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CAMELOT:CAMELOT: Study Design Study Design

A Morbidity and Mortality StudyA Morbidity and Mortality StudyA Morbidity and Mortality StudyA Morbidity and Mortality Study

Patients with Patients with documented documented

CAD on CAD on standard-of-care standard-of-care

therapies*therapies*(n=(n=19971997))

Patients with Patients with documented documented

CAD on CAD on standard-of-care standard-of-care

therapies*therapies*(n=(n=19971997))

Clinical events Clinical events (morbidity (morbidity

and mortality)and mortality)

Clinical events Clinical events (morbidity (morbidity

and mortality)and mortality)2 Yr2 Yr2 Yr2 Yr

PlaceboPlaceborun-inrun-in

(2-6 wk)(2-6 wk)

Placebo-controlled, multicenter, randomized, double-blind, Placebo-controlled, multicenter, randomized, double-blind, comparative, parallel trial comparative, parallel trial

Enalapril 10-20 mgEnalapril 10-20 mg

Amlodipine 5-10 mgAmlodipine 5-10 mg

PlaceboPlacebo

PCI indicates percutaneous coronary intervention.

Initial sample size was 3000 patients. This was reduced in an amendment to 2000.*Patients stratified by PCI/stent status.

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CAMELOT:CAMELOT: Primary End Point Primary End Point

Time to first composite major CV event (MACE): CV death Nonfatal MI Resuscitated cardiac arrest Need for coronary revascularization Hospitalization for:

– Angina– CHF– PVD procedure

Stoke (fatal or nonfatal) or TIA PVD (new diagnosis)

PVD indicates peripheral vascular disease; and TIA, transient ischemic attack.

3

CAMELOT:CAMELOT: Secondary End Points Secondary End Points

Individual MACE components of the primary end pointIndividual MACE components of the primary end point

Requirement for revascularization in vessels that have undergone Requirement for revascularization in vessels that have undergone stenting at baselinestenting at baseline

All-cause mortalityAll-cause mortality

Correlation between change from baseline in BP and time Correlation between change from baseline in BP and time to first MACEto first MACE

– – Rate of MACE tabulated by categories of mean SBP reductionRate of MACE tabulated by categories of mean SBP reduction

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PlaceboPlaceborun-inrun-in

(2-6 wk)(2-6 wk)Enalapril 10-20 mgEnalapril 10-20 mg

Amlodipine 5-10 mgAmlodipine 5-10 mg

NORMALISE Substudy of CAMELOT:NORMALISE Substudy of CAMELOT:Study DesignStudy Design

CAMELOT CAMELOT patients patients (n=(n=431431))

CAMELOT CAMELOT patients patients (n=(n=431431))

2 Yr2 Yr2 Yr2 Yr

An IVUS Study of Coronary Artery PlaqueAn IVUS Study of Coronary Artery Plaque

IIVVUUSS

PlaquePlaqueprogression/progression/regressionregression

PlaquePlaqueprogression/progression/regressionregression

PlaceboPlacebo

• Multicenter, randomized, double-blind IVUS substudy of CAMELOT

QQCCAA

IIVVUUSS

QQCCAA

N = 274

Initial sample size was 750 patients. This was reduced in an amendment to 360, after 431 patients had undergone their initial IVUS. Ultimately, 274 patients received their second IVUS.

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NORMALISE:NORMALISE: IVUS End Points IVUS End Points

Primary:Primary:

Change from baseline in IVUS percent atheroma volume Change from baseline in IVUS percent atheroma volume (PAV) for all slices of the target vessel(PAV) for all slices of the target vessel

Important secondary:Important secondary:

Change in normalized total atheroma volume (TAV)Change in normalized total atheroma volume (TAV)

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Age, years 57.2 (9.5) 58.5 (9.9) 57.3 (9.7) 0.02

Male gender 73.0% 71.9% 76.3% 0.16

Caucasian 89.0% 89.3% 89.4% 0.97

BMI 29.7±5.0 29.7±5.5 29.9±5.5 0.72

History of hypertension 60.3% 59.7% 61.4% 0.82

BP, mm Hg 129/78 129/77 130/78 N/A

History of dyslipidemia 84.4% 83.7% 83.0% N/A

LDL-cholesterol, mg/dL 100 (32) 101 (31) 104 (32) 0.04

Diabetes 19.8% 17.5% 17.3% 0.42

Unstable angina† 9.9% 8.3% 8.1% 0.45

Prior bypass surgery 8.2% 6.8% 8.0% 0.59

Prior MI 37.7% 40.3% 37.4% 0.50

Current smoker 27.9% 24.8% 27.0% 0.41

Baseline DataBaseline DataBaseline Characteristics, Mean (SD) or Percentage of PatientsBaseline Characteristics, Mean (SD) or Percentage of PatientsBaseline Characteristics, Mean (SD) or Percentage of PatientsBaseline Characteristics, Mean (SD) or Percentage of Patients

Placebo(n=655)

Enalapril(n=673)

Amlodipine(n=663) P value*

*Analysis of variance *Analysis of variance PP value. value. ††Canadian Cardiovascular Society Class 4.Canadian Cardiovascular Society Class 4.

