SCDHeFT Sudden Cardiac Death in Heart Failure Trial

1
SCD-HeFTSudden Cardiac Death in Heart Failure
Trial
Bardy GH. N Engl J Med. 2005352225-237.
2
SCD-HeFT Sponsors

• NHLBI All research costs at CCC, ICD Core, DCC,
  QoL
• Medtronic Site clinical costs, ICD donations,
  meetings/travel
• Wyeth-Ayerst Placebo and Amiodarone
• Duke University Pharmacy Study drug distribution
• Washington DC Veterans Hospital Holter Core Lab
• Cambridge Heart Meetings, TWA sub-study
• Knoll Pharmaceuticals Meetings
• NIH Nursing Institute Psychosocial sub-study

Bardy GH. N Engl J Med. 2005352225-237.
3
SCD-HeFT Hypothesis

• Determine if amiodarone or ICD will decrease the
  risk of death from any cause in patients with
  mild-to-moderate heart failure

Bardy GH. N Engl J Med. 2005352225-237.
4
SCD-HeFT Inclusion Criteria

• Symptomatic CHF (NYHA Class II and III) due to
  ischemic or non-ischemic dilated cardiomyopathy
• LVEF 35
• 18 years of age no upper age limitation
• CHF 3 months
• On optimal medical therapy for gt 3 months
• Appropriate dose of ACE-I
• Beta blocker, if tolerated

Bardy GH. N Engl J Med. 2005352225-237.
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SCD-HeFT Exclusion Criteria

• Asymptomatic patients with LV dysfunction
• NYHA Class I or IV
• Class I ICD indications
• Pacemaker indications
• lt 18 years
• Death expected 1 year due to cardiac causes
• Amiodarone or other AA drugs contraindicated

• Current Class I or II AA drugs
• Unexplained syncope 5 years
• AF patients requiring catheter ablation or
  amiodarone
• MI 30 days
• CABG or PTCA 30 days

Bardy GH. N Engl J Med. 2005352225-237.
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SCD-HeFT Centers
(4)
(2)
(2)
(2)
(2)
(2)
(5)
(8)
(10)
(3)
(2)
(2)
(3)
(3)
(2)
(2)
(3)
(2)
(2)
Enrollment 2521
(3)
148 sites in the US, Canada,and New Zealand.
(2)
Bardy GH. N Engl J Med. 2005352225-237.
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SCD-HeFT Endpoints

• Primary
• Overall Mortality
• Secondary
• Mortality ischemic vs. non-ischemic
• Mortality NYHA Class II vs. III
• Mortality by Sub Groups age, gender, LVEF, MI
  Hx, time of MI, QRS width
• Cause-Specific Death
• HF Morbidity and Mortality
• Quality of Life
• Cost of Care and Cost-Effectiveness

Bardy GH. N Engl J Med. 2005352225-237.
8
SCD-HeFT Protocol
DCM CAD and CHF
EF lt 35
NYHA Class II or III
6-Minute Walk, Holter
2521 Patients
R
Placebo N 847
ICD Implant N 829
Amiodarone N 845
Minimum of 2.5 years follow-up required 45 months
average follow-up
Optimized ?B, ACE-I, Diuretics
Bardy GH. N Engl J Med. 2005352225-237.
9
Study Power Calculations

• Predicted control mortality rate10 per year
• Presumed minimum follow-up 2.5 years
• 90 power to detect a 25 in mortality in
  either amiodarone or ICD arm compared to placebo
• Alpha 0.025 for each comparison
• Intention-to-treat study design

Bardy GH. N Engl J Med. 2005352225-237.
10
SCD-HeFT Assessments Background Medical Therapies

• Electrocardiography
• 6-minute walk test
• 24-hour ambulatory electrocardiography
• Liver and thyroid function tests
• Chest radiography
• Drugs if required beta blocker, ACE-I,
  aldosterone, aspirin, and statins

Bardy GH. N Engl J Med. 2005352225-237.
11
SCD-HeFT Background Medications

• Baseline Last Follow-Up
• ACE Inhibitor 85 72
• ACE Inhibitor or ARB 96 87
• Beta Blocker 69 78
• Spironolactone 19 31
• Loop Diuretics 82 80
• Aspirin 56 55
• Statin 38 47

Bardy GH. N Engl J Med. 2005352225-237.
12
SCD-HeFT Study Drug Dosing

• Outpatient administration
• lt 800 mg qd for week 1
• lt 400 mg qd for weeks 2-4
• Chronic dose weight dependent
• 200 mg/d if lt 150 lbs
• 300 mg/d if 150-200 lbs
• 400 mg/d if gt 200 lbs

