Improvement in Left Ventricular Function following Successful Rescue Percutaneous Coronary Intervention Is Independent of Time-t

aKanarath P. Balachandran, MBBS, MD, MRCP, bColin Berry, MBChB, BSc, PhD, MRCP, cAlastair C. Pell, MBChB, BSc, MD, MRCP, cBarry D. Vallance, MBChB, FRCP(Glas), FRCP(Edin), bKeith G. Oldroyd, MBChB, MD(Hons), FRCP
aKanarath P. Balachandran, MBBS, MD, MRCP, bColin Berry, MBChB, BSc, PhD, MRCP, cAlastair C. Pell, MBChB, BSc, MD, MRCP, cBarry D. Vallance, MBChB, FRCP(Glas), FRCP(Edin), bKeith G. Oldroyd, MBChB, MD(Hons), FRCP
Thrombolysis remains the most commonly used reperfusion therapy in acute myocardial infarction (AMI) in the United Kingdom, Europe and the developing world. Recent evidence suggests that thrombolysis may be equivalent to primary percutaneous coronary intervention (PCI) in establishing reperfusion in the infarct-related artery, if administered within 2 hours of onset of pain.1 Despite this, angiographic data from the thrombolytic mega-trials have demonstrated failure to establish TIMI 3 flow in 30–50% of patients at 90 minutes following institution of thrombolysis.2,3 Optimal treatment for failed reperfusion is controversial despite the recent REACT trial, which demonstrated superiority of the interventional arm.4 Even less is known of the factors that influence outcome in left ventricular (LV) function following rescue PCI. We performed an angiographic follow-up study of 102 patients who underwent rescue PCI at our center between 1997 and 2002. Baseline and follow-up ventricular function were assessed. We report on the factors that influenced changes in LV function. Methods The primary criteria for consideration of rescue PCI were: 1. Failure of resolution of ST segments by > 50% in the lead, with maximum ST-elevation at 90 minutes following commencement of thrombolysis. 2. Ability to perform PCI within 12 hours of the onset of pain. This was not a strict criterion, and PCI was performed beyond this window of time if there was persistent chest pain and/or fluctuating ST segments. One hundred seventy six patients underwent rescue PCI between January 1997 and March 2002. The use of stents and glycoprotein (GP) IIb/IIIa inhibitors were left to the discretion of individual operators. All operators were encouraged to perform left ventriculography (single-plane) at the end of the procedure. One hundred two of the 176 patients agreed to undergo repeat cardiac catheterization following informed consent. Patients who underwent the procedure for cardiogenic shock were excluded from follow up. Quantitative assessment of baseline and follow-up coronary angiograms/ventriculograms were performed offline with the software incorporated in the Phillips Inturis Suite (an automated edge detection technique with manual override). Eighty-two patients had paired ventriculograms that were suitable for analysis. The patients were divided into two groups based on the outcomes in global LV function: Group I = patients with improved LV function, and Group II = those in whom LV function deteriorated. The regional LV function was assessed by: Regional wall motion, 5-segment model: anterobasal (AB), anterolateral (AL), apical (AP), diaphragmatic (DM) and posterobasal (PB). Segments AB, AL and AP represent left anterior descending artery territory, and segments PB, DM and AP represent right coronary/left circumflex artery territories.5 Pre- and post-PCI TIMI flow in the infarct-related artery and post-PCI TIMI myocardial perfusion grade (TMP grade) were performed by an observer blinded to the study protocol. TMP was graded as follows: Grade 1 = no blush; 2 = minimal blush; 3 = good blush with slow clear-out of contrast; and 4 = good blush with rapid clear-out of contrast Statistical analysis. Continuous data were expressed as mean ± standard deviation (SD), except for covariates, which had a non-normal distribution where the median value and interquartile range (IQR) were reported. Categorical data were evaluated using the Fisher’s Exact test. Continuous variables were compared using paired or unpaired t-tests, as appropriate (or Wilcoxon rank sum tests or Mann-Whitney tests for non-symmetrically distributed). A probability value Results The clinical characteristics of the study population are detailed in Table 1. Seventy-eight percent were male, with a mean age of 60 years. There was no difference in the distribution of risk factors between the two groups, nor in the pattern of the infarct-related artery. The median pain-to-thrombolysis and pain-to-PCI times were similar in both groups. PCI was completed within 24 hours of the onset of pain in all patients (within 12 hours in 70 of 82). A total of 80 of the 82 (98%) patients underwent