Banerjee

A Comparison of
Sirolimus and Paclitaxel

By: Sumona Banerjee

Niles North High School

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Table of Contents

Title..........1

Table of Contents....2

Acknowledgements..........3

Purpose........4

Hypothesis.......5

Variables..........7

Review of Literature.....8

Materials & Procedure.......19

Results...........20

Data Analysis.........25

Discussion......28

Experimental Error.........31

Conclusion.....33

Impact........37

Reference List............38

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Acknowledgments

I would like to thank Mrs. Camel for supporting and mentoring me extensively throughout this
project. I would also like to thank Mrs. France for helping me statistically analyze my data.

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Purpose

The purpose of this project is to compare the effectiveness of the drugs sirolimus and

paclitaxel in reducing the progression of restenosis. The purpose of this project is also to

compare the effectiveness of drug application through a slow releasing or moderate releasing

method.

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Hypotheses

Hypothesis 1

If the amount of neointimal area after 2 years of treatment is determined and compared

between stents coated with sirolimus and paclitaxel, then the change in area resulting from

sirolimus treatment will be less than the change resulting from paclitaxel treatment. This is

because sirolimus directly inhibits enzyme mTOR which regulates proliferation, metabolism, and

angiogenesis, while paclitaxel only reverses the cells back to G0 phase to stop neointimal

proliferation. Inhibition of enzyme mTOR is more effective than the reversal of the cell cycle.

Hypothesis 2

If the amount of neointimal area after 2 years of treatment is determined and compared

between stents coated with slow releasing sirolimus and moderate releasing sirolimus, then the

change in area resulting from moderate releasing sirolimus will be less than the change resulting

from slow releasing sirolimus. This is because the reduction of neointimal proliferation is dose

dependent. Moderate releasing therapy will result in greater levels of sirolimus in the vessel, in a

certain amount of time, as compared to slow releasing therapy. This will allow for more

treatment to occur with the moderate releasing therapy during the 2 years of experimentation.

Hypothesis 3

If the amount of neointimal area after 2 years of treatment is determined and compared

between stents coated with slow releasing paclitaxel and moderate releasing paclitaxel, then the

change in area resulting from moderate releasing paclitaxel will be less than the change resulting

from slow releasing paclitaxel. This is because the reduction of neointimal proliferation is dose

dependent. Moderate releasing therapy will result in greater levels of paxlitaxel in the vessel, in a

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certain amount of time, as compared to slow releasing therapy. This will allow for more

treatment to occur with the moderate releasing therapy during the 2 years of experimentation.

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Variables

Independent Variable: Treatment Method --

Option 1: Sirolimus-eluting stent through a moderate releasing method (Sirolimus MR)

Option 2: Sirolimus-eluting stent through a slow releasing method (Sirolimus SR)

Option 3: Paclitaxel-eluting stent through a moderate releasing method (Paclitaxel MR)

Option 4: Paclitaxel-eluting stent through a slow releasing method (Paclitaxel SR)

Dependent Variable: Neointimal area (mm2)

Control Group: Treatment without drug -- through a bare metal stent (BMS)

Constants: Drug dosage (1.0 g/mm2), stent diameter (3.0 or 3.5mm), stent application

technique (predilation before stent implantation with a balloon), data collection through an

intravascular ultrasound (IVUS)

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Review of Literature

According to the American Heart Association, heart disease is the leading global cause

of death, accounting for 17.3 million deaths per year, a number that is expected to grow to more

than 23.6 million by 2030 (Mozaffarian 2014). The most prevalent type of heart disease is

coronary artery disease. Plaque build up is the main cause of this disease as it leads to the

hardening the blood vessels and it limits the flow of oxygen rich blood to vital organs and areas

in the body. Eventually, so much plaque can develop that there can be a blockage in the arteries.

Recent research has allowed the creation of drug eluting stents as a treatment of option for

coronary artery disease. In order to ensure the best treatment possible, it is beneficial to compare

the two most prominent drugs being used in drug eluting stents: paclitaxel and sirolimus.

Coronary Artery Disease & Stents

Coronary artery disease is a condition in which plaque builds up in the arteries. Arteries

are blood vessels that transport oxygen rich blood to the heart and the rest of the body. Plaque is

a jumble of cholesterol, cells, and debris that creates a bump on the artery wall (WebMD n.d.).

When plaque is deposited into the arteries they release sticky chemicals that allow other

substances flowing through the bloodstream like inflammatory cells, lipoproteins and calcium to

stick to the inside of the vessel wall (WebMD n.d.). Over time, plaque build up will harden the

blood vessels and limit the flow of oxygen rich blood to vital organs and areas in the body.

