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EverolimusIntravascular Ultrasound (IVUS)

Results of Study B253 in De Novo Heart Transplantation

Jon A. Kobashigawa, MD

Clinical Professor of Medicine/CardiologyChief, Division of Clinical Faculty Medicine

The David Geffen School of Medicine at UCLA

Medical Director, UCLA Heart Transplant Program

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CV-2

Outline of the IVUS Presentation

IVUS background IVUS B253 study

– Primary analysis results

– Bias assessments

– Sensitivity analysis Summary

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3.1 mm3.1 mm

3.1 mm3.1 mm

Angiography vs Intravascular UltrasoundAngiography vs Intravascular UltrasoundQC

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Intimal Area

Intimal Area

Media-adventitialarea

Media-adventitialarea

Media-adventitia (MA)

Cross sectional area (mm2)

Maximal diameter (mm)

Minimal diameter (mm)

Minimal intimal

thickness

Minimal intimal

thickness

Maximalintimal

thickness (MIT)

Maximalintimal

thickness (MIT)

Intimal thickness

Maximal intimal thickness (mm)

Intimal area (mm2)

Minimal intimal thickness (mm)

Lumen areaLumen areaLumen

Cross sectional area (mm2)

Maximal diameter (mm)

Minimal diameter (mm)

Courtesy of R. Starling, Cleveland Clinic.

Intravascular Ultrasound Measurements

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Segment and Image Selection

18181717

1414

1212

1010

88

66

44

22

16161515

1313

1111

99

77

55

33

11

18 mm18 images

Segments were identified: Automatic pullback (0.5 mm/sec), side branches.Frames at 1-mm intervals for measurements, minimum of 11 matched images.

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MIT = 0 MIT > 0.5 mm

Baseline (4 to 6 weeks) Year 1

Site-to-Site IVUS Analysis

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CV-7Measurement of Maximal Intimal Thickness (MIT) for Transplant Vasculopathy and Outcome

MIT accepted as standard method for CAV measurementa

Change in MIT ≥ 0.5 mm associated withb-d

– Increased major adverse cardiovascular events (MACE: AMI, CHF, PCI, CABG, ICD, SD, CVA, PVD)

– Reduced cardiac and overall survivale

– Represents an important intermediate outcome

a Mintz GS, et al. J Am Coll Cardiol. 2001;37:1478-1492.b Mehra MR, et al. J Heart Lung Transplant. 1995;4:632-639.c Kapadia SR, et al. Curr Opin Cardiol. 1999; 14:140-150.d Kobashigawa, et al. J Am Coll Cardiol. 2005;45:1532-1537.e Tuzcu EM, et al. J Am Coll Cardiol. 2005;45:1538-1542.

112-10

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Kobashigawa J, et al. J Am Coll Cardiol. 2005;45:1532-1537.

Multicenter IVUS Validation Study in Heart Transplantation (CAV: Change in MIT ≥ 0.5 mm)

Without CAV at 1 year (n = 101)With CAV at 1 year (n = 24)

Death

Time to event (months)

0 12 24 36 48 60

Fre

edo

m f

rom

eve

nt

(%)

P = 0.025

0

Time to event (months)

Fre

edo

m f

rom

eve

nt

(%)

Nonfatal MACE/death

12 24 36 48 600

10

20

30

40

50

60

70

80

90

100

P = 0.001

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0

10

20

30

40

50

60

70

80

90

100

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CAV at 1 year and Mortality and Myocardial Infarction (CAV: Change in MIT ≥ 0.5 mm)

CAV = Cardiac allograft vasculopathy.Tuzcu EM, et al. J Am Coll Cardiol. 2005;45;1538-1542.

100

80

60

40

00 20 40 60 80 100 120

Time, months

Death

Fre

edo

m f

rom

eve

nt

(%) 100

80

60

40

00 20 40 60 80 100 120

Time, months

Nonfatal MI and death

P = 0.0002P = 0.029

Without CAV at 1 year (n = 89)

With CAV at 1 year (n = 54)

155-2 Tuzcu - JACC Vol 45 No. 9 2005.pdf Figure 4

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Fre

edo

m f

rom

eve

nt

(%)

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IVUS MethodologyB253 Heart Study

IVUS efficacy assessments performed at baseline and 12 months for patients remaining on study drug

IVUS analysis conducted centrally at an experienced core laboratory at the Cleveland Clinic Foundation by cardiologists blinded to treatment assignments

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IVUS Efficacy AssessmentsB253 Heart Study

Primary IVUS endpoint: change in mean maximal intimal thickness (MIT) from baseline to 1 year– Choice of vessels:

• Left anterior descending coronary artery (LAD)• Right coronary artery if LAD not feasible

– Minimum of 11 matched images Secondary endpoints

– Incidence of CAV, defined as MIT ≥ 0.5-mm increase from baseline in at least 1 matched site

– Intimal area, intimal volume, and cross-sectional area of stenosis (mean and maximum change from baseline)

CAV = Cardiac allograft vasculopathy.

