RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES, KARNATAKA, BANGALORE.

PROFORMA FOR REGISTRATION OF SUBJECTS FOR DISSERTATION
1. / NAME OF THE CANDIDATE AND ADDRESS
ADDRESS FOR CORRESPONDANCE / DR ANIL KUMAR M. H.
S/O RANGAIAH
# 549/20, SARASWATHI NAGAR
DAVANAGERE 577004
DR ANIL KUMAR M.H.
PG IN PHARMACOLOGY
DEPT OF PHARMACOLOGY
M.S. RAMAIAH MEDICAL COLLEGE
BANGALORE 560054
2. / NAME OF THE INSTITUTION / M.S.RAMAIAH MEDICAL COLLEGE BANGALORE 560054
3. / COURSE OF THE STUDY AND SUBJECT / M.D PHARMACOLOGY
4. / DATE OF ADMISSION TO THE COURSE / 21-05-08
5. / TITLE OF THE TOPIC / OPEN LABEL RANDOMIZED CONTROLLED TRIAL COMPARING THE EFFICACY OF ATORVASTATIN ALONE AND COMBINATION OF ATORVASTATIN AND EZETIMIBE IN PRIMARY DYSLIPIDEMIA.

6. Brief resume of intended work.

6.1 Introduction and need for the study:

Coronary Artery Disease (CAD), is assuming increased importance among the adult population

in both developed and developing countries.The prevalence of CAD is showing an upward trend

in most of countries and has taken “epidemic”course.CAD among Asian Indians is more severe,

diffuse, associated with serious complications and increased mortality in younger age group.

The probable reasons might be Insulin resistance syndrome, metabolic syndrome, atherogenic

dyslipidemic phenotype, genetic susceptibility associated with a modest abnormality in lipid

profile and life style factors.

Statins acts by inhibiting 3-hydroxy 3-methyl glutaryl coenzyme A(HMG-CoA) reductase, key

enzyme involved in cholesterol synthesis. Statins also increase hepatic low density lipoprotein

receptor activity and cause accelerated clearance of circulating Low Density Lipoprotein

Cholesterol (LDL-C), resulting in dose dependent reduction in plasma level of LDL-C.

These are remarkably safe and most widely used hypolipidemic drugs. 1

Ezetimibe inhibits intestinal absorption of cholesterol at the brush border level of the enterocyte.

This results in reduction of hepatic cholesterol level and an increase in Hepatic LDL-receptor

expression. Ezetimibe has demonstrated a 17-20% reduction in serum LDL-C level. Ezetimibe

has become a preferred drug to add to a statin in patients, who require further LDL-C reduction

with out increase of adverse effects.1

6.2 Review of literature:

Clinical and epidemiological studies clearly establish the link between dyslipidemia and CAD.

Dyslipidemia is one of the main risk factor for the development of CAD. Indeed, there is direct

relationship between serum LDL-C level and cardio vascular risk. This relationship is linear,

such that reduction in serum LDL-C level results in proportional reduction in

cardiovascular risk. 2

Based on various compelling evidence, the National Cholesterol Education Program (NCEP)

Expert Panel on Detection, Evaluation and Treatment of High Cholesterol in Adults (Adult

Treatment Panel 3) issued treatment guidelines in 2001, identified serum LDL-C as a

causative factor for CAD and as the target for lipid lowering therapy. The NCEP guidelines

emphasize to maintain the LDL-C level below 100 mg/dl in high-risk patients.2

Several clinical studies have demonstrated that a 25-35% reduction in serum LDL-C level

because of statin treatment is associated with 23-37% reduction in cardiovascular mortality.

Further, 1mmol reduction in serum LDL-C level leads to 24% decrease in death in subjects

with or without coronary heart disease, regardless of their serum LDL-C at baseline.3

Despite proven efficacy of statin therapy, not all patients reach the treatment goal specified

for their coronary risk group by NCEP-3. This translates into a need to either use higher

dosage of statin which might lead to greater incidence of adverse effects (ex. elevation of

liver enzymes, myopathy) or to add other lipid lowering drugs to statin therapy which

could lead to greater drug intolerance or other adverse effects.

The ezetimibe and statin combination is more effective than statin alone in lowering LDL-C.4

The lipid lowering effect of this combination extends to High-risk patients to reach their

serum LDL-C target of less than 100 mg/dl.5 Since there are no such studies in India, the

present study aims to compare the efficacy of Atorvastatin alone with combination

of Atorvastatin with Ezetimibe in primary dyslipidemic patients.

6.3 Objective of the study:

To compare the efficacy of Atorvastatin alone and combination of Atorvastatin with

Ezetimibe in primary dyslipidemic patients.

