2009 Kk Talk Jupiter

8/14/2019 2009 Kk Talk Jupiter

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Expanding The Orbit of StatinExpanding The Orbit of Statin

Dr. Tang Sie HingDr. Tang Sie HingConsultant Interventional

Cardiologist

Chief, Cardiology Department


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Justification for the Use ofstatins in Primary prevention: anIntervention TrialEvaluating

Rosuvastatin

Ridker P et al. N Eng J Med2008;359: 2195-2207


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UPITERJUPITER is the first large-scale, prospective study to examine

the role of statin therapy in individuals with low to normalLDL-C levels, but with increased cardiovascular risk identifiedby elevated CRP

It assessed the long-term impact of rosuvastatin (CRESTOR)in individuals potentially at increased cardiovascular (CV) riskdue to elevated CRP levels who do not qualify for lipid-lowering treatment according to current guidelines



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JUPITER - RationaleNearly half of all cardiovascular events occur in patients who

are apparently healthy and who have low or normal levels ofLDL-C

hsCRP predicts cardiovascular disease independent of LDL-Clevels

Along with improved screening there is a need to examine the

use of lipid-lowering agents as a method of reducing the risk

Ridker PM. New Engl J Med2002; 347: 15571565


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Prevalence of conventional risk

factors in atients with CHD

None

One

Two

Three

Four(0.9%)

Total patients=87 869CHD=coronary heart diseasesmoking, hypertension, hypercholesterolaemia and diabetes mellitus

19.4%

43.0%

27.8%

8.9%

Khot UN et al.JAMA 2003; 290: 898904


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CRP is a strong independentpredictor of CV events in women

Apo=apolipoprotein; CRP=C-reactive protein; CV=cardiovascular; HDL-C=high-density lipoprotein cholesterol; IL=interleukin;LDL-C=low-density lipoprotein cholesterol; Lp(a)=lipoprotein (a); SAA=serum amyloid A; sICAM-1=soluble intercellular adhesionmolecule 1; TC=total cholesterol

0

Lp(a)

Homocysteine

IL-6

TC

LDL-C

sICAM-1

SAAApoB

TC/HDL-C

CRP

CRP + TC HDL-C

Relative risk of future CV

1.0 2.0 4.0 6.0

Blake GJ, Ridker PM. Circ Res 2001; 89: 763771


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CRP predicts risk of MI and stroke

in apparently healthy men

CRP=C-reactive protein; MI=myocardial infarction*p=0.02 versus quartile 1; ***p


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CV event-free survival in women using

CV=cardiovascular; hsCRP=high-sensitivity C-reactive protein; LDL-C=low-density lipoprotein cholesterol

Low LDL-C, low hsCRP

High LDL-C, high

High LDL-C, low hsCRP

Low LDL-C, high hsCRP

Probabilityof event-free

survival

Ridker PM et al. N Engl J Med2002; 347: 15571565


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Efficacy of Lovastatin in

Median LDL-C=3.9 mmol/L (149 mg/dL). Median hsCRP=1.6 mg/LAFCAPS/TexCAPS=Air Force/Texas Coronary Atherosclerosis Prevention Study; hsCRP=high-sensitivity C-reactive protein; LDL-C=low-density lipoprotein cholesterol; N/A=not applicable; NNT=number needed to treat to prevent one coronary event

Ridker PM et al. N Engl J Med2001; 344: 19591965


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JUPITER - Objective The primary objective was to investigate

whether long-term treatment with rosuvastatin

20 mg decreases the rate of first majorcardiovascular events compared with placeboin patients with low to normal LDL-C but atincreased cardiovascular risk as identified by

elevated CRP levels

Ridker PM. Circulation 2003; 108: 22922297


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JUPITER study design

Lipids

CRPTolerability

Lipids

CRPTolerability

HbA1C

Placebo

run-in

16

24

30

413 Final6-monthly

Visit:Week:

Randomisation Lipids

CRPTolerability

Rosuvastatin 20 mg (n=8901)

Placebo (n=8901)

Lead-in/

eligibility

No history of CAD

men 50 yrs

women 60 yrs

LDL-C


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UPITER - Stud End oints Primary EndpointTime to the first occurrence of a major cardiovascular event,

composite of: cardiovascular death Stroke MI unstable angina arterial revascularisation

Secondary Endpoints total mortality

non-cardiovascular mortality development of diabetes mellitus development of venous thromboembolic events bone fractures discontinuation of study medication due to adverse effects.



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UPITER - Major inclusion

Men aged 50 years; women aged 60 years

Fasting LDL-C levels 130 mg/dL3.4 mmol/L),

CRP levels 2.0 mg/L and TG levels 500mg/dL(5.7 mmol/L) on initial screening.



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UPITER - Major exclusion Current use of statinsor other lipid-lowering therapies

Current use of hormone replacement therapy

Prior history of cardiovascular or cerebrovascular events, such as MI,unstable angina, prior arterial revascularisation or stroke, or CHD-riskequivalents

Chronic inflammatory condition, such as severe arthritis, lupus orinflammatory bowel disease and/or treatment with immunosuppressants

Uncontrolled:

hypertension: SBP > 190 mmHg or DBP > 100 mmHg

hypothyroidism: TSH > 1.5 x ULN

CK3 x ULN

Serum creatinine > 2.0 mg/dL

Evidence of hepatic dysfunction (ALT > 2 x ULN)

History of prior malignancy, alcohol or drug abuseRidker PM. Circulation 2003; 108: 22922297

CHD = coronary heart disease; CK = creatinine kinase; ULN = upper limit ofnormal; SBP = systolic blood pressure; DBP = diastolic blood pressure



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JUPITER - Patient Flow89,890 subjects screened

17,802 randomized

Rosuvastatin 20mg

n=8,901

Placebo

n=8,901

Lost to follow upn=44

Completed studyn=8,857

Lost to follow upn=37

Completed studyn=8,864



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Age (years) 66 (60-71) 66 (60-71)

Male sex (%) 61.5 62.1

Race (%)

White 71.4 71.1Black 12.4 12.6

Hispanic 12.6 12.8

Other 3.6 3.5

BMI (kg/m2) 28.3 (25.3-32.0) 28.4 (25.3-32.0)

Systolic BP (mmHg) 134 (124-145) 134 (124-145)Diastolic BP (mmHg) 80 (75-87) 80 (75-87)

Rosuvastatin Placebon=8901 n=8901

JUPITER - Baseline characteristics*

*All values are median (interquartile range) or N (%).



