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Initial Classification Based on Total Cholesterol and HDL-Cholesterol (NCEP Guidelines). Total Cholesterol <200 mg/dLDesirable Blood Cholesterol 200-239 mg/dLBorderline-High Blood Cholesterol > 240 mg/dLHigh Blood Cholesterol HDL-Cholesterol <35 mg/dLLow HDL-Cholesterol

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Initial Classification Based on Total Cholesterol and HDL-Cholesterol (NCEP Guidelines)

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Initial Classification Based on TotalCholesterol and HDL-Cholesterol (NCEP Guidelines)

Total Cholesterol

<200 mg/dLDesirable BloodCholesterol

200-239 mg/dLBorderline-High BloodCholesterol

> 240 mg/dLHigh Blood Cholesterol

HDL-Cholesterol

<35 mg/dLLow HDL-Cholesterol

Ref.: NIH Publication No. 93-3096, September 1993


Treatment Decisions Based on LDL-Cholesterol (NCEP Guidelines)

Dietary Therapy

Initiation levelLDL Goal

Without CHD & with fewer than 2 risk factors>160 mg/dL<160 mg/dL

Without CHD & with 2 or more risk factors>130 mg/dL<130 mg/dL

With CHD>100 mg/dL <100 mg/dL

Drug Treatment

ConsiderationLDL GoalLevel

Without CHD & with fewer than 2 risk factors>190 mg/dL*<160 mg/dL

Without CHD & with 2 or more risk factors>160 mg/dL <130 mg/dL

With CHD>130 mg/dL**<100 mg/dL

*In men under 35 years of age and premenopausal women with LDL-cholesterol levels 190-219 mg/dL, drug therapy should be delayed except in high-risk patients such as those with diabetes.

**In CHD patients with LDL-cholesterol levels 100-219 mg/dL, the physician should exercise clinical judgement in deciding whether to initiate drug treatment.

Ref.: NIH Publication No. 93-3096, September 1993


CHD Risk Factors

  • Positive

    • AgesSmoking

    • Male > 45 yearss Hypertension

    • Female > 55 years orsHDL-cholesterolpremature menopause without< 35 mg/dLestrogen replacement therapy sDiabetes

    • Family history of premature CHD

  • Negative

    • HDL-cholesterol > 60 mg/dL


Effect of Statins on CardiovascularEvent Reduction and LDL-Cholesterol Levels

ClinicalActiveDosage, StudyBaseline%On-treatmentCHD

TrialTreatmentmg/dSampleLDL-C ReductionLDL-C,Red-

sizeLevels, of LDL-C mmol/Luction

mmol/L%

WOSCOPSPravastatin4065954.97263.8731

PLAC IIPravastatin20-401514.29273.1060

REGRESSPravastatin408854.32283.0342

CAREPravastatin4041593.59282.5924

CCAITLovastatin40-803314.47293.2625

MAASSimvastatin203814.40313.0024

4SSimvastatin20-4044444.87343.1534

MARSLovastatin802703.90382.4024

JAMA 1998; 279: 1643-1650.


Vascular mechanisms by which cholesterol lowering may reduce coronary events

Potential Beneficial Effects

Of Lipid Lowering

Cells Present in Atheroma

­

Endothelial Dependent Vasodilation

-

¯

Superoxide (O

) Production

2

¯

Leukocyte Adhesion Molecule Expression

Endothelial Cell

¯

Secretion of Matrix-Degrading Proteases

¯

Release of Inflammatory Cytokines

Macrophage

¯

Procoagulant Tissue Factor Expression

Foam-Cell

¯

Growth Factor Production

Smooth

¯

Macrophage Stimulator

Muscle

Production (M-CSF & MCP-1)

Cell

¯

Modified Lipoprotein Antigen Stimulation

¯

Production of Gamma Interferon

(a macrophage stimulator and matrix

T-Lymphocyte

synthesis inhibitor)


Simvastatin - Pharmacodynamics

  • Orally administered prodrug, hydrolysed to b-hydroxyacid simvastatin, the active metabolite

  • Potent inhibitor of cholesterol biosynthesis

  • Upregulates LDL receptors

  • Reduces total cholesterol, LDL cholesterol, triglycerides & increases HDL cholesterol

  • Decreases apolipoprotein B and increases apolipoproteins AI and AII

  • Inhibits platelet activation, decreases factor VIIc activity, produces modest reduction or no change in fibrinogen levels

  • Unlikely to alter adrenal function

  • Does not increase cataract formation

SIMCARD


4S Trial: Summary

Parameter% Reduction

Total cholesterol25%

LDL cholesterol35%

Triglycerides10%

Total mortality30%

Coronary mortality42%

Non-fatal acute MI37%

Cerebrovascular events30%

Revascularisation procedures37%

No. of hospital admissions26%

Average length of stay10%

Total days spent in hospital34%

SIMCARD

Ref.: Lancet 1994; 344:1383-1389.


