Perfusion Cardiovascular Magnetic Resonance Research Articles

Clinical implementation of a fully automated quantitative perfusion cardiovascular magnetic resonance imaging workflow with a simplified dual-bolus contrast administration scheme

This study clinically implemented a ready-to-use quantitative perfusion (QP) cardiovascular magnetic resonance (QP CMR) workflow, encompassing a simplified dual-bolus gadolinium-based contrast agent (GBCA) administration scheme and fully automated QP image post-processing. Twenty-five patients with suspected obstructive coronary artery disease (CAD) underwent both adenosine stress perfusion CMR and an invasive coronary angiography or coronary computed tomography angiography. The dual-bolus protocol consisted of a pre-bolus (0.0075 mmol/kg GBCA at 0.5 mmol/ml concentration + 20 ml saline) and a main bolus (0.075 mmol/kg GBCA at 0.5 mmol/ml concentration + 20 ml saline) at an infusion rate of 3 ml/s. The arterial input function curves showed excellent quality. Stress MBF ≤ 1.84 ml/g/min accurately detected obstructive CAD (area under the curve 0.79; 95% Confidence Interval: 0.66 to 0.89). Combined visual assessment of color pixel QP maps and conventional perfusion images yielded a diagnostic accuracy of 84%, sensitivity of 70% and specificity of 93%. The proposed easy-to-use dual-bolus QP CMR workflow provides good image quality and holds promise for high accuracy in diagnosis of obstructive CAD. Implementation of this approach has the potential to serve as an alternative to current methods thus increasing the accessibility to offer high-quality QP CMR imaging by a wide range of CMR laboratories.

High-Resolution Free-Breathing Automated Quantitative Myocardial Perfusion by Cardiovascular Magnetic Resonance for the Detection of Functionally Significant Coronary Artery Disease.

Current assessment of myocardial ischaemia from stress perfusion cardiovascular magnetic resonance (SP-CMR) largely relies on visual interpretation. This study investigated the use of high-resolution free-breathing SP-CMR with automated quantitative mapping in the diagnosis of coronary artery disease (CAD). Diagnostic performance was evaluated against invasive coronary angiography (ICA) with fractional flow reserve (FFR) measurement. Seven-hundred and three patients were recruited for SP-CMR using the research sequence at 3 Tesla. Of those receiving ICA within 6 months, 80 patients either had FFR measurement, or identification of a chronic total occlusion (CTO) with inducible perfusion defects seen on SP-CMR. Myocardial blood flow (MBF) maps were automatically generated in-line on the scanner following image acquisition at hyperaemic stress and rest, allowing myocardial perfusion reserve (MPR) calculation. 75 coronary vessels assessed by FFR, and 28 vessels with CTO were evaluated at both segmental and coronary territory level. Coronary territory stress MBF and MPR were reduced in FFR-positive (≤ 0.80) regions (median stress MBF: 1.74 [0.90-2.17] ml/min/g; MPR: 1.67 [1.10-1.89]) compared with FFR-negative regions (stress MBF: 2.50 [2.15-2.95] ml/min/g; MPR 2.35 [2.06-2.54] p < 0.001 for both). Stress MBF ≤ 1.94 ml/min/g and MPR ≤ 1.97 accurately detected FFR-positive CAD on a per-vessel basis (area under the curve: 0.85 and 0.96 respectively; p < 0.001 for both). A novel scanner-integrated high-resolution free-breathing SP-CMR sequence with automated in-line perfusion mapping is presented which accurately detects functionally significant CAD.

Myocardial perfusion in cardiac amyloidosis.

