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Assessment of Inducible Myocardial Ischemia, Quality of Life, and Functional Status After Successful Percutaneous Revascularization in Patients With Chronic Total Coronary Occlusion
Assessment of Inducible Myocardial Ischemia, Quality of Life, and Functional Status After Successful Percutaneous Revascularization in Patients With Chronic Total Coronary Occlusion Xavier Rossello, MD*, Sandra Pujadas, MD, Antoni Serra, MD, PhD, Ester Bajo, RN, Francesc Carreras, MD, Antonio Barros, MD, Juan Cinca, MD, PhD, Guillermo Pons-Lladó, MD, and Beatriz Vaquerizo, MD, PhD The benefits of chronic total coronary occlusion (CTO) revascularization are not well established. In this prospective cohort study, 47 consecutive patients with successful percutaneous recanalization of CTO underwent adenosine stress cardiac magnetic resonance (CMR), 6-minute walk test (6MWT), and the Short Form-36 Health Survey before and 6 months after the procedure. Successful recanalization of a CTO was followed by significant improvement of (1) global physical and mental health status; (2) the distance walked in the 6MWT; (3) the incidence of chest pain at the end of the 6MWT; and (4) the score of a novel CMR ischemic burden index on the basis of the characteristics of adenosine stress perfusion defects (extension, persistence, transmurality, and induced contractile regional dysfunction). Patients with greater CMR ischemic index before percutaneous revascularization showed better improvement in the 6MWT. In conclusion, successful recanalization of a CTO leads to a concurrent improvement in ischemic burden, exercise tolerance, angina frequency, and quality of life scores. Patients with a high ischemic CMR score before CTO recanalization showed the better improvement in exercise tolerance. Ó 2016 Elsevier Inc. All rights reserved. (Am J Cardiol 2016;117:720e726) Current guidelines recommend percutaneous coronary intervention (PCI) of a chronic total coronary occlusion (CTO) when symptoms are present and there is evidence of significant ischemia and viable myocardium in the territory supplied by the occluded vessel.1e3 CTO revascularization has been found to improve global left ventricular (LV) function and regional wall motion,4e6 as well as viability and ischemic burden.4 Most of this parameters are increasingly measured by cardiac magnetic resonance (CMR),4,7 with special emphasis in the presence and extent of inducible ischemia. Despite the well-known improvement in these CMR parameters, the benefits of CTO revascularization on survival still remain controversial,8e12 and the potential improvement of symptoms, physical activity, and quality of life are even less studied.4,10,13,14 Thus, there is a growing need to understand whether a reduction in pre-PCI ischemic burden relates with a subsequent clinical improvement. This study was primarily addressed to evaluate the improvement of quality of life, functional status, and inducible myocardial ischemia assessed by adenosine stress CMR at 6 months after successful CTO percutaneous revascularization. In addition, we aimed to evaluate the relation between 4 prePCI ischemic CMR parameters and the patient clinical improvement after CTO recanalization.
Cardiology Department, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain. Manuscript received October 26, 2015; revised manuscript received and accepted December 1, 2015. See page 725 for disclosure information. *Corresponding author: Tel: (þ34) 935565940; fax: (þ34) 935565603. E-mail address: [email protected] (X. Rossello). 0002-9149/15/$ - see front matter Ó 2016 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.amjcard.2015.12.001
Methods Consecutive patients who underwent successful PCI of a CTO vessel from September 2012 to December 2013 were prospectively recruited. From 52 patients in whom percutaneous CTO recanalization had been attempted, success was observed in 47 patients (90.4%). The inclusion and exclusion criteria are detailed in Figure 1. Of note, all patients included presented with angina and/or one of the following CMR criteria: (1) the presence of ischemia related to CTO and (2) the presence of myocardial viability at the segments of the target vessel, defined as <25% of contrast delayed-enhancement transmurality. The study flow chart is also summarized in Figure 1. Briefly, all patients underwent stress adenosine CMR imaging before PCI, and this study was repeated 6 months later. Quality of life and functional status were also assessed before and after PCI. The study was conducted in accordance with the standards set by the “Declaration of Helsinki,” and it was approved by the Clinical Research Ethics Committee at the Hospital de la Santa Creu i Sant Pau. Informed consent was obtained from all patients before starting the study protocol. According to Euro-CTO criteria, CTO was defined as an occlusion existing for at least 3 months.15 The duration of the occlusion was verified by a previous angiogram showing the occluded vessel or, in its absence, on clinical data indicating the occurrence of a clinical ischemic event potentially related to the CTO. Acute procedural success was defined as the ability to cross the occluded segment with both a wire and balloon and successfully open the artery with a final in-stent residual stenosis <30% and TIMI flow 3 in the target vessel. All patients were treated with www.ajconline.org
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Figure 1. Study flow chart. This figure shows a flow chart of our subgroup analysis. SF-36 ¼ Short Form (36) Health Survey.
