Surgical Treatment for IschemicSurgical Treatment for IschemicHeart Failure (STICH) Trial:Heart Failure (STICH) Trial:CABG versus CABG + SVRCABG versus CABG + SVR

Robert H. Jones, M.D.Robert H. Jones, M.D.March 29, 2009March 29, 2009

Surgical Treatment for IschemicSurgical Treatment for IschemicHeart Failure (STICH) Trial:Heart Failure (STICH) Trial:CABG versus CABG + SVRCABG versus CABG + SVR

Robert H. Jones, M.D.Robert H. Jones, M.D.March 29, 2009March 29, 2009

STICH Financial DisclosuresSTICH Financial Disclosures

Original Recipient InstitutionOriginal Recipient Institution Principal InvestigatorPrincipal Investigator ActivityActivity

Duke University Medical CenterDuke University Medical Center Robert H. JonesRobert H. Jones Clinical Coordinating CtrClinical Coordinating Ctr

Duke University Medical CenterDuke University Medical Center Kerry L. LeeKerry L. Lee Statistical and Data CCStatistical and Data CC

Duke University Medical CenterDuke University Medical Center Daniel B. MarkDaniel B. Mark EQOL Core LaboratoryEQOL Core Laboratory

Univ of Alabama-BirminghamUniv of Alabama-Birmingham Gerald M. PohostGerald M. Pohost CMR Core LaboratoryCMR Core Laboratory

Mayo ClinicMayo Clinic Jae K. OhJae K. Oh ECHO Core LaboratoryECHO Core Laboratory

University of PittsburghUniversity of Pittsburgh Arthur M. FeldmanArthur M. Feldman NCG Core LaboratoryNCG Core Laboratory

Northwestern UniversityNorthwestern University Robert O. BonowRobert O. Bonow RN Core LaboratoryRN Core Laboratory

Washington Hospital CenterWashington Hospital Center Julio A. PanzaJulio A. Panza DECIPHER SubstudyDECIPHER Substudy

Baylor University Medical CtrBaylor University Medical Ctr Paul GrayburnPaul Grayburn MR TEE SubstudyMR TEE Substudy

Funding Sources:Funding Sources:

National Heart, Lung and Blood Institute 97.3%National Heart, Lung and Blood Institute 97.3% Chase Medical 0.3%Chase Medical 0.3%

Abbott Laboratories 2.3%Abbott Laboratories 2.3% CV Therapeutics 0.1%CV Therapeutics 0.1%

Core STICH Study OrganizationCore STICH Study Organization

Principal Investigator: Robert H JonesPrincipal Investigator: Robert H Jones

Co-Principal investigator: Eric VelazquezCo-Principal investigator: Eric Velazquez

DCC Principal Investigator: Kerry L LeeDCC Principal Investigator: Kerry L Lee

Study Chair: Jean L RouleauStudy Chair: Jean L Rouleau

Executive Committee: Robert H Jones, Eric Velazquez, Kerry L Executive Committee: Robert H Jones, Eric Velazquez, Kerry L Lee, Jean L Rouleau, Patrice Desvigne-Nickens, George Sopko, Lee, Jean L Rouleau, Patrice Desvigne-Nickens, George Sopko, Chris O’Connor, Robert Michler, and Jae Oh. Chris O’Connor, Robert Michler, and Jae Oh.

DSMB chair: Sid GoldsteinDSMB chair: Sid Goldstein

Publications Committee chair: James HillPublications Committee chair: James Hill

Clinical Endpoints Committee: Peter CarsonClinical Endpoints Committee: Peter Carson

Hypothesis 2 Enrollment by CountryHypothesis 2 Enrollment by Country

1000 patients

96 clinical sites

23 countries

1231 days

1000 patients

96 clinical sites

23 countries

1231 days

Randomized PatientsRandomized Patients

Numbers for AnalysisNumbers for Analysisby Hypothesisby HypothesisMED

+CABG

(610)

MED+

CABG

(610)

MED+

CABG

(499)

MED+

CABG

(499)

CAD, EF CAD, EF 0.35 0.35CAD, EF CAD, EF 0.35 0.35

Eligible for MED-only treatment?Eligible for MED-only treatment?Eligible for MED-only treatment?Eligible for MED-only treatment?

