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FRACTIONAL FLOW RESERVE CLINICAL STUDY COMMITMENT

Contents: (click title to navigate)

CONTRAST: Highlights . . . . . . . . . . . . . . . . 2 Clinical Summary . . . . . . . . . . 3 DEFER: Highlights . . . . . . . . . . . . . . . . 4 Clinical Summary . . . . . . . . . . 5

Version 0 .6, July 2015 . This PDF has been optimized for use with Adobe Acrobat Reader .® Navigation and other functionality may be limited in other applications .

2012–2015

Future

Past

DEFERIt is safe to defer non-ischemic stenosis based on FFR ≥ 0.75.

FAMEFFR-guided PCI reduced mortality and MI at two years by 34%.

FAME 2FFR-guided PCI + OMT subjects had a 77% reduction in the risk of urgent revascularization vs. patients receiving OMT alone.

DEFER 15-Year Follow-up Stenting a non-ischemic stenosis has no benefit compared to medical therapy.

FAMOUS NSTEMI Angio-guided management showed higher rates of revascularization compared with FFR-guided management.

CONTRAST Contrast FFR is superior to resting Pd/Pa and iFR™ assessment for predicting FFR.

PRIMULTI FFR-guided revascularization of MVD in STEMI patients resulted in lower risk of primary composite endpoint vs. standard care.

FAME 3 Compare FFR-guided PCI of MVD with angio-guided CABG.

Compare-ACUTE FFR FFR-guided PCI in MVD STEMI

FAMOUS STEMI Compare FFR to angio in non-culprit lesions in STEMI patients

POST-IT/R3F FFR guided Dx vs. angio-guided Dx

FFR/ACS Registry

Resting Indices Registry Pd/Pa, cFFR, and Pd/Pa Min

References Brief Summary

CONTRAST DATA ››CONTRAST HIGHLIGHTS ›› DEFER HIGHLIGHTS ›› DEFER DATA ›› ABBREVIATIONS ››

1 FORWARD

CLINICAL HIGHLIGHTS FROM THE CONTRAST STUDY1

Hyperemic FFR remains the reference standard for diagnostic accuracy.

Contrast FFR is superior to resting Pd/Pa and iFR™ assessment for predicting FFR.

Resting Pd/Pa and iFR™ assessment provide equivalent diagnostic accuracy.

#1 #2 #3

65%

80%

85%

85-95%

100%

Angio Alone6

Contrast FFR1

Hybrid Approach 2-5

FFR (IV/IC Adenosine†)

Pd/Pa and iFR™ Single Cutoff2,4

DIAG

NOST

IC AC

CURA

CY

0

20

40

60

80

100

RESOLVE2 ADVISE II3,4

Accu

racy

Com

pare

d to

FFR

(%)

VERIFY 27 CONTRAST 1

Pd/Pa iFR™ Assessment

100 90 10080 806040200

0 0

20 20

40 40

60 60

80 80

100 100

Binary Approach1 = No Adenosine Used

Hybrid Approach1 = Selective Adenosine Used

True

Pos

itive

s (%

)

False Positives (%)

Contrast FFR = 0.929

Contrast FFR

iFR™ Assessment

= 0.879iFR™

Assessment

Pd/Pa = 0.874 Pd/Pa

Accuracy (%)

Free

dom

from

Ade

nosin

e (%

)

†Prior to using hyperemic agents, please review the Instructions for Use for a complete listing of indications, contraindications, warnings, precautions, potential adverse events and directions.References Brief Summary