Bardy GH. N Engl J Med. 2005352225-237.
13
SCD-HeFT ICD Guidelines

• Medtronic Model 7223Cx Micro Jewel II
• Follow-Up 1-week, 1-month, 3-month,
  then every 3 months
• Nominals
• VF Settings ON, 320 ms, NID 18/24, 30 J
• FVT and VT Settings OFF
• VVI 50 (Hysteresis 34 bpm)
• Pre-VT/VF memory activation

Bardy GH. N Engl J Med. 2005352225-237.
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SCD-HeFT Baseline Patient Characteristics
Bardy GH. N Engl J Med. 2005352225-237.
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SCD-HeFT Baseline Patient Characteristics
Bardy GH. N Engl J Med. 2005352225-237.
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SCD-HeFT Baseline Patient Characteristics
Bardy GH. N Engl J Med. 2005352225-237.
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SCD-HeFT Baseline Patient Characteristics
Bardy GH. N Engl J Med. 2005352225-237.
18
SCD-HeFT Medication Use
Last Follow-Up
Bardy GH. N Engl J Med. 2005352225-237.
19
SCD-HeFT Medication Use Last Follow-Up
Bardy GH. N Engl J Med. 2005352225-237.
20
SCD-HeFT Mortality Rate Overall Results
Hazard Ratio (97.5 Cl) P-Value Amiodarone vs.
Placebo 1.06 (0.86 - 1.30) 0.53 ICD vs.
Placebo 0.77 (0.62 - 0.96) 0.007
0.4
0.3
Mortality Rate
0.2
0.1
Amiodarone
Placebo
ICD
0.0
48
36
24
12
0
60
Months of Follow-Up
No. at Risk Amiodarone 845 772 715 484 280 97 Plac
ebo 847 797 724 505 304 89 ICD 829 778 733 501 30
4 103
Bardy GH. N Engl J Med. 2005352225-237.
21
SCD-HeFT Overall Mortality Results
ICDs reduce mortality by 23
Bardy GH. N Engl J Med. 2005352225-237.
22
SCD-HeFT 5-Year Mortality RateOverall Results
36.1
34
28.9
Mortality Rate
Bardy GH. N Engl J Med. 2005352225-237.
23
SCD-HeFT Mortality Rate Ischemic CHF Patients
Hazard Ratio (97.5 Cl) P-Value Amiodarone vs.
Placebo 1.05 (0.91 - 1.36) 0.66 ICD vs.
Placebo 0.79 (0.60 - 1.04) 0.05
0.4
0.3
Mortality Rate
0.2
0.1
Amiodarone
Placebo
ICD
0.0
48
36
24
12
0
60
Months of Follow-Up
No. at Risk Amiodarone 426 384 346 227 130 46 Plac
ebo 453 415 370 244 152 48 ICD 431 395 365 244 14
4 48
Bardy GH. N Engl J Med. 2005352225-237.
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SCD-HeFT Mortality RateNon-Ischemic CHF Patients
Hazard Ratio (97.5 Cl) P-Value Amiodarone vs.
Placebo 1.07 (0.76 - 1.51) 0.65 ICD vs.
Placebo 0.73 (0.50 - 1.07) 0.06
0.5
0.4
Amiodarone
Placebo
ICD
0.3
Mortality Rate
0.2
0.1
0.0
48
36
24
12
0
60
Months of Follow-Up
No. at Risk Amiodarone 419 388 369 257 150 51 Plac
ebo 394 382 354 261 152 41 ICD 398 383 368 257 16
0 55
Bardy GH. N Engl J Med. 2005352225-237.
25
SCD-HeFT 5-Year Mortality RateIschemic vs.
Non-Ischemic
43.2
41.7
35.9
27.9
25.8
Mortality Rate
21.4
Ischemic
Non-Ischemic
Ischemic
Non-Ischemic
Ischemic
Non-Ischemic
Placebo
ICD
Amiodarone
Bardy GH. N Engl J Med. 2005352225-237.
26
SCD-HeFT Mortality RateNYHA Class II Patients
Hazard Ratio (97.5 Cl) P-Value Amiodarone vs.
Placebo 0.85 (0.65 - 1.11) 0.17 ICD vs.
Placebo 0.54 (0.40 - 0.74) lt 0.001
0.6
0.5
Amiodarone
Placebo
ICD
0.4
0.3
Mortality Rate
0.2
0.1
0.0
48
36
24
12
0
60
Months of Follow-Up
No. at Risk Amiodarone 601 563 536 378 222 76 Plac
ebo 594 563 522 367 218 72 ICD 566 550 531 371 23
6 80
Bardy GH. N Engl J Med. 2005352225-237.
27
SCD-HeFT Mortality RateNYHA Class III Patients
Hazard Ratio (97.5 Cl) P-Value Amiodarone vs.
Placebo 1.44 (1.05 - 1.97) 0.010 ICD vs.
Placebo 1.16 (0.84 - 1.61) 0.30
0.6
Amiodarone
0.5
Placebo
ICD
0.4
0.3
Mortality Rate
0.2
0.1
0.0
48
36
24
12
0
60
No. at Risk Amiodarone 244 209 179 106 58 21 Place
bo 253 234 202 138 86 17 ICD 263 228 202 130 68 2
3
Months of Follow-Up
Bardy GH. N Engl J Med. 2005352225-237.
28
SCD-HeFT 5-Year Mortality RateNYHA Class II vs.
III
52.8
48.4
45.6
32
Mortality Rate
26.4
20
NYHA II
NYHA III
NYHA II
NYHA III
NYHA II
NYHA III
Placebo
ICD
Amiodarone
Bardy GH. N Engl J Med. 2005352225-237.
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SCD-HeFT Mortality Results NYHA Class III
Patients

