intravascular ultrasound: eight insights for the clinical ...follow-up ivus of originally imaged...

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Intravascular Ultrasound:Eight Insights for the Clinical Lipidologist

Intravascular Ultrasound:Eight Insights for the Clinical Lipidologist

Steven E. Nissen MD MACCSteven E. Nissen MD MACC

Disclosure

Consulting: Many companies

Clinical Trials: Amgen, AstraZeneca, Eli Lilly, Takeda, Novartis, The Medicine Company, Cerenis, Esperion, Novo Nordisk and Pfizer.

Companies are directed to pay any honoraria directly to charity. No personal reimbursement is accepted for directing or participating in clinical trials.

Disclosure

Consulting: Many companies

Clinical Trials: Amgen, AstraZeneca, Eli Lilly, Takeda, Novartis, The Medicine Company, Cerenis, Esperion, Novo Nordisk and Pfizer.

Companies are directed to pay any honoraria directly to charity. No personal reimbursement is accepted for directing or participating in clinical trials.

Insight 1:Coronary Disease

is Not a Plumbing Problem


is Not a Plumbing Problem

2

Single Vessel Left Anterior Descending DiseaseSingle Vessel Left Anterior Descending Disease

3

Intravascular Ultrasound Coronary ImagingIntravascular Ultrasound Coronary ImagingRotating Transducer Coronary Atheroma

Glagov Remodeling PhenomenonGlagov Remodeling PhenomenonEarly Atherosclerosis Advanced Disease

3.5 mm 3.5 mm

4

Angiographically NormalSegment of LAD

Angiographically NormalSegment of LAD

5

Low Grade Stenoses Cause Most InfarctionsLow Grade Stenoses Cause Most Infarctions

CAD: The Diagnosis Often Comes Too LateCAD: The Diagnosis Often Comes Too Late

6

Insight 2:Coronary Disease is Ubiquitous

and Starts at a Young Age

Insight 2:Coronary Disease is Ubiquitous

and Starts at a Young Age

7

Transplant Donor: 33 Year Old MaleTransplant Donor: 33 Year Old MaleLeft Anterior DescendingLeft Anterior Descending Left Circumflex Left Circumflex

Donor Atherosclerosis: 17 Year Old MaleDonor Atherosclerosis: 17 Year Old MaleLeft Anterior DescendingLeft Anterior Descending Magnified View Magnified View

8

Tuzcu et al,, in press.

Insight 3:Coronary Disease is Exquisitely

Sensitive to LDL-C Levels

Insight 3:Coronary Disease is Exquisitely

Sensitive to LDL-C Levels

9

654 patients at 34 centersSymptomatic CAD, coronary angiography with >20% stenosis

LDL 125 to 210 mg/dL after 8 week washout

pravastatin 40 mg atorvastatin 80 mg18 monthstreatment

249 pravastatin patients 253 atorvastatin patients

74 patients withdrew78 patients withdrew

Follow-up IVUS of originally imaged “target” vessel (n=502)

Intravascular ultrasound with 30 MHz transducerMotorized pullback at 0.5 mm/sec through >30 mm

length of single “target” coronary artery

LumenArea

EEM Area

Atheroma Area

Ultrasound Measurement of Atheroma AreaPrecise Manual Planimetry of EEM and Lumen Borders

10

1 mm spacing

Cross-section 10Cross-section 26Cross-section 48

Ultrasound Measurement of Atheroma VolumeMotorized Pullback: Cross-sections Selected at 1 mm Intervals

11

Final Lipid Values and Percent Change Final Lipid Values and Percent Change

* ANOVA

Primary Endpoint

Percent Change in Atheroma VolumePrimary Endpoint

Percent Change in Atheroma Volume

PercentChange

InAtheromaVolume

p = 0.02†

Progression (p=0.001*)

No change (p=0.98*)

Pravastatin Atorvastatin *Wilcoxon signed rank test †ANCOVA of rank transformed results

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is an Inflammatory Disorder


is an Inflammatory Disorder

-0.5

0

0.5

1

1.5

2

2.5

3

3.5

-120 -100 -80 -60 -40 -20 0 20

Change in LDL-C (mg/dL)

Cha

nge:

Per

cent

Ath

ero

ma

volu

me

(%)

LDL-C Change vs. Atherosclerosis ProgressionLDL-C Change vs. Atherosclerosis Progression

Combined atorvastatinand pravastatintreatment groups

Nissen et al. N Engl J Med 2005;352:29-38.

