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Failed reperfusion after thrombolytic therapy: Recognition and management
Failed reperfusion after thrombolytic therapy: Recognition and management Angela Marie Kucia, BN, MA,a,b and Christopher James Zeitz, MBBS, PhD,c Adelaide, Australia
BACKGROUND: Failed reperfusion after thrombolysis occurs in as many as 30% of patients with acute myocardial infarction (MI). Furthermore, some patients have incomplete tissue perfusion despite reperfusion of the infarct-related artery. Close assessment of the efficacy of thrombolytic administration in people with evolving acute MI is necessary, particularly with regard to myocardial perfusion status, because some patients may benefit from incremental pharmacologic or invasive reperfusion strategies. PURPOSE AND METHOD: This article reviews a number of strategies to assess infarct-related artery patency and myocardial tissue perfusion. These include coronary angiography, continuous ST-segment monitoring, serial electrocardiography, obtaining serial serum biochemical markers of myocardial necrosis, monitoring for reperfusion arrhythmias, and assessment of changes in chest pain intensity. CONCLUSION: The early detection of failed reperfusion is critical if incremental strategies to enhance myocardial salvage are to be considered. Continuous ST-segment monitoring is a relatively inexpensive, reliable, and accurate tool for assessing real-time myocardial perfusion. (Heart Lung® 2002;31:113-21.)
I
n the past 2 decades, numerous large scale, randomized clinical trials have demonstrated that treatment of acute myocardial infarction (MI) with thrombolytic therapy results in a marked reduction in mortality and improved left ventricular function.1-4 However it has been reported that only 50% to 70% of patients achieve Thrombolytics in Myocardial Infarction (TIMI) Grade 3 (normal) flow after thrombolytic therapy, and of these, only two thirds achieve this within 90 minutes.5,6 Furthermore, patients with persistent occlusion of the infarct-related artery have been demonstrated to have a poorer prognosis when compared with those patients with a recanalized artery.7-9 In all, it is generally recognized that only 25% to 40% of patients treated with thrombolysis achieve normal myocardial perfusion. This low number of patients
From the aUniversity of South Australia School of Nursing and Midwifery, the bQueen Elizabeth Hospital, and the cUniversity of Adelaide Department of Cardiology, Adelaide, Australia. Reprint requests: Angela Marie Kucia, BN, MA, Coronary Care Unit, The Queen Elizabeth Hospital, 28 Woodville Rd, Woodville, South Australia 5011, Australia. Copyright 2002, Mosby, Inc. All rights reserved. 0147-9563/2002/$35.00 + 0 2/1/122649 doi:10.1067/mhl.2002.122649
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includes a subgroup that has incomplete tissue perfusion despite reperfusion of the infarct-related artery.10 It is therefore necessary to closely assess the efficacy of thrombolytic administration in individuals with evolving acute MI, particularly with regard to myocardial perfusion status because some patients may benefit from incremental pharmacologic or invasive reperfusion strategies.11,12 The critical-care nurse has a central role in the early detection of failed reperfusion and nursing management of the patient requiring additional pharmacologic or percutaneous coronary intervention. This article reviews a number of strategies to assess infarct-related artery patency and myocardial tissue perfusion. These strategies include coronary angiography, continuous ST-segment monitoring, serial electrocardiography, obtaining serial serum biochemical markers of myocardial necrosis, monitoring for reperfusion arrhythmias, and assessment of changes in chest pain intensity.
WHAT SHOULD WE EXPECT FROM THROMBOLYTIC THERAPY? The goal of thrombolysis is to restore normal myocardial perfusion (TIMI 3 flow to the infarctrelated artery with associated full tissue perfusion) within 60 to 90 minutes. TIMI 3 flow in the infarct-
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related artery after thrombolysis has been associated with decreased mortality when compared with TIMI 2 (slow) flow and TIMI 0 or 1 (none or minimal) flow, as well as decreased incidence of congestive cardiac failure, recurrent ischemia and improved left ventricular ejection fraction.13 However it has been reported that reperfusion fails to occur at all in 25% of patients,6,14,15 and in 50% to 70% of patients at 90 minutes after thrombolytic administration.5,6
Other factors that may affect reperfusion include use of adjuvant therapies, as well as the type of thrombolytic used. Finally, it should be added that thrombolytic regimens have been developed to balance incremental thrombolysis rates with low risk of catastrophic hemorrhage. Failure of thrombolysis in some cases simply may reflect underlying variability in pharmacokinetic:dynamic interactions.
WHY DOES THROMBOLYSIS FAIL IN SOME PATIENTS?
HOW CAN FAILED REPERFUSION BE DETECTED? Coronary angiography
It is not entirely clear why some patients fail to reperfuse with thrombolytic therapy. There are some proposed mechanisms for failure of thrombolysis, including thrombolytic resistance or failure to reach a lytic state. This may occur in some patients as a result of differences in circulating levels of fibrinogen,16,17 lipoproteins,18 thrombin or antithrombin III complexes,19,20 and perhaps increased levels of plasminogen-activator-inhibitor type 1.21 There is no convincing evidence that antibodies to streptokinase are responsible for most cases of failed reperfusion.17,22 It has also been postulated that mechanical factors, such as arterial pressure proximal to the occluding thrombus, myocardial wall tension, thrombus burden,23 lesion complexity,24 residual stenosis, and presence of subintimal hemorrhage,25 may contribute to impaired reperfusion. Thrombus composition may also contribute to failed or incomplete reperfusion. Atherosclerotic plaque rupture precedes the thrombotic process. The breach of the vessel wall sets up “white” platelet-thrombus, which is followed by the formation of “red” fibrin-rich thrombus. So-called “thrombolytic” therapies are actually fibrinolytic therapies, in that they target the red clot component of the thrombus and can only dissolve the fibrin strands, leaving enmeshed thrombin exposed. Exposed activated thrombin results in a prothrombotic state and may contribute to microvascular obstruction; therefore, fibrinolytic therapies probably only achieve partial clot dissolution at the expense of potentiating embolization of part of the thrombus into the microcirculation. Failed reperfusion tends to be associated with a greater delay to thrombolytic treatment.26-28 Excessive time delays to treatment may contribute to extensive myocardial damage, myocardial edema, leukostasis and inflammatory changes that may result in impaired perfusion at the tissue level29 and so timely delivery of treatment is essential to avoid these impediments to full tissue reperfusion.
