A 43-Year-Old Man With Angina, Elevated Troponin, and Lateral ST Depression
Management of Acute Coronary Syndromes
- Duane S. Pinto, MD, MPH, Discussant
- Author Affiliations: Dr Pinto is Assistant Professor of Medicine, Harvard Medical School, and Director, Cardiology Fellowship Training Program, and Associate Director, Cardiac Catheterization Laboratory, Beth Israel Deaconess Medical Center, Boston, Massachusetts.
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Corresponding Author: Duane S. Pinto, MD, MPH, Beth Israel Deaconess Medical Center, Interventional Cardiology Section, 1 Deaconess Rd, Baker 4, Boston, MA 02215 (dpinto@bidmc.harvard.edu).
Abstract
Each year, approximately 2 million people in the United States experience acute coronary syndromes related to thrombosis and ulceration of atherosclerotic plaque within a coronary artery. The case of Mr C, a 43-year-old man with non–ST-segment elevation myocardial infarction, which is most often caused by subtotal thrombosis, illustrates the complex decision-making process involved in selecting treatment for each patient and in determining whether invasive procedures are warranted. Cardiac catheterization is performed in moderate- and high-risk individuals to define the extent of disease so the proper strategy—medications alone, percutaneous revascularization, or coronary artery bypass graft surgery—can be selected. Medications to disrupt platelet function as well as the coagulation system are used. Treatments are designed to minimize the extent of infarction and prevent reinfarction, thereby improving outcomes. The timing of cardiac catheterization, for whom catheterization is indicated, and the rationale for medication treatment are discussed.
- KEYWORDS:
- ACUTE CORONARY SYNDROME
- ANGINA PECTORIS
- ANGIOGRAPHY
- CARDIOVASCULAR DISEASES
- CONGENITAL ABNORMALITIES
- CORONARY INTERVENTION, PERCUTANEOUS
- DIAGNOSIS
- DRUG THERAPY
- ELECTROCARDIOGRAPHY
- HEART DEFECTS, CONGENITAL
- HEART SEPTAL DEFECTS, VENTRICULAR
- MYOCARDIAL INFARCTION
- NAUSEA
- TROPONIN
DR SHIP: Mr C is a 43-year-old man who was transferred to the emergency department for exertional nausea and lateral ST-segment depressions on electrocardiogram (ECG). He has health maintenance organization insurance.
Mr C's symptoms began 5 days prior to admission, when he noticed significant nausea and chest tightness after running on his treadmill for about 10 minutes. He jogged regularly 30 minutes a day approximately 4 times a week. Symptoms resolved when he stopped running but recurred when he resumed exercise. He had no shortness of breath or chest pain. He did not exercise for the intervening few days and was seen at his internist's office 4 days later. He was asymptomatic at the time of the visit, but his ECG showed new lateral ST-segment depressions and T-wave inversions. He was transferred to the emergency department.
Mr C's medical history is significant for a congenital ventricular septal defect (VSD) managed with serial echocardiography and endocarditis prophylaxis, hypertension, anxiety, and depression. At baseline, his blood pressure was well controlled. His lipid levels 8 months before admission were as follows: total cholesterol, 120 mg/dL; high-density lipoprotein cholesterol (HDL-C), 40 mg/dL; low-density lipoprotein cholesterol (LDL-C) (calculated), 70 mg/dL; total cholesterol/HDL-C ratio, 3.0; and triglycerides, 50 mg/dL. (To convert total cholesterol, HDL-C, and LDL-C to millimoles per liter, multiply by 0.0259. To convert triglycerides to millimoles per liter, multiply by 0.0113.) Mr C exercised regularly, using a treadmill at least 3 times a week for about an hour. His family history includes myocardial infarction in his mother at age 62 years; his father had no premature heart disease. His medications include quinapril, 30 mg/d; desipramine, 25 mg/d; and citalopram, 20 mg/d. He does not use tobacco. A divorced professional, he lives alone.
In the emergency department, his temperature was 98.1°F (36.8°C), pulse was 72/min, blood pressure was 144/98 mm Hg, and respiratory rate was 16/min. His weight was 75 kg and height was 168 cm, giving him a body mass index of 26.6 (calculated as weight in kilograms divided by height in meters squared). His physical examination did not reveal abnormalities. His fasting glucose was 89 mg/dL (to convert to millimoles per liter, multiply by 0.055).
Mr C was free of chest pain. His electrocardiogram (Figure 1) showed lateral ST depressions and T-wave inversions, with ST elevation in V1-V3 that had been evident on prior tracings. His creatine kinase measurements were normal, but his troponin T was elevated at 0.39 ng/mL (upper limit of normal, 0.10 ng/mL). In the emergency department, he was treated with aspirin, metoprolol, clopidogrel, eptifibatide, unfractionated heparin, and atorvastatin. He was referred for coronary angiography.
