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FF ractional Flractional Fl oo w w ReRe serve Derived from serve Derived from CComputed omputed Tomography Coronary Tomography Coronary AAngiography in the Assessment & ngiography in the Assessment &

Management of Management of StSt able Chest Painable Chest Pain

N CurzenN Curzen , Z Nicholas, B Stuart, S Wilding, K Hill, J Shambrook, Z Eminton, D Ball, C Barrett, L Johnson, , Z Nicholas, B Stuart, S Wilding, K Hill, J Shambrook, Z Eminton, D Ball, C Barrett, L Johnson, J Nuttall, K Fox, D Connolly, P O’Kane, A Hobson, A Chauhan, N Uren, G McCann, C Berry, J Carter, J Nuttall, K Fox, D Connolly, P O’Kane, A Hobson, A Chauhan, N Uren, G McCann, C Berry, J Carter,

C Roobottom, M Mamas, R Rajani, I Ford, P Douglas, M Hlatky C Roobottom, M Mamas, R Rajani, I Ford, P Douglas, M Hlatky

on behalf of the FORECAST Investigators.on behalf of the FORECAST Investigators.

NCT03187639NCT03187639

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Conflicts of Interest

FORECAST is an investigator-initiated trial

NC applied for & was awarded an unrestricted research grant from HeartFlow …

The company had no formal role in the design, prosecution, data collection, analysis of the trial

The sponsor for FORECAST is R&D Department, University Hospital Southampton NHS FT

NC has received speaker fees and travel sponsorship from HeartFlow in the last 3 years

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BACKGROUND

§ There is wide variation in practice in the assessment of stable new onset chest pain

§ There is value in determining the presence of both atheroma (anatomy) & ischaemia (physiology)…

§ Most commonly used tests focus on only 1 of these parameters

§ FFR CT is a well validated test that provides both anatomical & physiological information non-invasively 1-3

§ FFR CT utilises the output from CTCA & derives FFR in major epicardial vessels using FD & 3D modelling

1J Am Coll Cardiol . 2011;58(19):1989-1997

2 JAMA. 2012;308(12):1237-1245

3 J Am Coll Cardiol . 2014;63(12):1145-1155

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BACKGROUND 2

§ In the PLATFORM study 4, CTCA with FFR CT resulted in a 61% reduction in the need for ICA compared with routine care

§ In a prespecified economic analysis of PLATFORM 5, CTCA+FFR CT was associated with significantly lower cost thanroutine care in the cohort assigned to ICA, but not in the cohort assigned to non-invasive assessment

§ In FFR CT RIPCORD 6, the availability of FFR CT led to a change in management in 36% of 200 cases cf CTCA alone

§ In the ADVANCE Registry 7, the rate of unobstructed coronaries at ICA was 14.4% in patients with FFR CT <0.8 vs.43.8% in those with FFR CT>0.8 (p<0.001)

§ In the UK, NICE Technology Appraisal 8

4 Eur Heart J . 2015;36(47):3359-3367

7 Eur Heart J . 2018;39(41):3701-3711

6 JACC Cardiovasc Imaging . 2016;9(10):1188-1194

5 J Am Coll Cardiol . 2015 Dec 1;66(21):2315-23

8 NICE Medical Technologies Guidance MTG32, Feb 2017

No randomized trial has compared FFR CT with routine assessment as the initial testing strategy

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TRIAL RATIONALE: Why is resource utilisation the primary endpoint?

Previous data suggest that FFRPrevious data suggest that FFR CTCT will reduce ICA without increased rates will reduce ICA without increased rates of death, MI or revascularisation… of death, MI or revascularisation…

BUT: BUT: will it be cost effective as an initial strategy in patients with will it be cost effective as an initial strategy in patients with stable chest pain?stable chest pain?

§ Evidence so far from non-randomized clinical studies suggests that FFR CT:-reduces rate of ICA & reduces ICA showing no significant CAD-is associated with lower costs… ? But only in those allocated to an invasive strategy?-is not associated with an increase in ischaemic events in the FFR CT patient cohorts (ie it is SAFE)

§ NICE recommends CTCA+FFR CT as a frontline test that is clinically effective and will save money

§ NHS Innovation & Technology Payment Scheme invests in FFR CT for front line clinical practice

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STUDY HYPOTHESIS & PRIMARY OBJECTIVE

To determine whether, in a population of patients presenting to Rapid Access Chest Pain Clinics (RACPC) in the To determine whether, in a population of patients presenting to Rapid Access Chest Pain Clinics (RACPC) in the UK, routine CTCA+FFRUK, routine CTCA+FFR CTCT as a default test is superior, in terms of as a default test is superior, in terms of resource utilisationresource utilisation , , when compared with routine clinical pathway algorithms recommended by NICE CG95when compared with routine clinical pathway algorithms recommended by NICE CG95

STUDY SECONDARY OBJECTIVES

1. To compare clinical outcomes between the 2 groups at 9 months2. To compare the effect on general wellbeing between the 2 groups at 9 months

Sample Size Calculation

Based upon PLATFORM cost analysis… randomizing 700 patients in each group would provide 90% power to detect 20% difference in costs

