2.2% vs 4.1%, respectively; P < .001). However, additional safety data for these patients revealed the presence of excessive catheter clots with the use of fondaparinux compared with enoxaparin. According to the 2007 ACC/AHA guidelines, full-dose UFH (IV 50-60 U/kg bolus) is recommended if the patient receives fondaparinux prior to PCI.[1] In addition, the use of fondaparinux is a preferred anticoagulant strategy in patients at higher risk for bleeding who are managed with a noninvasive strategy.[1]
Bivalirudin
Bivalirudin is a synthetic direct thrombin inhibitor with properties that make it an attractive alternative to heparin. It inhibits thrombin-mediated platelet activation, has a short plasma half-life, and there is no requirement for anticoagulant monitoring.[32]
Previous studies in patients undergoing PCI (for mostly stable angina) have shown that bivalirudin provides a level of protection from ischemic events similar to that afforded by a strategy of UFH + GPI, with a significant reduction in bleeding complications.[33] Similar results were noted in the Acute Catheterization and Urgent Intervention Triage Strategy (ACUITY)[34,35] trial, which assessed the effectiveness of bivalirudin (with or without GPI) vs UFH or LMWH + GPI in 13,819 moderate- to high-risk ACS patients (59% had NSTEMI) undergoing an invasive management strategy. At 30 days, a strategy of bivalirudin + GPI vs UFH or LMWH + GPI was associated with similar rates of the composite ischemia endpoint (7.7% and 7.3%, respectively) and major bleeding (5.3% and 5.7%, respectively). In addition, bivalirudin monotherapy (without GPI) yielded similar rates of the composite ischemic endpoint, but with significantly lower rates of major bleeding complications (3.0% vs 5.7%, respectively; P < .001) compared with patients who were treated with UFH or LMWH + GPI. Long-term (1-year) results of ACUITY remained consistent, with no significant differences in the primary composite endpoint among the 3 groups at 1-year follow-up.[35]
Of note, at 30-day follow-up, subgroup analysis found that bivalirudin was comparable to heparin + GPI in patients who received a thienopyridine before angiography or PCI, but the agent was found to be inferior when used in patients who were not pretreated with thienopyridine therapy.[36] On the basis of the 30-day findings from ACUITY, the guidelines recommend that UA/NSTEMI patients in whom a bivalirudin-based anticoagulant strategy will be used should be treated with concomitant GPI or clopidogrel prior to angiography.[1]
GP IIb/IIIa Inhibitors
GP IIb/IIIa inhibitors have been shown to be effective in reducing the risk for ischemic events in both the medical management phase of treatment (tirofiban and eptifibatide) as well as for patients treated with invasive strategies (abciximab and eptifibatide). According to the ACC/AHA guidelines,[1] the benefits of GPI in UA/NSTEMI are the highest among patients who undergo PCI, with slightly less benefit noted in patients who are not routinely scheduled for revascularization.
A large meta-analysis of trials evaluating GPI in UA/NSTEMI patients not routinely scheduled to undergo revascularization (N = 31,402) found that GPI was associated with a modest overall benefit in reducing the incidence of death or MI by 30 days, with only a modest increase in major bleeding rates.[37] Subgroup analyses found that the benefit of GP IIb/IIIa inhibitors was greatest in higher-risk patients with troponin elevation and NSTEMI, which emphasizes the importance of considering troponin levels to guide therapeutic decisions in UA/NSTEMI.
Multiple trials have demonstrated that early upstream administration (prior to angiography or PCI) of GP IIb/IIIa inhibitors significantly reduces the incidence of events in ACS patients.[38] On the basis of these trials, in the UA/NSTEMI setting, when angiography or PCI is planned within 24 hours, any of the 3 GP IIb/IIIa inhibitors can be started. However, when an early invasive strategy is not planned, either eptifibatide or tirofiban is the preferred agent if upstream use is
undertaken.[39,40]
In troponin-positive and other high-risk UA/NSTEMI patients in whom an invasive strategy is selected, the concomitant use of GP IIb/IIIa inhibitors and clopidogrel is recommended on the basis of the results of the Intracoronary Stenting and Antithrombotic Regimen: Rapid Early Action for Coronary Treatment 2 (ISAR-REACT 2) trial.[41] ISAR-REACT 2 found that in patients pretreated with 600 mg of clopidogrel and 500 mg of aspirin, the addition of abciximab at standard doses resulted in a 25% reduction in the primary endpoint compared with placebo. However, and as noted by other trials and meta-analyses, the benefit was limited to patients with elevated cTn levels. Bleeding rates were similar between the 2 groups.