Electrocardiogram (ECG) demonstrates new ST-segment depression and T-wave abnormalities in the lateral leads with ST elevation in leads V1-V3 that was present on prior ECGs.
Angiography revealed origin and proximal disease of the left anterior descending artery involving a large, bifurcating diagonal branch (Figure 2A). There was diffuse disease in the mid portion followed by long segment occlusion with collateral filling of the distal vessel (Figure 2B). The right coronary artery had severe stenosis in the mid portion (Figure 2C). (See a video of Mr C's angiography.) No percutaneous intervention was performed, and he was admitted for coronary artery bypass graft (CABG) surgery. The following day, his lipid results were as follows: total cholesterol, 211 mg/dL; HDL-C, 34 mg/dL; LDL-C (calculated), 137 mg/dL; total cholesterol/HDL ratio, 6.2; and triglycerides, 199 mg/dL.
The figure shows disease at the origin of the left anterior descending artery (LAD) and proximal disease in a large diagonal branch (A) followed by occlusion, diffuse disease, and reconstitution in the distal LAD via collaterals (B) and severe stenosis involving the right coronary artery (arrowhead) (C). LAO indicates left anterior oblique. See the video of the angiography.
MR C: HIS VIEW
I have a VSD that has been followed throughout my life. I’ve had it since birth. That's why I have a cardiologist who I meet with at least once a year.
It was my second or third run of the week. I was about a mile into it, and then I started experiencing nausea, and sort of a burning sensation and tightness in the throat. I had been experiencing something like this for the last 2 or 3 weeks, so I just thought it was acid reflux. I took a break, got some water, and then got back on the treadmill. I was fine for about another 10 to 15 minutes and then experienced the nausea again with burning in the chest; however, it was not as bad as the first episode. I got off the treadmill.
I just didn't think that this was something to be concerned about. I thought in the back of my mind, “Well, maybe this is a symptom of a heart attack,” but I didn't have the other classic symptoms that I had heard about. I had no shooting pain, no numbness in the hand, and no light-headedness.
I decided to call my primary care physician. At the office, my doctor did an EKG. He saw that there was a wave in the EKG that was not where it should be. He called my cardiologist, and the next thing I knew, he said, “We want to send you to the emergency room.”
I think there were 6 types of tests that they had to run. Well, 5 of the results came back and were normal. Then the troponin came back and suddenly there was a whirl of activity. There was a catheterization team, and they were explaining to me the risk with catheterization and asking me to sign consent forms. At that point, I didn't have anybody in the emergency department with me. I had the feeling I was just being bombarded. I live by myself. I’m divorced. So that was very stressful and overwhelming.
They were thinking that just 1 vessel was blocked. So they were going to do a stent, or maybe angioplasty. But as it turns out, they found more than 1 vessel.
What was very helpful was that the attending physician, my cardiologist, stopped by. He explained to me what I needed to know. It was extremely helpful. He said, “You have all the reason in the world to be optimistic. You're young. There hasn't been significant damage to the heart. We want to prevent you from having some serious damage in the heart, so I think we should do the catheterization.”
AT THE CROSSROADS: QUESTIONS FOR DR PINTO
How should an acute coronary syndrome/non–ST-segment elevation myocardial infarction (ACS/NSTEMI) be diagnosed and evaluated? How should patients be risk stratified? What is the evidence that medical treatment can improve outcomes in ACS/NSTEMI? How should patients be selected for coronary angiography and in what time frame? What is the evidence that revascularization can improve outcomes? What do you recommend for Mr C?
DR PINTO: Mr C is a 43-year-old man with a history of congenital VSD, a family history of premature coronary disease, and hypertension who developed exertional chest pain that has increased in frequency and intensity. He has evidence of an ACS with abnormal cardiac biomarkers and ST-segment depression on 12-lead ECG.
ACS Pathophysiology
An ACS most frequently is caused by atherosclerotic plaque rupture exposing thrombogenic subendothelial components, leading to platelet deposition and activation.1 Platelets are activated expressing larger numbers of glycoprotein (GP) IIb/IIIa receptors available to bind fibrin strands and stimulate platelet cross-linking. In addition, activated platelets release local mediators that can induce further platelet accumulation and activation, vasoconstriction, thrombosis, and mitogenesis. These platelet-rich thrombi lead to distal embolization and plugging of the microcirculation, which have been associated with poor outcomes.2,3 Given Mr C's known VSD, paradoxical embolism should be considered as an etiology of ACS, and systemic embolization should be considered in any patient, but the lack of symptoms or findings on physical examination suggestive of infection or deep venous thrombosis make endocarditis or deep venous thrombosis unlikely causes of the current illness. Mr C's accelerating tempo and intensity of chest pain culminating in symptoms with minimal exertion are also not typical for these etiologies of ACS, in which there is often abrupt onset of severe chest pain at rest. The presence of the VSD does not affect Ms C's initial management.
