Ignite Creation Date:
2024-05-05 @ 10:40 PM
Last Modification Date:
2024-10-26 @ 10:22 AM
Study NCT ID:
NCT01166685
Status:
COMPLETED
Last Update Posted:
2014-06-05
First Post:
2010-07-19
Brief Title:
Safety and Efficacy Study Comparing 3 New Types of Coronary Stents
Sponsor:
University Hospital Basel Switzerland
Organization:
University Hospital Basel Switzerland
Study Overview
Official Title:
Evaluation of Late Clinical Events After Drug-eluting Versus Bare-metal Stents in Patients at Risk BAsel Stent Kosten Effektivitäts Trial - PROspective Validation Examination Part II BASKET-PROVE II
Status:
COMPLETED
Status Verified Date:
2014-06
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
Background
Retrospective analyses of long-term BASKET findings identified patients with large drug-eluting stents DES 25mm Stents as patients at risk for late cardiac deathnonfatal myocardial infarction In view of new DES with absorbable polymers and new bare metal stents BMS with thin struts and biocompatible polymers BP-II will be launched to test their comparative clinical safety up to 12 years if treated with an aspirinprasugrel combination since prasugrel halved stent thrombosis rates compared to clopidogrel in a large ACS trial
The primary objective is to demonstrate non-inferiority of the Nobori DES stent compared to the Xience Prime DES stent on safety and e cacy in patients requiring stents 30mm in diameter on the background of contemporary dual antiplatelet therapy DAPT with prasugrel and aspirin
Set-up
Multicenter open-label randomized trial
Patient inclusion
Unselected series of patients in need of large 3mm stents only in native vessels irrespective of clinical indication
Patient exclusion
In-stent restenosis Left-main disease cardiogenic shock planned surgery 12months increased bleeding risk no compliance expected History of stroke or transient ischemic attack TIA
Randomization
By centre using sealed envelopes 111 NoboriXience PrimeProkinetik-stent
Retrospective analyses of long-term BASKET findings identified patients with large drug-eluting stents DES 25mm Stents as patients at risk for late cardiac deathnonfatal myocardial infarction In view of new DES with absorbable polymers and new bare metal stents BMS with thin struts and biocompatible polymers BP-II will be launched to test their comparative clinical safety up to 12 years if treated with an aspirinprasugrel combination since prasugrel halved stent thrombosis rates compared to clopidogrel in a large ACS trial
The primary objective is to demonstrate non-inferiority of the Nobori DES stent compared to the Xience Prime DES stent on safety and e cacy in patients requiring stents 30mm in diameter on the background of contemporary dual antiplatelet therapy DAPT with prasugrel and aspirin
Set-up
Multicenter open-label randomized trial
Patient inclusion
Unselected series of patients in need of large 3mm stents only in native vessels irrespective of clinical indication
Patient exclusion
In-stent restenosis Left-main disease cardiogenic shock planned surgery 12months increased bleeding risk no compliance expected History of stroke or transient ischemic attack TIA
Randomization
By centre using sealed envelopes 111 NoboriXience PrimeProkinetik-stent
Detailed Description:
Background and Study Design
The study is a multicentre prospective randomized open-label trial comparing safety and efficacy of the Nobori drug-eluting stent DES the Xience Prime DES and the ProKinetic bare-metal stent BMS in patients at low risk of restenosis ie receiving stents 30mm diameter only on the background of contemporary antiplatelet therapy
2289 patients were recruited at 8 centres in 5 countries and randomized 21 to DES or BMS and 11 to either DES subgroup Randomization was stratified according to centre
Analysis Datasets
The full analysis set FAS will include all randomized patients of whom written informed consent was obtained Patients needing an urgent PCI were asked for oral consent prior to the percutaneous coronary intervention PCI and for written informed consent afterwards This means that some randomized patients gave oral but not written informed consent Patients who gave oral informed consent and died before written informed consent could be obtained will be included in the FAS All other patients without signed informed consent will be excluded regardless of oral informed consent In accordance with the intention-to-treat principle all patients will be analysed according to the allocated treatment group
The per-protocol set PPS will include only those patients from the FAS who did not have one of the following major protocol violations
inclusion criteria not met
exclusion criteria met
procedures performed that were not approved by Institutional Review Board IRBEthics Committee EC
