University of Groningen

Transcription

1 University of Groningen Computer assisted decision support in acutely ill patients. Application in glucose management and quantification of myocardial reperfusion Vogelzang, Mathijs IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite from it. Please check the document version below. Document Version Publisher's PDF, also known as Version of record Publication date: 2008 Link to publication in University of Groningen/UMCG research database Citation for published version (APA): Vogelzang, M. (2008). Computer assisted decision support in acutely ill patients. Application in glucose management and quantification of myocardial reperfusion Mathijs Vogelzang Copyright Other than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons). Take-down policy If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim. Downloaded from the University of Groningen/UMCG research database (Pure): For technical reasons the number of authors shown on this cover page is limited to 10 maximum. Download date:

2 Computer assisted myocardial blush quantification in acute myocardial infarction Mathijs Vogelzang, Pieter J. Vlaar, Tone Svilaas, Diny Amo, Maarten WN Nijsten, Felix Zijlstra Submitted

3 Abstract Background Myocardial reperfusion after acute myocardial infarction can be angiographically assessed by the Myocardial Blush Grade (MBG) or TIMI Perfusion Grade. These scores are based on subjective human judgment and lead to a score of 4 categories. A more operator-independent way of scoring myocardial perfusion may facilitate research in this area. Methods and Results We designed the Quantitative Blush Evaluator (QuBE), a computer program which calculates a score for myocardial perfusion. This program will be freely available as open source software. Assessment of an angiogram typically took one minute per angiogram. The inter-observer agreement was 96%. We calculated values on prospectively collected angiograms in patients with acute ST-elevation myocardial infarction from a recently completed randomized clinical trial. QuBE values could be assessed on 748 out of 894 collected angiograms (84%). The QuBE score correlated significantly with MBG as determined by a core lab. The QuBE score predicted complete ST-elevation resolution, low enzyme levels and 1-year survival (all P<0.001). QuBE value was an independent predictor of mortality at one year (OR 0.29 ( ), P=0.003). QuBE score remained predictive in patients with optimal conventional perfusion parameters (TIMI flow 3 and MBG 2/3). Conclusions The QuBE program provides a practical, freely available computer-assisted assessment of myocardial perfusion, which correlates well with outcome. The QuBE score provides a useful surrogate endpoint in trials of therapies aimed at improving myocardial reperfusion. Introduction Mechanical reperfusion is the preferred treatment modality for acute ST-elevation myocardial infarction (STEMI). 1 Despite adequate restoration of epicardial coronary flow, the incidence of adverse outcomes remain high in certain subgroups. Impaired myocardial reperfusion is an important determinant of adverse outcome in patients with restored epicardial flow. 2,3 The myocardial blush grade (MBG) has been devised for the visual assessment of myocardial reperfusion after primary percutaneous coronary intervention, and this score is an independent predictor for adverse outcome. 2,4 Similarly, the TIMI myocardial perfusion grade has been designed for patients receiving thrombolytic therapy. 5 Although the visual assessment of myocardial reperfusion has been successfully 66