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Coronary angiography is the gold standard for direct visualization of epicardial coronary artery patency. However the assessment of thrombolytic efficacy by coronary angiography soon after thrombolysis is costly, carries an inherent risk of bleeding, and is not available at all institutions.30 Furthermore, coronary angiography is not an indicator of the stability of reperfusion; coronary angiography only provides a “snapshot” view of the coronary artery, but thrombolysis is a dynamic process resulting in episodes of cyclic patency or occlusion of the infarct-related artery in 25% to 50% of patients31,32 that will not be captured in entirety during angiography.31-34 Importantly, coronary angiography does not necessarily reflect the adequacy of tissue perfusion. The nature of failed or slow tissue reperfusion is not constant, in that nonreperfusion may result from continued coronary artery occlusion; however, in some cases, it may be a result of “no-reflow” through a recanalized infarct-related artery. Epicardial coronary artery patency does not guarantee microvascular flow.35,36 Perfusion at the myocardial tissue level can be assessed more directly by serial (eg, 4 per hour) 12-lead electrocardiograph (ECG) or continuous 12-lead ST-segment monitoring; continued ST-segment elevation = continued myocardial ischemia.
Continuous ST-segment monitoring Reduction of ST-segment elevation is recognized as a noninvasive marker of reperfusion.37 Continuous ST-segment monitoring can be used to predict coronary artery patency; a reduction of STsegments by ≥50% (Figs 1 and 2) has been associated with patency of the infarct-related artery in several studies,34,37-40 but it should be noted that myocardial tissue may be perfused by collaterals to varying degrees,41,42 which may result in reduction of ischemia and reduction of ST-segment ele-
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Fig 1 The resolution of ST-segment elevation and the development of terminal T wave inversion are predictors of coronary artery patency. Screen capture from GE Marquette ST-Guard.
vation in the presence of continued coronary artery occlusion. It is not uncommon for ST-segment elevation to become transiently more pronounced or for re-elevation to occur (Fig 3) just before reperfusion,43 and this may result from reperfusion injury. T wave changes may be of incremental significance in assessment of reperfusion. Early T wave inversion in the infarct-related ECG leads has been associated with TIMI 3 flow (Fig 4),44-46 however it has been suggested that this does not occur early enough to be of clinical value.44 The development of terminal T wave inversion (Fig 1)3,47 occurs somewhat sooner, however, and may be a useful predictor of reperfusion. To date, there has not been any large study with continuous T wave monitoring and trending to assess whether changes in T wave amplitude or polarity of proximal, terminal, or T wave peak has any value in predicting reperfusion or re-occlusion.
12-Lead ECG For several years, the 12-lead ECG has been used to detect changes in myocardial perfusion. The standard 12-lead ECG is likely to miss important information regarding ST-segment recovery or re-elevation during the early dynamic periods of acute MI because it only documents electrical com-
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plexes at a single moment.48 However a standard ECG machine is readily available in most institutions and may need to suffice if continuous ST-segment monitoring is unavailable. In this case, an ECG should be obtained at completion of thrombolytic therapy and then at 30-minute intervals until 90 minutes has elapsed from commencement of thrombolytic therapy. ECGs should be compared for evidence of reduction in ST-segment elevation following the same criteria for reperfusion as those used for continuous ST-segment monitoring.
Biochemical markers A biochemical approach for detecting failed thrombolysis with creatine kinase isoenzymes,49 cardiac troponin T,50, troponin I,51 or myoglobin50,52,53 has a high specificity and sensitivity. Stewart et al27 suggest comparisons of the aforementioned markers at 60 and 90 minutes to prethrombolytic values; significantly increased levels of these markers at 60 and 90 minutes were associated with TIMI 3 flow at 90-minute angiography. Despite the potential usefulness of this approach, none of these tests have found favor in routine clinical practice,54 perhaps as a result of delays in the availability of results. Peak creatine kinase activity within 12 hours of thrombolytic therapy is considered to be a sign of
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Fig 2 A single lead (Lead II) linear trend of ST-segment amplitude (microvolts, y-axis) plotted against time (hours, x-axis) showing resolution of ST-segment elevation. Screen capture from GE Marquette ST-Guard.
Fig 3 ST-segment and T wave trends. The top trend represents ST-segment amplitude. Note that ST-segment amplitude becomes more pronounced just before reperfusion. The lower trend represents T wave amplitude. Screen capture from GE Marquette ST-Guard.
reperfusion55 but occurs too late to be anything more than a posthoc confirmation of reperfusion.56 The availability of point-of-care troponin T testing could be a valuable addition to future assessment of reperfusion.