Management of UA/NSTEMI
Therapy for unstable angina (UA) and NSTEMI is administered to relieve ischemia and avoid death, minimize the extent of infarction, and prevent reinfarction; it is tailored to a patient's risk of complications. Cardiac catheterization, revascularization, and aggressive medical therapy are used to avoid or reduce the sequelae of atherothrombosis.4
Risk Stratification and Early Invasive Management
Risk stratification directs decisions regarding the aggressiveness of invasive workup and medical therapy, balancing a patient's risk of ischemic events such as death or MI with the risk of bleeding and procedural complications.
Characteristics that place a patient at high risk for ischemic complications during UA/NSTEMI include age greater than 75 years; prolonged (>20 minutes) ongoing or accelerating anginal symptoms during the preceding 48 hours; signs of congestive heart failure, a new or worsening mitral regurgitation murmur, tachycardia, bradycardia, or hypotension; the presence of transient ST-segment deviation greater than 0.5 mm with angina at rest; new or presumed new bundle branch block on 12-lead ECG; sustained ventricular tachycardia; and presence of elevated cardiac biomarkers (eg, creatine kinase–MB, troponin).4 A patient with 1 of these features is at high risk of death or MI during UA/NSTEMI according to the American College of Cardiology/American Heart Association (ACC/AHA) guidelines.4 Troponin is the preferred biomarker and elevation above the 99th percentile of a normal reference population is considered significant5; Mr C's abnormal troponin level of 0.39 ng/mL indicates increased risk of ischemic complications.4,6
Among those without high-risk features, factors indicating intermediate risk include a history of vascular disease (eg, prior MI, CABG surgery, peripheral arterial disease), rest angina (>20 minutes or relieved with nitroglycerine or rest) that is resolved, nocturnal angina, progression in severity of angina over the prior 2 weeks, T-wave changes, pathologic Q waves, or resting ST-segment depression (<1 mm) in multiple lead groups (anterior, inferior, lateral) on ECG or slight elevation in cardiac biomarkers (eg, troponin T >0.01 ng/mL but <0.1 ng/mL).4
Using factors individually from a list of predictors to assess risk, however, is limited because any single factor lacks sensitivity despite high specificity,7 and a more accurate quantification of risk requires multivariable analysis to simultaneously adjust for the interaction of several prognostic variables, some or all of which may be present in a given patient.4 To refine assessment of a patient's risk for ischemic complications, the TIMI risk score for UA/NSTEMI8 and Global Registry of Acute Coronary Events (GRACE) prediction score6 have been widely used. The predictive factors as well as Web-based calculators are available at http://www.timi.org/ and http://www.outcomes-umassmed.org/grace. These models provide good discriminatory capacity (C statistic, 0.65 for TIMI risk score and 0.83 for GRACE),6,8 and have been validated in both clinical trials and other ACS populations.4,8,9,10
The TIMI and GRACE prediction scores are based on models that simultaneously account for some of the aforementioned high-risk features as well as other factors such as previous aspirin use, history of coronary artery disease, and risk factors for coronary artery disease to form a more quantifiable assessment of risk. The TIMI risk score uses 7 (1-point) risk indicators rated on presentation. As the TIMI risk score increases, ischemic risk increases and patients can be divided into categories of risk: low (0-2), intermediate (3-4), and high (5-7).
Using these risk models, Mr C's prognosis can be estimated more accurately. For example, Mr C's TIMI risk score was 3, which is associated with a rate of death or MI at 14 days of 5%, while the estimated rates of death or MI at 14 days with TRS of 0 to 2, 4, 5, and 6/7 are 3%, 7%, 12%, and 19%, respectively.8 Similarly, the GRACE model would predict a rate of death or MI of 13% in the hospital and 18% at 6 months for Mr C.