Consequently, the heart will begin to pump blood poorly due to the restrictions created by plaque

(Gibbons 2014). Eventually, so much plaque can build up that there can be a complete blockage

in the arteries, causing a heart attack.

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Cholesterol-laden plaque can begin to build up from a very young age. More plaque is

accumulated into the artery walls as one gets older. Generally, a poor lifestyle is the main factor

in causing coronary artery disease. The use of tobacco and the practice of a high cholesterol diet

allows for the increase in low-density lipoproteins (LDL) and the decrease of high-density

lipoproteins (HDL) (Singh 2014). LDL is also known as bad cholesterol because it allows for

plaque buildup in the arteries. When LDL cholesterol deposits into the arteries walls, white blood

cells quickly try to swallow the LDL in an attempt to protect the artery. However, by doing this,

the white blood cells convert the LDL into its toxic form. Defensively, more white blood cells

move to this area and consequently create a low-grade inflammation in the blood vessel. Over

time, the cell and LDL build up result in a layer of plaque on the artery wall (WebMD n.d.).

Contrary to LDL, HDL is known as the good cholesterol because it absorbs extra cholesterol in

the bloodstream and carries it to the liver. The liver then flushes it from the body. Having high

levels of HDL is linked to a reduced risk for coronary artery disease (CDC 2015).

Several potential methods of treatment for coronary artery disease are lifestyle changes,

medications to lower cholesterol levels and medical procedures. In 1958, the Seven Countries

Study looked at 12,763 men aged 40-59. These men formed 16 cohort groups from the United

States, Finland, the Netherlands, Italy, Greece, the former Yugoslavia, and Japan (Kromhout et

al 2002). In addition to physical examination, history on biological risk factors were searched for

and an electrocardiogram, a test used to check for problems with the electrical activity of the

heart, was taken. Data on the food consumed by the men was collected from small samples of

each cohort. The risk factor surveys were then repeated after 5 and 10 years. In this time period,

over 6000 men died with 1500 of them dying from coronary heart disease. After the food records

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were examined, scientists determined that the average consumption of animal food groups except

fish were positively correlated with high coronary heart disease mortality rates. There was an

inverse correlation with vegetable food groups. Also, the consumption of high amounts of

saturated fats caused high levels of serum cholesterol and it had a negative effect on coronary

heart disease. The Seven Countries Study demonstrated the long term effects on people when

consuming a poor diet (Kromhout et al 2002).

A study was also conducted testing the effects of smoking on 124 woman aged 30-55

years old. The results indicated that nurses who smoked more than 12 cigarettes per day,

compared to never-smokers, had a risk of 95% more in getting coronary artery disease. The same

results were shown when the woman were tested for the effects of alcohol on heart health

(Stampfer 2000).

In response to the Seven Countries Study and the smoking and alcohol analysis, another

experiment was conducted, testing the effects of dietary and smoking advice on 1232 men aged

from 40-49 years old. These men had high serum cholesterol levels, were smokers and had

systolic blood pressure below 150 mmHg. They were at a very high risk for coronary artery

disease. The men were randomized into two groups. One group received dietary and antismoking

advice and the control group did not receive any advice or intervention. The advised diet

consisted of foods low in saturated fats and high in fiber. This resulted in a 13% difference in

serum cholesterol between the experimental and control groups. Furthermore, 25% of the

smokers in the experimental group quit smoking as compared to 17% in the control group. At the

end of the trial, the serum cholesterol level of the experimental group was still very high, but it

had decreased from 8.3 mmol/L to 5.6mmol/L. It was therefore concluded that by a healthy diet

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and antismoking advice there would have been a substantial reduction in major coronary

events (Hijermann 1981). As a result of these studies, doctors have emphasized the importance

of lifestyle changes to help treat coronary artery disease.

In addition to lifestyle changes, extensive research has allowed for the development of

various medications for coronary artery disease. Often, cholesterol-modifying medications are

given to the patient. The most commonly prescribed include niacin and fibrates (Mayo Clinic

2014). Niacin has the ability to increase the levels of HDL by about 30% to 35% (Duggal et al

2010). A recent study was performed to test the effectiveness of niacin on patients with coronary

artery disease. Seven trials, with a total of 5,137 patients ranging from 30 to 76 years of age,

were conducted. The patients were randomly split into a control, placebo or experimental group.

The experimental group was treated daily with dose of niacin. After eight years, a follow up was

conducted and the patient's treatment history during that time as well as their amount of coronary

artery revascularization, the process of returning blood to the heart, was measured. The results

showed that compared to the placebo group, niacin significantly reduced the risk of coronary

artery revascularization, non-fatal myocardial infarction and stroke. This indicated that niacin

was associated with a significant reduction in cardiovascular events, (Duggal et al 2010).

