¹ Clinical Pharmacologist, HCG Cancer Centre, Healthcare Global Enterprises, Kalburagi, Karnataka-585102, India;

² Practice, Al Shifa College of Pharmacy, Kizhattur- 679325, Perinthalmanna, Malappuram, Kerala, India

Corresponding Author: Dr. John Thomas Palathingal, HCG Cancer center, Health Care Global Enterprises, Kalburgi-585102, Karnataka, India. Tel: 9791140261; E-mail: johnpt1993@gmail.com.

Running title: Statin versus statin plus ezetimibe therapy in patients with acute coronary syndrome

	ABSTRACT
	INTRODUCTION
	AIM
	METHODOLOGY
	RESULTS
	DISCUSSION
	CONCLUSION
	REFERENCES

	ABSTRACT

AIM: To assess the efficacy of statin and ezetimibe combination compared to statin given as monotherapy in maintaining optimum cholesterol level. METHODOLOGY: A Prospective Randomized Interventional study was conducted including 68 patients with ACS with the duration of six months carried out in the Cardiology Department of tertiary care Hospital, Kerala. SPSS 20 version was used to perform the statistical analysis of the collected data. Independent t-test was used to compare quantitative variables between control and case group and paired t-test for comparison of demographic variables. The level of significance was 0.05. RESULTS AND DISCUSSION: Mean LDL-C of control group at baseline was found to be 129.64mg/dL and that of case group was found to be 125.73mg/dL. Mean difference was found to be 3.90. On using Independent t-test, there was no significant difference in LDL-C between the groups with p= 0.664 (t value= 0.437). Mean LDL-C of control group on review was found to be 125.42mg/dL and that of case group was found to be 109.33mg/ dl. Mean difference was found to be 16.09. On using Independent t-test, there was significant difference in LDL-C between the groups with p<0.05 (t value=2.036). CONCLUSION: The LDL-C levels plummets the most in patients who are at highest risk of recurrent coronary event. Therapy using a combination of statin and ezetimibe resulted in remarkable reduction in elevated lipid cholesterol with a similar safety profile compared with doubling of statin dose. Its superior lipid altering efficacy by dual inhibition of cholesterol synthesis and intestinal absorption makes it a drug of choice for ACS.

	INTRODUCTION

   Acute coronary syndrome (ACS) is a broad term for the clinical signs and symptoms of myocardial ischaemia: unstable angina, non-ST-segment elevation myocardial infarction, ST-segment elevation myocardial infarction (15).

   Coronary artery disease (CAD) is a condition in which atherosclerotic plaque builds up inside the coronary arteries and restricts the flow of blood to the heart. Coronary artery disease can lead to acute coronary syndrome which describes any condition characterised by signs and symptoms of sudden myocardial ischaemia (16).

   The term ACS was adopted since it clearly reflects the disease progression associated with myocardial ischaemia. Unstable angina and myocardial infarction (MI) both come under the term ACS. The early period following an ACS represents a critical stage of coronary heart disease with a high risk of recurrent events and death due to vessel occlusions from vulnerable coronary plaques.

   Risk factors

   1. Non-modifiable factors – age, sex, family history and ethnicity or race.

   2. Modifiable factors – elevated levels of serum cholesterol, low density lipoprotein cholesterol (LDL) and triglycerides; lower levels of high density lipoprotein cholesterol (HDL); presence of type II diabetes, cigarette smoking, obesity, a sedentary lifestyle, hypertension and stress.

   Pathophysiology

   ACS begins with disruption of atherosclerotic plaque in a coronary artery that stimulates platelet aggregation and thrombus formation. The thrombus occluded in the vessel prevents myocardial perfusion. Myocardial cells need oxygen and adenosine 5β- triphosphate (ATP) to maintain contractility and electrical stability required for normal conduction.

   When myocardial cells are deprived of oxygen, anaerobic metabolism of glycogen takes over and less ATP is produced that leads to failure of Na⁺- K⁺ and Ca²⁺ pumps and accumulation of H⁺ ions and lactate resulting in acidosis that cause infarction leads to cell death.

   In response to this sympathetic nervous system causes decrease in CO and BP, stimulating the release of hormones epinephrine and norepinephrine that increase heart rate, BP and afterload, which increases myocardial demand for oxygen. Due to increased demand of oxygen and its reduced supply to heart muscles, ischemic tissues become necrotic.

   Reduction in cardiac output causes renal perfusion that stimulates release of renin and angiotensin, resulting in further vasoconstriction.

   Clinical presentation

   Angina or chest pain is recognized as the classic symptom of ACS. Pain occurs with or without radiation to the arm, neck, back or epigastric area.

   Patients with ACS also present with diaphoresis, shortness of breath, light-headedness and nausea.

   Changes in vital signs like hypertension/hypotension, tachycardia, tacypnoea, decreased oxygen saturation or cardiac rhythm abnormalities can be observed.

   Atypical symptoms of ACS include shortness of breath, fatigue, lethargy, indigestion, anxiety prior to acute MI, palpitation, numbness in hands.Silent ischemia can also occur without any obvious signs or symptoms.