LIFE SAVING BENEFITS OF SIMVASTATIN MAINTAINED FOR UP TO EIGHT YEARS

  • 30% reduction in mortality observed during 5-year study maintained during the extended two-year follow-up of 4S trial

% Mortality

- 71st Scientific Sessions of American Heart Association, Nov 1998


Simvastatin approved by US FDA inpatients with elevated triglyceride levels

Results of analysis of 5 studies (n=359)

Baseline triglyceridePercentage reduction levelswith simvastatin

TG > 200 mg/dL31%

TG 150-200 mg/dL21%

TG < 150 mg/dL11%

SCRIP 1997; No. 2284:19

SIMCARD


Simvastatin approved for use in patients with isolated hypertriglyceridemia (Frederickson type IV) and in patients with type III hyperlipoproteinemiaInpharma 1999; 1218: 22


Main angiographic findings of the Multicentre Anti-Atheroma Study (MAAS)after 4 years of treatment with simvastatin 20 mg/day

Angiographic parameterAngiographic classification (per patient)(per patient)[mean change[no. (%) of patients]from baseline]

simvastatinplacebosimvastatinplacebo

Diffuse disease

Mean lumen–0.02–0.08*diameter (mm)

Focal disease

Minimum lumen–0.04–0.13**diameter (mm)

Diameter stenosis (%)1.03.6**

Progressor41 (23.0)54 (32.3)*a

Regressor33 (18.6)20 (12.0)*a

a Statistically significant difference between treatment groups only for combined treatment effect.Statistically significant difference between treatment groups: *p < 0.05, **p < 0.01

Ref.: Lancet 1994; 344: 633-638.

SIMCARD


SIMVASTATIN/ENALAPRIL CORONARY ATHEROSCLEROSIS TRIAL (SCAT)

  • 460 patients with normal cholesterol levels (160 mg/dl - 240 mg/dl) and established CAD

  • Simvastatin significantly reduced LDL cholesterol, total cholesterol and triglycerides and increased HDL cholesterol

  • Simvastatin reduced need for revascularisation procedures by 53.6%; need for angioplasty was reduced by 61.9%

  • Addition of enalapril to the regimen had a neutral impact on the progression of CAD

Simvastatin slows CAD progression in patients of normal cholesterol

- 48th Annual Scientific Sessions of American College of Cardiology, March 1999


EFFECT OF SIMVASTATIN ON HEART FAILURE (SUBSET ANALYSIS OF 4S TRIAL)

Patients withheart failure (%)

- Journal of Failure 1997; 3: 249-254


SIMVASTATIN APPROVED BY US FDA FOR RAISING HDL LEVELS

  • New approval based on four studies

  • In one study (n=130), simvastatin lowered LDL cholesterol by 29-36%, triglycerides by 28-33% and raised HDL levels by 13-16%

  • HDL is anti-atherogenic; high levels of HDL reduce CHD risk

  • HDL-C > 60mg/dl is a negative risk factor for CHD and HDL-C < 35 mg/dl is a positive risk factor for CHD (NCEP guidelines)

- SCRIP 1999; 2463: 19


Safety of simvastatin

Common adverse effects include

  • increase in liver enzymes

  • myopathy (increase in creatine kinase)

  • GI problems

  • CNS disturbances

    Discontinuation rates : 0.3 to 0.7%

SIMCARD

Ref.: Annals of Pharmacotherapy 1995; 29:743-759.


Simvastatin Vs. Lovastatin (Twice as potent)

ReferenceNo. ofDosageMean percentage change in serum lipid/

evaluableregimenlipoprotein levels versus baselinea

patients(mg/day)Total-CLDL-CHDL-CTGLDL-C/HDL-C

Farmer134S10-19.6-27.5+4.6-3.9-29.5et al 135S20-25.4*b-34.7*b+4.6-10.3-37.1*b(24-week137L20-18.6-25.4+4.2-10.5-27.4study)134L40-22.6-31.2+7.4-10.3-34.9

Frohlich149S10-40-26 to-34 to+8-16 toet al-30-37-17(18-week149L20-80-26 to-34 to+4 to-11 tostudy)-31-38+10-22

S=Simvastatin; L=Lovastatin; a All changes in total-C & LDL-C were statistically significant compared with baseline, b Statistically significant difference between treatment groups refers to S 20 versus L20. *indicates p < 0.01.

SIMCARD

- Drugs 1995; 50(2): 334-363. - Can. J. Cardiol. 1993; 9:405-412.


Simvastatin Vs. Lovastatin (Greater percentage of responders)

% of patients with LDL Cholesterol< 130 mg/dL at 18 weeks

SIMCARD

Ref.: Annals of Pharmacotherapy 1995; 29: 743-759.


Simvastatin vs. Lovastatin(Contd.)

Adverse Event % incidence of adverse eventsSimvastatinLovastatin20 mg twice daily20 mg twice daily(n=84)(n=42)

Headaches3.6%7.1%

Abdominal discomfort2.4%4.8%

Sleep disorders3.6%7.1%

Muscle pain2.4%4.8%

­in creatine kinase4.8%11.9%

­in liver enzymes4.8%11.9%

Discontinuation rates with simvastatin have been reported to range between 0.3 and 0.7% as compared to 2.8 to 4% with lovastatin.

SIMCARD


Simvastatin: Dosage and Administration

  • The recommended starting dose is 5-10 mg once daily in the evening. Doses should be individualised according to baseline LDL cholesterol levels and the LDL goal recommended by the NCEP. Patients requiring reductions in LDL-C of 20% or more to achieve their goal should be started on 10 mg/day. A starting dose of 5 mg should be considered for patients requiring smaller reduction in LDL-C, for the elderly and in patients with severe renal insufficiency

  • The recommended dosing range is 5-80 mg/day; the maximum recommended dose is 80 mg/day

  • Adjustments of dosage should be made at intervals of 4 weeks or more


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