Changes in chest pain It has been suggested that a reduction of ischemic chest pain39,57,58 is a clinically predictive
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sign that reperfusion has occurred. A transient worsening of chest pain may be associated with imminent reperfusion, and it has been postulated that this may result from reperfusion injury.46 However, chest pain may be reduced or not present at all as a result of opiate administration. Moreover, it has been reported in a large study59 that around one third of patients with confirmed acute MI did not have chest pain when they arrived at the hospital. People at risk of silent ischemia include diabetics, women, older patients, those with previous heart failure or stroke, nonwhite racial or ethnic groups,59 patients with increased degrees of pulmonary congestion on admission,60 and possibly those with heavy alcohol intake.61 Patients presenting with acute MI in the absence of chest pain are less likely to be treated with reperfusion therapy, have a significantly longer door to needle time for thrombolytics or primary angioplasty, are less likely to receive adjunctive anti-ischemic or antiplatelet pharmacotherapy, are less likely to undergo percutaneous coronary intervention or revascularization, and are more likely to die in the hospital.59 Silent ischemia is common after acute MI and is associated with a poor prognosis.62,63 Chest pain is not a particularly good marker of
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Fig 4 Early T wave inversion has been associated with TIMI grade 3 flow after acute MI. Screen capture from GE Marquette ST-Guard.
reperfusion used in isolation and should only be used in conjunction with other more objective markers.56
Reperfusion arrhythmias Reperfusion of the ischemic myocardium is often followed by ventricular arrhythmias.64 These so-called “reperfusion arrhythmias” include accelerated ideoventricular rhythm,47,65,66 nonsustained ventricular tachycardia, bradycardia,43 and an increase in frequency of ventricular premature complexes.47 Disturbances of rhythm occur in some patients, but not all, and the timing of these arrhythmias is not always specifically related to the moment of reperfusion; it is not uncommon for them to continue for 8 to 12 hours after reperfusion.67 Reperfusion arrhythmias may occur as a result of reperfusion, but like chest pain, cannot be used in isolation as an indicator of reperfusion.
Other methods of assessing reperfusion Other proposed methods of assessing microvascular flow include contrast echocardiography,35 magnetic resonance imaging, intracoronary Doppler flow velocity,29 or technetium Tc 99m ses-
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tamibi single-photon emission computed tomographic imaging.68 The disadvantage of these strategies is that they involve moving a critically ill patient away from a critical-care area for the duration of the procedure.
WHAT STRATEGIES ARE AVAILABLE FOR FAILED THROMBOLYTIC REPERFUSION? Late69 and failed26 reperfusion post thrombolysis is associated with increased mortality and incidence of left ventricular dysfunction. Failed recanalization (
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and involve excessive risks; however, a rescue strategy that is offered too late results in reduced potential for myocardial salvage.23
Additional thrombolytic therapy Repeat thrombolysis with another agent has been explored as a rescue therapy for failed thrombolysis, but the potential benefit of this strategy is offset by the risk of major bleeding,73 and the benefit appears to be confined to those patients who have failed to reach lytic state after initial thrombolytic administration.74
Rescue percutaneous transluminal coronary angioplasty (PTCA) Restoration of coronary artery patency and myocardial tissue perfusion to preserve left ventricular function and reduce mortality are the major therapeutic goals for patients with acute MI. The role of rescue PTCA (PTCA to the infarct-related artery after failed thrombolysis) in achieving these goals is unclear. Rescue angioplasty is a procedure that is commonly performed, but there are few data describing the clinical outcome for patients undergoing this procedure. Results of early nonrandomized studies of outcomes for patients undergoing rescue PTCA were less than promising in terms of mortality and left ventricular function,75 however it should be noted that those patients selected for rescue PTCA were generally those with poor prognostic indicators before the procedure. Ethically, it is difficult to withhold PTCA from a patient with ongoing ischemia and angiographically-demonstrated continued coronary artery occlusion. Randomizing patients to rescue PTCA versus conservative management is therefore problematic, particularly as there are some later unrandomized reports that describe some beneficial effects of successful rescue PTCA.11,76-79 Evidence suggests that rescue stenting may help to improve the results of rescue angioplasty80 despite a significantly longer time-to-reperfusion,81 and this supports the concept that aggressive treatment after failed thrombolysis can be pursued with satisfactory results. Failed rescue PTCA has been shown to be associated with adverse outcomes including increased mortality and congestive cardiac failure in several studies.73,78,79,82-84 The “no-reflow” phenomenon (TIMI Grade 1-2 flow in the absence of residual stenosis) after primary or rescue PTCA is a complication that is associated with poorer left ventricular function and prognosis for patients with acute MI,83,85 and often results in persistent ST-segment
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elevation on the ECG that reflects ongoing myocardial ischemia at the cellular level. Like failed reperfusion after thrombolytic therapy, it is not entirely clear why some patients sustain no-reflow. It is thought that the cause of this may be occlusion of microvessels as a result of platelet microthrombi.86 It has also been suggested that this phenomenon may be associated with the absence of preinfarction angina; preinfarction angina may confer a protective effect on patients with acute MI, possibly by initiating ischemic preconditioning, which is thought to limit infarct size and be associated with fewer cardiac events after acute MI.87-90 Routine concomitant treatment with thrombolytic therapy and primary PTCA increases in-hospital complications for patients with acute MI91 and is not recommended. Several studies have failed to find a benefit in routine percutaneous intervention for patients with an uncomplicated MI immediately or soon after thrombolytic therapy,92-100 even in the case of significant residual stenosis of the infarct vessel.
Antithrombotic drugs Some evidence indicates that the use of abciximab for rescue PTCA after failed thrombolysis results in a trend toward lower 30-day mortality but at the expense of an increased risk of severe bleeding.101 However this strategy does show some promise and additional clinical trials are planned to investigate potential risks and benefits of new antiplatelet agents in conjunction with thrombolytic therapy for the treatment of patients with acute MI.
Intra-aortic balloon pumping Some evidence shows that the insertion of an intra-aortic balloon pump in conjunction with rescue PTCA may prevent reocclusion of the infarct-related artery, presumably through augmented coronary perfusion and enhance recovery of left ventricular function through left ventricular unloading.102
CONCLUSION Acute MI therapies result in a dynamic process of reperfusion over a relatively short time frame. Continuous ST-segment monitoring is the only currently available strategy that gives real time insight into myocardial tissue perfusion. It has the added advantages of being noninvasive, readily available, and appropriate for the management of critically ill patients. Additional studies into the use of continuous ST-segment monitoring are likely to assist in identifying, at an early stage, a subgroup of
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patients having a sub-optimal response to thrombolysis. By limiting rescue strategies to this group, only the optimal management will more readily be identifiable.
