Cardiology Cardiology

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Cardiology Cardiology

  1. 1. Cardiology A Teaching Hospital of HARVARD MEDICAL SCHOOL SCIENTIFIC UPDATE A REPORT BY THE CARDIOVASCULAR DIVISION OF BRIGHAM AND WOMEN’S HOSPITAL, BOSTON, MASSACHUSETTS New Strategies for the Treatment of Acute Coronary Syndromes Presented by: Joseph Ornato, MD, Christopher P. Cannon, MD, Elliott M. Antman, MD, Eugene Braunwald, MD, Eric J. Topol, MD, James T. Willerson, MD Satellite symposium at the 71st Scientific Sessions of the American Heart Association Dallas, Texas November, 1998 Reported and discussed by: • Track 3 and 4 is for patients with intermittent dis- CHRISTOPHER P. CANNON, MD comfort and normal or nondiagnostic ECGs. Dr. Joseph Ornato related that at the Brigham and Women’s Hospital, Improving initial diagnosis and triage of track 3 is for patients with chest pain >15 minutes; they are patients with acute care syndromes (ACS) observed in a 9-hour observation status and serial cardiac Joseph Ornato, MD markers are obtained. With more than five million patients presenting annually • Track 5 is for patients with apparent noncardiac pain; to Emergency Departments (ED) with a chief complaint of if their ECG is normal, they go directly home. chest pain, great efforts are currently being focused on A unique aspect of these pathways is that rest Sesta- improving ED triage and management. One of the first ED MIBI nuclear scans are obtained in patients in both tracks 3 observation units (sometimes called chest pain centers) was and 4. Injection is performed 24 hours per day, seven days developed by Gibler and colleagues who developed a ‘fast- per week, as quickly after ED arrival as possible; imaging is track’ rule-out myocardial infarction (MI) protocol using carried out within 60 to 90 minutes. If the MIBI is negative serial cardiac markers over a nine-hour period.1 This in track 4, patients are discharged home and return the next approach led to a nearly 50% reduction in the cost of workday for an exercise MIBI. Patients on track 3 first evaluating patients compared with inpatient evaluation. undergo a 9-hour rule-out MI protocol. If negative, it is fol- lowed by a stress-MIBI. Emergency department critical pathways Importantly, these pathways have reduced the average At the Medical College of Virginia, there are five clinical length of ED stay for rule-out MIs to only 11 hours. In addi- pathways or “tracks” for the full spectrum of patients with tion, with these pathways, despite the additional diagnostic ACS (Figure 1).2 testing up front, there has been a reduction by approximately • Track 1 is for ST elevation MI treated with thrombolysis 35% in the number of hospital admissions in these patients. or primary angioplasty where the focus is on rapid time to In translating these pathways to other institutions, it is treatment. Recent evidence has shown that a critical pathway worthwhile to note that other modalities can be used in the in the ED can significantly shorten door-to-needle times.3 pathways such as cardiac echo, or even serum cardiac mark- • Track 2 is for patients with prolonged chest discomfort ers and exercise stress testing, as done at Brigham and suggesting unstable angina or non-ST elevation MI. Women’s Hospital.4 Cardiovascular Division J. Michael Gaziano, MD Arthur M. Lee, MD Campbell Rogers, MD Brigham and Women’s Hospital Marie Gerhard-Hermen, MD James Liao, MD Maria Rupnick, MD 75 Francis Street Elliott Antman, MD Gary Gibbons, MD Peter Libby, MD (Division Chief) Arthur Sasahara, MD Boston, Massachusetts 02115 Joshua Beckman, MD Samuel Z. Goldhaber, MD Leonard Lilly, MD Jay Schneider, MD Fax: (617) 732-5291 Charles M. Blatt, MD Thomas B. Graboys, MD Bernard Lown, MD Christine Seidman, MD Cardiovascular Division Website: Eugene Braunwald, MD Robert Giugliano, MD Thomas Michel, MD Andrew Selwyn, MD www.heartdoc.org Christopher Cannon, MD Howard Hartley, MD Gilbert Mudge, MD Nicholas Sibinga, MD The editorial content of Michael Chin, MD John Jarcho, MD Patrick O’Gara, MD Daniel Simon, MD Cardiology Scientific Update Mark Creager, MD Paula Johnson, MD Oglesby Paul, MD Laurence Sloss, MD is determined independently by Victor Dzau, MD Wendy Johnson, MD Marc A. Pfeffer, MD, PhD (Editor) Scott Solomon, MD the Cardiovascular Division of Elazer Edelman, MD, PhD Ralph Kelly, MD Robert Piana, MD Lynne Stevenson, MD Brigham and Women’s Kristin Ellison, MD James Kirshenbaum, MD Jorge Plutzky, MD William Stevenson, MD Hospital. This publication is James Fang, MD Gideon Koren, MD Jeffrey Popma, MD Peter Stone, MD made possible by an Peter Friedman, MD, PhD Michael J. Landzberg, MD Shmuel Ravid, MD Michael Sweeney, MD educational grant. Jonas Galper, MD, PhD Dara Lee, MD Sharon Reimold, MD Frederick Welt, MD Peter Ganz, MD Richard Lee, MD Paul Ridker, MD