Eligible for SVR?Eligible for SVR?Eligible for SVR?Eligible for SVR? Not in trialNot in trialNot in trialNot in trialNoNo

Hypothesis 1Hypothesis 1n = 1212n = 1212

Hypothesis 2Hypothesis 2n = 1000n = 1000

MED

(602)

MED

(602)

MED+

CABG+

SVR(501)

MED+

CABG+

SVR(501)

Stratum An = 1061Stratum An = 1061

1MED

(527)

1MED

(527)

2MED

+CABG

(534)

2MED

+CABG

(534)

Eligible for SVR?Eligible for SVR?Eligible for SVR?Eligible for SVR?

Stratum Cn = 859

Stratum Cn = 859

YesYes

6MED

+CABG

(423)

6MED

+CABG

(423)

7MED

+CABG

+SVR(436)

7MED

+CABG

+SVR(436)

Stratum Bn = 216

Stratum Bn = 216

3MED

(75)

3MED

(75)

5MED

+CABG

+SVR(65)

5MED

+CABG

+SVR(65)

4MED

+CABG

(76)

4MED

+CABG

(76)

++ 21362136 Randomized ptsRandomized pts==++

++ 602602 MED onlyMED only

10331033 CABG addedCABG added

501501 CABG + SVR addedCABG + SVR added==++

NoNo YesYes

YesYes NoNo

Hypothesis 2Hypothesis 2 Surgical ventricular reconstruction (SVR) combined with Surgical ventricular reconstruction (SVR) combined with

CABG and evidence-based medical therapy (MED) CABG and evidence-based medical therapy (MED) decreases death or cardiac hospitalization compared to decreases death or cardiac hospitalization compared to CABG and MED without SVR.CABG and MED without SVR.

90% power for 20% reduction assuming 90% power for 20% reduction assuming ≥45% 3-year event ≥45% 3-year event rate allowing for 20% treatment crossovers.rate allowing for 20% treatment crossovers.

7% of CABG and 9% of CABG + SVR patients did not 7% of CABG and 9% of CABG + SVR patients did not receive assigned operation.receive assigned operation.

Follow-up 99% complete over median of 48 months.Follow-up 99% complete over median of 48 months.

All outcomes reported by operation assigned by All outcomes reported by operation assigned by randomization.randomization.

Conduct of operation reported by procedure receivedConduct of operation reported by procedure received ..

Baseline Clinical CharacteristicsBaseline Clinical Characteristics

Characteristic CABGN = 499

CABG + SVRN = 501

Age, median 25Age, median 25thth, 75, 75thth, years, years 62 (54, 66)62 (54, 66) 62 (56, 69)62 (56, 69)

FemaleFemale 78 (16%)78 (16%) 69 (14%)69 (14%)

WhiteWhite 90%90% 92%92%

DiabetesDiabetes 35%35% 34%34%

Creatinine, >0.5 mg/dLCreatinine, >0.5 mg/dL 8%8% 9%9%

Prior stroke 6% 6%

Mitral Regurgitation by Treatment in 1,000 Mitral Regurgitation by Treatment in 1,000 Hypothesis 2 PatientsHypothesis 2 Patients

Mitral Regurgitation Severity

CABGN = 499

CABG + SVRN = 501

None or trace 173 (35%) 190 (38%)

Mild (≤2+) 233 (47%) 216 (44%)

Moderate (3+) 72 (15%) 70 (14%)

Severe (4+) 16 (3%) 20 (4%)

Not assessed 5 (4%) 5 (3%)

18%18%18%18%

Site Reported Left Ventricular Function for Site Reported Left Ventricular Function for 1,000 Hypothesis 2 Patients by Treatment1,000 Hypothesis 2 Patients by Treatment

LV Function CABGN = 499

CABG + SVRN = 501

Site Qualifying Study

Echocardiogram (%) 66% 63%

Contrast ventriculogram 13% 18%

CMR 11% 9%

Gated SPECT 10% 10%

LVEF, median (25th, 75th) .28 (.23, .31) .28 (.24, .31)

ESVI, median (25th, 75th), mL/m2 82 (65, 102) 82 (66, 105)

% anterior wall with akinesia/dyskinesia, median (25th, 75th) 56 (40, 60) 50 (40, 60)

Coronary Anatomy by Treatment for Coronary Anatomy by Treatment for 1,000 Hypothesis 2 Patients1,000 Hypothesis 2 Patients