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73. Gill S, Haastrup B, Haghfelt T, et al. Early reperfusion assessment and repeated thrombolysis in acute myocardial infarction estimated by repeated standard electrocardiography, a randomised, double-blind, placebo-controlled pilot study. Cardiology 2000;94:58-65. 74. Mounsey JP, Skinner JS, Hawkins T. Rescue thrombolysis: alteplase as adjuvant treatment after streptokinase in acute myocardial infarction. Br Heart J 1995;74:348-53. 75. Ross AM, Lundergan CF, Rohrbeck SC, et al. Rescue angioplasty after failed thrombolysis: technical and clinical outcomes in a large thrombolysis trial. GUSTO-1 angiographic investigators. Global utilization of streptokinase and tissue plasminogen activator for occluded coronary arteries. J Am Coll Cardiol 1998;3:1151-7. 76. Bar FW, Ophnis TJ, Frederiks J, et al. Rescue PTCA following failed thrombolysis and primary PTCA: a retrospective study of angiographic and clinical outcome. J Thromb Thrombolysis 1997;4:281-8. 77. Zijlstra F, de Boer MJ, Hoorntje JC, et al. A comparison of immediate coronary angioplasty with intravenous streptokinase in acute myocardial infarction. N Engl J Med 1993;328:680-4. 78. Gorfinkel HJ, Berger SM, Klaus AP, et al. Rescue angioplasty in failed thrombolysis in acute myocardial infarction: a community hospital experience. J Invasive Cardiol 1997;9:83-7. 79. Gibson CM, Cannon CP, Greene RM, et al. Rescue angioplasty in the thrombolysis in myocardial infarction (TIMI) 4 trial. Am J Cardiol 1997;80:21-6. 80. Grines CL, Cox DA, Stone GW, et al. Coronary angioplasty with or without stent implantation for acute myocardial infarction. Stent primary angioplasty in myocardial infarction study group. N Engl J Med 1999;341:1949-56. 81. La Vecchia L, Martini M, Bedogni F, et al. Procedural results, in-hospital course and six-month follow-up after rescue compared to primary stenting in acute myocardial infarction. Ital Heart J 2000;1:50-5. 82. Sutton AG, Campbell PG, Grech ED, et al. Failure of thrombolysis: experience with a policy of early angiography and rescue angioplasty for electrocardiographic evidence of failed thrombolysis. Heart 2000;84:197-204. 83. Takahashi T, Anzai T, Yoshikawa T, et al. Absence of preinfarction angina is associated with a risk of no-reflow phenomenon after primary coronary angioplasty for a first anterior wall acute myocardial infarction. Int J Cardiol 2000;75:253-60. 84. Kenner MD, Zajac EJ, Kondos GT, et al. Ability of the no-reflow phenomenon during an acute myocardial infarction to predict left ventricular dysfunction at one-month follow-up. Am J Cardiol 1995;76:861-8. 85. Abbo KM, Dooris M, Glazier S, et al. Features and outcome of no-reflow after percutaneous coronary intervention. Am J Cardiol 1995;75:778-82. 86. Topol EJ. Toward a new frontier in myocardial reperfusion therapy: emerging platelet preeminence. Circulation 1998;97:211-8. 87. Anzi T, Yoshikawa T, Asakura Y, et al. Effect on short-term prognosis in left ventricular function of angina pectoris prior to first Q-wave anterior wall infarction. Am J Cardiol 1994;74:755-9. 88. Ottani F, Galvani M, Ferrini D, et al. Prodromal angina limits infarct size: a role for ischaemic preconditioning. Circulation 1995;21:291-7.
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89. Kloner RA, Yellon D. Does ischaemic conditioning occur in patients? J Am Coll Cardiol 1994;24:1133-42. 90. Kloner and the TIMI-9B Investigators. Prospective temporal analysis of the onset of preinfarction angina versus outcome: an ancillary study in TIMI-9B. Circulation 1998;97:1042-5. 91. O’Neill WW, Weintraub R, Grines CL, et al. A prospective, placebo-controlled, randomized trial of intravenous streptokinase and angioplasty versus lone angioplasty therapy of acute myocardial infarction. Circulation 1992;86:1710-7. 92. Guerci AD, Gerstenblith G, Brinker JA, et al. A randomized trial of intravenous tissue plasminogen activator for acute myocardial infarction with subsequent randomization to elective coronary angioplasty. N Engl J Med 1987;317:1613-8. 93. Topol EJ, Califf RM, George BS, et al and the Thrombolysis and Angioplasty in Myocardial Infarction (TAMI) Study Group. A randomised trial of immediate versus delayed angioplasty after intravenous tissue plasminogen activator in acute myocardial infarction. N Engl J Med 1987;317:581-8. 94. The TIMI Research Group. Immediate vs delayed catheterization and angioplasty following thrombolytic therapy for acute myocardial infarction. TIMI II A results. JAMA 1988;260:284958. 95. 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 Eng J Med 1988;320:618-27. 96. de Bono DP. The European Cooperative Study Group trial of intravenous recombinant tissue-type plasminogen activator (rtPA) and conservative therapy versus rt-PA and immediate coronary angioplasty. J Am Coll Cardiol 1988;12(Suppl A):20A-23A. 97. Rogers WJ, Baim DS, Gore JM, et al. Comparison of immediate invasive, delayed invasive, and conservative strategies after tissue-type plasminogen activator. Results of the thrombolysis in myocardial infarction (TIMI) phase II-A trial. Circulation 1990 May;81(5):1457-76. 98. SWIFT (Should We Intervene Following Thrombolysis?) Trial Study Group. SWIFT trial of delayed elective intervention vs conservative treatment after thrombolysis with anistreplase in acute myocardial infarction. Br Med J 1991;302:555-60. 99. Arnold AE, Simoons ML, Van de Werf F, et al. Recombinant tissue-type plasminogen activator and immediate angioplasty in acute myocardial infarction. One-year follow-up. The European Cooperative Study Group. Circulation 1992;86:111-20. 100. Ellis SG, Mooney MR, George BS. Randomized trial of late elective angioplasty versus conservative management for patients with residual stenoses after thrombolytic treatment of myocardial infarction. Treatment of post-thrombolytic stenoses (TOPS) study group. Circulation 1992;86:1400-6. 101. Miller JM, Smalling R, Ohman EM, et al. Effectiveness of early coronary angioplasty and abciximab for failed thrombolysis (reteplase or alteplase) during acute myocardial infarction (results from the GUSTO-III trial). Global use of strategies to open occluded coronary arteries. Am J Cardiol 1999;84:779-84. 102. Ishihara M, Sato H, Tateisha H, et al. Intra-aortic balloon pumping as adjunctive therapy to rescue coronary angioplasty after failed thrombolysis in anterior wall acute myocardial infarction. Am J Cardiol 1995;76:73-5.