13

0

0.5

1

1.5

2

2.5

-90 -80 -70 -60 -50 -40 -30 -20 -10 0

Cha

nge

in P

erce

nt A

ther

oma

Vol

ume

(%)

Change in LDL-cholesterol (mg/dL)

LDL-C Change vs. Atherosclerosis ProgressionLDL-C Change vs. Atherosclerosis Progression

Percent reduction in CRP (mean baseline level =2.9 mg/dL)

Secondary Endpoint: C-reactive ProteinSecondary Endpoint: C-reactive Protein

PercentChange

(%)

Pravastatin Atorvastatin

p < 0.0001*

*Wilcoxon rank sum test

14

-2.5

-2

-1.5

-1

-0.5

0

0.5

1

1.5

2

2.5

3

3.5

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

Change in C-Reactive Protein (mg/L)

Cha

nge

in P

erce

nt A

ther

oma

Vol

ume

(%)

CRP Change vs. Atherosclerosis ProgressionCRP Change vs. Atherosclerosis Progression

Combined atorvastatinand pravastatintreatment groups

Insight 5:HDL Matters

(even if we don’t fully understand how)

Insight 5:HDL Matters

(even if we don’t fully understand how)

15

Obsrvational and Pre-Clinical StudiesObsrvational and Pre-Clinical Studies

• Apolipoprotein A1 Milano is a variant derived from 40 subjects in the Italian village of Limone sul Garda.

• Apo A1 Milano carriers exhibit mean HDL levels of 17 mg/dL (0.44 mmol/L) with normal longevity and no atherosclerosis.A cysteine is substituted for arginine at position 173.

• Recombinant Apo A1 Milano has been complexed with phospholipid to produce nascent HDL-like particle. (Esperion)

• Infusions of Apo A1 Milano phospholipid complex in Apo E deficient mice rapidly (48 hours!!) mobilized lipid and reduced macrophage content within atherosclerotic lesions.*

• Apolipoprotein A1 Milano is a variant derived from 40 subjects in the Italian village of Limone sul Garda.

• Apo A1 Milano carriers exhibit mean HDL levels of 17 mg/dL (0.44 mmol/L) with normal longevity and no atherosclerosis.A cysteine is substituted for arginine at position 173.

• Recombinant Apo A1 Milano has been complexed with phospholipid to produce nascent HDL-like particle. (Esperion)

• Infusions of Apo A1 Milano phospholipid complex in Apo E deficient mice rapidly (48 hours!!) mobilized lipid and reduced macrophage content within atherosclerotic lesions.*

*Shah PK et al. Circulation 1998;97:780-785 and Circulation 2001;103:3047-3050.

123 patients at 10 centers screenedRecent myocardial infarction or Acute coronary syndrome

>20% stenosis in a non-intervened vessel


Follow-up IVUS of originally imaged “target” vessel (n=47)

Intravascular ultrasound with 40 MHz transducerMotorized pullback at 0.5 mm/sec through >30 mm

length of single “target” coronary artery

ETC-216 high (22 pts)

Placebo 11 pts ETC-216 high (15 pts)

2 patients withdrew

Placebo 12 pts ETC-216 low (23 pts)

5 weeks

ETC-216 low (21 pts)

16

ApoA1 Milano: Change in Total Atheroma VolumeApoA1 Milano: Change in Total Atheroma Volume

-18

-16

-14

-12

-10

-8

-6

-4

-2

0 Column1

Tota

l Ath

erom

a V

olum

e (m

m3)

