SCD-HeFT Sudden Cardiac Death in Heart Failure Trial Bardy GH. N Engl J Med. 2005;352:225-237

SCD-HeFTSudden Cardiac Death in

Heart Failure Trial

Bardy GH. N Engl J Med. 2005;352:225-237.

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


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


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 > 3 months

– Appropriate dose of ACE-I

– Beta blocker, if tolerated


SCD-HeFT Exclusion Criteria

• Asymptomatic patients with LV dysfunction

• NYHA Class I or IV

• Class I ICD indications

• Pacemaker indications

• < 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


SCD-HeFT Centers

(2)

(2)

(2)

(3)

(2)

(2)

(4)

(2)

(8)

(2)

(2)

(2)

(3)

(2)

(2)

(5)(2)(3)

(3)

148 sites in the US, Canada,and New Zealand.

Enrollment 2521

(10)

(3)


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. 2005;352:225-237.

SCD-HeFT Protocol

DCM + CAD and CHF

Placebo N = 847 ICD Implant N = 829

Minimum of 2.5 years follow-up required

45 months average follow-up Optimized B, ACE-I, Diuretics

Amiodarone N = 845

EF < 35%

NYHA Class II or III

6-Minute Walk, Holter

R 2521 Patients


Study Power Calculations

• Predicted control mortality rate:10% 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


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


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%


SCD-HeFT Study Drug Dosing

• Outpatient administration

• < 800 mg qd for week 1

• < 400 mg qd for weeks 2-4

• Chronic dose weight dependent:

– 200 mg/d if < 150 lbs

– 300 mg/d if 150-200 lbs

– 400 mg/d if > 200 lbs


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


SCD-HeFT Baseline Patient Characteristics

AmiodaroneN = 845

PlaceboN = 847

ICDN = 829

NYHA II 71% 70% 68%

NYHA III 29% 30% 32%

Ischemic CHF 50% 53% 52%

Non-ischemic CHF 50% 47% 48%



AmiodaroneN = 845

PlaceboN = 847

ICDN = 829

Age (median) 60 60 60

Male 76% 77% 77%

Caucasian 77% 76% 77%

Weight (median) 190 190 190

SBP mm Hg (median) 118 120 118

DBP mm Hg (median) 70 70 70

Hypertension 56% 56% 55%



AmiodaroneN = 845

PlaceboN = 847

ICDN = 829

LVEF (median) 0.25 0.25 0.24

Diabetes 29% 32% 31%

Pulmonary Disease 17% 19% 21%

AF or Atrial Flutter 16% 14% 17%

NSVT 23% 21% 25%

Syncope 6% 7% 6%

Heart Rate bpm (median) 72 73 74



AmiodaroneN = 845

PlaceboN = 847

ICDN = 829

Hypercholesterolemia (median)

52% 54% 52%

EP study 18% 15% 16%

Serum Sodium mEq/liter(median)

139 139 139

Serum Creatinine mg/dl(median)

1.1 1.1 1.1


SCD-HeFT Medication Use Last Follow-Up

AmiodaroneN = 845

PlaceboN = 847

ICDN = 829

ACE-I 71% 74% 70%

ARB 18% 17% 18%

ACE or ARB 85% 88% 86%

Beta Blocker 72% 79% 82%

Aspirin 56% 54% 55%

Warfarin 32% 36% 34%


SCD-HeFT Medication Use Last Follow-Up

AmiodaroneN = 845

PlaceboN = 847

ICDN = 829

Digoxin 59% 62% 63%

Statin 48% 46% 48%

Diuretic:

Loop 79% 80% 79%

Potassium-Sparing 28% 33% 32%

Thiazide 11% 11% 10%


SCD-HeFT Mortality Rate Overall Results

Months of Follow-Up

Mo

rtal

ity

Rat

e

483624120

Amiodarone

PlaceboICD

0.4

0.3

0.2

0.1

0.0

60

No. at RiskAmiodarone 845 772 715 484 280 97Placebo 847 797 724 505 304 89ICD 829 778 733 501 304 103

Hazard Ratio (97.5% Cl) P-ValueAmiodarone vs. Placebo 1.06 (0.86 - 1.30) 0.53ICD vs. Placebo 0.77 (0.62 - 0.96) 0.007


SCD-HeFT Overall Mortality Results

Hazard Ratio (97.5% CI)

