Original article
941
Authors
Claes Soderlund1, Stefan Linder2, Per E. Bergenzaun3, Tomas Grape4, Hans-Olof Hakansson5, Anders Kilander6, Gert Lindell3, Martin Ljungman7, Bo Ohlin8, Jorgen Nielsen10, Claes Rudberg7, Per-Ove Stotzer6, Erik Svartholm9, Ervin Toth10, Farshad Frozanpor11
Institutions
Institutions are listed at the end of article.
submitted 18. November 2013 accepted after revision 18. May 2014
Background and study aims: Covered nitinol alloy self-expandable metal stents (SEMSs) have been developed to overcome the shortcomings of steel SEMS in patients with malignant biliary obstruction. In a randomized, multicenter trial, we compared stent patency, patient survival, and adverse events in patients with partly covered stents made from steel or nitinol. Patients and methods: A total of 400 patients with unresectable distal malignant biliary obstruction were randomized at endoscopic retrograde cholangiopancreatography (ERCP) to insertion of a steel or nitinol partially covered SEMS, with 200 patients in each group. The primary outcome was confirmed stent failure during 300 days of follow-up. Results: At 300 days, the proportion of patients with patent stents was 77 % in the steel group, compared with 89 % in the nitinol group (P =
0.01). Confirmed stent failure occurred more often in the steel SEMS group compared with the nitinol SEMS group, in 30 versus 14 patients (P = 0.02). Stent migration occurred in 13 patients in the steel group and in 3 patients in the nitinol group (P = 0.01). Median patient survival (secondary outcome) was 137 days and 120 days in the steel SEMS and nitinol SEMS groups, respectively (P = 0.59). Conclusions: The nitinol SEMS showed longer patency time, and the nitinol group had fewer patients with stent failure, compared with the steel SEMS group. We could not detect any differences between the two groups regarding survival time, and regarding adverse event rate.
Previous oral presentation at Digestive Diseases Week (DDW) 2012, San Diego, California, 19 May, abstract 145; DDW 2013, Orlando, Florida, 19 May, abstr 288; and UEGW 2012, Amsterdam, Holland, 22 October, abstr OP 63.
biliary stenosis; no advantage of the covering was demonstrated [4]. However, in studies comparing covered and uncovered SEMSs, results are conflicting [5 – 7]. The metallic mesh of the SEMS is nowadays usually made of nitinol, i. e., a nickel-titanium alloy, described as being flexible, strong. and easy for the endoscopist to handle [8]. The clinical importance of this, i. e., the patency rate in comparison with the older steel alloy SEMS (steel SEMS), has not been investigated, in a large RCT however, as pointed out in a Cochrane Review [9] and by Gardner [10]. Some nonrandomized data indicate that covered nitinol SEMSs are superior to the older covered steel SEMSs [11, 12]. Uncovered SEMSs made of the two types of material seem to show the same performance according to one RCT [11]. The objective of the present study was to investigate, by means of an adequately powered RCT the impact of the material used, i. e., steel alloy or nitinol alloy, in partially covered SEMSs placed in
Bibliography DOI http://dx.doi.org/ 10.1055/s-0034-1377936 Published online: 16.10.2014 Endoscopy 2014; 46: 941–948 © Georg Thieme Verlag KG Stuttgart · New York ISSN 0013-726X Corresponding author Claes Soderlund, MD PhD Department of Surgery South Hospital SE-118 83, Stockholm Sweden Fax: +46–8-6162436 [email protected]
Introduction !
The vast majority of patients with malignant stricture of the common bile duct (CBD) are not suitable candidates for resection with curative intent [1]. Thus, endoscopically placed stents have been used for many years for palliation of jaundice in these patients. Use of self-expandable metal stents (SEMSs) has improved the patency rate compared with plastic stents [2, 3]. Recently, a multicenter, randomized controlled trial (RCT) compared partially covered versus noncovered nitinol SEMS, inserted at endoscopic retrograde cholangiopancreatography (ERCP) in 400 patients with nonresectable distal malignant
Clinical trial registration : NCT 00980889
Soderlund Claes et al. Partially covered nitinol versus steel selfxpandable metal stent for malignant distal biliary obstruction … Endoscopy 2014; 46: 941–948
This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.
