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 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
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
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.
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.
Most 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.
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, 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, 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.
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 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).
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 = 0.0498).
A significantly greater benefit was seen in patients with ST segment changes and in those with positive troponin values compared with negative values.23 In patients with a troponin T of more than 0.01 ng/mL, there was a relative 39% risk reduction in the primary endpoint with the invasive versus conservative strategy (P < 0.001), whereas patients with a negative troponin have similar outcomes with either strategy. Using the TIMI risk score, there was significant benefit of the early invasive strategy in intermediate (score, 3-4) and high-risk patients (5-7), whereas low-risk (0-2) patients had similar outcomes when managed with either strategy.23 Accordingly, this strategy is recommended for intermediate- to high-risk patients, and an invasive strategy is recommended. For lower risk patients, either strategy is acceptable.
Secondary Prevention and Follow-Up
Because follow-up is critical, we ensure that both a phone call and a letter summarizing the hospital events are sent to the primary care physician and all other physicians caring for the patient. This allows continuity of care and is an opportunity for the cardiologist to provide a rationale for the long-term management with key medications such as aspirin, clopidogrel, beta-blockers, and cholesterol-lowering medications. Given the long-term benefit of aspirin in secondary prevention and those of clopidogrel in both Clopidogrel Versus Aspirin in Patients at Risk of Ischaemic Events (CAPRIE) and CURE,22,47,48 the combination of aspirin and clopidogrel is recommended for most patients, with treatment for at least 1 year based on CURE; based on the benefit seen in CAPRIE, treatment should be for at least 3 years or indefinitely.
Similarly, beta-blockers are recommended for long-term management in all patients without contraindications. Recently, with the results of the Heart Outcomes Prevention Evaluation trial,55 consideration of angiotensin-converting enzyme inhibitors at discharge has been added for all patients. Cholesterol-lowering therapy is a key component of a long-term secondary prevention program and is thus recommended.56–58 Follow-up care with the primary care physician to achieve a low-density lipoprotein of less than 100 mg/dL is recommended by the National Cholesterol Education Program.59 Finally, cardiac rehabilitation is a key component after acute coronary syndromes (Table 2). For patients with severe limitation of exercise capacity, such as the very elderly, transfer to a rehabilitation facility is arranged, especially after coronary artery bypass graft when needed. Patients are approached for participation in a cardiac rehabilitation program, either at our hospital or one near to their home. All patients receive a booklet outlining an exercise program, and its outline is briefly reviewed by the cardiologist and the nurse.
The format of the pathways has evolved from a several-page pathway listing all the indications, contraindications, and doses for each medicine (e.g., fibrinolytic therapy, heparin, beta-blockers)60–63 to a one-page document with all five pathways in a simple “checklist” format.59 This checklist format was developed to simplify the pathway and increase its usability and use. The design is such that it serves as a quick reminder of the key goals, tests to perform, and medications to consider using. In this way, a busy emergency department physician could use the pathway rapidly to improve care, but the pathway would not be a burden of paperwork for the physician. We have similarly just developed a checklist for the time of hospital discharge (Figure 2).
We have recently moved to make these checklists standardized order sets for the emergency department physician and nurse to use (Figure 3). Because all medications and other orders are now entered electronically, having a template with the critical pathway ensures that the physician sees the checklist of orders. The physician simply chooses a pathway based on the clinical diagnosis and clicks on the medications he or she wishes. It is hoped that this system, which guarantees that physicians will see the critical pathway for every patient, will further increase the use of evidence-based medications. A complete set of admission orders also exists.
Our critical pathway has evolved over the past 6 years. The goals remain the same: to improve the use of evidence-based medications, now including the clopidogrel, LMWH, and GP IIb/IIIa inhibitors, while also improving the cost-efficiency of care by reducing the length of stay. We believe that this critical pathway has been beneficial in managing patients and in providing patients optimal care.
1. Steering Committee of the Physicians' Health Study Research Group. Final report on the aspirin component of the ongoing Physicians' Health Study. N Engl J Med 1989; 321: 129-35.
2. Antiplatelet Trialist' Collaboration. Collaborative overview of randomised trials of antiplatelet therapy: I. Prevention of death myocardial infarction and stroke by prolonged antiplatelet therapy in various categories of patients. Br Med J 1994; 308: 81-106.
3. Lewis HD, Davis JW, Archibald DG, et al. Protective effects of aspirin against acute myocardial infarction and death in men with unstable angina. N Engl J Med 1983; 309: 396-403.