aspirin open-endedly and received heparin at the time of the procedure to achieve an activated clotting time of 250 to 350 seconds. Time of fluoroscopy and total volume of contrast administered were recorded. A 6-minute walk test (6MWT) was performed in an indoor unobstructed 30-m long corridor, according to the American Thoracic Society guidelines.16 Patients were instructed to walk the corridor from one end to the other at their own pace, as many times as possible, in the permitted time. The patients were advised on the possibility of slowing down the pace and stopping or resting if needed. After 6 minutes had elapsed, patients were instructed to stop walking, and the total distance walked was measured. Baseline and postwalk vital signs were reported, as well as the presence of chest pain at the end of the test. Quality of life was measured using the Short Form-36 Health Survey (SF-36). The SF-36 Health Survey is a patient-reported survey used to assess patient health status and monitoring and comparing disease burden. It consists of 36 questions grouped into 8 scaled domains, which are the weighted sums of the questions in their section. These domains are combined into 2 metascores, the physical component summary and the mental component summary, reflecting global physical and mental functioning. These 8 item domains and 2 metascores are ranged on a scale from 0 to 100, with higher scores indicating better functional status.17,18 According to previous publications, the normal range is between 40 and 60 and it has clinical relevance when a difference of at least 5 points between the baseline and post-PCI results17 is detected. Reference values in general population in our geographical area were reported previously by Lopez-Garcia et al.19 All CMR studies were performed with a Philips Achieva 1.5 T scanner. Steady-state free precession cine MR images
were acquired in long-axis planes and in multiple 8 mmthick short-axis slices/2 mm gap from the atrioventricular groove to the LV apex. Perfusion studies were performed using a balanced turbo field echo sequence in 3 short-axis slices (basal, mid, and apical levels). Image acquisition started after 4 minutes of adenosine infusion at 140 mcg/kg/min using gadolinium doses of 0.1 mmol/kg. Ten minutes after stress, rest perfusion imaging was performed repeating the same protocol. Also, cine MR images were obtained in the same 3 short-axis slices during stress and repeated at rest. A 3-dimensional inversion recovery segmented gradient echo sequence was acquired 10 minutes after contrast administration to assess delayedenhancement. This sequence was used in multiple short-axis planes using the same orientation as the cine MR images. The study duration was 45 minutes. Cine loops and contrast-enhanced images were assessed on dedicated software (QMass MR 7.1, Medis, Leiden, the Netherlands). Overall LV and necrotic mass, as well as LV ejection fraction were reported in each case. CMR perfusion images and their subsequent cine sequences were assessed during adenosine infusion and at rest, using the American Heart Association 17-segment model and excluding the apical segment. According to clinical practice, an inducible perfusion defect was considered if the signal intensity on stress perfusion images was reduced in at least 2 contiguous myocardial segments, for at least 3 dynamic images, compared with remote myocardium, and this was not present in the rest study. The ischemia was evaluated using 4 different parameters in each LV segment: (1) the presence of perfusion defect; (2) persistence of the defect along the duration of the perfusion sequence; (3) LV transmural extension of the defect; and (4) inducibility of regional contractililty dysfunction under
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Figure 2. Patients with CTO of a right coronary artery with a total IBI of 20%. (A) Coronary angiography: CTO of a right coronary artery; (B) late gadolinium enhancement study showing the absence of myocardial necrosis; (C) perfusion study before PCI in basal and mid inferior and inferoseptal segments (white arrows). The defect is also persistent in all these 4 segments and transmurality is appreciated in basal and mid inferior segments; (D) stress images before PCI showing an adenosine-induced akinesia in the basal and mid inferior segments, as well as basal inferoseptal segment (black arrows; not present in the basal study); (E) summarize of all items included in the IBI calculation. Total IBI was 20%.
adenosine perfusion. Moreover, we formulated an unexplored index of ischemic burden (IBI) based on the presence of the previously described 4 CMR parameters in each single LV segment. Each parameter was weighted with one point, except for the inducible contractile regional dysfunction parameter, to which we assigned 2 points considering that entails an advanced degree of inducible ischemia.20 Hence, each single LV segment may range between 0 and 5, and the whole 16-segment score may range between 0 and 80. A representative example of IBI assessment is shown in Figure 2. Continuous variables are presented as mean SD. Comparisons between before and 6-month after PCI CMRs, SF-36 and walked distance were performed by paired t tests. McNemar’s test was used to compare the presence of chest
pain in pre-PCI and post-PCI 6MWT. The cohort was stratified into 2 groups using the median of the IBI on prePCI CMR to generate mild severity ischemia group (below the median) and a moderateesevere ischemia group (above the median). Paired t tests and McNemar’s test were separately carried out for comparisons in each of the group. A 2tailed p <0.05 was considered statistically significant. All statistical tests were performed with IBM SPSS Statistics software, version.20.0, (IBM Corp., Armonk, New York). Results The baseline demographics for our cohort are summarized in Table 1. The CTO vessel was the right coronary artery in 29 patients (61.7%), the left anterior descending coronary
Coronary Artery Disease/Concurrent Benefits of CTO Revascularization Table 1 Demographic and clinical characteristics of the study group Overall population (n ¼ 47)
Variable Age (years) Men Diabetes mellitus Hypertension Dyslipidemia Smoker Familiar history of coronary heart disease Serum creatinine (>1.5 mg/dl) Peripheral artery disease Prior stroke Prior myocardial infarction Previous percutaneous coronary intervention Previous coronary bypass
Table 3 Comparison of 6-minute walk test findings at baseline and at 6-month follow-up after chronic total coronary occlusion revascularization (n ¼ 40) Variable
62 10 42 (89%) 19 (40%) 35 (75%) 36 (77%) 31 (66%) 2 (4%) 1 (2%) 6 (13%) 1 (2%) 13 (28%) 15 (32%) 2 (4%)
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Systolic blood pressure (mm Hg) Diastolic blood pressure (mm Hg) Heart rate (bpm) Oxygen Saturation by Pulse Oximetry (%) Walked distance (meters) Chest pain at the end of the test
Basal
6 m post-PCI
14920 839 7412 971
15219 8112 7913 971
417126 15 (39%)
463103 3 (8%)
P-value 0.385 0.198 0.030 0.208 0.002 <0.001
Continuous variables are expressed as mean SD. Categorical data are expressed as n (%).