Cardiac involvement is the main driver of clinical outcomes in systemic amyloidosis and preliminary studies support the hypothesis that myocardial ischaemia contributes to cellular damage. The aims of this study were to assess the presence and mechanisms of myocardial ischaemia using cardiovascular magnetic resonance (CMR) with multiparametric mapping and histopathological assessment. Ninety-three patients with cardiac amyloidosis (CA) (light-chain amyloidosis n = 42, transthyretin amyloidosis n = 51) and 97 without CA (three-vessel coronary disease [3VD] n = 47, unobstructed coronary arteries n = 26, healthy volunteers [HV] n = 24) underwent quantitative stress perfusion CMR with myocardial blood flow (MBF) mapping. Twenty-four myocardial biopsies and three explanted hearts with CA were analysed histopathologically. Stress MBF was severely reduced in patients with CA with lower values than patients with 3VD, unobstructed coronary arteries and HV (CA: 1.04 ± 0.51 ml/min/g, 3VD: 1.35 ± 0.50 ml/min/g, unobstructed coronary arteries: 2.92 ± 0.52 ml/min/g, HV: 2.91 ± 0.73 ml/min/g; CA vs. 3VD p = 0.011, CA vs. unobstructed coronary arteries p < 0.001, CA vs. HV p < 0.001). Myocardial perfusion abnormalities correlated with amyloid burden, systolic and diastolic function, structural parameters and blood biomarkers (p < 0.05). Biopsies demonstrated abnormal vascular endothelial growth factor staining in cardiomyocytes and endothelial cells, which may be related to hypoxia conditions. Amyloid infiltration in intramural arteries was associated with severe lumen reduction and severe reduction in capillary density. Cardiac amyloidosis is associated with severe inducible myocardial ischaemia demonstrable by histology and CMR stress perfusion mapping. Histological evaluation indicates a complex pathophysiology, where in addition to systolic and diastolic dysfunction, amyloid infiltration of the epicardial arteries and disruption and rarefaction of the capillaries play a role in contributing to myocardial ischaemia.

Kiosk 9R-FB-08 - Quantitative Perfusion Cardiovascular Magnetic Resonance Imaging: Clinical Implementation of a Simplified Dual-bolus Workflow

Kiosk 9R-FB-08 - Quantitative Perfusion Cardiovascular Magnetic Resonance Imaging: Clinical Implementation of a Simplified Dual-bolus Workflow

CMR 4-129 - High Resolution Quantitative Perfusion CMR with the Spatio-temporal CNN Imaging Transformer

CMR 4-129 - High Resolution Quantitative Perfusion CMR with the Spatio-temporal CNN Imaging Transformer

Kiosk 9R-TA-10 - Automatic Segmentation of Multi-center Multi-field-strength Perfusion CMR Datasets with Deep Learning-based Uncertainty-guided Analysis: Preliminary Findings Using the SCMR Registry

Kiosk 9R-TA-10 - Automatic Segmentation of Multi-center Multi-field-strength Perfusion CMR Datasets with Deep Learning-based Uncertainty-guided Analysis: Preliminary Findings Using the SCMR Registry

CMR 2-65 - Quality-control of Stress Perfusion CMR Segmentations with Weakly Supervised Contrast-enhancement Anomaly Detection

CMR 2-65 - Quality-control of Stress Perfusion CMR Segmentations with Weakly Supervised Contrast-enhancement Anomaly Detection

Kiosk 9R-TC-12 - Clinician-in-the-loop Analysis of FBee-breathing Stress Perfusion CMR Datasets with Dynamic Quality Control: Preliminary Evaluation Using the SCMR Registry

Kiosk 9R-TC-12 - Clinician-in-the-loop Analysis of FBee-breathing Stress Perfusion CMR Datasets with Dynamic Quality Control: Preliminary Evaluation Using the SCMR Registry

Kiosk 7R-FC-04 - Value of Quantitative Perfusion CMR Beyond Vasculopathy Assessment Among Orthotopic Heart Transplant Recipients

Kiosk 7R-FC-04 - Value of Quantitative Perfusion CMR Beyond Vasculopathy Assessment Among Orthotopic Heart Transplant Recipients

CMR 3-85 - Reducing the Contrast Dose by 80% in Quantitative Perfusion CMR Enabled by Patch-wise Deep Learning

CMR 3-85 - Reducing the Contrast Dose by 80% in Quantitative Perfusion CMR Enabled by Patch-wise Deep Learning

Kiosk 1R-TA-07 - Microvascular Dysfunction Assessed by Quantitative Perfusion CMR Is a Common Condition in Patients with MINOCA (myocardial Infarction with Non-obstructive Coronary Arteries) and Otherwise Normal CMR

Kiosk 1R-TA-07 - Microvascular Dysfunction Assessed by Quantitative Perfusion CMR Is a Common Condition in Patients with MINOCA (myocardial Infarction with Non-obstructive Coronary Arteries) and Otherwise Normal CMR