Major Coronary Major Coronary Arteries with Arteries with

StenosisStenosis

% Stenosis% Stenosis CABGCABGN = 499N = 499

CABG + SVRCABG + SVRN = 501N = 501

OneOne ≥≥50%50% 7%7% 10%10%

LM stenosisLM stenosis 50-74%50-74% 14%14% 12%12%

OneOne ≥≥ 75%75% 17%17% 20%20%

TwoTwo ≥≥ 75%75% 41%41% 42%42%

ThreeThree ≥≥ 75%75% 41%41% 36%36%

Proximal LADProximal LAD ≥≥ 75%75% 78%78% 74%74%

LM stenosisLM stenosis ≥≥ 75%75% 6%6% 7%7%

Duke coronary Duke coronary disease index*disease index*

MedianMedian(25(25thth, 75, 75thth)) 65 (43, 91)65 (43, 91) 65 (39, 91)65 (39, 91)

* 0 = coronary angiogram shows no coronary disease, 100 = * 0 = coronary angiogram shows no coronary disease, 100 = ≥95% LM stenosis≥95% LM stenosis* 0 = coronary angiogram shows no coronary disease, 100 = * 0 = coronary angiogram shows no coronary disease, 100 = ≥95% LM stenosis≥95% LM stenosis

Medication at BaselineMedication at Baseline

Medication CABGN = 499

CABG + SVRN = 501

Beta blockerBeta blocker 85%85% 87%87%

ACE inhibitor or angiotensin ACE inhibitor or angiotensin receptor blockerreceptor blocker

87%87% 89%89%

ACE inhibitorACE inhibitor 80%80% 82%82%

DigoxinDigoxin 17%17% 14%14%

DiureticDiuretic 69%69% 66%66%

AspirinAspirin 77%77% 77%77%

Aspirin or warfarinAspirin or warfarin 81%81% 83%83%

StatinStatin 79%79% 75%75%

Operative Conduct by Operation Received Operative Conduct by Operation Received in 979 Hypothesis 2 Patientsin 979 Hypothesis 2 Patients

VariableVariable CABGCABGN = 490N = 490

CABG + SVRCABG + SVRN = 489N = 489

PP

Status at Operation

Elective operation 84% 83% 0.54

Urgent 13% 13%

Emergency 3% 4%

Bypass Grafts 0.34

1 or more arterial grafts 93% 89%

2 or less total grafts 27% 30%

3 or more total grafts 73% 70%

Mitral surgery 17% 19% 0.50

SVR patch 59%

Efficiency of Operative Care Efficiency of Operative Care in 979 Hypothesis 2 Patientsin 979 Hypothesis 2 Patients

Duration of OperationDuration of Operation CABGCABGN = 490N = 490

CABG + SVRCABG + SVRN = 489N = 489

PP

Total time in operating room (median, 25th, 75th), hours

4.9 (4.1, 6.0) 5.5 (4.7, 6.6) <0.001

Cardiopulmonary bypass time(median, 25th, 75th), minutes

99 (73, 125) 124 (99, 158) <0.001

Aortic occlusion (median, 25th, 75th), minutes

62 (45, 84) 80 (62, 106) <0.001

Requirements for Postoperative Care

Endotracheal intubation (median, 25th, 75th), hours

15.1 (10.9, 22.1) 16.6 (12.0, 25.2) 0.002

Acute care (median, 25th, 75th), hours

49.8 (28.8, 95.5) 69.5 (42, 137) <0.001

Hospitalization >30 days 22 (5%) 31 (6%) 0.20

Baseline 4 Months0

20

40

60

80

CABG(N = 212)

Baseline 4 MonthsCABG+SVR

(N = 161)

Baseline and Four Month End-Systolic Volume Baseline and Four Month End-Systolic Volume Index (ESVI) in 373 Hypothesis 2 Patients With Index (ESVI) in 373 Hypothesis 2 Patients With Quantitative Echocardiogram at Both IntervalsQuantitative Echocardiogram at Both Intervals

ESVI 82 ml/m2 77 ml/m2 83 ml/m2 67 ml/m2

P<0.001P<0.001P<0.001P<0.001

Baseline(N = 499)

LatestFollow-up(N = 435)

0

100

200

300

400

500

CABGCCS Angina Class

Baseline(N = 501)

LatestFollow-up(N = 428)

CABG+SVRCCS Angina Class

Canadian Cardiovascular Society Angina Class in Canadian Cardiovascular Society Angina Class in Hypothesis 2 Patients at Baseline and Latest Follow-upHypothesis 2 Patients at Baseline and Latest Follow-up

Patients

No Angina121

Class I-II130

Class III-IV248

No Angina339

Class I-II88 Class III-IV

8

No Angina128

Class I-II129

Class III-IV244

No Angina339

Class I-II83 Class III-IV

6

Angina symptoms improved by an average of 1.7 classes in both cohorts (P=0.84).Angina symptoms improved by an average of 1.7 classes in both cohorts (P=0.84).

