Critical Pathway for Unstable Angina and Non-ST Elevation Myocardial Infarction

At Brigham and Women's Hospital, we developed a critical pathway for unstable angina and non-ST elevation myocardial infarction (UA/NSTEMI) in 1996. The first goal was to ensure optimal use of guideline-recommended medications and treatments. In addition, we sought to reduce hospital length of stay, with an overall goal of optimizing clinical care and at the same time making it more cost-effective. More recently, several new treatments have become available, such as low molecular weight heparin (LMWH), glycoprotein (GP) IIb/IIIa inhibitors, and now clopidogrel for UA/NSTEMI, we have used the critical pathway as a means of introducing these agents into the standard of care at our hospital and to provide clinicians specific recommendations on which patients should be treated with the new agents. Targeting Underuse of Guideline-Recommended Medications A major rationale for the development of a critical pathway for unstable angina was the emerging information from registries showing underuse of cardiac medications. As an example, aspirin has been shown to be beneficial across the entire spectrum of ischemic coronary syndromes, from primary prevention,1 secondary prevention,2 to unstable angina and acute MI.3–7 In particular, in unstable angina, aspirin leads to a 50% to 70% reduction in death or MI.3–6 However, in the first National Registry of Myocardial Infarction, involving 240,989 patients among acute MI patients not receiving thrombolytic therapy (i.e., largely non-ST elevation MI), only 63% received aspirin.8 In the Thrombolysis in Myocardial Ischemia (TIMI) III Registry of unstable angina/non-ST elevation MI conducted in 1992-1993, 80% of patients received aspirin,9,10 and in the Global Unstable Angina Registry and Treatment Evaluation registry conducted in 1996, 83% of patients received aspirin. Similar findings have been observed for beta-blockers and heparin,9–13 with heparin being used in only 57% of patients in the TIMI III Registry and in 67% of patients in the Global Unstable Angina Registry and Treatment Evaluation registry.10,11,13 Importantly, recent evidence has suggested that if patients are treated according to the Unstable Angina Guideline recommendations, their adjusted 1-year mortality is lower compared with patients who do not receive all guideline-recommended therapies.14 Thus, with these data available nationally, we set this as our major focus to ensure that all our patients received recommended therapies. More recently, several new classes of drugs have become available for the treatment of unstable angina/non-ST elevation MI. The LMWH, the GP IIb/IIIa inhibitors, and clopidogrel have been shown to be beneficial in reducing death or MI in unstable angina and non-ST elevation MI.15–22 Furthermore, an invasive strategy using early GP IIb/IIIa inhibition has also recently been shown to be beneficial in intermediate and high-risk patients, especially those who are troponin-positive.23,24 Accordingly, we are constantly adapting our pathway to incorporate these new therapies. Reducing Hospital (and Intensive Care Unit) Length of Stay Reduction in hospital length of stay has been a driving force behind the creation of critical pathways and is a relatively easy and efficient way to reduce costs (and thus increase cost-effectiveness). In unstable angina, length of stay was long just 5 years ago. In patients with UA/NSTEMI enrolled in the TIMI IIIB trial, the average length of stay was more than 9 days. In the parallel TIMI 3 Registry of patients not entered into the trial, length of stay was also 9 days. Length of stay has shortened over recent years, documented to be on average 4.4 days in 1996 in the Global Unstable Angina Registry and Treatment Evaluation registry.13,25 However, opportunities exist for further reductions in length of stay, which should have a very favorable impact on costs, which allows these resources to be allocated for the newer drug therapies (which will further improve outcomes and, thus, cost-effectiveness). Brigham and Women's Hospital Pathway Patient Population Patient eligibility for our pathway is based on clinical criteria for UA/NSTEMI, i.e., patients who presented with typical angina at rest or with minimal exertion were eligible. It is thought that broad entry criteria are warranted to allow the pathway to potentially benefit as many patients as possible. Because this spectrum of acute coronary syndrome is not distinct, several other pathways have been developed in parallel with this unstable angina pathway.26–28 For patients in whom the clinical history was less certain for unstable angina, diagnostic chest pain pathways to “rule out MI” were developed.27,29 Risk Stratification The presence of ST depression and transient ST elevation are strong markers of high risk for adverse outcomes. Notably, an ST change of 0.5 mm appears to have equal significance to ST depression of 1 mm or more.10 Because only a third of patients presenting with unstable angina have electrocardiogram changes,10 the admission diagnosis relies predominantly on the history. Similarly, benefit of more aggressive therapies is greatest in patients with ST segment changes.18,23 Cardiac Markers The pathway includes three creatine kinase-MB determinations and troponin I drawn at baseline and at 8 and 16 hours. Because