  2. 2. Figure 1: The five ‘tracks’ or critical pathways for the triage and treatment of patients presenting with chest pain.2 I II III IV V ST elevation Non-Q AMI Probable U/A Possible U/A Non-cardiac AMI or U/A r/o MI ↓ chest pain ↓ ↓ ↓ ↓ Thrombolysis Heparin, ASA, Variable Variable Analgesics, or PTCA IV NTG ↓ ↓ antacids ↓ ↓ ↓ Admit CCU Admit CCU CCU Fast- ED evaluation, Home ECG + ECGs + Track ST seg, sestamibi enzymes enzymes sestamibi Incorporating glycoprotein IIb/IIIa inhibitors patients undergoing elective stenting had a mortality of 2.4% into today’s critical pathways vs. 1.0% for patients receiving abciximab plus stent Christopher Cannon, MD (p=0.037). This data was presented at the AHA by Dr. A. With the recognition of the importance of platelets in Michael Lincoff. ACS, the use of glycoprotein IIb/IIIa (GP IIb/IIIa) inhibitors There is now a paradigm shift in the understanding of the has become a major focus in improving care. These agents benefit of GP IIb/IIIa inhibitors (Figure 2). These agents have been studied in more than 15 large trials involving over inhibit platelets, increase resolution of coronary thrombus, 32,000 patients. This has led to approval of three agents by improve coronary flow, and thus prevent early recurrent the Food and Drug Administration for the treatment of unsta- ischemic events (MI or refractory ischemia/urgent revascular- ble angina/non-ST elevation MI and for percutaneous coro- ization). Recent data suggest that these benefits translate into nary intervention (PCI).5 The key now is to actually use these a late mortality benefit and emphasize the importance of agents, and one way is to incorporate them into critical path- effective platelet inhibition during PCI and in the early treat- ways at your hospital. ment of patients with ACS. Mortality benefit of GP IIb/IIIa inhibitors Mechanism of benefit of IIb/IIIa inhibitors The clinical benefit of IIb/IIIa inhibitors has been shown How do these therapies work? First of all, in both the in numerous trials using abciximab (ReoPro), tirofiban CAPTURE and PRISM-PLUS trials, the incidence of MI (Aggrastat), and eptifibatide (Integrilin) in patients undergo- (and/or refractory ischemia) was reduced during the period of ing PCI and in ACS. The most recent data in PCI come from medical therapy with IIb/IIIa inhibitor compared with aspirin the EPISTENT trial that compared state of the art coronary and heparin alone.7,8 Secondly, during PCI, intra-procedural intervention—stenting—with stenting plus abciximab, and MIs were reduced markedly by the addition of a IIb/IIIa balloon angioplasty plus abciximab. The addition of abcix- imab led to a >50% reduction in death, MI, and urgent revas- Figure 3: Resolution of thrombus with a GP IIb/IIIa cularization at 30 days, an absolute reduction of 5.5%.6 At inhibitor plus aspirin and heparin7 one year, there was a mortality benefit with abciximab: 60 Thrombus resolution (% patients) P = 0.038 Figure 2: A paradigm shift for the benefit of GP IIb/IIIa 50 inhibitors Inhibition of platelet aggregation 40 42.5% 30 Resolution of thrombus 20 Improvement of coronary flow 20.5% 10 Reduction in MI and ischemia 0 Placebo Abciximab Improved survival n=39 n=45 Cardiology S C I E N T I F I C U P D AT E
