DEFER STUDY: 5-YEAR FOLLOW-UP

Nico H.J. Pijls, MD, PhD Catharina Hospital Eindhoven, The Netherlands

Bernard De Bruyne, MD, PhDCardiovascular Center AalstAalst, Belgium

Principal investigators

A Multicenter Randomized Study A Multicenter Randomized Study to Compare Deferral Versus Performance of PCI to Compare Deferral Versus Performance of PCI of Non-Ischemia-Producing Stenosesof Non-Ischemia-Producing Stenoses

Any treatment in health care should be directedeither to

• Releave symptoms ( improve functional class )

or to

• Improve outcome ( prognosis, longevity)

No other justification for any treatment is possible !

NOTE

In patients with coronary artery disease,the most important factor with respect to both

• functional class (symptoms)

• and prognosis (outcome)

Is the presence and extent of inducible ischemia

(many invasive & non-invasive studies in > 100,000 patients)

If a stenosis is responsible for reversible ischemia, revascularization improves symptoms(if present) and outcome…..

DEFER study: background (1)

DEFER study: background (2)

If a stenosis is responsible for reversible ischemia, revascularization is justified……

……But what if a stenosis or “plaque” is NOT responsible for reversible ischemia ? (functionally “non-significant” , “non-culprit”)

PCI is often performed in such lesions,yet the benefit of such treatment is not clear

158 vb38/interm.RCA/Buddem (1)

• female, 58-y-old• underwent PCI of severe LCX lesion a minute before • 50 % stenosis in mid RCA

Should this lesion be stented ??

• Fractional Flow Reserve, Fractional Flow Reserve, calculated fromcalculated from coronary pressure measurement, coronary pressure measurement, is an accurate, is an accurate, invasive, and lesion-specific invasive, and lesion-specific indexindex to demonstrate to demonstrate or exclude whether a particular coronary stenosisor exclude whether a particular coronary stenosis can cause can cause reversible ischemiareversible ischemia..

• FFRFFR can be determined easily, in the cath-lab, can be determined easily, in the cath-lab, immediately prior to a planned interventionimmediately prior to a planned intervention

DEFER study: background (3)

FFR based strategy for PCI in equivocal stenosis( DEFER – Study)

The DEFER Study: DesignThe DEFER Study: Design

prospective randomized multicentric trial prospective randomized multicentric trial (14 centers) in 325 patients with stable (14 centers) in 325 patients with stable chest pain and an intermediate stenosis chest pain and an intermediate stenosis without objective evidence of ischemiawithout objective evidence of ischemia

AalstAmsterdamEindhoven Essen Gothenborg Hamburg Liège

Maastricht Madrid Osaka Rotterdam Seoul Utrecht Zwolle

data collection & analysis: Jan Willem Bech, MD, PhDPepijn van Schaardenburgh, MD

The DEFER Study: The DEFER Study: ObjectivesObjectives

• to test to test safetysafety of deferring PCI of stenoses of deferring PCI of stenoses not responsible for inducible ischemia as not responsible for inducible ischemia as indicated by FFR > 0.75 ( indicated by FFR > 0.75 ( ““outcomeoutcome”” ))

Secondary objectiveSecondary objective

• to compare to compare quality of lifequality of life in such patients, in such patients, whether or not treated by PCI whether or not treated by PCI (CCS-class, need for anti-anginal drugs)(CCS-class, need for anti-anginal drugs) (“symptoms”)(“symptoms”)

Primary objective

DEFER Group

REFERENCE Group PERFORM Group

The DEFER Study: Flow ChartPatients scheduled for PCI without Proof of Ischemia

(n=325)

performance of PTCA (158)

deferral of PTCA (167)

FFR 0.75 (91)

No PTCA

FFR 0.75(90)

PTCA

FFR < 0.75(76)

PTCA

FFR < 0.75(68)

PTCA

RandomizationRandomization

THE DEFER STUDY: RANDOMIZATION

1 : 1 randomization

deferral of PCI

performance of PCI

If FFR < 0.75 performance anyway reference group

If FFR > 0.75 randomization followed

defer PCI perform PCI

The DEFER Study: The DEFER Study: CatheterizationCatheterization

• 6 or 7 F guiding catheter for measurement of aortic pressure ( Pa)

• QCA from 2 orthogonal views

• Coronary pressure measurement (Pd ) by 0.014” pressure wire (Radi Medical Systems)

• Maximum hyperemia by i.v. adenosine (140 ug/kg/min)

• Calculation of Fractional Flow Reserve by:

FFR = Pd / Pa

The DEFER Study: Base line data

Randomized to Randomized to Deferral of PTCA Performance of

PTCA N=167 N=158

Diabetes (%) 13 12Hypertension (%) 41 35Hyperlipidemia (%) 47 48Current Smoker (%) 30 25Family History CAD (%) 50 49