Kiosk 9R-FB-10 - High-resolution Stress Perfusion CMR with Inline Quantitative Mapping to Assess the Relationship Between Left Ventricular Ejection FBaction and Myocardial Blood Flow in the Absence of Coronary Disease

Kiosk 9R-FB-10 - High-resolution Stress Perfusion CMR with Inline Quantitative Mapping to Assess the Relationship Between Left Ventricular Ejection FBaction and Myocardial Blood Flow in the Absence of Coronary Disease

Diagnostic confidence with quantitative cardiovascular magnetic resonance perfusion mapping increases with increased coverage of the left ventricle

BackgroundQuantitative cardiovascular magnetic resonance (CMR) first pass perfusion maps are conventionally acquired with 3 short-axis (SAX) views (basal, mid, and apical) in every heartbeat (3SAX/1RR). Thus, a significant part of the left ventricle (LV) myocardium, including the apex, is not covered. The aims of this study were 1) to investigate if perfusion maps acquired with 3 short-axis views sampled every other RR-interval (2RR) yield comparable quantitative measures of myocardial perfusion (MP) as 1RR and 2) to assess if acquiring 3 additional perfusion views (i.e., total of 6) every other RR-interval (2RR) increases diagnostic confidence. MethodsIn 287 patients with suspected ischemic heart disease stress and rest MP were performed on clinical indication on a 1.5T MR scanner. Eighty-three patients were examined by acquiring 3 short-axis perfusion maps with 1RR sampling (3SAX/1RR); for which also 2RR maps were reconstructed. Additionally, in 103 patients 3 short-axis and 3 long-axis (LAX; 2-, 3, and 4-chamber view) perfusion maps were acquired using 2RR sampling (3SAX + 3LAX/2RR) and in 101 patients 6 short-axis perfusion maps using 2RR sampling (6SAX/2RR) were acquired. The diagnostic confidence for ruling in or out stress-induced ischemia was scored according to a Likert scale (certain ischemia [2 points], probably ischemia [1 point], uncertain [0 points], probably no ischemia [1 point], certain no ischemia [2 points]). ResultsThere was a strong correlation (R = 0.99) between 3SAX/1RR and 3SAX/2RR for global MP (mL/min/g). The diagnostic confidence score increased significantly when the number of perfusion views was increased from 3 to 6 (1.24 ± 0.68 vs 1.54 ± 0.64, p < 0.001 with similar increase for 3SAX+3LAX/2RR (1.29 ± 0.68 vs 1.55 ± 0.65, p < 0.001) and for 6SAX/2RR (1.19 ± 0.69 vs 1.53 ± 0.63, p < 0.001). ConclusionQuantitative perfusion mapping with 2RR sampling of data yields comparable perfusion values as 1RR sampling, allowing for the acquisition of additional views within the same perfusion scan. The diagnostic confidence for stress-induced ischemia increases when adding 3 additional views, short- or long axes, to the conventional 3 short-axis views. Thus, future development and clinical implementation of quantitative CMR perfusion should aim at increasing the LV coverage from the current standard using 3 short-axis views.

CMR 3-86 - Stress CMR Perfusion Imaging in the Medicare Eligible Population: Insights from the Stress CMR Perfusion Imaging in the United States (SPINS) Study

CMR 3-86 - Stress CMR Perfusion Imaging in the Medicare Eligible Population: Insights from the Stress CMR Perfusion Imaging in the United States (SPINS) Study

Reduced stress perfusion in myocardial infarction with nonobstructive coronary arteries