serial troponin values have been found to improve the sensitivity of detecting high-risk patients (without ST elevation),30 we have included serial troponins to the pathway. As noted below, this is helpful in determining a high-risk group in whom IIb/IIIa inhibitors would have the greatest benefit. Thrombolysis in Myocardial Infarction Risk Score The TIMI risk score was developed using multivariate analysis to predict the occurrence of death, MI, or recurrent ischemia leading to urgent revascularization in the TIMI 11B trial. Seven independent risk factors emerged: age of 65 years or more, more than three risk factors for coronary artery disease, documented coronary artery disease at catheterization, prior aspirin, more than two episodes of angina in past 24 hours, ST deviation of 0.5 mm or more, and elevated cardiac markers. Use of this scoring system was able to risk stratify patients across a 10-fold gradient of risk, from 4.7% to 40.9% (P < 0.001).31 More importantly, the relative benefit of the newer therapies (enoxaparin vs. unfractionated heparin, tirofiban vs. heparin, and an invasive vs. conservative strategy) was seen to increase as the risk increased.23,31,32 Thus, these findings emphasize the importance of risk stratification being the first task in evaluating patients who present with UA/NSTEMI.33 In our Emergency Department order set, we have incorporated all three of these markers of risk, ST segment changes, positive troponin or creatine kinase-MB, and the TIMI Risk score to direct care and select the more aggressive approach. Medical Management As shown in Figure 1, initial management is with aspirin, clopidogrel, beta-blockers, and nitrates to control ischemic pain. Intravenous nitroglycerin is used if pain persists despite three sublingual nitroglycerin tablets. Calcium antagonists are used if needed to control ischemia after these agents are at optimal therapeutic doses.Figure 1Most recently, we have added GP IIb/IIIa inhibitors, enoxaparin, and clopidogrel to the pathway (Table 1). Following is the brief overview of the new data that were provided to all clinicians to assist them in learning about the new agents and understanding the new pathway recommendations.Table 1Tirofiban Glycoprotein IIb/IIIa inhibitors bind to the GP IIb/IIIa receptor and prevent the formation (or progression) of a platelet aggregate. Tirofiban is a nonpeptide antagonist of the GP IIb/IIIa receptor. In the Platelet Receptor Inhibition for Ischemic Syndrome Management in Patients Limited by Unstable Signs and Symptoms (PRISM-PLUS) trial involving 1,915 patients with unstable angina and non-ST elevation MI, tirofiban plus heparin and aspirin led to a significantly lower rate of death, MI, or refractory ischemia at 7 days compared with heparin and aspirin (12.9% vs. 17.9%, a 32% risk reduction [P = 0.004]).20 This result comprised a 45% reduction in MI and a 30% reduction in refractory ischemia. Death or MI at 30 days was reduced by 30%, from 11.9% to 8.7% (P = 0.03), and the improvement was consistent across all subgroups and management strategies (i.e., medical therapy [25% reduction], percutaneous transluminal coronary angioplasty [35% reduction], and coronary artery bypass graft [30% reduction]). In the PRISM trial involving 3,232 patients, tirofiban reduced the rate of death, MI, or refractory ischemia at 48 hours (3.8% vs. 5.6% for heparin, a 32% reduction [P = 0.01]).19 A recent analysis from the PRISM-PLUS trial found that early use of GP IIb/IIIa inhibitors can reduce the size of an evolving non-ST elevation: patients randomized to tirofiban plus heparin had a significantly lower peak troponin.34 Similar data were observed in the PURSUIT trial,35 emphasizing the need to initiate therapy early to reduce the severity of the presenting ischemic episode. Finally, the overall strategy of early IIb/IIIa inhibition and invasive approach (see Treatment Strategy section) was validated in the Treat Angina with Aggrastat and determine the Cost of Therapy with an Invasive or Conservative Strategy (TACTICS)-TIMI 18 trial.23 In this trial, a benefit of an invasive strategy was seen. Comparing this trial to prior trials, an apparent benefit of IIb/IIIa inhibition was seen: All four prior trials had found an early hazard, with higher event rates over the first several weeks.36–40 In contrast, in TACTICS-TIMI 18, which used early IIb/IIIa inhibition, an early benefit was seen, which can be attributed to the well documented benefit of IIb/IIIa inhibition in invasively managed patients.41 The cost of tirofiban therapy is approximately $750 per 2-day course of therapy. Eptifibatide Eptifibatide, a synthetic heptapeptide inhibitor of the GP IIb/IIIa receptor, was studied in the PURSUIT trial involving 10,948 patients. Eptifibatide reduced the rate of death or MI at 30 days by a relative 10% (from 15.7% to 14.2%, P = 0.042).21 A greater benefit was observed in patients who underwent early percutaneous coronary intervention (PCI) on eptifibatide (31% reduction in death or MI at 30 days, 16.7 vs. 11.6%, P = 0.01) and those treated in the United States (25-35% reductions). In the setting of PCI, significant benefit was observed with a double-bolus and infusion regimen of eptifibatide (death, MI, urgent revascularization at 30 days 10.4% for placebo vs. 6.8% for eptifibatide, P = 0.004), with an even greater reduction in patients