Continuous variables are expressed as mean SD. Categorical data are expressed as n (%).
Table 2 Comparison of SF-36 survey results at baseline and at 6-month follow-up after chronic total coronary occlusion revascularization (n ¼ 43) Variable
Basal
6 m post-PCI
P-value
Physical Functioning Role-Physical Bodily Pain General Health Vitality Social Functioning Role-Emotional Mental Health Global Physical Health Global Mental Health
3910 3913 4211 409 4011 3714 3915 4412 3910 4116
469 4712 4710 4510 4811 4313 4514 4812 469 4614
<0.001 <0.001 0.015 <0.001 <0.001 0.003 0.005 0.018 <0.001 0.029
Continuous variables are expressed as mean SD. These items are ranged on a scale from 0 to 100, with higher scores indicating better health status.
artery in 10 patients (21.3%), and the left circumflex coronary artery in 8 patients (17%). In regard to angiography, mean time of fluoroscopy was 70 43.8 minutes and volume of contrast administered was 371 139.9 ml. Forty-three of all consecutive patients (91.5%) answered the SF-36 survey at baseline and 6-month follow-up. Score results for the 8 scales, as well as their changes from preprocedural scores are reported in Table 2. At follow-up, patients showed an improvement in each item of the SF-36 survey compared with baseline situation, which was also reflected in global physical and mental functioning scores. Six items (physical functioning, role physical, general health, vitality, social functioning, and role emotional) showed a clinically relevant improvement, according to a threshold of 5. Conversely, the improvement in 2 items (Bodily Pain and Mental Health) was not of clinical relevance. CTO recanalization showed a positive clinical impact in terms of global physical health, but not in global mental health. Forty of all consecutive patients (85.1%) underwent 6MWT at baseline and 6-month follow-up. Vital signs, clinical data during the test and final walked distance are reported in Table 3. No differences were found in vital signs at the end of the 6MWT in pre-PCI study compared with
6 months after PCI study, with the exception of the heart rate. However, after revascularization, patients showed a better physical activity performance (416.5 125.71 vs 463.0 102.61 m; p ¼ 0.002), as well as a reduction in chest pain frequency (39% vs 8%; p <0.001). In all patients, a complete CMR study protocol could be performed. A total of 1,504 segments were available for perfusion analysis (16 segments 47 patients 2 CMR). Table 4 lists the comparison of CMR findings before and after PCI. All parameters measuring ischemia were significantly reduced. The IBI was also reduced 16 points (from 19% to 3%, p <0.001). Mean LV ejection fraction was normal before PCI and did not change significantly after PCI. There were no differences in the necrotic mass between the 2 studies. The pre-PCI IBI median was 20%, which was used as a cutoff to stratify the patients sample into 2 subcohorts, one containing patients with higher scores and the other containing patients with lower scores. Patients with 20% of IBI on pre-PCI CMR improved significantly the walked distance on 6MWT after PCI, whereas the other group did not. A reduction in chest pain frequency at the end of the 6MWT was observed in almost the same proportion in both groups. According to the SF-36, the global physical health status improved at follow-up in both groups (<20% and 20%), being more important in the group with IBI >20%. The global mental health did not improve in any group at 6month follow-up, although the IBI <20% group showed a trend toward significance. Table 5 summarizes the improvements on functional status and quality of life for each studied group. Discussion This study affords an integrative clinical, functional, and myocardial ischemia imaging analysis of the beneficial effects of successful percutaneous recanalization of a CTO. Moreover, we formulated a new CMR index of ischemic burden that helps identifying patients with better clinical functional response. At 6 months after successful recanalization of the CTO, the patients presented with a reduced ischemic burden experienced less limited physical activity and less angina at the 6MWT and had a significantly higher quality of life as assessed by the SF-36. Patients with higher ischemic scores (IBI >20%) showed a significant
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Table 4 Comparison of cardiac magnetic resonance findings before percutaneous intervention and at 6-month follow-up after chronic total coronary occlusion revascularization (n ¼ 47) Variable Necrotic mass (g) Necrotic percentage (%) Left ventricular ejection fraction (%) Number of segments with perfusion defect (n, % of total segments) Number of segments with persistent perfusion defect (n, % of total segments) Number of segments with transmural perfusion defect (n, % of total segments) Number of segments with inducible contractile dysfunction (n, % of total segments) Ischemic burden index (%)
Basal
6 m post-PCI
P-value
4.35.4 3.54.36 6210 4.92.3 (3114%) 1.71.6 (1010%) 1.41.7 (911%) 1.61.8 (1011%) 1910
3.83.9 3.03.1 649 1.11.8 (711%) 0.30.7 (24%) 0.30.7 (24%) 0.20. (14%) 36
0.131 0.108 0.097 <0.001 <0.001 <0.001 <0.001 <0.001
Continuous variables are expressed as mean SD. Categorical data are expressed as n (%). Table 5 Comparison of SF-36 survey and 6-minute walk test parameters between higher and lower index of ischemic burden scoring patients in the first of cardiac magnetic resonance Basal
6 m post-PCI
P-value
Walked istance at the end of 6-minute walk test, meters (n¼40) Ischemic score < 20% 391158 425 118 0.172 Ischemic score 20% 43987 49676 0.004 Chest pain at the end of 6-minute walk test, n (%) (n¼40) Ischemic score < 20% 8 (42%) 2 (11%) 0.031 Ischemic score 20% 7 (37%) 1 (5%) 0.031 Global Physical Health in the SF-36 Survey* (n¼43) Ischemic score < 20% 3911 4510 0.004 Ischemic score 20% 3910 479 <0.001 Global Mental Health in the SF-36 Survey* (n¼43) Ischemic score < 20% 3915 4516 0.052 Ischemic score 20% 4416 4612 0.492 Continuous variables are expressed as mean SD. Categorical data are expressed as n (%). * These items are ranged on a scale from 0 to 100, with higher scores indicating better health status.
