Does Cyclosporine ImpRove Clinical oUtcomein ST-elevation myocardial infarction patients ?

(the CIRCUS study)

Michel OVIZE, MD, PhDLouis Pradel Hospital and Claude Bernard University,

Lyon, France

Reperfusion injury contributes to MI

Reperfusion injury

Ca2+

Transition pore

REPERFUSION NECROSISIschemia / Reperfusion

-

ATPPiCa2+ROS

Cyclosporine

Mitochondria

Onset ofchest pain

CORONARY ARTERY OCCLUSION - TIMI flow grade =0-1

WINDOW TO STARTTREATMENT OF REPERFUSION INJURY

30 minutes to 12 hours

First medicalcare

Cath labadmission

AMBULANCE PCI CARDIOLOGIST

PCI Reperfusion

Ischemia injury

Reperfusion injury is reduced by cyclosporine

0

1000

2000

3000

4000

5000

6000 CK release

Adm.

4h 8h 12h

16h

20h

24h

30h

36h

42h

48h

54h

60h

66h

72h

ControlCyclo

(UI/

L)

Piot et al. NEJM 2008

Direct stenting

Day 1-3CK / TnI release

Day 5 MRI

Infarct size

STEMI < 12 hrsPCI treatmentTIMI flow grade 0-1No visible collateral

Cyclosporine (or saline)(2.5 mg/kg, IV bolus)

0control cyclosporine

area

of h

yper

enha

ncem

ent (

g)10

20

30

40

50

60

70

120

*

CMR infarct size

OBJECTIVE To determine whether cyclosporine improves clinical outcomes in STEMI patients

PRIMARY ENDPOINTCombined incidence within 1 year of :

- all-cause mortality

- worsening of heart failure during initial hospitalization or re-hospitalisation for heart failure

- adverse LV remodeling*

* (adverse LV remodeling (echo): increase > 15% of LVEDV at 1 year versus baseline)

Objective & Primary Endpoint

LAD occluded (TIMI 0-1)

Coronary angiography

e-randomization

CicloMulsion® (Neurovive Pharmaceuticals): lipid emulsion of cyclosporine (no cremophor content)

Initial Echo

Final Echo

Discharge

PCICicloMulsion® :(2.5 mg/kg, IV bolus)

1 year

Anterior STEMI

Experimental design

• > 18 years• symptom onset < 12 hrs • ST shift ≥ 0.2 mV in two contiguous anterior leads • LAD as culprit artery with TIMI flow grade : 0 – 1

Results

Study coordination: Centre for Clinical Investigation (Hospices Civils de Lyon (HCL), France)

Independent, blinded corelabs (HCL): Coronary angiography / Echocardiography / ECG

Independent Statistical CRO (Itech, France)

févr

ier-

11m

ars-

11av

ril-1

1m

ai-1

1ju

in-1

1ju

illet

-11

août

-11

sept

embr

e-11

octo

bre-

11no

vem

bre-

11dé

cem

bre-

11ja

nvie

r-12

févr

ier-

12m

ars-

12av

ril-1

2m

ai-1

2ju

in-1

2ju

illet

-12

août

-12

sept

embr

e-12

octo

bre-

12no

vem

bre-

12dé

cem

bre-

12ja

nvie

r-13

févr

ier-

13m

ars-

13av

ril-1

3m

ai-1

3ju

in-1

3ju

illet

-13

août

-13

sept

embr

e-13

octo

bre-

13no

vem

bre-

13dé

cem

bre-

13ja

nvie

r-14

févr

ier-

14

0

100

200

300

400

500

600

700

800

900

1000

Cumulative inclusionsTarget enrollement

Num

ber o

f pati

ents

enr

olle

d

First patient included : 2011 April, 19 Last patient included : 2014 February, 16Last visit last patient : 2015 April 2nd

Cumulative inclusionsTarget enrollment

42 investigation centres in 3 countriesRecruitment rate

ITT Analysis

Primary endpointAnalysis

Anterior STEMIs

Randomized(n= 970)