• No survival benefits for ICD therapy in NYHA
  Class III patients in SCD-HeFT1
• These results are not consistent with other
  trial results and need to be further evaluated
• DEFINITE Class III patients had the largest
  survival benefits with ICD therapy2
• Patients with the worst LVEF in MADIT-II and
  AVID trials had the largest benefit from ICD
  therapy3,4

1 Bardy GH. N Engl J Med. 2005352225-237. 2
Kadish A. N Engl J Med. 20043502151-2158. 3
Moss AJ. N Engl J Med. 2002346877-883. 4 AVID
Investigators. N Engl J Med. 19973371576-1884.
30
SCD-HeFT Mortality Results Ischemic
Non-Ischemic and NYHA Class II-III
Bardy GH. N Engl J Med. 2005352225-237.
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SCD-HeFT Discontinuations and Crossovers
Bardy GH. N Engl J Med. 2005352225-237.
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SCD-HeFT Complications

• Amiodarone (different than placebo)
• 4 increased tremor (P 0.02)
• 6 increased hypothyroidism (P lt 0.001)
• ICD Therapy
• 5 implant complications
• 9 follow-up complications

Bardy GH. N Engl J Med. 2005352225-237.
33
SCD-HeFT ICD Shock History Results

• 31 received shock for any reason
• 21 received shock for rapid VT or VF
• During 5 years follow-up the average annual
  rate of shock for rapid VT or VF was 5.1

Bardy GH. N Engl J Med. 2005352225-237.
34
SCD-HeFT Rhythm Precursors to VT/VF
Poole JE. Heart Rhythm 2005. May2
(1suppl)AB20-5.
35
SCD-HeFT Change in NYHA ClassBaseline to 3 Years
Changes in NYHA Class
2
1
0
Patients
-1
-2
Surviving patients HF condition appeared to
improve progressively over time. Good drug
management likely contributed to these results.
Bardy GH. Heart Rhythm 2005. May2
(1suppl)AB20-3.
36
SCD-HeFT Mode of Death
Packer DL. Heart Rhythm 2005. May2
(1suppl)AB20-2.
37
SCD-HeFT Tachyarrhythmia Deaths
ICD therapy reduced tachyarrhythmia deaths by 60
Packer DL. Heart Rhythm 2005. May2
(1suppl)AB20-2.
38
SCD-HeFT Hazard Rate ResultsICD vs. Placebo
ICD Therapy vs. Placebo
Subgroup
N Hazard Ratio (97.5 Cl) Female Sex
382 0.96 (0.58 - 1.61)Male Sex 1294 0.73 (0.57 -
0.93)
Age lt 65 Yrs 1098 0.68 (0.50 - 0.93)Age gt 65
Yrs 578 0.86 (0.62 - 1.18)
White Race 1283 0.78 (0.61 - 1.00)Nonwhite Race
393 0.75 (0.48 - 1.17)
LVEF lt 30 1390 0.73 (0.57 - 0.92)LVEF gt 30
285 1.08 (0.57 - 2.07)
4.0
2.0
1.0
0.5
0.25
Placebo Better
ICDBetter
Bardy GH. N Engl J Med. 2005352225-237.
39
SCD-HeFT Hazard Rate ResultsICD vs. Placebo
Subgroup
ICD Therapy vs. Placebo
N Hazard Ratio (97.5 Cl) QRS lt 120 ms
977 0.84 (0.62 - 1.14)QRS gt 120 ms 699 0.67
(0.49 - 0.93)
6-Min Walk Test lt 950 ft 526 1.14 (0.81 -
1.60) 950 1275 ft 536 0.57 (0.38 - 0.88)
gt 1275 ft 526 0.45 (0.27 - 0.76)
Beta Blocker 1157 0.68 (0.51 - 0.91)No Beta
Blocker 519 0.92 (0.65 - 1.30)
Diabetes 524 0.95 (0.68 - 1.33)No
Diabetes 1152 0.67 (0.50 - 0.90)
4.0
2.0
1.0
0.5
0.25
PlaceboBetter
ICDBetter
Bardy GH. N Engl J Med. 2005352225-237.
40
New SCD-HeFT Cost-Effectiveness Analysis