Myocardial infarction with nonobstructive coronary arteries (MINOCA) has several possible underlying causes, including coronary microvascular dysfunction (CMD). Early cardiovascular magnetic resonance imaging (CMR) is recommended, however cannot provide a diagnosis in 25% of cases. Quantitative stress CMR perfusion mapping can identify CMD, however it is unknown if CMD is present during long-term follow-up of MINOCA patients. Therefore, this study aimed to evaluate presence of CMD during long-term follow-up in MINOCA patients with an initial normal CMR scan. MINOCA patients from the second Stockholm myocardial infarction with normal coronaries study (SMINC-2), with a normal CMR scan at median 3 days after hospitalization were investigated with comprehensive CMR including stress perfusion mapping a median of 5 years after the index event, together with age- and sex-matched volunteers without symptomatic ischemic heart disease. Cardiovascular risk factors, medication and symptoms of myocardial ischemia measured by the Seattle Angina Questionnaire 7 (SAQ-7), were registered. In total, 15 patients with MINOCA and an initial normal CMR scan (59 ± 7 years old, 60% female), and 15 age- and sex-matched volunteers, underwent CMR. Patients with MINOCA and an initial normal CMR scan had lower global stress perfusion compared to volunteers (2.83 ± 1.8 vs 3.53 ± 0.7 ml/min/g, p = 0.02). There were no differences in other CMR parameters, hemodynamic parameters, or cardiovascular risk factors, except for more frequent use of statins in the MINOCA patient group compared to volunteers. In conclusion, global stress perfusion is lower in MINOCA patients during follow-up, compared to age- and sex-matched volunteers, suggesting that CMD may be a possible pathophysiological mechanism in MINOCA.Clinical Trial Registration: Clinicaltrials.gov identifier NCT02318498. Registered 2014-12-17.

Comparison of Stress-Rest and Stress-LGE Analysis Strategy in Patients Undergoing Stress Perfusion Cardiovascular Magnetic Resonance.

Stress perfusion cardiovascular magnetic resonance can be performed without rest perfusion for the quantification of ischemia burden. However, the optimal method of analysis is uncertain. We identified 666 patients from CE-MARC (Clinical Evaluation of Magnetic Resonance Imaging in Coronary Heart Disease) with complete stress perfusion, rest perfusion, late gadolinium enhancement (LGE), and quantitative coronary angiography data. For each segment of the 16-segment model, perfusion was visually graded during stress and rest imaging, with infarct transmurality assessed from LGE imaging. In the stress-LGE analysis, a segment was defined as ischemic if it had a subendocardial perfusion defect with no infarction. Rest perfusion was not used in this analysis. We compared the diagnostic accuracy of stress-LGE analysis against quantitative coronary angiography and the stress-rest method validated in the original CE-MARC analysis. The diagnostic accuracy of the stress-LGE method was evaluated with different thresholds of infarct transmurality used to define whether an infarcted segment had peri-infarct ischemia. The optimal stress-LGE analysis classified all segments with a stress perfusion defect as ischemic unless they had >75% infarct transmurality (area under the curve, 0.843; sensitivity, 75.6%; specificity, 93.1%; P<0.001). This analysis method has superior diagnostic accuracy to the stress-rest method (area under the curve, 0.834; sensitivity, 73.6%; specificity, 93.1%; P<0.001, P value for difference=0.02). Patients were followed-up for median 6.5 years for major adverse cardiovascular events, with the presence of inducible ischemia by either the stress-LGE or stress-rest analysis being similar and strongly predictive (hazard ratio, 2.65; P<0.001, for both). In this analysis of CE-MARC, the optimum definition of inducible ischemia was the presence of a stress-induced perfusion defect without transmural infarction. This definition improved the diagnostic accuracy compared with the stress-rest analysis validated in the original study. The absence of ischemia by either analysis strategy conferred a favorable long-term prognosis.

Prognostic value of first pass perfusion transit time beyond the pulmonary circulation