Control(n=495)

No informed content (n=1)Imprisoned and therefore ineligible (n=1)Did not receive any treatment (n=4) Missing or poor echographic data (n=74)

Did not receive any treatment (n=4) Missing or poor echographic data (n=95)

Cyclosporine(n = 475)

Cyclosporine(n = 395)

Control(n=396)

modified as treatedanalysis

Consort Diagram

(80% power to detect a 20% relative risk reduction)

Baseline characteristics

Baseline characteristicsCyclosporine

(n=474)

Control

(n=495)

Age (years) 60.4 ± 13.1 59.5 ± 12.7

Male sex 84.2 % 80.0 %

Body Mass Index (kg/m2) 26.9 ± 4.3 26.8 ± 4.1

Killip class I at admission 87.4 % 87.2 %

Current smoker 39.0 % * 45.7 %

Hypertension 37.6 % 37.0 %

Diabetes mellitus 13.7 % 11.7 %

Dyslipidemia 39.2 % 37.8 %

Previous ischemic heart disease 6.5 % 6.5 %

Previous Heart Failure 0.2 % 1.0 %

PCI procedure

ProcedureCyclosporine

(n=474)

Control

(n=495)

Total ischemic time 4.4 ± 3.0 hrs 4.5 ± 2.9 hrs

Door-to-treatment time 1.0 ± 1.3 hrs 1.1 ± 1.7 hrs

Time from symptom onset to treatment : 2-6 hours 70.8 % 68.8 %

Medication from 1st medical care to PCI    

Glycoprotein IIb/IIIa inhibitors 38.2 % 37.5 %

P2Y12 inhibitors loading dose (clopidogrel, prasugrel, ticagrelor) 90.3 % 88.2 %

LAD site of occlusion: Proximal / Main left 45.1 % 41.0 %

Multi-vessel disease ≥ 2 40.9 % * 33.1 %

Area at risk size 37 ± 8 % 36 ± 9 %

Thrombus aspiration 75.7 % 76.2 %

Stenting 89.0 % 87.7 %

Final TIMI flow = 2 or 3 96.0 % 96.0 %

Discharge medication

Discharge medication Cyclosporine

(n=474)

Control

(n=495)

Antiplatelet agents 96.6 % 97.2 %

Beta-blockers 90.4 % 93.8 %

Statins 95.5 % 95.9 %

ACE inhibitors or ARBs 86.4 % 88.0 %

Calcium Antagonists 2.3 % 2.9 %

Nitrates 13.0 % 13.2 %

Diuretic 21.5 % 22.0 %

Soludactone / Eplerenone 24.9 % 23.3 %

Primary outcome at 1 year

Combined incidence of [all-cause mortality; worsening of heart failure during initial hospitalization or re-hospitalisation for heart failure ; LV remodeling] within 1 year after acute MI

(LV remodeling (echo): increase > 15% of LVEDV at 1 year versus initial discharge)

Cyclosporine(n=395)

Control(n=396)

Odds Ratio(95% CI)

P value

(Death / HF / LV remodeling)

233 (59.0 %) 230 (58.1%) 1.04 [0.78; 1.39] 0.77

Secondary outcomes at 1 year

Cyclosporine(n=395)

Control(n=396)

Odds Ratio(95% CI)

P value

Death: all-cause 7.1 % 6.6 %1.09

[0.63 ; 1.90]0.76

Death: cardiovascular 6.1 % 6.1 %1.01

[0.56 ; 1.81]0.98

HF worsening or re-hospitalization for HF 22.8 % 22.7 %1.01

[0.72 ; 1.41]0.97

HF worsening 15.7 % 16.9 %0.92

[0.63 ; 1.34]0.65

Re-hospitalization for HF 10.6 % 10.4 %1.03

[0.65 ; 1.63]0.89

Cardiogenic shock 6.6 % 6.1 %1.09

[0.61 ; 1.94]0.77

Recurrent Myocardial infarction 2.3 % 3.8 %0.59

[0.26 ; 1.37]0.22

Stroke 1.8 % 3.0 %0.58

[0.22 ; 1.48]0.25

Major bleeding 1.8 % 2.3 %0.73

[0.27 ; 2.00]0.54

HF: heart failure

Prespecified subgroup analysis

Cyclosporine Better Control Better

LV volumes and function

baseline one year0

20

40

60

80

100

120

140 LVEDV

ml/

m2

baseline one year

LVESV

control

cyclosporine

baseline one year45

46

47

48

49

50

51

52 LVEF

control

cyclosporine

(%)

