Pepper Ischaemic mitral regurgitation V2 - Struttura … · Ischaemic mitral regurgitation...

Ischaemic mitral regurgitation aetiology and size of the problem

John Pepper

ERICE

MONDAY 13TH May 2013

Functional Ischaemic MR Pathophysiology

Functional Ischaemic MR

• Prevalence: 20% of patients after MI. •  200,000 MI/year in the U.K. •  40,000 new cases a year in the U.K. •  2x risk of severe heart failure within 3

years. •  2x risk of death within 3 years.

Functional Ischaemic MR Unresolved questions

•  Does correcting moderate FIMR improve outcome?

Ø  Cardiac function

Ø  Cardiac reverse remodelling

Ø  Functional capacity

Ø  Quality of life

Ø  Survival

Mitral Valve Annuloplasty plus CABG versus CABG alone

in moderate Func9onal Ischemic Mitral Regurgita9on: final results of the Randomized

Ischemic Mitral Evalua9on (RIME) Trial K. M. John Chan,1,2 Prakash P. Punjabi,1,3 Marcus D. Flather,2,4

Riccardo Wage,2 Karen Symmonds,2 Isabelle Roussin,2 Shelley Rahman-Haley,2 Dudley J. Pennell,1,2 Philip J. Kilner,1,2 Gilles D. Dreyfus,1,2,5

John R. Pepper,1,2 on behalf of the RIME Investigators

National Heart & Lung Institute, Imperial College London1, London, U.K.; Royal Brompton & Harefield NHS Foundation Trust2, London, U.K.; Imperial

College Healthcare NHS Trust3, London, U.K.; Norwich Medical School, University of East Anglia4, Norwich, U.K.; Cardiothoracic Centre of Monaco5,

Monte Carlo, Monaco.

Background: Functional Ischemic MR

•  Occurs in up to 40% of patients following

myocardial infarction.

•  Result of LV remodeling & dilatation.

•  Mitral valve tethered and pulled apart.

•  MR usually mild or moderate in severity.

•  Heart failure and death increased up to 3x.

•  Most have 3-vessel coronary artery disease,

benefit from CABG.

Chan KMJ, et al. Prog Cardiovasc Dis 2009; 51(6):460-471

•  Persistent increased risk of heart failure and death (up to 1.5x)

with coronary artery revascularization alone.

•  Efficacy of adding mitral valve repair to CABG uncertain: reduction

in MR severity reported in observational, non-randomized studies,

but no improvement in functional capacity, heart failure or survival.

•  Significant recurrence rates of MR reported in studies due to

suboptimal surgical techniques (use of flexible annuloplasty

bands, inadequate downsizing, incomplete coronary

revascularization).

Background: Functional Ischemic MR

•  Single blinded randomized controlled trial: 7

centers.

•  Randomization into two groups (1:1 ratio):

•  Group 1: CABG only § Complete coronary artery revascularization. §  Pedicled left internal mammary artery grafted

to the LAD.

•  Group 2: CABG + Mitral Valve Repair § Complete rigid or semi-rigid mitral

annuloplasty ring used. § Carpentier-McCarthy-Adams IMR ETlogix ring

recommended. §  Sized by measurement of anterior mitral valve

leaflet. § Downsized by 2 sizes if alternative complete

ring used. §  Aim: coaptation length of at least 8 mm

between the anterior and posterior mitral valve leaflets with no more than trace MR.

Methods: Study design

•  Inclusion criteria §  Patients referred for elective CABG. §  Moderate functional ischemic MR as defined by the

AHA/ACC/ASE criteria measured at rest or peak exercise by echocardiography:

§  Effective Regurgitant Orifice Area (EROA) 0.20–0.39 cm2

§  Regurgitant Volume 30-59 ml/beat

o Regurgitant Fraction 30-49%

o Vena Contracta Width 0.3-0.69 cm

Methods: Eligibility

Main Exclusion criteria §  Severe LV dysfunction: EF < 30%.

§  Structural abnormalities of the mitral valve (including papillary

muscle rupture).

§  Significant aortic valve disease.

§  Previous or active endocarditis.

§  Significant co-morbidities: severe renal, liver or respiratory

impairment.

§  NYHA class IV, unstable angina, acute pulmonary edema,

cardiogenic shock.

§  Previous cardiac surgery.

•  Primary hypothesis

§ Adding mitral valve annuloplasty to CABG in patients with

moderate functional ischemic MR improves functional capacity.