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*Analysis of variance *Analysis of variance PP value. value.

Statins 84.3% 81.7% 83.1% 0.46

Diuretics 33.4% 26.8% 32.1% 0.02

Beta-blockers 78.8% 74.7% 74.2% 0.11

Aspirin 95.4% 94.7% 94.4% 0.69

ACEs 12.8% 7.0% 7.4% <0.001

ARBs 2.3% 1.6% 1.7% 0.61

CCBs 12.1% 6.1% 5.0% <0.001

Placebo(n=655)

Enalapril(n=673)

Amlodipine(n=663) P value*

Treatments Received and Concomitant Treatments Received and Concomitant MedicationsMedications

Mean (SD) or Percentage of PatientsMean (SD) or Percentage of PatientsMean (SD) or Percentage of PatientsMean (SD) or Percentage of Patients

Titrated to Full Target Dosage 89.80% 84.30% 86.70% 0.01

Mean (SD) Dose Received, mg N/A 17.4 (3.7) 8.6 (2.0) N/A

Completed Trial 93.7% 92.4% 93.4% 0.62

Discontinued Study Medication 31.1% 35.1% 29.3% 0.07

Treatments ReceivedTreatments ReceivedTreatments ReceivedTreatments Received

Concomitant MedicationsConcomitant Medications(Percentage of Patients)(Percentage of Patients)Concomitant MedicationsConcomitant Medications(Percentage of Patients)(Percentage of Patients)

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CAMELOT Results—Cumulative Event RatesCAMELOT Results—Cumulative Event Rates

Cu

mu

lati

ve e

ven

ts,

pro

po

rtio

n

Months

0 6 12 18 240

0.25

0.20

0.15

0.10

0.5

PlaceboEnalaprilAmlodipine

No. at riskPlacebo 655 588 558 525 488Enalapril 673 608 572 553 529Amlodipine 663 623 599 574 535

31% Risk reduction for Amlodipine vs placebo (P=0.003)

19% Risk reduction for Amlodipine vs enalapril (P=0.10)

15% Risk reduction for enalapril vs placebo (P=0.16)

31%31%

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CAMELOT Results—CAMELOT Results—Primary and Secondary End PointsPrimary and Secondary End PointsAmlodipine vs PlaceboAmlodipine vs Placebo

Major adverse CV eventMajor adverse CV event

Individual components Individual components of the primary end pointof the primary end point

Coronary revascularizationCoronary revascularization

Hospitalization for anginaHospitalization for anginaNonfatal MINonfatal MI

Stroke or TIAStroke or TIA

CV deathCV death

Hospitalization for CHFHospitalization for CHF

Resuscitated cardiac arrestResuscitated cardiac arrest

New onset of PVDNew onset of PVD

Secondary end pointsSecondary end points

Revascularization after baseline stentRevascularization after baseline stent

All-cause mortalityAll-cause mortality

Hazard Ratio (95% CI)Hazard Ratio (95% CI)Risk

ReductionRisk

Reduction P valueP value AmlodipineAmlodipine PlaceboPlacebo

2-year event rates2-year event rates

0.50.5 0.750.75 1.01.0 1.51.5 2.02.0Favors AmlodipineFavors Amlodipine Favors PlaceboFavors Placebo

31%31% 0.0030.003 16.6%16.6% 23.23.1%1%

27%27% 0.030.03 11.8%11.8% 15.7%15.7%

42%42% 0.0020.002 7.7%7.7% 12.8%12.8%NMNM 0.370.37 2.1%2.1% 2.9%2.9%

NMNM 0.150.15 0.9%0.9% 1.8%1.8%

NMNM 0.270.27 0.8%0.8% 0.3%0.3%

NMNM 0.460.46 0.5%0.5% 0.8%0.8%

NMNM 0.040.04 0.0%0.0% 0.6%0.6%

NMNM 0.240.24 0.8%0.8% 0.3%0.3%

51%51% 0.0020.002 4.1%4.1% 7.9%7.9%NMNM 0.820.82 1.1%1.1% 0.9%0.9%

NM=Not meaningful because too few events were reported.

