BASIL TRIALS Investigators Meeting, VSGBI, Manchester, 23 November - PowerPoint PPT Presentation

BASIL TRIALS Investigators’ Meeting, VSGBI, Manchester, 23 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

BASIL - HEFT PCS (screening log) 01/07/2014 to 31/10/2017 - 388 new SLI patients 185/388 (48%) IP +/- INFLOW disease Primary amputation Revascularisation attempted Conservative 29 (16%) 115 (62%) 39 (22%) 8 other surgery Randomised to B2 = 16 Vein bypass Endovascular Angioplasty x 5 (outside trial) (outside trial) 29 (25%) 62 (54%) Vein Bypass x 11 B3 randomising from 29/01/16 – 01/10/16 14% 143 patients screened with CLTI Randomised to B3 w/IP = 6 45/143 randomised to B3 (32%)

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

10 12 14 16 18 0 2 4 6 8 Current recruitment Jul-14 Aug-14 Sep-14 Oct-14 Recruitment Nov-14 Dec-14 Jan-15 Feb-15 Mar-15 Apr-15 May-15 Jun-15 Jul-15 Aug-15 Sep-15 Oct-15 Nov-15 Data up to 21 November 2017 Dec-15 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 N = 252 May-17 Jun-17 Jul-17 Aug-17 Sep-17 Oct-17 252 Nov-17 0 50 100 150 200 250 300

100 150 200 250 300 350 400 450 500 550 600 50 0 Target recruitment Aug-14 Oct-14 Dec-14 Feb-15 Apr-15 Jun-15 Aug-15 Oct-15 Dec-15 Feb-16 Projection Apr-16 Jun-16 Aug-16 Oct-16 Target Dec-16 Feb-17 Actual Apr-17 Jun-17 Aug-17 395 Oct-17 252 Dec-17 Feb-18 Apr-18 Jun-18 Aug-18 Oct-18 Dec-18

10 15 20 25 30 0 5 (39 out of a total 55) Only sites recruiting one or more patient shown St Thomas' Recruitment by centre 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 Queen Elizabeth Birmingham University Hospital Coventry (Walsgrave) Doncaster Royal Infirmary Wythenshawe, Manchester University Hospital Wales Preston North Durham Norfolk & Norwich Musgrove Park, Taunton Lincoln James Cook, Middlesbrough John Radcliffe Royal Cornwall (Treliske) Royal Sussex County Barts & The London Outreach Clinics Northwick Park Queen Alexandra Southampton General Worcestershire Royal York Health Services Trust

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

Evidence for DCB/DES in CLTI Most trials are industry sponsored Most patients are claudicants Most CLTI patients have rest pain only (Rutherford 4) Highly selected (centres, patients, lesions) Exclusions and short (incomplete) follow-up Few “head to head” comparisons Anatomic, not clinical, end-points No cost-effectiveness analysis UK NICE: no credible evidence of real world clinical benefit at current ‘willingness to pay’ thresholds; await BASIL-3 before recommending DCB/DES

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

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