Nitinol versus steel partially covered self-expandable metal stent for malignant distal biliary obstruction: a randomized trial
Original article
distal malignant obstruction. The primary outcome was the stent patency of the steel SEMSs and the nitinol SEMSs.
Patients and methods !
Between May 2009 and June 2012, 400 patients were included in the trial; 200 were randomized to the steel SEMS group and 200 to the nitinol SEMS group. " Table 1. The criteria for eligibility and exclusion are shown in ● " Fig. 1 (a Consolidated The study flowchart is displayed in ● Standards for Reporting Trials [CONSORT] chart).
Design As in a recent trial by our group [4], this study was a multicenter trial involving nine Swedish hospitals, i. e., three university hospitals, one large and university-affiliated general hospital, and five general hospitals, with a catchment area of altogether approximately 2.8 million inhabitants. A total of 21 endoscopists participated. The study protocol and case report form (CRF) were approved by the Ethics Committee of the Karolinska Institute, Stockholm. Informed consent was obtained from each patient taking part in the trial. Consent could be withdrawn at any time by the patient following inclusion.
Stents The trial compared the use of the steel alloy SEMS (Wallstent; Boston Scientific Nordic AB, Helsingborg, Sweden) with the nitinol alloy SEMS (Wallflex; Boston Scientific Nordic AB) in jaundiced patients with distal malignant biliary stenosis that was considered to be nonresectable and/or when the patient was not considered suitable for major surgery. The steel alloy SEMS used was10 mm with partial Permalume silicone interior covering (5 mm in each end was free from covering), and was 4 cm, 6 cm or 8 cm in length; the nitinol alloy SEMS used had the same width, length, and partial covering. The Wallflex is a recently developed stent with a proximal antimigration flare and is said to have an expansion force (radial) similar to that of the Wallstent, but to be more flexible, i. e., to have less axial force, defined as the force required to prevent a bent stent from becoming straight again [13]. It is constructed with a closed loop platinum-cored nitinol wire mesh with looped and flared antimigration ends, which are said to be less traumatic (i. e., probably causing less tissue reaction) than the open ends of " Fig. 2). the Wallstent (●
Randomization When their informed consent had been obtained, and if the patients met the inclusion criteria and displayed none of the exclu" Table 1), they were randomized, using the opaque sion criteria (● sealed envelope and computer-generated random numbers method, to one of two groups: the steel SEMS group or the nitinol SEMS group. The randomization process was done by one of the participating endoscopists in the ERCP suite; after the guidewire had been correctly placed, and the stricture had been passed, the stent was then inserted immediately. Blinding was not attempted, although the patient was not told what kind of SEMS he or she had received. If appropriate investigations (e. g. computed tomography [CT]) or patient evaluations (for possible radical surgery) had not yet been done, a temporary plastic stent might have been inserted. In such cases, then at a second session (as soon as possible but al-
Table 1 Nitinol versus steel partially covered self-expandable metal stent (SEMS) for malignant distal biliary obstruction: eligibility and exclusion criteria in a randomized trial.
Eligibility criteria – ≥ 20 years of age – Information given and informed consent obtained – Clinical data in accord with malignant bile duct obstruction – Bilirubin > 50 µmol/L (normal < 26 µmol/L) – Ultrasound and/or CT performed before inclusion. Findings in accord with malignant common bile duct obstruction – Typical radiological appearance of malignant common bile duct stenosis at ERCP – Proximal margin of malignant bile duct stenosis ≥ 2 cm from the hepatic confluence – Patient considered not suitable for radical surgery. If in doubt, temporary stenting with a plastic stent could be done, and the patient would still be eligible if they were randomized with replacement of the endoprosthesis by a metal stent within 4 weeks (see text). Exclusion criteria – Informed consent not obtained – Possible candidate for curative surgical resection – Active hepatitis or other hepatic diseases that may cause jaundice – Multiple hepatic metastases with significant blockage of one or more liver segments (if no segment blockage, metastasis is not an exclusion criterion) – Stenosis located within 2 cm from the hepatic confluence – Suspicion of nonmalignant bile duct obstruction – Severe coagulation disturbance (PK-INR > 1.6, normal 0.9 – 1.2) – Previous Billroth II or Roux-en-Y gastric resection, or a significant duodenal obstruction making ERCP difficult – Previous inclusion in the study CT, computed tomography; ERCP, endoscopic retrograde cholangiopancreatography; PK-INR, prothrombinkomplex-international normalized ratio
ways within 1 month) it was permitted to include the patient for randomization with the change of stent to an SEMS. This was similar to the procedures in previous trials by our group [3, 4]. Endoscopic sphincterotomy was performed routinely before stent insertion. The endoscopist decided what SEMS length to use, 4 cm, 6 cm or 8 cm. Positioning of the stent in the center of the stricture was encouraged and the SEMS should be visible in the duodenum. The central study nurse received by fax the randomization sheet and the initial CRF for her continued surveillance. She also visited every center at least twice to ensure that the protocol and the CRF were adhered to, including the follow-up.