  3. 3. Table 1: Cost-effectiveness of IIb/IIIa inhibitors and Figure 4: Protocol schema for the ER-TIMI 19 study other medical therapies Therapy Cost /Year of life saved Early reteplase prehospital trial: ER-TIMI 19 Abciximab in PCI for UA* Savings Ischemic discomfort ≥30 min ST ↑ ≥1mm (confirmed) CABG for Left Main disease $ 7,000 No contraindications to thrombolytic Abciximab for all PCI – adjusted $ 7,000 Cervical cancer screening $ 12,000 Reteplase 10 U in ambulance Kidney transplantation $ 19,000 TPA vs. streptokinase $ 32,000 Evaluation on arrival in ED Hemodialysis for kidney failure $ 35,000 Further management paths Heart transplantation $ 54,000 Cholesterol — Primary prevention 40 y.o. $ 154,000 Lysis Medical therapy PCI *Data from EPIC trial13 2nd bolus of (no further lysis,* + Abciximab prn PCI = percutaneous coronary intervention r-PA 10 U no PCI) TPA = tissue plasminogen activator UA = unstable angina *Contraindications identified. Diagnosis of MI rejected. inhibitor. Thus, the IIb/IIIa inhibitor provides initial stabiliza- tion of the complex lesion, as well as benefit during PCI estimated to cost $32,000 per year of life saved. Thus, in (Figure 3). these analyses, the use of abciximab for PCI appears to be cost-effective. Primary PCI for ST elevation MI There are now data from three randomized trials showing Pre-hospital thrombolysis the benefit of abciximab in patients undergoing primary PCI Elliott M. Antman, MD for acute ST elevation MI.9-11 In the RAPPORT trial, the rate Because of the importance of rapid time to treatment in of death, MI, or urgent revascularization at 30 days was sig- acute MI, the concept of pre-hospital thrombolytic therapy nificantly reduced by 56%. In addition, benefit has recently has been pursued as a means of reducing this important time. been shown in the GUSTO III trial for patients undergoing Several trials of pre-hospital treatment with thrombolytic rescue PCI, especially for patients who received reteplase therapy have shown reductions in both time to treatment and followed by abciximab. At Brigham and Women’s Hospital mortality, especially in rural areas.14,15 and at many others, use of abciximab for primary PCI is In the Myocardial Infarction Triage Intervention (MITI) becoming the standard of care. trial, patients treated in the pre-hospital phase had a signifi- Thus, we are in an era of IIb/IIIa inhibitor inhibition in cant reduction in time to treatment with thrombolytic therapy both ACS and coronary intervention. A meta-analysis of over by 33 minutes (p < 0.001).16 In the GREAT trial, conducted in 32,000 patients demonstrated that the addition of a IIb/IIIa a rural area in England, prehospital or “home” thrombolysis inhibitor to aspirin plus heparin leads to a 20% reduction in produced a >2 hour time saving that was associated with a death or MI at 30 days (p<0.0001).12 These data provide 50% reduction in mortality, 10.4% vs. 21.6% at one year strong support for cardiologists to incorporate these therapies (p=0.007).14 into critical pathways at their institutions. The European Myocardial Infarction Project randomized 5,469 patients and achieved a 55-minute reduction in time to Cost-effectiveness of IIb/IIIa inhibition treatment with pre-hospital thrombolysis. This was associ- Table 1 shows data comparing the cost-effectiveness of ated with a strong trend towards reduction in overall 30-day IIb/IIIa inhibitors with that of other medical interventions. In mortality from 11.1% to 9.7 % (p=0.08), and a significant the EPIC trial, use of abciximab led to a reduction in subse- reduction in cardiovascular mortality from 9.8% to 8.3% quent cardiac procedures and a parallel cost savings in (p=0.05). 15 A meta-analysis of all the major pre-hospital patients with unstable angina.13 A recent analysis, carried out thrombolysis trials found a 17% reduction in mortality, prior to the above-mentioned EPISTENT data, estimated that p=0.03).15 use of abciximab for PCI would cost $18,000 per year of life saved. A benchmark for cost-effectiveness analysis comes ER-TIMI 19 from the comparison of tissue plasminogen activator (tPA) The ER-TIMI 19 study (Early Reteplase) is a Phase 4, with streptokinase in the GUSTO-I trial, where use of tPA is open-label trial that will examine the benefits of pre-hospital Cardiology S C I E N T I F I C U P D AT E