successful rescue PCI (TIMI 2 or 3 flow post-PCI), with TIMI 3 flow established in 72 patients (88%). During follow up, no difference was observed in the use of aspirin, beta-blockers or angiotensin converting enzyme inhibitors between the two groups. Intracoronary stents were used more often in patients in whom LV systolic function improved in the territory of the infarct-related artery compared to those with no improvement: (42 [76%] versus 15 [56%]; p = 0.058). A heparin infusion (12 to 24 hours post-PCI) tended to be used less often in patients with subsequent improvement in LV systolic function compared to those who had no improvement in LV systolic function (22 [41%] versus 16 [59%]; p = 0.12). The use of GP IIb/IIIa inhibitors was similar in both groups. In the complete patient cohort, LV ejection fraction and regional wall motion in the area supplied by the infarct-related artery was improved at follow up, but there was progressive ventricular remodeling as evidenced by increases in both end-diastolic and systolic volumes (Table 2). Baseline global ejection fraction was lower, and baseline end-systolic volume index was higher in patients with improved regional wall motion at follow up (Table 3). Predictors of left ventricular function. The univariate associates of LV systolic function at follow-up angiography are shown in Table 4. When included in a multivariate model, ejection fraction at the time of rescue PCI and stent use were independent predictors of LV function (Table 5). Among various quantitative angiographic parameters, the preprocedure reference diameter of the infarct-related artery was the only variable that almost reached statistical significance (p = 0.09; OR = 2.1). There was no difference between the pattern of infarct-related artery involvement (p = 0.72), TIMI flow pre- or post-PCI (p = 0.45; p = 0.84), and TMP grade post-PCI (p = 0.13) between the two groups. Discussion Management strategies for patients who fail to reperfuse following thrombolytic therapy has remained variable and partly dependent on the availability of on-site cardiac catheterization facilities. Some centers in the United Kingdom offer “rescue” percutaneous coronary intervention as a salvage modality, and two centers have reported good in-hospital and medium-term outcomes.6–8 Enthusiasm for an interventional approach has been tempered by the equivocal results of some of the earlier nonrandomized studies and the recently published MERLIN trial.9–12 The MERLIN trial had a relatively small sample size and, unfortunately, was underpowered to detect differences in mortality. However, data from the REACT, RESCUE and the PACT trials suggest that a policy of early intervention following failed thrombolysis is associated with improved clinical and LV functional outcomes that may be equivalent to primary PCI.4,13,14 Pain-to-PCI times. Clinical outcomes following thrombolysis are strongly influenced by the “pain-to-lysis” time, with little or no benefit after 12 hours of onset of pain.15 Primary PCI, however, has demonstrated clinical benefit more than 12 hours following onset of pain.16–18 We found no relation between the time interval between the onset of pain to completion of PCI and outcomes in regional LV function in our study. PCI was completed after 3 hours and within 24 hours of the onset of pain in all of our patients (Table 1). These observations indicate that outcomes following PCI in AMI, whether primary or rescue, may have no discernible temporal relationship if performed beyond 3 hours from the onset of pain. TIMI myocardial perfusion grade and TIMI Flow. Angiographic TIMI myocardial perfusion (TMP) grade has emerged as a semi-quantitative method of assessing tissue perfusion following reperfusion therapy. Higher TMP grades have been shown to be associated with improved microvascular perfusion and superior clinical outcomes.19–22 The majority of the patients (67%) in our study had TMP 0/1 grade post-PCI, and no association existed between TMP grades and LV systolic function. This may be due to the limited number of patients in our study, but other investigators have also failed to demonstrate improved outcomes with superior TMP grades.23 TIMI flow post-thrombolysis is a marker of successful recanalization of the infarct-related artery. TIMI 3 flow secondary to spontaneous reperfusion before primary PCI has been shown to be an independent determinant of survival.24 Pre-PCI TIMI 2 or 3 flow in our study did not predict improved regional wall motion. Our patients continued to demonstrate ECG evidence of failed reperfusion despite angiographic patency of the infarct-related artery. These patients have evidence of tissue-level hypoperfusion, and studies have