Without troponin elevation, the GRACE model would predict that Mr C would have a risk of in-hospital death or MI of 7%, and this increases to 13% based simply on the elevated troponin. The ACC/AHA Guidelines for the Management of UA/STEMI select intermediate-risk and high-risk individuals for aggressive anticoagulation, antiplatelet medications, and invasive therapy since these patients have a relatively greater benefit compared with low-risk patients in clinical trials.11,12,13,14,15 Guideline-based management (ie, targeting therapy to individuals at elevated risk), though imperfect when applied to all patients in all scenarios, has been associated with improved outcomes in MI.16 Although Mr C can be considered at low risk in terms of clinical features and history, his significant ST-segment deviation and biomarker elevation during UA/NSTEMI places him at increased risk.17
While helpful in the context of UA/NSTEMI, biomarker testing may also be misleading outside of the UA/NSTEMI clinical scenario. Circulating troponin reflects myocardial cell death from any cause, so not all troponin elevations stem from plaque ulceration and thrombosis, particularly among patients with severe noncardiac illness.18 Furthermore, risk models are imperfect. Individuals assessed as being at low risk by the GRACE score have been shown to develop recurrent ischemia as frequently as those with high scores.19 Management decisions are affected by the fact that the risk factors for ischemic complications during UA/NSTEMI, such as female sex, congestive heart failure, diabetes, and renal insufficiency, also are risk factors for complications, such as bleeding, stemming from the treatment of ACS.8,20 For example, the odds ratio (OR) for bleeding is 1.33 (95% confidence interval [CI], 1.15-1.50) for female patients, 1.13 (95% CI, 1.01-1.28) for those with CHF, 1.25 (95% CI, 1.12-1.40) for those with diabetes, and 1.11 (95% CI, 1.09-1.13) per 10 mL/min decrease in creatinine clearance.21
Early Invasive Therapy for High-Risk Individuals With UA/NSTEMI
The ACC/AHA guidelines for UA/NSTEMI4 suggest that patients with the high-risk features described above or recurrent angina or ischemia at rest with low-level activities despite intensive medical therapy, hemodynamic instability, PCI within 6 months, prior CABG surgery, left ventricular ejection fraction less than 40%, or high-risk TIMI or GRACE scores be selected for an invasive strategy. This recommendation is based on the weight of available evidence (Table 1)4 suggesting that for patients with UA/NSTEMI who are at increased risk of ischemic complications, a routine, early invasive strategy of cardiac catheterization results in fewer ischemic complications and is preferable to a selectively invasive strategy unless, because of factors such as acute renal failure, ongoing bleeding or stroke, severe peripheral vascular compromise, or thrombocytopenia or clotting abnormality, there is a high risk of procedural complications.30
Table 1. Selected Trials Evaluating Early Invasive vs Conservative Therapy Among Moderate- and High-Risk Patients With Unstable Angina/Non–ST-Segment MIa
Based on meta-analyses of contemporary randomized trials in NSTEMI, a routine invasive strategy, defined as referral of all patients with unstable angina or NSTEMI for coronary angiography followed by revascularization in those with suitable coronary anatomy, has a long-term mortality and morbidity benefit compared with an initially conservative, selectively invasive strategy, in which catheterization is reserved only for patients with recurrent symptoms or objective evidence of inducible ischemia.15,31 A routine invasive strategy was associated with reductions in nonfatal MI at 2 years (7.6% vs 9.1%, respectively; risk ratio, 0.83; 95% CI, 0.72-0.96; P = .01; number needed to treat [NNT], 67) and hospitalization at 13 months (risk ratio, 0.69; 95% CI, 0.65-0.74; P < .001).31 However, benefit was related to patient risk: those with elevated cardiac biomarkers experienced significant benefit (OR, 0.82; 95% CI, 0.70-0.96; P = .01), whereas those with normal biomarker levels did not (OR, 0.90; 95% CI, 0.72-1.14; P = .40).15 In the TIMACS study, significant benefit was found in patients defined as high-risk by the GRACE score but no benefit was found in non–high-risk patients28 (Table 1).
The magnitude of clinical benefit seen in randomized studies correlates with the difference in time to catheterization between the early invasive group and the delayed group. The ISAR-COOL24 study reported an absolute risk reduction in clinical outcomes (Table 1) of 5.7% (NNT, 18) with a difference of 83 hours between the groups. The absolute risk reduction decreased to 1.7% (NNT, 59) with a difference of 36 hours among high-risk (defined by GRACE score) patients from TIMACS.28 An extremely small difference—19 hours (means of 70 minutes vs 21 hours)—in the ABOARD study translated into no significant difference in clinical or biochemical end points.29 One trial, ICTUS, demonstrated no benefit with a routine invasive strategy, perhaps because of the high rate of revascularization (47%) in the selectively invasive group, the definition of MI, duration of follow-up, or smaller sample size (n = 1200).27 Thus, it is reasonable to perform urgent but not emergent angiography in high-risk individuals, while those at lower risk can be managed with either early or delayed angiography.