-14.1mm3-14.1mm3

PlaceboPlacebo Low DoseLow Dose High DoseHigh Dose

-12.6mm3-12.6mm3

-15.1 mm3-15.1 mm3

-2.9mm3-2.9mm3

CombinedCombined

P = 0.97

P = 0.02

P = 0.007

P < 0.001

SideBranch

SideBranch

EEM area14.37 mm2

EEM area 11.58 mm2

Lumen area6.23 mm2

Lumen area6.27 mm2

Atheromaarea - 8.10 mm2

Atheromaarea - 5.35 mm2

17

Percent Atheroma Volume: LDL-C and HDL-CPercent Atheroma Volume: LDL-C and HDL-C

-0.6

-0.4

-0.2

0

0.2

0.4

0.6

0.8

1

1.2

1.4

Column1

Per

cent

Ath

erom

a V

olum

e (%

) 1.3%1.3%

0.9%0.9%

0.2%0.2%

-0.2%-0.2%

LDL-C worseHDL-C worseLDL-C worseHDL-C worse

LDL-C worseHDL-C betterLDL-C worseHDL-C better

LDL-C betterHDL-C worseLDL-C betterHDL-C worse

LDL-C betterHDL-C betterLDL-C betterHDL-C better

Median LDL-C - 87.5 mg/dLMedian HDL-C change - 7.5%

Insight 6:It’s Not Just Lipids

Blood Pressures Also Matters

Insight 6:It’s Not Just Lipids

Blood Pressures Also Matters

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1991 patients at 100 centers, North America and EuropeSymptomatic CAD, coronary angiography with >20% stenosis

Diastolic BP ≤ 100 mm Hg

placebo

Intent-to-treat analysis of cardiovascular events (1991 patients)Repeat intravascular ultrasound examination (274 patients)

enalapril 20 mg amlodipine 10 mg

Baseline intravascular ultrasound in 428 participants

24 months treatment

Nissen et al. JAMA. 2004;292(18); 2217-2226. Dr Steven Nissen, Cleveland Clinic Foundation.

Months after randomization

Systolic Pressure: All Three Treatment GroupsSystolic Pressure: All Three Treatment Groups

Nissen et al. JAMA. 2004;292(18); 2217-2226.Dr Steven Nissen, Cleveland Clinic Foundation.

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Comparison: Events Rates and IVUS ProgressionComparison: Events Rates and IVUS Progression

Patients with baseline systolic blood pressure ≥ mean Patients with baseline systolic blood pressure ≥ mean

0

0.4

0.8

1.2

1.6

2

2.4

Placebo Enalapril AmlodipineC

hang

e in

Per

cent

Ath

erom

a V

olum

e (%

)

p < 0.001

p = 0.20

p = 0.76

p = 0.02

Nissen et al. JAMA. 2004;292(18); 2217-2226.

0%

4%

8%

12%

16%

20%

24%

28%

0 4 8 12 16 20 24

Time (months)

Even

t R

ate

(%)

Amlodipine

EnalaprilPlacebo

24.7%

21.1%

18.3%

Blood Pressure Classification and ProgressionBlood Pressure Classification and Progression

-20

-15

-10

-5

0

5

10

15

20

25

30

0

ChangesIn Atheroma

Volume(mm3)

Normal Pre-HTN HTN

p<0.001

p=0.01

p=0.039

JACC. 2006 15;48(4):833-8

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Effect of LDL and SBP on Atheroma ProgressionEffect of LDL and SBP on Atheroma Progression

0.15

0.3

0.51

0.61

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

Column1

Per

cent

Ath

erom

a V

olum

e (%

)

J Am Coll Cardiol 2009:53:1110-52009

LDL-C <70SBP <120

LDL-C <70SBP ≥120

LDL-C ≥70SBP <120

LDL-C ≥70SBP ≥120

Insight 7:A Lower LDL-C

is Almost Always Better

Insight 7:A Lower LDL-C

is Almost Always Better

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Mean

Baseline During

treatment* Percent

Change†p

value

Total Cholesterol (mg/dL )

204 133.8 -33. 8 <0.001

LDL-C (mg/dL )