Studies have also shown fibrates to be an effective medication as well. A total of 36,489

patients were placed under the same conditions as the patients were for niacin. However, instead

of niacin, they were treated with fibrates. It was shown that fibrates significantly reduced the

total cholesterol and triglyceride level by about 8% and 30% respectively. Also, it raised the

HDL levels by about 9% as compared with the placebo. Fibrates also significantly reduced the

risks of nonfatal myocardial infarction by 22%. It, however, did not decrease the risk for stroke.

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The researchers concluded that fibrates was an effective antilipidemic agent, promoting the

reduction of lipid levels in the bloodstream, that would be beneficial in treating coronary artery

disease with. (Saha et al 2007)

Even with medication use and lifestyle changes, doctors may feel the need to take

extensive measures to prevent a heart attack or other

fatal heart events that may result from coronary artery

disease. Doctors often use medical procedures such as

bypass grafting, carotid endarterectomy, or coronary

angioplasty to treat the patient with. Coronary

angioplasty is the most prevalent and it is a method that

opens blocked arteries. During the procedure, a thin,

flexible catheter (tube) with a balloon at its tip is

threaded through a blood vessel to the affected artery.

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Once in place, the balloon is inflated to compress the plaque against the artery wall (NIH 2014).

As shown in figure 1, as soon as the balloon leaves the area, the artery is relatively clear and

blood is able to freely pass through.

At first, blocked arteries were only reopened with a balloon. However, technological

advances have allowed for the placement of a small metal mesh tube called a stent inside the

clogged area. By placing a stent in the artery, the area becomes supported and all of the fat is

pushed away back, thus allowing for the flow of oxygen rich blood (Dangas 2002). As illustrated

in figure 2, the balloon allows for the stent to be fitted inside the affected area in the artery. Once

the stent is inserted into the area, more blood is able to pass through and it provides support to

the artery, thus alleviating the chance of it becoming narrow again (NHLBI 2014). The stent is

also a practical and often used for treatment because it is minimally invasive and allows the

patient to return home the day of their procedure (Cardiac Solutions 2014).

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Although the creation of the stent was a novel idea, it yields a few problems. The most

prevalent is restenosis. Restenosis occurs as a direct result of the stent being placed in the artery.

When the stent is being placed in the artery, it pushes against the muscle wall which causes an

ongoing stress on the artery wall (Hamid et al 2007). This leads to endothelial cell loss which

then exposes the underlying vessel wall. This results in the immediate accumulation of platelets,

macrophages and polymorphonuclear neutrophils, aiming to cover the location of the injury

(Tsigkas et al 2011). The platelets, which are released into the area, contain chemokines that

induce the remodeling of smooth muscle cells. The muscle grows into to the struts of the stent,

eventually blocking the artery again (Dangas 2002). As shown in figure 3, this action defies the

initial purpose of the stent because after restenosis, the artery becomes blocked with muscle

instead of fat.

Furthermore, two specific mechanisms that cause the development of restenosis are

elastic recoil and neointimal proliferation. Elastic recoil is the tendency of the artery tissue to

return to its original shape once it has been deformed (Hamid et al 2007). Neointimal

proliferation refers to the increase of smooth muscle cells in the tunica intima, the innermost

layer of an artery or vein. This results in the thickening of the arterial walls. To solve restenosis,

scientists have designed drug eluting stents (DES). Stents are coated with an outer layer of

polymer and then are loaded with drugs. After the stent is placed in the artery, the drug is locally

released every so often so that it inhibits elastic recoil, neointimal proliferation and essentially

the growth of the muscle (Tsigkas et al 2011). Two prominent drugs being used in clinical

practice right now are sirolimus and paclitaxel. Both of the drugs are antiproliferative which

retards the spread of the cells (Garcia-Garcia et al 2006).

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Sirolimus

Sirolimus was isolated for the first time in 1972 from Streptomyces hygroscopicus, a

bacterial specie, on the island of Rapa Nui. (Abzaid 2007) Initially, when scientists first began to

study this substance, they began applying it for its antifungal characteristic. However, upon

further research they discovered that sirolimus contained potent antiproliferative and

immunosuppressive properties due to its ability to inhibit mTOR. (Abzaid 2007) mTOR is an

enzyme that regulates proliferation, the production of cells; metabolism, the maintenance of cell

structures; and angiogenesis, the development of new blood vessels. (Riaz 2012) The enzyme is

found in two distinct protein complexes: mTORC1 and mTORC2. Sirolimus, sometimes referred

to as rapamycin, first associates itself with an intracellular receptor, FKBP12. Then the two bind

on to the FKBP12-Rapamycin Binding domain of mTOR, completely inhibiting its activity.

