CLINICAL RESEARCH: MYOCARDIAL INFARCTION
Association of Impaired Thrombolysis In Myocardial Infarction Myocardial Perfusion Grade With Ventricular Tachycardia and Ventricular Fibrillation Following Fibrinolytic Therapy for ST-Segment Elevation Myocardial Infarction
C. Michael Gibson, MS, MD, FACC*,*,
Yuri B. Pride, MD ,
Jacqueline L. Buros, BA*,
Erin Lord, BA*,
Amy Shui, MA*,
Sabina A. Murphy, MPH*,
Duane S. Pinto, MD, FACC,
Peter J. Zimetbaum, MD, FACC,
Marc S. Sabatine, MD, MPH, FACC ,
Christopher P. Cannon, MD, FACC,
Mark E. Josephson, MD, FACC for the TIMI Study Group
* TIMI Study Group, Beth Israel Deaconess Medical Center, Boston, Massachusetts
Brigham & Women’s Hospital, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts
Division of Cardiology and Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts.
Manuscript received June 18, 2007;
revised manuscript received August 24, 2007,
accepted August 27, 2007.
* Reprint requests and correspondence: Dr. C. Michael Gibson, Director, TIMI Data Coordinating Center, 350 Longwood Avenue, First Floor, Boston, Masschusetts 02115. (Email: mgibson{at}perfuse.org).
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Abstract
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Objectives: The goal of this analysis was to evaluate the association of impaired Thrombolysis In Myocardial Infarction myocardial perfusion grade (TMPG) with sustained ventricular tachycardia (VT) or ventricular fibrillation (VF).
Background: Impaired TMPG after successful restoration of epicardial flow among patients treated with fibrinolytic therapy for ST-segment elevation myocardial infarction (STEMI) has been associated with adverse clinical outcomes, but its relationship to VT/VF has not been evaluated.
Methods: In the CLARITY-TIMI 28 (Clopidogrel as Adjunctive Reperfusion Therapy–Thrombolysis In Myocardial Infarction 28) study, 3,491 patients underwent angiography a median of 3.5 days after fibrinolytic administration for STEMI; TMPG was assessed, and its association with VT/VF was evaluated.
Results: We observed VT/VF in 4.8% of patients. Impaired myocardial perfusion (TMPG 0/1/2) was associated with an increased incidence of VT/VF (7.1% vs. 2.6% with TMPG 3; log-rank p < 0.001). Among patients with restoration of normal epicardial flow (Thrombolysis In Myocardial Infarction flow grade 3), the incidence of VT/VF was increased among patients with impaired TMPG (4.7% vs. 2.7%; p = 0.02). Among patients with left ventricular ejection fraction  30%, impaired TMPG remained associated with an increased incidence of VT/VF (4.7% vs. 2.5%; p = 0.03). We found that VT/VF was associated with increased mortality (25.2% vs. 3.5%; p < 0.0001). Furthermore, among patients with VT/VF, impaired TMPG was associated with increased mortality (17.1% vs. 2.3%; p = 0.02). All but 1 death among patients who had VT/VF were among patients with impaired myocardial perfusion.
Conclusions: Despite restoration of normal epicardial flow or a left ventricular ejection fraction 30%, impaired myocardial perfusion on angiography 3.5 days after fibrinolytic administration for STEMI is associated with an increased incidence of VT/VF.
