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

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.^4,13,14Pain-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.

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