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Interventional therapy is the best approach for acute coronary syndromes
International Journal of Cardiology 68 (Suppl. 1) (1999) S73–S78
Interventional therapy is the best approach for acute coronary syndromes Spencer B. King III Emory University Hospital, N.E. Suite F606, 1364 Clifton Road, Atlanta, GA 30322, USA Accepted 18 September 1998
1. Introduction Acute myocardial infarction and unstable angina pectoris are manifestations of an altered coronary physiology which is often dynamic. Although pharmacologic therapies have been effective in reducing the final insult of platelet-mediated thrombosis and advanced vascular tone, the underlying severe obstructive lesion may limit the therapeutic benefit. A direct approach to acute coronary syndromes by coronary angioplasty, including stenting, can be of significant benefit. Restoration of coronary flow in itself is proven an effective anti-thrombotic measure and numerous observational studies have confirmed the value of angioplasty in unstable angina pectoris. Acute myocardial infarction has been addressed in its acute phase by primary angioplasty in several randomized trials, all of which have shown the superiority of the direct approach over thrombolytic therapy. Unstable and non-Q wave myocardial infarction have recently been addressed in several trials of medical therapy vs. intervention. The results of those trials are somewhat divergent and will be explored. The recent development of glycoprotein IIb / IIIa blockers have improved outcomes of angioplasty in several trials and have recently been tested in combination with stenting. The availability of such agents has opened up the possibility of combining thrombolytic therapy and interventional therapy safely. Finally, it is obvious that patients with acute coronary syndromes vary widely in terms of their risk profile. Improved triage of patients could add materially to
the proper selection of therapies, the outcomes, and the economic impact.
2. Acute myocardial infarction Several developments have resulted in important improvements in mortality from acute myocardial infarction. One of the earliest was the broad acceptance of coronary care units in the 1960s and another was the use of thrombolytic therapy for acute myocardial infarction. A series of thrombolytic trials resulted in important reductions in mortality [1–5]. It was recognized that with the early interventional trials, a high percentage of arteries were not opening within a time frame that could salvage a sufficient amount of myocardium. Improved thrombolytic regimens using tissue plasminogen activator were somewhat controversial until the GUSTO trial, which showed a small but significant benefit for this agent [6]. Still, it was apparent that all arteries were not opening and therefore following thrombolysis urgent angioplasty was advocated. Unfortunately intervention in the setting of thrombolysis resulted in increased complications secondary to the activated state of the platelets and the unstable highly thrombogenic character of the arteries being treated [7,8]. Direct angioplasty in the absence of thrombolytic therapy was first advocated by Geoffrey Hartzler in the early 1980s [9]. The first attempt to compare thrombolytic therapy with primary angioplasty was performed in a small randomized trial by O’Neill
0167-5273 / 99 / $ – see front matter 1999 Elsevier Science Ireland Ltd. All rights reserved. PII: S0167-5273( 98 )00294-0
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S.B. King III / International Journal of Cardiology 68 ( Suppl. 1) (1999) S73 –S78
[10]. These early experiences taught that primary angioplasty could open over 90% of infarct-related arteries and restore TIMI 3 flow. The pivotal trials comparing thrombolytic therapy to primary angioplasty were published in the same issue of the New England Journal of Medicine in 1993 [11–13]. These studies enrolled 779 patients randomized to thrombolytic therapy or an aggressive strategy of primary angioplasty. Although the thrombolytic regimens used were not as effective as those available today, the results remain interesting. Of the patients randomized to primary angioplasty, 91% received the procedure and 94% of those achieved TIMI 3 flow in the Primary Angioplasty vs. Myocardial Infarction (PAMI) and in the trial from Zwolle, The Netherlands. Combining those trials, the early mortality favored angioplasty by a ratio of 2.5% to 6.4%, reinfarction by a ratio of 2.2% to 7.9%, and stroke by a ratio of 0.3% vs. 2.6%. The time spent in the hospital was also shorter. Multivariate analysis of the PAMI trial results showed that an independent predictor of survival was the assignment to the primary angioplasty group. These trials were performed by highly experienced centers organized to provide primary angioplasty. A major concern was whether these results could be extended more broadly. The GUSTO IIb study [14] compared primary angioplasty to thrombolytic therapy in 1138 patients spread over 57 centers worldwide. In this study a more modern thrombolytic regimen of accelerated tPa was used. This regimen had previously been shown to improve the 90 min patency rates. The results of the GUSTO IIb trial were revealing in that primary angioplasty still maintained a trend toward improved survival although the difference did not reach statistical significance. The overall hospital mortality rate was just over 1% better in the primary angioplasty group than in the thrombolytic therapy group. In addition, disabling stroke and intracranial hemorrhage favored the angioplasty group. This trial has been interpreted as showing that primary angioplasty is best suited to centers that are highly trained in performing it and that thrombolytic therapy may be preferred when applied more broadly. This conclusion, however, seems inappropriate since the directional results were in favor of angioplasty even when applied in such a generalized fashion. An explanation of the more modest improvement
in GUSTO IIb compared to the earlier trials relates to the number of vessels achieving TIMI 3 flow. This was approximately 95% in the PAMI and Zwolle trials but was roughly 75% in GUSTO IIb. It is now well known that achieving TIMI 3 flow is the best correlate of long-term survival. The PAMI trial also identified patients who benefited the most from the approach of primary angioplasty. The overall reduction in death was from 6.5% in the thrombolytic group to 2.6 in the PTCA group. A low-risk group, however, was identified in which there was no difference in the incidence of death or reinfarction, however the high-risk group showed a significant reduction from 10.4% in the thrombolytic group to 2.0% in the PTCA group. A subsequent study, PAMI II, was organized in an effort to determine whether patients in the high-risk group could benefit further from intra-aortic balloon pumping and whether patients at low risk could be treated more economically utilizing early hospital discharge. That study confirmed the later assumption and showed that early discharge in low-risk patients was not associated with further complications, however intra-aortic balloon pumping did not provide additional benefit to those patients in the high-risk group. With the recent proliferation of stenting as a predominant procedure in interventional cardiology, a study comparing patients undergoing primary angioplasty for infarction with patients undergoing stenting for infarction was carried out. This study was recently completed (PAMI stent) and has been evaluated only for the 30 day outcomes. There was no significant improvement in mortality or acute complications in the stented cohort. Longer-term follow-up will show whether the stenting resulted in a decreased reintervention rate or not.