4 Computer assisted myocardial blush quantification used for risk stratification and as surrogate endpoint in clinical trials, important drawbacks complicate the widespread use of this measure. The visual assessment requires an experienced observer, and is associated with marked variability and an intrinsic limited reproducibility. 6 Recently, myocardial blush was quantified by computer in a small cohort of patients with STEMI and predicted left ventricular ejection fraction as measured by echocardiography. 7 We hypothesized that computer analysis of myocardial reperfusion on the digital coronary angiogram should be feasible in routine practice and should predict adverse clinical outcome after STEMI. In addition to being less observer-dependent, computer assisted analysis may yield a more fine-grained assessment of reperfusion, facilitating comparisons between patients and patient groups. Materials and Methods Quantitative Blush Evaluation program We developed a computer program for the analysis of digital coronary angiograms in-house, named QuBE (Quantitative Blush Evaluator). This program loads cineangiograms in standard DICOM format. From the different runs taken during one procedure, the operator selects the angiogram to use for assessment. On this angiogram, the operator indicates a polygonal shape that contains the distal infarct related area. Figure 1A shows a typical screenshot of the program. Calculation by the program starts with correction of small panning motions. The program then filters background features such as the diaphragm to only keep smaller sized structures. These features are quantified for each single frame in the angiogram, and therefore there is no need to specifically indicate end-diastolic frames. The myocardial blush grade primarily aims to quantify the increase in grayvalue over time. 2,4 The grading of TIMI myocardial perfusion grade includes the amount of washout of contrast from the myocardium. 5 We therefore let the QuBE value reflect both the filling and emptying phase of the vessels, by summing the maximum increase in grayvalue and the maximum decrease after that. Figure 1B shows the agreement of the method when scored twice by a single operator, or when scored by two different operators. Scoring of a QuBE value typically took 1 minute in total. After publication, the QuBE program will be provided as open source software on the site Distribution as open source software makes the program free to use, redistribute and modify. 67

5 Figure 6.1: The QuBE program Part A shows a typical screenshot in which an operator has indicated the region of interest on a coronary angiogram of a right coronary artery. The curve representing the quantified value in all frames is shown to the right. The QuBE value equals the maximum increment (from frame 8 to 24) plus the maximum decrement after that (frame 24 to 92). Part B shows the agreement of QuBE scores of 30 angiograms assessed twice by the same operator and twice by different operators. Patients We included patients who were enrolled in the TAPAS trial. 8,9 The TAPAS trial was a randomized trial, aimed at including typical STEMI patients, and therefore had wide inclusion criteria and few exclusion criteria. Patients were recruited from January 2005 to December Details of the study protocol, patient selection, baseline characteristics, pharmacological and interventional therapies have been described. 8,9 In the current analysis, we included all patients who underwent primary percutaneous coronary intervention who had an angiogram on which the corelab had been able to 68

6 Computer assisted myocardial blush quantification visually assess the myocardial blush grade and who had completed one-year follow up at the time of this study. Table 6.1: Patient characteristics 1st QuBE tertile 2nd QuBE tertile 3rd QuBE tertile P N QuBE value (median, range) 7.6 ( ) 13.0 ( ) 18.9 ( ) Age 68 ( ) 62 (54-72) 61 (52-69) < Male sex 68% 75% 71% ns Ischemic time (min) 202 ( ) 187 ( ) 187 ( ) Body mass index 26.8 ( ) 26.5 ( ) 26.0 ( ) Heart rate 80 (69-93) 79 (64-89) 76 (63-87) Systolic blood pressure 127 ( ) 126 ( ) 128 ( ) ns Diastolic blood pressure 75 (64-86) 72 (65-85) 75 (63-83) ns Culprit vessel < RCA 24% 42% 53% LAD 45% 45% 38% Cx 29% 13% 8% TIMI flow pre PCI /1 67% 59% 51% 2 16% 19% 23% 3 17% 21% 26% Stent placement 89% 95% 96% GP IIb/IIIa inhibitor treatment 90% 92% 95% TIMI flow post PCI < /1 4.5% 1.6% 0.4% 2 18% 14% 7.5% 3 77% 84% 92% Values are represented as median (IQR) or percentage, unless otherwise indicated. MI: myocardial infarction, CABG: coronary artery bypass grafting, PCI: percutaneous coronary intervention, RCA: right coronary artery, LAD: left anterior descending artery, Cx: circumflex artery. QuBE values and myocardial blush grading QuBE values were scored on angiograms made at the end of the primary angioplasty procedure and following administration of nitroglycerin. All angiograms were filmed at 12.5 frames per second in a single plane catheterization lab (Siemens AG, Ger- 69