P-Value

Amiodarone vs. Placebo

1.06 (0.86 - 1.30) 0.53

ICD vs. Placebo

0.77 (0.62 - 0.96) 0.007ICDs reduce

mortality by 23%


0

5

10

15

20

25

30

35

40

Amiodarone Placebo ICD

SCD-HeFT 5-Year Mortality RateOverall Results

34% 36.1%

28.9%

Mo

rtal

ity

Rat

e


SCD-HeFT Mortality Rate Ischemic CHF Patients

Months of Follow-Up

Mo

rtal

ity

Rat

e

483624120

Amiodarone

PlaceboICD

0.4

0.3

0.2

0.1

0.0

60





SCD-HeFT Mortality RateNon-Ischemic CHF Patients

Months of Follow-Up

Mo

rtal

ity

Rat

e

483624120

Amiodarone

PlaceboICD

0.4

0.3

0.2

0.1

0.0

60


0.5


05

101520253035404550

SCD-HeFT 5-Year Mortality RateIschemic vs. Non-Ischemic

41.7% 43.2%

21.4%25.8%

27.9%

35.9%

Ischemic Non-Ischemic




Mo

rtal

ity

Rat

e



SCD-HeFT Mortality RateNYHA Class II Patients

Months of Follow-Up

Mo

rtal

ity

Rat

e

483624120

Amiodarone

PlaceboICD0.4

0.3

0.2

0.1

0.0

60

Hazard Ratio (97.5% Cl) P-ValueAmiodarone vs. Placebo 0.85 (0.65 - 1.11) 0.17ICD vs. Placebo 0.54 (0.40 - 0.74) < 0.001


0.5

0.6


SCD-HeFT Mortality RateNYHA Class III Patients

Months of Follow-Up

Mo

rtal

ity

Rat

e

483624120

Amiodarone

PlaceboICD

60



0.4

0.3

0.2

0.1

0.0

0.5

0.6

0

10

20

30

40

50

60

SCD-HeFT 5-Year Mortality RateNYHA Class II vs. III

26.4%

32%

48.4%52.8%

45.6%

20%

NYHA II NYHA III NYHA II NYHA III NYHA II NYHA III


Mo

rtal

ity

Rat

e


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. 2005;352:225-237. 2 Kadish A. N Engl J Med. 2004;350:2151-2158. 3 Moss AJ. N Engl J Med. 2002;346:877-883. 4 AVID Investigators. N Engl J Med. 1997;337:1576-1884.

SCD-HeFT Mortality Results Ischemic – Non-Ischemic and

NYHA Class II-III

Hazard Ratio (97.5% CI) ICD vs. Placebo

P-ValueReduction in Death w/ICD

Ischemic CHF 0.79 (0.60 -1.04) 0.05 21%

Non-Ischemic CHF 0.73 (0.50 - 1.07) 0.06 27%

NYHA Class II 0.54 (0.40 - 0.74) < 0.001 46%

NYHA Class III 1.16 (0.84 - 1.61) 0.30 None


SCD-HeFT Discontinuations and Crossovers

Discontinue Study Rx

ICD Crossover

Amiodarone Crossover

Amiodarone 32%11%

Placebo 22% 10%

ICD 6% 14%


SCD-HeFT Complications

Amiodarone (different than placebo):

• 4% increased tremor (P = 0.02)

• 6% increased hypothyroidism (P < 0.001)

ICD Therapy:

• 5% implant complications

• 9% follow-up complications


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


SCD-HeFT Rhythm Precursors to VT/VF

VT VF VT VF

Frequent Extra Systoles

52.3% 58.8% Decel. by > 100 ms of Prevailing Rhythms

7.3% 10.3%

Accel. > 100ms of Prevailing Rhythms

22.9% 22.1% Sustained SVT, not AF

7.3% 1.5%

Short-Long-Short Sequence

13.8% 32.4% Acute Onset AF 1.8% 1.5%

Initiating Beat of VT Morphology Different

20.2% NA VVI Pacing Triggered by Bradycardia

0% 4.4%

NSVT 11% 8.8% None Identified 17.4% 17.7%

Poole JE. Heart Rhythm 2005. May;2 (1suppl):AB20-5.

SCD-HeFT Change in NYHA ClassBaseline to 3 Years

Surviving patient’s HF condition appeared to improve progressively over time. Good drug management likely contributed to these results.

0

10

20

30

40

50

60

70

All ICD Placebo Amiodarone

% P

atie

nts

-2

-1

0

+1

+2

Changes in NYHA Class

Bardy GH. Heart Rhythm 2005. May;2 (1suppl):AB20-3.

