Coronary Artery Bypass Graft Coronary Artery Bypass Graft Surgery in Patients with Ischemic Surgery in Patients with Ischemic

Heart FailureHeart Failure

Coronary Artery Bypass Graft Coronary Artery Bypass Graft Surgery in Patients with Ischemic Surgery in Patients with Ischemic

Heart FailureHeart Failure

Eric J. Velazquez, MD Eric J. Velazquez, MD on behalf of the STICH Investigatorson behalf of the STICH Investigators

April 4, 2011April 4, 2011

Eric J. Velazquez, MD Eric J. Velazquez, MD on behalf of the STICH Investigatorson behalf of the STICH Investigators

April 4, 2011April 4, 2011

STICH Financial DisclosuresSTICH Financial Disclosures

Original Recipient InstitutionOriginal Recipient Institution Principal Principal InvestigatorInvestigator

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 CenterBaylor University Medical Center Paul GrayburnPaul Grayburn MR TEE SubstudyMR TEE Substudy

Funding Sources:Funding Sources:

National Heart, Lung and Blood InstituteNational Heart, Lung and Blood Institute 97.7%97.7%

Abbott LaboratoriesAbbott Laboratories 2.3%2.3%

Background — IBackground — I

• Coronary artery disease (CAD) is a major Coronary artery disease (CAD) is a major substrate for heart failure (HF) and left substrate for heart failure (HF) and left ventricular dysfunction (LVD).ventricular dysfunction (LVD).

• The role of coronary artery bypass graft The role of coronary artery bypass graft surgery (CABG) in patients with CAD and surgery (CABG) in patients with CAD and HF has not been clearly established.HF has not been clearly established.

Background — IIBackground — II

• In the 1970s, RCTs of CABG vs. medical therapy for In the 1970s, RCTs of CABG vs. medical therapy for chronic stable angina excluded patients with severe LVD chronic stable angina excluded patients with severe LVD Only 4.0% symptomatic with HFOnly 4.0% symptomatic with HF

• Major advances in surgical care and medical therapy (MED) Major advances in surgical care and medical therapy (MED) render previous data obsolete for clinical decision makingrender previous data obsolete for clinical decision making

• Observational analyses suggest a role for CABG for HF Observational analyses suggest a role for CABG for HF and LVDand LVD CABG is increasingly utilized for these patients CABG is increasingly utilized for these patients Yet, substantial clinical uncertainty remainsYet, substantial clinical uncertainty remains

Surgical Treatment for Ischemic Heart Surgical Treatment for Ischemic Heart Failure Trial (STICH)Failure Trial (STICH)

Surgical Revascularization HypothesisSurgical Revascularization Hypothesis

In patients with HF, LVD and CAD amenable In patients with HF, LVD and CAD amenable to surgical revascularization, CABG added to to surgical revascularization, CABG added to intensive MED will decrease all-cause intensive MED will decrease all-cause mortality compared to MED alone.mortality compared to MED alone.

Study DesignStudy Design

• Randomized controlled trial, non-blindedRandomized controlled trial, non-blinded

• Investigator-initiated and ledInvestigator-initiated and led

• National Heart, Lung and Blood Institute fundedNational Heart, Lung and Blood Institute funded

• Duke Clinical Research Institute managedDuke Clinical Research Institute managed

• Independent Data and Safety Monitoring CommitteeIndependent Data and Safety Monitoring Committee

• Clinical Events Adjudication CommitteeClinical Events Adjudication Committee

• Blinded Core LaboratoriesBlinded Core Laboratories

EndpointsEndpoints

Primary EndpointPrimary Endpoint All-cause mortalityAll-cause mortality

Major Secondary EndpointsMajor Secondary Endpoints Cardiovascular mortalityCardiovascular mortality Death (all-cause) + cardiovascular Death (all-cause) + cardiovascular

hospitalizationhospitalization

Statistical Assumptions and AnalysesStatistical Assumptions and Analyses

Statistical AssumptionsStatistical Assumptions

•MED mortality of 25% at 3 MED mortality of 25% at 3 yearsyears

•CABG would reduce CABG would reduce mortality by 25%mortality by 25%

•20% or fewer crossovers 20% or fewer crossovers from MED to CABG from MED to CABG