improvement in terms of functional status in comparison with those patients with IBI <20%. Chest pain frequency after the 6MWT and global mental and physical health status were not associated with higher ischemic burden. At present, most of CTO studies use myocardial viability tests with the purpose of identifying those patients who might benefit the most from CTO-PCI,7 although the assessment of the ischemic burden is playing a progressively major role in this setting. In this sense, it has recently been suggested that revascularization might be appropriate in patients with extensive myocardial ischemia, even in the absence of symptoms.21 Also, a revascularization procedure would be considered as appropriate when its expected benefits in terms of survival or health outcomes (symptoms, functional status, and/or quality of life) exceed its expected risks by a sufficiently wide margin. According to previous studies,4 we showed that a successful CTO-PCI leads to a reduction in inducible myocardial ischemia. We found a significant reduction not only in each of the 4 perfusion parameters studied but also in the global ischemic score calculated. Noteworthy, no increase in the amount of myocardial necrosis was found at follow-up. Thus, in spite the well-known complexity of CTO-PCI, new areas of infarction were not present after PCI procedures.
The clinical benefit of a successful CTO-PCI in terms of quality of life is not well established. To our knowledge, this study is the first to demonstrate an improvement in the quality of life using the objective criteria of the SF-36. Other validated surveys have been used in this setting, such as the Seattle Angina Questionnaire that evaluates the improvement in the incidence of chest pain.10 The SF-36 is one of the most widely used surveys measuring health status. Furthermore, the Spanish version has been validated as a suitable instrument for use in medical research and clinical practice in our population.17 In our study, patients with CTO recanalization significantly improved the quality of life at follow-up, compared to baseline situation. Of note, baseline scores were greatly inferior compared with reference values in a nonadmitted population of our country.19 Previous studies reported improvement in physical activity and frequency of angina episodes in patients who underwent CTO-PCI after a successful revascularization.10,22 Borgia et al10 showed that patients with successful CTO-PCI experienced less physical activity limitation based on Seattle Angina Questionnaire-UK-version questionnaire. Olivari et al22 showed in a multicenter study that patients with a successful CTO-PCI were able to perform more frequently a negative stress exercise test than patients with an unsuccessful procedure. In our study we used the 6MWT to evaluate functional status. Compared with baseline situation, patients with CTO recanalization significantly presented with less angina symptoms and were able to reach a longer walked distance at the end of the 6MWT, demonstrating the good functional outcome after the procedure. The reduction on angina frequency is of great interest in this setting, given that the main indication to revascularization in patients with CTO is symptoms relief rather than survival benefit, as evidenced by the most common cause for attempted angioplasty on a CTO is the presence of angina.23 To our knowledge, this is the first study assessing the changes in angina symptoms perception and physical activity limitation in patients with CTO using a 6MWT. However, it has to be noted that although angina was the main symptom in all patients who underwent CTO-PCI, only 39% of them presented with chest pain at the end of the pre-PCI 6MWT. These findings might indicate that the 6MWT is underpowered to detect angina, hence underestimating the improvement in angina relief in the second test. However, patients with CTO are known to present other co-morbidities and poor quality of life at baseline and this may prevent achieving
Coronary Artery Disease/Concurrent Benefits of CTO Revascularization
an adequate physical demand threshold during the exercise stress test. Despite this intrinsic limitation, our results showed an objective improvement in symptoms. Furthermore, it can be expected that the symptom relief improvement in patients with low angina threshold can be extrapolated to patients with higher angina threshold. To anticipate which patients with CTO are more likely to improve after revascularization, the severity of ischemia was assessed by means of a novel IBI. A higher IBI was related to better exercise tolerance after PCI but did not show differences in chest pain. Actually, chest pain at the end of 6MWT significantly improved in both groups (IBI >20% and <20%). Again, 6MWT might not be the ideal test to assess angina improvement given its lower physical demand compared to other tests. In the same way, no trend toward a better differentiation was observed regarding the SF-36 results. This study has no statistical power to set a cut-off value to better predict functional status and quality of life improvement from pre-PCI CMR. Previous studies with single photon emission computed tomography suggested a threshold of 12.5% ischemic burden as a criterion for performing PCI in the setting of CTO.24 In patients with coronary artery disease, the risk associated with a threshold of 10% ischemic myocardium has been applied to denote high-risk status.25 Given that the expected beneficial prognostic effect of CTO revascularization is believed to be associated with the amount of ischemic myocardium,26 further research is needed to quantify accurately the ischemic burden. This study presents several limitations. No comparator group that assessed the potential placebo effects of the intervention. The results of the study may have been influenced by selection criteria and operator experience. Also, patients with unsuccessful revascularization are not represented in this cohort. Thus, our conclusions cannot be interpreted as better prediction for a procedural success, but as an additional criteria for a patient selection who may be most benefited. Sustained recanalization at follow-up was not confirmed by coronary angiography. However, no clinical evidence of recurrent ischemia was reported, and all patients received a drug-eluting stent. We did not report procedural complications. Finally, the use of the IBI median to demonstrate benefits of revascularization on those patients with higher burden had limitations and larger studies are needed to elucidate which threshold better associates clinical improvement.