no study stent NoboriXience Prime or ProKinetic received
only stents 3mm in nominal size provided that the maximum vessel size measured during the procedure was 275mm
undergoing multiple step procedure with a different stent received than randomised for the second or subsequent step
Inclusion of patients older than 75 years was not approved by the local ethics committee of the Canton StGallen Switzerland and consequently age 75 years was added to the exclusion criteria for the center Cantonal Hospital St Gallen Patients who did not receive the randomly allocated stent but another study stent according to the study protocol will be included and analysed according to the stent received per protocol analysis
Demographic and Baseline Characteristics
Demographic and baseline data will be presented for each treatment arm using the FAS Continuous variables will be presented as mean standard deviation median 1st and 3rd quartile Categorical variables will be presented as frequencies and percentages Comparisons of continuous data will be done using a non-parametric Kruskal-Wallis rank sum test Comparisons of categorical data will be done using a chi-squared test if the expected number of observations in each cell exceeds 5 - otherwise Fishers exact test will be applied
Primary Objective
The primary objective is to demonstrate non-inferiority of the Nobori DES stent compared to the Xience Prime DES stent on safety and efficacy in patients requiring stents 30mm in diameter on the background of contemporary dual antiplatelet therapy DAPT with prasugrel and aspirin
Primary Endpoint
The primary endpoint is the time to the first major adverse cardiac event MACE observed within 24 months MACE is a composite endpoint including cardiac death myocardial infarction MI and target-vessel revascularization TVR
Statistical Hypothesis Model and Method of Analysis
Statistical Hypothesis
The statistical null-hypothesis is that Nobori DES is inferior to Xience Prime DES regarding the MACE rate pi at 24 months when using a prespecified non-inferiority margin delta in terms of absolute risk difference
H0 pi_Nobori - pi_XiencePrime delta
The alternate hypothesis is that the e ect of Nobori DES is non-inferior to Xience Prime DES using the same non-inferiority margin as above
alternate hypothesis HA pi_Nobori - pi_XiencePrime delta
We will use a non-inferiority margin of 38 absolute risk difference The sample size calculation was based on delta 38 assuming a MACE rate in the Xience Prime arm of 76 as observed in the BASKET-PROVE BP trial for both DES Kaiser et al 2010 The stated non-inferiority margin considers a 50 relative excess of events or more in the Nobori DES arm as inferior This threshold is similar to that of the LEADERS trial Windecker et al 2008
Statistical Model and Method of Analysis
The absolute risk difference of MACE at 24 months between the Nobori DES and the Xience Prime DES will be compared to the non-inferiority margin using a two-sided 95 confidence interval CI applying a continuity-corrected modification of the Wilsons score method Newcombe 1998 Non-inferiority will be declared if the upper limit of the 95 CI of the absolute risk difference does not exceed delta The probability of MACE within 24 months will be calculated and graphically visualized using the Kaplan-Meier estimator
We will estimate the hazard ratio of the Nobori DES versus the Xience Prime DES using Cox proportional hazards PH survival analysis allowing to test for superiority if non-inferiority can be established The model will contain the factor stent type Nobori DES vs Xience Prime DES and be stratified according to the variable centre Hazard ratios will be presented with the corresponding 95 CI
The proportional hazards assumption will be assessed in two steps 1 Visually through log-log curves and 2 Testing Schoenfelds residuals for time-dependency In case of non-proportional hazards a time-independent logistic regression model will be used to analyze the incidence of the primary endpoint within 24 months as binary variable
An additional landmark analysis will be performed for the time-intervals 0-12 months and 12-24 months We will t a time-strati ed Cox PH model including an interaction term between the factor stent type and time-interval 0-12 vs 12-24 months The interaction term will be compared to the null hypothesis of no-interaction using a log-likelihood ratio test
The analyses are performed on the PPS but see sensitivity analyses All tests will have a two-sided significance level alpha of 005
Handling of Data and Missing Values
Data will be analysed for potential extreme outliers If present each outlier will be investigated However outliers will be included in the analysis except if a clinical cause can be excluded There will be no missing values for the primary endpoint since losses to follow-up can be incorporated in the Cox proportional hazards models by censoring the time observed at the last follow-uplast contact date right censoring