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Abbreviations and Acronyms
| | MRI = magnetic resonance imaging | | PCI = percutaneous coronary intervention | | SCD = sudden cardiac death | | STEMI = ST-segment elevation myocardial infarction | | TFG = Thrombolysis In Myocardial Infarction flow grade | | TMPG = Thrombolysis In Myocardial Infarction myocardial perfusion grade | | VF = ventricular fibrillation | | VT = ventricular tachycardia |
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One potentially fatal complication after ST-segment elevation myocardial infarction (STEMI) is ventricular tachyarrhythmia, the most common cause of sudden cardiac death (SCD) (1). Approximately one-third to one-half of all cardiac deaths after acute myocardial infarction (MI) have been attributed to SCD (2). Identification of simply assessed clinical variables associated with subsequent ventricular tachycardia (VT) and ventricular fibrillation (VF) could prove useful in the triage of patients to more aggressive pharmacologic- or device-based therapies. Previous observational studies have demonstrated that traditional cardiac risk factors, such as age, hypertension, and tobacco use, are associated with an increased risk of VT/VF after MI (3–5). In addition, impaired systolic function, prior episodes of ventricular arrhythmia, certain electrocardiographic findings, and the inducibility of arrhythmias on electrophysiologic studies are associated with future VT/VF (6).
Impairment of the Thrombolysis In Myocardial Infarction myocardial perfusion grade (TMPG) on coronary angiography has been associated with evidence of scar development, as imaged on magnetic resonance imaging (MRI) (7), poorer left ventricular (LV) function (8), increased LV filling pressures (9), and a reduced salvage index (recovery of LV function) after MI (10). Given the association of impaired TMPG with scar and reduced LV function, we hypothesized that impaired TMPG might be associated with an increased risk of VT/VF. This hypothesis was tested in the CLARITY-TIMI 28 (Clopidogrel as Adjunctive Reperfusion Therapy–Thrombolysis in Myocardial Infarction 28) study, in which patients presenting with STEMI underwent angiography a median of 3.5 days after fibrinolytic administration (11).
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Methods
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The CLARITY-TIMI 28 study was a multicenter, international, randomized, double-blind, placebo-controlled trial of aspirin versus aspirin plus clopidogrel in 3,491 patients who were treated with fibrinolytic therapy for STEMI (11). In brief, patients were 18 to 75 years of age, presented within 12 h of the onset of STEMI, and were scheduled to undergo coronary angiography 2 to 8 days after randomization. When clinically indicated, patients underwent earlier angiography. Patients underwent percutaneous coronary intervention (PCI) at the discretion of the treating physician. Episodes of VT/VF were recorded in patients through death, hospital discharge, or 30 days after randomization, whichever occurred first. Telephone follow-up occurred at day 30 to assess for any interim clinical end points or adverse events, which were confirmed by means of the medical record. Only episodes of sustained VT and VF were reported as defined by the individual investigators.
Angiographic analysis.
All angiograms were analyzed off-line and blinded to treatment assignment at a central core laboratory. Flow and perfusion in the infarct-related artery were evaluated using the Thrombolysis In Myocardial Infarction flow grade (TFG) and TMPG. A single author (C.M.G.) evaluated TMPG. The intraobserver (92.5%) and interobserver (85.0%) agreement of TMPG have been reported to be high (12). Ventriculography was performed at the discretion of the physician.
Statistical analysis.
All analyses were performed with Stata version 9.2 (College Station, Texas). All continuous variables are reported as the median and interquartile range and were tested using the nonparametric Wilcoxon rank-sum test. The chi-square test or Fisher exact test was used for the analysis of categorical variables when appropriate.
Cox proportional-hazards regression and Kaplan-Meier survival analysis were used to evaluate associations with VT/VF. Incidence rates of VT/VF are reported with Kaplan-Meier hazard rates through discharge or 30 days. The proportional-hazards assumption was tested before running the Cox models, and time-varying covariates were added as needed.
Analyses of VT/VF and subsequent mortality are reported as evaluated in the context of a model in which VT/VF was modeled as a time-variant covariate of mortality. Associations between VT/VF as a time-invariant covariate of mortality also were evaluated; where these results are discordant with those with time-varying covariates, they are noted in the text.
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Results
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Baseline characteristics.
Patients underwent angiography a median of 3.5 days after randomization (interquartile range 2.1 to 5.2). There were a total of 180 VT/VF events among 167 patients (Fig. 1). Patients with VT/VF were more often of nonwhite race, of lower body weight, and more often had sustained a previous MI and an anterior MI; they were less likely to have been administered beta-blockers, statins, angiotensin-converting enzyme inhibitors or angiotensin-receptor blockers, or low-molecular-weight heparin (Table 1).