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Immediate results and one-year clinical outcome after percutaneous coronary interventions in chronic total occlusions: data from a multicenter, prospective, observational study (TOAST-GISE). J Am Coll Cardiol 2003;41:1672e1678. Puma JA, Sketch MH, Tcheng JE, Harrington RA, Phillips HR, Stack RS, Califf RM. Percutaneous revascularization of chronic coronary occlusions: an overview. J Am Coll Cardiol 1995;26:1e11. Safley DM, Koshy S, Grantham JA, Bybee KA, House JA, Kennedy KF, Rutherford BD. Changes in myocardial ischemic burden following percutaneous coronary intervention of chronic total occlusions. Catheter Cardiovasc Interv 2011;78:337e343. Shaw LJ, Berman DS, Maron DJ, Mancini GBJ, Hayes SW, Hartigan PM, Weintraub WS, O’Rourke RA, Dada M, Spertus JA, Chaitman BR, Friedman J, Slomka P, Heller GV, Germano G, Gosselin G, Berger P, Kostuk WJ, Schwartz RG, Knudtson M, Veledar E, Bates ER, McCallister B, Teo KK, Boden WE. Optimal medical therapy with or without percutaneous coronary intervention to reduce ischemic burden: results from the Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation (COURAGE) trial nuclear substudy. Circulation 2008;117:1283e1291. Hoebers LP, Claessen BE, Dangas GD, Råmunddal T, Mehran R, Henriques JPS. Contemporary overview and clinical perspectives of chronic total occlusions. Nat Rev Cardiol 2014;11:458e469.
Cardiology Department, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain. Manuscript received October 26, 2015; revised manuscript received and accepted December 1, 2015. See page 725 for disclosure information. *Corresponding author: Tel: (þ34) 935565940; fax: (þ34) 935565603. E-mail address: [email protected] (X. Rossello). 0002-9149/15/$ - see front matter Ó 2016 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.amjcard.2015.12.001
Methods Consecutive patients who underwent successful PCI of a CTO vessel from September 2012 to December 2013 were prospectively recruited. From 52 patients in whom percutaneous CTO recanalization had been attempted, success was observed in 47 patients (90.4%). The inclusion and exclusion criteria are detailed in Figure 1. Of note, all patients included presented with angina and/or one of the following CMR criteria: (1) the presence of ischemia related to CTO and (2) the presence of myocardial viability at the segments of the target vessel, defined as <25% of contrast delayed-enhancement transmurality. The study flow chart is also summarized in Figure 1. Briefly, all patients underwent stress adenosine CMR imaging before PCI, and this study was repeated 6 months later. Quality of life and functional status were also assessed before and after PCI. The study was conducted in accordance with the standards set by the “Declaration of Helsinki,” and it was approved by the Clinical Research Ethics Committee at the Hospital de la Santa Creu i Sant Pau. Informed consent was obtained from all patients before starting the study protocol. According to Euro-CTO criteria, CTO was defined as an occlusion existing for at least 3 months.15 The duration of the occlusion was verified by a previous angiogram showing the occluded vessel or, in its absence, on clinical data indicating the occurrence of a clinical ischemic event potentially related to the CTO. Acute procedural success was defined as the ability to cross the occluded segment with both a wire and balloon and successfully open the artery with a final in-stent residual stenosis <30% and TIMI flow 3 in the target vessel. All patients were treated with www.ajconline.org
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Figure 1. Study flow chart. This figure shows a flow chart of our subgroup analysis. SF-36 ¼ Short Form (36) Health Survey.