  4. 4. administration of thrombolysis. There is no randomiza- TIMI 14: Combination therapy with tion, but rather, it is designed to look at what time sav- abciximab and low-dose thrombolysis ings can be achieved when building a system of care Eugene Braunwald, MD involving early recognition of patients with ST elevation MI, incorporating new 12-lead ECG technologies and Despite all of the advances in thrombolytic therapy, initiation of a bolus thrombolytic in the ambulance. The 1 in 4 patients who receives the optimal thrombolytic primary endpoint of the study will be the time between regimen still has an occluded vessel at 90 minutes. One arrival of the ambulance in the field to administration of in two does not have full reperfusion (so-called TIMI 3 the thrombolytic agent (reteplase). The study will flow), and about 1 in 10 patients reocclude the coronary involve 20 Emergency Medical Systems in the US and artery after successful reperfusion. Thus, thrombolytic Canada. The term ‘systems’ is the operative word here therapy still has a long way to go. Because the thrombi — this is not just a single hospital, but an ambulance in acute MI are quite rich in platelets, more effective system that might serve several hospitals. The study platelet inhibition (eg, with GP IIb/IIIa inhibitors) is a period will be between February and December 1999 logical new means of improving a thrombolytic- and approximately 1,000 patients will be enrolled. The antithrombotic regimen. Accordingly, the hypothesis of comparison group will be from historical controls at the the TIMI 14 trial is that the platelet inhibitor, abciximab, participating hospitals. is a potent and safe addition to thrombolytic regimens The protocol schema for ER-TIMI 19 is shown in for acute MI. Figure 4. For a suspected acute MI patient in the field, a The international TIMI-14 trial dose-ranging phase 12-lead ECG is obtained and is transmitted to a medical enrolled 681 patients with ST-segment elevation MI, control station where it is reviewed; a checklist is also meeting standard eligibility criteria.18 Patients were ran- reviewed. A medical control officer also approves the domized within 12 hours of acute ST-segment elevation administration of thrombolysis. The first bolus of MI symptom onset to one of four reperfusion regimens reteplase is given in the ambulance. If the ambulance (each encompassing several dosage levels): transport time is more than 30 minutes, the second bolus • standard-dose tPA alone (the control arm) will be administered after 30 minutes in the ambulance. • reduced-dose tPA plus abciximab Once the patient arrives in the ED, there are three possi- • reduced-dose streptokinase plus abciximab ble care pathways that they might follow: • abciximab alone. • The left pathway (Figure 4) would involve a sec- All patients received aspirin and heparin. The initial ond bolus of reteplase being administered because the heparin dosage was a 70 U/kg bolus and a 15 U/kg/h patient is felt to indeed have an ST elevation MI and is a infusion in the tPA control arm, and a 60 U/kg bolus with candidate for continued thrombolytic therapy. This, of a 7 U/kg/h infusion in the arms that included abciximab. course, is the first bit of flexibility that we have with the Abciximab alone was associated with 90-minute ‘double-bolus’ regimen with reteplase. TIMI grade 3 flow rates in 32% of patients and 90- • Another care pathway, shown in the center in minute patency in 48% of patients.18 The combination of Figure 4, is to take the patient to the cardiac catheteriza- streptokinase and abciximab produced only modest tion lab and perform an interventional procedure sup- improvement in early TIMI grade 3 flow. TIMI grade 3 ported by abciximab, shown to be effective in this setting. flow at 90 minutes was achieved in 42% of patients in • The third pathway involves patients who are felt the 0.5 MU group, 39% of patients in the 0.75 MU to be having an ST elevation MI, but upon further group, and 47% of patients in the 1.25 MU group. The review of the data, are felt not to be good candidates for 1.5 MU regimen, plus abciximab, was discontinued after thrombolytic therapy. These patients would not get the four of six patients developed a major hemorrhage, one second bolus. of whom developed an intra-cranial hemorrhage (ICH). The ER-TIMI 19 protocol will specify lower doses of In the dose-ranging phase, the 50 mg dose (given as heparin that appear to improve safety without compro- a 15 mg bolus and a 35 mg infusion over 60 minutes) mising efficacy.17 The dose in the protocol will be 60 achieved substantial improvement in TIMI grade 3 flow: U/kg (maximum 4000 units) and a 12 U/kg/hr (maximum 79% at 90 minutes compared with 57% for tPA alone. 800 U/hr) infusion. The study will have >99% power to Overall patency of the IRA was achieved in 94% of detect the mean difference of 30 minutes in time to treat- patients with the combination of abciximab and tPA, ment between reteplase-treated patients in ER-TIMI 19 compared with 79% for tPA, alone. An even greater dif- and historical controls that will be obtained from the 20 ference was observed at 60 minutes when adding GP EMS systems that will be participating in TIMI-19. IIb/IIIa inhibition. The standard tPA dose achieved only Cardiology S C I E N T I F I C U P D AT E