3. Unstable angina and non-Q wave myocardial infarction The pathophysiology of unstable angina pectoris and non-Q wave myocardial infarction may be very similar and these conditions are frequently are treated as a continuum. The only distinguishing feature is the elevation and the cardiac enzymes indicating myocardial necrosis. Common to both entities is diminished coronary flow in relation to the myocardial needs
S.B. King III / International Journal of Cardiology 68 ( Suppl. 1) (1999) S73 –S78
brought on primarily by reduction in the cross-sectional area of the artery supplying the ischemic zone rather than increased oxygen demand. This decreased perfusion is driven primarily by platelet-mediated thrombosis and by increased vascular tone acting in consort. The initiating event is often a plaque ulceration or fissure or thrombogenic surface stimulated by lipid-rich core underlying of thin fibrous cap. Regardless of the physiology of the lesion, the common occurrence of intermittent platelet adhesion activation and aggregation sets the stage for therapeutic interventions. Unstable syndromes almost always indicate a severe obstructive lesion and therefore an aggressive interventional approach seems logical. This approach has been investigated in a number of clinical trials which differ in design and the baseline characteristics of the patients studied. The TIMI 3B study [15] looked at patients with unstable angina and non-Q wave myocardial infarction randomized to either an early invasive strategy or an early medical treatment strategy. The early invasive patients underwent catheterization and the early conservative patients were treated at least initially with vigorous medical intervention. Looking at the long-term results, it is evident that at one year there was no significant difference in myocardial infarction or death with these events occurring in 12.2% of the early conservative group and in 10.8% of the early invasive group. The occurrence of angioplasty or bypass surgery was approximately 60% initially in the early invasive group but over 40% of the early conservative group also underwent catheterization and intervention within the first few months. At the end of one year, 64% of the early invasive patients had undergone angioplasty or surgery compared to 58% of the early conservative patients. This study reflects the difficulty with performing a study of continued medical therapy in this day of availability of acute interventions to interrupt ongoing ischemic syndromes. The RITA II [16] trial found no advantage for an early invasive strategy in these patients. The VANQWISH trial [17], which studied non-Q wave myocardial infarction patients only, found in late follow-up more death or myocardial infarction in the invasive arm. 29.9% for the invasive group vs. 26.9% for the conservative group. Mortality was also higher in the invasive group, 17.3% vs. 12.9%, but it should be noted that
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the in-hospital mortality that occurred in this trial was entirely in the group that went on to coronary bypass surgery. There was no mortality in patients undergoing angioplasty. The Asymptomatic Cardiac Ischemia Pilot study [18], aiming to control patients with mildly symptomatic or asymptomatic electrocardiographically documented ischemia, found that patients undergoing intervention either with surgery or angioplasty fared better than those who were continued on medical management.
4. The impact of antiplatelet therapy in unstable ischemic syndromes As indicated earlier, the centrality of platelet aggregation in unstable angina syndromes calls for a powerful approach to preventing this phenomenon. Such became possible with the development of the antibody to the glycoprotein IIb / IIIa (abciximab). This agent produces irreversible binding to platelets and has a biologic effect much longer than its prescribed 12 h infusion. The first study of this agent, EPIC [19] was designed to study patients with unstable angina pectoris and myocardial infarction who were scheduled to undergo a coronary interventional procedure with balloon angioplasty or atherectomy. The drug was given in two forms, one by bolus only and one by bolus and infusion lasting 12 h. The bolus plus infusion strategy proved to be the most effective and was compared to the placebo group. In this study there was a dramatic reduction in initial events which included death, myocardial infarction or the need for urgent revascularization. At 48 h these events were reduced from 9.8% in the placebo group to 6.6% in the treatment group. That benefit was maintained and widened somewhat by 30 days and continued to be seen at 6 month follow-up. There was, however, a greater incidence of bleeding in the patients treated with the IIb / IIIa antibody, abciximab. Major bleeding occurred in 14% of the treatment group and only 7% of the control group. Because of that, the heparin dosing was altered in a pilot study and the bleeding propensity seemed to diminish significantly. Other trials carried out with the agent utilized this lower heparin dosing schedule. Another trial of unstable angina patients, CAPTURE [20], was carried out in Europe. In this trial,