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CAMELOT Results—CAMELOT Results—Primary and Secondary End PointsPrimary and Secondary End PointsAmlodipine vs EnalaprilAmlodipine vs Enalapril

Major adverse CV eventsMajor adverse CV events

Individual components Individual components of the primary end pointof the primary end point

Coronary revascularizationCoronary revascularization

Hospitalization for anginaHospitalization for angina

Nonfatal MINonfatal MI

Stroke or TIAStroke or TIA

CV deathCV death

Hospitalization for CHFHospitalization for CHF

Resuscitated cardiac arrestResuscitated cardiac arrest

New onset of PVDNew onset of PVD

Hazard Ratio (95% CI)Hazard Ratio (95% CI) AmlodioineAmlodioine EnalaprilEnalapril

2-year event rates2-year event rates

0.50.5 0.750.75 1.01.0 1.51.5 2.02.0Favors AmlodipineFavors Amlodipine Favors EnalaprilFavors Enalapril

19%19% 0.100.10 16.6%16.6%20.2%20.2%

16%16% 0.240.24 11.8%11.8% 14.1%14.1%

41%41% 0.0030.003 7.7%7.7% 12.8%12.8%NMNM 0.490.49 2.1%2.1% 1.6%1.6%

NMNM 0.610.61 0.9%0.9% 1.2%1.2%

NMNM 0.910.91 0.8%0.8% 0.7%0.7%

NMNM 0.740.74 0.5%0.5% 0.6%0.6%

NMNM 0.310.31 0.0%0.0% 0.1%0.1%

NMNM 0.410.41 0.8%0.8% 1.2%1.2%

34%34% 0.090.09 4.1%4.1% 6.2%6.2%

NMNM 0.870.87 1.1%1.1% 1.2%1.2%

Risk Reduction

Risk Reduction P valueP value

Secondary end pointsSecondary end points

Revascularization after baseline stentRevascularization after baseline stent

All-cause mortalityAll-cause mortality

NM=Not meaningful because too few events were reported.

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NORMALISE Results—NORMALISE Results—IVUS for All Substudy PatientsIVUS for All Substudy Patients

All Patients (n=274)

**PP value by ANCOVA (adjusting for randomization stratum and baseline values as covariates). value by ANCOVA (adjusting for randomization stratum and baseline values as covariates). ††PP value for change from baseline from least square mean using the same ANCOVA model. value for change from baseline from least square mean using the same ANCOVA model.

ANCOVA indicates analysis of covariance.ANCOVA indicates analysis of covariance.

Note: Since there were only 5–7 patients per treatment group in the stent stratum, the stent and non-stent intervention groups were combined into a stratum withNote: Since there were only 5–7 patients per treatment group in the stent stratum, the stent and non-stent intervention groups were combined into a stratum withcoronary intervention for the ANCOVA model.coronary intervention for the ANCOVA model.

Placebo(n=95)

Placebo(n=95)

Enalapril(n=88)

Enalapril(n=88)

Amlodipine(n=91)

Amlodipine(n=91)

P value Enalapril vs

placebo*

P value Enalapril vs

placebo*

P value Amlodipine vs

placebo*

P value Amlodipine vs

placebo*

P value Enalapril vs Amlodipine*

P value Enalapril vs Amlodipine*

Baseline percent atheroma volumeBaseline percent atheroma volume

Mean (SD)Mean (SD) 42.142.1 41.641.6 39.939.9 0.750.75 0.140.14 0.250.25(9.3)(9.3) (9.8)(9.8) (10.5)(10.5)

Follow-up percent atheroma volumeFollow-up percent atheroma volume

Mean (SD)Mean (SD) 43.443.4 42.442.4 40.440.4 0.500.50 0.050.05 0.200.20(9.6)(9.6) (10.4)(10.4) (10.8)(10.8)

Change in percent atheroma volumeChange in percent atheroma volume

Mean (SD)Mean (SD) 1.31.3 0.80.8 0.50.5 0.320.32 0.120.12 0.590.59(4.4)(4.4) (3.7)(3.7) (3.9)(3.9)

PP value compared value compared with baselinewith baseline†† 0.0010.001 0.080.08 0.310.31

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Results—Summary Results—Summary

Amlodipine reduced: Amlodipine reduced: – The primary end point, major adverse CV event, by 31%The primary end point, major adverse CV event, by 31%– Hospitalization for angina by 42% vs placeboHospitalization for angina by 42% vs placebo

And 41% vs enalaprilAnd 41% vs enalapril

– Coronary revascularization by 27% Coronary revascularization by 27% – Enalapril was not statistically different vs placeboEnalapril was not statistically different vs placebo

IVUS results demonstrate that Amlodipine appears toIVUS results demonstrate that Amlodipine appears toslow atherosclerotic progressionslow atherosclerotic progression