BACK 2 FORWARD

CONTRAST HIGHLIGHTS

Quality assessment, then: Pd/Pa, iFR™ assessment,

cFFR, FFR

Tracings blinded and sent to central

CRF core lab

Rest, IC contrast, IC adenosine, IV adenosine

(each repeated), plus drift check

750 patients undergoing clinical

FFR assessment

OVERVIEWTitle: CONTRAST (Can cONTrast Injection Better Approximate FFR compAred to Pure reSTing Physiology?)ID: NCT02184117Sponsor: The University of Texas Health Science Center, Houston and St . Jude MedicalPurpose: To determine the diagnostic performances of iodine contrast medium and resting conditions to predict fractional flow reserve (FFR) . Reference FFR will be measured using standard adenosine . We hypothesize that contrast FFR will offer superior diagnostic agreement compared to resting conditions .PRIMARY To determine the diagnostic performances of iodine contrast medium and OBJECTIVE: resting conditions to predict fractional flow reserve (FFR) .SECONDARY To describe the diagnostic performance of resting conditions and contrast OBJECTIVES: medium injection using sensitivity and specificity, positive and negative predictive value, and area under the receiver operating characteristic (ROC) curve, compared to adenosine-derived FFR ≤ 0 .8 as the reference standard .PUBLICATION: EuroPCR 2015 Hotline Session presented by Nils P. Johnson, MD, MS, FACC, University of Texas, Houston, USA, on behalf of the CONTRAST investigators

STUDY DESIGN AND ENROLLMENT�� 750 subjects (prospective) with 1 lesion/patient .�� Any lesion fulfilling a clinical indication for FFR were assessed .�� 3 variations of hyperemic drugs were examined:�� IC contrast: Medium and volume per local practice .�� IC adenosine: Recommended dose 100-200 μg .�� IV adenosine: Standard infusion rate (140 μg/kg/min) .

�� iFR™ assessment and Pd/Pa cutoffs for comparison with FFR were based on previous studies .

�� iFR™ value < 0 .90 (DEFINE-FLAIR), Pd/Pa < 0 .92 (RESOLVE) .

INCLUSION - Age 18 years or older .CRITERIA: - Undergoing FFR assessment for standard clinical indications . - Ability to understand and willingness to sign a written informed consent .

EXCLUSION - Prior coronary artery bypass grafting (CABG) .CRITERIA: - Extremely tortuous or calcified coronary arteries precluding intracoronary physiologic measurements . - Known severe LVH (septal wall thickness at echo of > 13 mm) . - Inability to receive adenosine . - Recent (within 3 weeks prior to cardiac catheterization) STEMI . - Culprit lesions (based on clinical judgment of the operator) for either STEMI or non-STEMI cannot be included . - Severe cardiomyopathy (ejection fraction < 30%) . - Renal insufficiency such that an additional 12 to 20 mL of contrast would, in the opinion of the operator, pose unwarranted risk to the patient .

CONTRAST STUDY OVERVIEW1 KEY DATA

�� Age 66 ± 10 years, 72% male .�� Average 8 ± 2 mL of IC contrast, 8 different agents:

iomeron = 29%, iodixanol = 25%, iohexol = 14%, ioversol = 9%, iopromide = 9%

HIGHLIGHTS IN CONTEXT

SUMMARY AND CONCLUSIONS

�� Contrast FFR is superior to resting Pd/Pa and iFR™ assessment for predicting FFR (using binary or hybrid approach) .

�� iFR™ assessment and resting Pd/Pa provide equivalent diagnostic accuracy .

�� Hyperemic FFR remains the reference standard for diagnostic accuracy .

In healthcare systems in which adenosine is prohibitively expensive or in the rare cases when adenosine is contraindicated, contrast FFR:

�� Is easy, inexpensive, and safe;

�� Displays excellent test/retest stability;

�� Does not depend on a specific software platform (available on all pressure-wire systems) or ECG gating (core lab excluded 14% of ECG tracings) .

11 sites in 9 countries

Figure 1. Contrast FFR is Superior to Resting Pd/Pa and iFR™ Assessment for Predicting FFR.1

Figure 3. Resting Pd/Pa and iFR™ Assessment Provide Equivalent Diagnostic Accuracy in Multiple Clinical Trials.