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the drug was started approximately 36 h prior to the planned procedure. There was a reduction in myocardial infarction in the group assigned to the abciximab but the greatest reduction in events occurred when the interventional procedure was performed. The composite endpoint was reduced at 48 h from 13.2% to 8.4%. There was some attrition primarily due to reintervention for non-urgent reasons over the next few months. A third trial, EPILOG [21], studied unstable patients but also broadened it to all patients undergoing interventional procedures. That study of angioplasty and atherectomy patients showed an early 48 h reduction in the composite ischemic endpoint from 9.2% to 4.0%. The long-term follow-up of those patients showed a 3 percentage point difference in all events at 6 months. Other agents have also been investigated in patients with unstable ischemic syndromes. The RESTORE trial [22] studied tirofiban, a small molecule peptidomymetic drug, that binds in a reversible fashion to the IIb / IIIa receptor of the platelet. This drug produces similar inhibition of platelet aggregation while being given but its effect is rapidly reversible after discontinuing the agent. Patients in the RESTORE trial had a similar dramatic reduction in ischemic events of death, myocardial infarction or urgent revascularization while the drug was being administered. At 48 h those events were reduced from 8.2% to 5.1%. The relative difference persisted throughout the 6 month follow-up and there was a 3 percentage point difference in total events at 6 months. A unifying concept common among all these acute intervention trials was the significant reduction in the non-Q wave myocardial infarction judged by CK MB elevation following the procedures. This was most marked in the trials in which CK MB was measured on a routine basis (EPIC, CAPTURE, EPILOG) and another trial of eptifibatide (IMPACT II) [23]. It was less evident in the RESTORE trial where routine CK measures were not obtained. Since the CK elevation is the major endpoint in the trials of IIb / IIIa blockade, it is very important to understand the long-term implication of elevation of the CK post procedure. In the EPIC, EPILOG and CAPTURE studies, a CK elevation of 5–10 times the normal value resulted in a probability of death at 6 months of approximately 6%. This differed significantly when compared to
patients who had either no elevation or less than 3 times CK elevation in whom the 6 month mortality rate was only approximately 2%. It is still not completely clear whether CK elevation in the absence of other events, such as Q wave myocardial infarction, evident vessel closure, or return for urgent intervention, had as powerful an impact. Several trials have looked at patients with unstable angina who were not immediately scheduled for interventional therapies. The PURSUIT trial [24] of 10 948 patients studied eptifibatide compared to placebo in patients with either transient EKG changes or CK MB elevations. In that trial there was a 16% reduction in the composite endpoint of death, myocardial infarction or urgent revascularization at 7 days. Two trials tested tirofiban. The PRISM trial examined tirofiban compared to heparin in patients with unstable ischemic syndromes. There was a significant reduction in ischemic events at 30 days. A second trial, PRISM PLUS [25], compared the use of tirofiban plus heparin with heparin alone. In that study there was a reduction in the composite ischemic endpoint from 17.9% to 12.9% at 7 days. Death or myocardial infarction was reduced from 8.3% to 4.9% in that study of unstable angina patients. In this study, a large percentage of the patients went on for angiography and subsequently PTCA. Of those who had an intervention, the reduction in events was even greater. The 30 day composite endpoint was reduced from 15.2% in the heparin group to 8.8% in the tirofiban plus heparin group and death or MI was reduced from 10.2% to 5.9%. These reductions were more dramatic than the reductions found in the PURSUIT trial. One potential explanation is that 90% of the patients in PRISM PLUS underwent angiography and 54% of those had revascularization. In the PURSUIT trial, only 60% of the patients had angiography and only 21% of those went on for interventional therapy. It seems clear that IIb / IIIa agents will be effective for unstable angina pectoris and will be even more powerfully effective in reducing those endpoints following interventional procedures. Taken in toto, IIb / IIIa agents all have shown benefit in reducing ischemic complications, especially the need for urgent revascularization and the elevation of CK MB enzymes. Currently there is a lot of interest in studying IIb / IIIa agents in conjunction with fibrinolytics. Approximately ten studies have
S.B. King III / International Journal of Cardiology 68 ( Suppl. 1) (1999) S73 –S78
been performed in experimental models and have shown prevention of reocclusion, increased reperfusion and increased speed of reperfusion. The TAMI 8 study [26], the IMPACT AMI study [27], and the study PARADIGM, have looked at IIb / IIIa agents with fibrinolytics in the clinical setting. These trials seem to support the concept that earlier patency, a high rate patency and less reocclusion may be possible when using IIb / IIIa agents in conjunction with thrombolytics. The most recently reported trial, EPISTENT, examined patients going for interventional therapy receiving balloon angioplasty with abciximab, stenting with abciximab, and stenting without abciximab. The early 30 day results of that trial have been reported and show dramatic reductions in the ischemic endpoints, notably the CK MB release in the two groups of patients receiving abciximab. Interestingly, the ischemic complications in patients undergoing balloon angioplasty with abciximab was significantly lower than the complication rate of those undergoing stenting without abciximab. Stenting plus the IIb / IIIa agent showed the best 30 day outcome.