•400 or more deaths400 or more deaths

•90% power90% power

Planned AnalysesPlanned Analyses

•Intention to treat (as Intention to treat (as randomized)randomized)

•Covariate-adjustedCovariate-adjusted

•As treatedAs treated

Time-dependentTime-dependent

•Per protocolPer protocol

Important Inclusion CriteriaImportant Inclusion Criteria

• LVEF ≤ 0.35 within 3 months of trial entryLVEF ≤ 0.35 within 3 months of trial entry

• CAD suitable for CABGCAD suitable for CABG

• MED eligibleMED eligible Absence of left main CAD as defined by an Absence of left main CAD as defined by an

intraluminal stenosis of ≥ 50%intraluminal stenosis of ≥ 50% Absence of CCS III angina or greater Absence of CCS III angina or greater

(angina markedly limiting ordinary activity)(angina markedly limiting ordinary activity)

Major Exclusion CriteriaMajor Exclusion Criteria

• Recent acute MI (within 30 days)Recent acute MI (within 30 days)

• Cardiogenic shock (within 72 hours of randomization)Cardiogenic shock (within 72 hours of randomization)

• Plan for percutaneous intervention Plan for percutaneous intervention

• Aortic valve disease requiring valve repair or replacementAortic valve disease requiring valve repair or replacement

• Non-cardiac illness with a life expectancy of less than 3 Non-cardiac illness with a life expectancy of less than 3 years or imposing substantial operative mortalityyears or imposing substantial operative mortality

1212

RandomizedCABG

Randomized MED only

610602

STICH Revascularization HypothesisSTICH Revascularization Hypothesis

• 99 clinical sites in 22 countries99 clinical sites in 22 countries

• Enrollment: July 2002 – May 2007Enrollment: July 2002 – May 2007

Selected Baseline CharacteristicsSelected Baseline Characteristics

Variable MED (N=602) CABG (N=610)

Age, median (IQR), yrs 59 (53, 67)  60 (54, 68) 

Female, % 12 12

Diabetes, % 40 39

Prior Myocardial infarction, % 78 76

Prior Heart Failure within 3 months, % 95 94

Prior PCI or CABG, % 15 16

LVEF (%) — median 28 27

Multi-vessel disease (>50%), % 91  91 

Proximal LAD stenosis (>75%), % 69 67

Medical TherapyMedical Therapy

  MED (N=602) CABG (N=610)

Medication, % Baseline Latest

Follow-up Baseline Latest

Follow-up

Aspirin 85 84 80 84

Aspirin or warfarin 91 93 84 92

ACE inhibitor or ARB 88 89 91 89

Beta-blocker 88 90 83 90

Statin 83 87 79 90

K+ sparing diuretic 46 53 46 54

ICD 2 19 2 15

CABG ConductCABG Conduct

VariableCABG

(N=610)

CABG received — no (%) 555 (91)

Time to CABG, days — Median (IQR) 10 (5, 16)

Performed electively, % 95

Arterial conduits ≥ 1, % 91

Venous conduits ≥ 1, % 86

Total grafts ≥ 2, % 88

Length of stay, days — Median (IQR) 9 (7, 13)

Patient Follow-upPatient Follow-up

• Last follow-up period: August – November 2010Last follow-up period: August – November 2010

• Final follow-up ascertained: 1207 (99.6%) Final follow-up ascertained: 1207 (99.6%) Only 5 patients were not evaluable with median Only 5 patients were not evaluable with median

follow-up of 40 monthsfollow-up of 40 months

• Overall duration of follow-up: 56 monthsOverall duration of follow-up: 56 months

All-Cause Mortality All-Cause Mortality — As Randomized— As Randomized

HR 0.86 (0.72, 1.04)

P = 0.123

HR 0.86 (0.72, 1.04)

P = 0.123

0.460.41

All-Cause Mortality All-Cause Mortality — As Randomized— As Randomized

HR 0.86 (0.72, 1.04)

P = 0.123

Adjusted HR 0.82 (0.68, 0.99)

Adjusted P = 0.039

HR 0.86 (0.72, 1.04)

P = 0.123

Adjusted HR 0.82 (0.68, 0.99)

Adjusted P = 0.039

0.460.41

HR 0.81 (0.66, 1.00)