7 many). The QuBE value was determined for all included patients by one observer. TIMI flow and the myocardial blush grade were assessed by an independent observer at a corelab (Cordinamo, Zwolle, The Netherlands). We included all baseline variables for all patients in our study, and used these to assess which variables at baseline correlate with the calculated QuBE value. We hypothesized that good perfusion would be correlated to age, infarct location, ischemic time and patency (TIMI flow) before and after intervention, as found in earlier studies. 2,4 Because the quantification uses absolute intensities, we hypothesized that patients with a high body mass index might have lower QuBE values. Outcome measures The study protocol included analysis of the ECG both before and after the intervention. The sum of ST-elevation over all leads was determined on the initial ECG. Full ST-elevation resolution was defined as a residual elevation of less than 30% on the post procedural ECG. Enzyme release was routinely measured during the stay at the coronary care unit after the primary percutaneous coronary intervention (PCI). We calculated the area under the serum creatine kinase curve over the first 24 hours post-pci. No curve was calculated for patients having less than 2 measurements, or only measurements with a timespan less than 16 hours. This mainly occurred in patients referred early to one of the 6 hospitals in our catchment area with no PCI facility. Clinical follow up was obtained by written interviews and telephone interviews. To assess the added value of QuBE, its association with outcome measures was analyzed both in the complete patient group and in the subgroup of patients in which adequate reperfusion was achieved. Adequate reperfusion has previously been defined as TIMI flow 3 post PCI and MBG 2/3. 4 Statistical analysis Statistics are expressed as median (interquartile range, IQR). Groups were compared with the Mann-Whitney U test for continuous or ordinal variables and the Chi-square or Fisher s exact test for categorical data when appropriate. To allow group comparisons, patients were classified according to the tertile of their QuBE value. Factors predicting 1-year mortality were tested in a binary logistic regression model. Variables were tested in univariate and multivariate analysis. Backward elimination was performed on all variables with a P value <0.10 in univariate analysis. A two-tailed P value lower than 0.05 was considered statistically significant. All statistics were performed by the R software package (version 2.5.1). The authors had full access to 70

8 Computer assisted myocardial blush quantification the data and take responsibility for its integrity. All authors have read and agree to the manuscript as written. Results Figure 2 shows a flow diagram of patients in this study. Out of 1071 included patients in the TAPAS trial, 894 met the inclusion criteria of a performed PCI, complete 1-year follow-up and MBG scored by the core lab. Of these patients, a number of angiograms were not assessable, mainly due to large panning or diaphragm motion artifacts. The flexible identification of a polygonal area allowed the operator to circumvent overlapping arteries, and therefore only 5 angiograms could not be used due to overlap of the region of interest with non-infarcted blood vessels. Figure 6.2: Flow diagram of analyzed patients and angiograms. Reasons of exclusion before and after QuBE evaluation are shown. MBG: myocardial blush grade. IRA: infarct related artery. Table 1 shows baseline patient characteristics according to tertiles of QuBE values. In a multivariate linear regression model including the variables with a P value <0.10, age, body mass index, heart rate and TIMI flow both pre and post PCI remained as significant factors predicting the QuBE value. These factors accounted for 18% variance in QuBE value according to the r 2 value of the multivariate regression. 71

9 QuBE and one-year mortality Per the inclusion criteria, one-year all-cause mortality was available in 748/748 (100%) of patients. Total 1-year mortality was 42/748 (5.6%). Figure 3 shows mortality per tertile of QuBE value. Similar as previously found for MBG, only the lowest QuBE values directly translated to increased one year mortality. 4 Figure 6.3: 1-year mortality and QuBE value Mortality is shown per tertile of QuBE value, in all patients (empty bars) and in patients with optimal reperfusion (gray bars). MBG: Myocardial Blush Grade. In our study group, 558/748 (74.6%) of patients met criteria for optimal reperfusion (TIMI 3 flow combined with MBG 2 or 3). Within this group, the QuBE value still had discriminating power with respect to one year mortality (Figure 3). Table 2 shows univariate and multivariate analysis of predictors of 1-year mortality. In multivariate analysis, the QuBE value remained as the only independent angiographical predictor of mortality at one year (P = 0.003). When TIMI flow and MBG were re-entered into the model, QuBE score remained the most significant angiographical parameter. QuBE and MBG, ECG and enzyme parameters Myocardial blush grade was available for analysis in all patients. Both ECGs needed for analysis of ST resolution were available in 698/748 patients (93%), and the 24h area under the curve of serum creatine kinase measurements could be assessed in 72