   Diagnosis

   Evaluation of patient’s clinical history, presenting symptoms, biomarker levels and electrocardiographic result is done to diagnose ACS.

   Cardiac Biomarkers. The injured myocardial cells release proteins and enzymes into the blood which are called cardiac biomarkers.

   The cardiac troponins, troponin T and troponin I are the most cardiac specific biomarkers whose elevated serum levels predict degree of thrombus formation and microvascular embolization associated with coronary lesions. Myoglobin, a heme protein though not a cardiac specific marker, is still considered a valuable biomarker because it is first to rise after myocardial damage.

   Electrocardiographic Findings. The AHA and ACC recommend a 12 lead ECG to be performed in patients with symptoms consistent with ACS.ECG findings that reflect unstable angina or NSTEMI includes ST-segment depression and inverted T wave.ST elevation in ECG leads to diagnosis of STEMI.Abnormal Q waves appear in presence of an MI but once an abnormal Q wave has developed, it remains permanently on ECG indicating not only current acute MI but an old MI as well.

   Treatment

   Drug Therapy

   Initial drug therapy

   a) Aspirin. Patient must be given 160-325mg of aspirin by mouth as soon as onset of symptoms occurs. Aspirin inhibit platelet aggregation and vasoconstriction by inhibiting production of thromboxane A₂.

   b) Oxygen. It is administered at 2-4 L/min by nasal cannula to maintain an Sa O2 levelgreater than 90%

   c) Nitroglycerine. 0.3-0.4 mg should be administered sublingually every few minutes upto 3 doses. Nitroglycerin causes venous and arterial dilation that reduces both preload and afterload which ultimately decreases myocardial oxygen demand.

   d) Morphine sulphate. When patient’s pain has not improved after administration of nitroglycerine, morphine sulphate is administered. Initially a dose of 2-4 mg iv repeated every 5-15 minutes until pain is controlled.

   Adjunctive drug therapy:

   a) β- Blockers decrease rates of reinfarction and death from arrhythmias in non-ST-segment elevation myocardial infarction (NSTEMI) and ST-segment elevation myocardial infarction (STEMI) patients.

   b) ACE inhibitors decrease the risk of left ventricular dysfunction and death in ACS patients and should be administered within 24 hours.

   c) Statins should be prescribed in patients with unstable angina, NSTEMI, STEMI whose LDL-C is above 100mg/dl.

   d) Clopidogrel inhibits platelet aggregation and administered to unstable angina and NSTEMI patients with known allergy to aspirin.

   e) Glycoprotein IIb/IIIa inhibitors are the platelet agents used in unstable angina and NSTEMI patients who are scheduled for an invasive diagnostic procedure.

   f) Anticoagulant therapy like enoxaparin, unfractioned heparin, bivalirudin and fondaparinux are treatment options for patients with unstable angina and NSTEMI.

   Reperfusion therapy:

   It is recommended in patients diagnosed with STEMI. Strategies include variety of invasive procedure like PCIs and fibrinolytic drug therapy.

   Statins

   Statins are class of hypolipidaemic drugs that are most efficacious and best tolerated. They are also known as HMG-CoA reductase inhibitors.

   They competitively inhibit the conversion of 3-Hydroxy-3-methyl glutaryl coenzyme A (HMG-CoA) to mevalonate (rate limiting step in cholesterol synthesis) by the enzyme HMG-CoA reductase. Decreased hepatic cholesterol synthesis upregulates LDL receptor synthesis, increasing LDL clearance from plasma into liver cells.

   The main biochemical effect of statin is to reduce plasma LDL. There is also some reduction in plasma triglyceride and increase in HDL. Over long term, feedback induction of HMG CoA reductase tends to increase cholesterol synthesis, but a steady state is finally attained with a dose dependant lowering of LDL-C levels.

   Different statins differ in their potency and maximal efficacy in reducing LDL-C. Simvastatin, lovastatin and pravastatin are specific, reversible, competitive HMG-CoA reductase inhibitors. Atorvastatin and rosuvastatin are long-lasting inhibitors.

   The daily dose for lowering LDL-C by 30-35% is lovastatin 40mg, pravastatin 40mg, simvastatin 20 mg, atorvastatin 10 mg, rosuvastatin 5 mg, and pitavastatin 2 mg. All statins produce peak LDL-C lowering after 1-2 weeks therapy. Because HMG-CoA reductase activity is maximum at midnight, all statins are administered at bed time to obtain maximum effectiveness. All statins, except rosuvastatin are metabolised primarily by CYP3A4.Inhibitors and inducers of this isoenzyme respectively increase and decrease statin blood levels. All statins are remarkably well tolerated; notable side effects are- muscle ache, gastrointestinal complaints, headache.

   Statins are first choice drugs for primary hyperlipidaemias with raised LDL and total cholesterol levels with or without raised triglyceride levels as well as for secondary hypercholesterolemia. Since the dose-response relationship of each statin is quite well documented, the initial dose of selected statin should aim to bring down the LDL-C to the target level. It should then be adjusted by LDL-C measurements every 3-4 weeks.