5. Conclusions Given the evidence presented above, what is the current approach to patients with unstable angina syndromes? Much of the argument for medical therapy, thrombolysis and watchful waiting of the past was aimed at passivation of the plaque and restoration of a more stable situation that could either be tolerated on its own or would cause the patient to become a better candidate for interventional therapies. Currently with the availability of coronary stenting to stabilize the mechanical recoil and vascular dissections that sometimes occur with interventions and with the availability of potent antiplatelet agents to decrease the chance of post-procedure thrombosis, an early intervention seems reasonable for patients with unstable angina and non-Q wave myocardial infarction. For patients in the evolving stage of transmural myocardial infarction, these approaches also show great promise. Primary angioplasty has, in all studies, been as effective or more effective than thrombolysis in achieving TIMI 3 flow
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and in early recurrent infarction-free survival. A recently completed study, PACT, looked at combining thrombolysis with acute interventional therapy. Patients received front-loaded tPa and then went for urgent catheterization. In this way, high-risk patients were identified. As opposed to the TIMI 2 trial, patients with patent arteries and TIMI 3 flow were not intervened on even though they may have had a significant underlying lesion. Conversely, patients with arteries that remained occluded had those arteries opened at the time of the early catheterization. By withholding thrombolysis after the initial bolus, the platelet activation that was seen and was problematic in the TIMI 2 trial was likely avoided in this study. Ultimately, potent antiplatelet agents will be added to this protocol so that patients can receive the maximum benefit of all therapies. Patients who likely have occluded arteries will benefit from the very earliest thrombolysis. Urgent catheterization will then be possible with the use of IIb / IIIa blocking agents so that those patients at high risk can be identified early. Patients at highest risk may need the benefit of bypass surgery but most of those patients will be suitable for interventional approaches which will then be much safer to perform than in the previous experience. Although many unstable angina syndromes can likely be stabilized with medical therapy, especially with the modern agents available, the interventional approach will likely predominate in centers where this is available. It is also likely that overall costs will be reduced by the interventional approach, given the dramatically shortened hospital stay and decreased need for subsequent interventional procedures.
References [1] Chesebro JH, Knatterud G, Roberts R, et al. Thrombolysis In Myocardial Infarction (TIMI) Trial, Phase I: A comparison between intravenous tissue plasminogen activator and intravenous streptokinase: Clinical findings through hospital discharge. Circulation 1987;76:142–54. [2] 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;2:349–360. [3] Gruppo Italiano per lo Studio della Streptochinasi nell’Infarto Miocardico (GISSI). Effectiveness of intravenous thrombolytic treatment in acute myocardial infarction. Lancet 1986;1:397–402.
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[4] Kennedy JW, Ritchie IL, Davis KB, Stadius ML, Maynard C, Fritz JK. The Western Washington randomized trial of intracoronary streptokinase in acute myocardial infarction: A 12-month follow-up report. N Engl J Med 1985;312:1073–8. [5] Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto Miocardico. GISSI-2: A factorial randomised trial of alteplase versus streptokinase and heparin versus no heparin among 12 490 patients with acute myocardial infarction. Lancet 1990;336:65–71. [6] The GUSTO Investigators. An international randomized trial comparing four thrombolytic regimens consisting of tissue plasminogen activator, streptokinase, or both for acute myocardial infarction. N Engl J Med 1993;329:673–682. [7] The TIMI Study Group. Comparison of invasive and conservative strategies after treatment with intravenous tissue plasminogen activator in acute myocardial infarction: Results of the Thrombolysis In Myocardial Infarction (TIMI) Phase II Trial. N Engl J Med 1989;320:618–627. [8] Simoons ML, Arnold AER, Betriu A, et al. Thrombolysis with tissue plasminogen activator in acute myocardial infarction: No additional benefit from immediate percutaneous coronary angioplasty. Lancet 1988;1:197–203. [9] O’Keefe JO, Bailey WL, Rutherford BD, Hartzler GO. Primary angioplasty for acute myocardial infarction in 1000 consecutive patients. Am J Cardiol 1993;72:107G–15G. [10] O’Neill W, Timmis CC, Bourdillon PD, et al. A prospective randomized clinical trial of intracoronary streptokinase versus coronary angioplasty for acute myocardial infarction. N Engl J Med 1986;314:812–8. [11] Grines CL, Browne KIF, Marco J, et al. (For the Primary Angioplasty in Myocardial Infarction Study Group.) A comparison of immediate angioplasty with thrombolytic therapy for acute myocardial infarction. N Engl J Med 1993;328:673–9. [12] Zijlstra F, de Boer MJ, Hoorntje JCA, et al. A comparison of immediate coronary angioplasty with intravenous streptokinase in acute myocardial infarction. N Engl J Med 1993;328:680–4. [13] Gibbons RI, Holmes DR, Reeder GS, et al. Immediate angioplasty compared with the administration of a thrombolytic agent followed by conservative treatment for myocardial infarction. N Engl J Med 1993;328:685–91. [14] Angioplasty Substudy Investigators. A clinical trial comparing primary coronary angioplasty with tissue plasminogen activator for acute myocardial infarction: The global use of strategies to open occluded coronary arteries in acute coronary syndromes (GUSTO IIb). N Engl J Med 1997;336:1621–1628. [15] 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. [16] RITA-2 Trial Participants. Coronary angioplasty versus medical therapy for angina: The second Randomised Interventional Treatment of Angina (RITA-2) trial. Lancet 1997;350:461–468.