Abstract Background Pulmonary transit time (PTT), defined as the time required for a bolus of contrast agent to pass from the right cavities to the left cavities, is an emerging parameter reflective of cardiopulmonary hemodynamics that can be measured in first-pass perfusion cardiovascular magnetic resonance (CMR). Transit times along the left heart (LHTT) and perfusion times of peripheral organs have not been explored so far. Purpose To assess the prognostic value of LHTT and peripheral organs perfusion time in a cohort of patients with left ventricular (LV) disfunction. Methods 50 consecutive patients with LV disfunction (ejection fraction ≤45%) and 56 normal controls who underwent a CMR at our institution were selected. Transit time was calculated as the peak-to-peak time interval between two different areas of the cardiovascular system. PTT was assessed between right ventricle (RV) and left ventricle. LHTT was assessed between left atrium and ascending aorta. Myocardial perfusion time (MyoPT) was measured between left ventricle and the peak of myocardial perfusion. Peripheral organ perfusion (kidney, KPT; spleen, SPT and liver, LPT) between abdominal aorta and the peak organ perfusion. The primary end point was a composite of cardiovascular death, hospitalization, ventricular arrhythmias and the need of any cardiac invasive intervention within the first year. Results Compared with controls, LV disfunction patients presented higher PTT (7.4 [5.9-8.4] vs 11.9 [9.5-13.9] s, p&amp;lt;0.001), LHTT (1.9 [1.05-2.3] vs 3.3 [1.9-4.8] s, p&amp;lt;0.01), MyoPT (9.9 [7.8-11.5] vs 13.1 [9.7-18.6] s, p&amp;lt;0.01), KPT (9.4[7.8-11.2] vs 11.5[8.3-15.5] s, p = 0.012). SPT showed a non-significant trend (9.4[8.1-11.9] vs 11.5[7.9-13.4]s , p = 0.058) . There were no differences in LPT (28.9[24.4-35] vs 33.3[23.3-41.1] s, p = 0.267). Among the patients with LV disfunction, 16 subjects reached the composite end-point; compared to those who did not, these patients had significant higher values of PTT (10.1 [8.7-13.7] vs 13.4[10-15.7] s, p = 0.04), LHTT (2.3[1.8-4] vs 4.3 [3.3-5.8] s, p = 0.008) and MyoPT (10.5[8.8-17.5] vs 13.3[11.9-20.5] s, p = 0.049). SPT showed a non-significant trend (10.3[6.9-12.6] vs 12.6[10.9-17.1] s, p = 0.078), KPT and LPT showed no significant differences. Patients with worse prognosis also presented lower LV ejection fraction (LV: 34.7± 9.5 vs 25.5±9 %, p&amp;lt;0.001) but no significant differences in RV ejection fraction: 52.9±14 vs 49.3±13.8 %, p = 0.473). Due to the small number of events we did not performed a multivariate analysis. KPT showed a weak but significant positive correlation with the creatinine measured at the time of the CMR study (r = 0.262, p = 0.024) and also at follow-up (r = 0.247, p = 0.042). Conclusions Transit time is a surrogate marker of the heamodynamic status that can be assessed beyond the pulmonary circulation. LHTT and organ perfusion times are markedly altered in patients with LV disfunction and are associated with poor prognosis.

Safety and incremental prognostic value of stress CMR in patients with known chronic kidney disease

Abstract Background Cardiovascular disease (CVD) is the main cause of mortality in patients with chronic kidney disease (CKD). Although several studies have demonstrated the consistently high prognostic value of stress cardiovascular magnetic resonance (CMR), its prognostic value in patients with CKD is not well established. We aimed to assess the safety and the incremental prognostic value of vasodilator stress perfusion CMR in consecutive symptomatic patients with known CKD. Methods Between 2008 and 2021, we conducted a bi-center longitudinal study with all consecutive symptomatic patients with known CKD, defined by estimated glomerular filtration rate (eGFR) between 30 and 60 ml/min/1.73 m2, referred for vasodilator stress CMR. All patients with eGFR &amp;lt;30 ml/min/1.73 m² (n=62) were excluded due the risk of nephrogenic systemic fibrosis. All patients were followed for the occurrence of major adverse cardiovascular events (MACE) defined as cardiac death or recurrent nonfatal myocardial infarction (MI). Cox regressions were used to determine the prognostic value of stress CMR parameters. Results Of 825 patients with known CKD (71.4±8.8 years, 70% men), 769 (93%) completed the CMR protocol, and among those 702 (91%) completed the follow-up (median follow-up 6.4 (4.0–8.2) years). Stress CMR was well tolerated without occurrence of death or severe adverse event related to the injection of gadolinium or nephrogenic systemic fibrosis case. The presence of inducible ischemia was associated with the occurrence of MACE (hazard ratio [HR] 12.50; 95% confidence interval [CI]: 7.50–20.8; p&amp;lt;0.001). In multivariable analysis, ischemia and late gadolinium enhancement were independent predictors of MACE (HR 15.5; 95% CI: 7.72 to 30.9; and HR:4.67 [95%CI: 2.83-7.68]; respectively, both p&amp;lt;0.001). After adjustment, stress CMR findings showed the best improvement in model discrimination and reclassification above traditional risk factors (C-statistic improvement: 0.13; NRI=0.477; IDI=0.049). Conclusions In patients with known CKD, stress CMR is safe and its findings have an incremental prognostic value to predict MACE over traditional risk factors.Cumulative rates of MACECompeting risk analysis