Age, (yr) 629 6310Female sex (%) 29 29Ejection Fraction (%) 6710 689

The DEFER Study: Baseline QCA and FFR

Ref. diam. (mm) 2.960.63 2.980.57

MLD (mm) 1.420.40

DS (%) 5210

1.420.38 5211

Randomized to Randomized to Deferral of PTCA Performance of PTCA

N=167 N=158

FFR 0.720.19 0.730.19

All baseline characteristics were identical between both groups

The DEFER Study: Diameter Stenosis versus FFR

20

30

40

50

60

70

80

90

FFR < 0.75FFR 0.75

DS

%

No. at risk

Defer group 90 85 82 74 73 72

Perform group 88 78 73 70 67 65

Reference gr 135 105 103 96 90 88

78.8

72.7

64.4

0 1 2 3 4 50

25

50

75

100

Defer

Perform

Reference(FFR < 0.75)

p=0.52

p=0.17p=0.03

Years of Follow-up

event – free survival (%)

72 %72 % 58 %58 %68 %68 %Pts free of angina(%)Pts free of angina(%)

52 (39 %)52 (39 %)24 (27 %)24 (27 %)19 (21 %)19 (21 %)Patients Patients ≥1 event (%)≥1 event (%)

707029292121Total eventsTotal events

2 (1.5)2 (1.5)1 (1.1)1 (1.1)00Other (%)Other (%)

11 (8.2)11 (8.2)6 (6.8)6 (6.8)6 (6.7)6 (6.7)Non-TLR(%)Non-TLR(%)

14 (10.4)14 (10.4)4 (4.5)4 (4.5)1 (1.1) 1 (1.1) CABG(%)CABG(%)

7 (5.2)7 (5.2)1 (1.1)1 (1.1)00Non-Q wave MI(%)Non-Q wave MI(%)

6 (4.5)6 (4.5)4 (4.5)4 (4.5)00Q wave MI (%)Q wave MI (%)

4 (3.0)4 (3.0)3 (3.4)3 (3.4)3 (3.3)3 (3.3)Non Cardiac Death(%)Non Cardiac Death(%)

8 (6.0)8 (6.0)2 (2.3)2 (2.3)3 (3.3)3 (3.3)Cardiac Death(%)Cardiac Death(%)

14414490909191Number of patientsNumber of patients

ReferenceReferencePerformPerformDeferDefer

FFR<0.75FFR<0.75FFR FFR ≥0.75≥0.75

18 (13.4)18 (13.4)8 (9.1)8 (9.1)8 (8.9)8 (8.9)TLR(%)TLR(%)

DEFER: Clinical Outcome at 5 YearsDEFER: Clinical Outcome at 5 Years

Lost to follow-up 1 2 10Lost to follow-up 1 2 10

Cardiac Death And Acute MI After 5 Years

3.3

7.9

15.7

0

5

10

15

20 %

P=0.20

P< 0.03

P< 0.005

DEFER PERFORM REFERENCE

FFR > 0.75 FFR < 0.75

0%

20%

40%

60%

80%

100%

baseline 1month 1 year 2 year 5 year

Defer group Perform group Reference group

freedom from chest pain

FFR > 0.75 FFR > 0.75 FFR < 0.75

* *

* *

* **

*

DEFER: Summary and Conclusions (1)DEFER: Summary and Conclusions (1)

1.1. In patients with stable chest pain, the most important In patients with stable chest pain, the most important prognostic factor of a given coronary artery stenosis, prognostic factor of a given coronary artery stenosis, is its ability of inducing myocardial ischemia (as is its ability of inducing myocardial ischemia (as reflected by FFR < 0.75)reflected by FFR < 0.75)

2.2. In those patients, clinical outcome of such “ischemic” In those patients, clinical outcome of such “ischemic” stenosis, even when treated by PCI, is much worse stenosis, even when treated by PCI, is much worse than that of a functionally “non-significant” stenosis.than that of a functionally “non-significant” stenosis.

3. The prognosis of “non-ischemic” stenosis (FFR > 0.75) 3. The prognosis of “non-ischemic” stenosis (FFR > 0.75) is excellent and the risk of such “non-significant” is excellent and the risk of such “non-significant” stenosis or plaque to cause death or AMI is < 1% per stenosis or plaque to cause death or AMI is < 1% per year, year, and not decreased by stentingand not decreased by stenting

DEFER: Summary and Conclusions (2)DEFER: Summary and Conclusions (2)

Conclusion

Stenting a “non-ischemic” stenosis does not Stenting a “non-ischemic” stenosis does not benefit patients with stable chest pain, neither benefit patients with stable chest pain, neither

in prognostic nor symptomatic respect.in prognostic nor symptomatic respect.

No. at risk

FFR ≥ 0.75 178 162 154 143 138 136

FFR < 0.75 135 105 103 96 90 88

75.8

64.4

0 1 2 3 4 50

25

50

75

100

FFR 0.75

FFR < 0.75p=0.03

Years of Follow-up

event – free survival (%)