(Huang 2003) With this inhibition, the cell cycle past the S phase (DNA replication) is

interrupted and the cell returns to its resting G0 state, preventing smooth muscle cell growth.

(Lamming 2012) As a result of this finding, scientists began thinking how this mechanism of

inhibition could be utilized to stop restenosis.

A research group in 2002 conducted a randomized, double blind experiment evaluating

the efficacy of sirolimus in reducing neointimal formation in rabbit coronary models. Arteries

were randomized to one of four stent groups: uncoated stents; polymer control stents; low-dose

sirolimus-eluting stents; and high-dose sirolimus-eluting stents. (Klugherz 2002) A

histomorphometry, an examination measuring of the shape or form of a tissue, was conducted

after 8, 14, and 28 days. The results showed that treatment with the low-dose sirolimus was

associated with a 23% reduction in neointimal area and 45% for treatment with the high-dose

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sirolimus. The group concluded that the local delivery of sirolimus reduced neointimal formation

in a dose-dependent manner and represented a promising method for preventing restenosis.

(Klugherz 2002)

Following this experiment, the first in-man study was conducted. Thirty patients with

coronary disease were implanted with sirolimus-eluting stents. The patients were split between

fast and slow releasing treatment formulations. To collect data, angiographic and volumetric

ultrasounds were obtained 4, 12, and 24 months later. (Pompa 2003) At 4 months, there wasnt

any significant change in the diameter of the stenosis within the stent. At 12 months, however,

neointimal hyperplasia, the thickening of arterial walls, was virtually absent. Twenty-four

months later, persistent reduction in intimal hyperplasia was found and no patient had in-stent

restenosis. (Pompa 2003) Subsequently, many other randomized clinical trials were performed

before sirolimus was finally approved to be used the pharmacological market. Today, it is often

used to treat restenosis with due to its consistent antiproliferative qualities.

Paclitaxel

In 1962, paclitaxel was first isolated from the bark of pacific yew. Upon extensive

research, scientists found that paclitaxel had the ability to bind to a cells microtubule assembly

and reduce the rate of cell division. Consequently, the cells reverse to the G-phase of the cell

cycle and chromosomes are unable to separate. (Bharadwaj 2004) Since this was indication that

paclitaxel had antiproliferative characteristics, further research was conducted in 2001, when a

research group at John Hopkins Hospital evaluated if paclitaxel eluting stents had the ability to

inhibit neointimal hyperplasia in a porcine model of coronary restenosis. Forty-one minipigs

were treated with paclitaxel eluting stents and the treatment effect was assessed 4 weeks after the

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stent was implanted. (Heldman 2001) The results exhibited that the diameter of stenosis within

the stent decreased with increasing paclitaxel dose. At the highest dose, the diameter decreased

by 84.3%. It was concluded that the pacliatxel eluting stents worked effectively in inhibiting

neointimal hyperplasia on a dose-dependent system. The results also displayed a promising

therapeutic benefit of paclitaxel-eluting stents in treating restenosis. (Heldman 2001)

As a result of this experiment, the first in-human investigation was conducted. Sixty one

patients with coronary artery disease were treated with paclitaxel coated stents and compared to a

control group. (Grube 2002) There was no stent thrombosis, clotting of blood, reported in 1, 6, 9,

or 12 months after implantation. At 6 months restenosis rates were 0% for the paclitaxel-coated

stent group versus 10% for the control. There were also significant improvements in the diameter

of the artery and an ultrasound analysis showed significant improvements in neointimal

hyperplasia in the paclitaxel-coated stent group as compared to the control group. The study

showed that the paclitaxel was well tolerated and significantly able to reduce restenosis. (Grube

2002)

Coronary artery disease is progressive disease mainly caused by poor lifestyle choices. It

is often treated by medications such as niacin and fibrates to lower LDL levels and increase HDL

levels. However, when the disease has progressed so that it is not treatable by medications, stents

containing sirolimus or paclitaxel are implanted into the patients affected artery. These drug

eluting stents help open up the artery and allow for blood to flow freely throughout the body.

Although both sirolimus and paclitaxel have been proven to be antiproliferative and are used

widely in the market, it is valuable to compare the two drugs and determine if there is a

significant difference between the effectiveness of the two.