Clinical outcomes.
Impaired TMPG was associated with an increased incidence of VT/VF (hazard ratio [HR] 2.4, 95% confidence interval [CI] 1.68 to 3.54, p = 0.01) (Fig. 2). Among patients with TFG 3 at angiography, those with impaired TMPG had a greater incidence of VT/VF (HR 1.8, 95% CI 1.13 to 2.90; p = 0.01) (Fig. 3A). In addition, among patients with normal to moderately reduced systolic function (left ventricular ejection fraction [LVEF] 30%) at angiography, TMPG 0/1/2 was associated with an increased incidence of VT/VF (HR 1.9, 95% CI 1.04 to 3.36; p = 0.04) (Fig. 3B). Impaired myocardial perfusion was associated with both an increased incidence of having had VT/VF before angiography and having VT/VF after angiography, even among patients with patent infarct-related arteries (TFG 2 or 3) (Figs. 4 and 5).
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Figure 2 VT/VF Among Patients With TMPG 0/1/2 Compared With TMPG 3
Impaired myocardial perfusion at angiography was associated with a significantly greater incidence of ventricular tachycardia (VT) or ventricular fibrillation (VF). TMPG = Thrombolysis In Myocardial Infarction myocardial perfusion grade.
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Figure 3 VT/VF Among Subgroups
Even among patients with normal epicardial flow (Thrombolysis In Myocardial Infarction flow grade 3), impaired myocardial perfusion was associated with a significantly greater incidence of VT/VF than normal perfusion (A). Similarly, among patients with relatively preserved systolic function (left ventricular ejection fraction >35%), impaired myocardial perfusion was associated with an increased incidence of VT/VF (B). Abbreviations as in Figure 2.
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Figure 5 VT/VF Before and After Angiography Among Patients With Preserved Epicardial Flow
Among patients with an open artery at angiography (Thrombolysis In Myocardial Infarction flow grade 2 or 3), impaired myocardial perfusion was associated with a significantly greater incidence of VT/VF both before (A) and after angiography (B). Abbreviations as in Figure 2.
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Patients who underwent PCI during the index hospitalization had the same incidence of VT/VF as those who did not (Fig. 6A). However, of those undergoing PCI, patients with poor myocardial perfusion both before and after PCI had a greater incidence of VT/VF after PCI than those who had normal myocardial perfusion either before PCI, after PCI, or at both times (Fig. 6B). Patients with TMPG 3 both before and after PCI had a lower incidence of VT/VF after PCI when compared with those who had impaired myocardial perfusion before PCI, after PCI, or at both times (0.2% vs. 7.9%; log-rank p = 0.03).
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Figure 6 VT/VF Among Patients Undergoing PCI
No significant differences were found in the incidence of VT/VF among patients who underwent percutaneous coronary intervention (PCI) compared with those who did not (A). Normal perfusion before, after, or both before and after PCI was associated with a significantly lower incidence of VT/VF than poor perfusion both before and after PCI (B). Abbreviations as in Figure 2.
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Despite the fact that patients without VT/VF were more likely to have been prescribed statins, beta-blockers, or angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, multivariate analysis revealed that the use of these medications was not associated with the incidence of VT/VF, nor did they alter the point estimates for the relationship between TMPG and VT/VF. Multivariate analysis did not reveal any association between clopidogrel administration and the incidence of VT/VF, nor did it alter the point estimates for the relationship between TMPG and VT/VF. In addition, although anterior MI was associated with a trend toward a greater incidence of VT/VF, after adjusting for this, the association between impaired TMPG and VT/VF remained significant.
