Action Duchenne, London – November 2014
Cardiomyopathy in DMD
Current state of evidence for heart-specific therapy…
John P. Bourke
Consultant Cardiologist & Senior Lecturer
Cardiology Department
Freeman Hospital & Newcastle University
Newcastle upon Tyne
United Kingdom
Heart involvement in DMD..?
Natural History
of Heart Involvement
in DMD
A non-invasive longitudinal
study without treatments
LV FS%
Most boys with DMD
develop a severe,
progressive form of
cardiomyopathy
Backman & Nylander
Eur Heart J 1992, 13:1239-1244
LV EF%
Cardio-myocyte damage & cell death
Inflammatory cascade response
initiated
Loss of functioning muscle cells Fibrocollagenous scar tissue formation
leading to fibrosis
Exon skipping &
Gene therapies
Steroids / ACEi – ARB / betablockers/ spironolactone /
eplerenone
Reduced contraction,
thinning & stretching of
fibrotic regions
Dilation of LV chamber
DMD dilated cardiomyopathy
Heart Failure with Symptoms
Ivabridine /diuretics
Sildenafil
Ameen V & Robson LG - Open
Cardiovascular Medicine Journal
2010, 4:265-77.
Therapy aimed at all aspects of DMD
and
Heart Specific Therapies
Current focus is on therapies for the whole condition
Gene-manipulation for DMD
Disease modifying interventions
(Oligo-medications / Gene therapies / Stem Cells)
DMD disease-modifying therapies – Heart Issues(?)
Nature of therapy
Action
Engrafted foetal
cardiomyocytes
mdx mouse & canine models
Selective repair seems deleterious to rest of
the heart
Cell based therapies
- Satellite cells (x)
- Mesangioblasts (√)
Multi-potent progenitor cells capable of
making any mesodermal tissue (including
skeletal or cardiac muscle)
Gene therapy
Mini- or micro-dystrophin
constructs
Aiming to improve the phenotype (DMD to
BMD); Harder to target the heart
Anti-sense
oligonucleotides
Exon-skipping
Allows production of truncated functional
protein (systemic or organ specific delivery)
Not all penetrate / benefit the heart
[phosphorodiamidate morpholinooligomers (PMOs)]
Multiple parallel research programmes in various DMD models ongoing ...
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
100%
(Oligo-medications / Gene therapies / Stem cells)
LV Function
80
Drugs to ‘reduce reaction to damage’
(Steroids / Anti-fibrois agents / ARBs)
60
Drugs to reduce ‘heart strain’
(ACE-inhibitors / ARBs / Beta-blockers /
Sinus node slowing agents)
40
20
Drugs to reduce symptoms
Normal
range
Symptoms
(Milrinone / Sildenafil / Diuretics / Digoxin)
0
0
6
12
18
24
Age (years)
30
36
Mechnaical Pump-support
(Pacing / LVAD / Transplant)
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 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
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 DMD
► 20% (17/86) died in 11.3 + 3.6 (steroids) & 11.3 + 5.1 (no steroids) yrs follow-up
11% (7/63) Steroid (+) vs 43% (10/23) Steroid (-) died (p = 0.001)
Schram G, et al. J Am Coll Cardiol 2013, 61:948-54
Development of Cardiomyopathy
► 28% (21/86) developed LV-dysfunction during follow-up
11% (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 cardiomyopathy during follow-up:
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
► Rate of decline in LVEF% & FS% lower in steroid treated patients
Schram G, et al. J Am Coll Cardiol 2013, 61:948-54
Steroid effects & the heart in DMD
Steroid agent
Design
Age of starting Rx
Duration of Rx
Patient Number
Evaluation method
Results
Silversides et al , 2003
Markham et al, 2005
Deflazacort vs Never
Any steroid vs Never
Retrospective
Retrospective
8.4 + 2 yrs
< 21 yrs
> 3 yrs
---
33
111
Echocardiogram
Echocardiogram
Steroid (+) vs (-)
Steroid (+) vs (-)
Lost ambulation
48% vs 100%
Cardio-active Rx
LVEF < 45%
LVFS%
LVESD (mm)
10% vs 42%
5% vs 58%
33 + 7% vs 21 + 8%
30 + 6 vs 37 + 8
Freedom from cardiomyopathy
Lower if steroid (-)
< 10 yrs x 4.4 FS% < 28
> 10 yrs x 15
93% vs 53%
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
Allen HD, et al. PLoS Curr 2013, Dec
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
♥ 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
Perindopril
Throughout
Placebo
Initially
(n=28)
(n=29)
Baseline
characteristics
---
---
NS
Alive at 10 yrs
26 (93%)
19 (66%)
0.02
---
---
0.013
Kaplan-Meier plot
p
Duboc et al - Am Heart J, 2007, 154:596-602
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 ...
◊ 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
???
Special role in fibrosisprevention in DMD
Spironolactone
reduced risk of
death by 30%
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
Treatments already available for Cardiomyopathy in DMD
Drug Class
Action
Prolong ambulation / reduce
inflammation / maintain cardiorespiratory function
Established therapy
Perindopril
Enalapril
Losartan
Delay / prevent remodelling of left
ventricle / Anti-fibrotic action
(angiotensin & TGF-ß1 blockade)
Established therapy
Beta-blockers
Metoprolol
Bisoprolol
Carvedilol
Slow heart / reduce force of LVcontraction
Established therapy
(early deployment
probably better)
Aldosterone antagonists
Spironolactone
Eplerenone
Reduce / prevent fibrosis
Theoretical data & use
in other contexts
supports use
Glucocorticoid steroids
ACE-inhibitors / ARBs
Prednisolone
Deflazacort
Evidence
until non-ambulant
(adverse effects limit use)
(early deployment better)
(high K-risk with ACEi)
Calcium channel blockers
Diltiazem
Flunarizine
Anti-oxidants
Q10
Idebenone
?? Reduce calcium influx into cells
No benefit to date
No benefit to date
How far should we escalate therapies for
cardiomyopathy in DMD …?
Defibrillator implant to prevent sudden death in DMD ..?
Risk of sudden death in scarred or severely damaged hearts
100%
LV Function
80
60
Normal
range
40
Phase of increasing
‘heart irritability’
(fatal arrhythmias)
20
Symptoms
0
0
6
12
18
Age (years)
24
30
36
Chaotic rhythm
Normal rhythm
Shock delivered
automatically
Implantable
defibrillator
therapy
for patients
with DMD ??
Impact of ICD therapy on QoL in DMD?
A registry of DMD-patient experiences
& outcomes of ICD therapy, if deployed?
Implantable LV-Assist Device
A less invasive approach to cardiac-assist device therapy
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 ...
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)
To determine in a major clinical trial whether starting:
◊
combination therapy with ACE-inhibitor & beta-blocker
◊
before the onset of 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’
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’
Recruitment Status (Nov ’14)
Target N = 140
80
= Recruited
= Projected
70
46
60
50
40
Oct ‘14
24
30
5
20
1
10
0
Newcastle
[35]
GOS, London
[70]
Oxford
[15]
Birmingham 1
[10]
Liverpool
[15]
Final push to maximise recruitment - before 31st Dec ’14 end