4. Cairns JA, Gent M, Singer J, et al. Aspirin, sulfinpyrazone, or both in unstable angina. N Engl J Med 1985; 313: 1369-75.
5. Theroux P, Ouimet H, McCans J, et al. Aspirin, heparin or both to treat unstable angina. N Engl J Med 1988; 319: 1105-11.
6. RISC Group. Risk of myocardial infarction and death during treatment with low dose aspirin and intravenous heparin in men with unstable coronary artery disease. Lancet 1990; 336: 827-30.
7. ISIS-2 (Second International Study of Infarct Survival) Collaborative Group. Randomised trial of intravenous streptokinase, oral aspirin, both, or neither among 17,187 cases of suspected acute myocardial infarction: ISIS-2. Lancet 1988; 2: 349-60.
8. Rogers WJ, Bowlby LJ, Chandra NC, et al. Treatment of myocardial infarction in the United States (1990 to 1993): observations from the National Registry of Myocardial Infarction. Circulation 1994; 90: 2103-14.
9. Stone PH, Thompson B, Anderson HV, et al. Influence of race, sex, and age on management of unstable angina and non-Q-wave myocardial infarction: the TIMI III Registry. JAMA 1996; 275: 1104-12.
10. Cannon CP, McCabe CH, Stone PH, et al. The electrocardiogram predicts one-year outcome of patients with unstable angina and non-Q wave myocardial infarction: results of the TIMI III Registry ECG Ancillary Study. J Am Coll Cardiol 1997; 30: 133-40.
11. Cannon CP, Moliterno DJ, Every N, et al. Implementation of AHCPR guidelines for unstable angina in 1996: unfortunate differences between men & women. Results from the multicenter GUARANTEE registry. J Am Coll Cardiol 1997; 29(suppl A): 217A.
12. Alexander KP, Peterson ED, Granger CB, et al. Potential impact of evidence-based medicine in acute coronary syndromes: insights from GUSTO-IIb. J Am Coll Cardiol 1998; 32: 2023-30.
13. Scirica BM, Moliterno DJ, Every NR, et al. Differences between men and women in the management of unstable angina pectoris (the GUARANTEE Registry). Am J Cardiol 1999; 84: 1145-50.
14. Giugliano RP, Lloyd-Jones DM, Camargo CA Jr, et al. Association of unstable angina guideline care with improved survival. Arch Intern Med 2000; 160: 1775-80.
15. Fragmin During Instability in Coronary Artery Disease (FRISC) Study Group. Low-molecular-weight heparin during instability in coronary artery disease. Lancet 1996; 347: 561-8.
16. Cohen M, Demers C, Gurfinkel EP, et al. A comparison of low-molecular-weight heparin with unfractionated heparin for unstable coronary artery disease. N Engl J Med 1997; 337: 447-52.
17. Antman EM, Cohen M, Radley D, et al. Assessment of the treatment effect of enoxaparin for unstable angina/non-Q-wave myocardial infarction: TIMI 11B-ESSENCE meta- analysis. Circulation 1999; 100: 1602-8.
18. Antman EM, McCabe CH, Gurfinkel EP, et al. Enoxaparin prevents death and cardiac ischemic events in unstable angina/non-Q-wave myocardial infarction: results of the Thrombolysis In Myocardial Infarction (TIMI) 11B trial. Circulation 1999; 100: 1593-601.
19. Platelet Receptor Inhibition for Ischemic Syndrome Management (PRISM) Study Investigators. A comparison of aspirin plus tirofiban with aspirin plus heparin for unstable angina. N Engl J Med 1998; 338: 1498-505.
20. Platelet Receptor Inhibition for Ischemic Syndrome Management in Patients Limited by Unstable Signs and Symptoms (PRISM-PLUS) Trial Investigators. Inhibition of the platelet glycoprotein IIb/IIIa receptor with tirofiban in unstable angina and non-Q-wave myocardial infarction. N Engl J Med 1998; 338: 1488-97.
21. PURSUIT Trial Investigators. Inhibition of platelet glycoprotein IIb/IIIa with eptifibatide in patients with acute coronary syndromes. N Engl J Med 1998; 339: 436-43.
22. CURE Study Investigators. The Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) trial programme: rationale, design and baseline characteristics including a meta-analysis of the effects of thienopyridines in vascular disease. Eur Heart J 2000; 21: 2033-41.
23. Cannon CP, Weintraub WS, Demopoulos LA, et al. Comparison of early invasive and conservative strategies in patients with unstable coronary syndromes treated with the glycoprotein IIb/IIIa inhibitor tirofiban. N Engl J Med 2001; 344: 1879-87.