P = 0.050

Adjusted HR 0.77 (0.62, 0.94)

Adjusted P = 0.012

HR 0.81 (0.66, 1.00)

P = 0.050

Adjusted HR 0.77 (0.62, 0.94)

Adjusted P = 0.012

Cardiovascular MortalityCardiovascular Mortality— As Randomized— As Randomized

0.39

0.32

HR 0.74 (0.64, 0.85)

P < 0.001

Adjusted HR 0.70 (0.61, 0.81)

P < 0.001

HR 0.74 (0.64, 0.85)

P < 0.001

Adjusted HR 0.70 (0.61, 0.81)

P < 0.001

Death or Cardiovascular Death or Cardiovascular Hospitalization — As RandomizedHospitalization — As Randomized

0.58

0.68

Time-varying Hazard Ratios Time-varying Hazard Ratios — As Randomized— As Randomized

STICH Revascularization HypothesisSTICH Revascularization HypothesisTreatment As ReceivedTreatment As Received

As treated MED (592) vs. CABG (620)

1212

RandomizedCABG

Randomized MED only

610602

Received MED only

Received CABG

555537 55 65

17% 9%

All-Cause Mortality All-Cause Mortality — As Treated — As Treated

HR 0.70 (0.58 – 0.84)

P < 0.001

HR 0.70 (0.58 – 0.84)

P < 0.001

0.49

0.38

STICH Revascularization HypothesisSTICH Revascularization HypothesisTreatment Per ProtocolTreatment Per Protocol

Per protocol: MED (537) vs. CABG (555)

1212

RandomizedCABG

Randomized MED only

610602

Received MED only

Received CABG

555537 55 65

17% 9%

All-Cause MortalityAll-Cause Mortality— Per Protocol— Per Protocol

HR 0.76 (0.62, 0.92)

P = 0.005

HR 0.76 (0.62, 0.92)

P = 0.005

0.37

0.48

LimitationsLimitations

• The adjusted, as treated and per protocol The adjusted, as treated and per protocol analyses of the primary endpoint although analyses of the primary endpoint although informative should be considered informative should be considered provisionalprovisional

• The STICH trial was not blinded and non-The STICH trial was not blinded and non-fatal outcomes could have been influenced fatal outcomes could have been influenced by the knowledge of the treatment receivedby the knowledge of the treatment received

SummarySummary

• We compared CABG with contemporary We compared CABG with contemporary evidence-based MED alone among high-risk evidence-based MED alone among high-risk patients with CAD, HF and LVDpatients with CAD, HF and LVD

• Despite the medical adherence and Despite the medical adherence and operative results achieved, STICH-like operative results achieved, STICH-like patients remain at substantial risk patients remain at substantial risk 5-year mortality risk with MED only = 40%5-year mortality risk with MED only = 40%

Conclusions Conclusions

• In patients randomized to STICH, there was In patients randomized to STICH, there was no statistically significant difference in all-no statistically significant difference in all-cause mortality between medical therapy cause mortality between medical therapy alone and medical therapy with CABG alone and medical therapy with CABG

• Medical therapy with CABG reduces Medical therapy with CABG reduces cardiovascular mortality and morbidity compared cardiovascular mortality and morbidity compared to medical therapy aloneto medical therapy alone

• When randomized to CABG, patients are When randomized to CABG, patients are exposed to an early riskexposed to an early risk

Clinical ImplicationsClinical Implications

• CAD should be assessed and medical therapy CAD should be assessed and medical therapy optimized for all patients presenting with HF.optimized for all patients presenting with HF.

• Decision making for CABG is complex, should Decision making for CABG is complex, should be individualized and take into account the be individualized and take into account the short-term risk for long-term benefit.short-term risk for long-term benefit.

• The STICH Extension Study will test the The STICH Extension Study will test the durability of these results at 10 years. durability of these results at 10 years.

THANK YOUTHANK YOU

Thank youThank you to the STICH Investigators and to the STICH Investigators and CoordinatorsCoordinators

……and the STICH patients without whose and the STICH patients without whose participation in clinical research the STICH participation in clinical research the STICH trial would never have been completedtrial would never have been completed

Full report available online at NEJM.orgFull report available online at NEJM.org