GP IIb/IIIa inhibitors increase the rate of bleeding complications, especially in patients undergoing PCI. These patients should be monitored closely for signs of bleeding, including hemoglobin and platelet counts. Concomitant therapy with low-dose heparin (as opposed to higher doses of heparin) has been shown to diminish the bleeding risk associated with GPI in patients undergoing PCI (with and without stenting) and may reduce the risk for bleeding during the medical phase of management.[1] Therefore, the guidelines endorse concomitant use of weight-adjusted heparin with GP IIb/IIIa inhibitors.
Bleeding Risks With Excess Dosing
The risks of bleeding associated with these agents warrant careful consideration when selecting specific antiplatelet/anticoagulant regimens, especially since major bleeding is an independent predictor of death. The Can Rapid Risk Stratification of Unstable Angina Patients Suppress Adverse Outcomes With Early Implementation of the ACC/AHA Guidelines (CRUSADE) registry[42] containing data on the bleeding risk for antithrombotic agents from 30,000 patient admissions found that excessive antithrombotic dosing occurs relatively frequently, including among 33% of patients who received UFH, 14% of patients who received an LMWH, 26.8% of patients who received a GP IIb/IIIa inhibitor, and 42% of patients who received a heparin (UFH or LMWH) and a GP IIb/IIIa inhibitor. Furthermore, investigators attributed this excess antithrombotic dosing to approximately 15% of major bleeding events reported.
Research remains ongoing to identify optimal dosing strategies and combination therapies to maximize clinical benefit, especially in high-risk patients. The likely emergence of novel antiplatelet and anticoagulant agents shows initial promise in overcoming dosing and bleeding concerns associated with currently available antithrombotic regimens.
Discharge Therapies
After receiving initial care in the hospital, most patients with UA/NSTEMI but no complications can be discharged on the day after PCI or 4 to 7 days after CABG. Low-risk patients who are treated conservatively can be discharged soon after noninvasive testing.[1]
Nitrates should be continued after hospital discharge to control symptoms in patients with UA/NSTEMI who do not undergo coronary revascularization, patients with unsuccessful revascularization, and patients with recurrent symptoms after revascularization.
Among other anti-ischemic medications, beta-blockers are recommended for use in most patients (ie, without contraindications such as second- or third-degree atrioventricular block). ACE inhibitors should be given and continued indefinitely for higher-risk patients, such as those with left ventricular dysfunction, hypertension, or diabetes.
According to the ACC/AHA guidelines, in patients treated medically without stenting aspirin (75-162 mg/day) should be prescribed indefinitely and clopidogrel should be prescribed for at least 1 month, but ideally for up to 1 year. Patients treated with bare-metal stents require aspirin (162-325 mg/day) for at least 1 month, continued indefinitely at a dose of 75-162 mg/day; clopidogrel (75 mg/day) should be prescribed for a minimum of 1 month and ideally for up to 1 year. Patients treated with drug-eluting stents should be prescribed aspirin (162-325 mg/day) for at least 3 months after sirolimus-eluting stent implantation and 6 months after paclitaxel-eluting stent implantation, continued indefinitely at a dose of 75-162 mg/day.[1] All post-PCI patients receiving drug-eluting stents should also take clopidogrel 75 mg/day for at least 1 year (Figure 3).[1]
Figure 3. ACC/AHA 2007 Guidelines: long-term antithrombotic therapy at hospital discharge after UA/NSTEMI.
Beta-blockers are indicated for all patients recovering from UA/NSTEMI unless contraindicated.[1] If not initiated acutely, treatment should begin within a few days of the event and be continued indefinitely.
In addition to emphasizing the importance of remaining compliant with medical therapy, ACS patients also should be counseled on the importance of risk factor modification, with particular focus on smoking cessation programs, weight loss, exercise, and proper diet. Importantly, they should also be informed of the signs and symptoms of other ACS events and the urgency of seeking immediate care.
This activity is supported by an independent educational grant from Eli Lilly and Daiichi Sankyo.
References
