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Cardiomyopathy in DMD Current state of evidence for heart-specific therapy…

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…

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  1. 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

  2. Heart involvement in DMD..?

  3. 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

  4. 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.

  5. Therapy aimed at all aspects of DMDand Heart Specific Therapies Current focus is on therapies for the whole condition

  6. Disease modifying interventions (Oligo-medications / Gene therapies / Stem Cells) Gene-manipulation for DMD

  7. DMD disease-modifying therapies – Heart Issues(?) Multiple parallel research programmes in various DMD models ongoing ...

  8. 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

  9. 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)

  10. Glucocorticoid steroid therapy in DMD Benefits & Adverse Effects

  11. 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

  12. 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

  13. 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

  14. 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

  15. Steroid effects & the heart in DMD

  16. ACE-inhibitors & Beta-blockers in DMD Benefits when heart already involved

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

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

  19. A randomised, double-blind trial of lisonopril & losartan in DMD Allen HD, et al. PLoSCurr2013, Dec

  20. Beneficial effects of beta-blockers & ACEi in DMD Ogata H, et al. J Cardiol 2009, 53(1):72-8

  21. ACE-inhibitors & Beta-blockers before LV-dysfunction in DMD / BMD Can DCM be prevented?

  22. 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.

  23. 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

  24. 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

  25. 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)

  26. 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

  27. 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

  28. 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

  29. Treatments already available for Cardiomyopathy in DMD

  30. How far should we escalate therapies for cardiomyopathy in DMD …?

  31. Defibrillator implant to prevent sudden death in 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)

  32. Implantable defibrillator therapyfor patients with DMD ?? Chaotic rhythm Normal rhythm Shock delivered automatically

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

  34. Implantable LV-Assist Device

  35. 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% !!

  36. 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

  37. The BHF-funded ‘DMD Heart-Protection Trial’ (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)

  38. 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

  39. ‘DMD Heart-Protection Trial’ Target N = 140 46 Oct ‘14 24 5 1

  40. Final push to maximise recruitment - before 31st Dec ’14 end

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