10 Computer assisted myocardial blush quantification Variable Table 6.2: Multivariate binary logistic model for 1-year mortality univariate OR (95% CI) P multivariate OR (95% CI) Age (per year) 1.07 ( ) < ( ) QuBE value (per 10 points) 0.23 ( ) < ( ) History of diabetes 4.35 ( ) ( ) Visual MBG 0.51 ( ) ns Culprit RCA 0.19 ( ) ( ) 0.01 Culprit LDA 3.22 ( ) ns Stent placement 0.25 ( ) ns TIMI flow post PCI 0.49 ( ) ns Full ST resolution 0.31 ( ) ns CK-AUC 24h (per 100) 1.06 ( ) ns History of stroke 3.82 ( ) 0.01 ns GP IIb/IIIa inhibitor treatment 0.37 ( ) 0.02 ns Previous PCI 2.41 ( ) 0.06 ns Diastolic blood pressure 0.98 ( ) 0.07 ns OR: odds ratio, CI: confidence interval, MBG: myocardial blush grade, CK-AUC: area under the curve of serial creatine kinase measurements. P 545/748 patients (73%). Figure 4 shows patterns of myocardial blush grades, ST resolution, and enzyme levels per tertile of QuBE value. All three parameters showed a strong correlation to the QuBE score (all P<0.0001). Linear regression of QuBE values with the area under the curve of serum CK showed a significant correlation (P<0.0001). This correlation remained significant in subsets of patients with only TIMI flow 3 post PCI and patients with myocardial blush grade 2 or 3. Discussion In this study we developed and evaluated QuBE, a computer program for quantification of myocardial perfusion after PCI in STEMI patients. We found that perfusion values as quantified by QuBE were associated high MBG scored at a corelab, ST-segment resolution, smaller infarct sizes as measured by enzyme release, and survival at one year. Current reperfusion strategies are generally successful at achieving epicardial reperfusion. However, mortality rates after adequate infarct-related vessel reperfusion (TIMI flow 3) are still high in subgroups with inadequate myocardial reperfusion 73

11 Figure 6.4: Blush, ECG and enzyme parameters Visual myocardial blush grade (MBG), full ST resolution and myocardial enzyme levels (CK-AUC 24h: area under the curve of creatine kinase) according to tertiles of QuBE score. and loss of ventricular function with subsequent heart failure remains an important problem. 2,4,10 For the development of new therapies it is important to be able to identify high-risk subgroups, and have adequate surrogate endpoints to measure the desired effect. The QuBE method provides a practical and efficient method to quantify myocardial perfusion. Although advanced techniques such as perfusion MRI may give a more exact assessment of perfusion, 11 these methods require additional diagnostic procedures, and are therefore not applicable in large scale trials. The QuBE value only requires one specific angiogram taken at the end of the angioplasty procedure, and the result can be made immediately readily available. We were able to quantify perfusion in the majority of scored angiograms from a recently completed randomized controlled trial, despite the fact that they were not specifically made for this goal. 74