with acute coronary syndromes (10.5% vs. 5.4%, P = 0.01). Emerging evidence shows that there appears to be a greater benefit of treatment when administered earlier relative to the onset of pain. In PURSUIT the absolute reduction in death or MI with eptifibatide was 2.8% for patients treated within 6 hours from the onset of pain, 2.3% for those treated between 6 and 12 hours, and 1.7% for those treated 12 to 24 hours after the onset of pain. No benefit was observed in patients treated 24 hours after the onset of pain, thereby emphasizing the importance of starting therapy as possible, ideally in the emergency department. Cost is approximately $750 per 2-day course of therapy and approximately $300 for a 12- to 18-hour course of therapy for PCI. Abciximab Abciximab, a monoclonal antibody fragment directed at the GP IIb/IIIa receptor, has been shown in numerous trials to reduce death or MI in patients undergoing PCI.42–45 In patients with unstable angina, benefit was observed in patients treated for 24 hours before PCI.45 However, most recently, in the Global Utilization of Strategies to Open Occluded Arteries (GUSTO) IV-ACS trial, in patients not planned to undergo PCI, no benefit was observed. Cost is approximately $1,400 per 12-hour course of therapy. Enoxaparin Low molecular weight heparins are combined factor Xa and thrombin inhibitors. As compared with unfractionated heparin, which has equal antithrombin (factor IIa) and anti-Xa activity, enoxaparin has an increased ratio of anti-Xa to IIa activity of 3:1. The ESSENCE and TIMI 11B trials compared enoxaparin with unfractionated heparin in unstable angina and non-ST elevation MI in 3,171 and 3,910 patients, respectively. In ESSENCE, death, MI, or recurrent ischemia at 14 days was reduced by a relative 16% (16.6% vs. 19.8%, P = 0.019).16 In addition, the need for cardiac catheterization and percutaneous transluminal coronary angioplasty was significantly reduced. In TIMI 11B, death, MI, or urgent revascularization at 14 days was reduced by a relative 15% by enoxaparin (14.2% vs. 16.7% for unfractionated heparin, P = 0.029).18 In the combined meta-analysis, death or MI at 42 days was significantly reduced by 18% (P = 0.02).17 In the trials for catheterization and PCI, enoxaparin was usually stopped and unfractionated heparin was used. Recent experience has shown enoxaparin to be safely used during PCI, and a large new trial is ongoing to assess this strategy. The cost is approximately $150 for a 2-day course of therapy, and a formal cost-effectiveness study showed it was a cost savings to use enoxaparin because the greater medical stabilization led to fewer cardiac events and revascularization procedures.46 Clopidogrel Clopidogrel blocks the adenosine diphosphate receptor on platelets, which decreases platelet activation, with consequent aggregation. In the Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) trial, 12,562 patients were randomized to receive aspirin alone (75-325 mg/d) or aspirin plus clopidogrel (300-mg loading dose, then 75 mg/d).22 The primary endpoint, cardiovascular death, MI, or stroke, was reduced by 20%, from 11.4%, and 9.3%, respectively (P < 0.0001).47 The reduction was seen in all subgroups, including patients with ST segment depression, those without ST changes, and those with positive or negative markers. Interestingly, both patients who had positive cardiac markers and those with negative markers had similar 20% reductions in the primary endpoint. In patients who went on to PCI, a significant 30% reduction was observed through follow-up. The Kaplan-Meier event rates began to show a reduction in events starting just 2 hours after randomization. This is consistent with the early onset of action of clopidogrel. In addition, when analyzing the benefit in the first 30 days versus after 30 days, there was a similar 20% relative risk reduction during both time periods. Thus, it appears that clopidogrel afforded both an early benefit and an ongoing benefit out to 1 year. The combination of clopidogrel plus aspirin was associated with a relative 35% increase in major bleeding (using the CURE trial definition), but the absolute increase was only 1%: from 2.7% to 3.7%. However, using the standard TIMI definition, there was no significant increase, nor was there an increase in intracranial hemorrhage. Of note, when clopidogrel was used alone, it was associated with a significantly lower rate of gastrointestinal bleeding compared with aspirin.48 Thus, for patients with gastrointestinal intolerance to aspirin or those who develop bleeding on the combination of aspirin plus clopidogrel, an attractive antithrombotic strategy is clopidogrel alone. Choosing Antithrombotic Agents Initial treatment involves aspirin, clopidogrel, and heparin or the LMWH enoxaparin for all patients. We are moving to adopt enoxaparin (as preferred to unfractionated heparin) for all patients, except for those who have renal dysfunction (creatinine, >2.0 mg/dL) or those going immediately (within 1 hour) to the cardiac cath lab. Several recent studies have shown the safety of combining LMWH and GP IIb/IIIa inhibition.49,50 The use of clopidogrel is for all risk strata of patients because there is a 20% significant reduction in events with clopidogrel in essentially all subgroups of patients, including those with either positive or negative cardiac markers (Figure 2).51 