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Materials

Data from Persistent Remodeling and Neointimal Suppression 2 Years After

Polymer-Based, Paclitaxel-Eluting Stent Implantation
Data from Persistent Inhibition of Neointimal Hyperplasia After Sirolimus-Eluting Stent
Implantation

Procedure
1. Collect data on neointimal area (mm2) from the following databases:
a. Data from Persistent Remodeling and Neointimal Suppression 2 Years After
Polymer-Based, Paclitaxel-Eluting Stent Implantation
i. Sample Size= 161 event-free patients
b. Data from Persistent Inhibition of Neointimal Hyperplasia After
Sirolimus-Eluting Stent Implantation
i. Sample Size= 109 event-free patients
2. Collect data for after the procedure, six months after the procedure, and 2 years after the
procedure.
a. Criteria for choosing data
i. Patients must not have experienced any clinical events throughout the 2
year follow-up
ii. Patients must have single de novo coronary lesions treatable with a single
stent
iii. Quantitative data must have been collected through IVUS (intravascular
ultrasound)
iv. Stent must have 3.5mm diameter

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Results

Bare Metal Stents (Control)

Neointimal Area (mm2) Sirolimus Paclitaxel

After procedure 0.380.19 0.14.97

6 months after 3.450.22 1.491.12

2 years after 3.651.23 1.711.38

Moderate Releasing (MR) Stents

Neointimal Area (mm2) Sirolimus Paclitaxel

After procedure 0.290.09 0.07.74

6 months after 3.030.92 0.660.83

2 years after 3.340.99 1.060.90

Slow Releasing (SR) Stents

Neointimal Area (mm2) Sirolimus Paclitaxel

After procedure 0.260.05 0.06.63

6 months after 2.951.43 0.640.81

2 years after 3.231.76 0.940.76

*Data is expressed as meanstandard deviation

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Statistical Analysis

Moderate Releasing: Control versus Stent Application of Sirolimus

P value Mean Difference

After procedure 0.0001 0.0900

6 months after 0.0001 0.4200

2 years after 0.0416 0.3100

Average Mean Difference 0.27333

Slow Releasing: Control versus Stent Application of Sirolimus

P value Mean Difference

After procedure 0.0001 0.1200

6 months after 0.0004 0.5000

2 years after 0.0424 0.4200

Average Mean Difference 0.34667

Moderate Releasing: Control versus Stent Application of Paclitaxel

P value Mean Difference

After procedure 0.4671 0.0700

6 months after 0.0001 0.8300

2 years after 0.0001 0.6500

Average Mean Difference 0.51667

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Slow Releasing: Control versus Stent Application of Paclitaxel

P value Mean Difference

After procedure 0.3808 0.0800

6 months after 0.0001 0.8500

2 years after 0.0001 0.7700

Average Mean Difference 0.56667

Stent Treatment Type versus Change in Area(mm2)

Sirolimus Paclitaxel

Bare Metal Stent (Control) 3.27 1.57

Moderate Releasing (MR) 3.05 0.99

Slow Releasing (SR) 2.97 0.88

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Data Analysis

Control versus Moderate Releasing Stents (Sirolimus and Paclitaxel)

For the sirolimus control, the neointimal area was 0.38mm2 after the procedure, 3.45mm2

six months after, and 3.65mm2 two years after. When the patient was treated with a moderate

releasing stent coated with sirolimus (Sirolimus MR), the neointimal area after the procedure was

0.29mm2, 3.03mm2 six months after, and 3.34mm2 two years after. The neointimal area for

Sirolimus MR two years after the procedure was significantly less than its control, as the areas

had a mean difference of 0.31mm2. This same trend is demonstrated with paclitaxl and its

control.

After the procedure, the paclitaxel control had a neointimal area of 0.14mm2. Six months

after the area increased to 1.49mm2 and two years after it increased again to 1.71mm2. When the

patient was treated with a moderate releasing stent coated with paclitaxel (Paclitaxel MR), the

neointimal area after the procedure was 0.07mm2. Six months after it was 0.66mm2 and two

years after it increased to 1.06mm2. The neointimal area for Paclitaxel MR two years after the

procedure was significantly less than its control for the same point in time, as the areas had a

mean difference of 0.65mm2.

When comparing the mean differences of Sirolimus MR to Paclitaxel MR, Paclitacel MR,

overall, had a greater mean difference. The mean difference of Sirolimus MR compared to its

control was 0.0900mm2 0.4200mm2 and 0.3100mm2 for after the procedure, six months after,

and two years after respectively. The average mean difference was 0.2733mm2. The mean

difference of Paclitaxel MR compared to its control was 0.0700mm2, 0.8300mm2, and

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0.6500mm2 for after the procedure, six months after, and two years after respectively. The

average mean difference for Paclitaxel MR was 0.5167mm2.

