Author's Accepted Manuscript
German Ablation Registry: Cryoballoon Versus RF Ablation in Paroxysmal Atrial Fibrillation – One Year Outcome Data Martin Schmidt MD, Uwe Dorwarth MD, Dietrich Andresen MD, Johannes Brachmann MD, Karlheinz Kuck MD, Malte Kuniss MD, Stephan Willems MD, Thomas Deneke MD, Jürgen Tebbenjohanns MD, Jin-Hong Gerds-Li MD, Stefan Spitzer MD, Jochen Senges MD, Matthias Hochadel MD, Ellen Hoffmann MD
PII: DOI: Reference:
S1547-5271(15)01520-9 http://dx.doi.org/10.1016/j.hrthm.2015.12.007 HRTHM6538
To appear in:
Heart Rhythm
www.elsevier.com/locate/buildenv
Cite this article as: Martin Schmidt MD, Uwe Dorwarth MD, Dietrich Andresen MD, Johannes Brachmann MD, Karlheinz Kuck MD, Malte Kuniss MD, Stephan Willems MD, Thomas Deneke MD, Jürgen Tebbenjohanns MD, Jin-Hong Gerds-Li MD, Stefan Spitzer MD, Jochen Senges MD, Matthias Hochadel MD, Ellen Hoffmann MD, German Ablation Registry: Cryoballoon Versus RF Ablation in Paroxysmal Atrial Fibrillation – One Year Outcome Data, Heart Rhythm, http://dx.doi.org/10.1016/j.hrthm.2015.12.007 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
German Ablation Registry: Cryoballoon versus RF ablation in paroxysmal atrial fibrillation – One year Outcome data Schmidt M, Dorwarth U, Andresen D, Brachmann J, Kuck KH, Kuniss M, Lewalter T, Spitzer S, Willems S, Senges J, Hochadel M, Hoffmann E Authors: 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14.
Martin Schmidt, MD1 Uwe Dorwarth, MD1 Dietrich Andresen, MD2 Johannes Brachmann, MD3 Karlheinz Kuck, MD4 Malte Kuniss, MD5 Stephan Willems, MD6 Thomas Deneke, MD7 Jürgen Tebbenjohanns, MD8 Jin-Hong Gerds-Li, MD9 Stefan Spitzer, MD10 Jochen Senges, MD11 Matthias Hochadel, MD11 Ellen Hoffmann, MD1
1
Department of Cardiology, Klinikum Bogenhausen, Munich, Germany Department of Cardiology, Vivantes Klinikum am Urban, Berlin, Germany 3 Department of Cardiology, Klinikum Coburg, Coburg, Germany 4 Department of Cardiology, Asklepios Klinik St. Georg, Hamburg, Germany 5 Department of Cardiology, Kerckhoff-Klinik, Bad Nauheim, Germany 6 Department of Cardiology, Universitäres Herzzentrum Hamburg, Hamburg Germany 7 Department of Cardiology, Herz- und Gefäß-Klinik, Bad Neustadt, Germany 8 Department of Cardiology, HELIOS Klinikum Hildesheim, Hildesheim, Germany 9 Deutsches Herzzentrum Berlin, Berlin, Germany 10 Praxisklinik Herz und Gefäße, Dresden, Germany 11 Stiftung Institut für Herzinfarktforschung, IHF, Ludwigshafen, Germany 2
Running Title: German ablation registry – One year outcome in AF ablation
Disclosures: No disclosures relevant to the manuscript have to be declared
Corresponding Author: Martin Schmidt, MD Klinikum München-Bogenhausen Englschalkingerstr. 77, 81925 Munich, Germany Phone: (+49) 89 - 92702237 Fax: (+49) 89 - 92704502 Email: [email protected]
Abstract BACKGROUND: Radiofrequency ablation has long been standard of care in atrial fibrillation (AF) ablation, cryoballoon technology has emerged a feasible approach with promising results. Prospective multicenter registry data referring to both ablation technologies in AF ablation are lacking so far. OBJECTIVE: We report data of the German ablation registry with respect to efficacy and safety in PV ablation with different energy sources for paroxysmal (px) AF after 1 year follow-up (FU). METHODS: 2306 patients with symptomatic px AF of the German ablation registry were included in this analysis. The cohort was divided into two groups according to the ablation energy source used, cryoballoon and RF ablation. MACCE was defined as a combination of death, myocardial infarction or stroke. RESULTS: AF recurrence rate after a single ablation procedure at 1 year FU was not significantly different between both groups (45.8% after cryoablation and 45.4% after RF ablation; p=0.87). Also the rate of patients without AF recurrence and free of AAD at 12 months FU was similar (cryo 44.2%, RF 41.4%; p=0.25). MACCE occurred with an incidence of 0.7% within 500 days after cryoablation, and of 1.4% after RF ablation (p=0.30). Persistent phrenic