BASIL TRIALS BSIR, Birmingham, 2 November 2017 Introduction - PowerPoint PPT Presentation

BASIL TRIALS BSIR, Birmingham, 2 November 2017

Introduction Professor Andrew Bradbury BASIL-2 and 3 Chief Investigator

BASIL-1 Trial • Still the only RCT! • NIHR HTA funding 1998 • Between 1999 and 2003 • 452 SLI patients randomised : • Bypass first (25% prosthetic ) • PBA first (6 stents ) • 75% femoro-popliteal • After 2 years – (vein) bypass better than PBA in terms of: • Amputation free survival • Overall survival • Quality of revascularisation

BASIL- 1: the usual interpretation Patient with SLI due to femoro-popliteal (FP) disease Anticipated life expectancy? < 2 years? > 2 years? Vein? No Angioplasty Yes Bypass

NICE Research Recommendations CLTI recommendations based on BASIL- 1, but… What about infra- popliteal disease? What about drug coated balloons and eluting stents?

BASIL 2/3 Co-applicants Southampton (Professor Shearman, Dr Odurny) VSGBI St George’s (Mr Hinchliffe and Professor Belli) Imperial (Professor Davies, Dr Burfitt) Oxford (Mr Perkins, Dr Uberoi ) BSIR Birmingham / WM (Mr Claridge, Dr Ganeshan) Leicester (Professor Naylor, Dr Adair) ESVS Hull (Professor Chetter, Professor Ettles) Leeds (Professor Scott, Dr Patel) CF Sheffield (Professor Beard, Dr Cleveland ) Newcastle (Professor Stansby, Dr Jackson) Diabetes-UK Scotland (Professor Brittenden, Mr Stuart)

£2.02m http://www.nets.nihr.ac.uk/projects/hta/123545 http://www.nets.nihr.ac.uk/projects/hta/138102 £2.54m

BASIL-2 – infra-popliteal (IP) SLI Vein Bypass first Best Endovascular (n = 300) Treatment first (n = 300) BASIL-3 – femoro-popliteal (FP) SLI DES PBA DCB (n = 282) +/- BMS +/- BMS (n = 282) (n = 282) Follow-up 24-60 months Quality of revascularisation Quality of life Amputation free survival Functional status Overall Survival Health economic Clinical end-points

The academic case for Mr Matthew Popplewell University of Birmingham BASIL-2 Research Fellow

Why BASIL-2? “Why do we need BASIL -2 when it is obvious that endovascular revascularisation is the best strategy for almost all patients requiring infra-popliteal intervention for SLI?”

Current best evidence Plain Balloon Angioplasty Immediate technical success of IP angioplasty of 89% (pooled estimate) Outcomes suboptimal at 12-months Mortality 15.1% Major Amputation 14.9% Primary patency 63.1% Re-intervention rate 18.2%

BASIL-1 IP Subgroup Analysis

BASIL-1 IP: overall survival N only 104 but P = 0.06 Vein bypass D 18% HR=0.60, 95% CI: 0.36-1.02 PBA D 22%

BASIL-1 IP: amputation free survival HR=0.68, 95% CI: 0.42-1.10, p = 0.1 Vein bypass D 21% PBA

BASIL-1 IP: relief of rest pain HR=2.19, 95% CI: 1.27-2.78, p=0.005 Vein bypass D 28% PBA

BASIL-1 IP: time to wound healing HR=1.69, 95% CI: 0.88-3.26, p=0.1 D17 % Vein bypass PBA

BASIL-1 IP: Statistical Interpretation While the BASIL-1 results do not meet standard criteria for statistical significance, the direction of the effect consistently favours bypass and confidence intervals rule out the possibility of clinically important effects in favour of balloon angioplasty

BASIL-1 outcomes outdated? NO , despite fewer technical failures, AFS and OS after IP BASIL-1 P = 0.3 endovascular Contemporary Amputation free survival intervention in our unit (HEFT) are currently ( 2009-2014 ) P = 0.2 no better than those BASIL-1 observed in Overall Survival BASIL-1 ( 1999-2004 ) Contemporary

Why BASIL-2? Because , there is no evidence to support endovascular intervention as the preferred treatment for SLI due to IP disease in patients who can have a vein bypass Indeed, what data we have indicates that endovascular is unlikely to be better and should usually be reserved for those who cannot have distal vein bypass

Recruitment update Lucy Casley University of Birmingham BASIL-2 Trial Co-ordinator

Current recruitment 10 12 14 16 18 0 2 4 6 8 Jul-14 Sep-14 Cumulative Recruitment Nov-14 Jan-15 Mar-15 Data up to 31 st October 2017 May-15 Jul-15 Sep-15 Nov-15 Jan-16 Mar-16 May-16 Jul-16 Sep-16 Nov-16 Jan-17 Mar-17 May-17 Jul-17 Sep-17 249 0 50 100 150 200 250 300