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METHOD

• Randomised controlled trial• 1400 patients attending RACPC in 11 UK centres

Primary Endpoint: Resource Utilisation at 9 months-non-invasive cardiac tests-invasive angiography-revascularization-hospitalization for cardiac event-cardiac meds-outpatient attendances

Secondary Endpoints : Clinical -MACCE (All cause mortality, non fatal MI, CVA)-Death + MI + CVA + unplanned revasc + cardiac hospitalization-Requirement for non-invasive cardiac tests-Requirement for ICA-procedural complications

Secondary Endpoints : QOL/Health -QOL-Patient satisfaction-angina status-time to definitive management plan-time to completion of initial management plan

Inclusion Criteria-age >18 yrs-chest pain deemed to require investigation

Exclusion Criteria-unstable angina or ACS -prior PCI/CABG-new onset AF-contraindications to CTCA-prosthetic valve-life expectancy<12 months

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METHOD 2

“Those patients with a coronary stenosis of >40% in at least one major epicardial vessel of stentable/graftable diameter will be referred for FFR CT. (NB Lesions in distal vessels beyond the reach of stents or grafts or vessels of a diameter not suitable for stenting/grafting will not qualify for FFR CT if there are no other more significant lesions ).“

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RESULTS: CONSORT & DEMOGRAPHICS

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RESULTS

N=699

Test Arm

FFR CT performed? Yes 220 (31.5%)No 479 (68.5%)

Reason not performed?No CTCA done 25 (5.2%)No lesion >40% 415 (86.6%)Not analysable 39 (8.2%)

Any FFR CT <0.8 57.3%

FFR CT result used in Mx plan? 98.2%

ICA after FFR CT? 100 (45.5%)

Non-invasive test after FFR CT? 14 (6.4%)

Initial Tests Undertaken

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RESULTS: 9 month tests & revascularisation

§ 14% lower total ICA in test vs. reference group (p=0.02)

§ 22% fewer patients had ICA in test vs reference group(p=0.01)

Data are numbers of tests (number of patients)

66% 96%

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RESULTS: PRIMARY ENDPOINT

TOTAL CARDIAC COSTSTOTAL CARDIAC COSTS

RESULTS: SECONDARY CLINICAL ENDPOINT

MACCE/CLINICAL EVENTS

• Metastatic lung Ca

• Community acquired pneumonia

Reference Group Test Group

RESULTS: SECONDARY CLINICAL ENDPOINT

QoL/Angina status

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LIMITATIONS

§ The cut off for sending patients for FFR CT of > 40% stenosis was pragmatic

§ The proportion of patients in the Reference arm undergoing CTCA increased through the recruitment period, as anticipated from CG95 NICE guidelines, but at a rate of rise that was impossible to model at the start of the trial

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CONCLUSION

In patients presenting with new onset stable CP, a strategy of CTCA with FFRIn patients presenting with new onset stable CP, a strategy of CTCA with FFR CTCT ,, when compared with a strategy of routine care: when compared with a strategy of routine care:

üü dd id not id not significantly reduce costs in the NHS systemsignificantly reduce costs in the NHS system

üü is associated with a significantly lower rate of invasive angiography (22%)is associated with a significantly lower rate of invasive angiography (22%)

üü is not is not associated with significantly different rates of associated with significantly different rates of MACCE or revascularisationMACCE or revascularisation

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ACKNOWLEDGEMENTS

Site PI Main RN contactBirminghamBirmingham Dr Derek Connolly Ashley Turner

BlackpoolBlackpool Prof Anoop Chauhan Stephen Preston

BournemouthBournemouth Dr Peter O’Kane Nicki Wells

EdinburghEdinburgh Prof Neal Uren Belinda Rif

GlasgowGlasgow Prof Colin Berry Andrew Dougherty

LeicesterLeicester Prof Gerry McCann Debbie Lee (CRP)

North TeesNorth Tees Dr Justin Carter Julie Quigley

PlymouthPlymouth Prof Carl Roobottom Julie Alderton

PortsmouthPortsmouth Dr Alex Hobson Charlotte Turner

SouthamptonSouthampton Prof Nick Curzen Zoe Duke

StokeStoke Prof Mamas Mamas Ian Massey

Zoe Nicholas – Project ManagerCoronary Research Group, UHS

Trial Steering Committee

Prof K Fox (Chair)Prof I Ford (statistics)

Prof Pam DouglasDr Ronak Rajani

Mr J Mostyn (Patient rep)Mrs B Stuart (Senior Trial Statistician, CTU)

Mrs Z Eminton (CTU)Mr D Ball (CTU)

Miss Z Nicholas (Project Manager)Co-opted: Prof N Curzen (Chief Investigator)

Trial Management Committee

Prof N Curzen (Chair)Z Eminton (CTU)

D Ball (CTU)Miss Z Nicholas (Project Manager)

B Stuart (Senior Trial Statistician, CTU)S Wilding (Statistician, CTU)

L Johnson (Trial data Coordinator, CTU)Prof Colin Berry (co-PI)Mr I Harris (Patient Rep)

Prof M Hlatky (Resource Utilisation Model)Prof A Zaman

K Hill, (Statistician, CTU)Dr A Cook (Public Health, CTU)

Research& Development

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Reserve Slides

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