aspirin open-endedly and received heparin at the time of the procedure to achieve an activated clotting time of 250 to 350 seconds. Time of fluoroscopy and total volume of contrast administered were recorded. A 6-minute walk test (6MWT) was performed in an indoor unobstructed 30-m long corridor, according to the American Thoracic Society guidelines.16 Patients were instructed to walk the corridor from one end to the other at their own pace, as many times as possible, in the permitted time. The patients were advised on the possibility of slowing down the pace and stopping or resting if needed. After 6 minutes had elapsed, patients were instructed to stop walking, and the total distance walked was measured. Baseline and postwalk vital signs were reported, as well as the presence of chest pain at the end of the test. Quality of life was measured using the Short Form-36 Health Survey (SF-36). The SF-36 Health Survey is a patient-reported survey used to assess patient health status and monitoring and comparing disease burden. It consists of 36 questions grouped into 8 scaled domains, which are the weighted sums of the questions in their section. These domains are combined into 2 metascores, the physical component summary and the mental component summary, reflecting global physical and mental functioning. These 8 item domains and 2 metascores are ranged on a scale from 0 to 100, with higher scores indicating better functional status.17,18 According to previous publications, the normal range is between 40 and 60 and it has clinical relevance when a difference of at least 5 points between the baseline and post-PCI results17 is detected. Reference values in general population in our geographical area were reported previously by Lopez-Garcia et al.19 All CMR studies were performed with a Philips Achieva 1.5 T scanner. Steady-state free precession cine MR images
were acquired in long-axis planes and in multiple 8 mmthick short-axis slices/2 mm gap from the atrioventricular groove to the LV apex. Perfusion studies were performed using a balanced turbo field echo sequence in 3 short-axis slices (basal, mid, and apical levels). Image acquisition started after 4 minutes of adenosine infusion at 140 mcg/kg/min using gadolinium doses of 0.1 mmol/kg. Ten minutes after stress, rest perfusion imaging was performed repeating the same protocol. Also, cine MR images were obtained in the same 3 short-axis slices during stress and repeated at rest. A 3-dimensional inversion recovery segmented gradient echo sequence was acquired 10 minutes after contrast administration to assess delayedenhancement. This sequence was used in multiple short-axis planes using the same orientation as the cine MR images. The study duration was 45 minutes. Cine loops and contrast-enhanced images were assessed on dedicated software (QMass MR 7.1, Medis, Leiden, the Netherlands). Overall LV and necrotic mass, as well as LV ejection fraction were reported in each case. CMR perfusion images and their subsequent cine sequences were assessed during adenosine infusion and at rest, using the American Heart Association 17-segment model and excluding the apical segment. According to clinical practice, an inducible perfusion defect was considered if the signal intensity on stress perfusion images was reduced in at least 2 contiguous myocardial segments, for at least 3 dynamic images, compared with remote myocardium, and this was not present in the rest study. The ischemia was evaluated using 4 different parameters in each LV segment: (1) the presence of perfusion defect; (2) persistence of the defect along the duration of the perfusion sequence; (3) LV transmural extension of the defect; and (4) inducibility of regional contractililty dysfunction under
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Figure 2. Patients with CTO of a right coronary artery with a total IBI of 20%. (A) Coronary angiography: CTO of a right coronary artery; (B) late gadolinium enhancement study showing the absence of myocardial necrosis; (C) perfusion study before PCI in basal and mid inferior and inferoseptal segments (white arrows). The defect is also persistent in all these 4 segments and transmurality is appreciated in basal and mid inferior segments; (D) stress images before PCI showing an adenosine-induced akinesia in the basal and mid inferior segments, as well as basal inferoseptal segment (black arrows; not present in the basal study); (E) summarize of all items included in the IBI calculation. Total IBI was 20%.
adenosine perfusion. Moreover, we formulated an unexplored index of ischemic burden (IBI) based on the presence of the previously described 4 CMR parameters in each single LV segment. Each parameter was weighted with one point, except for the inducible contractile regional dysfunction parameter, to which we assigned 2 points considering that entails an advanced degree of inducible ischemia.20 Hence, each single LV segment may range between 0 and 5, and the whole 16-segment score may range between 0 and 80. A representative example of IBI assessment is shown in Figure 2. Continuous variables are presented as mean SD. Comparisons between before and 6-month after PCI CMRs, SF-36 and walked distance were performed by paired t tests. McNemar’s test was used to compare the presence of chest
pain in pre-PCI and post-PCI 6MWT. The cohort was stratified into 2 groups using the median of the IBI on prePCI CMR to generate mild severity ischemia group (below the median) and a moderateesevere ischemia group (above the median). Paired t tests and McNemar’s test were separately carried out for comparisons in each of the group. A 2tailed p <0.05 was considered statistically significant. All statistical tests were performed with IBM SPSS Statistics software, version.20.0, (IBM Corp., Armonk, New York). Results The baseline demographics for our cohort are summarized in Table 1. The CTO vessel was the right coronary artery in 29 patients (61.7%), the left anterior descending coronary
Coronary Artery Disease/Concurrent Benefits of CTO Revascularization Table 1 Demographic and clinical characteristics of the study group Overall population (n ¼ 47)
Variable Age (years) Men Diabetes mellitus Hypertension Dyslipidemia Smoker Familiar history of coronary heart disease Serum creatinine (>1.5 mg/dl) Peripheral artery disease Prior stroke Prior myocardial infarction Previous percutaneous coronary intervention Previous coronary bypass
Table 3 Comparison of 6-minute walk test findings at baseline and at 6-month follow-up after chronic total coronary occlusion revascularization (n ¼ 40) Variable
62 10 42 (89%) 19 (40%) 35 (75%) 36 (77%) 31 (66%) 2 (4%) 1 (2%) 6 (13%) 1 (2%) 13 (28%) 15 (32%) 2 (4%)
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Systolic blood pressure (mm Hg) Diastolic blood pressure (mm Hg) Heart rate (bpm) Oxygen Saturation by Pulse Oximetry (%) Walked distance (meters) Chest pain at the end of the test
Basal
6 m post-PCI
14920 839 7412 971
15219 8112 7913 971
417126 15 (39%)
463103 3 (8%)
P-value 0.385 0.198 0.030 0.208 0.002 <0.001
Continuous variables are expressed as mean SD. Categorical data are expressed as n (%).
Continuous variables are expressed as mean SD. Categorical data are expressed as n (%).