When comparing the changes in area of Sirolimus MR to Paclitaxel MR, Paclitaxel MR

had a lower change in area. The change in area of Sirolimus MR was 3.05mm2 while for

Paclitaxel MR it was 0.99mm2.

Control versus Slow Releasing Stents (Sirolimus and Paclitaxl)

For the sirolimus control, the neointimal area after the procedure was 0.38mm2. Six

months after it was 3.45mm2 and two years after it was 3.65mm2. When the patient was treated

with a slow releasing stent coated with sirolimus (Sirolimus SR), the neointimal area decreased

to 0.29mm2, 3.03mm2 and 3.34mm2 for after the procedure, six months after and two years after

respectively. The neointimal area for Sirolimus SR two years after the procedure was

significantly less than its control, as the areas had a mean difference of 0.4200mm2. The same

trend is present with paclitaxel and its control.

The neointimal area after the procedure, six months after, and two years after for the

paclitaxel control was 0.14mm2, 1.49mm2, and 1.71mm2 respectively. When the patient was

treated with a slow releasing stent coated with paclitaxel (Paclitaxel SR), the neointimal area

decreased to 0.06mm2, 0.64mm2 and 0.94mm2 for after the procedure, six months after, two years

after respectively. The neointimal area for Paclitaxel SR two years after the procedure was

significantly less than its control, as the areas had a mean difference of 0.7700mm2.

When comparing the mean differences of Sirolimus SR to Paclitaxel SR, Paclitacel SR,

overall, had a greater mean difference. The mean difference of Sirolimus SR compared to its

control was 0.1200mm2 0.5000mm2 and 0.4200mm2 for after the procedure, six months after,

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and two years after respectively. The average mean difference was 0.3467mm2. The mean

difference of Paclitaxel SR compared to its control was 0.0800mm2, 0.8500mm2, and 0.7700mm2

for after the procedure, six months after, and two years after respectively. The average mean

difference for Paclitaxel SR was 0.5667mm2.

When comparing the changes in area of Sirolimus SR to Paclitaxel SR, Paclitaxel SR had

a lower change in area. The change in area of Sirolimus SR was 2.97mm2 while for Paclitaxel SR

it was 0.88mm2.

Moderate Releasing versus Slow Releasing Stents (Sirolimus and Paclitaxel)

Overall, the average mean differences for both sirolimus and paclitaxel compared to their

own controls, were greater through the application of a slow releasing stent. The average mean

difference for the Paclitaxel SR was 0.5667mm2 and for Sirolimus SR it was 0.34667mm2. While

for the moderate releasing stents, Paclitaxel MR had an average mean difference of 0.51667mm2

and Sirolimus MR had one of 0.2733mm2.

In addition, the overall change in area was lower for both sirolimus and paclitaxel

through the application of a slow releasing stent as compared to the application of a moderate

releasing stent. The change in area for Sirolimus SR was 2.97mm2 and for Paclitaxel SR it was

0.88mm2. While for Sirolimus MR it was 3.05mm2 and for Paclitaxel MR it was 0.99mm2.

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Discussion

From the data collected during this experiment, several things can be concluded.

Neointimal area is positively correlated to the degree of restenosis. For all six treatment methods

(Sirolimus BMS, Paclitaxel BMS, Sirolimus MR, Paclitaxel MR, Sirolimus SR, Paclitaxel SR),

the amount of neointimal area gradually increased as the amount of treatment time increased.

This shows that restenosis was still occurring regardless of the treatment method. However,

when some treatment methods were applied, the neointimal area did not change as rapidly. In

addition, for all treatments that included either paclixel or sirolimus being applied to the stent,

the amount of neointimal area resulting after 2 years were significantly less as compared to their

controls (Paclitaxel BMS, Sirolimus BMS).

When comparing Sirolimus MR to Paclitaxel MR, Paclitaxel MR had a greater mean

difference. The average mean difference compares the experimental values to its control values.

For example, the average mean difference of 0.51667 for Paclitaxel MR means that the

experimental values (neointimal area resulting from the application of Paclitaxel MR) were, on

average, 0.51667mm2 less than its control values (neointimal area resulting from the application

of a bare metal stent). A greater amount of average mean difference is positively correlated to the

reduction of restenosis. Therefore, since Paclitaxel MR had a greater average mean difference

value than Sirolimus MR, it can be concluded that Paclitaxel MR was more effective in reducing

the amount of neointimal area and consequently the degree of restenosis. When comparing

Sirolimus SR to Paclitaxel SR, Paclitaxel SR had a greater mean difference. This, as well,

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indicates that Paclitaxel SR was more effective in reducing the amount of neointimal area and

thus the degree of restenosis since it had an average mean difference of 0.5667mm2 while

Sirolimus SR had an average mean difference of 0.3467mm2.