Although a routine invasive strategy is suggested in patients at elevated ischemic risk, certain subgroups at increased ischemic risk, such as elderly patients and those with diabetes, renal insufficiency, or heart failure, undergo catheterization and revascularization less frequently compared with those at lower clinical risk.32,33,34,35 There are various potential explanations for this apparent paradox. Certainly, the decision to perform cardiac catheterization in high-risk patients to avoid ischemic complications must be carefully balanced against their increased risk of procedural complications.34
Mr C did express feeling overwhelmed with the flurry of testing and activity associated with his care once his troponin levels were found to be elevated. The paradigm of early intervention has created an urgency to initiate cardiac catheterization, but as seen from the study results, the urgency is a matter of hours, not minutes. In Mr C's case, having time to call family members about the proposed catheterization and possibly having someone present for support and guidance could have helped him feel more prepared for the procedure. If a patient is likely to need an invasive procedure, recognizing the anxiety this provokes and explaining the relative merits of urgent catheterization may be helpful to patients and their families.
Medications for UA/NSTEMI
Medical therapy is complementary to catheter-based invasive therapy in NSTEMI. Medications are administered to alleviate symptoms and to arrest thrombus progression, thereby avoiding distal embolization and recurrent infarction. Anti-ischemic, antiplatelet, and anticoagulant agents are used. Aspirin should be administered immediately as well as anti-ischemic medications if symptoms are present. Anticoagulants should be administered as soon as possible when the diagnosis of ACS is confirmed, and additional antiplatelet medications are selected based on patient risk of complications (eg, bleeding) as well as whether the anticipated management strategy is invasive or conservative.4
Anti-ischemic Therapies. No large randomized trials have been conducted evaluating the effect of nitroglycerine and morphine on patient outcomes in ACS, but extensive clinical experience, the practical need to alleviate pain, and application of pathophysiologic principles are the reasoning for their widespread use during UA/NSTEMI.4 Nitroglycerin reduces myocardial oxygen demand by increasing venous capacitance and reducing myocardial preload. Coronary vasodilation and redistribution of blood flow to ischemic regions improves myocardial oxygen delivery. Morphine is administered for pain relief and has beneficial anxiolytic effects as well as hemodynamic effects. As with nitroglycerine, venodilation occurs with administration, reducing myocardial oxygen demand. Adverse effects include urticaria, nausea, and vomiting. Hypotension and respiratory depression can occur with excessive doses.4 If Mr C were hypertensive or describing ongoing ischemic symptoms, administration of these agents should be considered.
β-Blockers are administered to inhibit catecholamine effects on the myocardium, reducing heart rate, myocardial contractility, and blood pressure to reduce oxygen demand and improve coronary blood flow. Most trials evaluating the use of β-blockers in UA/NSTEMI have lacked sufficient power to detect effects on mortality and were conducted prior to widespread use of accepted antiplatelet and anticoagulant therapies for UA/NSTEMI. However, pooled results from 5 studies of efficacy of β-blocker therapy in patients with ACS who were undergoing percutaneous coronary intervention (PCI) (EPIC, EPILOG, EPISTENT, CAPTURE, and RAPPORT studies36) showed that at 30 days, mortality was significantly reduced among patients who received β-blocker therapy vs those who did not (0.6% vs 2.0%; P < .001; NNT, 71). At 6 months, death occurred in 1.7% of patients receiving β-blocker therapy vs 3.7% not receiving this therapy (P < .001; NNT, 50).36
The ACC/AHA Guidelines for the Management of UA/NSTEMI recommend that β-blockers be initiated orally, in the absence of contraindications, within the first 24 hours.4 Greater caution is now suggested in the early use of intravenous β-blockade, which should be targeted to specific indications and should be avoided with heart failure, hypotension, or hemodynamic instability.4
Antiplatelet Medications. Numerous trials consistently demonstrate the benefits of the antiplatelet effects of aspirin in patients with ACS37,38,39,40,41,42 (Table 2); thus, it is the foundation of medical management during UA/NSTEMI.