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BACKGROUND: Failed reperfusion after thrombolysis occurs in as many as 30% of patients with acute myocardial infarction (MI). Furthermore, some patients have incomplete tissue perfusion despite reperfusion of the infarct-related artery. Close assessment of the efficacy of thrombolytic administration in people with evolving acute MI is necessary, particularly with regard to myocardial perfusion status, because some patients may benefit from incremental pharmacologic or invasive reperfusion strategies. PURPOSE AND METHOD: This article reviews a number of strategies to assess infarct-related artery patency and myocardial tissue perfusion. These include coronary angiography, continuous ST-segment monitoring, serial electrocardiography, obtaining serial serum biochemical markers of myocardial necrosis, monitoring for reperfusion arrhythmias, and assessment of changes in chest pain intensity. CONCLUSION: The early detection of failed reperfusion is critical if incremental strategies to enhance myocardial salvage are to be considered. Continuous ST-segment monitoring is a relatively inexpensive, reliable, and accurate tool for assessing real-time myocardial perfusion. (Heart Lung® 2002;31:113-21.)
I
n the past 2 decades, numerous large scale, randomized clinical trials have demonstrated that treatment of acute myocardial infarction (MI) with thrombolytic therapy results in a marked reduction in mortality and improved left ventricular function.1-4 However it has been reported that only 50% to 70% of patients achieve Thrombolytics in Myocardial Infarction (TIMI) Grade 3 (normal) flow after thrombolytic therapy, and of these, only two thirds achieve this within 90 minutes.5,6 Furthermore, patients with persistent occlusion of the infarct-related artery have been demonstrated to have a poorer prognosis when compared with those patients with a recanalized artery.7-9 In all, it is generally recognized that only 25% to 40% of patients treated with thrombolysis achieve normal myocardial perfusion. This low number of patients
From the aUniversity of South Australia School of Nursing and Midwifery, the bQueen Elizabeth Hospital, and the cUniversity of Adelaide Department of Cardiology, Adelaide, Australia. Reprint requests: Angela Marie Kucia, BN, MA, Coronary Care Unit, The Queen Elizabeth Hospital, 28 Woodville Rd, Woodville, South Australia 5011, Australia. Copyright 2002, Mosby, Inc. All rights reserved. 0147-9563/2002/$35.00 + 0 2/1/122649 doi:10.1067/mhl.2002.122649
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includes a subgroup that has incomplete tissue perfusion despite reperfusion of the infarct-related artery.10 It is therefore necessary to closely assess the efficacy of thrombolytic administration in individuals with evolving acute MI, particularly with regard to myocardial perfusion status because some patients may benefit from incremental pharmacologic or invasive reperfusion strategies.11,12 The critical-care nurse has a central role in the early detection of failed reperfusion and nursing management of the patient requiring additional pharmacologic or percutaneous coronary intervention. This article reviews a number of strategies to assess infarct-related artery patency and myocardial tissue perfusion. These strategies include coronary angiography, continuous ST-segment monitoring, serial electrocardiography, obtaining serial serum biochemical markers of myocardial necrosis, monitoring for reperfusion arrhythmias, and assessment of changes in chest pain intensity.
WHAT SHOULD WE EXPECT FROM THROMBOLYTIC THERAPY? The goal of thrombolysis is to restore normal myocardial perfusion (TIMI 3 flow to the infarctrelated artery with associated full tissue perfusion) within 60 to 90 minutes. TIMI 3 flow in the infarct-
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related artery after thrombolysis has been associated with decreased mortality when compared with TIMI 2 (slow) flow and TIMI 0 or 1 (none or minimal) flow, as well as decreased incidence of congestive cardiac failure, recurrent ischemia and improved left ventricular ejection fraction.13 However it has been reported that reperfusion fails to occur at all in 25% of patients,6,14,15 and in 50% to 70% of patients at 90 minutes after thrombolytic administration.5,6
Other factors that may affect reperfusion include use of adjuvant therapies, as well as the type of thrombolytic used. Finally, it should be added that thrombolytic regimens have been developed to balance incremental thrombolysis rates with low risk of catastrophic hemorrhage. Failure of thrombolysis in some cases simply may reflect underlying variability in pharmacokinetic:dynamic interactions.
WHY DOES THROMBOLYSIS FAIL IN SOME PATIENTS?