7. Materials and methods:

7.1 Source of data:

Patients with primary dyslipidemia and coronary artery disease attending the outpatient

clinic in Department of Cardiology, M.S. Ramaiah medical college, Bangalore, from

September 2008.

7.2 Method of collection of data:

Two hundred (200) patients diagnosed for coronary artery disease and primary dyslipidemia, attending out patient clinic will be recruited based on the inclusion and exclusion criteria mentioned below. A baseline demographic data (age, sex, BMI, associated diseases, habits, family history, drug history) and lipid profile will be collected at the time of recruitment. The patients will be randomly assigned in (1:1) ratio to either of the two groups (100 in each group), One group to receive Atorvastatin 10mg or 20mg / once daily alone and the other group to receive combination of Atorvastatin 10mg and Ezetimibe 10mg / once daily for 3 months. Lipid profile will be repeated at the end of 3rd month. At the end of the study, changes in serum LDL-C, HDL-C, total cholesterol and triglycerides will be compared between the two groups.

Investigation:

Lipid profile

Inclusion criteria:

1) Patients with coronary artery disease (both stable angina and acute coronary syndrome)

and primary dyslipidemia.

1) 

2) Both male and female patients.

3) Age group of 30 to 65 years.

4) Patients with LDL-C

a) Above 160 mg/dl in patients with no documented CAD

b) Above 130mg/dl in patients with documented CAD

Exclusion criteria:

1) Uncontrolled diabetes mellitus

2) Severe liver dysfunction

3) Renal failure

4) Alcoholism

5) Patient on steroids, beta-blockers

6) Dyslipidemia due to thyroid disorders, biliary diseases.

Statistical analysis:

Statistical analysis will be done using the Paired difference test with student’s

t-distribution test for LDL-C, HDL-C, total cholesterol and triglycerides.

7.3 Does the study require any investigations or interventions to be conducted on patients

or other humans or animals?

Yes, as mentioned in (7.2). The cost of the investigation will be borne by the patient

themselves. Written informed consent will be taken from all the patients.

7.4 Has ethical clearance been obtained from your institution?

Yes, the certificate is enclosed.

8.0 List of references.

1. Robert W. M. and Thomas P.B. (2006) Drug therapy for Hypercholestrolemia and

Dyslipidemia. Goodman and Gillman’s “ The Pharmacological Basis of Therapeutics”.

11th edition, McGraw-Hill, NewYork.948-60.

2.Grundy S.M., Cleeman J.I., Bairey N. et al. (2004). For the coordinating committee of

the National Cholesterol Education Program. Implications of recent trials for National

Cholesterol Education Program Adult Treatment Panel 3 guidelines. 110:227-39.

3. Larson J.C., Grundy S.M.,et al.(2005)Intensive lipid lowering with Atorvastatin in patients

with stable coronary disease. N Engl J Med.352: 1425-35

4. Ballantyne C.M., Houri J., Notarbartolo A., et al. (2003) Effect of ezetimibe co administered

with atorvastatin in 628 patients with primary hypercholesterolemia: a prospective

randomized, double blind trial. Am Heart J, 107: 2409-15

5. Ballantyne C.M., Abate N., Yuan Z., et al. (2005) Dose comparison study of combination of

ezetimibe and simvastatin versus atorvastatin in primary hypercholesterolemia: VYtorin

Versus Atorvastatin (VYVA) study. Am Heart J, 149: 464-73

9 / SIGNATURE OF THE CANDIDATE
10 / REMARKS OF THE GUIDE
11 / NAME AND DESIGNATION OF
11.1 / GUIDE / Dr. SHIVAMURTHY M.C. M.D.
PROFESSOR AND HEAD
DEPARTMENT OF PHARMACOLOGY
M.S.RAMAIAH MEDICAL COLLEGE BANGALORE.
11.2 / SIGNATURE
11.3 /
CO GUIDE
/ Dr. PRAKASH V.S. M.D., D.M., F.I.S.E.
PROFESSOR AND HEAD DEPARTMENT OF CARDIOLOGY
M.S.RAMAIAH MEDICAL COLLEGE AND HOSPITAL, BANGALORE.
11.4 / SIGNATURE
11.5 / HEAD OF THE DEPARTMENT / Dr. SHIVAMURTHY M.C. M.D.
PROFESSOR AND HEAD
DEPARTMENT OF PHARMACOLOGY M.S.RAMAIAH MEDICAL COLLEGE
BANGALORE.
11.6 / SIGNATURE
12
12.1 / REMARKS OF DEAN AND PRINCIPAL
Dr. KUMAR S. M.D.
PRINCIPAL AND DEAN
M.S. RAMAIAH MEDICAL COLLEGE
BANGALORE.
12.2 / SIGNATURE