Table 2. Antiplatelet Therapies in Unstable Angina/Non–ST-Segment MI
Thienopyridine agents complement aspirin's antiplatelet effects by blocking the adenosine diphosphate receptor P2Y12 on the platelet surface, thereby inhibiting platelet activation. Three such agents, clopidogrel, ticlopidine, and prasugrel, are approved by the US Food and Drug Administration. Use of clopidogrel is based primarily on results of the CURE trial,43 which compared the benefit of aspirin plus clopidogrel (300 mg loading dose, then 75 mg/d) vs aspirin alone in 12 562 patients with UA/NSTEMI. Patients receiving clopidogrel plus aspirin were less likely to experience cardiovascular death, recurrent MI, or stroke than those receiving aspirin alone (9.3% vs 11.5%; relative risk, 0.80; 95% CI, 0.72-0.90; P < .001; NNT, 45). The primary end point of death, nonfatal MI, stroke, or refractory or severe ischemia was significantly lower in the combined group within 24 hours of randomization and remained so at 1-year follow-up (16.5% vs 18.8%; relative risk, 0.86; 95% CI, 0.79-0.94; P < .001; NNT, 43). Each component of the composite outcome also tended to be less frequent in the clopidogrel group.43 Bleeding events were more frequent among patients receiving clopidogrel within 5 days of CABG surgery (9.6% vs 6.3%; P = .06; number needed to harm [NNH], 30).43,48
Although not a UA/NSTEMI trial, subgroup analysis from the CREDO study offers data supporting pretreatment with clopidogrel prior to PCI. A 300-mg loading dose of clopidogrel compared with placebo administered at least 15 hours before PCI was associated with a reduction in the primary end point of death, MI, or urgent revascularization (9.7% vs 3.5%; P = .01; NNT, 17).49 However, since patients in the placebo group of CREDO did not receive a clopidogrel loading dose after PCI, it really is a comparison of upstream administration of a loading dose before PCI vs no loading dose. Nevertheless, guidelines suggest administration prior to diagnostic angiography.4 It may be prudent to administer clopidogrel if diagnostic angiography will be delayed (>24 hours) and to withhold treatment until the need for CABG is ascertained if angiography will be performed within 24 hours of admission.4 It has been postulated that administration of higher loading doses (600 mg, 900 mg) of clopidogrel by achieving more rapid inhibition of platelet aggregation and a higher absolute level of inhibition of platelet aggregation would be associated with improved clinical outcomes.50,51,52 This issue was assessed in the CURRENT OASIS-7 study, which used a 2×2 factorial design to compare a doubled loading dose (600 mg) and larger maintenance dose (150 mg) of clopidogrel given for 7 days with standard-dose clopidogrel (300-mg loading dose followed by 75 mg), plus daily high-dose (300-325 mg) aspirin vs low-dose (75-100 mg) aspirin. In the overall cohort of 25 087 patients, the composite end point of cardiovascular death, MI, and stroke did not differ at 30 days (4.4% standard dose vs 4.2% double dose; hazard ratio [HR], 0.95; 95% CI, 0.84-1.07; P = .37) but in the cohort of 17 232 patients undergoing PCI, those treated with higher-dose clopidogrel had lower rates of the composite end point (3.9% vs 4.5%; HR, 0.85; 95% CI, 0.74-0.99; P = .04; NNT, 167) as well as lower rates of definite stent thrombosis at 30 days (0.7% vs 1.2%; HR, 0.58; 95% CI, 0.42-0.79; P = .001; NNT, 200). The increased dose was associated with an increased risk of protocol-defined major bleeding by 30 days (1.6% vs 1.1%; HR, 1.44; 95% CI, 1.11-1.86; P = .006; NNH, 200). Patients treated conservatively without PCI had no benefit from higher-dose clopidogrel. Efficacy and bleeding did not differ between daily doses of aspirin, 300 to 325 mg, and aspirin, 75 to 100 mg.52
Prasugrel was evaluated in the TRITON–TIMI 38 study, in which 13 608 patients with ACS undergoing PCI were randomized to receive prasugrel or clopidogrel. Although prasugrel therapy was associated with reduced rates of ischemic events (death from cardiovascular causes, nonfatal MI, or nonfatal stroke) at 15 months (12.1% vs 9.9%; HR, 0.81; 95% CI, 0.73-0.90; P < .001; NNT, 45) and stent thrombosis (2.4% vs 1.1%; P < .001; NNT, 77), this benefit came at a cost of more major bleeding events (2.4% vs 1.8%; HR, 1.32; 95% CI, 1.03-1.68; P = .03; NNH, 167).45 Prasugrel is contraindicated in patients with a history of transient ischemic attack or stroke. Caution is recommended among those who are aged 75 years or older, those who weigh less than 60 kg, and those taking other medications that increase the risk of bleeding (eg, warfarin, heparin, fibrinolytic therapy, long-term use of nonsteroidal anti-inflammatory medications). It should be avoided among patients likely to undergo CABG surgery.