Baseline(N = 499)

LatestFollow-up(N = 436)

0

100

200

300

400

500

CABGNYHA HF Class

Baseline(N = 501)

LatestFollow-up(N = 435)

CABG+SVRNYHA HF Class

New York Heart Association Heart Failure Class in New York Heart Association Heart Failure Class in Hypothesis 2 Patients at Baseline and Latest Follow-upHypothesis 2 Patients at Baseline and Latest Follow-up

Patients

Class I 36

Class II222

Class III-IV241

Class I165

Class II190

Class III-IV80

Class I 50

Class II207

Class III-IV244

Class I179

Class II188

Class III-IV62

Heart failure symptoms improved by an average of one classIn both cohorts (P = 0.70).Heart failure symptoms improved by an average of one classIn both cohorts (P = 0.70).

Baseline and Four Month 6-Minute Walk in 693 Baseline and Four Month 6-Minute Walk in 693 Hypothesis 2 Patients with Baseline AssessmentHypothesis 2 Patients with Baseline Assessment

Patients

30-Day Mortality30-Day Mortality

OutcomeOutcome CABGCABGN = 499N = 499

CABG + SVRCABG + SVRN = 501N = 501

PP

Death Within 30 Days After Randomization

All patients by intention to treat

22/499 (4.4%) 30/501 (6.0%) 0.26

Death During or Within 30 Days of Operation

Operated patients by intention to treat

25/490 (5.1%) 26/489 (5.3%) 0.88

Operated patients by operation received

23/498 (4.6%) 28/481 (5.8%) 0.40

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0 1 2 3 4 5

Eve

nt R

ate

Years from Randomization

CABG

499501

319319

270275

220216

9911

2323

CABGCABG+SVR

No. at Risk

Death or Cardiac Hospitalization Death or Cardiac Hospitalization Kaplan-Meier Estimates of Primary Endpoint Kaplan-Meier Estimates of Primary Endpoint

292 events

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0 1 2 3 4 5

Eve

nt R

ate

Years from Randomization

CABG

CABG+SVR

HR 0.99 (95% CI: 0.84, 1.17), P=0.90

499501

319319

270275

220216

9911

2323

CABGCABG+SVR

No. at Risk

Death or Cardiac HospitalizationDeath or Cardiac Hospitalization Kaplan-Meier Estimates of Primary Endpoint Kaplan-Meier Estimates of Primary Endpoint

292 events

289 events

Mortality (All-Cause)Mortality (All-Cause) Kaplan-Meier Estimates Kaplan-Meier Estimates

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0 1 2 3 4 5

Mor

talit

y R

ate

Years from Randomization

CABG

499501

434429

417404

363352

201193

5953

CABGCABG+SVR

No. at Risk

141 deaths

Mortality (All-Cause)Mortality (All-Cause) Kaplan-Meier Estimates Kaplan-Meier Estimates

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0 1 2 3 4 5

Mor

talit

y R

ate

Years from Randomization

CABG+SVR

HR 1.00 (95% CI: 0.79, 1.26), P=0.98

499501

434429

417404

363352

201193

5953

CABGCABG+SVR

No. at Risk

141 deaths 138 deaths

CABG

Summary of Outcomes in STICH H2Summary of Outcomes in STICH H2OutcomesOutcomes CABGCABG

N = 499N = 499CABG + SVRCABG + SVR

N = 501N = 501Hazard RatioHazard Ratio

95% CI95% CIPP

Death or cardiac Death or cardiac hospitalizationhospitalization 292 (59%)292 (59%) 289 (58%)289 (58%) 0.99 (0.84, 1.17)0.99 (0.84, 1.17) 0.900.90

DeathDeath 141 (28%)141 (28%) 138 (28%)138 (28%) 1.00 (0.79, 1.26)1.00 (0.79, 1.26) 0.980.98