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Patient Disposition for IVUS AnalysisStudy B253

All randomizedn = 634

Baseline IVUS performedn = 419

12-month IVUS performedn = 262

Matched at 12 monthsn = 211

another CV slide.ppt205-11

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CV-13Reported Reasons for IVUS Data Loss at 12 monthsStudy B253

DRT1962.ppt205-2

Everolimus

AZA 1.5 mg 3.0 mg Total

No baseline assessment 62 68 65 195

Technical issues 7 9 5 21

D/C study, death, AEs 28 25 30 83

Due to renal problems 4 16 12 32

IVUS tape not analyzable 26 8 17 51

Administrative problems 10 8 6 24

No consent 1 4 6 11

Unknown 4 1 1 6

Total 142 139 142 423

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Baseline DemographicsStudy B253—ITT Population vs IVUS Population

ITT population (N = 634) 12-month IVUS population (N = 211)

RecipientsAZA

n = 214AZA

n = 72

Age, yr (mean ± SD)

50.5 ± 11.5 50.4 ±10.71

Male, n (%) 182 (85.0) 63 (87.5)

Race, n (%)

White 193 (90.2) 63 (87.5)

Black 13 (6.1) 6 (8.3)

Diabetes, n (%)at baseline

36 (16.8) 14 (19.4)

CAD, n (%)at baseline

68 (31.8) 27 (37.5)

GFR < 29 mL/min/1.73m2

at baseline

6 (2.8) 1 (1.4)

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10 (14.3)

27 (38.6)

4 (5.7)

5 (7.1)

62 (88.6)

57 (81.4)

51.2 ±10.16

1.5 mgn = 70

Everolimus

49 (23.2)

84 (39.8)

7 (3.3)

11 (5.2)

192 (91.0)

171 (81.0)

52.1 ± 10.8

3.0 mgn = 211

35 (16.7)

78 (37.3)

14 (6.7)

Everolimus

21 (10.0)

181 (86.6)

166 (79.4)

51.2 ± 11.1

1.5 mgn = 209

24 (34.8)*

30 (43.5)

3 (4.3)

4 (5.8)

62 (89.9)

54 (78.3)

51.9 ± 10.90

3.0 mgn = 69

PTT 3.1-4

*P = 0.057 vs AZA

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*P < 0.05 vs AZA; **P = 0.014 vs AZA; ***P < 0.01 vs AZA; ****P < 0.003 vs AZA

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Everolimus

IVUS measurement:Change from baseline

AZAn = 72

1.5 mgn = 70

3.0 mgn = 69

Mean maximal intimal thickness (MIT) (mm)

0.10 0.04** 0.03****

Mean intimal area (mm2) 0.93 0.41*** 0.22***

Mean cross-sectionalarea of stenosis (%)

5.56 2.07* 1.46*

Mean intimal volume (mm3) 16.56 9.70*** 8.24***

Incidence of vasculopathy (%)(MIT increase ≥ 0.5 mm)

52.8 35.7* 30.4*

12-month IVUS Endpoints Study B253 (Baseline to 1 year)

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CV-16Treatment Comparisons of IVUS Variables at 12 months95% CI for Everolimus Minus AZA

Mean Intimal area (mm2)

Mean change in MIT (mm)a

Everolimus 1.5 mg vs AZA Everolimus 3.0 mg vs AZA

–0.06

–0.07

–0.52

–0.71

-1.0 -0.9 -0.8 -0.7 -0.6 -0.5 -0.4 -0.3 -0.2 -0.1 0

Difference (95% CI)

Everolimus better AZA better

a Primary IVUS endpoint.

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CV-17Treatment Comparisons of IVUS Variables at 12 months95% CI for Everolimus Minus AZA

-14 -12 -10 -8 -6 -4 -2 0

Difference (95% CI)

Intimal volume (mm3)

Cross-sectional areaof stenosis: mean % change

Cross-sectional areaof stenosis: max % change

Everolimus 1.5 mg vs AZA Everolimus 3.0 mg vs AZA

IVUS back-up - Aug 10th.ppt205-12

–7.15

–8.8

–3.4

–4.1

–3.71

–5.4

Everolimus better AZA better

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52.8%

35.7%30.4%

0

20

40

60

80

Inc

ide

nc

e o

f C

AV

(%

)Incidence of CAV (Change in MIT ≥ 0.5 mm) at 12 months

P = 0.010

P = 0.045

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MIT = Maximal intimal thickness; CAV = Cardiac allograft vasculopathy.Pairwise comparison with Fisher’s exact test.Eisen H, et al. N Engl J Med. 2003;349:847-858.