   Statin therapy reduces serum LDL-C by inhibiting hepatic cholesterol production through inhibition of the rate-limiting step in the cholesterol synthesis catalysed by HMG CoA reductase. In response to statin therapy, there is a compensatory increase in intestinal cholesterol absorption, possibly through the induction of gene expression of such proteins like NPC1L1 (Niemann-Pick-C1-like-1protein) (12).

   Lovastatin: administered at a dose of 10-40 mg/day upto a maximum of 80mg.It is the first clinically used statin and is lipophilic and is given orally in the precursor lactone form. Its t1/2 is short (1-4 hours).

   Simvastatin: It is twice as potent as lovastatin; its dose is 5-20 mg/dl. It is lipophilic and given in the lactone precursor form. Its t_1/2 is 2-3 hours. Oral absorption is better and first pass metabolism is extensive.

   Pravastatin: It is hydrophilic and given in the active form. At low doses it is equipotent to lovastatin, but at higher dose, cholesterol lowering effect is less. Its t_1/2 is 1-3 hours.

   Atorvastatin: It is the newer and most popular statin is more potent and appears to have the highest LDL-C lowering efficacy at maximal daily dose of 80 mg. It has a much longer plasma t1/2 of 18-24 hour than other statins. It is administered at a dose of 10-40 mg/day.

   Rosuvastatin: It is newer, commonly used and potent statin with a plasma t_1/2 of 18-24 hours. In patients with raised triglyceride levels, rosuvastatin raises HDL-C by 15-20%. It is administered at start with 5mg once daily and increased upto 20 mg/day.

   Pitavastatin: It is the latest and most potent statin. The plasma t_1/2 is 12 hours. Its dose is 1-4 mg/day. There are no specific advantages compared to other statins.

   Statins have early beneficial effects by improving the endothelial function of arteries, decreasing platelet aggregation and thrombus formation and reducing vascular inflammation (13).

   Evidence from randomised controlled trials focusing on patients with an ACS indicates that statins may reduce combined endpoints that include recurrent angina, re-angioplasty and re-hospitalisation.

   Statins impact lipid profile within days of administration and in-vitro studies showed an immediate inhibition of smooth muscle cell proliferation and stimulation of re-endothelialisation by statins.

   Although statins play a pivotal role in LDL reduction, they may also exhibit a pleotropic effect by decreasing extent of myocardial ischaemia, remodelling and promoting plaque stabilisation and endothelial function.

   Initiation of statin therapy within 14 days following ACS does not reduce death, myocardial infarction or stroke upto four months, but reduces the occurrence of unstable angina at four months following ACS (1).

   Long term therapy with statins have been shown to reduce the risk of heart attack, shock and all causes of mortality in patients with or without established coronary heart disease (1).

   Statins are found to reduce the risk of death or cardiovascular events across a wide range of cholesterol levels in patients with or without history of coronary artery disease (1).

   Intensive therapy with high dose of atorvastatin has a consistent beneficial effect on cardiac events including a significant reduction in the risk of recurrent unstable angina (2).

   The current guidelines of the American College of Cardiology and American Heart Association recommend instituting lipid-lowering therapy at the time of hospital discharge in patients with acute coronary syndrome (2).

   Patients with acute coronary syndrome who receive early and intensive lipid-lowering therapy continues to derive benefits in the chronic phase of atherosclerosis when high-dose statin therapy is maintained (2).

   The statins are highly efficacious; however not all patients are able to tolerate the higher dose of these medications due to ADR- hepatotoxicity and myotoxicity. Myalgia with or without myositis and elevations in creatinine kinase are commonly reported with treatment with statins (5).

   Ezetimibe

   It is the first member of the new class of selective cholesterol absorption inhibitors that effectively block intestinal absorption of dietary and biliary cholesterol without affecting absorption of fat soluble vitamins and triglycerides. It is the first member of a group of drugs that inhibit intestinal absorption of phytosterols and cholesterol. It interferes with a specific cholesterol transport protein NPC1L1 in the intestinal mucosa and reduces absorption of both dietary and biliary cholesterol. Pre-clinical studies demonstrated the lipid-lowering and anti-atherosclerotic properties of ezetimibe. The efficacy and safety of ezetimibe monotherapy have been determined in phase II/III studies (10).