•  Secondary hypothesis

§ Adding mitral valve annuloplasty to CABG in patients with

moderate functional ischemic MR improves LV reverse

remodelling, MR severity, and BNP levels.

Methods: Hypothesis

Methods: Endpoints

•  Primary endpoint (one year):

§  Functional capacity (Peak oxygen consumption)

•  Secondary endpoints (one year):

§  LV reverse remodeling (LVESVI)

§  Mitral regurgitation (MR volume)

§  BNP levels.

Methods: Statistics •  Power calculations

§  Using 90% power, α = 0.05, and S.D. = 3.5, 82 patients required

to detect difference of ≥ 2.5 ml/kg/min in primary endpoint, peak

VO2.

§  Two planned interim analysis performed.

§  Benefit demonstrated for CABG + MVR group, (P=0.008 for

primary endpoint).

§  Recruitment stopped after results of second interim analysis (73

patients randomised).

Results: Enrollment

Results: Treatment Allocation & Follow-up

Baseline data M i t r a l

regurgitation

EROA (cm2)

R e g u r g i t a n t

volume (ml/beat)

0.18 ±

0.10

30.3 ±

13.8

0.21 ±

0.09

35.5 ±

13.3

Left ventricle

LVESD (mm)

LVEDD (mm)

L V E j e c t i o n

fraction (%)

43.3 ±

9.5

56.5 ±

12.0

40.3 ±

16.1

45.7 ±

7.4

56.5 ±

12.6

40.0 ±

17.3

CABG CABG + MVR

Age (years) –

mean (range)

Female sex (%)

70

(51-83)

26

71

(47-86)

26

NYHA class (%)

I

II

III

3

64

33

3

65

32

CABG CABG + MVR P-

value

Number of bypass grafts (%)

2

3

4

CPB time (min) – median (Q1-Q3)

Cross clamp time (min) – median

(Q1-Q3)

8

74

18

84 (70-106)

51 (41-55)

9

70

21

147 (133-169)

95 (90-110)

<0.00

1

<0.00

1

Mitral Annuloplasty ring

• CMA IMR ETlogix (%)

• CE Physio (%)

• Mean ring size (mm)

85

15

28

Results: Primary endpoint Functional Capacity at 1 Year

Improvement in functional capacity was greater following CABG + MV repair compared to CABG alone.

CABG CABG + MVR

Peak VO2 (% change) 5 22

-2

3

8

13

18

23

28

CABG CABG + MVR

P<0.001

Peak VO2 (% change)

Mean ± 95% CI

Results: Secondary endpoints LV reverse remodelling at 1 Year

LV reverse remodelling was greater following CABG + MV repair compared to CABG alone.

CABG CABG + MVR

LVESVI (% change) -6 -28

-40 -35 -30 -25 -20 -15 -10

-5 0 5

10

CABG CABG + MVR

LVESVI (% change)

Mean ± 95% CI

P=0.002

Results: Secondary endpoints Mitral regurgitation at 1 Year

Reduction in mitral regurgitation was greater following CABG + MV repair compared to CABG only.

CABG CABG + MVR MR volume (% change) -29 -80

-110

-90

-70

-50

-30

-10

10

CABG CABG + MVR

MR volume (% change)

Mean ± 95% CI

P=0.001

Results: Secondary endpoints Mitral regurgitation at 1 Year

Mitral regurgitation was less following CABG + MV repair compared to CABG only.

Results: Secondary endpoints BNP at 1 Year

Reduction in BNP was greater following CABG + MV repair compared to CABG only.

CABG CABG + MVR BNP (% change) -58 -75

-90 -80 -70 -60 -50 -40 -30 -20 -10

0

CABG CABG + MVR

BNP (% change)

Mean ± 95% CI

P=0.003

Results: Symptoms at 1 Year

NYHA class was better following CABG + MV repair compared to CABG only.

P=0.03

Limitations

• Study stopped early for benefit after review of

interim results.

• Single (not double) blinded study.

• Endpoints determined at one year; longer follow-

up necessary.

• Study not designed and not powered to evaluate

clinical events and survival.

Conclusions • Compared to CABG alone, addition of MV annuloplasty to CABG in patients with moderate functional ischemic MR improves:

§ Functional capacity and symptoms § LV reverse remodelling § Mitral regurgitation § BNP levels

• The impact of these benefits on longer term clinical outcomes remain to be defined.

