Cowie Inverness Nov 2011 New Solutions in HF
Upcoming SlideShare
Loading in...5
×

Like this? Share it with your network

Share
  • Full Name Full Name Comment goes here.
    Are you sure you want to
    Your message goes here
    Be the first to comment
    Be the first to like this
No Downloads

Views

Total Views
748
On Slideshare
748
From Embeds
0
Number of Embeds
0

Actions

Shares
Downloads
20
Comments
0
Likes
0

Embeds 0

No embeds

Report content

Flagged as inappropriate Flag as inappropriate
Flag as inappropriate

Select your reason for flagging this presentation as inappropriate.

Cancel
    No notes for slide
  • 1 For more information on drug treatment see appendix D of the NICE guideline and ‘Chronic kidney disease’ (NICE clinical guideline 73).2 Consider an ICD in line with ‘Implantable cardiovascular defibrillators for arrhythmias’ (NICE technology appraisal guidance 95).3 NYHA class III–IV.4 Not all ARBs are licensed for use in heart failure in combination with ACE inhibitors.5 NYHA class II–III.6 This does not include mixed race. For more information see the full guideline at www.nice.org.uk/guidance/CG1087 Consider CRT in line with ‘Cardiac resynchronisation therapy for the treatment of heart failure’ (NICE technology appraisal guidance 120).Additional informationThere is evidence of improved outcome for patients with heart failure due to left ventricular systolic dysfunction who are offered ACE inhibitors and beta-blockers for first-line treatment. There is also evidence that beta-blockers can be safely used by all patients.Those who remain symptomatic despite optimal first-line treatment will have several choices of second-line treatments: aldosterone antagonists, angiotensin II receptor antagonists (ARBs) or hydralazine in combination with nitrate. This recommendation is based on evidence for better outcomes for particular second-line treatments in certain subgroups.There was no clear evidence of benefit for drug treatment in heart failure with preserved ejection fraction (HFPEF), but advice on drug treatments for comorbid conditions is stressed.

