Overview of the ISCHEMIA Trial Results - PowerPoint Presentation

Slide1

Overview of the

ISCHEMIA Trial Results

Gregg W. Stone, MD

The Zena and Michael A. Wiener Cardiovascular Institute,

Icahn School of Medicine at Mount Sinai, NY

and the Cardiovascular Research Foundation

Slide2

Relevant Financial Disclosures

Supported by NHLBI grants

Consultant to

HeartFlow

Slide3

ISCHEMIA Trial:

BackgroundPrior trials (most notably COURAGE and BARI-2D) did not show that revascularization in stable CAD prevents death or MILimitations:- Enrolled after angiography → Low risk pts enrolled- Highest risk anatomical pts were excluded- Most pts had minimal to only moderate ischemiaDid not use contemporary stents, physiologic guidance, bilateral IMA, pharmacotherapy, etc.

Slide4

Revascularization vs. Medical Rx. According to Ischemic Risk

(n=3,251; F/U 1.9 yr)Hachamovitch R et al. Circulation 2003;107:2900-7

Cox proportional hazards regression model

P<0.0001

P

interaction

= 0.03

Revascularization

% Total ischemic myocardium

6

5

4

3

Log HR Cardiac Death

2

1

0

0

12.5%

25%

32.5%

50%

Medical therapy

~10% ischemic

myocardium

Slide5

Stable Patients (n=8518)

Moderate or severe ischemia(determined by site; read by core lab)CCTA not required:eGFR 30 to <60 mL/min or coronary anatomy previously defined

Blinded CCTA (73% of pts)

Core lab anatomy eligible?

RANDOMIZE (n=5179)

Screen failure

ISCHEMIA Trial:

Patient Flow

INVASIVE Strategy

OMT + Cath +

Optimal Revascularization

(n=2588)

CONSERVATIVE Strategy

OMT alone

Cath reserved for OMT failure

(n=2591)

NO

YES

Inclusion Criteria

≥50% stenosis in a major epicardial vessel (stress imaging participants)

≥70% stenosis in a proximal or mid vessel (ETT participants)

Major Exclusion Criteria:

≥50% LM ds.

- 8.7% of CTAs

Major Exclusion Criteria

Unacceptable angina despite medical therapy

ACS within 2 months

PCI or CABG within 1 year

NYHA Class III-IV HF

LVEF <35%

eGFR <30 mL/min or dialysis →

ISCHEMIA CKD

Median FU 3.2 years

Maron DJ et al. N

Engl

J Med. 2020;382:1395-1407

13.5% of CTAs

Slide6

ISCHEMIA

OrganizationStudy Chair: Judith S. Hochman (New York University) Study Co-Chair: David J. Maron

(Stanford University)Clinical Coordinating Center:

NYU Cardiovascular Clinical Research Center

Harmony Reynolds

Sripal

Bangalore

Jeffrey Berger, Jonathan Newman

Stephanie Mavromichalis

Mandeep

Sidhu (Albany Medical

Ctr

)

Statistical and Data Coordinating Center

:

Duke Clinical Research Institute

Sean O’Brien

Karen Alexander

Lisa Hatch

Frank Harrell (Vanderbilt)

National Heart Lung & Blood Institute:

Yves Rosenberg, Jerome Fleg, Neal Jeffries, Ruth Kirby

Data Safety Monitoring Board:

Lawrence Friedman, Chair; Jeffrey Anderson; Jessica Berg; David

DeMets

; C. Michael Gibson;

Gervasio A. Lamas; Pamela Ouyang; Pamela K. Woodard

Executive Committee:

Karen Alexander

Sripal Bangalore

Jeffrey Berger

Daniel Mark

Sean O’Brien

Harmony Reynolds

Yves Rosenberg

Leslee

Shaw

John Spertus

Leadership Committee:

Judith Hochman, Chair

David Maron, Co-Chair

William Boden, Co-PI

Bruce Ferguson, Co-PI

Robert Harrington, Co-PI

Gregg W. Stone, Co-PI*

David Williams, Co-PI

Top Countries/Regions Leaders:

Balram Bhargava (India), Roxy Senior (UK), Shaun Goodman, Gilbert Gosselin (Canada), Renato Lopes (Brazil), Witold Ruzyllo, Hanna Szwed (Poland), Leo Bockeria

(Russia), José Lopez-Sendon (Spain), Aldo Maggioni (Italy), Harvey White (Singapore, New Zealand), Rolf Doerr (Germany)Clinical Event Adjudication Committee Chair:

Bernard Chaitman (Saint Louis University)

Imaging Coordinating Center

:Leslee Shaw (Emory/Weil Cornell Medicine)

EQOL

Coordinating Center

:

Daniel Mark (Duke University)

John Spertus (St. Luke’s Mid America Heart Institute)

*Chair of the PCI and CABG revascularization committee

Maron DJ et al. N

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Slide7

Baseline Characteristics

Characteristic

INV

(n=2588)

CON

(n=2591)

Clinical

Age (

yrs

), median

64 (58, 70)

64 (58, 70)

Female (%)

23

22

Hypertension (%)

73

73

Diabetes (%)

41

42

Prior MI (%)

19

19

LVEF (%), median (n=4637)

60 (55, 65)

60 (55, 65)

History of angina

90%

89%

Angina began or became more frequent over the past 3

mos

29%

29%

SAQ Angina Frequency Score

80.8

20

82.1

19

- Daily/Weekly Angina

21.6%

19.0%

- Several Times per Month

44.1%

44.5%

- No Angina

34.3%

36.6%

Characteristic

INV

(n=2588)

CON

(n=2591)

Clinical

Age (

yrs

), median

64 (58, 70)

64 (58, 70)

Female (%)

23

22

Hypertension (%)

73

73

Diabetes (%)

41

42

Prior MI (%)

19

19

LVEF (%), median (n=4637)

60 (55, 65)

60 (55, 65)

History of angina

90%

89%

Angina began or became more frequent over the past 3

mos

29%

29%

SAQ Angina Frequency Score

- Daily/Weekly Angina

21.6%

19.0%

- Several Times per Month

44.1%

44.5%

- No Angina

34.3%

36.6%

Maron DJ et al. N

Engl

J Med. 2020;382:1395-1407

Slide8

Qualifying Stress Test: Core Lab Interpretation

*Only severe qualified by ETT

INV

(n=2588)

CON

(n=2591)

Stress Test Modality

Stress imaging

75%

76%

Exercise tolerance test (ETT)

25%

24%

Baseline Inducible Ischemia*

Severe

53%

55%

Moderate

34%

32%

Mild/None

12%

12%

Uninterpretable

1%

1%

Maron DJ et al. N

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Slide9

Baseline Coronary Artery Anatomy by CCTA

# of Vessels with ≥50 % Stenosis (%)(% of total)

Specific Vessels with ≥50% Stenosis (%)N=2982

N=3739

77% MVD

Maron DJ et al. N

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Slide10

Maron DJ et al. N

Engl J Med. 2020;382:1395-1407Risk Factor Management in the TrialNo between group differences INV vs CON

High Level of Medical Therapy Optimization was defined as a participant meeting all of the following goals: LDL <70 mg/dL and on any statin, SBP <140 mm/Hg, on aspirin or other antiplatelet or anticoagulant, and not smoking.

Baseline LDL 83 mg/dL

Last visit LDL 65 mg/dL

Slide11

Cardiac Catheterization

RevascularizationCardiac Catheterization and Revascularization

12%

95%

96%

9%

28%

76%

79%

80%

23%

7%

Maron DJ et al. N

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Indications for

cath

in CON

Suspected/confirmed event: 13.8%

OMT

f

ailure

: 3.9%

Non-adherence: 8.1%

Revascularization in CON

at 4 years not preceded by a primary endpoint event: 16%

vs. 32% in COURAGE

Slide12

Mode of Revascularization

First Procedure for Those

Revascularized

in Invasive Group

(~80% of INV)

First Procedure

Total

PCI

74% 

Successful,

s

tent

implanted

93%

Of stents placed, drug- eluting

98%

First Procedure

Total

CABG

26%

Arterial Grafts

93%

IMA

92%

Of the ~ 20% with no revascularization

:

~ 2/3 had insignificant disease on coronary angiogram

~1/3 had extensive disease unsuitable for any mode of revascularization

Maron DJ et al. N

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Slide13

CON

INVAdjusted HR (95% CI) = 0.93 (0.80, 1.08)

P-value = 0.34 Subjects at Risk

CON

2591

2431

1907

1300

733

293

INV

2588

2364

1908

1291

730

271

Primary Outcome:

CV Death, MI, hospitalization for UA,

HF or resuscitated cardiac arrest

4 years:

Δ = -2.2% (-4.4%, 0.0%)

15.5%

13.3%

Maron DJ et al. N

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J Med. 2020;382:1395-1407

Median 3.2-year follow-up

Restricted mean event-free time difference:

9.5 days (-17.8 to 36.9) for INV vs. CON

6 months:

Δ = 1.9% (0.8%, 3.0%)

3.4

%

5.3%

352

vs.