   Ezetimibe is readily absorbed and conjugated in the intestine to an active glucuronide, reaching peak blood levels in 12-14 hours. It undergoes enterohepatic circulation, and its half-life is 22 hours. Approximately 80% of the drug is excreted in faeces. It is metabolised through glucuronidation in small intestine and liver, ezetimibe is excreted in bile back into the intestinal lumen where it again can inhibit NPC1L1 protein. It does not undergo metabolism via the cytochrome p450 pathway so that it does not have significant interaction with other medications that are metabolised by cytochrome p450 pathway like statins, fibrates etc. Ezetimibe has no significant effect on the pharmacokinetics of simvastatin or atorvastatin. Circulating plasma levels of cholesterol are obtained from: cholesterol production from liver and peripheral tissues and the absorption of dietary and biliary cholesterol in gastrointestinal tract. Cholesterol synthesis begins with conversion of acetyl-CoA to mevalonate, a reaction catalysed by HMG CoA reductase. Ezetimibe hinders the interaction of the NPC1L1/ cholesterol complex with the AP2 (adaptor protein 2) - Clathrin complex. It is suggested that ezetimibe prevents the NPC1L1/ sterol complex from interacting with AP2 in Clathrin coated vesicles. Ezetimibe may change the shape of NPC1L1 so as to render it incapable of binding to sterol or may interfere with the binding of free cholesterol to the cell membrane. Carveolin-1 (CAV1) is a small 22-k Da protein which forms atleast two distinct chaperone complexes that regulate both total cellular and caveolar cholesterol level. Annexins are a family of calcium and phospholipid- binding proteins that mediate cholesterol uptake. Ezetimibe effectively disrupts the CAV1- annexin 2 heterocomplex in-vivo and thereby reduces sterol absorption. By reducing enterocyte cholesterol absorption, chylomicron formation and secretion, as well as the back flux of cholesterol from the bile, ezetimibe depletes hepatic pools of cholesterol and increases expression of the LDL receptor on the surface of hepatocytes, resulting in reduction in serum LDL-C levels. Ezetimibe does not affect absorption of dietary triglycerides, fat-soluble vitamins or drugs such as warfarin. The effect of ezetimibe on cholesterol absorption is constant over the dosage range of 5-20 mg/day. Average reduction in LDL-C with ezetimibe alone in patients with primary hypercholesterolemia is about 18% with minimal increase in HDL-C. Experience to date reveals a low incidence of reversible impaired hepatic function with a small increase in incidence when given with a reductase inhibitor. In addition to anti-lipidaemic effect, it has been shown to inhibit the progression of aortic and carotid atherosclerosis in ApoE knockout mice treated with varying diets. Ezetimibe is indicated in the treatment of disorders of elevated cholesterol levels, including LDL-C and ApoB, as monotherapy or in combination with statins. The effectiveness of ezetimibe to lower cholesterol and positively change lipid profiles has been noted in a number of clinical trials. The effectiveness of ezetimibe in lowering cholesterol has been tested in various dyslipidaemic populations including familial hypercholesterolemia. Ezetimibe can effectively lower sterol levels in subjects with sitosterol (condition caused by mutation in the ABC transporter genes) that reduces the ability of intestinal cells to transfer free cholesterol back to the intestinal lumen and from liver into the bile which leads to increase in serum sterol levels of sitosterol and campestrol, resulting in development of early onset atherosclerotic vascular disease. The safety of ezetimibe as monotherapy or in combination with other lipid-modifying agents such as statins is well documented. In terms of elevation in liver function tests, ezetimibe appears to cause similar elevation in transaminases as compared to placebo in trials. Life-threatening liver failure with ezetimibe as monotherapy or in combination with statins is extremely rare with only a handful of published reported cases (12).

   Combination of statins and ezetimibe

   The lowering of LDL-C is the primary target of therapy in the primary and secondary prevention of cardiovascular events. Although statin therapy is the mainstay for LDL-C lowering, a significant percentage of patients prescribed with these agents either do not achieve target with statin therapy alone or have partial/ incomplete intolerance to them. For such patients, adjuvant therapies are considered (11).

   Ezetimibe 10 mg co-administered with the starting dose of any statin induces a mean 18% additive LDL-C lowering effect. This 18% reduction in LDL-C is achieved in one step compared with the three step necessary with statin monotherapy (10).

   Patients with ACS on ezetimibe combined with statins had a significantly lower risk of re-hospitalisation due to ACS, percutaneous transluminal coronary angiopathy and re-vascularisation than those on statins alone (3).

   A therapy with simvastatin and ezetimibe results in a significant reduction in the risk of ischaemic cardiovascular events, mainly through fewer CABG procedures (6).

   While statin therapy is the recommended initial treatment of choice along with lifestyle intervention, many familial hypercholesterolemia subjects are frequently unable to reach LDL-C goals even on high dose statin. The additive effect of the addition of ezetimibe to statin therapy makes ezetimibe an attractive add-on option for undertreated familial hypertrophy subjects.In addition to a great ability to lower LDL-C, combination therapy with ezetimibe was found to be better in lowering total cholesterol and non-HDL-C and in raising HDL-C (12).

   As combination therapy ezetimibe and statins do not significantly cause an increase in liver enzymes more than is observed with statin therapy alone. The addition of ezetimibe to statin therapy does not appear to increase the incidence of elevated creatinine kinase levels beyond what is noted with treatment with statin alone (14).

   Lipid profile testing

   The National Cholesterol Education Program Adult Treatment Panel guideline update recommended an optional LDL treatment goal of <70 mg/dl for patients with ACS. The current guidelines of the American College of Cardiology/ American Heart Association recommended measurement of lipid levels on admission and instituting lipid lowering therapy before hospital discharge in patients with ACS (14).

   Total cholesterol is a measure of total amount of cholesterol in the blood including LDL cholesterol and HDL cholesterol.

   LDL cholesterol is the main source of cholesterol in the build-up and blockage of arteries.

   HDL cholesterol helps to remove cholesterol from the arteries.

   Triglycerides are another form of fat in the blood that can raise the risk of heart disease.