130.4 60.8 -53. 2 <0.001

HDL-C (mg/dL )

43.1 49.0 +14. 7 <0.001

Triglycerides (mg/dL )

152.2 121.2 -14. 5 <0.001

LDL-C/HDL-C ratio

3.2 1.3 -58.5 <0.001

* Time-weighted average † From least square mean

Rosuvastatin: Percent Change in Lipids (n=349)

Dual Primary IVUS Efficacy ParametersDual Primary IVUS Efficacy ParametersMedian Change in Percent

Atheroma VolumeMedian Change in

Most Diseased Subsegment

Regressionp<0.001*

*Wilcoxon signed rank test for comparison with baseline

Regressionp<0.001*

ChangeIn

AtheromaVolume(mm3)

ChangeIn

PercentAtheromaVolume

(%)

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Distribution: Percent Atheroma VolumeDistribution: Percent Atheroma Volume

0

20

40

60

80

-7 -6 -5 -4 -3 -2 -1 0 1 2 3 4 5

Numberof

Patients

Regression63.6%

Progression36.4%

Change in Percent Atheroma Volume (%)

Coronary IVUS Regression-Progression TrialsCoronary IVUS Regression-Progression Trials

-1.2

-0.6

0

0.6

1.2

1.8

50 60 70 80 90 100 110 120

MedianChange

In PercentAtheromaVolume

(%)

Mean Low-Density Lipoprotein Cholesterol (mg/dL)

REVERSALpravastatin

REVERSALatorvastatin

CAMELOTplacebo

A-Plusplacebo

ACTIVATEplacebo

Relationship between LDL-C and Progression Rate

ASTEROIDrosuvastatin

r2= 0.95p<0.001

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Impact of LDL-C Lowering on Plaque ProgressionImpact of LDL-C Lowering on Plaque Progression

Nicholls S. et al. JAMA. 2007;297:499-508.

40 50 60 70 80 90 100 110-2

-1-1

00

11

22

LDL-C During Treatment, mg/dLLDL-C During Treatment, mg/dL

40 50 60 70 80 90 100 110

Insight 8:Many Promising Therapies Don’t Work

Insight 8:Many Promising Therapies Don’t Work

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446 atorvastatin patients 464 torcetrapib patients


24 Month follow-up IVUS of originally imaged “target” vessel (n=910)

4-10 week run-in atorvastatin 10-80 mgto achieve LDL-C of 100±15 mg/dL

Intravascular ultrasound with 40 MHz transducerMotorized pullback at 0.5 mm/sec through >40 mm segment

1188 patients at 137 centers in North America and EuropeSymptomatic CAD, coronary angiography with >20% stenosis

Atorvastatinmonotherapy

Torcetrapib 60mg-atorvastatin

24 monthstreatment

40

50

60

70

80

90

100

0 1 3 6 9 12 15 18 21 24

Time (months)

LD

L c

ho

les

tero

l Le

vel (

mg

/dL

)

Time Course: Change in LDL-C Levels

Torcetrapib-Atorvastatin

Atorvastatin Monotherapy

Difference 19.9%

25

20

30

40

50

60

70

80

90

0 1 3 6 9 12 15 18 21 24

Time (months)

HD

L-c

ho

lest

ero

l Lev

el (

mg

/dL

)

Time Course: Change in HDL-C Levels

Torcetrapib-Atorvastatin

Atorvastatin Monotherapy

Difference 60.8%

Primary Efficacy Parameter

Change in Percent Atheroma VolumePrimary Efficacy Parameter

Change in Percent Atheroma Volume

Changein percentatheromavolume

Atorvastatinmonotherapy

Torcetrapib-atorvastatin

p = 0.72†

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ACAT Inhibition: Mechanism of ActionACAT Inhibition: Mechanism of Action

Change in Atheroma Volume(mm3)*

Change in Atheroma Volume(mm3)

p=0.04 p=0.01

placebo pactimibe

Pactimibe vs. Placebo: Atheroma VolumePactimibe vs. Placebo: Atheroma Volume

Entire Ultrasound PullbackEntire Ultrasound Pullback Most Diseased 10 mmMost Diseased 10 mm

p<.001

p=0.39

p<.001

p=0.02

†

†

† median

Nissen SE et al. N Engl J Med. 2006 Mar 23;354(12):1253-63.