Follow-up and endpoints We recorded all procedure-related adverse events according to current routine [14]. In order to confirm that the drainage procedure was successful, liver function test findings were obtained 2 – 5 days after stent insertion. The criteria for successful stent insertion included radiological confirmation at ERCP that the stent was in an adequate position and that at least a 30 % decline in bilirubin level was seen during the first 5 days after stent insertion.
Soderlund Claes et al. Partially covered nitinol versus steel selfxpandable metal stent for malignant distal biliary obstruction … Endoscopy 2014; 46: 941–948
This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.
942
Original article
Fig. 1 Nitinol versus steel partially covered selfexpandable metal stent (SEMS) for malignant distal biliary obstruction: CONSORT flowchart illustrating the progress of patients throughout the randomized controlled trial. (CONSORT, Consolidated Standards for Reporting Trials.)
Assessed for eligibility n = 857
Not randomized: n = 457 – Did not meet inclusion criteria: – Refused to participate: – Whipple resection: – Possible benign stenosis: – Failed cannulation: – Duodenal obstruction: – Multiple strictures or close to hilus:
943
63 15 100 31 50 37 161
Steel SEMS n = 200
Protocol violations: n = 31 – Wrong stent: – Multiple stents: – Bilirubin
941
Authors
Claes Soderlund1, Stefan Linder2, Per E. Bergenzaun3, Tomas Grape4, Hans-Olof Hakansson5, Anders Kilander6, Gert Lindell3, Martin Ljungman7, Bo Ohlin8, Jorgen Nielsen10, Claes Rudberg7, Per-Ove Stotzer6, Erik Svartholm9, Ervin Toth10, Farshad Frozanpor11
Institutions
Institutions are listed at the end of article.
submitted 18. November 2013 accepted after revision 18. May 2014
Background and study aims: Covered nitinol alloy self-expandable metal stents (SEMSs) have been developed to overcome the shortcomings of steel SEMS in patients with malignant biliary obstruction. In a randomized, multicenter trial, we compared stent patency, patient survival, and adverse events in patients with partly covered stents made from steel or nitinol. Patients and methods: A total of 400 patients with unresectable distal malignant biliary obstruction were randomized at endoscopic retrograde cholangiopancreatography (ERCP) to insertion of a steel or nitinol partially covered SEMS, with 200 patients in each group. The primary outcome was confirmed stent failure during 300 days of follow-up. Results: At 300 days, the proportion of patients with patent stents was 77 % in the steel group, compared with 89 % in the nitinol group (P =
0.01). Confirmed stent failure occurred more often in the steel SEMS group compared with the nitinol SEMS group, in 30 versus 14 patients (P = 0.02). Stent migration occurred in 13 patients in the steel group and in 3 patients in the nitinol group (P = 0.01). Median patient survival (secondary outcome) was 137 days and 120 days in the steel SEMS and nitinol SEMS groups, respectively (P = 0.59). Conclusions: The nitinol SEMS showed longer patency time, and the nitinol group had fewer patients with stent failure, compared with the steel SEMS group. We could not detect any differences between the two groups regarding survival time, and regarding adverse event rate.