HOW CAN FAILED REPERFUSION BE DETECTED? Coronary angiography
It is not entirely clear why some patients fail to reperfuse with thrombolytic therapy. There are some proposed mechanisms for failure of thrombolysis, including thrombolytic resistance or failure to reach a lytic state. This may occur in some patients as a result of differences in circulating levels of fibrinogen,16,17 lipoproteins,18 thrombin or antithrombin III complexes,19,20 and perhaps increased levels of plasminogen-activator-inhibitor type 1.21 There is no convincing evidence that antibodies to streptokinase are responsible for most cases of failed reperfusion.17,22 It has also been postulated that mechanical factors, such as arterial pressure proximal to the occluding thrombus, myocardial wall tension, thrombus burden,23 lesion complexity,24 residual stenosis, and presence of subintimal hemorrhage,25 may contribute to impaired reperfusion. Thrombus composition may also contribute to failed or incomplete reperfusion. Atherosclerotic plaque rupture precedes the thrombotic process. The breach of the vessel wall sets up “white” platelet-thrombus, which is followed by the formation of “red” fibrin-rich thrombus. So-called “thrombolytic” therapies are actually fibrinolytic therapies, in that they target the red clot component of the thrombus and can only dissolve the fibrin strands, leaving enmeshed thrombin exposed. Exposed activated thrombin results in a prothrombotic state and may contribute to microvascular obstruction; therefore, fibrinolytic therapies probably only achieve partial clot dissolution at the expense of potentiating embolization of part of the thrombus into the microcirculation. Failed reperfusion tends to be associated with a greater delay to thrombolytic treatment.26-28 Excessive time delays to treatment may contribute to extensive myocardial damage, myocardial edema, leukostasis and inflammatory changes that may result in impaired perfusion at the tissue level29 and so timely delivery of treatment is essential to avoid these impediments to full tissue reperfusion.
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Coronary angiography is the gold standard for direct visualization of epicardial coronary artery patency. However the assessment of thrombolytic efficacy by coronary angiography soon after thrombolysis is costly, carries an inherent risk of bleeding, and is not available at all institutions.30 Furthermore, coronary angiography is not an indicator of the stability of reperfusion; coronary angiography only provides a “snapshot” view of the coronary artery, but thrombolysis is a dynamic process resulting in episodes of cyclic patency or occlusion of the infarct-related artery in 25% to 50% of patients31,32 that will not be captured in entirety during angiography.31-34 Importantly, coronary angiography does not necessarily reflect the adequacy of tissue perfusion. The nature of failed or slow tissue reperfusion is not constant, in that nonreperfusion may result from continued coronary artery occlusion; however, in some cases, it may be a result of “no-reflow” through a recanalized infarct-related artery. Epicardial coronary artery patency does not guarantee microvascular flow.35,36 Perfusion at the myocardial tissue level can be assessed more directly by serial (eg, 4 per hour) 12-lead electrocardiograph (ECG) or continuous 12-lead ST-segment monitoring; continued ST-segment elevation = continued myocardial ischemia.
Continuous ST-segment monitoring Reduction of ST-segment elevation is recognized as a noninvasive marker of reperfusion.37 Continuous ST-segment monitoring can be used to predict coronary artery patency; a reduction of STsegments by ≥50% (Figs 1 and 2) has been associated with patency of the infarct-related artery in several studies,34,37-40 but it should be noted that myocardial tissue may be perfused by collaterals to varying degrees,41,42 which may result in reduction of ischemia and reduction of ST-segment ele-
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Failed reperfusion after thrombolytic therapy
Fig 1 The resolution of ST-segment elevation and the development of terminal T wave inversion are predictors of coronary artery patency. Screen capture from GE Marquette ST-Guard.
vation in the presence of continued coronary artery occlusion. It is not uncommon for ST-segment elevation to become transiently more pronounced or for re-elevation to occur (Fig 3) just before reperfusion,43 and this may result from reperfusion injury. T wave changes may be of incremental significance in assessment of reperfusion. Early T wave inversion in the infarct-related ECG leads has been associated with TIMI 3 flow (Fig 4),44-46 however it has been suggested that this does not occur early enough to be of clinical value.44 The development of terminal T wave inversion (Fig 1)3,47 occurs somewhat sooner, however, and may be a useful predictor of reperfusion. To date, there has not been any large study with continuous T wave monitoring and trending to assess whether changes in T wave amplitude or polarity of proximal, terminal, or T wave peak has any value in predicting reperfusion or re-occlusion.
12-Lead ECG For several years, the 12-lead ECG has been used to detect changes in myocardial perfusion. The standard 12-lead ECG is likely to miss important information regarding ST-segment recovery or re-elevation during the early dynamic periods of acute MI because it only documents electrical com-
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plexes at a single moment.48 However a standard ECG machine is readily available in most institutions and may need to suffice if continuous ST-segment monitoring is unavailable. In this case, an ECG should be obtained at completion of thrombolytic therapy and then at 30-minute intervals until 90 minutes has elapsed from commencement of thrombolytic therapy. ECGs should be compared for evidence of reduction in ST-segment elevation following the same criteria for reperfusion as those used for continuous ST-segment monitoring.
Biochemical markers A biochemical approach for detecting failed thrombolysis with creatine kinase isoenzymes,49 cardiac troponin T,50, troponin I,51 or myoglobin50,52,53 has a high specificity and sensitivity. Stewart et al27 suggest comparisons of the aforementioned markers at 60 and 90 minutes to prethrombolytic values; significantly increased levels of these markers at 60 and 90 minutes were associated with TIMI 3 flow at 90-minute angiography. Despite the potential usefulness of this approach, none of these tests have found favor in routine clinical practice,54 perhaps as a result of delays in the availability of results. Peak creatine kinase activity within 12 hours of thrombolytic therapy is considered to be a sign of
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Fig 2 A single lead (Lead II) linear trend of ST-segment amplitude (microvolts, y-axis) plotted against time (hours, x-axis) showing resolution of ST-segment elevation. Screen capture from GE Marquette ST-Guard.