In contrast, for GP IIb/IIIa inhibitors, all the benefit is seen in patients who are troponin-positive or who have a higher TIMI risk score.32,52–55 This benefit, however, is greatly magnified and ranges from 60% to 80% in the four trials with troponin data (Figure 2).52–55 Similar large benefits have been seen for the IIb/IIIa inhibitors in diabetes, those with ST segment changes and higher TIMI risk scores, as noted above. Thus, clopidogrel is recommended for all patients and the small molecule GP IIb/IIIa inhibitors are recommended for high-risk patients, (i.e., those who are troponin-positive, who have ST segment changes, or who have a TIMI risk score >3).Figure 2Treatment Strategy The invasive strategy in the pathway includes the medical management as previously described and catheterization within the first 18 hours from admission; thus, for some patients admitted in the morning, the catheterization is performed later in the afternoon. Patients admitted in the afternoon or early evening usually have a catheterization the following morning. Based on the anatomic findings, revascularization is carried out as appropriate. An early conservative strategy involves aggressive medical management and clinical monitoring, but this is usually reserved for patients who are clearly not revascularization candidates, those who do not want catheterization, or in those who are at lower risk. In addition, if a patient is admitted with chest pain but has an unclear diagnosis of coronary artery disease, a diagnostic stress test is done. Of the five randomized trials that have compared invasive and conservative strategies, the first four had mixed results.36–40 Importantly, these trials were conducted before two major advances in the field: platelet GP IIb/IIIa inhibition and coronary stenting. In the Treat Angina With Aggrastat and Determine Cost of Therapy With an Invasive or Conservative Strategy (TACTICS) TIMI 18 trial, it was hypothesized that with these advances an early invasive strategy is superior to a more conservative approach.23 All patients received aspirin, heparin, and the GP IIb/IIIa inhibitor tirofiban at the time of randomization for 48 hours, including at least 12 hours after PCI. The rate of the primary endpoint, death, MI, or rehospitalization for an acute coronary syndrome at 6 months was reduced with the early invasive strategy, from 19.4% in the conservative group to 15.9% in the early invasive group (odds ratio, 0.78; P = 0.025).23 Similarly, death or nonfatal MI was significantly reduced at 30 days (7.0% vs. 4.7%, respectively; P = 0.02) and at 6 months (P = Risk Stratification A significantly greater benefit was seen in patients with ST segment changes and in those with positive troponin values compared with negative In patients with a troponin of more than there was a relative risk reduction in the primary with the invasive versus conservative strategy (P < patients with a negative troponin have similar outcomes with either strategy. the TIMI risk there was significant benefit of the early invasive strategy in intermediate and high-risk patients patients had similar outcomes when managed with either Accordingly, this strategy is recommended for to high-risk patients, and an invasive strategy is For lower risk patients, either strategy is and Because is we ensure that both a and a the hospital events are to the primary care and all other for the This allows of care and is an for the to provide a rationale for the management with medications such as aspirin, clopidogrel, beta-blockers, and medications. the benefit of aspirin in secondary and those of clopidogrel in both Clopidogrel in Patients at Risk of Events and the combination of aspirin and clopidogrel is recommended for most patients, with treatment for at least 1 based on based on the benefit seen in treatment should be for at least 3 years or Similarly, beta-blockers are recommended for management in all patients without with the of the Evaluation of inhibitors at has been added for all patients. therapy is a of a secondary and is thus care with the primary care to a of less than is recommended by the National Finally, cardiac is a after acute coronary syndromes (Table For patients with of such as the very to a is especially after coronary artery bypass graft when Patients are for in a cardiac either at our hospital or to their All patients receive a an and is by the and the The of the pathways has from a pathway all the and for therapy, heparin, to a with all five pathways in a This was developed to the pathway and increase and The is such that it as a of the to and medications to In this a emergency use the pathway to improve but the pathway would not be a of for the We have just developed a for the time of hospital (Figure We have recently to these order for the emergency and to use (Figure Because all medications and other are now entered a with the critical pathway that the the of The a pathway based on the clinical diagnosis and on the medications or It is that this which that will the critical pathway for will further increase the use of medications. A set of admission also critical pathway has over the past 6 The the to improve the use of now including the clopidogrel, LMWH, and GP IIb/IIIa inhibitors, also the of care by reducing the length of We that this critical pathway has been beneficial in patients and in patients optimal