0

20

40

60

80

100

RESOLVE 2 ADVISE II 3,4

Accu

racy

Com

pare

d to

FFR

(%)

VERIFY 2 7 CONTRAST 1

Pd/Pa iFR™ Assessment

Figure 2. Hyperemic FFR Remains the Reference Standard for Diagnostic Accuracy.

65%

80%

85%

85-95%

100%

Angio Alone6

Contrast FFR1

Hybrid Approach2-5

FFR (IV/IC Adenosine†)

DIAG

NOST

IC AC

CURA

CY

Pd/Pa and iFR™ Single Cutoff2,4

†Prior to using hyperemic agents, please review the Instructions for Use for a complete listing of indications, contraindications, warnings, precautions, potential adverse events and directions.

100 90 10080 8060402000 0

20 20

40 40

60 60

80 80

100 100

Binary Approach = No Adenosine Used

Hybrid Approach = Selective Adenosine Used

True

Pos

itive

s (%

)

False Positives (%)

Contrast FFR = 0.929

Contrast FFR

iFR™ Assessment

= 0.879iFR™

Assessment

Pd/Pa = 0.874 Pd/Pa

Accuracy (%)

Free

dom

from

Ade

nosin

e (%

)



BACK 3 FORWARD

CONTRAST DATA

CLINICAL HIGHLIGHTS FROM THE DEFER STUDY 15-YEAR FOLLOW-UP8

Performing PCI of a non-ischemic stenosis still has no prognostic or symptomatic long-term benefits as compared to medical treatment.

#1Rates of MI showed a significant advantage in the Defer Group versus the Perform and Reference Groups and most infarctions were related to the target vessel.

#2

There was a significant difference in MI between the Defer Group and Perform Group.

#3

All Cumulative Events

n

Defer Group

(n = 91)

Perform Group

(n = 90)

Reference Group

(n = 144)

Any Death 30 28 53

Any Myocardial Infarction

2 13 19

Any Revascularization 60 53 86

14

12

10

8

6

4

2

0

Myo

card

ial I

nfar

ctio

ns (n

)

Defer Group Perform Group

TARGET

UNKNOWN

UNKNOWN

NON-TARGET

NON-TARGET

DEFER STUDY 15-YEAR FOLLOW-UP: RATES OF MI

MOST INFARCTIONS WERE RELATED TO THE TARGET VESSEL

Defer GroupPerform GroupReference Group

Defer vs. Perform, log-rank p = 0.03

0

25

20

15

10

5

0

5 10 15 20

Myo

card

ial I

nfar

ctio

n (%

)

Years



BACK 4 FORWARD

DEFER HIGHLIGHTS

OVERVIEW

TITLE: The DEFER Study – 15 Year Follow-upSPONSOR: Catharina Hospital, Eindhoven, The Netherlands PURPOSE: The purpose of this study was to investigate the appropriateness of stenting a functionally non-significant stenosis (≥ 0 .75)PUBLICATION: EuroPCR 2015 Session presented by Nico Pijls, MD, PhD, Catharina Hospital Eindhoven, Eindhoven, the Netherlands PRIMARY Freedom from major adverse cardiac events (MACE) . ENDPOINT: Note: 15-year follow-up was not a pre-defined endpoint .SECONDARY MACE at 5 years, individual components of MACE at 2 and 5 years, ENDPOINTS: and functional class at 2 and 5 years .

STUDY DESIGN AND ENROLLMENT

�� International, multi-center, prospective and randomized study performed in 12 hospitals in Europe and 2 hospitals in Asia between June 1997 and December 1998 .

�� Out of 325 patients, 167 were randomly assigned to deferral and 158 to performance of PCI .

INCLUSION - Referral for elective PCI of a single angiographically significant de novo CRITERIA: stenosis (more than 50% diameter stenosis by visual assessment) in a native coronary artery with a reference diameter of more than 2 .5 mm . - No evidence of reversible ischemia documented by noninvasive testing within the last 2 months .