Fig 3 ST-segment and T wave trends. The top trend represents ST-segment amplitude. Note that ST-segment amplitude becomes more pronounced just before reperfusion. The lower trend represents T wave amplitude. Screen capture from GE Marquette ST-Guard.
reperfusion55 but occurs too late to be anything more than a posthoc confirmation of reperfusion.56 The availability of point-of-care troponin T testing could be a valuable addition to future assessment of reperfusion.
Changes in chest pain It has been suggested that a reduction of ischemic chest pain39,57,58 is a clinically predictive
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sign that reperfusion has occurred. A transient worsening of chest pain may be associated with imminent reperfusion, and it has been postulated that this may result from reperfusion injury.46 However, chest pain may be reduced or not present at all as a result of opiate administration. Moreover, it has been reported in a large study59 that around one third of patients with confirmed acute MI did not have chest pain when they arrived at the hospital. People at risk of silent ischemia include diabetics, women, older patients, those with previous heart failure or stroke, nonwhite racial or ethnic groups,59 patients with increased degrees of pulmonary congestion on admission,60 and possibly those with heavy alcohol intake.61 Patients presenting with acute MI in the absence of chest pain are less likely to be treated with reperfusion therapy, have a significantly longer door to needle time for thrombolytics or primary angioplasty, are less likely to receive adjunctive anti-ischemic or antiplatelet pharmacotherapy, are less likely to undergo percutaneous coronary intervention or revascularization, and are more likely to die in the hospital.59 Silent ischemia is common after acute MI and is associated with a poor prognosis.62,63 Chest pain is not a particularly good marker of
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Failed reperfusion after thrombolytic therapy
Fig 4 Early T wave inversion has been associated with TIMI grade 3 flow after acute MI. Screen capture from GE Marquette ST-Guard.
reperfusion used in isolation and should only be used in conjunction with other more objective markers.56
Reperfusion arrhythmias Reperfusion of the ischemic myocardium is often followed by ventricular arrhythmias.64 These so-called “reperfusion arrhythmias” include accelerated ideoventricular rhythm,47,65,66 nonsustained ventricular tachycardia, bradycardia,43 and an increase in frequency of ventricular premature complexes.47 Disturbances of rhythm occur in some patients, but not all, and the timing of these arrhythmias is not always specifically related to the moment of reperfusion; it is not uncommon for them to continue for 8 to 12 hours after reperfusion.67 Reperfusion arrhythmias may occur as a result of reperfusion, but like chest pain, cannot be used in isolation as an indicator of reperfusion.
Other methods of assessing reperfusion Other proposed methods of assessing microvascular flow include contrast echocardiography,35 magnetic resonance imaging, intracoronary Doppler flow velocity,29 or technetium Tc 99m ses-
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tamibi single-photon emission computed tomographic imaging.68 The disadvantage of these strategies is that they involve moving a critically ill patient away from a critical-care area for the duration of the procedure.
WHAT STRATEGIES ARE AVAILABLE FOR FAILED THROMBOLYTIC REPERFUSION? Late69 and failed26 reperfusion post thrombolysis is associated with increased mortality and incidence of left ventricular dysfunction. Failed recanalization (
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and involve excessive risks; however, a rescue strategy that is offered too late results in reduced potential for myocardial salvage.23
Additional thrombolytic therapy Repeat thrombolysis with another agent has been explored as a rescue therapy for failed thrombolysis, but the potential benefit of this strategy is offset by the risk of major bleeding,73 and the benefit appears to be confined to those patients who have failed to reach lytic state after initial thrombolytic administration.74
Rescue percutaneous transluminal coronary angioplasty (PTCA) Restoration of coronary artery patency and myocardial tissue perfusion to preserve left ventricular function and reduce mortality are the major therapeutic goals for patients with acute MI. The role of rescue PTCA (PTCA to the infarct-related artery after failed thrombolysis) in achieving these goals is unclear. Rescue angioplasty is a procedure that is commonly performed, but there are few data describing the clinical outcome for patients undergoing this procedure. Results of early nonrandomized studies of outcomes for patients undergoing rescue PTCA were less than promising in terms of mortality and left ventricular function,75 however it should be noted that those patients selected for rescue PTCA were generally those with poor prognostic indicators before the procedure. Ethically, it is difficult to withhold PTCA from a patient with ongoing ischemia and angiographically-demonstrated continued coronary artery occlusion. Randomizing patients to rescue PTCA versus conservative management is therefore problematic, particularly as there are some later unrandomized reports that describe some beneficial effects of successful rescue PTCA.11,76-79 Evidence suggests that rescue stenting may help to improve the results of rescue angioplasty80 despite a significantly longer time-to-reperfusion,81 and this supports the concept that aggressive treatment after failed thrombolysis can be pursued with satisfactory results. Failed rescue PTCA has been shown to be associated with adverse outcomes including increased mortality and congestive cardiac failure in several studies.73,78,79,82-84 The “no-reflow” phenomenon (TIMI Grade 1-2 flow in the absence of residual stenosis) after primary or rescue PTCA is a complication that is associated with poorer left ventricular function and prognosis for patients with acute MI,83,85 and often results in persistent ST-segment
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elevation on the ECG that reflects ongoing myocardial ischemia at the cellular level. Like failed reperfusion after thrombolytic therapy, it is not entirely clear why some patients sustain no-reflow. It is thought that the cause of this may be occlusion of microvessels as a result of platelet microthrombi.86 It has also been suggested that this phenomenon may be associated with the absence of preinfarction angina; preinfarction angina may confer a protective effect on patients with acute MI, possibly by initiating ischemic preconditioning, which is thought to limit infarct size and be associated with fewer cardiac events after acute MI.87-90 Routine concomitant treatment with thrombolytic therapy and primary PTCA increases in-hospital complications for patients with acute MI91 and is not recommended. Several studies have failed to find a benefit in routine percutaneous intervention for patients with an uncomplicated MI immediately or soon after thrombolytic therapy,92-100 even in the case of significant residual stenosis of the infarct vessel.