nerve palsy was more common after cryo(1.1%) compared to RF ablation (0.3%; p200 ablations per year, 69.2% of the RF patients and 67.5% of the patients undergoing cryoablation (p=0.18). Severity of AF related symptoms was assessed using the SAF scale. The SAF scale has been validated to qualify AF related symptoms and their functional consequences on patient’s daily life with respect to AF documentation and therapy. The SAF score is rated on a scale from 0 (asymptomatic) to 4 (severe impact of symptoms on quality of life) 20 PV ablation procedure AF ablation strategies were pre-classified into circumferential or segmental PV isolation, deployment of linear lesions, and/or ablation of complex fractionated atrial electrograms (CFAE). In all patients, the aim of all ablation strategies was to completely disconnect the PVs from the left atrium. The electrical endpoint of ablation was pulmonary vein isolation.
At least PV entrance block had to be documented for each PV by use of a circular mapping catheter. PV ablation procedures were performed according to the operator`s and the performing institution’s standard of care. All patients underwent transthoracic echocardiography to assess LA diameter, left ventricular ejection fraction and transesophageal echocardiography to rule out LA thrombus formation prior to ablation. Within 24 hours post-ablation transthoracic echocardiography was performed routinely to rule out pericardial effusion, in case of symptoms as hypotension, tachycardia, chest pain or shortness of breathing a repeat echocardiography was performed. For procedural catheter guiding different cardiac mapping strategies were used. AF mapping was separated into conventional mapping or utilization of a 3-dimensional (3D) mapping system such as the CARTOTM (Biosense Webster, U.S.) or NAVXTM system (St. Jude Medical, U.S.). Additional cardiac imaging modalities included MRI, CT, or intracardiac echocardiography (ICE). Anticoagulation: During the procedure, the activated clotting time was kept between 250 and 400 seconds by intravenous heparin administration. All patients had to be anticoagulated using phenprocoumon aiming an INR of 2.0 – 3.0 at least 3 months after the procedure. Sedation: Procedures were performed under deep sedation utilizing fractionated intravenous bolus of midazolam and fentanyl or continuous infusion of propofol with preservation of spontaneous breathing and continuous monitoring of oxygen saturation. The ablation methods used in RF and cryoballoon ablation within the German Ablation Registry I have been described in detail recently by our group.18
In all patients the first generation cryoballoon (ArcticFront™, Medtronic, U.S.) was used since patient inclusion to the registry was terminated in January 2010 when the second generation cryoballoon (ArcticFront™ Advance, Medtronic, U.S.) was not available yet. The duration of the freezing cycle was left to the discretion of the physician. Using first generation cryoballoon freezing cycles were applied 4 – 5 minutes. Definition of complications Ablation procedure-related complications were categorized into major (fatal), moderate (non-fatal) and minor (prolonged hospitalization). Major complications included stroke or transient ischemic attack (TIA), myocardial infarction, pericardial tamponades, PV stenosis, need for emergency cardiac surgery, resuscitation and atrioesophageal fistula. Moderate complications included hematoma requiring transfusion (major bleeding), femoral atriovenous fistula or pseudoaneurysm, phrenic nerve paresis (PNP) and AV block III. PNP was defined as any PNP which was persistent at the end of the ablation procedure. Transient PNPs of less than 2 minutes have not been included since this was not systematically documented in the questionnaire. Apart from prolonged hospitalization also minor bleeding without intervention, new AV block type I or II or bundle branch block were categorized as minor complications. MACCE was defined as a combination of death, myocardial infarction or stroke.