[17] Boden WE, Dai H. (On behalf of the VANQWISH Trial Investigators.) Long-term outcomes in non-Q-wave infarction patients randomized to an ‘invasive’ versus ‘conservative’ strategy: Results of the multicenter VA Non-Q-Wave Infarction Strategies in-Hospital (VANQWISH) trial (Abstr.). Eur Heart J 1997;18(1):351. [18] Rogers WJ, Bourassa MG, Andrews TC. (For the ACIP Investigators.) Asymptomatic Cardiac Ischemia Pilot (ACIP) Study: Outcome at 1 year for patients with asymptomatic cardiac ischemia randomized to medical therapy or revascularization. J Am Coll Cardiol 1995;26:594–605. [19] The EPIC Investigators. Use of a monoclonal antibody directed against the platelet glycoprotein IIb / IIIa receptor in high-risk coronary angioplasty. N Engl J Med 1994;330:956–961. [20] The 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. [21] The EPILOG Investigators. Platelet glycoprotein IIb / IIIa receptor blockade and low-dose heparin during percutaneous coronary revascularization. N Engl J Med 1997;336:1689–1696. [22] The RESTORE Investigators. Effects of platelet glycoprotein IIb / IIIa blockade with tirofiban on adverse cardiac events in patients with unstable angina or acute myocardial infarction undergoing coronary angioplasty. Circulation 1997;96:1445–1453. [23] The IMPACT II Investigators. Effects of competitive platelet glycoprotein IIb / IIIa inhibition with Integrilin in reducing complications of percutaneous coronary intervention. Lancet 1997;349:1422– 1428. [24] Harrington RA. Design and methodology of the PURSUIT trial: Evaluating entifibatide for acute ischemic coronary syndromes (Platelet glycoprotein IIb / IIIa in unstable angina: Receptor suppression using integrilin therapy trial). Am J Cardiol 1997;80:3413–813. [25] Barr E, Snapinn SM, Sax FL, Theroux P. (For the PRISM Plus Investigators.) Improved long-term clinical outcomes in unstable angina-patients undergoing coronary angioplasty following therapy with tirofiban and heparin. J Am Coll Cardiol 1998;31:55A. [26] Kleiman NS, Ohman EM, Califf RM, et al. Profound inhibition of platelet aggregation with monoclonal antibody 7E3 Fab after thrombolytic therapy: Results of the Thrombolysis and Angioplasty in Myocardial Infarction (TAMI) 8 pilot study. J Allergy Clin Immunol 1993;22:381–9. [27] Ohman EM, Kleiman NS, Gacioch G, et al. (For the IMPACT-AMI Investigators.) Combined accelerated tissue-plasminogen activator and platelet glycoprotein IIb / IIIa integrin receptor blockade with integrilin in acute myocardial infarction. Circulation 1997;95:846– 54.
Interventional therapy is the best approach for acute coronary syndromes Spencer B. King III Emory University Hospital, N.E. Suite F606, 1364 Clifton Road, Atlanta, GA 30322, USA Accepted 18 September 1998
1. Introduction Acute myocardial infarction and unstable angina pectoris are manifestations of an altered coronary physiology which is often dynamic. Although pharmacologic therapies have been effective in reducing the final insult of platelet-mediated thrombosis and advanced vascular tone, the underlying severe obstructive lesion may limit the therapeutic benefit. A direct approach to acute coronary syndromes by coronary angioplasty, including stenting, can be of significant benefit. Restoration of coronary flow in itself is proven an effective anti-thrombotic measure and numerous observational studies have confirmed the value of angioplasty in unstable angina pectoris. Acute myocardial infarction has been addressed in its acute phase by primary angioplasty in several randomized trials, all of which have shown the superiority of the direct approach over thrombolytic therapy. Unstable and non-Q wave myocardial infarction have recently been addressed in several trials of medical therapy vs. intervention. The results of those trials are somewhat divergent and will be explored. The recent development of glycoprotein IIb / IIIa blockers have improved outcomes of angioplasty in several trials and have recently been tested in combination with stenting. The availability of such agents has opened up the possibility of combining thrombolytic therapy and interventional therapy safely. Finally, it is obvious that patients with acute coronary syndromes vary widely in terms of their risk profile. Improved triage of patients could add materially to
the proper selection of therapies, the outcomes, and the economic impact.
2. Acute myocardial infarction Several developments have resulted in important improvements in mortality from acute myocardial infarction. One of the earliest was the broad acceptance of coronary care units in the 1960s and another was the use of thrombolytic therapy for acute myocardial infarction. A series of thrombolytic trials resulted in important reductions in mortality [1–5]. It was recognized that with the early interventional trials, a high percentage of arteries were not opening within a time frame that could salvage a sufficient amount of myocardium. Improved thrombolytic regimens using tissue plasminogen activator were somewhat controversial until the GUSTO trial, which showed a small but significant benefit for this agent [6]. Still, it was apparent that all arteries were not opening and therefore following thrombolysis urgent angioplasty was advocated. Unfortunately intervention in the setting of thrombolysis resulted in increased complications secondary to the activated state of the platelets and the unstable highly thrombogenic character of the arteries being treated [7,8]. Direct angioplasty in the absence of thrombolytic therapy was first advocated by Geoffrey Hartzler in the early 1980s [9]. The first attempt to compare thrombolytic therapy with primary angioplasty was performed in a small randomized trial by O’Neill
0167-5273 / 99 / $ – see front matter 1999 Elsevier Science Ireland Ltd. All rights reserved. PII: S0167-5273( 98 )00294-0
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S.B. King III / International Journal of Cardiology 68 ( Suppl. 1) (1999) S73 –S78
