Contemporary View of the Acute Coronary Syndromes (Part II of II)

The dilemma of invasive versus conservative strategies. After patients with unstable angina and NSTEMI have been stabilized with medical therapy, a decision must be made regarding risk stratification. Several randomized trials have compared outcomes with early conservative versus early invasive management in ACS. Results of these trials were conflicting and most antedated the use of platelet GP IIb/IIIa receptor inhibitors and coronary stenting (Table 3). These include TIMI-IIIB,60 VANQWISH,61,62 MATE,63 FRISC II,64,65 and TACTICS-TIMI 18.66 The TIMI-IIIB trial60 used a 2 x 2 factorial design to compare tissue-type plasminogen activator and placebo, and an early invasive strategy versus an early conservative strategy in patients with unstable angina or NSTEMI. Both strategies resulted in a similar incidence of death or myocardial infarction, with apparently similar costs (at 1-year follow-up, the incidence of death or myocardial infarction was 10.8% for early invasive versus 12.2% for early conservative strategy). In the Veterans Affairs Non-Q Wave Infarction Strategies In-Hospital (VANQWISH) trial,61,62 patients with a non-Q wave MI were randomized to an early invasive strategy versus an early conservative strategy. During the first year, there was a significantly higher incidence of both the primary endpoint and death in the invasive arm (111 events versus 85 events, p = 0.05 for the primary endpoint; 58 deaths versus 36 deaths, p = 0.024). This difference was largely related to excess in-hospital mortality (21 patients versus 6 patients; p = 0.007), most of which were post-CABG deaths. Important limitations of this trial include marked delays in angiography and revascularization in the invasive group. The MATE trial63 was a small, randomized trial that evaluated the outcomes of 201 patients with ACS who were ineligible for thrombolytic therapy. At hospital discharge, the primary endpoint of recurrent ischemic events or death occurred in 14 patients (13%) in the triage angiography group versus 31 patients (34%) in the conservative group (risk reduction, 45%; 95% confidence interval, 27–59%; p = 0.0002). However, long-term follow-up at a median of 21 months revealed no significant differences in the endpoints in both groups. The FRISC II trial64,65 was the first to compare early invasive and early conservative strategies in the stenting era. At 1 year, patients randomized to the invasive arm had lower rates of death (2.2% versus 3.9%; p = 0.016), myocardial infarction (8.6% versus 11.6%; p = 0.015), death or myocardial infarction (10.4% versus 14.1%; p = 0.005). They also had less hospital readmission (37% versus 57%; p Risk stratification in acute coronary syndromes. A possible explanation of the conflicting results in the above trials is the fact that patients with ACS present with a wide spectrum of clinical risk for death and cardiac ischemic events. Ideally, one ought to be able to identify high-risk patients who might benefit mostly from an aggressive invasive approach, and those with lower risk where conservative management might be more appropriate. Several analyses have been performed attempting to identify prognostic risk factors in patients with ACS. The most comprehensive risk assessment model to date is the TIMI risk score proposed by Antman et al.67 The TIMI risk score was derived by selection of independent prognostic factors using multivariate logistic regression, and the number of factors present were added to categorize patients into risk strata. The seven TIMI risk score predictor variables were: age >= 65 years; >= 3 risk factors for coronary artery disease; prior coronary stenosis > 50%; ST-segment deviation on electrocardiogram on presentation; >= 2 anginal events in less than 24 hours; use of aspirin in prior 7 days; and elevated serum markers (Table 4). Event rates increased significantly as the TIMI risk score increased, and ranged from 4.7% when no or one risk factor was present to 40.9% when 6 or 7 risk factors were present (Figure 7). Using the TIMI risk score model in the TACTICS-TIMI 18 trial,66 an invasive approach was most beneficial when the TIMI risk score was 5–7 (odds ratio, 0.55; 95% confidence interval, 0.33–0.91). When the TIMI risk score is 0–2, on the other hand, early invasive or conservative approaches were similar (Figure 8). Based on these studies, it seems that patients with ACS who are at higher risk are likely to benefit the most from an early invasive approach. In lower risk patients, both approaches yield similar outcomes, but a conservative approach might be more cost-effective. Further studies will help clarify these points. Conclusion. ACS remains a vexing clinical problem. Past research has confirmed that plaque rupture with subsequent thrombosis is the final mechanism of ACS. New research is now uncovering the myriad processes that lead to plaque rupture. Some of the known factors include a thin fibrous cap, large lipid-rich core and predominance of inflammatory cells. Impressive clinical strides have been made in dealing with the antithrombotic approach to the treatment of ACS. Beneficial medications include aspirin, clopidogrel, unfractionated and low-molecular-weight heparins, and platelet GP IIb/IIIa receptor inhibitors. We are only now beginning to develop therapies for the earlier stages of ACS, such as the inflammatory component. Trials comparing early invasive with early conservative approaches have yielded conflicting results. Nevertheless, it appears that patients who are at higher risk by the TIMI criteria are likely to benefit the most from an early invasive approach, whereas both approaches yield similar outcomes in lower risk patients.