Registry management The IHF Ludwigshafen was responsible for project development and management, data management, and was the central contract research organisation for the registry. Documentation and data acquisition were voluntary, paperless, and were carried out on an internet-based case report form system.
Follow-up Follow-up was performed according to each ablation center’s protocols including scheduled visits in the outpatient department of the participating hospital. Furthermore, 12 months after the index ablation procedure telephone interviews were obtained by the IHF (Ludwigshafen, Germany). Patients were interrogated for complications, medication, AF symptoms, and 12-lead ECG documentation. Statistical analysis Continuous variables are presented as median and interquartile range, and categorical variables as percentages. Comparison of continuous variables was performed using the Mann-Whitney-Wilcoxon test. For comparison of categorical variables the chi² test was used, respectively. These statistics are based on the available cases. In order to combine the incidence of MACCE (death, myocardial infarction, or stroke) during index hospital stay and one-year follow-up, methods of survival analysis (Kaplan-Meier curves, log-rank test) were used to analyze one-year survival free from MACCE after the ablation procedure. All statistical tests were two-tailed, and a p≤0.05 was considered significant. Statistical computations were performed at the biometrics department of the IHF using the SAS 9.3 software package (SAS Institute Inc., Cary, NC). All authors have read and agreed to the written manuscript.
Results Patients characteristics and severity of AF related symptoms Overall 2306 patients were included with a median age of 62 [53 - 68] years, 1465 (63.5%) of them were males. The proportion of males was similar in the RF and cryoballoon group (63.3% vs. 64.3%; p=0.67). Patient characteristics did not differ
significantly between both groups, an overview of co-morbidities and patient characteristics is given in Table 1. Symptomatic AF episodes prior to inclusion in the registry showed no significant differences between both groups. In patients undergoing RF ablation frequent AF episodes (≥ 1 episode per month, 90.9% vs. 89.1%; p=0.20) were similar but drug resistant AF episodes (94.8% vs 66.6%; p200 ablations/year. 2306 patients with a median age of 62 years suffering from paroxysmal AF who underwent their first AF ablation procedure have been enrolled. After 1 year of follow-up the AF recurrence rate was 45.8% after cryo and 45.4% after RF ablation (p=0.87). Thus, freedom from AF recurrence after a single AF ablation was lower than that of previously published trials in px AF patients. The overall complication rate was 4.8% in RF ablation and 4.5% in cryoballoon ablation. However, spectrum and type of complications differed significantly between both ablation methods. As expected the rate of post procedure persistent phrenic nerve paresis was significantly higher after cryoballoon compared to RF ablation (2.2% vs. 0.1%). Other procedural complications where mainly driven by major vascular complications (1.2% RF vs. 0.7% cryo), pericardial tamponades (1.5% RF vs. 0.5% cryo) and major bleeding requiring intervention (1.1% RF vs. 0.7% cryo). Complication rates were comparable to those in randomized trials and large reported patient cohorts. Our data reflect the heterogeneity of AF ablation methods all over Germany. Since efficacy and overall complication rates were similar no conclusion towards a single
AF ablation method “one fits all” with respect to RF or cryoballoon ablation should be drawn. Still, the operator`s experience and preference plays an important role in AF ablation. Futural data from the “Freeze cohort study” and the “Fire and ICE” trial comparing second generation cryoballoon and RF ablation in a randomized fashion in also large patient cohorts have to be awaited.