Transcript

  • 1. New solutions in heart failure: Drugs and Devices Martin R Cowie Professor of Cardiology Imperial College London (Royal Brompton Hospital) m.cowie@imperial.ac.uk
  • 2. NICE 2010 Low Ejection FractionHF with normalEjection Fraction
  • 3. Ever increasing evidence base.... EMPHASIS SHIFT RAFT
  • 4. Ever increasing evidence base.... EMPHASIS SHIFT RAFT
  • 5. Neurohormonal activation
  • 6. Neurohormonal antagonism Post-MI HF Mild Moderate Severe LV dysfunction CHF CHF CHF AIRE/SAVE/TRACE SOLVD Treatment CONSENSUS ACE-I (ramipril/captopril/trando) (enalapril) (enalapril) Beta CAPRICORN US Carvedilol/MERIT/CIBIS COPERNICUS Blocker (carvedilol) (carvedilol/metoprolol/biso) (carvedilol) RALES Aldosterone EPHESUS EMPHASIS-HF (spironolactone) Blocker (eplerenone) (eplerenone) Moderate-Severe HF NYHA II mild CHF NYHA III/IV OPTIMAAL ELITE (Losartan) ARB (Losartan) ValHEFT/CHARM VALIANT (Valsartan/Candesartan) (Valsartan)ACE-I: Angiotensin Converting Enzyme-InhibitorARB: Angiotensin II Receptor Blocker
  • 7. Aldosterone antagonist therapy for heart failure due to LVSDProbabilityof Survival • The Randomised Aldactone Evaluation 1.00 Study (RALES) 0.95 0.90 • 1663 patients with NYHA III or IV heart RRR=0.30 (0.18-0.40) failure and ejection fraction ≤35% who 0.85 RRR = 30% were already treated with ACE inhibitor, 0.80 P<0.001 diuretic digoxin 0.75 Spironolactone 0.70 • Spironolactone 25mg od vs placebo, 0.65 with patients followed for an average of 0.60 2 years Placebo 0.55 P < 0.001 • 30% reduction in the risk of death 0.50 (p<0.001) and 35% reduction in risk of 0.45 hospitalisation (p<0.001) among 0.00 patients randomised to spironolactone 0 3 6 9 12 15 18 21 24 27 30 33 36 Months Pitt et al, N Engl J Med, 1999
  • 8. Aldosterone antagonist therapy for heart failure after MI EPHESUS trial • 3313 patients were randomised to eplerenone Cumulative Incidence (%) 25 mg/day and 3319 to placebo (in addition to ‘standard’ medical therapy). 40 35 p=0.008 • Mean follow-up of 16-months. Among those 30 RRR=0.15 taking eplerenone there was: 25 Placebo – 15% relative risk reduction in all-cause death 20 (p=0.008) 15 Eplerenone – 13% relative risk reduction in cardiovascular 10 death or hospitalisation (p=0.002) 5 – 21% relative risk reduction in sudden cardiac 0 death ( p=0.03) 0 3 6 9 121518212427303336 Months since Randomization • Compared with spironolactone, eplerenone wasNo. at RiskPlacebo 3313 3064 3319 3125 2983 2830 2418 1801 1213 709 323 99 2 0 0 less likely to cause gynaecomastia or breastEplerenone 3044 2896 2463 1857 1260 728 336 110 0 0 0 tenderness, but K+ monitoring was still essential. Pitt et al, N Engl J Med, 2003
  • 9. NEJM 2011; 364: 11-21
  • 10. NEJM 2011; 364: 11-21
  • 11. Concomitant medication NEJM 2011; 364: 11-21
  • 12. 37% RRRNEJM 2011; 364: 11-21
  • 13. 24% RRR
  • 14. 23% RRR 42% RRR
  • 15. EMPHASIS-HF Study SAFETY ADVERSE EVENTS Patients with an adverse event (AE)* Outcome Eplerenone Placebo (N=1373) P Value (N=1360) All 979 (72) 1007 (73.6) 0.37 Hyperkalemia – n (%) 109 (8) 50 (3.7) <0.001 Hypokalemia – n (%) 16 (1.2) 30 (2.2) 0.05 Renal failure – n (%) 38 (2.8) 41 (3.0) 0.82 Hypotension – n (%) 46 (3.4) 37 (2.7) 0.32 Gynecomastia and other 10 (0.7) 14 (1.0) 0.54 breast disorders – n (%)*Investigator reported adverse events
  • 16. EMPHASIS-HF Study SAFETY: DRUG DISCONTINUATIONS DUE TO AE Patients with an adverse event* leading to drug withdrawal — no. (%) Outcome Eplerenone Placebo P Value (N=1360) (N=1373) All 188 (13.8) 222 (16.2) 0.09 Hyperkalemia – n (%) 15 (1.1) 12 (0.9) 0.57 Hypokalemia – n (%) 0 3 (0.2) 0.25 Renal failure – n (%) 4 (0.3) 6 (0.4) 0.75 Hypotension – n (%) 0 3 (0.2) 0.25 Gynecomastia and other 2 (0.1) 2 (0.1) 1.00 breast disorders – n (%)*Investigator reported adverse events