   A variety of things can affect cholesterol levels. They are:

   1. Diet: saturated fat and cholesterol in food we eat make blood cholesterol levels rise. Reducing amount of saturated fat and cholesterol in diet helps lower your blood cholesterol level.

   2. Weight: being overweight is a risk factor for heart disease. It also increase cholesterol level. Losing weight can help lower LDL and total cholesterol levels, as well as raise in HDL and lower triglyceride levels.

   3. Physical activity: not being physically active is a risk factor for heart disease. Regular physical activity can help lower LDL-C and raise HDL levels.

   4. Age and gender: as women and men get older, their cholesterol levels rise before the age of menopause, women have lower total levels than men of same age.

   Risk factors that affect LDL goal:

   · Cigarette smoking

   · High blood pressure (140/90 mmHg)

    · Low HDL cholesterol (less than 40 mg/dl)

   · Family history of early heart disease

   · Age

   Lowering cholesterol using therapeutic lifestyle changes (TLC):TLC is a set of lifestyle changes that can be used to help lower the LDL-C. The main parts of TLC are:

   1. TLC diet- low saturated fat, low cholesterol eating plan that calls for less than 7% of calories from saturated fat and less than 200 mg of dietary cholesterol per day. The TLC diet recommends only enough calories to maintain desirable weight and avoid weight gain. If LDL is not lowered enough by reducing saturated fat and cholesterol intake, the amount of soluble fibre in diet can be increased.

   2. Weight management – losing weight if the patient is overweight can help to lower LDL and is especially important for those with a cluster of risk factors that includes high triglycerides or low HDL levels and being overweight with a large waist measurement.

   3. Physical activity – regular physical activity (30 minutes on most if not all days) is recommended for everyone.

   4. Drug treatment – it includes:

   a. Statins- block liver from making cholesterol

   b. Bile acid sequestrants- which decrease amount of fat absorbed from food.

   c. Cholesterol absorption inhibitors- decrease amount of cholesterol absorbed from food and lower triglycerides.

   d. Vitamins and supplements- niacin, which blocks liver from removing HDL and lower triglycerides and omega-3 fatty acids, which increase levels of HDL and lowers triglycerides (Table 1).

	AIM

   To compare the effectiveness of combination of statins and ezetimibe with statin monotherapy in the treatment of Acute Coronary Syndrome.

	METHODOLOGY

   It is a prospective, randomized interventional study with duration of six months carried out among ACS patients in the Cardiology Department of tertiary care hospital, Kerala. To assess the efficacy of statin and ezetimibe combination compared to statin given as monotherapy in maintaining optimum cholesterol level. Cardiology inpatients and outpatients with condition of acute coronary syndrome and Patients with age > 40 years are included in the study. Pregnant women, Patients who have undergone cholecystectomy, Patients diagnosed with active liver damage, Patients diagnosed with cancer are excluded from the study. All patients were followed up until their discharge from the hospital to ensure a full picture of their treatment process and corresponding treatment outcomes. Monitored baseline laboratory values and lipid profile and collected in data collection form after collecting informed consent form..The study was approved by the Ethical Committee of the hospital and number is KAS/ADMN/AC/EC/153/2016.

   Study procedure

   The study was carried out in three phases.

   Phase 1: Pre-interventional phase:

   · The current practice of statin therapy in Acute Coronary Syndrome was audited.

   · The sample size was determined for the study to be statistically significant.

   · The study population was randomized by statistician using randomized block design.

   Phase 2: Interventional phase:

   · The study population was divided into two categories-One group prescribed with statin monotherapy and other group prescribed with combination of statin and ezetimibe.

   · All the patients were monitored for their lipid profile values.

   Phase 3: Post-interventional phase:

   · Re-audit of the practices was carried out to estimate the effectiveness of clinical pharmacist assisted intervention.

   Statistical analysis

   SPSS 20Windows Version was used to perform the statistical analysis of the data.

   The tests used were:

   · X₂ Test for testing association of qualitative variables in each group of the study.

   · Independent t- test to compare quantitative variables between control and case group of the study.

   · Paired t-test for comparison of demographic variables.

   The level of significance used for the statistical analysis was 0.05.

	RESULTS

   Demographics (Figure 1)

   A total of 68 Acute Coronary Syndrome patients were enrolled in the study for the pre-intervention phase among which 30 patients received intervention (statin plus ezetimibe) and 38 patients were taken as control group (statin monotherapy). All the 30 patients from the intervention group were followed and only 28 patients from control group showed up for review. So that 10 missing control group subjects were excluded from post-intervention phase.

   Distribution Based on Gender (Figure 2). On using Chi-square test there was no significant difference in gender distribution with p=0.954 (X² = 0.003).

   Distribution Based on Duration of Stay (Figure 3). On using Chi-square test there was no significant difference in the duration of stay among group prescribed with statins and group prescribed with combination of statin and ezetimibe with p =0.066 (X² = 3.389).

   Distribution Based on The Type of Acute Coronary Syndrome (Figure 4). The difference in distribution of type of ACS among the study populations was found to be non-significant using Chi-square test with p =0.716 (X²= 0.667).

   Distribution of Diabetes Mellitus (Figure 5). On using Chi-square test there was no significant difference in the distribution of diabetes mellitus in both control group and case group with p=0.707 (X² = 0.141).