Table 1: Patient characteristics RF ablation Variable (n=1699)
Cryoballoon (n=607)
Male gender (%) Age (yrs) [median, IQR] Diabetes mellitus (%) Hypertension (%) Coronary artery disease (%) Cardiomyopathy (%) Valve disease (%) Prior stroke (%) Prior pacemaker implant (%) Prior ICD implant (%) Chronic kidney disease (%) Ejection fraction (>50%) (%) Ejection fraction (≤40%) (%)
64.3 61 [53-68] 8.2 51.5 15.7 2.1 3.5 5.1 3.6 1.0 2.0 91.6 1.5
63.3 62 [53-68] 7.3 60.8 17.5 2.4 6.5 5.8 5.2 1.4 2.5 89.5 2.5
p-value 0.67 0.42 0.45 0.10 0.30 0.76
German Ablation Registry: Cryoballoon Versus RF Ablation in Paroxysmal Atrial Fibrillation – One Year Outcome Data Martin Schmidt MD, Uwe Dorwarth MD, Dietrich Andresen MD, Johannes Brachmann MD, Karlheinz Kuck MD, Malte Kuniss MD, Stephan Willems MD, Thomas Deneke MD, Jürgen Tebbenjohanns MD, Jin-Hong Gerds-Li MD, Stefan Spitzer MD, Jochen Senges MD, Matthias Hochadel MD, Ellen Hoffmann MD
PII: DOI: Reference:
S1547-5271(15)01520-9 http://dx.doi.org/10.1016/j.hrthm.2015.12.007 HRTHM6538
To appear in:
Heart Rhythm
www.elsevier.com/locate/buildenv
Cite this article as: Martin Schmidt MD, Uwe Dorwarth MD, Dietrich Andresen MD, Johannes Brachmann MD, Karlheinz Kuck MD, Malte Kuniss MD, Stephan Willems MD, Thomas Deneke MD, Jürgen Tebbenjohanns MD, Jin-Hong Gerds-Li MD, Stefan Spitzer MD, Jochen Senges MD, Matthias Hochadel MD, Ellen Hoffmann MD, German Ablation Registry: Cryoballoon Versus RF Ablation in Paroxysmal Atrial Fibrillation – One Year Outcome Data, Heart Rhythm, http://dx.doi.org/10.1016/j.hrthm.2015.12.007 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
German Ablation Registry: Cryoballoon versus RF ablation in paroxysmal atrial fibrillation – One year Outcome data Schmidt M, Dorwarth U, Andresen D, Brachmann J, Kuck KH, Kuniss M, Lewalter T, Spitzer S, Willems S, Senges J, Hochadel M, Hoffmann E Authors: 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14.
Martin Schmidt, MD1 Uwe Dorwarth, MD1 Dietrich Andresen, MD2 Johannes Brachmann, MD3 Karlheinz Kuck, MD4 Malte Kuniss, MD5 Stephan Willems, MD6 Thomas Deneke, MD7 Jürgen Tebbenjohanns, MD8 Jin-Hong Gerds-Li, MD9 Stefan Spitzer, MD10 Jochen Senges, MD11 Matthias Hochadel, MD11 Ellen Hoffmann, MD1
1
Department of Cardiology, Klinikum Bogenhausen, Munich, Germany Department of Cardiology, Vivantes Klinikum am Urban, Berlin, Germany 3 Department of Cardiology, Klinikum Coburg, Coburg, Germany 4 Department of Cardiology, Asklepios Klinik St. Georg, Hamburg, Germany 5 Department of Cardiology, Kerckhoff-Klinik, Bad Nauheim, Germany 6 Department of Cardiology, Universitäres Herzzentrum Hamburg, Hamburg Germany 7 Department of Cardiology, Herz- und Gefäß-Klinik, Bad Neustadt, Germany 8 Department of Cardiology, HELIOS Klinikum Hildesheim, Hildesheim, Germany 9 Deutsches Herzzentrum Berlin, Berlin, Germany 10 Praxisklinik Herz und Gefäße, Dresden, Germany 11 Stiftung Institut für Herzinfarktforschung, IHF, Ludwigshafen, Germany 2
Running Title: German ablation registry – One year outcome in AF ablation
Disclosures: No disclosures relevant to the manuscript have to be declared
Corresponding Author: Martin Schmidt, MD Klinikum München-Bogenhausen Englschalkingerstr. 77, 81925 Munich, Germany Phone: (+49) 89 - 92702237 Fax: (+49) 89 - 92704502 Email: [email protected]
Abstract BACKGROUND: Radiofrequency ablation has long been standard of care in atrial fibrillation (AF) ablation, cryoballoon technology has emerged a feasible approach with promising results. Prospective multicenter registry data referring to both ablation technologies in AF ablation are lacking so far. OBJECTIVE: We report data of the German ablation registry with respect to efficacy and safety in PV ablation with different energy sources for paroxysmal (px) AF after 1 year follow-up (FU). METHODS: 2306 patients with symptomatic px AF of the German ablation registry were included in this analysis. The cohort was divided into two groups according to the ablation energy source used, cryoballoon and RF ablation. MACCE was defined as a combination of death, myocardial infarction or stroke. RESULTS: AF recurrence rate after a single ablation procedure at 1 year FU was not significantly different between both groups (45.8% after cryoablation and 45.4% after RF ablation; p=0.87). Also