• CABG plus MV annuloplasty required longer operation times, increased intubation and hospital stay duration, and blood transfusion.

• Concomitant CABG plus MV annuloplasty should be considered in patients with moderate functional ischemic MR.

Acknowledgement Funders: U.K. Department of Health, Na4onal Ins4tute of Health Research (NIHR), Bri4sh Heart Founda4on, Bri4sh Medical Associa4on, NIHR Biomedical Research Unit of the Royal Brompton & Harefield NHS Founda4on Trust and Imperial College London. Sponsor: Imperial College London. Par9cipa9ng centres: Royal Brompton Hospital, Harefield Hospital, Hammersmith Hospital, Blackpool Victoria Hospital, Bristol Royal Infirmary, Glenfield Hospital Leicester, Heart Hospital, Medical University of Silesia Poland. Principal Inves9gators: John Pepper, Marcus Flather, K M John Chan, Prakash Punjabi, Gilles

Dreyfus, Mohammed Amrani, Augus4ne Tang, George Asimakopoulos, Tom Sypt, John Yap, Andrzej Bochenek.

Echo, CMR and Peak VO2 Core Labs: Isabelle Roussin, Shelley Rahman-‐Haley, Riccardo Wage,

Karen Symmonds, Philip Kilner, Dudley Pennell, David Firmin, Robert Bougard, Stephanie Bayne, Wayne Arthur.

Co-‐ordinators: Belinda Lees, Tollene Riley, Jemyrr Gavino, Sarah Isbell, Shu Fang Wang, CharloVe Waterhouse, Emma Brennan, Lukasz Krzych, Elaine Logtens, Pradeep Narayan.

RIME Trial Primary Hypothesis

Mitral annuloplasty in addition to CABG improves functional capacity compared to CABG alone, in patients with moderate functional ischaemic mitral regurgitation.

RIME Trial Secondary Hypothesis

1.  In patients with moderate functional ischaemic mitral regurgitation, mitral annuloplasty in addition to CABG:

•  Improves quality of life

•  Improves cardiac function

RIME Trial Secondary Hypothesis

2. In patients with moderate functional ischaemic mitral regurgitation, the outcome of CABG alone can be predicted by:

•  Stress echo and stress MRI

•  Myocardial viability

•  Completeness of revascularisation

RIME Trial

Open, prospective randomised controlled trial with blinded comparison of outcomes. 100 patients: 50 CABG alone.

50 CABG + mitral annuloplasty

RIME Trial Inclusion criteria

•  Patients referred for CABG with significant RCA or Cx stenoses. •  Moderate MR without leaflet prolapse (ERO 20-‐40 mm2)

RIME Trial Exclusion criteria

•  Severe LV dysfunction (EF < 30%)

•  Significant aortic valve disease

•  Atrial fibrillation or non sinus rhythm

•  Significant co-‐morbidities (creatinine > 160, INR > 2.0, bilirubin > 40, FEV1:FVC ratio < 0.6) •  NYHA IV, unstable angina, acute LVF, cardiogenic shock

•  Structural abnormalities of the mitral valve

•  Associated conditions significantly increasing risk of surgery

RIME Trial Recruitment

SCREENING

Review angiogram and clinical notes of all patients referred for CABG

MR on clinical examination, previous echo or LV angiogram

Request echo

Moderate functional MR Meets inclusion & exclusion criteria. Discuss at MDT.

Patient invited to take part in study. Written informed consent obtained.

RIME Trial Recruitment

BASELINE INVESTIGATIONS Echo

Peak oxygen consumption test Post-exercise echo

EQ-5D questionnaire Serum BNP CMR scan

RANDOMISATION 50 patients: CABG only

50 patients: CABG + Mitral Annuloplasty

RIME Trial Surgical Protocol

CABG •  Using CPB.

•  LIMA to LAD.

MITRAL ANNULOPLASTY •  Complete ring.

•  Size by measurement of anterior leaflet.

•  Downsize by 2 sizes.

•  Aim: leaflet coaptation depth of at least 8 mm & no MR.

CONCLUSION

•  Ischaemic MR is poorly understood •  MRI may help •  Molecular imaging may help to understand

the remodelling process •  Decision making can be difficult.