Hospitalization Hospitalization (cardiac)(cardiac) 211 (42%)211 (42%) 204 (41%)204 (41%) 0.97 (0.80, 1.18)0.97 (0.80, 1.18) 0.730.73

Hospitalization Hospitalization (all cause)(all cause) 272 (55%)272 (55%) 268 (53%)268 (53%) 0.98 (0.83, 1.16)0.98 (0.83, 1.16) 0.820.82

Acute MIAcute MI 22 (4%)22 (4%) 20 (4%)20 (4%) 1.01 (0.54, 1.87)1.01 (0.54, 1.87) 0.960.96

StrokeStroke 31 (6%)31 (6%) 23 (5%)23 (5%) 0.77 (0.45, 1.32)0.77 (0.45, 1.32) 0.350.35

0.5 1.0 2.0

CABG+SVG Better

CABGBetter

Hazard Ratios, Confidence Intervals, and Tests for InteractionHazard Ratios, Confidence Intervals, and Tests for Interaction

Subgroup N HR (95% CI) P ValueAll Subjects 1000 0.99 (0.84, 1.17)Age 0.48 ≥ 65 391 1.06 (0.83, 1.35) < 65 609 0.94 (0.76, 1.17)Gender 0.60 Male 853 1.01 (0.84, 1.20) Female 147 0.90 (0.58, 1.39)Race 0.44 Minority 124 0.83 (0.51, 1.36) Non-minority 876 1.01 (0.85, 1.20)Current NYHA HF class 0.97 I or II 515 0.99 (0.78, 1.25) III or IV 485 0.99 (0.79, 1.24)

0.5 1.0 2.0

CABG+SVG Better

CABGBetter

Subgroup N HR (95% CI) P ValueCCS angina class 0.39 ≤ Class II 508 0.92 (0.73, 1.16) Class III or IV 492 1.06 (0.85, 1.34)Baseline diabetes 0.20 Yes 344 1.14 (0.87, 1.50) No 656 0.92 (0.75, 1.12)LVEF (site reported) 0.33 ≤ 28 534 1.07 (0.86, 1.31) > 28 466 0.90 (0.70, 1.17)# of diseased vessels ≥ 50% 0.21 1 or 2 362 0.87 (0.65, 1.13) 3 638 1.07 (0.87, 1.31)Left main ≥ 50% or proximal LAD ≥ 75% 0.53 No 179 0.89 (0.61, 1.30) Yes 821 1.02 (0.85, 1.22)

0.5 1.0 2.0

CABG+SVG Better

CABGBetter

Subgroup N HR (95% CI) P ValueMitral regurgitation 0.44 None or trace 363 0.89 (0.68, 1.17) Mild (≤ 2+) 449 1.12 (0.88, 1.43) Mod. or severe 178 0.94 (0.65, 1.36)Stratum 0.44 B 141 1.15 (0.76, 1.76) C 859 0.96 (0.81, 1.15)Region 0.41 Poland 288 1.02 (0.76, 1.37) USA 200 1.10 (0.79, 1.54) Canada 154 0.77 (0.50, 1.18) West Europe 164 0.80 (0.53, 1.22) Other 194 1.24 (0.81, 1.91)

ConclusionsConclusions

The STICH trial definitively shows adding SVR to CABG The STICH trial definitively shows adding SVR to CABG provides no clinical benefit beyond that of CABG alone in provides no clinical benefit beyond that of CABG alone in the study population.the study population.

Both operative strategies provided similar short- and long-Both operative strategies provided similar short- and long-term relief of angina and HF and improvement in 6-minute term relief of angina and HF and improvement in 6-minute walk test performance.walk test performance.

SVR added to CABG decreased LV size significantly more SVR added to CABG decreased LV size significantly more than CABG alone and confirms the anatomic change than CABG alone and confirms the anatomic change reported in prior SVR studies.reported in prior SVR studies.

Further analyses of STICH Hypothesis 2 data may identify Further analyses of STICH Hypothesis 2 data may identify patient characteristics associated with benefit or harm from patient characteristics associated with benefit or harm from adding SVR to CABG.adding SVR to CABG.

To learn more about STICH and ongoing To learn more about STICH and ongoing Hypothesis 1, after the session look for Hypothesis 1, after the session look for investigators wearing STICH name tags.investigators wearing STICH name tags.

Visit Visit NEJM.org to read the Hypothesis 2 primary outcome article.