Sensitivity Analyses
S1 All analyses will be repeated for the FAS It is important to note that for non-inferiority analyses estimates from intention-to-treat analyses are less conservative ie more likely to establish non-inferiority than those from per-protocol analyses since differences may be blurred by including patients with major protocol violations
S2 In the Cox PH model described for the primary endpoint we will test for an interaction between stent type and centre using a log-likelihood ratio test A significant interaction means differences in treatment-effect across centres This will determine whether the treatment-effect was homogeneous which is important for the interpretation of results
S3 In case of non-proportional hazards time-independent analyses using logistic regression will be performed for the prespecified time-periods 0-12 months and 0-24 months
Subgroup Analyses
We will investigate the effect of Nobori DES versus Xience Prime DES across the following prespecified subgroups
1 Diabetes yes vs no
2 Acute coronary syndrome ACS ACS vs stable coronary artery disease
3 Stent length per segment
4 At least one stent 30mm received yes vs no
5 More than one stented segment yes vs no
6 Prior myocardial infarction yes vs no
7 Smoking current yes vs no
8 Gender female vs male
Interaction terms between the factor stent type and each of the above factors will be included in the Cox regression model together with the main effects of stent type and the respective factor and compared to the null hypothesis of no-interaction using a log-likelihood ratio test A significant interaction means that the effect of treatment differs between subgroups
Secondary Objectives
A1 To demonstrate superiority of the Nobori DES over the ProKinetic BMS in terms of MACE within 24 months This comparison will also act as an internal control for the non-inferiority analysis primary objective with the ProKinetic BMS as a putative placebo
A2 To compare the Nobori DES to the ProKinetic BMS and the Nobori DES to the Xience Prime DES in terms of late harm cardiac death MI and stent thrombosis from month 12-24
B To compare the Nobori DES to the Xience Prime DES and the Nobori DES to the ProKinetic BMS in terms of additional secondary endpoints
C To investigate the safety - or possible harm - of DAPT with prasugrel and aspirin in patients with stable coronary artery disease CAD versus acute coronary syndromes ACS regarding bleeding events
D To assess the effect of DAPT with aspirin plus prasugrel versus aspirin plus clopidogrel as used in a historical comparator cohort with BASKET-PROVE BP
Secondary Endpoints
1 Components of the primary endpoint
Cardiac death
Myocardial infarction MI
Any MI
Non-fatal MI
Target vessel revascularization TVR
Any TVR
Non-MI related TVR
2 Composite safety endpoint of cardiac death and non-fatal MI
3 Stent thrombosis according to ARC definitions
Definite
Definite or probable
Definite probable or possible
4 Major bleeding including fatal bleeding ie BARC 3
5 All cause death
6 Net clinical benefit Primary endpoint plus major bleeding
Statistical Hypothesis Model and Method of Analysis
A1 Nobori DES versus ProKinetic BMS MACE within 24 months
The statistical null hypothesis is that there is no difference between Nobori DES and ProKinetic BMS in terms of MACE The Cox PH model described for the primary end-point which includes the factor stent type now compares Nobori DES to ProKinetic BMS In case of non-proportional hazards a logistic regression model will be used to analyze the incidence of MACE within 24 months
A2 Nobori DES versus ProKinetic BMS and Nobori DES versus Xience Prime DES Late harm
The statistical null hypothesis is that there is no difference between Nobori DES and Prokinetic BMS and no difference between Nobori DES versus Xience Prime DES in terms of late harm We will use a Cox PH model landmark analysis and a time-strati ed Cox PH model for the time-intervals 0-12 months and 12-24 months as described in for the primary objective for the endpoints cardiac death non-fatal MI and stent thrombosis Assessment of the proportional hazards assumption will be performed in accordance to the method described for the primary endpoint In case of non-proportional hazards logistic regression models will be used to analyze the incidence of events
B Nobori DES versus ProKinetic BMS and Nobori DES versus Xience Prime DES Other secondary endpoints