  5. 5. 45% TIMI grade 3 flow at 60 minutes, compared with The second major area is defining complete reperfu- 75% for 50 mg tPA plus abciximab. Major hemorrhage sion. While achieving early TIMI grade 3 flow is a was similar among the tPA plus abciximab and control major goal of thrombolysis, improvement of myocardial groups, approximately 6% in each. In-hospital mortality perfusion is key. Recent studies with myocardial con- was similar in all groups, ranging from 3% to 5%. trast echocardiography have shown that a large propor- Thus, the addition of the GP IIb/IIIa receptor tion of patients with ‘successful reperfusion’ with early inhibitor abciximab to 50 mg of tPA was able to TIMI grade 3 flow do not have myocardial perfusion. increase the rate of TIMI grade 3 flow at 60 minutes by The contrast medium, sonicated renografin, is injected an absolute 30%, representing a relative 66% improve- into coronary arteries. In the acute phase of AMI, ment over standard therapy. At 90 minutes, the addition regional absence of perfusion delineates the area at risk of the GP IIb/IIIa receptor inhibitor improved TIMI of necrosis. If myocardial ischemia due to coronary grade 3 flow by an absolute 20% (a relative 30% occlusion has been sufficiently prolonged and severe, improvement). These results indicate that the combina- microvascular integrity is lost and there is failure of tis- tion of GP IIb/IIIa receptor inhibition with reduced-dose sue perfusion despite patency of the infarct-related thrombolytic therapy appears to be a promising new reg- artery. One study found that in 90 patients with an open imen for enhancing both the speed and extent of reper- infarct-related artery, the extent of myocardial perfusion fusion in acute ST elevation MI. within the infarct bed predicted left ventricular function one month later.19 Even among patients with TIMI grade Seeking complete reperfusion in acute MI 3, those with impaired myocardial perfusion on contrast Eric J. Topol, MD echo had a lower ejection fraction both acutely and 25 At present, the treatment of acute MI with throm- days later.20 Thus, these studies have demonstrated that bolysis relies almost entirely on a fibrinolytic agent to there is a need to improve not only epicardial coronary achieve early patency of the coronary artery. However, flow, but also myocardial perfusion. by understanding the clot itself, and the overall patho- The study by Neumann et al11 was a trial of primary physiology of acute MI, the view of what is necessary to stenting for acute MI, randomizing between abciximab achieve benefit in acute MI has expanded. The recogni- vs. heparin. Abcixmiab led to significant improvement in tion that fibrinolysis is prothrombotic is a key step in regional wall motion of the infarct zone and a significant this process. Lysing fibrin with a plasminogen activator improvement in ejection fraction when assessed pre-dis- exposes unbound thrombin, which can in turn stimulate charge. The explanation might be that abciximab led to platelet aggregation. The platelets secrete high quanti- marked improvement of coronary flow velocity under ties of plasminogen activator inhibitor 1, a potent and provocation. This suggests that microvascular obstruction naturally occurring inhibitor activator to plasminogen and its alleviation by abciximab may be correlated with activators. Thus, thrombolytic therapy sets up a pro- better outcomes in this study. There were better clinical thrombotic milieu. outcomes as well. The combination of abciximab and reduced-dose In the large GUSTO IV-AMI trial, the question to thrombolysis (which will be tested in the large GUSTO be resolved is whether a combined approach with