   Distribution of Hypertension (Figure 6). The difference in the distribution of hypertension as a comorbidity was found to be non-significant in control group and case group with p=0.504 (X² =0.447).

   Distribution of Clopidogrel (Figure 7). On using Chi-square test there was significant difference in the distribution of clopidogrel administration in both control group and case group with p< 0.05 (X² = 4.261).

   Distribution of Aspirin (Figure 8). On using Chi-square test there was no significant difference in the distribution of Aspirin administration in both case group and control group with p=0.058 (X² = 3.580).

   Distribution of Nicorandil (Figure 9). The difference in administration of nicorandil in case group and control group was found to be non-significant with p=0.103 (X² = 2.651).

   Comparison between case group and control group (Table 2)

   Comparison of Laboratory Values

   Liver Function Test (Table 3)

   Lipid Profile Test (Table 4)

   · LDL–C (Figure 10)

   Mean LDL of control group was found to be 4.21 mg/dL and that of case group was found to be 16.40 mg/dL. The mean difference was found to be 12.18. Onusing Independent t-test there was significant difference in the LDL among groups with p< 0.05 (t value = -2.76).

   Comparison among case group and control group: baseline vs review

   Liver Fuction Test

   ·Bilirubin Indirect (Figure 11). Mean indirect bilirubin of case group was found to be 0.53mg/dL at baseline and 0.46mg/dL on review. The mean difference was found to be 0.07. On using Paired t- test there was significant difference in the indirect bilirubin among the group with p< 0.05 (paired t value = 4.906).

   Mean indirect bilirubin of control group was found to be 0.43 mg/dL at baseline and 0.51 mg/dL on review. The mean difference was found to be 0.08. On using Paired t- test there was significant difference in the indirect bilirubin among the group with p< 0.05 (paired t value = 2.215).

   ·Total Protein (Figure 12). Mean total protein of case group at baseline was found to be 6.68 mg/dL and 6.31 mg/dL on review. The mean difference was found to be 0.37. On using Paired t- test there was significant difference in the total protein among the group with p< 0.05 (paired t value =7.191).

   Mean total protein of control group at baseline was found to be 4.69 mg/dL and 5.97 mg/dL on review. The mean difference was found to be 1.28. On using Paired t- test there was significant difference in the total protein among the group with p< 0.05 (paired t value =4.277).

   ·Serum Albumin (Figure 13). Mean serum albumin of case group was found to be 4.36 mg/dL at baseline and 4.22 mg/dL on review. The mean difference was found to be 0.15. On using Paired t-test there was significant difference in the serum albumin among the group with p<0.05 (paired t value = 2.446).

   Mean serum albumin of control group was found to be 3.93 mg/dL at baseline and 4.25 mg/dL on review. The mean difference was found to be 0.32. On using Paired t-test there was significant difference in the serum albumin among the group with p<0.05 (paired t value = 2.01).

   ·SGOT (Figure 14). Mean SGOT of case group was found to be 46.53 IU/L at baseline and 26.67 IU/L on review. The mean difference was found to be 19.86. On using Paired t-test there was significant difference in the SGOT among the group with p< 0.05 (paired t value = 7.939).

   Mean SGOT of control group was found to be 34.96 IU/L at baseline and 31.30 IU/L on review. The mean difference was found to be 3.65. On using Paired t-test there was significant difference in the SGOT among the group with p< 0.05 (paired t value = 2.243).

   ·SGPT (Figure 15). Mean SGPT of case group was found to be 41.27 IU/L at baseline and 28.77 IU/L on review. The mean difference was found to be 12.51. On using Paired t-test there was significant difference in the SGPT among the group with p< 0.05 (paired t value = 4.586).

   Mean SGPT of control group was found to be 26.80 IU/L at baseline and 25.89 IU/L on review. The mean difference was found to be 0.91. On using Paired t-test there was significant difference in the SGPT among the group with p< 0.05 (paired t value = 3.478).

   ·ALP (Figure 16). Mean ALP of case group was found to be 100.97 IU/L at baseline and 78.30 IU/L on review. The mean difference was found to be 22.67. On using Paired t-test there was significant difference in the ALP among the group with p< 0.05 (paired t value =5.458).

   Mean ALP of control group was found to be 93.36 IU/L at baseline and 85.39 IU/L on review. The mean difference was found to be 7.96. On using Paired t-test there was significant difference in the ALP among the group with p< 0.05 (paired t value =2.531).

   Lipid Profile Test

   ·Serum Cholesterol (Figure 17). Mean serum cholesterol of case group was found to be 232.80 mg/dL at baseline and 181.23 mg/dL on review. The mean difference was found to be 51.57. On using Paired t-test there was significant difference in the serum cholesterol among the group with p< 0.05 (paired t value = 7.225). Mean serum cholesterol of control group was found to be 196.93 mg/dL at baseline and 178.39 mg/dL on review. The mean difference was found to be 18.54. On using Paired t-test there was significant difference in the serum cholesterol among the group with p< 0.05 (paired t value = 7.8).

