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Cardiomyopathy in DMD Current state of evidence for heart-specific therapy…. Action Duchenne, London – November 2014. John P. Bourke Consultant Cardiologist & Senior Lecturer. Cardiology Department Freeman Hospital & Newcastle University Newcastle upon Tyne United Kingdom.

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Cardiomyopathy in dmd current state of evidence for heart specific therapy
Cardiomyopathy in DMDCurrent state of evidence for heart-specific therapy…

Action Duchenne, London – November 2014

John P. Bourke

Consultant Cardiologist & Senior Lecturer

Cardiology Department

Freeman Hospital & Newcastle University

Newcastle upon Tyne

United Kingdom



Natural history of heart involvement in dmd a non invasive longitudinal study without treatments
Natural History of Heart Involvement in DMDA non-invasive longitudinal study without treatments

LV FS%

Most boys with DMD develop a severe, progressive form of cardiomyopathy

LV EF%

Backman & Nylander

Eur Heart J 1992, 13:1239-1244


Cardio-myocyte damage & cell death

Exon skipping &

Gene therapies

Inflammatory cascade response initiated

Steroids / ACEi – ARB / beta-blockers/ spironolactone / eplerenone

Loss of functioning muscle cells Fibro-collagenousscar tissue formation leading to fibrosis

Reduced contraction, thinning & stretching of fibrotic regions

Dilation of LV chamber

Ivabridine /diuretics Sildenafil

DMD dilated cardiomyopathy

Heart Failure with Symptoms

Ameen V & Robson LG - Open Cardiovascular Medicine Journal 2010, 4:265-77.


Therapy aimed at all aspects of dmd and heart specific therapies
Therapy aimed at all aspects of DMDand Heart Specific Therapies

Current focus is on therapies for the whole condition


Disease modifying interventions (Oligo-medications / Gene therapies / Stem Cells)

Gene-manipulation for DMD


Dmd disease modifying therapies heart issues
DMD disease-modifying therapies – Heart Issues(?)

Multiple parallel research programmes in various DMD models ongoing ...


Success of an intervention will be time dependent
Success of an intervention will be time dependent ..!

Therapy of DMD-adults cannot compensate for therapies needed in childhood !

Smoke Detector / Fire Extinguisher

Fire Brigade

& Rescue

Insurance & Investigation


Medication & other therapies for Heart Involvement in DMD

Changing the natural history of heart involvement in DMD

Disease modifying interventions (Oligo-medications / Gene therapies / Stem cells)

100%

80

Drugs to ‘reduce reaction to damage’

(Steroids / Anti-fibrois agents / ARBs)

60

Normal range

LV Function

Drugs to reduce ‘heart strain’

(ACE-inhibitors / ARBs / Beta-blockers / Sinus node slowing agents)

40

20

Drugs to reduce symptoms

(Milrinone / Sildenafil / Diuretics / Digoxin)

Symptoms

0

Mechnaical Pump-support (Pacing / LVAD / Transplant)

0

6

12

18

24

30

36

Age (years)


Glucocorticoid steroid therapy in DMD

Benefits & Adverse Effects


All cause mortality cardiovascular outcomes with prophylactic steroid therapy in dmd
All cause mortality & cardiovascular outcomes with prophylactic steroid therapy in DMD

► Aim: impact of steroid therapy on cardiomyopathy & mortality in DMD

► Retrospective cohort review of DMD pts on ACEi +/- steroid therapy

► 86 DMD patients (9.1 + 3.5 yrs & followed for 11.3 + 4.1 yrs) - 1972-2006

‘... All received ACEi / ARB therapy but steroids at discretion of caregivers & family ..’

► Serial echos & ECGs every 6-12 months

► Deflazacort or prednisolone initiated at 8.6 + 3.5 yrs of age

‘..Pts starting steroids were seen by cardiology & ACEi/ARB started at a younger age..’

Schram G, et al. J Am Coll Cardiol 2013, 61:948-54


Freedom from cardiomyopathy lvef 45 death from heart failure
Freedom from cardiomyopathy (LVEF < 45%) & Death from heart failure

Fewer heart failure related deaths

Freedom from CM

Overall Survival

Schram G, et al. J Am Coll Cardiol 2013, 61:948-54


All cause mortality cardiovascular outcomes with prophylactic steroid therapy in dmd1
All cause mortality & cardiovascular outcomes with prophylactic steroid therapy in DMD

► 20% (17/86) died in 11.3 + 3.6 (steroids) & 11.3 + 5.1 (no steroids) yrs follow-up

11% (7/63) Steroid (+) vs43% (10/23) Steroid (-) died (p = 0.001)

Schram G, et al. J Am Coll Cardiol 2013, 61:948-54


Development of cardiomyopathy
Development of Cardiomyopathy

► 28% (21/86) developed LV-dysfunction during follow-up

11% (7/63) Steroid (+) vs61% (14/23) Steroid (-) (p < 0.0001)

► No differences in ECG changes & No arrhythmias in any patient

► Freedom from new-onset cardiomyopathy during follow-up:

► Rate of decline in LVEF% & FS% lower in steroid treated patients

Schram G, et al. J Am Coll Cardiol 2013, 61:948-54



ACE-inhibitors & Beta-blockers in DMD

Benefits when heart already involved


Jefferies JL, et al. Circulation 2005, 112:2799-2804


Ramaciotti C, et al. Am J Cardiol 2006, 98(6):825-7


A randomised double blind trial of lisonopril losartan in dmd
A randomised, double-blind trial of lisonopril & losartan in DMD

Allen HD, et al. PLoSCurr2013, Dec


Beneficial effects of beta blockers acei in dmd
Beneficial effects of beta-blockers & ACEi in DMD

Ogata H, et al. J Cardiol 2009, 53(1):72-8


ACE-inhibitors & Beta-blockers

before LV-dysfunction in DMD / BMD

Can DCM be prevented?