The statistical null hypothesis is that there is no difference between Nobori DES and ProKinetic BMS and Nobori DES and Xience Prime DES in terms of secondary endpoints All secondary endpoints 1-6 will be analysed using Cox PH models including the factor stent type and strati ed according to centre for events within 24 months - as specified for the primary endpoint Assessment of the proportional hazards assumption will be performed in accordance to the method described for the primary endpoint In case of non-proportional hazards logistic regression models will be used to analyze the incidence of events Landmark analyses at 0-12 and 12-4 months will be performed Absolute probabilities of the event of interest will be calculated and graphically visualized using the Kaplan-Meier estimator Subgroup analyses as specified for the primary endpoint will be performed for all secondary endpoints
C Safety of DAPT with prasugrel and aspirin in patients with stable CAD regarding bleeding events
For this analysis we will generate four subgroups based on stent type DES vs BMS and indication 1 DESStable CAD 2 DESACS 3 BMSStable CAD and 4 BMSACS The endpoints major bleeding BARC 3 MACE including its components and stent thrombosis see definitions in Section 51 will be analysed using Kaplan-Meier curves and a Cox PH model including the above groups as the 4-level factor indication-by-stent type and the stratifying factor centre Thereby we will make the following comparisons a DES-ACS vs DES-stable CAD b BMS-ACS vs BMS-stable CAD and c DES-stable CAD vs BMS-stable CAD In case of non-proportional hazards the survival analysis will be complemented by a time-independent logistic regression analysis on major bleeding events at 24 months as well as at a cut-o point of 12 months
D Comparison between BP II and BP regarding DAPT with prasugrel plus aspirin versus clopidogrel plus aspirin
Two separate comparisons between trials will be made in terms of major bleeding events BARC 3 MACE including its components and stent thrombosis see definitions in Section 51 using the FAS from both trials BP as presented in Kaiser et al 2010
Comparison 1
DAPT 12 months duration with prasugrel and aspirin in DES patients BP II versus DAPT 12 months duration with clopidogrel and aspirin in DES patients BP
The statistical null-hypothesis is that there are no differences in rates of major bleeding events between DAPT treatment with prasugrel plus aspirin as in BP II versus clopidogrel plus aspirin as in BP in patients treated with DES The endpoint major bleeding BARC 3 will be compared between all DES patients in BP II and all DES patients in
BP using a Cox PH model Because patient populations come from two different trials rather than from one single randomised trial a propensity score weighted analysis will be used to balance the data for confounding effects The predictors for the calculation of propensity scores will include potential confounders ie variables that may affect the treatment DAPT as determined by trial as well as the outcome occurrence of bleeding events such as age sex body weight renal function hypertension diabetes prior MI etc We will use inverse probability weighting Hernan Robins 2006 to estimate the e ect of DAPT on the hazard of bleeding The Cox PH model will include DAPT prasugrel vs clopidogrel and indication stable CAD vs ACS as predictors In addition the model will include the interaction between DAPT and indication to test whether the difference due to type of DAPT depends on indication Hazard ratios along with corresponding 95 CI will be presented If the two DES in BP II Nobori and Xience Prime should differ with regard to bleeding events MACE and stent thrombosis we will also include stent type as predictor Cypher and Xience in BP were very similar
Comparison 2
DAPT with prasugrel and aspirin 1 month duration BP II versus DAPT with clopidogrel and aspirin 12 months duration BP in stable CAD patients with BMS
The statistical null-hypothesis is that there are no differences in rates of major bleeding events between DAPT treatment with prasugrel plus aspirin as in BP II versus clopidogrel plus aspirin as in BP in stable CAD patients treated with BMS The endpoint major bleeding BARC 3 will be compared between stable CAD patients with BMS from BP II and stable CAD patients with BMS from BP using a Cox PH model As for comparison 1 a propensity score weighted analysis will be performed and an inverse probability weighting used to estimate the effect of DAPT on the hazard of bleeding Hazard ratios along with corresponding 95 CI will be presented
General
In case of non-proportional hazards the survival analysis will be complemented by a time-independent logistic regression analysis on bleeding events at 12 and 24 months estimating odds ratios instead of hazard ratios
53 Handling of Data and Missing Values