   ·Serum Triglyceride (Figure 18). Mean serum triglyceride of case group was found to be 101.43 mg/dL at baseline and 93.00 mg/dL on review. The mean difference was found to be 8.43. On using Paired t-test there was no significant difference in the serum triglyceride among the group with p= 0.128(paired t value = 1.566).

   Mean serum triglyceride of control group was found to be 130.11 mg/dL at baseline and 115.86 mg/dL on review. The mean difference was found to be 14.25. On using Paired t-test there was significant difference in the serum triglyceride among the group with p<0.05(paired t value = 3.894).

   ·HDL (Figure 19). Mean HDL of case group was found to be 39.73 mg/dL at baseline and 47.50 mg/dL on review. The mean difference was found to be 7.77. On using Paired t-test there was significant difference in the HDL among the group with p< 0.05(paired t value = 6.218).

   Mean HDL of control group was found to be 48.79 mg/dL at baseline and 42.32 mg/dL on review. The mean difference was found to be 6.46. On using Paired t-test there was significant difference in the HDL among the group with p< 0.05(paired t value = 5.579).

   ·LDL (Figure 20). Mean LDL of case group was found to be 125.73 mg/dL at baseline and 109.33 mg/dL on review. The mean difference was found to be 16.4. On using Paired t-test there was significant difference in the LDL among the group with p<0.05(paired t value = 5.667).

   Mean LDL of control group was found to be 129.64 mg/dL at baseline and 125.42 mg/dL on review. The mean difference was found to be 4.21. On using Paired t-test there was no significant difference in the LDL among the group with p= 0.218(paired t value = 1.262).

   ·VLDL (Figure 21). Mean VLDL of case group was found to be 28.06 mg/dL at baseline and 22.69 mg/dL on review. The mean difference was found to be 5.37. On using Paired t-test there was significant difference in the VLDL among the group with p<0.05(paired t value = 5.969).

   Mean VLDL of control group was found to be 20.54 mg/dL at baseline and 19.82 mg/dL on review. The mean difference was found to be 0.71. On using Paired t-test there was no significant difference in the VLDL among the group with p=0.447(paired t value = 0.772).

   ·TG: HDL RATIO (Figure 22). Mean TG: HDL ratio of case group was found to be 4.25 mg/dL at baseline and 1.94 mg/dL on review. The mean difference was found to be 2.3. On using Paired t-test there was significant difference in the TG: HDL ratio among the group with p<0.05(paired t value = 10.00).

   Mean TG: HDL of control group was found to be 4.13 mg/dL at baseline and 2.85 mg/dL on review. The mean difference was found to be 1.28. On using Paired t-test there was significant difference in the TG: HDL ratio among the group with p<0.05(paired t value = 7.096).

   Cardiac Tests

   ·CPK-MB (Figure 23). Mean CPK-MB of case group was found to be 97.34 IU/L at baseline and 80.37 IU/L on review. The mean difference was found to be 16.97. On using Paired t-test there was significant difference in the CPK-MB among the group with p<0.05(paired t value = 6.004).

   Mean CPK-MB of control group was found to be 58.63 IU/L at baseline and 54.71 IU/L on review. The mean difference was found to be 3.91. On using Paired t-test there was no significant difference in the CPK-MB among the group with p=0.18(paired t value = 1.378).

   Serum Creatinine (Figure 24)

   Mean serum creatinine of case group was found to be 0.62 mg/dL at baseline and 0.76 mg/dL on review. The mean difference was found to be 0.14. On using Paired t-test there was significant difference in the serum creatinine among the group with p<0.05 (paired t value =2.426).

   Mean serum creatinine of control group was found to be 1.14 mg/dL at baseline and 0.99 mg/dL on review. The mean difference was found to be 0.15. On using Paired t-test there was significant difference in the serum creatinine among the group with p<0.05(paired t value =4.263).

   Comparison of difference in LDL-C among the groups: baseline (Table 5)

   Mean LDL-C of control group at baseline was found to be 129.64 mg/dL and that of case group was found to be 125.73 mg/dL. Mean difference was found to be 3.90. On using Independent t-test, there was no significant difference in LDL-C between the groups with p= 0.664 (t value= 0.437).

   Comparison of difference in LDL-C among the groups: review (Table 6)

   Mean LDL-C of control group on review was found to be 125.42 mg/dL and that of case group was found to be 109.33 mg/ dl. Mean difference was found to be 16.09. On using Independent t-test, there was significant difference in LDL-C between the groups with p<0.05 (t value=2.036).

View larger version : [in a new window] Fig 1: Consort diagram

 

View larger version : [in a new window] Figure 2. Distribution based on gender.

 

View larger version : [in a new window] Fig 3: Distribution based on duration of stay

 

View larger version : [in a new window] Fig 4: Distribution based on the type of ACS.

 

View larger version : [in a new window] Fig 5: Distribution of Diabetes Mellitus.

 

View larger version : [in a new window] Fig 6: Distribution of Hypertension.

 

View larger version : [in a new window] Fig 7: Distribution of Clopidogrel.

 

View larger version : [in a new window] Fig 8: Distribution of Aspirin.

 

View larger version : [in a new window] Fig 9: Distribution of Nicorandil.