1. Constantinides P. Plaque fissuring in human coronary thrombosis. J Atheroscler Res 1966;6:1–6. 2. Davies MJ, Thomas AC. Plaque fissuring — The cause of acute myocardial infarction, sudden cardiac death, and crescendo angina. Br Heart J 1985;53:363–373. 3. Falk E. Plaque rupture with severe pre-existing stenosis precipitating coronary thrombosis. Characteristics of coronary atherosclerotic plaques underlying fatal occlusive thrombi. Br Heart J 1983;50:127–134. 4. Fuster V, Badimon L, Badimon JJ, Chesebro JH. The pathogenesis of coronary artery disease and the acute coronary syndromes. N Engl J Med 1992;326:242–250. 5. Libby P. Molecular bases of the acute coronary syndromes. Circulation 1995;91:2844–2850. 6. Tomassi S, Carluccio E, Bentivoglio M, et al. C-reactive protein as a marker of cardiac ischemic events in the year after a first, uncomplicated myocardial infarction. Am J Cardiol 1999;83:1595–1599. 7. Harb TS, Zareba W, Moss AJ, et al. Association of C-reactive protein and serum amyloid A with recurrent coronary events in stable patients after healing of acute myocardial infarction. Am J Cardiol 2002;89:216–221. 8. Ridker PM, Rifai N, Stampfer MJ, Hennekens CH. Plasma concentration of interleukin-6 and the risk of future myocardial infarction among apparently healthy men. Circulation 2000;101:1767–1772. 9. Biasucci LM, Liuzzo G, Caligiuri G, et al. Temporal relation between ischemic episodes and activation of the coagulation system in unstable angina. Circulation 1996;93:2121–2127. 10. Ma J, Hennekens CH, Ridker PM, Stampfer MJ. A prospective study of fibrinogen and risk of myocardial infarction in the Physicians’ Health Study. J Am Coll Cardiol 1999;33:1347–1352. 11. Amento EP, Ehsani N, Palmer H, Libby P. Cytokines positively and negatively regulate interstitial collagen gene expression in human vascular smooth muscle cells. Arteriosclerosis 1991;11:1223–1230. 12. Shah PK, Falk E, Badimon JJ, et al. Human monocyte-derived macrophages induce collagen breakdown in fibrous caps of atherosclerotic plaques. Potential role of matrix-degrading metalloproteinases and implications for plaque rupture. Circulation 1995;92:1565–1569. 13. Stefanadis C, Diamantopoulos L, Vlachopoulos C, et al. Thermal heterogeneity within human atherosclerotic coronary arteries detected in vivo: A new method of detection by application of a special thermography catheter. Circulation 1999;99:1965–1971. 14. MacIsaac AI, Thomas JD, Topol EJ. Toward the quiescent coronary plaque. J Am Coll Cardiol 1993;22:128–141. 15 Lewis HD Jr., Davis JW, Archibald DG, et al. Protective effects of aspirin against acute myocardial infarction and death in men with unstable angina: Results of the Veterans Administration Cooperative Study. N Engl J Med 1983;309:396–403. 16. Cairns JA, Gent M, Singer J, et al. Aspirin, sulfinpyrazone, or both in unstable angina. Results of a Canadian multicenter trial. N Engl J Med 1985;313:1369–1375. 17. Theroux P, Ouimet H, McCans J, et al. Aspirin, heparin, or both to treat acute unstable angina. N Engl J Med 1988;319:1105–1111. 18. 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;336:827–830. 19. Gum PA, Kottke-Marchant K, Poggio ED, et al. Profile and prevalence of aspirin resistance in patients with cardiovascular disease. Am J Cardiol 2001;88:230–235. 20. Eikelboom JW, Hirsh J, Weit JL, et al. Aspirin-resistant thromboxane biosynthesis and the risk of myocardial infarction, stroke, or cardiovascular death in patients at high risk for cardiovascular events. Circulation 2002;105:1650–1655. 21. CAPRIE Steering Committee. A randomized, blinded trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). Lancet 1996;348:1329–1339. 22. Bertrand ME, Rupprecht HJ, Gershlick AH, for the CLASSICS Investigators. Double-blind study of the safety of clopidogrel with and without a loading dose in combination with aspirin after coronary stenting: The clopidogrel aspirin stent international cooperative study (CLASSICS). Circulation 2000;102:624–629. 23. Mehta SR, Yusuf S. The Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) Study Investigators. The CURE trial programme: Rationale, design and baseline characteristics including a meta-analysis of the effects of thienopyridines in vascular disease. Eur Heart J 2000;2:2033–2041. 24. The 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. 25. Mehta SR, Yusuf S, Peters RJ, et al. Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) Trial Investigators. Effects of pretreatment with clopidogrel and aspirin followed by long-term therapy in patients undergoing percutaneous coronary intervention: The PCI-CURE Study. Lancet 2001;358:527–533. 26. Cohen M, Adams PC, Parry G, et al., for the Antithrombotic Therapy in Acute Coronary Syndromes Research Group: Combination antithrombotic therapy in unstable rest angina and non-Q wave infarction non-prior aspirin users: Primary endpoints analysis from the ATACS trial. Circulation 1994;89:81–88. 27. Cohen M, Adams PC, Hawkins L, et al. Usefulness of antithrombotic therapy in resting angina pectoris or non-Q wave myocardial infarction in preventing death and myocardial infarction (A pilot study from the Antithrombotic Therapy in Acute Coronary Syndromes Study Group). Am J Cardiol 1990;66:1287–1292. 28. Holdright D, Patel D, Cunningham D, et al. Comparison of the effect of heparin and aspirin versus aspirin alone on transient myocardial ischemia and in-hospital prognosis in patients with unstable angina. J Am Coll Cardiol 1994;24:39–45. 29. Gurfinkel EP, Manos EJ, Mejail RI, et al. Low molecular weight heparin versus regular heparin or aspirin in the treatment of unstable angina and silent ischemia. J Am Coll Cardiol 1995;26:313–318. 30. Oler A, Whooley MA, Oler J, Grady D. Adding heparin to aspirin reduces the incidence of myocardial infarction and death in patients with unstable angina. A meta-analysis. JAMA 1996;276:811–815. 31. 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;337:447–452. 32. Antman EM, McCabe CH, Gurfinkel EP, et al. Enoxaparin prevents death and cardiac ischaemic events in unstable angina/non-Q-wave myocardial infarction. Results of the Thrombolysis In Myocardial Infarction (TIMI) 11B trial. Circulation 1999;100:1593–1601. 33. 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;100:1602–1608. 34. Klein W, Buchwald A, Hillis SE, et al. Comparison of low-molecular-weight heparin with unfractionated heparin acutely and with placebo for 6 weeks in the management of unstable coronary artery disease. Fragmin in Unstable Coronary Artery Disease Study (FRIC). Circulation 1997;96:61–68. 35. Fragmin During Instability in Coronary Artery Disease (FRISC) study group: Low-molecular-weight heparin during instability in coronary artery disease. Lancet 1996;347:561–568. 36. FRISC II Investigators. Invasive compared with non-invasive treatment in unstable coronary-artery disease: FRISC II prospective randomized multicentre study. Fragmin and Fast Revascularization During Instability in Coronary Artery Disease Investigators. Lancet 1999;354:701–707. 37. FRISC II Investigators. Invasive compared with non-invasive treatment in unstable coronary artery disease: FRISC II prospective randomized multicentre study. Fragmin and Fast Revascularization During Instability in Coronary Artery Disease Investigators. Lancet 1999;354:708–715. 38. The FRAXIS Study Group: Comparison of two treatment durations (6 days and 14 days) of a low molecular weight heparin with a 6-day treatment of unfractionated heparin in the initial management of unstable angina or non-Q wave myocardial infarction: FRAXIS (FRAXiparine in Ischemic Syndrome). Eur Heart J 1999;20:1553–1562. 39. PRISM Study Investigators. A comparison of aspirin plus tirofiban with aspirin plus heparin for unstable angina. N Engl J Med 1998;338:1498–1505. 40. PRISM-PLUS Study 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;338:1488–1497. 41. PURSUIT Trial Investigators. Inhibition of platelet glycoprotein IIb/IIIa with eptifibatide in patients with acute coronary syndromes. N Engl J Med 1998;339:436–443. 42. PARAGON Investigators. International, randomized, controlled trial of lamifiban (a platelet glycoprotein IIb/IIIa inhibitor, heparin, or both in unstable angina). Circulation 1998;97:2386–2395. 43. GUSTO IV-ACS Investigators. Effect of glycoprotein IIb/IIIa receptor blocker abciximab on outcome in patients with acute coronary syndromes without early coronary revascularization: The GUSTO IV-ACS randomized trial. Lancet 2001;357:1915–1924. 44. Chew DP, Moliterno DJ. A critical appraisal of platelet glycoprotein IIb/IIIa inhibition. J Am Coll Cardiol 2000;36:2028–2035. 45. Kleiman NS, Lincoff AM, Flaker GC, et al. Early percutaneous coronary intervention, platelet inhibition with eptifibatide and clinical outcomes in patients with acute coronary syndromes. Circulation 2000;101:751–757. 