[10]. These early experiences taught that primary angioplasty could open over 90% of infarct-related arteries and restore TIMI 3 flow. The pivotal trials comparing thrombolytic therapy to primary angioplasty were published in the same issue of the New England Journal of Medicine in 1993 [11–13]. These studies enrolled 779 patients randomized to thrombolytic therapy or an aggressive strategy of primary angioplasty. Although the thrombolytic regimens used were not as effective as those available today, the results remain interesting. Of the patients randomized to primary angioplasty, 91% received the procedure and 94% of those achieved TIMI 3 flow in the Primary Angioplasty vs. Myocardial Infarction (PAMI) and in the trial from Zwolle, The Netherlands. Combining those trials, the early mortality favored angioplasty by a ratio of 2.5% to 6.4%, reinfarction by a ratio of 2.2% to 7.9%, and stroke by a ratio of 0.3% vs. 2.6%. The time spent in the hospital was also shorter. Multivariate analysis of the PAMI trial results showed that an independent predictor of survival was the assignment to the primary angioplasty group. These trials were performed by highly experienced centers organized to provide primary angioplasty. A major concern was whether these results could be extended more broadly. The GUSTO IIb study [14] compared primary angioplasty to thrombolytic therapy in 1138 patients spread over 57 centers worldwide. In this study a more modern thrombolytic regimen of accelerated tPa was used. This regimen had previously been shown to improve the 90 min patency rates. The results of the GUSTO IIb trial were revealing in that primary angioplasty still maintained a trend toward improved survival although the difference did not reach statistical significance. The overall hospital mortality rate was just over 1% better in the primary angioplasty group than in the thrombolytic therapy group. In addition, disabling stroke and intracranial hemorrhage favored the angioplasty group. This trial has been interpreted as showing that primary angioplasty is best suited to centers that are highly trained in performing it and that thrombolytic therapy may be preferred when applied more broadly. This conclusion, however, seems inappropriate since the directional results were in favor of angioplasty even when applied in such a generalized fashion. An explanation of the more modest improvement
in GUSTO IIb compared to the earlier trials relates to the number of vessels achieving TIMI 3 flow. This was approximately 95% in the PAMI and Zwolle trials but was roughly 75% in GUSTO IIb. It is now well known that achieving TIMI 3 flow is the best correlate of long-term survival. The PAMI trial also identified patients who benefited the most from the approach of primary angioplasty. The overall reduction in death was from 6.5% in the thrombolytic group to 2.6 in the PTCA group. A low-risk group, however, was identified in which there was no difference in the incidence of death or reinfarction, however the high-risk group showed a significant reduction from 10.4% in the thrombolytic group to 2.0% in the PTCA group. A subsequent study, PAMI II, was organized in an effort to determine whether patients in the high-risk group could benefit further from intra-aortic balloon pumping and whether patients at low risk could be treated more economically utilizing early hospital discharge. That study confirmed the later assumption and showed that early discharge in low-risk patients was not associated with further complications, however intra-aortic balloon pumping did not provide additional benefit to those patients in the high-risk group. With the recent proliferation of stenting as a predominant procedure in interventional cardiology, a study comparing patients undergoing primary angioplasty for infarction with patients undergoing stenting for infarction was carried out. This study was recently completed (PAMI stent) and has been evaluated only for the 30 day outcomes. There was no significant improvement in mortality or acute complications in the stented cohort. Longer-term follow-up will show whether the stenting resulted in a decreased reintervention rate or not.
3. Unstable angina and non-Q wave myocardial infarction The pathophysiology of unstable angina pectoris and non-Q wave myocardial infarction may be very similar and these conditions are frequently are treated as a continuum. The only distinguishing feature is the elevation and the cardiac enzymes indicating myocardial necrosis. Common to both entities is diminished coronary flow in relation to the myocardial needs
S.B. King III / International Journal of Cardiology 68 ( Suppl. 1) (1999) S73 –S78
brought on primarily by reduction in the cross-sectional area of the artery supplying the ischemic zone rather than increased oxygen demand. This decreased perfusion is driven primarily by platelet-mediated thrombosis and by increased vascular tone acting in consort. The initiating event is often a plaque ulceration or fissure or thrombogenic surface stimulated by lipid-rich core underlying of thin fibrous cap. Regardless of the physiology of the lesion, the common occurrence of intermittent platelet adhesion activation and aggregation sets the stage for therapeutic interventions. Unstable syndromes almost always indicate a severe obstructive lesion and therefore an aggressive interventional approach seems logical. This approach has been investigated in a number of clinical trials which differ in design and the baseline characteristics of the patients studied. The TIMI 3B study [15] looked at patients with unstable angina and non-Q wave myocardial infarction randomized to either an early invasive strategy or an early medical treatment strategy. The early invasive patients underwent catheterization and the early conservative patients were treated at least initially with vigorous medical intervention. Looking at the long-term results, it is evident that at one year there was no significant difference in myocardial infarction or death with these events occurring in 12.2% of the early conservative group and in 10.8% of the early invasive group. The occurrence of angioplasty or bypass surgery was approximately 60% initially in the early invasive group but over 40% of the early conservative group also underwent catheterization and intervention within the first few months. At the end of one year, 64% of the early invasive patients had undergone angioplasty or surgery compared to 58% of the early conservative patients. This study reflects the difficulty with performing a study of continued medical therapy in this day of availability of acute interventions to interrupt ongoing ischemic syndromes. The RITA II [16] trial found no advantage for an early invasive strategy in these patients. The VANQWISH trial [17], which studied non-Q wave myocardial infarction patients only, found in late follow-up more death or myocardial infarction in the invasive arm. 29.9% for the invasive group vs. 26.9% for the conservative group. Mortality was also higher in the invasive group, 17.3% vs. 12.9%, but it should be noted that
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the in-hospital mortality that occurred in this trial was entirely in the group that went on to coronary bypass surgery. There was no mortality in patients undergoing angioplasty. The Asymptomatic Cardiac Ischemia Pilot study [18], aiming to control patients with mildly symptomatic or asymptomatic electrocardiographically documented ischemia, found that patients undergoing intervention either with surgery or angioplasty fared better than those who were continued on medical management.