In addition, the change in area can be determined by subtracting the initial neointimal

area from the final neointimal area. If neointimal area is maintained throughout a treatment, then

this demonstrates that that treatment method was effective and it was able to inhibit the muscle

from growing and furthering restenosis. Thus, a lower change in neointimal area is associated

with a greater treatment efficacy. The data demonstrates that the change in neointimal area was

lower when the stent was coated with paclitaxel. Paclitaxel MR had a change in area of 0.99mm2

while Sirolimus MR had a change in area of 3.05mm2. Paclitael SR had a change in area of

0.88mm2 while Sirolimus SR had a change in area of 2.97mm2. Therefore, the data indicates that,

specifically, Paclitxel SR was the most effective in maintating the neointimal area of the artery

and slowing the progression of restenosis. However, since all of the treatment methods resulted

in some change in area, none of the treatment methods were effective inhibiting restenosis.

Overall, the slow releasing stents for both sirolimus and paclitaxel were more effective

than the moderate releasing stents. Sirolimus SR had a change in area of 2.97mm2 and Paclitaxel

SR had a change in area of 0.88mm2, while Sirolimus MR had a change in area of 3.05mm2 and

Paclitaxel MR had a change in area of 0.99m2. Also, overall, paclitaxel was more effective in

reducing the progression of restenosis as compared to sirolimus. Both Paclitaxel MR and

Paclitaxel SR had changes in area that were less than Sirolimus MR and Sirolimus SR.

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Experimental Error

A few issues throughout this project may have caused from experimental error. While

collecting data, there wasnt one source to gather all data points from. Data for sirolimus was

collected from the study Persistent Inhibition of Neointimal Hyperplasia After

Sirolimus-Eluting Stent Implantation and data for paclitaxel was collected from the study

Persistent Remodeling and Neointimal Suppression 2 Years After Polymer-Based,

Paclitaxel-Eluting Stent Implantation. Although, both of the studies had very similar

procedures, there were a few minor differences that may have caused a some error in the

comparison between sirolimus and paclitaxel. For example, for both of the studies, patients

received aspirin indefinitely. However, patients tested in the Persistent Remodeling and

Neointimal Suppression 2 Years After Polymer-Based, Paclitaxel-Eluting Stent Implantation

were given 75 mg/d while patients in the other study were given 325 mg/d. Also, for both studies

patients were prescribed with clopidogrel, a blood thinner. In the paclitaxel study, clopidogrel

was administered 48 hours before the stent implantation followed by 75 mg/d for 6 months.

However, in the sirolimus study, the drug was administered immediately after the stent

implantation followed by 75mg/d for 8 weeks. This minimal variation in procedure may have

caused a difference in the effect of either paclitaxel or sirolimus on the artery. Since clopidogrel

was administered for a longer time in the paclitaxel study, it may have had an effect on its

neointimal area measured at 6 months and 2 years. The difference in aspirin dosage, also, may

have caused a difference in the effect of sirolimus and paclitaxel.

In addition, some of the patients in the sirolimus study suffered from coronary lesions, an

abnormality of the coronary tissue. All lesions were predilated -- treated with a balloon -- before

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stent implantation. Although the lesions were treated prior to stent implantation, the abnormality

may have caused a difference in the neointimal areas collected. Since all data was averaged in

the individual study, if there was a difference in the neointimal areas collected from these

patients then the total average may have been skewed. All of the patients in the paclitaxel study

were selected so that they would be lesion-free. This difference in patient selection may have

consequently caused from distortion in the comparison between paclitaxel and sirolimus.

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Conclusion

Coronary artery disease is a progressive disease that is mainly caused by the buildup of

plaque in the arteries. It is the most prevalent type of heart disease and the leading global cause

of death. Doctors use a variety of medical procedures to treat patients with, however, the most

prevalent is stent placement. Although stenting clears the artery, it is not effective in the long

term as it leads to restenosis, the growth of muscle in the underlying artery wall. While recent

research has allowed the creation of drug eluting stents as a treatment method to reduce

restenosis and treat coronary artery disease, it is important to compare the available treatment

options and determine which one is the most effective. The purpose of this project is to compare

the effectiveness of the drugs sirolimus and paclitaxel in reducing the progression of restenosis.