SCD-HeFT Mode of Death

Cause of DeathAmiodarone

N = 845PlaceboN = 847

ICDN = 829

Cardiac 19% 20% 15%

Tachyarrhythmia 9% 11% 4%

Bradyarrhythmia < 1% < 1% < 1%

Heart Failure 8% 8% 9%

Nonarrhythmic 1% < 1% 1%

Packer DL. Heart Rhythm 2005. May;2 (1suppl):AB20-2.

SCD-HeFT Tachyarrhythmia Deaths

Cause of DeathAmiodarone

N = 845PlaceboN = 847

ICDN = 829

Tachyarrhythmia 9% 11% 4%

ICD therapy reduced tachyarrhythmia deaths by 60%

Packer DL. Heart Rhythm 2005. May;2 (1suppl):AB20-2.

SCD-HeFT Hazard Rate ResultsICD vs. Placebo

ICDBetter

4.02.01.00.50.25

Placebo Better

Subgroup ICD Therapy vs. Placebo

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 < 65 Yrs 1098 0.68 (0.50 - 0.93)Age > 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 < 30% 1390 0.73 (0.57 - 0.92)LVEF > 30% 285 1.08 (0.57 - 2.07)


SCD-HeFT Hazard Rate ResultsICD vs. Placebo

ICDBetter

4.02.01.00.50.25

PlaceboBetter

Subgroup ICD Therapy vs. Placebo

N Hazard Ratio (97.5% Cl)

QRS < 120 ms 977 0.84 (0.62 - 1.14)QRS > 120 ms 699 0.67 (0.49 - 0.93)6-Min Walk Test < 950 ft 526 1.14 (0.81 - 1.60) 950 – 1275 ft 536 0.57 (0.38 - 0.88) > 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)


New SCD-HeFT Cost-Effectiveness Analysis

Incremental Cost-Effectiveness

Analysis1

SCD-HeFT2

Total Cost A – Total Cost B

Life Expectancy A – Life Expectancy B

=

$ Per Life-Year Saved

$LYS

1 Roberts PR. European Heart Journal. 2001;21:712-719.2 Mark DB. www.theheart.org. AHA News. November 11, 2004.

ICD

=$33,192 LYS

(discounted 3%lifetime analysis)

Placebo

$159,147 $90,759

10.78 Years* 8.41 Years*

* ICD patients had an average increase in life expectancy of 2.5 years

http://www.theheart.org/

$0

$20,000

$40,000

$60,000

$80,000

$100,000

$120,000

$140,000

$160,000

$180,000

$200,000

Incremental Cost-EffectivenessCardiovascular Interventions

HypertensionTherapy(diastolic95 - 104mmHg)

Expensive

BorderlineCost-Effective

Cost-Effective

HighlyCost-Effective

Incr

emen

tal

Co

st p

er L

ife-

Yea

r S

aved

EconomicallyUnattractive

Lovastatin(chol. =

290 mg/dL,50 yrs old,

male, no riskfactors)

PTCA(chronic CAD,severe angina

1 VD)

CABG(chronic

CADmild angina,

3 VD)

End Stage Renal

Disease Treatment

Exercise SPECT (atypical

angina who can walk

on treadmill)

RoutineCoronary

Angiography(35 - 84 yrs

old, low risk MI,has CHF)

$8,461$17,701

$40,750

$67,000

$135,000

$150,000

Carotid Disease

Screening(65 yrs old,

male, no

symptoms)

$200,000

$120,000

$0

$20,000

$40,000

$60,000

$80,000

$100,000

$120,000

$140,000

$160,000

$180,000

$200,000

Incremental Cost-Effectiveness ICD, CRT, and CRT-D Therapies

COMPANIONCRT-D1

Incr

emen

tal

Co

st p

er L

ife-

Yea

r S

aved

COMPANIONCRT1

MADIT-IIICD3

AVIDICD4

$28,000 $38,200

$50,000$67,000

Expensive

BorderlineCost-Effective

Cost-Effective

HighlyCost-Effective

EconomicallyUnattractive

SCD-HeFTICD2

$33,000

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. 2005;142:593-600.4 Larsen G. Circulation. 2002;105:2049-2057.



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


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

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

Documents

SCD-HeFT Sudden Cardiac Death in Heart Failure Trial Bardy GH. N Engl J Med. 2005;352:225-237