RIME Trial Follow-up Investigations

Baseline Discharge 6 mths 1 year

Echo * * * * P e a k o x y g e n consumption

* * *

Post exercise echo * * * CMR scan * * EQ-5D questionnaire * * * Serum BNP * * *

RIME Trial End points

Primary end point •  Functional capacity at 1 year determined by peak oxygen consumption.

Secondary end points • Health-Related Quality of Life at 1 year determined by EQ-5D questionnaire. • Global and regional LV function at 1 year as determined by CMR. • MR grade at 1 year as determined by echo. • Serum BNP levels at 1 year.

Functional Ischaemic MR CABG alone

Mallidi, et al. JTCVS 2004;127:636-‐44

Survival

15 Dec 2006 Completion of CRF, study documents.

1 Jan 2007 – 1 July

2008

Enrollment period.

1 July 2009 Completion of follow up investigations.

Data analyses.

1 August 2009 Completion of data analyses. Report

writing.

30 September 2009 Completion of final report.

RIME Trial Investigators

Mitral valve terminology

LV function in chronic MR [Corin WJ. JACC 1995; 25: 113]

Pre-MV repair

Post-MV repair normal

Long term durability after MV repair for prolapse

[Mohty D. Circulation 2001; 104: 1-7]

Departments of Cardiothoracic Surgery, Cardiology, Cardiovascular Magnetic

Resonance, and the Clinical Trials and Evaluation Unit

Royal Brompton & Harefield NHS Trust and

Imperial College, London

Mitral regurgitation + hypertrophy

Post infarct patterns

Chronic IMR

ISCHAEMIA Mitral

regurgitation

LV remodelling

LV dilatation

A spectrum of disease

IMR

•  Acute myocardial infarction •  Papillary muscle rupture •  Papillary muscle ischaemia •  Ischaemic cardiomyopathy with impaired

LV function


Kaji, et al. Circulation 2005; 112[supplI]:409-‐414


Ahmad, Cosgrove, et al. Ann Thorac Surg 2004;78:2063-‐8

Functional Ischaemic MR Survival

Lamas, et al. Circulation 1997

SAVE substudy [Lamas. Circulation 1997]

No MR MR P

CV mortality

12 29 <0.001

Severe heart failure

16 24 0.015

Comb. EP <0.001

Functional Ischaemic MR Survival

Grigioni, et al. Circulation 2001;103:1759

Functional Ischaemic MR

•  Does CABG improve moderate functional ischaemic MR?

•  Does it improve outcome?


[Aklog L. Circulation 2001; 104: 68]

0%

10%

20%

30%

40%

50%

60%

0 1 2 3 4

TTE

0%

10%

20%

30%

40%

50%

60%

0 1 2 3 4

TOE

136 patients 1992 – 1999 isolated CABG


Lam B-‐K. et al. Ann Thorac Surg 2005;79:462

Survival


Lam BK. et al. Ann Thorac Surg 2005;79:462

Change in MR grade


Campwala SZ. et al. Eur J Cardiothorac Surg 2005;28:783-‐787

Change in MR grade


Paparella D. et al. Ann Thorac Surg 2003;76:1094

Survival


Duarte IG. et al. Ann Thorac Surg 1999;68:429

Survival

Functional Ischaemic MR CABG + Mitral Annuloplasty

Bax JJ. et al. Circulation 2004;110[suppl II]II-‐103

Change NYHA class


•  Does CABG + mitral annuloplasty improve outcome?


Bax JJ. et al. Circulation 2004;110[suppl II]II-‐103

51 patients LVEF 31 +/-‐8% severe MR 30 D mortality = 5.6%


Harris KM. et al. Ann Thorac Surg 2002;74:1468-‐75

Survival

Ischaemic mitral regurgitation

Results: Baseline CABG CABG +

MVR

Age (years) – mean

(range)

Female sex (%)

70 (51-83)

26

71

(47-86)

26

NYHA class (%)

I

II

III

3

64

33

3

65

32

M i t r a l

regurgitation

EROA (cm2)

R e g u r g i t a n t

volume (ml/beat)

0.18 ±

0.10

30.3 ±

13.8

0.21 ±

0.09

35.5 ±

13.3

Left ventricle

LVESD (mm)

LVEDD (mm)

L V E j e c t i o n

fraction (%)

43.3 ±

9.5

56.5 ±

12.0

40.3 ±

16.1

45.7 ±

7.4

56.5 ±

12.6

40.0 ±

17.3

Pepper Ischaemic mitral regurgitation V2 - Struttura … · Ischaemic mitral regurgitation...

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