12 Computer assisted myocardial blush quantification We hypothesize that with more effort by interventional cardiologists to instruct the patient to hold his/her breath and not pan while shooting the blush sequence, the percentage of adequately scorable angiograms can further increase. The fine-grained QuBE assessment will allow more precise angiographically measurements. We therefore have designed a randomized trial that includes two paired blush sequences, both before and after administrating intracoronary adenosine. 12 The visually scored blush value of 0 to 3 would lack adequate precision to make a paired assessment possible. The increased power of the QuBE value has the potential to identify beneficial interventions in patient cohorts with limited size. A number of limitations must be mentioned. Although we found good reproducibility of QuBE values, we have not assessed the differences that come from the specific acquisition machine and method used. At the moment, we do not know how parameters such as the amount of infused contrast, the exact quantity of nitrate administrated, and the heart rate of the patient influence the QuBE value. These parameters have previously been found to potentially confound the TIMI frame count, a measure for epicardial flow. 13 When a trial includes patients from different centers, QuBE values may not be comparable. If this is the case, a simple solution would be to use a cohort of patients as calibration at each site. The QuBE values of these patients can be used to calculate a mean and standard deviation, and for each site QuBE values can be normalized, for instance to values ranging from 0 to 100. As QuBE will be released as open source, groups other than ours are free to experiment, adjust and expand the QuBE program. We hope that future research will define the extent to which QuBE values are comparable between catheterization laboratories. We also hypothesize that further analysis may reveal additional parameters that can be derived from the perfusion score profiles as shown in figure 1. In summary, the QuBE method provides a practical and feasible way to quantify myocardial perfusion after PCI, and may therefore be useful as risk indicator or surrogate endpoint. References 1. Keeley EC, Boura JA, Grines CL. Primary angioplasty versus intravenous thrombolytic therapy for acute myocardial infarction: a quantitative review of 23 randomised trials. Lancet 2003;361(9351): van t Hof AW, Liem A, Suryapranata H, Hoorntje JC, de Boer MJ, Zijlstra F. Angiographic assessment of myocardial reperfusion in patients treated with primary angioplasty for acute myocardial infarction: myocardial blush grade. Circulation 1998;97(23): Haager PK, Christott P, Heussen N, Lepper W, Hanrath P, Hoffmann R. Prediction of clinical 75

13 outcome after mechanical revascularization in acute myocardial infarction by markers of myocardial reperfusion. J Am Coll Cardiol 2003;41(4): Henriques JP, Zijlstra F, van t Hof AW, et al. Angiographic assessment of reperfusion in acute myocardial infarction by myocardial blush grade. Circulation 2003;107(16): Gibson CM, Cannon CP, Murphy SA, et al. Relationship of TIMI myocardial perfusion grade to mortality after administration of thrombolytic drugs. Circulation 2000;101(2): Bertomeu-González V, Bodí V, Sanchis J, et al. Limitations of myocardial blush grade in the evaluation of myocardial perfusion in patients with acute myocardial infarction and TIMI grade 3 flow [spanish]. Rev Esp Cardiol 2006;59(6): Korosoglou G, Haars A, Gick M, et al. Quantitative evaluation of myocardial blush to assess tissue level reperfusion in patients with acute ST-elevation myocardial infarction: incremental prognostic value compared with visual assessment. Am Heart J 2007;153(4): Svilaas T, van der Horst IC, Zijlstra F. Thrombus Aspiration during Percutaneous coronary intervention in Acute myocardial infarction Study (TAPAS) study design. Am Heart J 2006; 151(3):597.e1 597.e7. 9. Svilaas T, Vlaar PJ, van der Horst IC, et al. Thrombus aspiration during primary percutaneous coronary intervention. N Engl J Med 2008;358(6): Costantini CO, Stone GW, Mehran R, et al. Frequency, correlates, and clinical implications of myocardial perfusion after primary angioplasty and stenting, with and without glycoprotein IIb/IIIa inhibition, in acute myocardial infarction. J Am Coll Cardiol 2004; 44(2): Wu KC, Zerhouni EA, Judd RM, et al. Prognostic significance of microvascular obstruction by magnetic resonance imaging in patients with acute myocardial infarction. Circulation 1998;97(8): ADenosine Administration during and after Primary percutaneous coronary intervention in acute myocardial infarction: a randomized controlled Trial (ADAPT). Dutch trial register. Accessed December 10, Abaci A, Oguzhan A, Eryol NK, Ergin A. Effect of potential confounding factors on the thrombolysis in myocardial infarction (TIMI) trial frame count and its reproducibility. Circulation 1999;100(22):