46. Heeschen C, Hamm CW, Goldmann B, et al., for the PRISM Study Investigators. Troponin concentrations for stratification of patients with acute coronary syndromes on relation to therapeutic efficacy of tirofiban. Platelet Receptor Inhibition in Ischemic Syndrome Management (PRISM). Lancet 1999;354:1757–1762. 47. CAPTURE Investigators. Randomised placebo-controlled trial of abciximab before and during coronary intervention in refractory unstable angina: The CAPTURE study. Lancet 1997;349:1429–1435. 48. 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 UA/NSTEMI in PRISM-PLUS. Eur Heart J 2002;23:223–229. 49. Topol EJ, Moliterno DJ, Herrmann HC. Comparison of two platelet glycoprotein IIb/IIIa inhibitors, tirofiban and abciximab, for the prevention of ischemic events with percutaneous coronary revascularization. N Engl J Med 2001;344:1888–1894. 50. Schwartz GC, Oliver MF, Ezekowitz MD, et al. Rationale and design of the Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) study that evaluates atorvastatin in unstable angina pectoris and in non-Q wave myocardial infarction. Am J Cardiol 1998;81:578–581. 51. Schwartz GG, Olsson AG, Ezekowitz MD, et al. Effects of atorvastatin on early recurrent ischemic events in acute coronary syndromes: The MIRACL study: A randomized controlled trial. Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) Study Investigators. JAMA 2001;285:1711–1718. 52. Crisby M, Nordin-Fredriksson G, Shah PK, et al. Pravastatin treatment increases collagen content and decreases lipid content, inflammation, metalloproteinases, and cell death in human carotid plaques: Implications for plaque stabilization. Circulation 2001;103:926–933. 53. Albert MA, Danielson E, Rifai N, Ridker PM, for the PRINCE Investigators. Effect of statin therapy on C-reactive protein levels: The pravastatin inflammation/CRP evaluation (PRINCE): A randomized trial and cohort study. JAMA 2001;286:64–70. 54. Ridker PM, Rifai N, Pfeffer MA, et al. Long-term effects of pravastatin on plasma concentration of C-reactive protein. The Cholesterol and Recurrent Events (CARE) Investigators. Circulation 1999;100:230–235. 55. Ridker PM, Cushman M, Stampfer MJ, et al. Inflammation, aspirin, and the risk of cardiovascular disease in apparently healthy men. N Engl J Med 1997;336:973–979. 56. Damas JK, Waehre T, Yndestad A, et al. Stromal cell-derived factor-1alpha in unstable angina: Potential antiinflammatory and matrix-stabilizing effects. Circulation 2002;106:36–42. 57. Herman MP, Sukhova GK, Kisiel W, et al. Tissue factor pathway inhibitor-2 is a novel inhibitor of matrix metalloproteinases with implications for atherosclerosis. J Clin Invest 2001;107:1117–1126. 58. Ambrose AJ, Martinez EE. A new paradigm for plaque stabilization. Circulation 2002;105:2000–2004. 59. Yusuf S, Sleight P, Pogue J, et al. Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high risk patients. The Heart Outcomes Prevention Evaluation Study Investigators. N Engl J Med 2000;34:145–153. 60. The 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;89:1545–1556. 61. Ferry DR, O’Rourke RA, Blaustein AS, et al. Design and baseline characteristics of the Veterans Affairs Non-Q Wave Infarction Strategies In-Hospital (VANQWISH) trial. VANQWISH Trial Research Investigators. J Am Coll Cardiol 1998;31:312–320. 62. 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 management strategy. Veterans Affairs Non-Q Wave Infarction Strategies in Hospital (VANQWISH) trial investigators. N Engl J Med 1998;338:1785–1792. 63. 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 trial (MATE) trial. J Am Coll Cardiol 1998;32:596–605. 64. FRISC II Investigators. Invasive compared with non-invasive treatment in unstable coronary-artery disease: FRISC II prospective randomized multicentre study. Fragmin and Fast Revascularization During Instability in Coronary Artery Disease Investigators. Lancet 1999;354:708–715. 65. Wallentin L, Lagerqvist B, Husted S, et al. Outcomes at one year after an invasive compared with a non-invasive strategy in unstable coronary-artery disease. The FRISC II invasive randomized trial. FRISC II Investigators. Fast Revascularization During Instability in Coronary Artery Disease. Lancet 2000;356:9–16. 66. Cannon CP, Weintraub WS, Demopoulos LA, et al. TACTICS (Treat Angina with Aggrastat and Determine Cost of Therapy with an Invasive or Conservative Strategy). Thrombolysis in Myocardial Infarction 18 Investigators. 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;344:1879–1887. 67. 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;284:835–842.