Data will be analysed for potential extreme outliers If present each outlier will be investigated However outliers will be included in the analysis except if a clinical cause can be excluded In case of missing values for secondary endpoints all available values will be used and no imputation of missing values will be performed
References
Hernan M A Robins J M 2006 Estimating causal e ects from epidemiological data J Epidemiol Community Health 60578-586
Kaiser C Galatius S Erne P Eberli F Alber H Rickli H Pedrazzini G Hornig B Bertel O Bonetti P De Servi S Brunner-La Rocca H-P Ricard I Pfisterer M 2010 Drug-eluting versus bare-metal stents in large coronary arteries New England Journal of Medicine 3632310-2319
Newcombe R G 1998 Interval estimation for the difference between independent pro-portions Comparison of eleven methods Statistics in Medicine 17873-890
Windecker S Serruys P W Wandel S Buszman P Trznadel S Linke A Lenk K Ischinger T Klauss V Eberli F et al 2008 Biolimus-eluting stent with biodegrad-able polymer versus sirolimus-eluting stent with durable polymer for coronary revascularisation leaders a randomised non-inferiority trial The Lancet 37296441163-1173
Clinical Relevance
The results of BPII will provide evidence for the performance of the newest-generation stents on the market in daily practice and insights about the efficacy and safety of current stent designs in an all-comer population Moreover BPII will assess the performance of DAPT with aspirin and prasugrel compared with aspirin plus clopidogrel in terms of ischemic and bleeding endpoints - Thus these findings should have major impact on the current use of coronary stents medical antiplatelet therapy regimes and our understanding of possible reasons for late stent thrombosis
The study is a multicentre prospective randomized open-label trial comparing safety and efficacy of the Nobori drug-eluting stent DES the Xience Prime DES and the ProKinetic bare-metal stent BMS in patients at low risk of restenosis ie receiving stents 30mm diameter only on the background of contemporary antiplatelet therapy
2289 patients were recruited at 8 centres in 5 countries and randomized 21 to DES or BMS and 11 to either DES subgroup Randomization was stratified according to centre
Analysis Datasets
The full analysis set FAS will include all randomized patients of whom written informed consent was obtained Patients needing an urgent PCI were asked for oral consent prior to the percutaneous coronary intervention PCI and for written informed consent afterwards This means that some randomized patients gave oral but not written informed consent Patients who gave oral informed consent and died before written informed consent could be obtained will be included in the FAS All other patients without signed informed consent will be excluded regardless of oral informed consent In accordance with the intention-to-treat principle all patients will be analysed according to the allocated treatment group
The per-protocol set PPS will include only those patients from the FAS who did not have one of the following major protocol violations
inclusion criteria not met
exclusion criteria met
procedures performed that were not approved by Institutional Review Board IRBEthics Committee EC
no study stent NoboriXience Prime or ProKinetic received
only stents 3mm in nominal size provided that the maximum vessel size measured during the procedure was 275mm
undergoing multiple step procedure with a different stent received than randomised for the second or subsequent step
Inclusion of patients older than 75 years was not approved by the local ethics committee of the Canton StGallen Switzerland and consequently age 75 years was added to the exclusion criteria for the center Cantonal Hospital St Gallen Patients who did not receive the randomly allocated stent but another study stent according to the study protocol will be included and analysed according to the stent received per protocol analysis
Demographic and Baseline Characteristics
Demographic and baseline data will be presented for each treatment arm using the FAS Continuous variables will be presented as mean standard deviation median 1st and 3rd quartile Categorical variables will be presented as frequencies and percentages Comparisons of continuous data will be done using a non-parametric Kruskal-Wallis rank sum test Comparisons of categorical data will be done using a chi-squared test if the expected number of observations in each cell exceeds 5 - otherwise Fishers exact test will be applied
Primary Objective
The primary objective is to demonstrate non-inferiority of the Nobori DES stent compared to the Xience Prime DES stent on safety and efficacy in patients requiring stents 30mm in diameter on the background of contemporary dual antiplatelet therapy DAPT with prasugrel and aspirin
Primary Endpoint