Previous oral presentation at Digestive Diseases Week (DDW) 2012, San Diego, California, 19 May, abstract 145; DDW 2013, Orlando, Florida, 19 May, abstr 288; and UEGW 2012, Amsterdam, Holland, 22 October, abstr OP 63.
biliary stenosis; no advantage of the covering was demonstrated [4]. However, in studies comparing covered and uncovered SEMSs, results are conflicting [5 – 7]. The metallic mesh of the SEMS is nowadays usually made of nitinol, i. e., a nickel-titanium alloy, described as being flexible, strong. and easy for the endoscopist to handle [8]. The clinical importance of this, i. e., the patency rate in comparison with the older steel alloy SEMS (steel SEMS), has not been investigated, in a large RCT however, as pointed out in a Cochrane Review [9] and by Gardner [10]. Some nonrandomized data indicate that covered nitinol SEMSs are superior to the older covered steel SEMSs [11, 12]. Uncovered SEMSs made of the two types of material seem to show the same performance according to one RCT [11]. The objective of the present study was to investigate, by means of an adequately powered RCT the impact of the material used, i. e., steel alloy or nitinol alloy, in partially covered SEMSs placed in
Bibliography DOI http://dx.doi.org/ 10.1055/s-0034-1377936 Published online: 16.10.2014 Endoscopy 2014; 46: 941–948 © Georg Thieme Verlag KG Stuttgart · New York ISSN 0013-726X Corresponding author Claes Soderlund, MD PhD Department of Surgery South Hospital SE-118 83, Stockholm Sweden Fax: +46–8-6162436 [email protected]
Introduction !
The vast majority of patients with malignant stricture of the common bile duct (CBD) are not suitable candidates for resection with curative intent [1]. Thus, endoscopically placed stents have been used for many years for palliation of jaundice in these patients. Use of self-expandable metal stents (SEMSs) has improved the patency rate compared with plastic stents [2, 3]. Recently, a multicenter, randomized controlled trial (RCT) compared partially covered versus noncovered nitinol SEMS, inserted at endoscopic retrograde cholangiopancreatography (ERCP) in 400 patients with nonresectable distal malignant
Clinical trial registration : NCT 00980889
Soderlund Claes et al. Partially covered nitinol versus steel selfxpandable metal stent for malignant distal biliary obstruction … Endoscopy 2014; 46: 941–948
This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.
Nitinol versus steel partially covered self-expandable metal stent for malignant distal biliary obstruction: a randomized trial
Original article
distal malignant obstruction. The primary outcome was the stent patency of the steel SEMSs and the nitinol SEMSs.
Patients and methods !
Between May 2009 and June 2012, 400 patients were included in the trial; 200 were randomized to the steel SEMS group and 200 to the nitinol SEMS group. " Table 1. The criteria for eligibility and exclusion are shown in ● " Fig. 1 (a Consolidated The study flowchart is displayed in ● Standards for Reporting Trials [CONSORT] chart).
Design As in a recent trial by our group [4], this study was a multicenter trial involving nine Swedish hospitals, i. e., three university hospitals, one large and university-affiliated general hospital, and five general hospitals, with a catchment area of altogether approximately 2.8 million inhabitants. A total of 21 endoscopists participated. The study protocol and case report form (CRF) were approved by the Ethics Committee of the Karolinska Institute, Stockholm. Informed consent was obtained from each patient taking part in the trial. Consent could be withdrawn at any time by the patient following inclusion.
Stents The trial compared the use of the steel alloy SEMS (Wallstent; Boston Scientific Nordic AB, Helsingborg, Sweden) with the nitinol alloy SEMS (Wallflex; Boston Scientific Nordic AB) in jaundiced patients with distal malignant biliary stenosis that was considered to be nonresectable and/or when the patient was not considered suitable for major surgery. The steel alloy SEMS used was10 mm with partial Permalume silicone interior covering (5 mm in each end was free from covering), and was 4 cm, 6 cm or 8 cm in length; the nitinol alloy SEMS used had the same width, length, and partial covering. The Wallflex is a recently developed stent with a proximal antimigration flare and is said to have an expansion force (radial) similar to that of the Wallstent, but to be more flexible, i. e., to have less axial force, defined as the force required to prevent a bent stent from becoming straight again [13]. It is constructed with a closed loop platinum-cored nitinol wire mesh with looped and flared antimigration ends, which are said to be less traumatic (i. e., probably causing less tissue reaction) than the open ends of " Fig. 2). the Wallstent (●
Randomization When their informed consent had been obtained, and if the patients met the inclusion criteria and displayed none of the exclu" Table 1), they were randomized, using the opaque sion criteria (● sealed envelope and computer-generated random numbers method, to one of two groups: the steel SEMS group or the nitinol SEMS group. The randomization process was done by one of the participating endoscopists in the ERCP suite; after the guidewire had been correctly placed, and the stricture had been passed, the stent was then inserted immediately. Blinding was not attempted, although the patient was not told what kind of SEMS he or she had received. If appropriate investigations (e. g. computed tomography [CT]) or patient evaluations (for possible radical surgery) had not yet been done, a temporary plastic stent might have been inserted. In such cases, then at a second session (as soon as possible but al-
Table 1 Nitinol versus steel partially covered self-expandable metal stent (SEMS) for malignant distal biliary obstruction: eligibility and exclusion criteria in a randomized trial.