Ticagrelor is a nonthienopyridine, reversible P2Y12 receptor antagonist that was evaluated in the recently reported PLATO study.44 Compared with clopidogrel, ticagrelor was associated with reductions in the primary end point of death due to vascular causes, MI, and stroke at 12 months (9.8% vs 11.7%; HR, 0.84; 95% CI, 0.77-0.92; P < .001; NNT, 53) and ischemic events, but at a cost of major bleeding unrelated to CABG surgery (4.5% vs 3.8%; P = .03; NNH, 143).44
Mr C was treated with clopidogrel during his hospitalization. Clopidogrel and ticlopidine were the only approved agents in this class at the time. Whether newer agents such as prasugrel or ticagrelor will be preferred for patients like him and whether increased loading and maintenance doses for clopidogrel would nullify the observed benefits of newer agents are currently matters of significant debate. Another class of agents, GP IIb/IIIa receptor inhibitors (GPIs), is used in high-risk ACS patients to inhibit platelet aggregation, based on several large, randomized clinical trials.4,53 The benefit from GPIs appears to be primarily among troponin-positive patients and those undergoing revascularization.4,54,55 Troponin-negative and low-risk patients, particularly women, experience less benefit and, therefore, are not recommended to receive a GPI even if an invasive or selective invasive strategy is selected.4,46,56
Although current guidelines suggest administration prior to angiography,4 the optimal timing of GPI administration is controversial, and greater attention has focused on the complications stemming from pharmacologic agents and from procedures during ACS.57 A meta-analysis of GPIs in 6 large trials involving 31 402 patients with UA/NSTEMI46 suggested an early benefit of GPIs during medical treatment in patients with ACS for the combined end point of death or MI at 30 days (10.8% vs 11.8%; OR, 0.91; 95% CI, 0.84-0.98; P = .02; NNT, 100). Major bleeding at 30 days was increased (2.4 vs 1.4%; P < .001; NNH, 100) (Table 2). Two randomized trials, however, have questioned the necessity of administering GPIs prior to angiography.58,59 Increased rates of bleeding and no significant reduction in ischemic events were found with administration of GPIs prior to angiography in these studies, so it may be reasonable administer GPIs only to patients selected for PCI after angiography is performed.
Anticoagulation. Anticoagulant therapy forms a basic element of UA/NSTEMI therapy in addition to aspirin and other antiplatelet agents, yet choosing an anticoagulant regimen has become increasingly complicated with the proliferation of available agents (Table 3). One must tailor the anticoagulant strategy to match the range of patient circumstance and consider efficacy, bleeding risk, cost-effectiveness, local experience, and anticipated need for revascularization, as well as specific pharmacodynamic advantages and disadvantages of the various agents.
Table 3. Anticoagulant Therapies in Unstable Angina/Non–ST-Segment MI
Unfractionated heparin has served as the standard against which newer agents are compared. A meta-analysis of 6 UA trials demonstrated reduced risk of death or MI at 2 to 12 weeks among patients treated with both unfractionated heparin and aspirin compared with aspirin alone (7.9% vs 10.4%; relative risk, 0.67; 95% CI, 0.44-1.02; P = .06).60 When combined with aspirin, the main benefit of unfractionated heparin was a reduction in recurrent MI. Unfractionated heparin has several important limitations, including a risk of rebound ischemia when the drug is stopped prematurely.67,68 Other disadvantages of unfractionated heparin include poor bioavailability, platelet activation, and the occurrence of autoimmune heparin-induced thrombocytopenia.
Low-molecular-weight (LMW) heparins are derived from heparin by chemical or enzymatic depolymerization to yield fragments approximately one-third the size of heparin. The LMW heparins inhibit factor Xa to a greater degree than factor IIa, with ratios ranging between 2:1 and 4:1.69 Randomized trials have compared LMW heparins with unfractionated heparin with mixed results, likely due to differences in patient population, trial design, and medication protocols. Pooled data suggest some benefit in the combined end point of death or reinfarction, primarily due to reductions in reinfarction (10.1% vs 11.0%; OR, 0.91; 95% CI, 0.83-0.99; NNT, 111).63 The SYNERGY trial evaluated enoxaparin vs unfractionated heparin in patients receiving intravenous GPIs and found that enoxaparin was not superior to unfractionated heparin but was noninferior for the treatment of high-risk patients with NSTEMI. There was an increased rate of bleeding with enoxaparin, especially if anticoagulants were switched from one agent to another.64 While more expensive and no more effective than unfractionated heparin, LMW heparins may be used for some patients because of the adverse effects of unfractionated heparin noted herein. However, LMW heparins are not recommended if CABG surgery will be performed within 24 hours of administration because of the risk of bleeding and difficulty in measuring the adequacy of anticoagulation while the patient is on cardiopulmonary bypass.