4. The impact of antiplatelet therapy in unstable ischemic syndromes As indicated earlier, the centrality of platelet aggregation in unstable angina syndromes calls for a powerful approach to preventing this phenomenon. Such became possible with the development of the antibody to the glycoprotein IIb / IIIa (abciximab). This agent produces irreversible binding to platelets and has a biologic effect much longer than its prescribed 12 h infusion. The first study of this agent, EPIC [19] was designed to study patients with unstable angina pectoris and myocardial infarction who were scheduled to undergo a coronary interventional procedure with balloon angioplasty or atherectomy. The drug was given in two forms, one by bolus only and one by bolus and infusion lasting 12 h. The bolus plus infusion strategy proved to be the most effective and was compared to the placebo group. In this study there was a dramatic reduction in initial events which included death, myocardial infarction or the need for urgent revascularization. At 48 h these events were reduced from 9.8% in the placebo group to 6.6% in the treatment group. That benefit was maintained and widened somewhat by 30 days and continued to be seen at 6 month follow-up. There was, however, a greater incidence of bleeding in the patients treated with the IIb / IIIa antibody, abciximab. Major bleeding occurred in 14% of the treatment group and only 7% of the control group. Because of that, the heparin dosing was altered in a pilot study and the bleeding propensity seemed to diminish significantly. Other trials carried out with the agent utilized this lower heparin dosing schedule. Another trial of unstable angina patients, CAPTURE [20], was carried out in Europe. In this trial,
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the drug was started approximately 36 h prior to the planned procedure. There was a reduction in myocardial infarction in the group assigned to the abciximab but the greatest reduction in events occurred when the interventional procedure was performed. The composite endpoint was reduced at 48 h from 13.2% to 8.4%. There was some attrition primarily due to reintervention for non-urgent reasons over the next few months. A third trial, EPILOG [21], studied unstable patients but also broadened it to all patients undergoing interventional procedures. That study of angioplasty and atherectomy patients showed an early 48 h reduction in the composite ischemic endpoint from 9.2% to 4.0%. The long-term follow-up of those patients showed a 3 percentage point difference in all events at 6 months. Other agents have also been investigated in patients with unstable ischemic syndromes. The RESTORE trial [22] studied tirofiban, a small molecule peptidomymetic drug, that binds in a reversible fashion to the IIb / IIIa receptor of the platelet. This drug produces similar inhibition of platelet aggregation while being given but its effect is rapidly reversible after discontinuing the agent. Patients in the RESTORE trial had a similar dramatic reduction in ischemic events of death, myocardial infarction or urgent revascularization while the drug was being administered. At 48 h those events were reduced from 8.2% to 5.1%. The relative difference persisted throughout the 6 month follow-up and there was a 3 percentage point difference in total events at 6 months. A unifying concept common among all these acute intervention trials was the significant reduction in the non-Q wave myocardial infarction judged by CK MB elevation following the procedures. This was most marked in the trials in which CK MB was measured on a routine basis (EPIC, CAPTURE, EPILOG) and another trial of eptifibatide (IMPACT II) [23]. It was less evident in the RESTORE trial where routine CK measures were not obtained. Since the CK elevation is the major endpoint in the trials of IIb / IIIa blockade, it is very important to understand the long-term implication of elevation of the CK post procedure. In the EPIC, EPILOG and CAPTURE studies, a CK elevation of 5–10 times the normal value resulted in a probability of death at 6 months of approximately 6%. This differed significantly when compared to
patients who had either no elevation or less than 3 times CK elevation in whom the 6 month mortality rate was only approximately 2%. It is still not completely clear whether CK elevation in the absence of other events, such as Q wave myocardial infarction, evident vessel closure, or return for urgent intervention, had as powerful an impact. Several trials have looked at patients with unstable angina who were not immediately scheduled for interventional therapies. The PURSUIT trial [24] of 10 948 patients studied eptifibatide compared to placebo in patients with either transient EKG changes or CK MB elevations. In that trial there was a 16% reduction in the composite endpoint of death, myocardial infarction or urgent revascularization at 7 days. Two trials tested tirofiban. The PRISM trial examined tirofiban compared to heparin in patients with unstable ischemic syndromes. There was a significant reduction in ischemic events at 30 days. A second trial, PRISM PLUS [25], compared the use of tirofiban plus heparin with heparin alone. In that study there was a reduction in the composite ischemic endpoint from 17.9% to 12.9% at 7 days. Death or myocardial infarction was reduced from 8.3% to 4.9% in that study of unstable angina patients. In this study, a large percentage of the patients went on for angiography and subsequently PTCA. Of those who had an intervention, the reduction in events was even greater. The 30 day composite endpoint was reduced from 15.2% in the heparin group to 8.8% in the tirofiban plus heparin group and death or MI was reduced from 10.2% to 5.9%. These reductions were more dramatic than the reductions found in the PURSUIT trial. One potential explanation is that 90% of the patients in PRISM PLUS underwent angiography and 54% of those had revascularization. In the PURSUIT trial, only 60% of the patients had angiography and only 21% of those went on for interventional therapy. It seems clear that IIb / IIIa agents will be effective for unstable angina pectoris and will be even more powerfully effective in reducing those endpoints following interventional procedures. Taken in toto, IIb / IIIa agents all have shown benefit in reducing ischemic complications, especially the need for urgent revascularization and the elevation of CK MB enzymes. Currently there is a lot of interest in studying IIb / IIIa agents in conjunction with fibrinolytics. Approximately ten studies have
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been performed in experimental models and have shown prevention of reocclusion, increased reperfusion and increased speed of reperfusion. The TAMI 8 study [26], the IMPACT AMI study [27], and the study PARADIGM, have looked at IIb / IIIa agents with fibrinolytics in the clinical setting. These trials seem to support the concept that earlier patency, a high rate patency and less reocclusion may be possible when using IIb / IIIa agents in conjunction with thrombolytics. The most recently reported trial, EPISTENT, examined patients going for interventional therapy receiving balloon angioplasty with abciximab, stenting with abciximab, and stenting without abciximab. The early 30 day results of that trial have been reported and show dramatic reductions in the ischemic endpoints, notably the CK MB release in the two groups of patients receiving abciximab. Interestingly, the ischemic complications in patients undergoing balloon angioplasty with abciximab was significantly lower than the complication rate of those undergoing stenting without abciximab. Stenting plus the IIb / IIIa agent showed the best 30 day outcome.