Table 2 Comparison of SF-36 survey results at baseline and at 6-month follow-up after chronic total coronary occlusion revascularization (n ¼ 43) Variable
Basal
6 m post-PCI
P-value
Physical Functioning Role-Physical Bodily Pain General Health Vitality Social Functioning Role-Emotional Mental Health Global Physical Health Global Mental Health
3910 3913 4211 409 4011 3714 3915 4412 3910 4116
469 4712 4710 4510 4811 4313 4514 4812 469 4614
<0.001 <0.001 0.015 <0.001 <0.001 0.003 0.005 0.018 <0.001 0.029
Continuous variables are expressed as mean SD. These items are ranged on a scale from 0 to 100, with higher scores indicating better health status.
artery in 10 patients (21.3%), and the left circumflex coronary artery in 8 patients (17%). In regard to angiography, mean time of fluoroscopy was 70 43.8 minutes and volume of contrast administered was 371 139.9 ml. Forty-three of all consecutive patients (91.5%) answered the SF-36 survey at baseline and 6-month follow-up. Score results for the 8 scales, as well as their changes from preprocedural scores are reported in Table 2. At follow-up, patients showed an improvement in each item of the SF-36 survey compared with baseline situation, which was also reflected in global physical and mental functioning scores. Six items (physical functioning, role physical, general health, vitality, social functioning, and role emotional) showed a clinically relevant improvement, according to a threshold of 5. Conversely, the improvement in 2 items (Bodily Pain and Mental Health) was not of clinical relevance. CTO recanalization showed a positive clinical impact in terms of global physical health, but not in global mental health. Forty of all consecutive patients (85.1%) underwent 6MWT at baseline and 6-month follow-up. Vital signs, clinical data during the test and final walked distance are reported in Table 3. No differences were found in vital signs at the end of the 6MWT in pre-PCI study compared with
6 months after PCI study, with the exception of the heart rate. However, after revascularization, patients showed a better physical activity performance (416.5 125.71 vs 463.0 102.61 m; p ¼ 0.002), as well as a reduction in chest pain frequency (39% vs 8%; p <0.001). In all patients, a complete CMR study protocol could be performed. A total of 1,504 segments were available for perfusion analysis (16 segments 47 patients 2 CMR). Table 4 lists the comparison of CMR findings before and after PCI. All parameters measuring ischemia were significantly reduced. The IBI was also reduced 16 points (from 19% to 3%, p <0.001). Mean LV ejection fraction was normal before PCI and did not change significantly after PCI. There were no differences in the necrotic mass between the 2 studies. The pre-PCI IBI median was 20%, which was used as a cutoff to stratify the patients sample into 2 subcohorts, one containing patients with higher scores and the other containing patients with lower scores. Patients with 20% of IBI on pre-PCI CMR improved significantly the walked distance on 6MWT after PCI, whereas the other group did not. A reduction in chest pain frequency at the end of the 6MWT was observed in almost the same proportion in both groups. According to the SF-36, the global physical health status improved at follow-up in both groups (<20% and 20%), being more important in the group with IBI >20%. The global mental health did not improve in any group at 6month follow-up, although the IBI <20% group showed a trend toward significance. Table 5 summarizes the improvements on functional status and quality of life for each studied group. Discussion This study affords an integrative clinical, functional, and myocardial ischemia imaging analysis of the beneficial effects of successful percutaneous recanalization of a CTO. Moreover, we formulated a new CMR index of ischemic burden that helps identifying patients with better clinical functional response. At 6 months after successful recanalization of the CTO, the patients presented with a reduced ischemic burden experienced less limited physical activity and less angina at the 6MWT and had a significantly higher quality of life as assessed by the SF-36. Patients with higher ischemic scores (IBI >20%) showed a significant
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Table 4 Comparison of cardiac magnetic resonance findings before percutaneous intervention and at 6-month follow-up after chronic total coronary occlusion revascularization (n ¼ 47) Variable Necrotic mass (g) Necrotic percentage (%) Left ventricular ejection fraction (%) Number of segments with perfusion defect (n, % of total segments) Number of segments with persistent perfusion defect (n, % of total segments) Number of segments with transmural perfusion defect (n, % of total segments) Number of segments with inducible contractile dysfunction (n, % of total segments) Ischemic burden index (%)
Basal
6 m post-PCI
P-value
4.35.4 3.54.36 6210 4.92.3 (3114%) 1.71.6 (1010%) 1.41.7 (911%) 1.61.8 (1011%) 1910
3.83.9 3.03.1 649 1.11.8 (711%) 0.30.7 (24%) 0.30.7 (24%) 0.20. (14%) 36
0.131 0.108 0.097 <0.001 <0.001 <0.001 <0.001 <0.001
Continuous variables are expressed as mean SD. Categorical data are expressed as n (%). Table 5 Comparison of SF-36 survey and 6-minute walk test parameters between higher and lower index of ischemic burden scoring patients in the first of cardiac magnetic resonance Basal
6 m post-PCI
P-value
Walked istance at the end of 6-minute walk test, meters (n¼40) Ischemic score < 20% 391158 425 118 0.172 Ischemic score 20% 43987 49676 0.004 Chest pain at the end of 6-minute walk test, n (%) (n¼40) Ischemic score < 20% 8 (42%) 2 (11%) 0.031 Ischemic score 20% 7 (37%) 1 (5%) 0.031 Global Physical Health in the SF-36 Survey* (n¼43) Ischemic score < 20% 3911 4510 0.004 Ischemic score 20% 3910 479 <0.001 Global Mental Health in the SF-36 Survey* (n¼43) Ischemic score < 20% 3915 4516 0.052 Ischemic score 20% 4416 4612 0.492 Continuous variables are expressed as mean SD. Categorical data are expressed as n (%). * These items are ranged on a scale from 0 to 100, with higher scores indicating better health status.