• Incremental Cost-Effectiveness Analysis1

SCD-HeFT2
ICD
Placebo
159,147
90,759
Total Cost A Total Cost B
Life Expectancy A Life Expectancy B
8.41 Years
10.78 Years


33,192 LYS(discounted 3lifetime analysis)
Per Life-Year Saved LYS
ICD patients had an average increase in life
expectancy of 2.5 years
1 Roberts PR. European Heart Journal.
200121712-719. 2 Mark DB. www.theheart.org. AHA
News. November 11, 2004.
41
Incremental Cost-EffectivenessCardiovascular
Interventions
200,000
Economically Unattractive
150,000
135,000
120,000
Incremental Cost per Life-Year Saved
Expensive
67,000
Borderline Cost-Effective
40,750
Cost-Effective
17,701
8,461
HighlyCost-Effective
HypertensionTherapy(diastolic95 - 104mmHg)
Lovastatin(chol. 290 mg/dL,50 yrs old,
male, no riskfactors)
PTCA (chronic CAD,severe angina1 VD)
CABG (chronic CADmild angina,3 VD)
End Stage Renal Disease Treatment
Exercise SPECT (atypical angina who can walk on
treadmill)
RoutineCoronaryAngiography (35 - 84 yrs old,
low risk MI,has CHF)
Carotid Disease Screening (65 yrs old, male,
no symptoms)
42
Incremental Cost-Effectiveness ICD, CRT, and
CRT-D Therapies
Economically Unattractive
Incremental Cost per Life-Year Saved
Expensive
67,000
50,000
Borderline Cost-Effective
28,000
33,000
38,200
Cost-Effective
HighlyCost-Effective
COMPANIONCRT-D1
COMPANIONCRT1
MADIT-IIICD3
AVIDICD4
SCD-HeFTICD2
1 Feldman AM. www.theheart.org. ACC News. March
16, 2005. 2 Mark DB. www.theheart.org. AHA News.
November 11, 2004. 3 Ak-Khatib S. Ann Intern Med.
2005142593-600. 4 Larsen G. Circulation.
20021052049-2057.
43
SCD-HeFT Conclusions

• SCD-HeFT was the largest device trial (ICD, CRT,
  CRT-D) ever completed and had a longer follow-up
  period than other major device trials
• In NYHA Class II-III patients with LVEF 35 on
  optimal drug therapy
• ICDs reduced mortality by 23
• ICDs reduced tachyarrhythmia deaths by 60
• Amiodarone did not improve survival

Bardy GH. N Engl J Med. 2005352225-237.
44
SCD-HeFT Conclusions

• ICD therapy provided the largest mortality
  reduction in NYHA Class II patients
• Surviving patients had improvements in their
  heart failure condition over time.Good drug
  management likely contributed to this
  improvement.
• Compared to other CV therapies, ICDs are a
  cost-effective therapy

45
SCD-HeFT Implications

• SCD-HeFT ischemic CHF results are similar to
  findings from recently completed post-MI ICD
  trials and provide additional support for ICD
  therapy in ischemic CHF patients
• SCD-HeFT non-ischemic CHF results support the new
  use of ICDs in the non-ischemic CHF patient
  population
• SCD-HeFT Class II results provide new evidence
  that less sick heart failure patients can
  benefit from ICD therapy
• Recent CMS Coverage Decisions allow reimbursement
  for all SCD-HeFT patients