Effects of perindopril on the onset & progression

of LV-systolic dysfunction in DMD

Duboc D, et al, J Am Coll Cardiol 2005, 45(6):855-7.


Perindopril preventive treatment on mortality in dmd 10 year follow up
Perindopril preventive treatment on mortality in DMD: 10-year follow-up

♥ DMD boys 9.5 to 13 yrs & normal LV function

Randomised to perindopril (2-4 mg) or placebo x 3 yrs

Open-label perindopril to all thereafter for < 10 yrs

Duboc et al - Am Heart J, 2007, 154:596-602


Ace inhibitors adverse effects
ACE-inhibitors: Adverse Effects

► Common hypotension, cough, hyperkalaemia, headache, dizziness, fatigue, nausea, renal impairment

- Persistent dry cough due to bradykinin increase

- Rash & taste disturbance commoner with captopril

- Particular risk of renal failure if renal impairment , NSAIDs & diuretics / dehydration

- Hyperkalaemia due to suppressed aldosterone levels

particularly if in combination with spironolactone / eplerenone


Other drugs for the heart
Other drugs for the heart ...

◊ Anti-fibrosis agents (spironolactone / eplerenone)

◊ Ivabradine(sinus node slowing agent)

◊ Growth Hormone (LV- hypertrophy effect)

In heart failure:

◊ Diuretics (furosemide / bendroflumethiazide)

◊ Nitrates (venodilators)

◊ Phosphodiesterase-5 inhibitors (Sildenafil)


N Engl J Med 1999, 341(10):709-717

► Double-blind study of adding spironolactone to existing therapy in severe heart failure

► N = 1663 - LVEF < 35%

ACEi, loop diuretic & digoxin

822 (spiro 25mg) & 842 (placebo)

End-Pt: Death from all causes

Spironolactone reduced risk of death by 30%

???

Special role in fibrosis-prevention in DMD


Aldosterone antagonists spironolactone eplerenone
Aldosterone Antagonists (spironolactone & eplerenone)

► Spironolactone (widespread effects)

Gynaecomastia, hyperkalaemia & renal dysfunction

Requires careful monitoring of urea, creatinine & electrolytes

Spironolactone dosage should be no < 25-50 mg/day

Contraindicated, if serum potassium > 5 mmol/l

or serum creatinine > 220micromoles/l

► Eplerenone(~ 1000 times more cardio-specific ....)

Less gynaecomastia but otherwise as for spironolactone


Ivabradine & outcomes in chronic heart failure

Addition of ivabradine(a pure sinus node slowing agent)

to optimum medical therapy

Benefit due to reduced hospital admissions for CCF

SHIFT - Swedberg K, et al. Lancet 2010, 376:875-885




Defibrillator implant to prevent sudden death in DMD ..? DMD …?

Risk of sudden death in scarred or severely damaged hearts

100%

80

60

Normal range

LV Function

40

Phase of increasing ‘heart irritability’

(fatal arrhythmias)

20

Symptoms

0

0

6

12

18

24

30

36

Age (years)


Implantable defibrillator therapy for patients with dmd
Implantable defibrillator therapy DMD …?for patients with DMD ??

Chaotic rhythm

Normal rhythm

Shock delivered automatically


Impact of ICD therapy on QoL in DMD? DMD …?A registry of DMD-patient experiences & outcomes of ICD therapy, if deployed?



A less invasive approach to cardiac assist device therapy
A less invasive approach to cardiac-assist device therapy DMD …?

C-Pulse System (Sunshine Heart)

Davies et al.

Heart Lung & Circulation

2005, 14:178-86

► Extra-aortic counter-pulsation device for long-term treatment

► NYHA class III & ambulatory class IV heart failure patients

►ECG gated inflation/deflation; Polyurethane balloon cuff;

►Pneumatically driven; Up to 26cc (depending on aortic size)

► Full or mini-sternotomy implanted;

► EF increased over time by up to 30% !!


Significant progress but much uncertainty
Significant progress but much uncertainty ... DMD …?

How far is it ethical / justified to escalate therapy?

► Stick with what we know is beneficial or begin to combine therapies?

Steroids alone until LV-impaired or

Steroids + ACEi + BB + spironolactone from early years

► Content to keep patients asymptomatic alone or push for longer survival?

Add ICD therapy to protect against SCD

► Add LV-assist devices when heart failure symptoms intervene despite drugs or time for palliative care pathways?

LVAD or Counter-pulsation devices


The bhf funded dmd heart protection trial ongoing
The BHF-funded ‘DMD Heart-Protection Trial’ DMD …?(Ongoing)

To determine in a major clinical trial whether starting:

◊combination therapywith ACE-inhibitor & beta-blocker

◊ before the onsetof echo-detectable LV dysfunction

◊ delays onset or slows progression rate of cardiomyopathy

◊ five-UK-centre, double-blind, randomised, placebo-controlled trial

◊ over 5 years (2 years recruitment / 3-5 years follow up)


The bhf funded dmd heart protection trial
The BHF-funded ‘DMD Heart-Protection Trial’ DMD …?

Inclusion Criteria Recruitment ends 31/12/2014 !!

◊Boys 7 – 12 years old with genetically proven DMD

◊LVEF > 60% by Simpson’s biplane method (normal range = 63 + 5%)

◊No global or regional wall motion abnormalities (echocardiogram)

◊Informed consent from parents / guardians & child’s assent

◊No contra-indication to perindopril or bisoprolol


Dmd heart protection trial
‘DMD Heart-Protection Trial’ DMD …?

Target N = 140

46

Oct ‘14

24

5

1



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