the rate of patients without AF recurrence and free of AAD at 12 months FU was similar (cryo 44.2%, RF 41.4%; p=0.25). MACCE occurred with an incidence of 0.7% within 500 days after cryoablation, and of 1.4% after RF ablation (p=0.30). Persistent phrenic nerve palsy was more common after cryo(1.1%) compared to RF ablation (0.3%; p200 ablations per year, 69.2% of the RF patients and 67.5% of the patients undergoing cryoablation (p=0.18). Severity of AF related symptoms was assessed using the SAF scale. The SAF scale has been validated to qualify AF related symptoms and their functional consequences on patient’s daily life with respect to AF documentation and therapy. The SAF score is rated on a scale from 0 (asymptomatic) to 4 (severe impact of symptoms on quality of life) 20 PV ablation procedure AF ablation strategies were pre-classified into circumferential or segmental PV isolation, deployment of linear lesions, and/or ablation of complex fractionated atrial electrograms (CFAE). In all patients, the aim of all ablation strategies was to completely disconnect the PVs from the left atrium. The electrical endpoint of ablation was pulmonary vein isolation.
At least PV entrance block had to be documented for each PV by use of a circular mapping catheter. PV ablation procedures were performed according to the operator`s and the performing institution’s standard of care. All patients underwent transthoracic echocardiography to assess LA diameter, left ventricular ejection fraction and transesophageal echocardiography to rule out LA thrombus formation prior to ablation. Within 24 hours post-ablation transthoracic echocardiography was performed routinely to rule out pericardial effusion, in case of symptoms as hypotension, tachycardia, chest pain or shortness of breathing a repeat echocardiography was performed. For procedural catheter guiding different cardiac mapping strategies were used. AF mapping was separated into conventional mapping or utilization of a 3-dimensional (3D) mapping system such as the CARTOTM (Biosense Webster, U.S.) or NAVXTM system (St. Jude Medical, U.S.). Additional cardiac imaging modalities included MRI, CT, or intracardiac echocardiography (ICE). Anticoagulation: During the procedure, the activated clotting time was kept between 250 and 400 seconds by intravenous heparin administration. All patients had to be anticoagulated using phenprocoumon aiming an INR of 2.0 – 3.0 at least 3 months after the procedure. Sedation: Procedures were performed under deep sedation utilizing fractionated intravenous bolus of midazolam and fentanyl or continuous infusion of propofol with preservation of spontaneous breathing and continuous monitoring of oxygen saturation. The ablation methods used in RF and cryoballoon ablation within the German Ablation Registry I have been described in detail recently by our group.18
In all patients the first generation cryoballoon (ArcticFront™, Medtronic, U.S.) was used since patient inclusion to the registry was terminated in January 2010 when the second generation cryoballoon (ArcticFront™ Advance, Medtronic, U.S.) was not available yet. The duration of the freezing cycle was left to the discretion of the physician. Using first generation cryoballoon freezing cycles were applied 4 – 5 minutes. Definition of complications Ablation procedure-related complications were categorized into major (fatal), moderate (non-fatal) and minor (prolonged hospitalization). Major complications included stroke or transient ischemic attack (TIA), myocardial infarction, pericardial tamponades, PV stenosis, need for emergency cardiac surgery, resuscitation and atrioesophageal fistula. Moderate complications included hematoma requiring transfusion (major bleeding), femoral atriovenous fistula or pseudoaneurysm, phrenic nerve paresis (PNP) and AV block III. PNP was defined as any PNP which was persistent at the end of the ablation procedure. Transient PNPs of less than 2 minutes have not been included since this was not systematically documented in the questionnaire. Apart from prolonged hospitalization also minor bleeding without intervention, new AV block type I or II or bundle branch block were categorized as minor complications. MACCE was defined as a combination of death, myocardial infarction or stroke.