Both drugs are widely used on patients today. In addition, the purpose of this project is also to

compare the effectiveness of drug application through a slow releasing or moderate releasing

method. It was hypothesized that sirolimus would be more effective in reducing the progression

of restenosis because it directly inhibits enzyme mTOR which regulates proliferation,

metabolism, and angiogenesis. It was also hypothesized that the moderate releasing method

would be more effective in reducing the progression of restenosis for both paclitaxel and

sirolimus because the reduction of neointimal proliferation is dose dependent.

Moderate-releasing therapy would result in greater levels of the drug in the vessel, in a certain

amount of time, as compared to slow-releasing therapy. Consequently it would allow for more

treatment to occur during the 2 years of experimentation.

In order to compare the two drugs and two treatment methods, data was collected from

the following studies: Persistent Remodeling and Neointimal Suppression 2 Years After

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Polymer-Based, Paclitaxel-Eluting Stent Implantation and Persistent Inhibition of Neointimal

Hyperplasia After Sirolimus-Eluting Stent Implantation. The data showed that restenosis was

still occurring regardless of the treatment method. For all six treatment methods, the amount of

neointimal area gradually increased as the amount of treatment time increased. Also, it showed

that Paclitaxel MR had a greater mean difference as compared to Sirolimus MR which indicated

that Paclitaxel MR was more effective in reducing the amount of neointimal area and

consequently reducing the progression of restenosis. This is because a greater amount of average

mean difference is positively correlated to the reduction of restenosis. The same trend was shown

with Sirolimus SR and Paclitaxel SR as Paclitaxel SR had a greater average mean difference as

well. In addition, since a lower change in neointimal area is associated with a greater treatment

efficacy, the data indicated that Paclitaxel SR was the most effective in maintaining the

neointimal area of the artery as it had a change in neointimal area of 0.88mm2. Overall, paclitaxel

was more effective in reducing the progression of restenosis as compared to sirolimus while the

slow releasing stents for both sirolimus and paclitaxel were more effective than the moderate

releasing stents.

In conclusion, neither of the hypotheses were supported. It was predicted that sirolimus

would have a lower change in area as compared to paclitaxel because sirolimus directly inhibits

enzyme mTOR. This enzyme reverses the cell cycle and therefore its inhibition would directly

halt restenosis. However this was proven false as paclitaxel had a lower change in area.

Paclitaxels mechanism of treating restenosis is reversing individual muscle cells back to the G0

phase. At the G0 phase the cells are neither dividing nor preparing to divide; they remain

dormant. On occasion, some cells fail to enter the G0 phase and continue on to the G1 phase,

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furthering restenosis. Although it was hypothesized that sirolimus would be more effective in

regressing restenosis because its mechanism would completely reverse the cell cycle, the data

collected in this project supports paclitaxels mechanism. The data showed that restenosis was

occurring regardless of what treatment was given to the patient. Thus the data showed that

sirolimus does not completely inhibit mTOR. Sirolimus diminishes mTORs effects but

restenosis still occurs. Also, the data concludes that when the drug is applied through a slow

releasing mechanism, the treatment is more effective. It was hypothesized that

moderate-releasing therapy would be more effective since the reduction of neointimal

proliferation is dose dependent. Since this was proven false, it can be concluded that neointimal

proliferation is not completely dose dependent. It is rather dose dependent until a certain point.

The data of this project proves that the time allowed for treatment is also a significant factor in

reducing neointimal proliferation. Through both the moderate and slow releasing methods, the

same dose of drug was given but through the moderate releasing method the dosage was given

more often as compared to the slow releasing. During the treatment of the slow releasing

method, the artery was given more time to react and administer the drug. While the total amount

of drug given to the artery may have been more through the moderate releasing method, the extra

amount of the drug did not affect the reduction of neointimal proliferation. Perhaps, the

additional amount may have been unnecessary and thus it may have been expelled.

Overall, it may be concluded that the combination of slow releasing method paired with

the drug paclitaxel was the most effective in reducing neointimal area change and therefore it

would be the most effective in treating restenosis with. In comparison, the combination of the

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moderate releasing method with sirolimus would be the least effective as it yielded the maximum

amount of neointimal area change.

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Impact

Although paclitaxel and sirolimus have both been proven to be effective in reducing the

progression of restenosis, it is important to compare the two drugs and determine which one is

the most effective. When treating patients, it is important to present them with the most effective

method of treatment. This project establishes that paclitaxel paired with a slow releasing method

is the most effective in reducing the progression of restenosis. To maximize the success of

treatment for coronary artery disease it would be beneficial to treat patients with

paclitaxel-eluting stents through a slow releasing method.

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