Best preventative actions in cardiac care

Cardiomyopathy in the adult with DMDCardiomyopathy in the adult with DMD

Cardiology DepartmentFreeman Hospital & Newcastle University

Newcastle upon TyneUnited Kingdom

John P. BourkeJohn P. BourkeConsultant Cardiologist & Senior Lecturer

Action Duchenne Meeting – November ‘15

International DMD Care Considerations Working Group International DMD Care Considerations Working Group Bushby K, et al. Lancet Neurol 2010, 9:77-93 & 177-89

Heart involvement in DMD..?

Natural History of Heart Involvement in DMD

A non-invasive longitudinal study without treatments

Backman & Nylander

Eur Heart J 1992, 13:1239-1244

LV FS%

LV EF%

Most boys with DMD develop a severe,

progressive form of cardiomyopathy

Gene-manipulation for DMD

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

Cardio-myocyte damage & cell death

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

Heart Failure with Symptoms

Inflammatory cascade response initiated

Loss of functioning muscle cells Fibro-collagenous scar tissue formation

leading to fibrosis

Reduced contraction, thinning & stretching of

fibrotic regions

Dilation of LV chamber

DMD dilated cardiomyopathy

Let’s start doing something …..

Cardio-myocyte damage & cell death

Inflammatory cascade response initiated

Loss of functioning muscle cells Fibro-collagenous scar tissue formation

leading to fibrosis

Reduced contraction, thinning & stretching of

fibrotic regions

DMD dilated cardiomyopathy

Dilation of LV chamber

Ameen V & Robson LG - Open Cardiovascular Medicine Journal

2010, 4:265-77.

Exon skipping, Stem cells & Gene therapies

Steroids / ACEi – ARB / Beta-blockers/ Spironolactone /

Eplerenone

Ivabridine /Sildenefil / Tadanafil

Heart Failure with Symptoms

Success of an intervention is time dependent ..!

Smoke Detector / Fire Extinguisher

Fire Brigade & Rescue

Insurance & Investigation

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

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Medication & other therapies for Heart Involvement in DMD

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

Drugs to reduce ‘heart strain’ (ACE-inhibitors / ARBs / Beta-blockers /

Sinus node slowing agents; PDE-5 inhibitors)

Drugs to reduce symptoms (Milrinone / PDE-5 inhibitors / Diuretics / Digoxin)

Drugs to ‘reduce reaction to damage’ (Steroids / Anti-fibrosis agents / ARBs)

Changing the natural history of heart involvement in DMD

Glucocorticoid steroid therapy in DMD

Benefits & Adverse Effects

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

► Aim: impact of steroid therapy on cardiomyopathy & mortality in DMDRetrospective cohort review of DMD pts on ACEi +/- steroid therapy

► 86 DMD patients 86 DMD patients (9.1 + 3.5 yrs & followed for 11.3 + 4.1 yrs) between 1972-2006‘... All received ACEi / ARB therapy but steroids at discretion of caregivers & family ..’

► 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..’

► Serial echos & ECGs every 6-12 months

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

Freedom from Cardiomyopathy & Death from Heart Failure

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

Development of Cardiomyopathy

► 28% (21/86) developed LV-dysfunction during follow-up11% (7/63) Steroid (+) vs 61% (14/23) Steroid (-) (p < 0.0001)

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

► Freedom from new-onset cardiomyopathyFreedom from new-onset cardiomyopathy (LVEF < 45%) (LVEF < 45%) during follow-up: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

Follow-up (yrs) Steroid (+) Steroid (-)

5 96.8% 95.2%

10 94.4% 73.9%

15 84.1% 29.6%Log-rank p < 0.0001

ACE-inhibitors & Beta-blockers in DMD

Preventing progressive heart dysfunction

ACE-inhibitors + Beta-blockers for DMD Cardiomyopathy

ACE-inhibitors + Beta-blockers are of benefit for DMD Cardiomyopathy

Therapy should start as soon as LV-dysfunction evident

ACEi / ARB + BB seems best

Echo suffices in determining the threshold for therapy

ACE-inhibitors & Beta-blockers before LV-dysfunction in DMD / BMD

Can DCM be prevented?Can DCM be prevented?

Effects of perindopril on onset & progression of DMD LV-systolic dysfunction Duboc D, et al, JACC 2005, 45(6):855-7

Perindopril preventive treatment on mortality in DMD: 10-year follow-up Duboc et al . Am Heart J, 2007, 154:596-602

DMD boys 9.5 to 13 yrs & normal LV function at baselineRCT perindopril (2-4 mg) vs placebo x 3 yrs; Open-label perindopril to all thereafter for < 10 yrs

Eplerenone for early cardiomyopathy in Duchenne muscular dystrophy: a randomised, double-blind, placebo-controlled trial

Raman SV, et al. Lancet Neurology 2015, 14:153–161

■ DMD boys > 7 yrs from 3 USA centres (Jan ‘12-July ‘13)Cardiomyopathy (+) with scars on Late-Gad MRI but normal range LVEF%

■ RCT of eplerenone (25mg/day) vs placebo in addition to ACEi / ARB

■ 10 End-point: Change in MRI-measured LV circumferential strain after 12 mths

Safety end-point: serial measures of renal function, including serum potassium

188 screened EplerenoneN=20

PlaceboN=22

P

Median decline in MRI-LV circumferential strain

1.0(IQR: 0.3-2.2)

2.2(IQR: 1.3-3.1)

0.02

In boys with DMD and preserved LVEF%, adding eplerenone to ACEI / ARB attenuates the progressive decline in LV systolic function.

Treatments already available for Cardiomyopathy in DMD

Drug Class Action Evidence

Glucocorticoid steroids PrednisoloneDeflazacort

Prolong ambulation / reduce inflammation / maintain cardio-respiratory function

Established therapy until non-ambulant(adverse effects limit use)

ACE-inhibitors / ARBs PerindoprilEnalaprilLosartan

Delay / prevent remodelling of left ventricle / Anti-fibrotic action (angiotensin & TGF-ß1 blockade)

Established therapy (early deployment better)

Aldosterone antagonists SpironolactoneEplerenone

Reduce / prevent fibrosis Established therapy(need for serum K-checks with ACEi)

Beta-blockers MetoprololBisoprololCarvedilol

Slow heart / reduce force of LV-contraction

(Ivabridine, if BB ci or not tolerated)

Probably established Theoretical data & use in other contexts

Calcium channel blockers DiltiazemFlunarizine

?? Reduce calcium influx into cells No benefit to date

Anti-oxidants Q10 Idebenone

No benefit to date

How far should we escalate cardiac therapies for advanced cardiomyopathy in DMD …?

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Defibrillator implant to prevent sudden death in DMD ..?

Risk of sudden death in severely damaged hearts

July ’15 – Complete AV Block

Mr MA – 21 yrs – DMD

LVEF 15-20% - No cardiac symptomsPerindopril, Bisoprolol & Bumetanide

Single chamber ICD - Oct ’12

Several shock therapies – May ’13

Complete AV-block – July ‘15

September ‘14

41 seconds from 1st onsetSept ‘15 (16 months post ICD implant)

Finsterer J & Cripe L. Nat Rev Cardiol 2014, doi: 10.1038/nr.cardio.2013.213

International DMD Care Considerations Working Group

Diagnosis & Management (Parts 1 & 2)

Bushby K, et al. Lancet Neurology- 2010, 9:77-93 &- 2010, 9:177-189