Bivalirudin, a synthetic analog of hirudin, was investigated in more than 13 000 patients with UA/NSTEMI in the ACUITY trial.65 When used with a GPI, bivalirudin was shown to be noninferior to heparin and GPI with respect to a 30-day net clinical outcome of composite ischemia and/or major bleeding (11.8% vs 11.7%; P = .93), with no significant difference in major bleeding (5.3% vs 5.7%; P = .38). When used alone, bivalirudin was noninferior to heparin with a GPI in avoiding ischemic outcomes (7.8% for bivalirudin vs 7.3% for heparin plus a GPI; P = .32) but was superior to heparin plus a GPI with respect to the rate of major bleeding (3.0% vs 5.7%; P < .001; NNT, 37).65 An economic analysis from ACUITY demonstrated cost savings with bivalirudin, mainly attributable to avoidance of bleeding complications.70
Synthetic pentasaccharides such as fondaparinux act proximally in the coagulation cascade by binding to antithrombin and provide very specific inhibition of factor Xa. The OASIS-5 trial evaluated the safety and efficacy of fondaparinux in 20 078 patients with UA/NSTEMI.66 Following standard treatment with aspirin, clopidogrel, and GPIs (according to local practice), patients were randomized to receive either once-daily fondaparinux or twice-daily enoxaparin. Fondaparinux and enoxaparin had similar rates of the primary composite end point of death, MI, or refractory ischemia at 9 days (5.8% vs 5.7%; P value reported as nonsignificant). However, the fondaparinux group had a 47% lower rate of major bleeding (2.2% vs 4.1%; P < .001; NNT, 53), and at 180 days, fondaparinux was associated with lower rates of death (5.8% vs 6.5%; P = .05; NNT, 142) and the combined end point of death, MI, and stroke (11.3% vs 12.5%; P = .007; NNT, 83).66 These favorable results for fondaparinux were tempered by an excess of catheter-associated thrombus in patients undergoing PCI. Fondaparinux is reasonable to consider in patients not managed with an early invasive strategy, especially if they are at high risk of bleeding. The use of supplemental unfractionated heparin at the time of PCI has been proposed to prevent catheter thrombus, but this may abrogate the beneficial effects of fondaparinux with regard to bleeding. Studies of this approach are ongoing.
Revascularization Decisions in UA/NSTEMI
After patients with intermediate- or high-risk UA/NSTEMI undergo coronary angiography, the cardiologist in consultation with the patient determines whether to perform revascularization with PCI, refer the patient for CABG surgery, or continue medical therapy. This decision is guided by numerous factors including angiographic burden of disease and patient characteristics predicting outcomes during and after revascularization procedures. In general, those with more diffuse disease who are surgical candidates are better suited to CABG surgery, while those with more discrete lesions are better served with PCI, assuming it can be performed. Appropriateness criteria for PCI have been published.4,71 In Mr C's case, while both PCI and CABG would be acceptable strategies, the diffuse nature of his disease involving almost the entirety of the left anterior descending artery and its major branch, coupled with severe disease in other vessels in a young patient with a large amount of myocardium at risk, suggests that CABG surgery, as recommended by the clinicians caring for Mr C, may be preferable over PCI. A detailed discussion of the relative merits of PCI vs CABG surgery in other circumstances is beyond the scope of this report.
RECOMMENDATIONS FOR MR C
In Mr C's case, he was treated with unfractionated heparin, aspirin, clopidogrel, and a GPI. To reduce Mr C's risk of ischemic complications, I would select him for an early invasive strategy. In most cases, PCI can be performed safely, and unless there is an indication for CABG surgery, I pursue this as an initial revascularization strategy. In Mr C's case, however, the location and severity of disease warranted consideration of CABG surgery, the management strategy that was ultimately selected. Of course, Mr C requires the standard interventions for secondary prevention for coronary artery disease, including lipid-lowering therapy, blood pressure control, a heart-healthy diet, and regular exercise.
QUESTION AND DISCUSSION
QUESTION: A study showed thrombus aspiration to be beneficial.72 The notion of pulling a clot back through a catheter strikes me as quite remarkable. What do you think of this as a future therapy?
DR PINTO: As an interventional cardiologist, I love mechanical therapies. The study you mention73 evaluated STEMI, in which the clot is often larger and occlusive than in NSTEMI. Using specialized catheters, the amount of suction is not excessive. The idea with this approach is that with less clot remaining in the artery, there is less chance of distal embolization during angioplasty and stent placement.
In the future, it could be that such a therapy may have even more benefit in NSTEMI, in which the artery is only partially occluded, and a major limitation of current therapies is distal embolization of clot. It is a good thought, and the future may bring combined mechanical and intracoronary pharmacologic therapies during NSTEMI.
Financial Disclosures: Dr Pinto reports that he has served as a consultant and on the speakers' bureau for the Medicines Company (the manufacturer of bivalirudin), on the speakers’ bureau for Lilly USA, LLC/Daiichi-Sankyo Inc (the manufacturer of prasugrel), and on the speakers’ bureau for Schering-Plough Inc (the manufacturer of eptifibatide).
Additional Contributions: We thank the patient for sharing his story and for providing permission to publish it.
This conference took place at the Medicine Grand Rounds at Beth Israel Deaconess Medical Center, Boston, Massachusetts, on February 14, 2008.
Clinical Crossroads at Beth Israel Deaconess Medical Center is produced and edited by Risa B. Burns, MD, series editor; Tom Delbanco, MD, Howard Libman, MD, Eileen E. Reynolds, MD, Amy N. Ship, MD, and Anjala V. Tess, MD.
Clinical Crossroads Section Editor: Margaret A. Winker, MD, Deputy Editor.