Target recruitment 100 150 200 250 300 350 400 450 500 550 600 50 0 Aug-14 Nov-14 Feb-15 May-15 Aug-15 Nov-15 Projection Feb-16 May-16 Aug-16 Target Nov-16 Feb-17 Actual May-17 Aug-17 249 380 Nov-17 Feb-18 May-18 Aug-18 Nov-18

recruit at least one patient Only 39 out of a total 55 centres have been able to 10 15 20 25 30 0 5 Recruitment by centre St Thomas' Hull Royal Infirmary Bham Heartlands Leeds General Infirmary Sodersjukhuset Manchester Royal Infirmary Russells Hall Royal Gwent Royal Free Leicester Royal Infirmary Southmead St Mary's Freeman Kent & Canterbury Kolding St George's Western Infirmary Pilgrim Frimley Park Northern General Royal Bournemouth Addenbrooke's Cheltenham & Gloucester Forth Valley, Stirling Edinburgh Royal Infirmary Bradford Blackburn Aberdeen Royal Infirmary Aalborg, Denmark Centres opened but that have not recruited City Birmingham Colchester General Cumberland Infirmary Ninewells Royal Oldham University Hospital Coventry (Walsgrave) Doncaster Royal Infirmary John Radcliffe Queen Elizabeth Birmingham Wythenshawe, Manchester University Hospital Wales North Durham Norfolk & Norwich Musgrove Park, Taunton James Cook, Middlesbrough Royal Cornwall (Treliske) Royal Sussex County Barts & The London Outreach Clinics Northwick Park Queen Alexandra Southampton General Worcestershire Royal York Health Services Trust

Outcomes: whole cohort Amputation free and overall survival observed in BASIL-2 are Amputation free survival (primary outcome measure) currently in line with those used in the sample size calculations which were based on BASIL-1 outcome data Overall survival (secondary outcome measure)

The academic case for Mr Lewis Meecham University of Birmingham BASIL-3 Research Fellow

Why do we need BASIL-3? “There are already randomised controlled trials between drug eluting technology and plain balloon angioplasty and we ‘know’ the outcomes are better, why do we need a new trial?”

Drug coated balloon Trial Device End Points Patients PACIFIER IN.PACT pacific Radiological – DCB N= 91 (1:1) (Medtronic) (2016) Clinical – No difference Claud = 87 LEVANT 2 Lutonix Radiological – DCB N=476 (2:1) (Bard) (2015) Clinical – No difference Claud = 438 BIOLUX P-1 Passeo-18 LUX Radiological – DCB N = 52 (1:1) (Biotronik) (2015) Clinical – No difference Claud = 50 IN.PACT SFA IN.PACT admiral Radiological – DCB N=331 (2:1) (Medtronic) (2015) Clinical – No difference Claud = 313 THUNDER Standard Balloon coated Radiological – DCB N = 102 (1:1) (2014) with Paclitaxel Clinical – No difference Claud = 82 LEVANT 1 Lutonix Radiological – DCB N = 92 (1:1) (Bard) (2014) Clinical – No difference Claud = 94 DEBELLUM IN.PACT admiral Radiological – DCB N = 50 (1:1) (Medtronic) (2012) Clinical – No difference Claud = 45 FemPac Coated PTA Balloon Radiological – DCB N = 87 (1:1) (Bavaria MT GmbH) (2008) Clinical – No difference Claud = 82

Drug eluting stent Trial Device End Points Patients 1 ° Patency (12m) – 83.1% vs 32.8% ZILVER PTX ZILVER PTX DES=241 PBA=238 (2011) (COOK) FF TLR – 90.5% vs 82.5% R2/3 - 91% Amputation – 0% vs 0% R4-6 – 9% Overall survival 100% vs 100% Some other stent trials comparing DES vs BMS in femoro-popliteal segment: • Duda et al. 2002 • Duda et al. 2006 SIROCCO trial Majority of DES trials in the infra-popliteal segment: • Rastan et al. 2012 • Scheinert et al. 2012 • Tepe et al 2010 BELOW study • Falkowski et al. 2009 • Siablis et al. 2014 IDEAS trial

DCB/DES trials Almost all industry sponsored Almost all claudicants CLI almost all rest pain only Highly selected (centres, patients, lesions) Exclusions and short (incomplete) follow-up Anatomic end-points No credible evidence of real world clinical benefit (Some evidence of possible harm?) No cost-effectiveness analysis NICE unconvinced (2012, 2017) – await BASIL

Has technical success improved? Technical Success of FP PTA in BASIL-1 (1999- 2003) vs contemporary series (2009-2013) 100% 80% 60% 40% 20% 0% B1 Endo CS Endo yes no p = 0.196

Amputation free survival after femoro-popliteal plain balloon angioplasty in BASIL-1 and in a contemporary series at HEFT BASIL-1 (1999-2003) D27 % Current outcomes highly significantly HEFT (2009-2013) worse than BASIL-1 (p = 0.0005) Years of follow-up

AFS in BASIL 2 and 3

Recruitment update Mr Hugh Jarrett University of Birmingham BASIL-3 Senior Trial Co-ordinator

Current recruitment 300 260 250 200 150 100 50 36 36 24 24 24 23 23 22 22 21 21 20 19 18 17 17 16 16 14 14 14 13 13 13 12 12 10 10 9 9 9 8 8 7 6 4 4 4 3 3 2 2 1 0 0 Jan-16 Feb-16 Mar-16 Apr-16 May-16 Jun-16 Jul-16 Aug-16 Sep-16 Oct-16 Nov-16 Dec-16 Jan-17 Feb-17 Mar-17 Apr-17 May-17 Jun-17 Jul-17 Aug-17 Sep-17 Oct-17 Actual Target Cummulative