shown poorer outcomes in such patients.25 Glycoprotein IIb/IIIa inhibitors. Glycoprotein IIb/IIIa inhibitor use, which was given to a majority of patients (71%), was at the discretion of the operator. The role of these drugs in rescue PCI remains debatable, with limited data showing improvements in clinical outcomes and LV function at the expense of an increased risk of bleeding.26–28 Their use in our study was not associated with improved regional wall motion. These agents were used when the thrombus burden was perceived to be “heavy” on subjective angiographic assessment, and were always used when the angiographic result post-PCI was considered unsuccessful or partially successful (TIMI 0 to 2). Their selective use is likely to have influenced outcomes in this study. Stents. Stenting has been shown to be safe and beneficial following thrombolysis.29–31 Other studies have found no difference in myocardial salvage between stenting and plain balloon angioplasty in AMI.18 In our study, stenting was a determinant of improved LV regional wall motion. Stent rates were fairly low compared to current practice, as a majority of patients who underwent rescue PCI during the earlier phase underwent plain balloon angioplasty, with stent use dramatically increasing later. Greater long-term patency of the infarct-related artery, with probable subsequent reduced ventricular remodeling, may be one explanation for this stent-related effect. Baseline ejection fraction. Patients in whom improved regional wall motion was observed had significantly lower baseline ejection fraction and nonsignificantly higher end-diastolic/end-systolic volumes. Eighty of the 82 patients in this study had a successful procedure. This suggests successful rescue PCI in larger infarcts leads to less remodeling and possibly improved outcomes. Study limitations. This study is based on observational, nonrandomized angiographic follow-up data at varying time intervals (median follow up = 20 months) (Table 1). The patients who underwent follow-up angiograms had predominantly successful rescue PCI, with TIMI 3 flow established post-PCI in 88% of the studied patients. The limited numbers may have masked potentially important determinants. Despite these limitations, we believe our study offers an insight into the “real world” clinical practice, and adds to the ongoing debate about rescue PCI. Conclusions In the United Kingdom, thrombolysis remains the primary modality of reperfusion therapy in acute ST-elevation myocardial infarction, and there will be a continuing demand for rescue PCI despite conflicting evidence. Coronary stenting, but not GP IIb/IIIa therapy, is associated with improved regional LV function following successful rescue PCI. Moreover, these improvements appear to be independent of the time taken to establish reperfusion, provided the intervention was performed between 3 to 24 hours after the onset of pain.
1. Bonnefoy E, Lapostolle F, Leizorovicz A, et al. Primary angioplasty versus prehospital fibrinolysis in acute myocardial infarction: A randomized study. Lancet 2002;360:825–829. 2. The GUSTO Angiographic Investigators. The comparative effects of tissue plasminogen activator, streptokinase or both on coronary artery patency, ventricular function and survival after acute myocardial infarction. N Eng J Med 1993;329:1615–1622. 3. Cannon CP, McCabe CH, Diver DJ, et al. Comparison of front loaded tissue type plasminogen activator, anistreplase and combination thrombolytic therapy for acute myocardial infarction: Results of the Thrombolysis in Myocardial Infarction (TIMI) 4 trial. J Am Coll Cardiol 1994;24:1602–1610. 4. Gershlick AH, Stephens-Lloyd A, Hughes S, et al. Rescue angioplasty for failed thrombolytic therapy after acute myocardial infarction. N Engl J Med 2005;353:2758–2768. 5. Wong WH, Kirkeeide RL, Gould KL. Computer application in angiography. In: Collins SM, Skorton DJ (eds.) Cardiac Imaging and Image Processing. New York: McGraw-Hill, 1986. 6. Balachandran KP, Miller J, Pell ACH, et al. Rescue percutaneous coronary intervention for failed thrombolysis: Results from a district general hospital. Postgrad Med J 2002;78:330–334. 7. Balachandran KP, Berry C, Norrie J, et al. Relation between coronary pressure derived collateral flow index, TIMI myocardial perfusion grade and outcome in left ventricular function after rescue percutaneous coronary intervention. Heart 2004;90:1450–1454. 8. 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. 9. Gibson CM, Cannon CP, Greene RM, et al. Rescue angioplasty in the thrombolysis in myocardial infarction (TIMI) 4 trial. Am J Cardiol 1997;80:21–26. 10. 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;31:1511–1517. 