improvement in terms of functional status in comparison with those patients with IBI <20%. Chest pain frequency after the 6MWT and global mental and physical health status were not associated with higher ischemic burden. At present, most of CTO studies use myocardial viability tests with the purpose of identifying those patients who might benefit the most from CTO-PCI,7 although the assessment of the ischemic burden is playing a progressively major role in this setting. In this sense, it has recently been suggested that revascularization might be appropriate in patients with extensive myocardial ischemia, even in the absence of symptoms.21 Also, a revascularization procedure would be considered as appropriate when its expected benefits in terms of survival or health outcomes (symptoms, functional status, and/or quality of life) exceed its expected risks by a sufficiently wide margin. According to previous studies,4 we showed that a successful CTO-PCI leads to a reduction in inducible myocardial ischemia. We found a significant reduction not only in each of the 4 perfusion parameters studied but also in the global ischemic score calculated. Noteworthy, no increase in the amount of myocardial necrosis was found at follow-up. Thus, in spite the well-known complexity of CTO-PCI, new areas of infarction were not present after PCI procedures.
The clinical benefit of a successful CTO-PCI in terms of quality of life is not well established. To our knowledge, this study is the first to demonstrate an improvement in the quality of life using the objective criteria of the SF-36. Other validated surveys have been used in this setting, such as the Seattle Angina Questionnaire that evaluates the improvement in the incidence of chest pain.10 The SF-36 is one of the most widely used surveys measuring health status. Furthermore, the Spanish version has been validated as a suitable instrument for use in medical research and clinical practice in our population.17 In our study, patients with CTO recanalization significantly improved the quality of life at follow-up, compared to baseline situation. Of note, baseline scores were greatly inferior compared with reference values in a nonadmitted population of our country.19 Previous studies reported improvement in physical activity and frequency of angina episodes in patients who underwent CTO-PCI after a successful revascularization.10,22 Borgia et al10 showed that patients with successful CTO-PCI experienced less physical activity limitation based on Seattle Angina Questionnaire-UK-version questionnaire. Olivari et al22 showed in a multicenter study that patients with a successful CTO-PCI were able to perform more frequently a negative stress exercise test than patients with an unsuccessful procedure. In our study we used the 6MWT to evaluate functional status. Compared with baseline situation, patients with CTO recanalization significantly presented with less angina symptoms and were able to reach a longer walked distance at the end of the 6MWT, demonstrating the good functional outcome after the procedure. The reduction on angina frequency is of great interest in this setting, given that the main indication to revascularization in patients with CTO is symptoms relief rather than survival benefit, as evidenced by the most common cause for attempted angioplasty on a CTO is the presence of angina.23 To our knowledge, this is the first study assessing the changes in angina symptoms perception and physical activity limitation in patients with CTO using a 6MWT. However, it has to be noted that although angina was the main symptom in all patients who underwent CTO-PCI, only 39% of them presented with chest pain at the end of the pre-PCI 6MWT. These findings might indicate that the 6MWT is underpowered to detect angina, hence underestimating the improvement in angina relief in the second test. However, patients with CTO are known to present other co-morbidities and poor quality of life at baseline and this may prevent achieving
Coronary Artery Disease/Concurrent Benefits of CTO Revascularization
an adequate physical demand threshold during the exercise stress test. Despite this intrinsic limitation, our results showed an objective improvement in symptoms. Furthermore, it can be expected that the symptom relief improvement in patients with low angina threshold can be extrapolated to patients with higher angina threshold. To anticipate which patients with CTO are more likely to improve after revascularization, the severity of ischemia was assessed by means of a novel IBI. A higher IBI was related to better exercise tolerance after PCI but did not show differences in chest pain. Actually, chest pain at the end of 6MWT significantly improved in both groups (IBI >20% and <20%). Again, 6MWT might not be the ideal test to assess angina improvement given its lower physical demand compared to other tests. In the same way, no trend toward a better differentiation was observed regarding the SF-36 results. This study has no statistical power to set a cut-off value to better predict functional status and quality of life improvement from pre-PCI CMR. Previous studies with single photon emission computed tomography suggested a threshold of 12.5% ischemic burden as a criterion for performing PCI in the setting of CTO.24 In patients with coronary artery disease, the risk associated with a threshold of 10% ischemic myocardium has been applied to denote high-risk status.25 Given that the expected beneficial prognostic effect of CTO revascularization is believed to be associated with the amount of ischemic myocardium,26 further research is needed to quantify accurately the ischemic burden. This study presents several limitations. No comparator group that assessed the potential placebo effects of the intervention. The results of the study may have been influenced by selection criteria and operator experience. Also, patients with unsuccessful revascularization are not represented in this cohort. Thus, our conclusions cannot be interpreted as better prediction for a procedural success, but as an additional criteria for a patient selection who may be most benefited. Sustained recanalization at follow-up was not confirmed by coronary angiography. However, no clinical evidence of recurrent ischemia was reported, and all patients received a drug-eluting stent. We did not report procedural complications. Finally, the use of the IBI median to demonstrate benefits of revascularization on those patients with higher burden had limitations and larger studies are needed to elucidate which threshold better associates clinical improvement.
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