Fully automated quantitative stress perfusion cardiac MRI to assess myocardial perfusion in adult patients with convalescent Kawasaki disease and coronary aneurysms: an age and sex-matched analysis

Abstract Introduction Coronary aneurysms are a well-documented complication of childhood Kawasaki disease. They may persist into adulthood predisposing to impaired myocardial blood flow, symptoms, and adverse cardiovascular events. Preliminary reports suggest that Kawasaki disease may also be associated with coronary microvascular dysfunction. The effect of coronary involvement from Kawasaki disease on myocardial perfusion in convalescent asymptomatic adults has not been studied using fully automated inline quantitative perfusion MRI (CMR). Purpose To assess the effect of coronary artery abnormalities on quantitative myocardial perfusion in adult patients with convalescent Kawasaki disease compared to an age and sex-matched control cohort. Methods Retrospective single centre cohort analysis of adult patients with convalescent Kawasaki disease who have undergone fully automated inline quantitative myocardial stress perfusion CMR. All patients had coronary involvement during their acute childhood illness. An age and sex-matched group (n=14) with normal CMRs was selected for comparison. Rest MBF was corrected for heart rate by dividing by the scan heart rate and multiplying by the mean resting heart rate among all subjects. A per-vessel analysis was performed using a linear mixed effects model with pairwise comparisons to assess the effect of coronary abnormalities (normal, aneurysmal with or without thrombosis, revascularised) on myocardial perfusion reserve (MPR). Results 28 patients were included (14 Kawasaki; 14 controls). All patients in the Kawasaki cohort had assessment of coronary anatomy either by CT (93%) or invasive (7%) coronary angiography. A total of 84 vessels were analysed. Mean age and sex were well matched (Kawasaki: 27±6.2 years; 13 males : 1 female vs. controls: 27±6.4 years; 13 males : 1 female). In patients with Kawasaki disease, thrombosed aneurysmal arteries were associated with a significantly impaired MPR compared to normal (mean Δ: -0.817; P=0.003) and aneurysmal (mean Δ: -0.957; P&amp;lt;0.001) arteries. MPR in aneurysmal and revascularised arteries were not significantly different from normal arteries in patients with Kawasaki disease. There was no significant difference in MPR between normal coronary arteries in patients with Kawasaki compared to controls. Conclusions Thrombosis in coronary aneurysms was associated with a significant impairment of myocardial perfusion in adult patients with convalescent Kawasaki disease. There was no significant reduction in perfusion in territories supplied by normal or aneurysmal arteries which does not support coronary microvascular dysfunction in these patients. Further studies are needed to confirm these preliminary findings.

Prognostic value of global coronary flow reserve improvement after percutaneous coronary intervention in patients with chronic coronary syndrome

Abstract Background Impaired global coronary flow reserve (g-CFR) evaluated by phase-contrast cine cardiovascular magnetic resonance (PC-CMR) has been reported to be associated with worse outcomes in patients with cardiovascular disease. Purpose This study aimed to evaluate the prognostic value of g-CFR improvement evaluated by PC-CMR in patients with chronic coronary syndrome (CCS). Methods A total of 320 patients with CCS who underwent pre- and post-PCI PC-CMR measurements and stress perfusion CMR were followed-up to determine the predictors of major adverse cardiovascular events (MACE). The association between CMR variables including changes in G-CFR after PCI and MACE (cardiac death, nonfatal myocardial infarction, hospitalization for heart failure, or ischemic stroke) was investigated. Results G-CFR improvement was observed in 162 (50.6%) and MACE occurred in 26 (8.1%) during follow-up (2.5 year, 1.3-4.0). G-CFR improvement was significantly associated with lower pre-PCI G-CFR (p&amp;lt;0.001). Patients with MACE showed lower pre-PCI G-CFR, a high prevalence of post-PCI positive stress perfusion, non-G-CFR improvement. In Kaplan-Meier analysis, patients without G-CFR improvement were significantly associated with poor prognosis (log-rank χ2=5.8, P=0.018). After adjusting the presence of post-PCI positive stress perfusion, non-G-CFR improvement was an independent predictor of MACE (P=0.007). Conclusion In addition to the association between lower pre-PCI G-CFR and worse prognosis, G-CFR improvement after PCI may provide a novel insight into the prognosis after PCI in patients with CCS.Kaplan-Meier analysis