The primary endpoint is the time to the first major adverse cardiac event MACE observed within 24 months MACE is a composite endpoint including cardiac death myocardial infarction MI and target-vessel revascularization TVR
Statistical Hypothesis Model and Method of Analysis
Statistical Hypothesis
The statistical null-hypothesis is that Nobori DES is inferior to Xience Prime DES regarding the MACE rate pi at 24 months when using a prespecified non-inferiority margin delta in terms of absolute risk difference
H0 pi_Nobori - pi_XiencePrime delta
The alternate hypothesis is that the e ect of Nobori DES is non-inferior to Xience Prime DES using the same non-inferiority margin as above
alternate hypothesis HA pi_Nobori - pi_XiencePrime delta
We will use a non-inferiority margin of 38 absolute risk difference The sample size calculation was based on delta 38 assuming a MACE rate in the Xience Prime arm of 76 as observed in the BASKET-PROVE BP trial for both DES Kaiser et al 2010 The stated non-inferiority margin considers a 50 relative excess of events or more in the Nobori DES arm as inferior This threshold is similar to that of the LEADERS trial Windecker et al 2008
Statistical Model and Method of Analysis
The absolute risk difference of MACE at 24 months between the Nobori DES and the Xience Prime DES will be compared to the non-inferiority margin using a two-sided 95 confidence interval CI applying a continuity-corrected modification of the Wilsons score method Newcombe 1998 Non-inferiority will be declared if the upper limit of the 95 CI of the absolute risk difference does not exceed delta The probability of MACE within 24 months will be calculated and graphically visualized using the Kaplan-Meier estimator
We will estimate the hazard ratio of the Nobori DES versus the Xience Prime DES using Cox proportional hazards PH survival analysis allowing to test for superiority if non-inferiority can be established The model will contain the factor stent type Nobori DES vs Xience Prime DES and be stratified according to the variable centre Hazard ratios will be presented with the corresponding 95 CI
The proportional hazards assumption will be assessed in two steps 1 Visually through log-log curves and 2 Testing Schoenfelds residuals for time-dependency In case of non-proportional hazards a time-independent logistic regression model will be used to analyze the incidence of the primary endpoint within 24 months as binary variable
An additional landmark analysis will be performed for the time-intervals 0-12 months and 12-24 months We will t a time-strati ed Cox PH model including an interaction term between the factor stent type and time-interval 0-12 vs 12-24 months The interaction term will be compared to the null hypothesis of no-interaction using a log-likelihood ratio test
The analyses are performed on the PPS but see sensitivity analyses All tests will have a two-sided significance level alpha of 005
Handling of Data and Missing Values
Data will be analysed for potential extreme outliers If present each outlier will be investigated However outliers will be included in the analysis except if a clinical cause can be excluded There will be no missing values for the primary endpoint since losses to follow-up can be incorporated in the Cox proportional hazards models by censoring the time observed at the last follow-uplast contact date right censoring
Sensitivity Analyses
S1 All analyses will be repeated for the FAS It is important to note that for non-inferiority analyses estimates from intention-to-treat analyses are less conservative ie more likely to establish non-inferiority than those from per-protocol analyses since differences may be blurred by including patients with major protocol violations
S2 In the Cox PH model described for the primary endpoint we will test for an interaction between stent type and centre using a log-likelihood ratio test A significant interaction means differences in treatment-effect across centres This will determine whether the treatment-effect was homogeneous which is important for the interpretation of results
S3 In case of non-proportional hazards time-independent analyses using logistic regression will be performed for the prespecified time-periods 0-12 months and 0-24 months
Subgroup Analyses
We will investigate the effect of Nobori DES versus Xience Prime DES across the following prespecified subgroups
1 Diabetes yes vs no
2 Acute coronary syndrome ACS ACS vs stable coronary artery disease
3 Stent length per segment
4 At least one stent 30mm received yes vs no
5 More than one stented segment yes vs no
6 Prior myocardial infarction yes vs no
7 Smoking current yes vs no
8 Gender female vs male
Interaction terms between the factor stent type and each of the above factors will be included in the Cox regression model together with the main effects of stent type and the respective factor and compared to the null hypothesis of no-interaction using a log-likelihood ratio test A significant interaction means that the effect of treatment differs between subgroups