  • 17. EMPHASIS-HF Study SAFETY: PRESPECIFIED ADJUDICATED EVENTS Eplerenone Placebo Hazard Ratio P Outcome (N=1364) (N=1373) (95% CI) Value Hospitalization for worsening renal 9 (0.7) 8 (0.6) 0.97 (0.37, 2.58) 0.95 failure* Hospitalization for 4 (0.3) 3 (0.2) 1.15 (0.25, 5.31) 0.85 hyperkalemia*EMPHASIS HF study results presentation. Presented at AHA congress 2010.http://click.heartemail.org/?qs=c809010216325f9c50c94e221d4e3fd62e92e966356857c348c68a0675e1e1a3. Accessed November 21, 2010
  • 18. Important addition to therapy.... For mild HF with low EF NNT • To prevent one patient experiencing the primary endpoint, per year of follow up, is 19 • To postpone one death, per year of follow up, is 51NB Eplerenone not yet licensed for treatment of EMPHASIS population
  • 19. Ever increasing evidence base.... EMPHASIS SHIFT RAFT
  • 20. Heart rate strongly associated with mortalityThe CIBIS-2 study (n=2539)One-year mortality (%) 18 16 Bisoprolol 14 Placebo 12 10 8 6 4 2 0 Baseline HR Baseline HR Baseline HR 72 bpm 72-84 bpm >84 bpm Lechat P, et al. Circulation. 2001;103:1428-1433.
  • 21. Reduction of heart rate and outcomes in CHF trials Changes in mortality (%) 60 PROFILE 40 XAMOTEROL 20 PROMISE VHeFT (prazosin) 0 CIBIS VHeFT -20 BHAT SOLVD (HDZ/ISDN) ANZ -40 NOR TIMOLOL GESICA CONSENSUS -60 MOCHA US -80 CARVEDILOL -100 -18 -16 -14 -12 -10 -8 -6 -4 -2 0 2 4 6 8 10 Changes in heart rate (bpm)Kjekshus J, et al. Eur Heart J. 1999;1(suppl.H):H64-H69.
  • 22. Ivabradine: ‘pure’ heart rate reduction open closed closed RR Pure 0 mV heart rate reduction -40 mV -70 mV Ivabradine If inhibition reduces the diastolic depolarization slope, and thereby lowers heart rate Thollon C, et al. Brit J Pharmacol. 1994;112:37-42.
  • 23. Systolic Heart failure treatment with the If inhibitor ivabradine Trial
  • 24. Primary objectiveTo evaluate whether the If inhibitor ivabradineimproves cardiovascular outcomes in patients with:1. Moderate to severe chronic heart failure2. Left ventricular ejection fraction  35%3. Heart rate  70 bpm in sinus rhythm4. Best recommended therapyIvabradine 5mg bd or placebo, titrated to7.5mg/5mg/2.5mg according to tolerability
  • 25. Study end points Primary composite end point  Cardiovascular death  Hospitalization for worsening heart failure Other end points  All-cause / CV / HF death  All-cause / CV / hospitalization for heart failure  Composite of CV death, hospitalization for HF or nonfatal MI  NYHA class / Patient & Physician Global Assessment Median study duration 22.9 months, maximum 41.7 monthsSwedberg K, et al. Eur J Heart Fail. 2010;12:75-81.
  • 26. Baseline characteristics Ivabradine Placebo 3241 3264 Mean age (y) 60.7 60.1 Male (%) 76 77 Ischemic etiology (%) 68 67 NYHA II (%) 49 49 NYHA III/IV (%) 51 51 Previous MI (%) 56 56 Diabetes (%) 30 31 Hypertension (%) 67 66Swedberg K, et al. Lancet. 2010;376:875-885.
  • 27. Baseline characteristics Ivabradine Placebo 3241 3264 Mean heart rate (bpm) 80 80 Mean LVEF (%) 29 29 Mean SBP (mm Hg) 122 121 Mean DBP (mm Hg) 76 76 eGFR (mL/min/1.73 m2) 75 75Swedberg K, et al. Lancet. 2010;376:875-885.
  • 28. Chronic heart failure background treatment Patients (%) 100 91 91 Ivabradine 89 90 84 83 Placebo 80 61 59 60 40 22 22 20 3 4 0 Beta-blockers ACEIs and/or ARBs Diuretics Aldosterone Digitalis ICD/CRT antagonistsSwedberg K, et al. Lancet. 2010;376:875-885.
  • 29. Background beta-blocker treatment Patients (%) 100 Ivabradine 89 89 Placebo 80 60 56 56 40 26 26 20 0 Beta-blockers at At least 50% target daily Target daily dose randomization doseSwedberg K, et al. Lancet. 2010;376:875-885.
  • 30. Heart rate is a predictor of CV death and/or hospitalizations for HF Patients with primary composite end point in the placebo group (%) 50 ≥87 bpm P<0.001 40 80 to <87 bpm 75 to <80 bpm 30 72 to <75 bpm 70 to <72 bpm 20 10 0 Months 0 6 12 18 24 30 Risk increases by 3% per 1 bpm increase, and by 16% per 5 bpm increaseBöhm M, et al. Lancet. 2010;376:886-894.