fibrin IV trial that is planned to start in 1999) is predicated on and platelet lysis will improve mortality via different four distinct directions, that the combination therapy will: • improve infarct vessel patency Table 2: Future directions in antithrombotic • reduce coronary reocclusion therapy for ACS • reduce microvascular obstruction • reduce the rate of intracranial hemorrhage. • Oral IIb/IIIa inhibitors With regard to infarct vessel patency, the SPEED • Clopidogrel plus aspirin trial has enrolled over 480 patients with Core Lab data available on approximately 250. Patients are randomized • Anti-inflammatory therapies to several doses of reteplase plus abciximab and the best — P-selectin inhibitors results come from the 5 U + 5 U reteplase plus abcix- — COX-2 inhibitors imab: 62% in TIMI 3 flow at 60 minutes. The combined TIMI 2 and 3 flow was 83%. The bleeding events in this • Platelet GP Ib inhibitors trial have not been of concern. There have been only two intracranial hemorrhages: one in the five U single bolus • Gene therapy and one in the 5 U +5 U combined with abciximab. Cardiology S C I E N T I F I C U P D AT E
  6. 6. mechanisms — infarct vessel patency, limiting or reducing 3. Cannon CP, Johnson EB, Cermignani M, Scirica BM, Sagarin MJ, Walls RM. Emergency Department Thrombolysis Critical Pathway Reduces occlusion, reducing microvascular obstruction — without Door-to-Drug Times in Acute Myocardial Infarction. Clin Cardiol 1999; increasing intracranial hemorrhage. 22:17-22. 4. Nichol G, Walls R, Goldman L, et al. A critical pathway for management Future directions in antithrombotic therapy of patient with acute chest pain at low risk for myocardial ischemia: Recommendations and potential impact. Ann Intern Med 1997;127:996- James T. Willerson, MD 1005. When a coronary artery is injured by plaque fissuring, 5. Cannon CP. Platelet glycoprotein IIb/IIIa inhibition in acute coronary syn- dromes. Cardiology Rounds 1998;2:1-8. ulceration, or an interventional procedure, a number of dif- 6. The EPISTENT Investigators. Randomised placebo-controlled and bal- ferent mediators accumulate that create an intensely pro- loon-angioplasty-controlled trial to assess the safety of coronary stenting thrombolytic environment. Thromboxane, serotonin, ADP, with use of platelet glycoprotein-IIb/IIIa blockade. Lancet 1998;352:87-92. platelet factor 4, tissue factor, endothelin, and oxygen- 7. The CAPTURE Investigators. Randomised placebo-controlled trial of abciximab before and during coronary intervention in refractory unstable derived free radicals all accumulate at that site. These are all angina: the CAPTURE study. Lancet 1997;349:1429-1435. potential targets for newer antithrombotic agents (Table 2). 8. The Platelet Receptor Inhibition for Ischemic Syndrome Management in The platelet GP IIb/IIIa receptor blockers inhibit platelet Patients Limited by Unstable Signs and Symptoms (PRISM-PLUS) Trial Investigators. Inhibition of the Platelet Glycoprotein IIb/IIIa Receptor With aggregation in response to all of the mediators mentioned Tirofiban in Unstable Angina and Non-Q-Wave Myocardial Infarction. N above. Thus antibodies, synthetic peptides, and low molecu- Engl J Med 1998;338:1488-1497. lar weight inhibitors of the platelet GP IIb/IIIa receptors, 9. Lefkovits J, Ivanhoe RJ, Califf RM, et al, for the EPIC Investigators. Effects of platelet glycoprotein IIb/IIIa receptor blockade by a chimeric markedly diminish the risk of thrombosis and its conse- monoclonal antibody (abciximab) on acute and six-month outcomes after quences after vascular injury. The ability to give such agents percutaneous transluminal coronary angioplasty for acute myocardial infarction. Am J Cardiol 1996;77:1045-1051. orally should provide more extended protection in a chronic 10. Brenner SJ, Barr LA, Burchenal JEB, et al, on behalf of the ReoPro and the form, diminishing the likelihood of the abrupt develop- Primary PTCA Organization and Randomized Trial (RAPPORT) ment of a thrombotic occlusion of a major artery. If this is Investigators. Randomized, placebo-controlled trial of platelet IIb/IIIa blockade with primary angioplasty for acute myocardial infarction. true, the incidence of MI and stroke will decline with the use Circulation 1998;98:734-741. of these