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Total cholesterol (mg/dL) 186 (168-200) 185 (169-199)

LDL cholesterol (mg/dL) 108 (94-119) 108 (94-119)

HDL cholesterol (mg/dL) 49 (40-60) 49 (40-60)

Triglycerides (mg/dL) 118 (85-169) 118 (86-169)

hsCRP (mg/L) 4.2 (2.8-7.1) 4.3 (2.8-7.2)

Glucose (mg/dL) 94 (87-102) 94 (88-102)

HbA1c(%) 5.7 (5.4-5.9) 5.7 (5.5-5.9)Glomerular filtration rate,

Rosuvastatin Placebon=8901 n=8901

-

For hsCRP, values are the average of the values obtained at two screening and visits

*All values are median (interquartile range) or N (%).Ridker P et al. N Eng J Med2008;359: 2195-2207


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Current smoker (%) 15.7 16.0

Family history CHD(%) 11.2 11.8

Metabolic syndrome(%) 41.0 41.8

Aspirin use (%) 16.6 16.6

Medical History RosuvastatinPlacebo

JUPITER - Medical History

Family history of premature CHD defined as first degree relative with CHD at age < 55 yrs (male), < 65 yrs



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JUPITER population compared with previoustrials in patients without established CHD

CVD=cardiovascular disease; CHD=coronary heart disease; LDL-C=low-density lipoprotein cholesterol; HDL-C=high-density lipoprotein cholesterol; hsCRP=high sensitivity C-reactive protein; *Baseline lipid levels are mean values.

Ridker PM et al.Am J Cardiol 2007; 100: 16591664 Ridker PM et al. N Engl J Med. 2001 344: 1959-65

UPITER P i E d i


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Placeb

Rosuvastatin 20 mg

UPITER - Primary EndpointTime to first occurrence of a CV death, non-fatal

stroke non-fatal MI unstable an ina or arterial

Hazard Ratio 0.56(95% CI 0.46-0.69)P


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UPITER - Primar End oint

Primary Endpoint 251 (1.36) 142 (0.77) 0.560.46-0.69


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Placeb

Rosuvastatin 20mg

JUPITER - Total MortalityDeath from any causeHazard Ratio 0.80(95% CI 0.67-0.97)

p=0.02


0 1 2 3 40

0

0

0

0

0

0

Cumulative

Incidence

Number at Risk Follow-up

Rosuvastati

Placeb

8,90 8,84 8,78 6,99 4,31 2,26 1,60 1,19 68 22

8,90 8,85 8,77 6,98 4,31 2,29 1,61 1,19 68 24


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UPITEREffects on LDL-C, HDL-C, TG and hsCRP at 12 months;Percenta e chan e between rosuvastatin and lacebo

-60

-50

-40

-30

-20

-10

0

10 LDL-C HDL-C TG hsCR

Pe

rcentagechan

ge

fromb

aseline(

%)

50%

4%

17%

37%

p


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UPITER


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UPITER Tolerability andSafet data

Adverse Events, (%)

Any serious adverse event 15.5 15.2 0.60

Muscle weakness, stiffness, pain 15.4 16.0 0.34

Myopathy 0.1 0.1 0.82

Rhabdomyolysis 0.0


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JUPITER Laboratory Safety Data

Laboratory Values, N (%)

Serum creatinine 10 (0.10) 16 (0.20)0.24

ALT > 3 x ULN# 17 (0.20) 23 (0.30)

0.34Glycosuria 32 (0.40) 36 (0.50)0.64

Laboratory Values, median values (IQR)

GFR*, (mL/min/1.73m2) 66.6 (58.8-76.2) 66.8 (59.1-76.5) 0.02

% HbA1c** 5.8 (5.6-6.1) 5.9 (5.7-6.1) 0.00

Placebo Rosuvastatin p-value

GFR = Glomerular filtration rate, HbA1c = Haemoglobin A1c

# on consecutive visits, >100% increase from baseline,*at 12 months, **at 24 months, >trace at 12 monthsRidker P et al. N Eng J Med2008;359: 2195-2207


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UPITER summary and

The JUPITER study included patients with low to normal LDL-C whowere at increased CV risk as identified by elevated CRP levels andwho did not require statin treatment based on current treatmentguidelines.

A 44% reduction in the primary endpoint of major cardiovascularevents (composite of: CV death, MI, stroke, unstable angina, arterialrevascularisation) was observed in patients who received rosuvastatin20 mg compared with placebo (p< 0.00001).

A 20% reduction in total mortality was observed in patients whoreceived rosuvastatin 20 mg compared with placebo (p=0.02), aunique finding for statins in a population without established CHD.

In JUPITER, long-term treatment with rosuvastatin 20 mg was welltolerated in nearly 9000 study participants.

There was no difference between treatment groups for muscleweakness, cancer, haematological disorders, gastrointestinal, hepaticor renal systems.



30/30THANK YOUTHANK YOU

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2009 Kk Talk Jupiter