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A Decade of IVUS Atherosclerosis TrialsA Decade of IVUS Atherosclerosis Trials

Name Trial Description Status

Reversal High intensity statins JAMA (2004)

Apo A1 Milano HDL mimetic JAMA (2003)

Camelot Blood pressure JAMA (2004)

Activate An ACAT inhibitor NEJM (April ‘06)

Asteroid Rosuvastatin 40 mg for regression JAMA (April ’06)

Illustrate Torcetrapib+statin vs. statin alone NEJM (March ’07)

Periscope Pioglitazone vs. glimepiride JAMA (April ’08)

Stradivarius Rimonabant vs usual care JAMA (April ’08)

Saturn Two potent statins NEJM (2011)

Aquarius Aliskerin in normotensive patients JAMA (2013)

Assure Apo A1 inducer (Resverlogix) Published 2015

Glagov PCSK9 Inhibitor AHA 2016

Apo A1 Milano HDL mimetic Underway 2016

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0%

20%

40%

60%

80%

100%

>-20 -15 -10 -5 0 5 10 15 20 25

Change in Systolic Blood Pressure (mmHg)

Pe

rce

nta

ge

of

Su

bje

cts

(%)

Cumulative Histogram: Change in Systolic BP

TorcetrapibAtorvastatin

AtorvastatinMonotherapy

LS Mean difference4.6 mm Hg

PERISCOPE: Glycohemoglobin LevelsPERISCOPE: Glycohemoglobin Levels

HbA1c(%)

Weeks after Randomization

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Percentage Changes: Biochemical ParametersPercentage Changes: Biochemical Parameters

P <0.001

P = 0.69

HDL-cholesterolHDL-cholesterol LDL-cholesterolLDL-cholesterol

4.1%

16.0%

-15.3%

0.6%

TriglyceridesTriglycerides

6.9% 6.6%

hs C-reactive Proteinhs C-reactive Protein

-18.0%

-44.9%

P <0.001P <0.001

Change in Percent Atheroma Volume (%)Change in Percent Atheroma Volume (%)

P < 0.001P < 0.001

P = 0.44P = 0.44

P = 0.002P = 0.002

Glimepiride Pioglitazone

Primary Efficacy ParameterPrimary Efficacy Parameter

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Rosuvastatin 40 mg (n =694)

Atorvastatin 80 mg (n=691)

Safety Safety LipidsSafety

IVUSLipids Safety

LipidsSafety

Safety Safety

Visit:Week:

1–4

30

413

526

639

752

865

978

1091

11104

Screening Period

2–2

Rosuva 20 mg

Atorva 40 mg

IVUSLipids

Lipids

Randomization Period

LipidsSafety

Safety

1385 patients with symptomatic CAD (angiographic stenosis >20%)

LDL‐C with (>80 mg/dL) or without (>100 mg/dL) statin use last 4 weeks

SATURN: Study Design

Primary Efficacy Parameter

Change in Percent Atheroma VolumePrimary Efficacy Parameter

Change in Percent Atheroma Volume

-0.99

-1.22

-1.5

-1.25

-1

-0.75

-0.5

-0.25

0

Changein percentatheromavolume

Atorvastatin 80 mg Rosuvstatin 40mg

p = 0.17

31

Correlation with Clinical Outcomes

Correlation with Clinical Outcomes

32

Q1Q2Q3Q4

0.6

0.7

0.8

0.9

1.0

Days

0 200 400

Survival

6000.6

0.7

0.8

0.9

1.0

Days

0 200 400

Survival

600

Q1Q2Q3Q4

IVUS Disease Burden and Cardiovascular Events

Nicholls J Amer Coll Cardiol 2010Nicholls J Amer Coll Cardiol 2010

Death, myocardial infarction and coronary revascularization

33

Cumulative Incidence of MACE (%)