24. Morrow DA, Cannon CP, Rifai N, et al. Ability of minor elevations of troponin I and T to predict benefit from an early invasive strategy in patients with unstable angina and non-ST elevation myocardial infarction: Results from a randomize trial. JAMA 2001; 286: 2405-12.
25. Moliterno DJ, Aguirre FV, Cannon CP, et al. The Global Unstable Angina Registry and Treatment Evaluation (GUARANTEE) Study [abstract]. Circulation 1996; 94(suppl I): 195.
26. Cannon CP, O'Gara PT, eds. Critical Pathways in Cardiology. Philadelphia: Lippincott, Williams & Wilkins, 2001.
27. Cannon CP, Richards CF. Emergency Department critical pathways for acute coronary syndromes. In: Cannon CP, O'Gara PT, eds. Critical Pathways in Cardiology. Philadelphia: Lippincott, Williams & Wilkins, 2001: 15-22.
28. Cannon CP. Critical pathway for thrombolysis in myocardial infarction. In: Cannon CP, O'Gara PT, eds. Critical Pathways in Cardiology. Philadelphia: Lippincott, Williams & Wilkins, 2001: 57-66.
29. Nichol G, Walls R, Goldman L, et al. A critical pathway for management of patients with acute chest pain at low risk for myocardial ischemia: recommendations and potential impact. Ann Intern Med 1997; 127: 996-1005.
30. Newby LK, Christenson RH, Ohman EM, et al. Value of serial troponin T measures for early and late risk stratification in patients with acute coronary syndromes: the GUSTO-IIa Investigators. Circulation 1998; 98: 1853-9.
31. Antman EM, Cohen M, Bernink PJ, et al. The TIMI risk score for unstable angina/non-ST elevation MI: a method for prognostication and therapeutic decision making. JAMA 2000; 284: 835-42.
32. Morrow DA, Antman EM, Snapinn SM, et al. An integrated clinical approach to predicting the benefit of tirofiban in non-ST elevation acute coronary syndromes: application of the TIMI risk score for US/NSTEMI in PRISM-PLUS. Eur Heart J (in press).
33. Braunwald E, Antman EM, Beasley JW, et al. ACC/AHA guidelines for the management of patients with unstable angina and non-ST segment elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on the Management of Unstable Angina and Non-ST Segment Elevation Myocardial Infarction). J Am Coll Cardiol 2000; 36: 970-1056.
34. Januzzi JL, Hahn SS, Chae CU, et al. Effects of tirofiban plus heparin versus heparin alone on Troponin I levels in patients with acute coronary syndromes. Am J Cardiol 2000; 86: 713-7.
35. Alexander JH, Sparapani RA, Mahaffey KW, et al. Eptifibatide reduces the size and incidence of myocardial infarction in patients with non-ST-elevation acute coronary syndromes [abstract]. J Am Coll Cardiol 1999; 33(suppl A): 331A.
36. TIMI IIIB Investigators. Effects of tissue plasminogen activator and a comparison of early invasive and conservative strategies in unstable angina and non-Q-wave myocardial infarction: results of the TIMI IIIB Trial. Circulation 1994; 89: 1545-56.
37. Anderson HV, Cannon CP, Stone PH, et al. One-year results of the Thrombolysis in Myocardial Infarction (TIMI) IIIB clinical trial: a randomized comparison of tissue-type plasminogen activator versus placebo and early invasive versus early conservative strategies in unstable angina and non-Q-wave myocardial infarction. J Am Coll Cardiol 1995; 26: 1643-50.
38. Boden WE, O'Rourke RA, Crawford MH, et al. Outcomes in patients with acute non-Q-wave myocardial infarction randomly assigned to an invasive as compared with a conservative strategy. N Engl J Med 1998; 338: 1785-92.
39. McCullough PA, O'Neill WW, Graham M, et al. A prospective randomized trial of triage angiography in acute coronary syndromes ineligible for thrombolytic therapy: results of the medicine versus angiography in thrombolytic exclusion (MATE) trial. J Am Coll Cardiol 1998; 32: 596-605.
40. Fragmin and Fast Revascularisation During Instability in Coronary Artery Disease Investigators. Invasive compared with non-invasive treatment in unstable coronary-artery disease: FRISC II prospective randomised multicentre study. Lancet 1999; 354: 708-15.
41. Boersma E, Akkerhuis KM, Theroux P, et al. Platelet glycoprotein IIb/IIIa receptor inhibition in non-ST-elevation acute coronary syndromes: early benefit during medical treatment only, with additional protection during percutaneous coronary intervention. Circulation 1999; 100: 2045-8.