Antithrombotic drugs Some evidence indicates that the use of abciximab for rescue PTCA after failed thrombolysis results in a trend toward lower 30-day mortality but at the expense of an increased risk of severe bleeding.101 However this strategy does show some promise and additional clinical trials are planned to investigate potential risks and benefits of new antiplatelet agents in conjunction with thrombolytic therapy for the treatment of patients with acute MI.
Intra-aortic balloon pumping Some evidence shows that the insertion of an intra-aortic balloon pump in conjunction with rescue PTCA may prevent reocclusion of the infarct-related artery, presumably through augmented coronary perfusion and enhance recovery of left ventricular function through left ventricular unloading.102
CONCLUSION Acute MI therapies result in a dynamic process of reperfusion over a relatively short time frame. Continuous ST-segment monitoring is the only currently available strategy that gives real time insight into myocardial tissue perfusion. It has the added advantages of being noninvasive, readily available, and appropriate for the management of critically ill patients. Additional studies into the use of continuous ST-segment monitoring are likely to assist in identifying, at an early stage, a subgroup of
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patients having a sub-optimal response to thrombolysis. By limiting rescue strategies to this group, only the optimal management will more readily be identifiable.
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after intravenous tissue plasminogen activator in acute myocardial infarction. N Engl J Med 1987;317:581-8. 16. Brugemann J, van der Meer J, Takens BH, et al. A systemic nonlytic state and local thrombolytic failure of anistreplase (anisoylated plasminogen streptokinase activator complex [APSAC]) in acute myocardial infarction. Br Heart J 1990;64:355-8. 17. el Gaylani N, Davies S, Tovey J, et al. Systemic lytic state is not a predictor of coronary reperfusion in acute myocardial infarction. Int J Cardiol 1996;57:45-50. 18. Moliterno DJ, Lange RA, Meidell RS, et al. Relation of plasma lipoprotein(a) to infarct artery patency in survivors of myocardial infarction. Circulation 1993;88:935-40. 19. Gulba DC, Barthels M, Westhoff Bleck M, et al. Increased thrombin levels during thrombolytic therapy in acute myocardial infarction: relevance for unsuccessful therapy. Circulation 1991;83:937-44. 20. Scharfstein JS, Abendschein DR, Eisenberg PR, et al and the TIMI-5 Investigators. Usefulness of fibrogenolytic and procoagulant markers during thrombolytic therapy in predicting clinical outcomes in acute myocardial infarction: thrombolysis in acute myocardial infarction. Am J Cardiol 1996;78:503-10. 21. Sinkovic A. Prognostic role of plasminogen-activatorinhibitor-1 levels in treatment with streptokinase of patients with acute myocardial infarction. Clin Cardiol 2000;23:486-9. 22. Fears R, Hearn J, Standring R, et al. Lack of influence of pretreatment antistreptokinase antibody on efficacy in a multicenter patency comparison of intravenous streptokinase and anistreplase in acute myocardial infarction. Am Heart J 1992;124:305-14. 23. De Belder M. Acute myocardial infarction: failed thrombolysis. Heart 2001;85:104-12. 24. Mattfeldt T, Schwarz F, Schuler G, et al. Necropsy evaluation in seven patients with evolving acute myocardial infarction treated with thrombolytic therapy. Am J Cardiol 1984;54:530-4. 25. Richardson PD, Davies MJ, Born GVR. Influence of plaque configuration and stress distribution on fissuring of atherosclerotic plaques. Lancet 1989;2:941-4. 26. Califf RM, Topol EJ, George BS, et al. Characteristics and outcome of patients in whom reperfusion with intravenous tissue-type plasminogen activator fails: results of the thrombolysis and angioplasty in myocardial infarction (TAMI) I trial. Circulation 1988;77:1090-9. 27. Stewart JT, French JK, Theroux P, et al. Early noninvasive identification of failed reperfusion after intravenous thrombolytic therapy in acute myocardial infarction. J Am Coll Cardiol 1998;31:1499-505. 28. Van’t Hof AWJ, Liem A, deBoer M. Zwolle myocardial infarction study group: clinical value of a 12-lead electrocardiogram after successful reperfusion therapy for acute myocardial infarction. Lancet 1997;350:615-9. 29. Topol EJ. Acute myocardial infarction: thrombolysis. Heart 2000;83:122-6. 30. Veldkamp RF, Pope JE, Sawchak ST, et al. ST-Segment recovery as an endpoint in acute myocardial infarction trials: past, present, and future. J Electrocardiol 1993;26 (Suppl):256-61. 31. Hackett D, Davies G, Chiera S, Maseri A. Intermittent coronary occlusion in acute myocardial infarction. Value of combined thrombolytic and vasodilator therapy. N Engl J Med 1987;317:1055-9. 32. Krucoff MW, Croll MA, Pope JE, et al. Continuously updated 12-lead ST-segment recovery analysis for myocardial infarct artery patency assessment and its correlation with multiple simultaneous early angiographic observations. Am J Cardiol 1993;71:145-51. 33. Langer A, Krucoff MW, Klootwijk P, et al for the GUSTO Investigators. Noninvasive assessment of speed and stability of infarct-related artery reperfusion: results of the GUSTO STsegment monitoring study. J Am Coll Cardiol 1995;25:1552-7. 34. Shah PK, Cercek B, Lew AS, Ganz W. Angiographic validation of bedside markers of reperfusion. J Am Coll Cardiol 1993;21:55-61.
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