Estimation of infarct size

Baseline H4 H12 H240

500

1000

1500

2000

2500

3000

3500

4000

4500

control

cyclosporine

Cre

ati

ne

Kin

as

e r

ele

as

e (

IU/L

)

Plasma total CK (IU/L) Cyclosporine

(n=474)

Control

(n=495)

Baseline 531 [103; 445] 626 [114; 541]

H4 4183 [1992; 5744] 3920 [1780; 5691]

H12 3191 [1855; 4182] 3220 [1840; 4224]

H24 1765 [1004; 2276] 1837 [1019; 2368]

Peak 3992 [1910; 5447] 3917 [1878; 5608]

Discussion

Limitations:

LV remodeling contributed to a large proportion of event rate in the primary endpoint

But, there was no evidence of effect of cyclosporine on any individual clinical endpoints

Discrepancy with our previous phase II trial:

- Different PCI procedures or conditions (stenting, thrombus aspiration, P2Y12 inhibitors, anterior infarcts)

- Different formulation of cyclosporine (Cremophor EL vers lipid emulsion)

- Phase II versus phase III trial (type I error)

Conclusion

In anterior STEMI, cyclosporine did not reduce the risk of the composite primary outcome

- One out of four patients died or experienced heart failure despite receiving state-of-the-art medical care.

- Despite the results of CIRCUS, reperfusion injury is clinically important. The impact on clinical outcomes of recent encouraging phase II trials remains to be determined.

AcknowledgementsCommittees

Steering Com: D.Garcia-Dorado, M.Claeys, F.Pinto, PG Steg, G.Derumeaux, C.Piot, L.Belle, P.Croisille, M.Ovize

Event-validation Com: N.Mewton, JF.Aupetit, I.Sanchez, G.Rioufol, H.Thibault

Data Monitoring & Safety: JL.Bonnet, A.Pathak, R.Porcher

Corelabs

Coronary angiography (G.Rioufol)

Echocardiography (C.Bergerot, M.Altman, H.Thibault, G.Derumeaux)

ECG (S.Pichot, M.Schaaf, N.Mewton)

Lyon Center for Clinical Investigation (CIC)Jossan C., Boussaha I, Mewton N.

Investigators

Thien-Tri Cung, Olivier Morel, Guillaume Cayla, Gilles Rioufol, David Garcia Dorado Denis Angoulvant, Eric Bonnefoy-Cudraz, Patrice Guérin, Meier Elbaz, Nicolas Delarche, Pierre Coste, Gerald Vanzetto, Marc Metge, Jean-François Aupetit, Bernard Jouve, Pascal Motreff, Christophe Tron, Jean-Noel Labeque, Philippe Gabriel Steg, Yves Cottin, Grégoire Range, Jérome Clerc, Marc Jérome Claeys, Patrick Coussement, Fabrice Prunier, Frédéric Moulin, Olivier Roth, Loïc Belle, Philippe Dubois, Paul Barragan,Martine Gilard, Christophe Piot, Patrice Colin, Fabien De Poli, Marie-Claude Morice, Omar Ider, Jean-Luc Dubois-Randé, Thierry Unterseeh, Hervé Le Breton, Thierry Béard, Didier Blanchard, Gilles Grollier, Vincent Malquarti, Patrick Staat, Arnaud Sudre, Eskil Elmer, Magnus J. Hansson, Cyrille Bergerot, Michel Ovize.

Publication

available online at nejm.org (http://www.nejm.org/)