agents. There is some evidence that the addition of 11. Neumann F-J, Blasini R, Schmitt C, et al. Effect of glycoprotein IIb/IIIa aspirin to platelet GP IIb/IIIa receptor inhibitors is additive in receptor blockade on recovery of coronary flow and left ventricular func- tion after placement of coronary-artery stents in acute myocardial infarc- protection, most likely due to the anti-inflammatory effects tion. Circulation 1998;98:2695-2701. of aspirin that reduce the risk of thrombosis and fibroprolifer- 12. Topol EJ, Byzova TV, Plow ER. Platelet GP IIb-IIIa blockers. Lancet ation. However, recognized limitations of oral IIb/IIIa inhibi- 1999;353:227-231. tion include the following: 13. Mark DB, Talley JD, Topol EJ, et al, for the EPIC Investigators. Economic assessment of platelet glycoprotein IIb/IIIa inhibition for prevention of • there is no reduction in platelet adhesion generally ischemic complications of high-risk coronary angioplasty. Circulation • there is no prevention of platelet activation and secretion 1996;94:629-635. • there may not be effective inhibition of tissue factor or of 14. Rawles J, on behalf of the GREAT Group. Halving of mortality at 1 year by domiciliary thrombolysis in the Grampian Region Early Anistreplase the thrombus-bound thrombin which may not be accessible Trial (GREAT). J Am Coll Cardiol 1994;23:1-5. to these inhibitors 15. The European Myocardial Infarction Project Group. Prehospital throm- • they do not inhibit inflammation. bolytic therapy in patients with suspected acute myocardial infarction. N Engl J Med 1993;329:383-389. For these reasons, one wishes to see the development of 16. Weaver WD, Cerqueira M, Hallstrom AP, et al, for the Myocardial additional antithrombotic strategies, including ones that pro- Infarction Triage and Intervention Project Group. Prehospital-initiated vs vide some protection in those areas in which the platelet GP hospital-initiated thrombolytic therapy. Myocardial Infarction Triage and Intervention Trial. JAMA 1993;270:1211-1216. IIb/IIIa receptor inhibitors are relatively ineffective. 17. Cannon CP, Gibson CM, McCabe CH, et al, for the TIMI 10B Thus, potentially valuable new anti-thrombotic interven- Investigators. TNK-tissue plasminogen activator compared with front- tions include inhibitors of platelet adhesion; inhibitors of tis- loaded alteplase in acute myocardial infarction: Results of the TIMI 10B trial. Circulation 1998;98:2805-2814. sue factor and of thrombin that might be administered locally 18. Antman EM, Giugliano RP, Gibson CM, et al, for the Thrombolysis in and be directly effective; and combined inhibitors of inflam- Myocardial Infarction (TIMI) 14 Investigators. Abciximab facilitates the mation and thrombosis (Table 2). These approaches are cur- rate and extent of thrombolysis: Results of TIMI 14 trial. Circulation (In press). rently being tested in experimental and clinical trials. 19. Sabia PJ, Powers ER, Ragosta M, Sarembock IJ, Burwell LR, Kaul S. An References association between collateral blood flow and myocardial viability in 1. Gibler WB, Runyon JP, Levy RC, et al. A rapid diagnostic and treatment patients with recent myocardial infarction. N Engl J Med 1992;327:1825- center for patients with acute chest pain in the emergency department. Ann 1831. Emerg Med 1995;25:1-8. 20. Ito H, Maruyama A, Iwakura K, et al. Clinical implications of the ‘no 2. Tatum JL, Jesse RL, Kontos MC, et al. Comprehensive strategy for the reflow’ phenomenon. A predictor of complications and left ventricular evaluation and triage of the chest pain patient. Ann Emerg Med 1997; remodeling in reperfused anterior wall myocardial infarction. Circulation 29:116-125. 1996;93:223-228. © 1999 Brigham and Women’s Hospital, Boston, Massachusetts, which is solely responsible for the contents. Publisher: Snell Medical Communication Inc. in cooperation with Brigham and Women’s Hospital, Boston, Massachusetts. All rights reserved. The administration of any therapies discussed or referred to in Cardiology Scientific Update should always be consistent with the recognized prescribing information as required by the FDA. Snell Medical Communication Inc. is committed to the development of superior Continuing Medical Education. 120-273

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