318

events

Slide14

Primary endpoint:

Pre-specified Important Subgroups High degree of medical therapy optimization

Slide15

CON

INVSubjects at Risk

CON2591

2453

1933

1325

746

298

INV

2588

2383

1933

1314

752

282

Major Secondary Outcome:

CV Death or MI

Maron DJ et al. N

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Adjusted HR (95% CI) = 0.90 (0.77, 1.06)

P-value = 0.21

4 years:

Δ = -2.2% (-4.4%, -0.1%)

13.9%

11.7%

Median 3.2-year follow-up

Restricted mean event-free time difference:

9.4 days (-16.5 to 35.2) for INV vs. CON

6 months:

Δ = 1.9% (0.9%, 3.0%)

2.9

%

4.8%

Slide16

Non-procedural MI

Types 1, 2, 4b, or 4c MI

Procedural MI

Types 4a or 5 MI

Myocardial Infarction

Maron DJ et al. N

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Slide17

All-Cause Death

The probability of at least a 10% relative risk reduction of all-cause mortality with INV is <10%, based on pre-specified Bayesian analysis

6.4%

6.5%

Maron DJ et al. N

Engl

J Med. 2020;382:1395-1407

Restricted mean event-free time difference:

-3.0 days (-19.6 to 13.6) for INV vs. CON

4 years

Δ

=

0.1

% (-

1.5

%, 0.8%)

145

vs.

144

deaths

Median 3.2-year follow-up

Slide18

Typical Patient in ISCHEMIA

QOL Primary Outcome: Benefit of Invasive Rx on SAQ Summary ScoreFavors InvasiveFavors Conservative

Favors InvasiveFavors ConservativeFavors Invasive

Favors Conservative

Posterior Mean = 4.1 (3.2, 5.0)*

*95% Highest Posterior Density Interval

Posterior Mean = 4.2 (3.3, 5.1) *

Posterior Mean = 2.9 (2.2, 3.7)*

Spertus

JA et al. N

Engl

J Med. 2020;382:1408-1419

Slide19

Probability of

No Angina by Baseline Angina Frequencyn=8867

30172

140

509

500

850

693

1635

Daily

Weekly

Monthly

None

15%

45%

NNT = ~3

~No

difference

Spertus

JA et al. N

Engl

J Med. 2020;382:1408-1419

Slide20

Probability of

No Angina by Baseline Angina Frequencyn=886730

172140

509

500

850

693

1635

Daily

Weekly

Monthly

None

15%

45%

NNT = ~3

~No

difference

Spertus

JA et al. N

Engl

J Med. 2020;382:1408-1419

Slide21

ISCHEMIA:

LimitationsUnblinded trial (but placebo effects are not usually long-lasting) Based on exclusion criteria, the trial results do not apply to patients with:Left main diseaseAcute coronary syndromes within 2 monthsHighly symptomatic patientsHeart failure or LVEF <35% (few pts with LVEF <50%)Trial findings may not be generalizable to centers with higher procedural complication rates The impact of completeness of revascularization has not yet been assessed

Slide22

What Have we Learned from ISCHEMIA?

In pts with stable CAD and moderate to severe ischemia with preserved LVEF, a routine invasive strategy compared with an initial conservative approach does not reduce mortality A routine invasive strategy does reduce the occurrence of late MIs, although at the cost of procedural MIs – as such there is no long-term impact on total MI, CV death or MI, or protocol-defined MACE (CV death, MI, hospitalization for UA, HF or resuscitated cardiac arrest)Patients with stable CAD and moderate to severe ischemia have a significant, durable improvement in angina control and quality of life with an invasive strategy if they have angina (daily/weekly or monthly)

Slide23

Interpretation of ISCHEMIA

Stable Ischemic Heart Ds. Management after ISCHEMIASupport for an initial conservative approach“Thus, provided there is strict adherence to GDMT, patients with SIHD who fit the profile of those in ISCHEMIA and do not have unacceptable levels of angina can be treated with an initial conservative strategy.” Support for an initial invasive approach“However, an invasive strategy, which more effectively relieves symptoms of angina (especially in patients with frequent episodes), is a reasonable approach at any point in time for symptom relief.”Antman EM,

Braunwald E. N Engl J Med. 2020;382:1468-70