Eligibility criteria – ≥ 20 years of age – Information given and informed consent obtained – Clinical data in accord with malignant bile duct obstruction – Bilirubin > 50 µmol/L (normal < 26 µmol/L) – Ultrasound and/or CT performed before inclusion. Findings in accord with malignant common bile duct obstruction – Typical radiological appearance of malignant common bile duct stenosis at ERCP – Proximal margin of malignant bile duct stenosis ≥ 2 cm from the hepatic confluence – Patient considered not suitable for radical surgery. If in doubt, temporary stenting with a plastic stent could be done, and the patient would still be eligible if they were randomized with replacement of the endoprosthesis by a metal stent within 4 weeks (see text). Exclusion criteria – Informed consent not obtained – Possible candidate for curative surgical resection – Active hepatitis or other hepatic diseases that may cause jaundice – Multiple hepatic metastases with significant blockage of one or more liver segments (if no segment blockage, metastasis is not an exclusion criterion) – Stenosis located within 2 cm from the hepatic confluence – Suspicion of nonmalignant bile duct obstruction – Severe coagulation disturbance (PK-INR > 1.6, normal 0.9 – 1.2) – Previous Billroth II or Roux-en-Y gastric resection, or a significant duodenal obstruction making ERCP difficult – Previous inclusion in the study CT, computed tomography; ERCP, endoscopic retrograde cholangiopancreatography; PK-INR, prothrombinkomplex-international normalized ratio
ways within 1 month) it was permitted to include the patient for randomization with the change of stent to an SEMS. This was similar to the procedures in previous trials by our group [3, 4]. Endoscopic sphincterotomy was performed routinely before stent insertion. The endoscopist decided what SEMS length to use, 4 cm, 6 cm or 8 cm. Positioning of the stent in the center of the stricture was encouraged and the SEMS should be visible in the duodenum. The central study nurse received by fax the randomization sheet and the initial CRF for her continued surveillance. She also visited every center at least twice to ensure that the protocol and the CRF were adhered to, including the follow-up.
Follow-up and endpoints We recorded all procedure-related adverse events according to current routine [14]. In order to confirm that the drainage procedure was successful, liver function test findings were obtained 2 – 5 days after stent insertion. The criteria for successful stent insertion included radiological confirmation at ERCP that the stent was in an adequate position and that at least a 30 % decline in bilirubin level was seen during the first 5 days after stent insertion.
Soderlund Claes et al. Partially covered nitinol versus steel selfxpandable metal stent for malignant distal biliary obstruction … Endoscopy 2014; 46: 941–948
This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.
942
Original article
Fig. 1 Nitinol versus steel partially covered selfexpandable metal stent (SEMS) for malignant distal biliary obstruction: CONSORT flowchart illustrating the progress of patients throughout the randomized controlled trial. (CONSORT, Consolidated Standards for Reporting Trials.)
Assessed for eligibility n = 857
Not randomized: n = 457 – Did not meet inclusion criteria: – Refused to participate: – Whipple resection: – Possible benign stenosis: – Failed cannulation: – Duodenal obstruction: – Multiple strictures or close to hilus:
943
63 15 100 31 50 37 161
Steel SEMS n = 200
Protocol violations: n = 31 – Wrong stent: – Multiple stents: – Bilirubin