5. Conclusions Given the evidence presented above, what is the current approach to patients with unstable angina syndromes? Much of the argument for medical therapy, thrombolysis and watchful waiting of the past was aimed at passivation of the plaque and restoration of a more stable situation that could either be tolerated on its own or would cause the patient to become a better candidate for interventional therapies. Currently with the availability of coronary stenting to stabilize the mechanical recoil and vascular dissections that sometimes occur with interventions and with the availability of potent antiplatelet agents to decrease the chance of post-procedure thrombosis, an early intervention seems reasonable for patients with unstable angina and non-Q wave myocardial infarction. For patients in the evolving stage of transmural myocardial infarction, these approaches also show great promise. Primary angioplasty has, in all studies, been as effective or more effective than thrombolysis in achieving TIMI 3 flow
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and in early recurrent infarction-free survival. A recently completed study, PACT, looked at combining thrombolysis with acute interventional therapy. Patients received front-loaded tPa and then went for urgent catheterization. In this way, high-risk patients were identified. As opposed to the TIMI 2 trial, patients with patent arteries and TIMI 3 flow were not intervened on even though they may have had a significant underlying lesion. Conversely, patients with arteries that remained occluded had those arteries opened at the time of the early catheterization. By withholding thrombolysis after the initial bolus, the platelet activation that was seen and was problematic in the TIMI 2 trial was likely avoided in this study. Ultimately, potent antiplatelet agents will be added to this protocol so that patients can receive the maximum benefit of all therapies. Patients who likely have occluded arteries will benefit from the very earliest thrombolysis. Urgent catheterization will then be possible with the use of IIb / IIIa blocking agents so that those patients at high risk can be identified early. Patients at highest risk may need the benefit of bypass surgery but most of those patients will be suitable for interventional approaches which will then be much safer to perform than in the previous experience. Although many unstable angina syndromes can likely be stabilized with medical therapy, especially with the modern agents available, the interventional approach will likely predominate in centers where this is available. It is also likely that overall costs will be reduced by the interventional approach, given the dramatically shortened hospital stay and decreased need for subsequent interventional procedures.
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[17] Boden WE, Dai H. (On behalf of the VANQWISH Trial Investigators.) Long-term outcomes in non-Q-wave infarction patients randomized to an ‘invasive’ versus ‘conservative’ strategy: Results of the multicenter VA Non-Q-Wave Infarction Strategies in-Hospital (VANQWISH) trial (Abstr.). Eur Heart J 1997;18(1):351. [18] Rogers WJ, Bourassa MG, Andrews TC. (For the ACIP Investigators.) Asymptomatic Cardiac Ischemia Pilot (ACIP) Study: Outcome at 1 year for patients with asymptomatic cardiac ischemia randomized to medical therapy or revascularization. J Am Coll Cardiol 1995;26:594–605. [19] The EPIC Investigators. Use of a monoclonal antibody directed against the platelet glycoprotein IIb / IIIa receptor in high-risk coronary angioplasty. N Engl J Med 1994;330:956–961. [20] The 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. [21] The EPILOG Investigators. Platelet glycoprotein IIb / IIIa receptor blockade and low-dose heparin during percutaneous coronary revascularization. N Engl J Med 1997;336:1689–1696. [22] The RESTORE Investigators. Effects of platelet glycoprotein IIb / IIIa blockade with tirofiban on adverse cardiac events in patients with unstable angina or acute myocardial infarction undergoing coronary angioplasty. Circulation 1997;96:1445–1453. [23] The IMPACT II Investigators. Effects of competitive platelet glycoprotein IIb / IIIa inhibition with Integrilin in reducing complications of percutaneous coronary intervention. Lancet 1997;349:1422– 1428. [24] Harrington RA. Design and methodology of the PURSUIT trial: Evaluating entifibatide for acute ischemic coronary syndromes (Platelet glycoprotein IIb / IIIa in unstable angina: Receptor suppression using integrilin therapy trial). Am J Cardiol 1997;80:3413–813. [25] Barr E, Snapinn SM, Sax FL, Theroux P. (For the PRISM Plus Investigators.) Improved long-term clinical outcomes in unstable angina-patients undergoing coronary angioplasty following therapy with tirofiban and heparin. J Am Coll Cardiol 1998;31:55A. [26] Kleiman NS, Ohman EM, Califf RM, et al. Profound inhibition of platelet aggregation with monoclonal antibody 7E3 Fab after thrombolytic therapy: Results of the Thrombolysis and Angioplasty in Myocardial Infarction (TAMI) 8 pilot study. J Allergy Clin Immunol 1993;22:381–9. [27] Ohman EM, Kleiman NS, Gacioch G, et al. (For the IMPACT-AMI Investigators.) Combined accelerated tissue-plasminogen activator and platelet glycoprotein IIb / IIIa integrin receptor blockade with integrilin in acute myocardial infarction. Circulation 1997;95:846– 54.