42. EPIC Investigators. Use of a monoclonal antibody directed against the platelet glycoprotein IIb/IIIa receptor in high risk angioplasty. N Engl J Med 1994; 330: 956-61.
43. EPILOG Investigators. Platelet glycoprotein IIb/IIIa receptor blockade and low-dose heparin during percutaneous coronary revascularization. N Engl J Med 1997; 336: 1689-96.
44. EPISTENT Investigators. Randomised placebo-controlled and balloon-angioplasty-controlled trail to assess the safety of coronary stenting with use of platelet glycoprotein-IIb/IIIa blockade. Lancet 1998; 352: 87-92.
45. CAPTURE Investigators. Randomised placebo-controlled trial of abciximab before and during coronary intervention in refractory unstable angina: the CAPTURE study. Lancet 1997; 349: 1429-35[published erratum appears in Lancet 1997;350:744].
46. Mark DB, Cowper PA, Berkowitz SD, et al. Economic assessment of low-molecular-weight heparin (enoxaparin) versus unfractionated heparin in acute coronary syndrome patients: results from the ESSENCE randomized trial. Circulation 1998; 97: 1702-7.
47. Clopidogrel in Unstable Angina to Prevent Recurrent Events Trial Investigators. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med 2001; 345: 494-502.
48. CAPRIE Steering Committee. A randomised, blinded, trial of Clopidogrel Versus Aspirin in Patients at Risk of Ischaemic Events (CAPRIE). Lancet 1996; 348: 1329-39.
49. Cohen M, Theroux P, Weber S, et al. Combination therapy with tirofiban and enoxaparin in acute coronary syndromes. Int J Cardiol 1999; 71: 273-81.
50. Cannon C, Brieger D, Van de Werf F, et al. Safety of the combination of low-molecular weight heparin and glycoprotein IIb/IIIa inhibitors: observations from the Global Registry of Acute Coronary Events (GRACE) [abstract]. Eur Heart J 2001; 22(suppl): 592.
51. Heeschen C, Hamm CW, Goldmann B, et al. Troponin concentrations for stratification of patients with acute coronary syndromes in relation to therapeutic efficacy of tirofiban. Lancet 1999; 354: 1757-62.
52. Januzzi JL, Chai CU, Sabatine MS, et al. Elevation in serum troponin I predicts the benefit of tirofiban. J Thromb Thrombolysis 2001; 11: 211-5.
53. Hamm CW, Heeschen C, Goldmann B, et al. Benefit of abciximab in patients with refractory unstable angina in relation to serum troponin T levels. N Engl J Med 1999; 340: 1623-9.
54. Newby LK, Ohman EM, Christenson RH, et al. Benefit of glycoprotein IIb/IIIa inhibition in patients with acute coronary syndromes and troponin t-positive status: the paragon-B troponin T substudy. Circulation 2001; 103: 2891-6.
55. Heart Outcomes Prevention Evaluation Study Investigators. Effects of ramipril on cardiovascular and microvascular outcomes in people with diabetes mellitus: results of the HOPE study and MICRO-HOPE substudy. Lancet 2000; 355: 253-9.
56. Scandinavian Simvastatin Survival Study Group. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet 1994; 344: 1383-9.
57. Sacks RM, Pfeffer MA, Moye LA, et al. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. N Engl J Med 1996; 335: 1001-9.
58. Long-Term Intervention With Pravastatin in Ischaemic Disease (LIPID) Study Group. Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. N Engl J Med 1998; 339: 1349-57.
59. Executive Summary of The Third Report of The National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, And Treatment of High Blood Cholesterol In Adults (Adult Treatment Panel III). JAMA 2001; 285: 2486-97.
60. Cannon CP, Antman EM, Walls R, et al. Time as an adjunctive agent to thrombolytic therapy. J Thromb Thrombolysis 1994; 1: 27-34.
61. Cannon CP. Optimizing the treatment of unstable angina. J Thromb Thrombolysis 1995; 2: 205-18.
62. Sagarin MJ, Cannon CP, Cermignani MS, et al. Delay in thrombolysis administration: causes of extended door-to-drug times and the asymptote effect. J Emerg Med 1998; 16: 557-65.
63. Cannon CP, Johnson EB, Cermignani M, et al. Emergency department thrombolysis critical pathway reduces door-to-drug times in acute myocardial infarction. Clin Cardiol 1999; 22: 17-22.