EXCLUSION - Patients with a total occlusion of the target artery, acute Q-wave infarction, or CRITERIA: unstable angina documented by transient ST-segment abnormality were excluded . - Patients with small-sized target arteries (reference diameter < 2 .5 mm) were excluded because these patients have less benefit from PCI and their inclusion could bias the outcome in favor of deferral of PCI .

DEFER 15-YEAR FOLLOW-UP STUDY OVERVIEW8

KEY DATA

SUMMARY AND CONCLUSIONS

Deferral vs . performance of PCI in non-ischemic stenosis (based upon FFR ≥ 0 .75) at 15 years showed:

�� No difference in mortality;�� Myocardial infarction significantly favored the Defer Group;�� There were no differences in repeated PCI and CABG.

As presented at EuroPCR 2015, Paris, May 19, 20152

TABLE 1. Baseline Characteristics of Patients in the Three Groups

FFR ≥ 0.75 FFR < 0.75

Defer Group (n = 91)

Perform Group (n = 90)

Reference Group (n = 144)

Age, years 61 ± 9 61 ± 11 60 ± 9

Gender, %

Male 65 63 80

Female 35 37 20

Risk Factors

Diabetes 15 9 13

Hypertension 36 34 42

Hyperlipidemia 43 48 49

Current Smoker 27 23 29

Family History of CAD 56 46 45

Ejection Fraction, % 67 ± 9 67 ± 10 68 ± 9

Angiography

Reference Diameter, mm 3 .00 ± 0 .64 2 .94 ± 0 .57 2 .97 ± 0 .58

DS, % 48 ± 9 48 ± 10 57 ± 12

MLD, mm 1 .55 ± 0 .37 1 .50 ± 0 .36 1 .28 ± 0 .39

Lesion Length, mm 9 .8 ± 5 .4 10 .2 ± 4 .3 9 .5 ± 3 .9

FFR 0 .87 ± 0 .07 0 .87 ± 0 .06 0 .56 ± 0 .16

�� Complete follow-up occurred in 91% of patients . Follow-up relative to mortality was 97% of all patients . Median follow-up was 16 .8 years .

TABLE 2. Performing PCI of a Non-ischemic Stenosis Still has No Prognostic or Symptomatic Long-term Benefits as Compared to Medical Treatment

n, (%) Defer Group (n = 91)



Cardiac 4 (4) 4 (4) 15 (10)

Unknown 15 (16) 11 (12) 10 (7)

Non-cardiac 11 (12) 13 (14) 27 (19)

Total 30 (33) 28 (31) 52 (36)

�� No statistical differences between Defer/Perform/Reference Groups .�� Mortality was mainly related to advanced age (79 .4 years at last follow-up) .

TABLE 3. All Cumulative Events (§Note the significant difference in MI in the Defer and Perform Groups .)

n Defer Group (n = 91)



Any Death 30 28 53

Any MI 2 13 19

Any Revascularization 60 53 86

Perform Group

PTCAPTCA

Reference Group

PTCA

Defer Group

No PTCA

FFR < 0.75 (n = 76)

FFR < 0.75 (n = 68)

FFR ≥ 0.75 (n = 90)

FFR ≥ 0.75 (n = 91)

Perform PTCA (n = 158)

Defer PTCA (n = 167)

Randomization

Patients Scheduled for PCI Without Proof of Ischemia (N = 325)

Figure 2. Rates of MI Showed a Significant Advantage in the Defer Group vs. the Perform and Reference Groups.

Defer Perform Reference

Defer vs. Perform, log-rank p = 0.03

0

25

20

15

10

5

0

5 10 15 20

Myo

card

ial I

nfar

ctio

n (%

)

Years

Figure 3. Most Infarctions Were Related to the Target Vessel.

14

12

10

8

6

4

2

0

Myo

card

ial I

nfar

ctio

ns (n

)

Defer Group Perform Group

TARGET

UNKNOWN

UNKNOWN

NON-TARGET

NON-TARGET

NS

NS

§



BACK 5 FORWARD

DEFER DATA

1. Johnson N, The CONTRAST Study. (Can contrast injection better approximate FFR compared to pure resting physiology?). EuroPCR. May 2015.