We found that VT/VF at any point during hospitalization was associated with increased mortality at 30 days (25.9% vs. 3.5%; log-rank p < 0.0001). Most patients with VT/VF died of SCD. We also found that VT/VF in the context of TMPG 0/1/2 was associated with increased mortality when compared with its occurrence in the presence of normal TMPG (17.5% vs. 2.4%; log-rank p = 0.02). All but 1 death among patients who had VT/VF were among patients with impaired myocardial perfusion. Furthermore, among patients with TFG 3 at angiography, all fatal VT/VF was observed among patients with TMPG 0/1/2.
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Discussion
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This analysis demonstrates that among STEMI patients treated with fibrinolytic therapy, impaired myocardial perfusion on coronary angiography, as assessed by TMPG, is associated with an increased incidence of VT/VF. Furthermore, among patients with successful restoration of TFG 3, those with impaired myocardial perfusion had an 80% greater risk of VT/VF. Even among patients with an LVEF 30%, the presence of impaired myocardial perfusion was associated with a nearly 2-fold greater incidence of VT/VF.
The prognosis of VT/VF varied depending upon myocardial perfusion. We found that VT/VF, in the context of impaired myocardial perfusion (TMPG 0/1/2), was associated with increased mortality when compared with its occurrence in the presence of normal TMPG 3. Indeed, all but 1 death among patients who had VT/VF were among patients with impaired TMPG.
It could be speculated that VT/VF in the context of normal perfusion represents a "reperfusion arrhythmia" and reflects successful restoration of epicardial patency, whereas VT/VF in the context of impaired perfusion may be the result of capillary plugging, edema, capillary leak, or scar. In addition, the increased incidence of malignant arrhythmia among patients with impaired myocardial perfusion could explain the previous observation of poorer survival among patients with TFG 3 who had impaired TMPG (13).
Most SCDs are caused by ventricular tachyarrhythmias (1). Approximately 65% of patients who experience SCD have underlying coronary artery disease (14). Abnormal myocardial perfusion among patients with VT/VF in the present analysis is consistent with SCD autopsy studies that demonstrate impaired myocardial perfusion on postmortem angiography (15,16).
The most plausible pathophysiologic mechanisms underlying the observations in the present analysis are the previously described association of impaired perfusion with ongoing ischemia, microvascular obstruction, edema, scar formation, and hyperenhancement on cardiac MRI, each of which are, in turn, associated with VT/VF (2,7,17–22). Alternatively, local metabolic derangements (23) as well as changes in the expression of cardiomyocyte membrane ion channels, could be induced by poor myocardial perfusion (24).
A number of epidemiologic risk factors associated with ventricular arrhythmia have been observed (3–5). Risk factor assessment is ever-changing as modern pharmacologic therapy for coronary artery disease and heart failure change (25). Attempts at SCD risk stratification have been made (6), taking into account noninvasive and invasive studies, including echocardiographic measurement of LVEF and electrocardiographic and electrophysiologic data. The ability of the TMPG to provide incremental discriminatory power to sudden death risk stratification tools warrants further evaluation.
Study limitations.
This analysis is a nonrandomized retrospective one and, as such, it is possible that both identified and unidentified confounders may have influenced the outcomes. Episodes of VT/VF were not prespecified as outcomes in the study, and individual investigators defined VT/VF rather than a core laboratory. Angiographic data were not available in those patients who died before angiography. Left ventricular function was not assessed in all patients. Follow-up from hospital discharge through 30 days was by report only, and there may have been incidences of VT/VF during this time period that were reported as deaths alone if there was no documentation of a fatal ventricular arrhythmia, thus possibly underestimating the incidence of VT/VF during this time. Although the findings presented here are provocative, because of the short-term follow-up and retrospective nature of the results, therapeutic decisions regarding the treatment of VT/VF should be based on prospective, randomized studies.
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Conclusions
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Despite restoration of Thrombolysis In Myocardial Infarction grade 3 epicardial flow or an LVEF 30%, impaired TMPG at angiography 3.5 days after fibrinolytic administration for STEMI is associated with an increased incidence of VT/VF.
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Footnotes
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Supported in part by a grant from Sanofi-Aventis, Antony, France.
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References
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Abstract
Methods