 

View larger version : [in a new window] Fig 10: Difference in LDL-C values between groups.

 

View larger version : [in a new window] Fig 11: Comparison of indirect bilirubin among the groups.

 

View larger version : [in a new window] Fig 12: Comparison of total protein among the groups.

 

View larger version : [in a new window] Fig 13: Comparison of serum albumin among groups.

 

View larger version : [in a new window] Fig 14: Comparison of SGOT among the groups.

 

View larger version : [in a new window] Fig 15: Comparison of SGPT among groups.

 

View larger version : [in a new window] Fig 16: Comparison of ALP among groups.

 

View larger version : [in a new window] Fig 17: Comparison of serum cholesterol among groups.

 

View larger version : [in a new window] FIGURE 18: Comparison of serum triglyceride among groups.

 

View larger version : [in a new window] Fig 19: Comparison of HDL among groups.

 

View larger version : [in a new window] Fig 20: Comparison of LDL among groups.

 

View larger version : [in a new window] Fig 21: Comparison of VLDL among groups.

 

View larger version : [in a new window] Fig 22: Comparison of TG:HDL ratio among groups.

 

View larger version : [in a new window] Fig 23: Comparison of CPK-MB among groups.

 

View larger version : [in a new window] Fig 24: Comparison of serum creatinine among groups.

	DISCUSSION

   Many studies have highlighted the need for reduction in LDL-C levels in cardio vascular diseases. Lipid lowering therapy plays an irremediable role in secondary prevention of CV events. Various cholesterol programs and guidelines has recommended targeting plasma concentration to low as <2.5 mmol. Traditionally the option was to reduce LDL-C levels by initiating statin therapy. But due to high dose statin adverse effects especially at high doses, another option of adding a drug urged. Taking this situation under consideration changing the brand name or statin was not advisable as it wouldn’t be readily acceptable for both physicians and patients. LDL-C levels would be able to reduce significantly if a cholesterol synthesizing inhibitor (Statins) and an absorption inhibitor (ezetimibe) were included as done in many studies.

   In our short term study of 16 weeks treatment period we couldn’t assess the reduction in cardiovascular events but lipid lowering effects were analyzed to demonstrate the efficacy of ezetimibe plus atorvastatin and atorvastatin alone. The study enrolled total of 68 patients with acute coronary syndrome and were randomized resulting in 30 patients in ezetimibe plus atorvastatingroup where only 28 were able to follow up and 38 patients in atorvastatin alone group where 30 patients were able to follow up. In this study the major finding observed was the degree of LDL-C reduction achieved by10mg/day ezetimibe in combination with 20mg/day and 40mg/day atorvastatin was significant than that obtained from 40mg/day, 80mg/day atorvastatin. In a double blinded trial Ballantyne et al reported that 10mg/day of ezetimibe combined with 10mg/day of atorvastatin had the same LDL-C reducing effect as 80mg/day of atorvastatin. This report emphasize the potency of ezetimibe plus atorvastatin combination in reducing LDL-C levels.

   The mean LDL-C levels in our control group was found to be 125.42mg/dL and that of our case group was found to be 109.33mg/dL, mean difference being 16.09.Hence ezetimibe as an adjunct therapy was proved to be effective than high dose statin monotherapy (p<0.05) Cruz Fernandez et al in a randomized double blinded placebo controlled study reported that ezetimibe as an adjunct to statin therapy can reduce the LDL-C levels significantly. Another study by Christopher P Cannon et al observed a 24% lipid lowering effects especially LDL-C and serum triglycerides. Davidson et al observed reduction in lipid profile on addition of ezetimibe with statin in a randomized open trial that, even though high dose statin should enable incremental lowering of LDL-C, as it is theoretically, the study couldn’t process a statistically significant result for the same. There was no significant difference in two groups in LDL-C and TG:HDL ratio levels at the baseline. Also this study subverts the ‘statin speculation’ that statins are the only important drug in reducing LDL-C levels in CV events1. The ENHANCE trial also supports the coadministration of a cholestrol absorption inhibitor to achieve the guideline supported LDL-C level (<2.5mmol).Reduced TG levels were observed in both the atorvastatin and the combination group which was similar to a previously conducted studies. Furthermore, there was no significant differences in CPK-MB, Troponin I , A:G ratio, indirect bilirubin at baseline of two groups. The gender distribution also did not have any significant difference with 47% being males and 53% being females totaly. In addition serum total cholesterol levels also showed a decrease but it did not express statistical significance. The main limitations that we faced were the small number of patients and single centric site.

	CONCLUSION

   The effectiveness of combination of statin plus ezetimibe versus statin monotherapy in ACS patients was evaluated and monitored during six months study period. Therapy using a combination of statin and ezetimibe resulted in remarkable reduction in elevated lipid cholesterol. It can be concluded that during treatment of ACS, the LDL-C levels plummets the most in patients who are at highest risk of recurrent coronary event. Thus combining statin and ezetimibe produces greater improvements in lipids with a similar safety profile compared with doubling of statin dose. Its superior lipid altering efficacy by dual inhibition of cholesterol synthesis and intestinal absorption makes it a drug of choice for ACS.

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