2. Jeremias, A., Maehara, A., Genereux, P., Asress, K. N., Berry, C., De Bruyne, B., Stone, G. W. (2014). Multicenter core laboratory comparison of the instantaneous wave-free ratio and resting Pd/Pa with fractional flow reserve: The Resolve Study. Journal of the American College of Cardiology, 63, 1253-1261.

3. Escaned, J., Echavarría-Pinto, M., Garcia-Garcia, H. M., van de Hoef, T. P., de Vries, T., Kaul, P., et al. Prospective Assessment of the Diagnostic Accuracy of Instantaneous Wave-Free Ratio to Assess Coronary Stenosis Relevance Results of ADVISE II International, Multicenter Study (ADenosine Vasodilator Independent Stenosis Evaluation II). JACC Cardiovascuar Intervention 2015;8;6:824-833. NCT01740895.

4. Echavarría-Pinto, M., van de Hoef, T. P., Garcia-Garcia, H. M., de Vries, T., Serruys, P. W., Samady, H., et al. Diagnostic Accuracy of Baseline Distal-to-Aortic Pressure Ratio to Assess Coronary Stenosis Severity A Post-Hoc Analysis of the ADVISE II Study. JACC Cardiovascuar Intervention 2015;8;6:834-6.

5. Johnson, N. P., Kirkeeide, R. L., Asrress, K. L., Fearon, W. F., Lockie T., Marques, K. M., Gould, K. L. (2013). Does the instantaneous wave-free ratio approximate the fractional flow reserve? Journal of the American College of Cardiology, 61, 1428-1435.

6. Park S.J., JACC Cardiovasc Interv. 2012 Oct;5(10):1029-36.

7. Watkins, S., Hennigan, B., Eteiba, H., Lindsay, M., McEntegart, M., Berry, C., & Oldroyd, K. (2014, May). VERIFY-2 presentation. SCAI presentation

8. Pijls N, et al. Deferral vs Performance of PCI in Functionally Non-Significant Coronary Artery Stenosis- 15 Year Follow-up of the DEFER Trial. EuroPCR. May 2015

AUC Area under ROC curve (Delong comparison)

CAD Coronary artery disease

CABG Coronary artery bypass grafting

cFFR Contrast FFR

DS Diameter stenosis

ECG Echocardiogram

FFR Fractional flow reserve

IC Interventional cardiology

IV Intravenous

LVH Left ventricular hypertrophy

MACE Major adverse cardiac event

MI Myocardial infarction

MLD Minimum lumen diameter

PCI Percutaneous coronary intervention

Pd/Pa Ratio of distal coronary pressure across a stenosis over the aortic pressure at rest (non-hyperemic) throughout the entire cardiac cycle

PTCA Percutaneous transluminal coronary angioplasty

STEMI ST-segment elevation myocardial infarction

ReferencesAbbreviations



BACK 6 FORWARDReferences

ABBREVIATIONS

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St. Jude Medical Australia Pty, Ltd. 17 Orion RoadLane Cove, NSW 2066AustraliaT +61 2 9936 1200 | F +61 2 9936 1222

St. Jude Medical Inc. Global Headquarters One St. Jude Medical Drive St. Paul, MN 55117 USA T +1 651 756 2000 | F +1 651 756 3301

St. Jude Medical S.C., Inc. Americas Division6300 Bee Cave RoadBldg. Two, Suite 100Austin, TX 78746USAT +1 512 286 4000 | F +1 512 732 2418

SJM Coordination Center BVBA The Corporate VillageDa Vincilaan 11-Box F1B-1935 Zaventem, BelgiumT +32 2 774 68 11 | F +32 2 772 83 84

SJMprofessional.com

Rx Only Brief Summary: Prior to using these devices, please review the Instructions for Use for a complete listing of indications, contraindications, warnings, precautions, potential adverse events and directions for use.

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