Secondary Objectives
A1 To demonstrate superiority of the Nobori DES over the ProKinetic BMS in terms of MACE within 24 months This comparison will also act as an internal control for the non-inferiority analysis primary objective with the ProKinetic BMS as a putative placebo
A2 To compare the Nobori DES to the ProKinetic BMS and the Nobori DES to the Xience Prime DES in terms of late harm cardiac death MI and stent thrombosis from month 12-24
B To compare the Nobori DES to the Xience Prime DES and the Nobori DES to the ProKinetic BMS in terms of additional secondary endpoints
C To investigate the safety - or possible harm - of DAPT with prasugrel and aspirin in patients with stable coronary artery disease CAD versus acute coronary syndromes ACS regarding bleeding events
D To assess the effect of DAPT with aspirin plus prasugrel versus aspirin plus clopidogrel as used in a historical comparator cohort with BASKET-PROVE BP
Secondary Endpoints
1 Components of the primary endpoint
Cardiac death
Myocardial infarction MI
Any MI
Non-fatal MI
Target vessel revascularization TVR
Any TVR
Non-MI related TVR
2 Composite safety endpoint of cardiac death and non-fatal MI
3 Stent thrombosis according to ARC definitions
Definite
Definite or probable
Definite probable or possible
4 Major bleeding including fatal bleeding ie BARC 3
5 All cause death
6 Net clinical benefit Primary endpoint plus major bleeding
Statistical Hypothesis Model and Method of Analysis
A1 Nobori DES versus ProKinetic BMS MACE within 24 months
The statistical null hypothesis is that there is no difference between Nobori DES and ProKinetic BMS in terms of MACE The Cox PH model described for the primary end-point which includes the factor stent type now compares Nobori DES to ProKinetic BMS In case of non-proportional hazards a logistic regression model will be used to analyze the incidence of MACE within 24 months
A2 Nobori DES versus ProKinetic BMS and Nobori DES versus Xience Prime DES Late harm
The statistical null hypothesis is that there is no difference between Nobori DES and Prokinetic BMS and no difference between Nobori DES versus Xience Prime DES in terms of late harm We will use a Cox PH model landmark analysis and a time-strati ed Cox PH model for the time-intervals 0-12 months and 12-24 months as described in for the primary objective for the endpoints cardiac death non-fatal MI and stent thrombosis Assessment of the proportional hazards assumption will be performed in accordance to the method described for the primary endpoint In case of non-proportional hazards logistic regression models will be used to analyze the incidence of events
B Nobori DES versus ProKinetic BMS and Nobori DES versus Xience Prime DES Other secondary endpoints
The statistical null hypothesis is that there is no difference between Nobori DES and ProKinetic BMS and Nobori DES and Xience Prime DES in terms of secondary endpoints All secondary endpoints 1-6 will be analysed using Cox PH models including the factor stent type and strati ed according to centre for events within 24 months - as specified for the primary endpoint Assessment of the proportional hazards assumption will be performed in accordance to the method described for the primary endpoint In case of non-proportional hazards logistic regression models will be used to analyze the incidence of events Landmark analyses at 0-12 and 12-4 months will be performed Absolute probabilities of the event of interest will be calculated and graphically visualized using the Kaplan-Meier estimator Subgroup analyses as specified for the primary endpoint will be performed for all secondary endpoints
C Safety of DAPT with prasugrel and aspirin in patients with stable CAD regarding bleeding events
For this analysis we will generate four subgroups based on stent type DES vs BMS and indication 1 DESStable CAD 2 DESACS 3 BMSStable CAD and 4 BMSACS The endpoints major bleeding BARC 3 MACE including its components and stent thrombosis see definitions in Section 51 will be analysed using Kaplan-Meier curves and a Cox PH model including the above groups as the 4-level factor indication-by-stent type and the stratifying factor centre Thereby we will make the following comparisons a DES-ACS vs DES-stable CAD b BMS-ACS vs BMS-stable CAD and c DES-stable CAD vs BMS-stable CAD In case of non-proportional hazards the survival analysis will be complemented by a time-independent logistic regression analysis on major bleeding events at 24 months as well as at a cut-o point of 12 months
D Comparison between BP II and BP regarding DAPT with prasugrel plus aspirin versus clopidogrel plus aspirin