Registry management The IHF Ludwigshafen was responsible for project development and management, data management, and was the central contract research organisation for the registry. Documentation and data acquisition were voluntary, paperless, and were carried out on an internet-based case report form system.
Follow-up Follow-up was performed according to each ablation center’s protocols including scheduled visits in the outpatient department of the participating hospital. Furthermore, 12 months after the index ablation procedure telephone interviews were obtained by the IHF (Ludwigshafen, Germany). Patients were interrogated for complications, medication, AF symptoms, and 12-lead ECG documentation. Statistical analysis Continuous variables are presented as median and interquartile range, and categorical variables as percentages. Comparison of continuous variables was performed using the Mann-Whitney-Wilcoxon test. For comparison of categorical variables the chi² test was used, respectively. These statistics are based on the available cases. In order to combine the incidence of MACCE (death, myocardial infarction, or stroke) during index hospital stay and one-year follow-up, methods of survival analysis (Kaplan-Meier curves, log-rank test) were used to analyze one-year survival free from MACCE after the ablation procedure. All statistical tests were two-tailed, and a p≤0.05 was considered significant. Statistical computations were performed at the biometrics department of the IHF using the SAS 9.3 software package (SAS Institute Inc., Cary, NC). All authors have read and agreed to the written manuscript.
Results Patients characteristics and severity of AF related symptoms Overall 2306 patients were included with a median age of 62 [53 - 68] years, 1465 (63.5%) of them were males. The proportion of males was similar in the RF and cryoballoon group (63.3% vs. 64.3%; p=0.67). Patient characteristics did not differ
significantly between both groups, an overview of co-morbidities and patient characteristics is given in Table 1. Symptomatic AF episodes prior to inclusion in the registry showed no significant differences between both groups. In patients undergoing RF ablation frequent AF episodes (≥ 1 episode per month, 90.9% vs. 89.1%; p=0.20) were similar but drug resistant AF episodes (94.8% vs 66.6%; p200 ablations/year. 2306 patients with a median age of 62 years suffering from paroxysmal AF who underwent their first AF ablation procedure have been enrolled. After 1 year of follow-up the AF recurrence rate was 45.8% after cryo and 45.4% after RF ablation (p=0.87). Thus, freedom from AF recurrence after a single AF ablation was lower than that of previously published trials in px AF patients. The overall complication rate was 4.8% in RF ablation and 4.5% in cryoballoon ablation. However, spectrum and type of complications differed significantly between both ablation methods. As expected the rate of post procedure persistent phrenic nerve paresis was significantly higher after cryoballoon compared to RF ablation (2.2% vs. 0.1%). Other procedural complications where mainly driven by major vascular complications (1.2% RF vs. 0.7% cryo), pericardial tamponades (1.5% RF vs. 0.5% cryo) and major bleeding requiring intervention (1.1% RF vs. 0.7% cryo). Complication rates were comparable to those in randomized trials and large reported patient cohorts. Our data reflect the heterogeneity of AF ablation methods all over Germany. Since efficacy and overall complication rates were similar no conclusion towards a single
AF ablation method “one fits all” with respect to RF or cryoballoon ablation should be drawn. Still, the operator`s experience and preference plays an important role in AF ablation. Futural data from the “Freeze cohort study” and the “Fire and ICE” trial comparing second generation cryoballoon and RF ablation in a randomized fashion in also large patient cohorts have to be awaited.
Table 1: Patient characteristics RF ablation Variable (n=1699)
Cryoballoon (n=607)
Male gender (%) Age (yrs) [median, IQR] Diabetes mellitus (%) Hypertension (%) Coronary artery disease (%) Cardiomyopathy (%) Valve disease (%) Prior stroke (%) Prior pacemaker implant (%) Prior ICD implant (%) Chronic kidney disease (%) Ejection fraction (>50%) (%) Ejection fraction (≤40%) (%)
64.3 61 [53-68] 8.2 51.5 15.7 2.1 3.5 5.1 3.6 1.0 2.0 91.6 1.5
63.3 62 [53-68] 7.3 60.8 17.5 2.4 6.5 5.8 5.2 1.4 2.5 89.5 2.5
p-value 0.67 0.42 0.45 0.10 0.30 0.76