Month1812963 5 21 240

12

2

6

8

10

4

0

14Cumulative Incidence of MACE (%)

Month1812963 5 21 24

12

2

6

8

10

4

0

14

0

Log Rank Test P value =0.001 for PAV quartile 4 vs.lower quartile

Baseline PAV Quartile 1 (14.78-30.73)Baseline PAV Quartile 2 (30.80-36.09)Baseline PAV Quartile 3 (36.12-41.74)Baseline PAV Quartile 4 (41.78-68.75)

Baseline PAV Quartile 1 (14.78-30.73)Baseline PAV Quartile 2 (30.80-36.09)Baseline PAV Quartile 3 (36.12-41.74)Baseline PAV Quartile 4 (41.78-68.75)

Plaque Burden Predicts MACE with High Intensity Statins

Puri Eur. Heart J 2013

CETP inhibitionwith torcetrapib

Infusion ofApoA1 Milano

34

Prior Coronary IVUS Progression TrialsPrior Coronary IVUS Progression Trials

-1.2

-0.6

0

0.6

1.2

1.8

50 60 70 80 90 100 110 120

MedianChange

In PercentAtheromaVolume

(%)

Mean LDL-C (mg/dL)

REVERSALpravastatin

REVERSALatorvastatin

CAMELOTplacebo

A-Plusplacebo

ACTIVATEplacebo

Relationship between LDL-C and Progression Rate

UnexploredRegionUnexploredRegion

Impact of HDL-C Raising on Plaque ProgressionImpact of HDL-C Raising on Plaque Progression

-2-2

-1-1

00

11

22

Nicholls S. et al. JAMA. 2007;297:499-508.

Increase in HDL (%)Increase in HDL (%)10 20 30 40

Changein PAV

(%)

35

Recent and Ongoing IVUS Atherosclerosis TrialsRecent and Ongoing IVUS Atherosclerosis Trials

Name Trial Description Status

Activate An ACAT inhibitor NEJM (April ‘06)

Asteroid Rosuvastatin 40 mg for regression JAMA (April ’06)

Illustrate Torcetrapib+statin vs. statin alone NEJM (March ’07)

Periscope Pioglitazone vs. glimepiride JAMA (April ’08)

Stradivarius Rimonabant vs usual care JAMA (April ’08)

Aquarius aliskerin in normotensive patients JAMA (2013)

Saturn Atorvastatin vs. rosuvastatin NEJM (2011)

Glagov PCSK9 Inhibitor Coming soon

36

Torcetrapib Results: Levels of HDL-C AchievedTorcetrapib Results: Levels of HDL-C Achieved

-0.8

-0.6

-0.4

-0.2

0

0.2

0.4

0.6

0.8

Column1

Per

cent

Ath

erom

a V

olum

e (%

)

Quartile 1<56 mg/dLQuartile 1<56 mg/dL

Quartile 256 to 69 mg/dL




Quartile 4>86 mg/dLQuartile 4>86 mg/dL

Percent Atheroma VolumePrimary Efficacy Parameter0.70%0.70%

0.30%0.30%0.18%0.18%

-0.69%-0.69%

Serum Potassium: Effect of TorcetrapibSerum Potassium: Effect of Torcetrapib

4

4.05

4.1

4.15

4.2

4.25

4.3

4.35

BaselineBaseline Follow-upFollow-up

AtorvastatinAtorvastatin Torcetrapib-AtorvastatinTorcetrapib-Atorvastatin

4

4.05

4.1

4.15

4.2

4.25

4.3

4.35

Baseline Baseline Follow-upFollow-up

P = 0.08P < 0.001

37

Correlation Between LDL-C and CRP ChangeCorrelation Between LDL-C and CRP ChangeAtorvastatin 80 mg Pravastatin 40 mg

r = -0.008p = 0.90

r = 0.08p = 0.17

intravascular ultrasound: eight insights for the clinical ...follow-up ivus of originally imaged...

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