Two separate comparisons between trials will be made in terms of major bleeding events BARC 3 MACE including its components and stent thrombosis see definitions in Section 51 using the FAS from both trials BP as presented in Kaiser et al 2010
Comparison 1
DAPT 12 months duration with prasugrel and aspirin in DES patients BP II versus DAPT 12 months duration with clopidogrel and aspirin in DES patients BP
The statistical null-hypothesis is that there are no differences in rates of major bleeding events between DAPT treatment with prasugrel plus aspirin as in BP II versus clopidogrel plus aspirin as in BP in patients treated with DES The endpoint major bleeding BARC 3 will be compared between all DES patients in BP II and all DES patients in
BP using a Cox PH model Because patient populations come from two different trials rather than from one single randomised trial a propensity score weighted analysis will be used to balance the data for confounding effects The predictors for the calculation of propensity scores will include potential confounders ie variables that may affect the treatment DAPT as determined by trial as well as the outcome occurrence of bleeding events such as age sex body weight renal function hypertension diabetes prior MI etc We will use inverse probability weighting Hernan Robins 2006 to estimate the e ect of DAPT on the hazard of bleeding The Cox PH model will include DAPT prasugrel vs clopidogrel and indication stable CAD vs ACS as predictors In addition the model will include the interaction between DAPT and indication to test whether the difference due to type of DAPT depends on indication Hazard ratios along with corresponding 95 CI will be presented If the two DES in BP II Nobori and Xience Prime should differ with regard to bleeding events MACE and stent thrombosis we will also include stent type as predictor Cypher and Xience in BP were very similar
Comparison 2
DAPT with prasugrel and aspirin 1 month duration BP II versus DAPT with clopidogrel and aspirin 12 months duration BP in stable CAD patients with BMS
The statistical null-hypothesis is that there are no differences in rates of major bleeding events between DAPT treatment with prasugrel plus aspirin as in BP II versus clopidogrel plus aspirin as in BP in stable CAD patients treated with BMS The endpoint major bleeding BARC 3 will be compared between stable CAD patients with BMS from BP II and stable CAD patients with BMS from BP using a Cox PH model As for comparison 1 a propensity score weighted analysis will be performed and an inverse probability weighting used to estimate the effect of DAPT on the hazard of bleeding Hazard ratios along with corresponding 95 CI will be presented
General
In case of non-proportional hazards the survival analysis will be complemented by a time-independent logistic regression analysis on bleeding events at 12 and 24 months estimating odds ratios instead of hazard ratios
53 Handling of Data and Missing Values
Data will be analysed for potential extreme outliers If present each outlier will be investigated However outliers will be included in the analysis except if a clinical cause can be excluded In case of missing values for secondary endpoints all available values will be used and no imputation of missing values will be performed
References
Hernan M A Robins J M 2006 Estimating causal e ects from epidemiological data J Epidemiol Community Health 60578-586
Kaiser C Galatius S Erne P Eberli F Alber H Rickli H Pedrazzini G Hornig B Bertel O Bonetti P De Servi S Brunner-La Rocca H-P Ricard I Pfisterer M 2010 Drug-eluting versus bare-metal stents in large coronary arteries New England Journal of Medicine 3632310-2319
Newcombe R G 1998 Interval estimation for the difference between independent pro-portions Comparison of eleven methods Statistics in Medicine 17873-890
Windecker S Serruys P W Wandel S Buszman P Trznadel S Linke A Lenk K Ischinger T Klauss V Eberli F et al 2008 Biolimus-eluting stent with biodegrad-able polymer versus sirolimus-eluting stent with durable polymer for coronary revascularisation leaders a randomised non-inferiority trial The Lancet 37296441163-1173
Clinical Relevance
The results of BPII will provide evidence for the performance of the newest-generation stents on the market in daily practice and insights about the efficacy and safety of current stent designs in an all-comer population Moreover BPII will assess the performance of DAPT with aspirin and prasugrel compared with aspirin plus clopidogrel in terms of ischemic and bleeding endpoints - Thus these findings should have major impact on the current use of coronary stents medical antiplatelet therapy regimes and our understanding of possible reasons for late stent thrombosis
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None