Download - Cowie Inverness Nov 2011 New Solutions in HF
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New solutions in heart failure:Drugs and Devices
Martin R CowieProfessor of Cardiology
Imperial College London (Royal Brompton Hospital)[email protected]
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Low Ejection Fraction
HF with normal Ejection Fraction
NICE 2010
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Ever increasing evidence base....
EMPHASIS
SHIFT
RAFT
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Ever increasing evidence base....
EMPHASIS
SHIFT
RAFT
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Neurohormonal activation
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ModerateCHF
SevereCHF
MildCHF
Post-MI HFLV dysfunction
SOLVD Treatment(enalapril)
CONSENSUS(enalapril)
AIRE/SAVE/TRACE(ramipril/captopril/trando)
US Carvedilol/MERIT/CIBIS(carvedilol/metoprolol/biso)
COPERNICUS(carvedilol)
CAPRICORN(carvedilol)
RALES(spironolactone)
Moderate-Severe HFNYHA III/IV
EPHESUS(eplerenone)
ELITE (Losartan)ValHEFT/CHARM
(Valsartan/Candesartan)
OPTIMAAL(Losartan)VALIANT
(Valsartan)
ACE-I
BetaBlocker
AldosteroneBlocker
ARB
EMPHASIS-HF(eplerenone)
NYHA II mild CHF
Neurohormonal antagonism
ACE-I: Angiotensin Converting Enzyme-InhibitorARB: Angiotensin II Receptor Blocker
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• The Randomised Aldactone Evaluation Study (RALES)
• 1663 patients with NYHA III or IV heart failure and ejection fraction ≤35% who were already treated with ACE inhibitor, diuretic ± digoxin
• Spironolactone 25mg od vs placebo, with patients followed for an average of 2 years
• 30% reduction in the risk of death (p<0.001) and 35% reduction in risk of hospitalisation (p<0.001) among patients randomised to spironolactone
Aldosterone antagonist therapy for heart failure due to LVSD
Pitt et al, N Engl J Med, 1999
Probabilityof Survival
P < 0.001
RRR=0.30 (0.18-0.40)
Spironolactone
Placebo
Months
0 3 6 9 12 15 18 21 24 27 30 33 360.00
0.45
0.50
0.55
0.60
0.650.70
0.75
0.80
0.85
0.900.95
1.00
RRR = 30% P<0.001
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• 3313 patients were randomised to eplerenone 25 mg/day and 3319 to placebo (in addition to ‘standard’ medical therapy).
• Mean follow-up of 16-months. Among those taking eplerenone there was:
– 15% relative risk reduction in all-cause death (p=0.008)
– 13% relative risk reduction in cardiovascular death or hospitalisation (p=0.002)
– 21% relative risk reduction in sudden cardiac death ( p=0.03)
• Compared with spironolactone, eplerenone was less likely to cause gynaecomastia or breast tenderness, but K+ monitoring was still essential.
Aldosterone antagonist therapy for heart failure after MI
EPHESUS trial
Pitt et al, N Engl J Med, 2003
36
No. at RiskPlaceboEplerenone
Cumulative Incidence (%)
Months since Randomization
p=0.008RRR=0.15
0 3 6 9 121518212427303305
10152025303540
Placebo
Eplerenone
33133319
30643125
29833044
28302896
24182463
18011857
12131260
709728
323336
99110
20
00
00
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NEJM 2011; 364: 11-21
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NEJM 2011; 364: 11-21
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Concomitant medication
NEJM 2011; 364: 11-21
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NEJM 2011; 364: 11-21
37% RRR
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24% RRR
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23% RRR 42% RRR
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EMPHASIS-HF StudySAFETY ADVERSE EVENTS
*Investigator reported adverse events
Patients with an adverse event (AE)*
Outcome Eplerenone (N=1360)
Placebo (N=1373) P Value
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 breast disorders – n (%)
10 (0.7) 14 (1.0) 0.54
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EMPHASIS-HF StudySAFETY: DRUG DISCONTINUATIONS DUE TO AE
*Investigator reported adverse events
Patients with an adverse event* leading to drug withdrawal — no. (%)
Outcome Eplerenone (N=1360)
Placebo (N=1373)
P Value
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 breast disorders – n (%)
2 (0.1) 2 (0.1) 1.00
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EMPHASIS-HF StudySAFETY: PRESPECIFIED ADJUDICATED EVENTS
Outcome Eplerenone (N=1364)
Placebo (N=1373)
Hazard Ratio(95% CI)
P Value
Hospitalization for worsening renal failure*
9 (0.7) 8 (0.6) 0.97 (0.37, 2.58) 0.95
Hospitalization for hyperkalemia* 4 (0.3) 3 (0.2) 1.15 (0.25, 5.31) 0.85
EMPHASIS HF study results presentation. Presented at AHA congress 2010. http://click.heartemail.org/?qs=c809010216325f9c50c94e221d4e3fd62e92e966356857c348c68a0675e1e1a3. Accessed November 21, 2010
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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 51
NB Eplerenone not yet licensed for treatment of EMPHASIS population
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Ever increasing evidence base....
EMPHASIS
SHIFT
RAFT
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Heart rate strongly associated with mortality
Lechat P, et al. Circulation. 2001;103:1428-1433.
18
6
2
0
One-year mortality (%)
Baseline HR72 bpm
4
8
10
12
14
16
Baseline HR72-84 bpm
Baseline HR>84 bpm
Bisoprolol
Placebo
The CIBIS-2 study (n=2539)
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Changes in heart rate (bpm)
Kjekshus J, et al. Eur Heart J. 1999;1(suppl.H):H64-H69.