  • 31. Mean heart rate reduction Heart rate (bpm) 90 80 80 75 Placebo 75 70 Ivabradine 67 64 60 50 Months 0 2 weeks 1 4 8 12 16 20 24 28 32Swedberg K, et al. Lancet. 2010;376:875-885.
  • 32. Primary composite end point (CV death or hospital admission for worsening HF) Cumulative frequency (%) 40 HR = 0.82 (0.75–0.90) P < 0.0001 Placebo 30 18% RRR Ivabradine 20 10 0 Months 0 6 12 18 24 30Swedberg K, et al. Lancet. 2010;376:875-885.
  • 33. Hospitalization for worsening heart failure Cumulative frequency (%) 30 HR = 0.74 (0.66–0.83) P < 0.0001 Placebo 26% RRR 20 Ivabradine 10 0 0 6 12 18 24 30 MonthsSwedberg K, et al. Lancet. 2010;376:875-885.
  • 34. Cardiovascular death Cumulative frequency (%) 30 HR = 0.91 (0.80–1.03) P = 0.128 9% RRR (P=0.12) Placebo 20 Ivabradine 10 0 0 6 12 18 24 30 MonthsSwedberg K, et al. Lancet. 2010;376:875-885.
  • 35. Death from heart failure Cumulative frequency (%) 10 HR = 0.74 (0.58–0.94) P = 0.014 26% RRR Placebo 5 Ivabradine 0 0 6 12 18 24 30 MonthsSwedberg K, et al. Lancet. 2010;376:875-885.
  • 36. Effect of ivabradine in prespecified subgroups Test for interaction Age <65 years ≥65 years Sex Male Female Beta-blockers No Yes Etiology of heart failure Nonischemic Ischemic NYHA class NYHA class II NYHA class III or IV Diabetes No Yes Hypertension No Yes Baseline heart rate <77 bpm P = 0.029 ≥77 bpm 0.5 1.0 1.5 Hazard ratio Favors ivabradine Favors placeboSwedberg K, et al. Lancet. 2010;376:875-885.
  • 37. Incidence of selected adverse events Patients with an event n= 6492 Ivabradine Placebo P value n=3232, n (%) n=3260, n (%) All serious adverse events 1450 (45%) 1553 (48%) 0.025 All adverse events 2439 (75%) 2423 (74%) 0.303 Symptomatic bradycardia 150 (5%) 32 (1%) <0.0001 Asymptomatic bradycardia 184 (6%) 48 (1%) <0.0001 Atrial fibrillation 306 (9%) 251 (8%) 0.012 Phosphenes 89 (3%) 17 (1%) <0.0001 Blurred vision 17 (1%) 7 (<1%) 0.042Swedberg K, et al. Lancet. 2010;376:875-885.
  • 38. Treatment discontinuation Patients with an adverse event, leading to withdrawal Ivabradine Placebo P value n=3232, n (%) n=3260, n (%) All adverse events 467 (14%) 416 (13%) 0.051 Symptomatic bradycardia 20 (1%) 5 (<1%) 0.002 Asymptomatic bradycardia 28 (1%) 5 (<1%) <0.0001 Atrial fibrillation 135 (4%) 113 (3%) 0.137 Phosphenes 7 (<1%) 3 (<1%) 0.224 Blurred vision 1 (<1%) 1 (<1%) 1.000Swedberg K, et al. Lancet. 2010;376:875-885.
  • 39. Important addition to therapy....For those in sinus rhythm with HR > 70bpm and low EF NNT • To prevent one patient experiencing the primary endpoint, per year of follow up, is 26 • To postpone one hospitalisation for HF, per year of follow up, is 27 NB Ivabradine not yet licensed for treatment of SHIFT population
  • 40. Ever increasing evidence base.... EMPHASIS SHIFT RAFT
  • 41. New device implant rate 1999-2009 ICD CRTTen year average growth rate 15.1%
  • 42. High energy device implant rates across Europe Source: Eucomed 2009
  • 43. NEJM 2010; 363: 2385-95
  • 44. RAFT design
  • 45. 25% RRR
  • 46. 25% RRR
  • 47. Subgroups with more benefit? QRS ≥ 150 msec LVEF < 20% LBBB
  • 48. Conclusions
  • 49. So – how should this affect practice for those with low EF HF?• Life-saving therapy should include: – ACEI (or ARB), – Β-blocker, and – aldosterone antagonist (eplerenone) or good reason for not!• Once β-blockade maximised, if in sinus rhythm and HR > 70bpm, ivabradine should be added• For patients with severe LV systolic dysfunction, mild- moderate HF, LBBB and optimal drug therapy, increasingly likely that CRT-D (rather than CRT-P or ICD alone) will be recommended• NICE will issue new guidance in 2012/13 for device therapy.• Good monitoring always required!! These statements are a personal opinion - NOT official recommendations!