11. Mckendall GR, Forman S, Sopko G, et al. Value of percutaneous transluminal coronary angioplasty following unsuccessful thrombolytic therapy in acute myocardial infarction. Thrombolysis in Myocardial Infarction Investigators. Am J Cardiol 1995;76:1108–1111. 12. Sutton AG, Campbell PG, Graham R, et al. A randomized trial of rescue angioplasty versus a conservative approach for failed thrombolysis in ST-segment elevation myocardial infarction. J Am Coll Cardiol 2004;44:287–296. 13. Ellis SG, daSilva SR, Heyndrickx G, et al. Ranndomized comparison of rescue angioplasty with conservative management of patients with early failure of thrombolysis for acute anterior myocardial infarction. Circulation 1994;90:2280–2284. 14. Ross AM, Coyne KS, Reiner JS, et al. A randomized trial comparing primary angioplasty with a strategy of short acting thrombolysis and immediate planned rescue angioplasty in acute myocardial infarction. J Am Coll Cardiol 1999;34:1954–1962. 15. Steg PG, Bonnnefoy E, Chabaud S, et al. Impact of time to treatment on mortality after prehospital thrombolysis or primary angioplasty: Data from the CAPTIM randomized clinical trial. Circulation 2003;108:2828–2830. 16. Zijlstra F, Patel A, Jones M, et al. Clinical characteristics and outcome of patients with early ( 4 h) treated by primary coronary angioplasty or thrombolytic therapy for acute myocardial infarction. Eur Heart J 2002;23:550–557. 17. Brodie BR, Stone GW, Morice MC, et al. Importance of time to reperfusion on outcomes with primary coronary angioplasty for acute myocardial infarction. Am J Cardiol 2001;88:1085–1090. 18. Kastrati A, Mehilli J, Nekolla S, et al. A randomized trial comparing myocardial salvage achieved by coronary stenting versus balloon angioplasty in patients with acute myocardial infarction considered ineligible for reperfusion therapy. J Am Coll Cardiol 2004;43:734–741. 19. Gibson CM, Cannon CP, Murphy SA, et al. Relationship of TIMI myocardial perfusion grade to mortality after administration of thrombolytic drugs. Circulation 2000;101:125–130. 20. Stone GW, Peterson MA, Lansky AJ, et al. Impact of normalized myocardial perfusion after successful angioplasty in acute myocardial infarction. J Am Coll Cardiol 2002;39:591–597. 21. Dibra A, Mehilli J, Dirschinger J, et al. Thrombolysis in myocardial infarction myocardial perfusion grade in angiography correlates with myocardial salvage in patients with acute myocardial infarction treated with stenting or thrombolysis. J Am Coll Cardiol 2003;41:925–929. 22. van’t Hof AW, Liem A, Suryapranata H, et al. Angiographic assessment of myocardial perfusion in patients treated with primary angioplasty for acute myocardial infarction: Myocardial blush grade. Circulation 1998;97:2302–2306. 23. Bax M, de Winter RJ, Schotborgh CE, et al. Short and long term recovery of left ventricular function predicted at the time of primary percutaneous coronary intervention in anterior myocardial infarction. J Am Coll Cardiol 2004;43:534–541. 24. Stone GW, Cox D, Garcia E, et al. Normal flow (TIMI 3) before mechanical reperfusion therapy is an independent determinant of survival in acute myocardial infarction: Analysis from the primary angioplasty in myocardial infarction trials. Circulation 2001;104:636–641. 25. Ito H, Tamooka T, Sakai N, et al. Lack of myocardial perfusion immediately after successful thrombolysis: A predictor of poor recovery of left ventricular function in anterior myocardial infarction. Circulation 1992;85:1699–1705. 26. Petronio AS, Musumeci G, Limbruno U, et al. Abciximab improves 6-month clinical outcomes after rescue coronary angioplasty. Am Heart J 2002;143:334–341. 27. Ronner E, van Domburg RT, van den Brand MJ, et al. Platelet GP IIb/IIIa receptor blockers for failed thrombolysis in acute myocardial infarction, alone and as adjunct to other rescue therapies. Eur Heart J 2002;23:1529–1537. 28. Gruberg L, Suleiman M, Kapeliovich M, et al. Glycoprotein IIb/IIIa inhibitors during rescue percutaneous coronary intervention in acute myocardial infarction. J Invasive Cardiol 2006;18:59–62. 29. Scheller B, Hennen B, Hammer B, et al. Beneficial effects of immediate stenting after thrombolysis in myocardial infarction. J Am Coll Cardiol 2003;42:634–641. 30. Fernandez-Aviles F, Alonso JJ, Gimeno F, et al. Safety of coronary stenting early after thrombolysis in patients with acute myocardial infarction: One and six-month clinical and angiographic evolution. Catheter Cardiovasc Interv 2002;55:467–476 . 31. Schomig A, Ndrepepa G, Mehilli J, et al. A randomized trial of coronary stenting versus balloon angioplasty as a rescue intervention after failed thrombolysis in patients with acute myocardial infarction. J Am Coll Cardiol 2004;44:2073–2079.