Changes in mortality (%)
-18 -16 -14 -12 -10 -8 -6 -4 -2 0 2 4 6 8 10-100
-80
-60
-40
-20
0
20
40
60
XAMOTEROLPROFILE
PROMISE
VHeFT(HDZ/ISDN)SOLVD
CONSENSUS
ANZ
USCARVEDILOL
BHATCIBIS
NORTIMOLOL
MOCHA
GESICA
VHeFT(prazosin)
Reduction of heart rate and outcomes in CHF trials
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Ivabradine: ‘pure’ heart rate reduction
If inhibition reduces the diastolic depolarization slope, and thereby lowers heart rate
RR
Pureheart ratereduction
0 mV
-40 mV
-70 mV
Thollon C, et al. Brit J Pharmacol. 1994;112:37-42.
closedopen
closed
Ivabradine
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Systolic Heart failure treatment with
the If inhibitor ivabradine Trial
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Primary objective
To evaluate whether the If inhibitor ivabradine
improves cardiovascular outcomes in patients with:
1. Moderate to severe chronic heart failure 2. Left ventricular ejection fraction 35% 3. Heart rate 70 bpm in sinus rhythm 4. Best recommended therapy
Ivabradine 5mg bd or placebo, titrated to 7.5mg/5mg/2.5mg according to tolerability
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Study end points
Cardiovascular death Hospitalization for worsening heart failure
Primary composite end point
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 months
Swedberg K, et al. Eur J Heart Fail. 2010;12:75-81.
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Ivabradine3241
Placebo3264
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 66
Swedberg K, et al. Lancet. 2010;376:875-885.
Baseline characteristics
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Baseline characteristics
Ivabradine3241
Placebo3264
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 75
Swedberg K, et al. Lancet. 2010;376:875-885.
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Chronic heart failure background treatment
Swedberg K, et al. Lancet. 2010;376:875-885.
Beta-blockers ACEIs and/or ARBs Diuretics Aldosterone an-tagonists
Digitalis ICD/CRT0
20
40
60
80
10089 91
84
61
22
3
90 91
83
59
22
4
Ivabradine
Placebo
Patients (%)
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Swedberg K, et al. Lancet. 2010;376:875-885.
Beta-blockers at random-ization
At least 50% target daily dose
Target daily dose0
20
40
60
80
10089
56
26
89
56
26
Ivabradine
Placebo
Patients (%)
Background beta-blocker treatment
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Heart rate is a predictor of CV death and/or hospitalizations for HF
Böhm M, et al. Lancet. 2010;376:886-894.
50
40
30
20
10
00 6 12 18 24 30
Months
≥87 bpm
80 to <87 bpm
75 to <80 bpm
72 to <75 bpm
70 to <72 bpm
P<0.001
Patients with primary composite end point in the placebo group (%)
Risk increases by 3% per 1 bpm increase, and by 16% per 5 bpm increase
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Mean heart rate reduction
0 2 weeks 1 4 8 12 16 20 24 28 32Months
90
80
70
60
50
67
7575
80
64
Heart rate (bpm)
Placebo
Ivabradine
Swedberg K, et al. Lancet. 2010;376:875-885.
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0 6 12 18 24 30
40
30
20
10
0
Primary composite end point (CV death or hospital admission for worsening HF)
Cumulative frequency (%)
Placebo
Ivabradine
HR = 0.82 (0.75–0.90) P < 0.0001
Swedberg K, et al. Lancet. 2010;376:875-885.
Months
18% RRR
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0 6 12 18 24 30
30
20
10
0
Hospitalization for worsening heart failure
Placebo
Ivabradine
HR = 0.74 (0.66–0.83)P < 0.0001
Cumulative frequency (%)
Swedberg K, et al. Lancet. 2010;376:875-885.
Months
26% RRR
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0 6 12 18 24 30
30
20
10
0
Cardiovascular death
Placebo
Ivabradine
HR = 0.91 (0.80–1.03)P = 0.128
Cumulative frequency (%)
Swedberg K, et al. Lancet. 2010;376:875-885.
Months
9% RRR (P=0.12)
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Death from heart failure
0 6 12 18 24 30
10
5
0
HR = 0.74 (0.58–0.94) P = 0.014
Placebo
Ivabradine
Cumulative frequency (%)
Swedberg K, et al. Lancet. 2010;376:875-885.
Months
26% RRR
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Age <65 years ≥65 years Sex Male Female Beta-blockers No YesEtiology of heart failure Nonischemic IschemicNYHA class NYHA class II NYHA class III or IV
Diabetes No YesHypertension No YesBaseline heart rate <77 bpm ≥77 bpm
Test for interaction
P = 0.029
1.51.00.5Hazard ratioFavors ivabradine Favors placebo
Effect of ivabradine in prespecified subgroups
Swedberg K, et al. Lancet. 2010;376:875-885.
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Incidence of selected adverse events
Patients with an event
n= 6492
Ivabradine
n=3232, n (%)
Placebo
n=3260, n (%)P value
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%) 0.042
Swedberg K, et al. Lancet. 2010;376:875-885.
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Patients with an adverse event, leading to withdrawal
Ivabradine n=3232, n (%)
Placebo n=3260, n (%)
P value
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%) 1.000
Treatment discontinuation
Swedberg K, et al. Lancet. 2010;376:875-885.
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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
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Ever increasing evidence base....
EMPHASIS
SHIFT
RAFT
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New device implant rate 1999-2009
Ten year average growth rate 15.1%
ICD
CRT
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High energy device implant rates across Europe
Source: Eucomed 2009
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NEJM 2010; 363: 2385-95
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RAFT design
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25% RRR
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25% RRR
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QRS ≥ 150 msec
LVEF < 20%
LBBB
Subgroups with more benefit?
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Conclusions
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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!