Everolimus1.5 mgn = 70

Everolimus3.0 mgn = 69

AZAn = 72

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Strengths and Limitations of the IVUS Study

Strengths Prospective, blinded study Met planned sample size

(n = 234) Blinded central core lab Blinded baseline and

12 months IVUS Centers

– 48/52 at baseline– 39/52 at 1 year

IVUS population characteristics similar to ITT

Limitations Not an ITT analysis

– Patient participation determined by investigator

– Only 12-month survivors

– Only patients on therapy at 1 year

DRT1962.ppt205-1

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Assessment of Potential Selection Bias in the IVUS Subpopulation

Purpose– Identify selection bias favoring everolimus

• Demographic and clinical characteristics Plan

– Identify patterns of bias in favor of everolimus arms

– Sensitivity analyses to investigate the impact of potential biases

DRT1962.ppt205-3

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CV-21Potential Sources of Selection Bias InvestigatedIVUS at 1 year Demographic characteristics Recipient age Recipient gender Recipient race Donor age Donor gender GFR < 29 (mL/min/1.73 m2) Coronary artery disease Diabetes history* BMI > 33 LVAD Hypertension CMV

Clinical characteristics BPAR ≥ 3A BPAR + HDC Treated AR Total cholesterol LDL cholesterol CsA trough levels Posttransplant diabetes Mean GFR at 12 months** Triglyceride ACE inhibitor Statin use

*Favors AZA and everolimus 1.5 mg over everolimus 3.0 mg.**Favors AZA over everolimus.

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Sensitivity Analyses Performed to Assess Impact of Missing IVUS Data

Imputation methods used for missing 12-month values

– Assigned with age-matched AZA patients outcome

– Assigned a CAV outcome (MIT > 0.5 mm) Imputations were done for two sets of missing

values

– Patients with no IVUS due to reported renal dysfunction

– Patients with no 12-month IVUS

DRT1962.ppt205-9

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Sensitivity Analysis for Missing Data for CAV (MIT ≥ 0.5 mm)

Difference in CAV (%)

Everolimus 1.5 mg vs AZA

Everolimus 3.0 mg vs AZA

DRT1962.ppt205-10

-40 -30 -20 -10 0 10

• Assigning age-matched AZA MIT

• Assigning CAV

No imputation for CAV (n = 211)12-month IVUS population

–8.5

–9.5

–9.1

–11.3

–17.0

–22.0

• Assigning age-matched AZA MIT

• Assigning CAV

Missing due to renal dysfunction (n = 243)

All missing 12 month values (n = 419)

–12.8

–19.4–8.2

–14.5

Everolimus better AZA better

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Kaplan-Meier Analysis of Time to First Graft-Related MACE From Month 1 to Month 48 Excluding Patients Who Died Within 30 Days of First Dose

0.5

0.6

0.7

0.8

0.9

1.0

0 180 360 540 720 900 1080 1260 1440 1620

Time (days)

Su

rviv

al d

istr

ibu

tio

n

Everolimus 1.5 mgEverolimus 3.0 mgAZA

Treatment Patients at risk/censored

AZA (n = 211) 186/7 168/18 98/80Everolimus 1.5 mg (n = 202) 184/8 172/15 106/78Everolimus 3.0 mg (n = 206) 175/14 163/23 96/85

emai

l 10/

11/0

5 ex

cel d

atas

ets

P = 0.052, 1.5 mg vs AZAP = 0.356, 3.0 mg vs AZA

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1.5 mg3.0 mgAZA

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MACE SummaryStudy B253—Month 1 to 48

Patients, n (%)a

Everolimus

AZAn = 214

1.5 mgn = 209

3.0 mgn = 211

MACE (total) 43 (22.8) 32 (19.3) 32 (17.5)

Graft-related 33 (17.4) 19 (10.4)* 25 (13.6)

Non–graft-related 14 (7.8) 15 (10.2) 8 (4.4)

Fatal 10 (5.2) 6 (3.7) 7 (4.2)

Nonfatal 39 (21.1) 27 (16.6) 26 (14.0)

A patient may be counted in more than one row.a Percent based on Kaplan-Meier rate. *P = 0.052 based on log-rank test

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IVUS 12-month Summary

Everolimus demonstrated significant benefit in all IVUS measures of allograft vasculopathy vs AZA

– Smaller increases in maximal intimal thickness

– Lower incidence of CAV

– Smaller increase in intimal area and volume,percent stenosis, and others

Sensitivity analyses support the primary IVUS CAV results

No bias favoring everolimus was detected 48-month MACE data suggest potential for

long-term benefit

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