i

AYASSE™A Ridaforolimus-containing Drug-Eluting Abdominal Stent

DEVICE DEVELOPMENT EVIDENCE DOSSIER

CLIN 512-01 – Medical Devices in Clinical Research Group 8 Assignment

February 25, 2013WORD COUNT: 6,578

GROUP MEMBERS

Authored by:

ABSIYE, Elham - 821 623 857

AFSANA, Shums-Orchee – 821 817 731

ASENSO, Abena – 802 973 594

AWOFODU, Olayinka – 821 460 698

NAMUBIRU, Susan – 821 763 398

ZANTINGE, Stephanie – 821 494 093

INSTRUCTOR: HEATHER DALGLEISH, MSC, CCRP

WORKLOAD STRUCTURE:

CHAPTER 1 AFSANA, S.

CHAPTER 2 ASENSO A.

CHAPTER 3 ABSIYE E., NAMUBIRU S.

CHAPTER 4 ASENSO A., AFSANA, S.

CHAPTER 5 ZANTINGE S., AWOFODU O.

CHAPTER 6 AFSANA, S.

i

AYASSE™A Ridaforolimus-containing Drug-Eluting Abdominal Stent

DEVICE DEVELOPMENT EVIDENCE DOSSIER

CLIN 512-01 – Medical Devices in Clinical Research Group 8 Assignment

CONTENTSCHAPTER 1...................................................................................................................................1

SCOPE AND OVERVIEW OF ABDOMINAL AORTIC ANEURYSM.........................................1

1.1: DEFINITION........................................................................................................................1

1.2: CAUSE................................................................................................................................1

1.3: SYMPTOMS........................................................................................................................2

1.4: DIAGNOSIS........................................................................................................................2

1.5: TREATMENT......................................................................................................................2

CHAPTER 2...................................................................................................................................3

CURRENT TREATMENTS OF ABDOMINAL AORTIC ANEURYSM........................................3

2.1: INTRODUCTION.................................................................................................................3

2.2: THE CURRENT TREATMENT OPTIONS..........................................................................4

2.3: DRUG ELUTING STENTS..................................................................................................7

CHAPTER 3.................................................................................................................................10

RESEARCH EVIDENCE REQUIREMENTS............................................................................10

3.1: STRUCTURE OF THE PRE-CLINICAL TRIALS..............................................................10

3.2: STRUCTURE OF CLINICAL STUDIES............................................................................12

3.3: FACTORS INFLUENCING DEVICE EFFECTIVENESS DATA........................................20

CHAPTER 4.................................................................................................................................21

REGULATORY CONSIDERATIONS.......................................................................................21

4.1: MEDICAL DEVICE CLASSIFICATION……………………………………………………… 21

4.2: POST‐MARKET SURVEILLANCE INFORMATION.........................................................23

CHAPTER 5.................................................................................................................................25

THE VALUE ARGUMENT (HEALTH TECHNOLOGY ASSESSMENT...................................25

5.1: THE DRUG-ELUTING ABDOMINAL STENTS VERSUS STANDARD OF CARE (CURRENT TREATMENT OPTIONS).....................................................................................25

5.2: EFFICIENCY, COST AND EASE OF USE THROUGH THE HEALTH CARE SYSTEM..28ii

5.3: CHALLENGES IN BRINGING THIS NEW GENERATION OF TECHNOLOGY TO MARKET..................................................................................................................................30

CHAPTER 6.................................................................................................................................33

ENVIRONMENTAL CONSIDERATIONS.................................................................................33

REFERENCES............................................................................................................................34

iii

CHAPTER 1

SCOPE AND OVERVIEW OF ABDOMINAL AORTIC ANEURYSM

1.1: DEFINITION

An abdominal aortic aneurysm (AAA) is an aortic degeneration, which dilates and weakens

segments of the abdominal aorta (Filipovic, Goldacre, & Gill, 2006). AAA can be life threatening

to a patient as the aorta is the body’s largest artery that transports oxygen-rich blood from the

heart to the rest of the body. An aortic aneurysm stretches the artery and creates a bulging

section in the wall of the aorta. Subsequently the enlarged vessel can rapture and cause

bleeding which can be life threatening (Zeller, Burke & Glass, 2009). The mortality rate of

patients with a ruptured aneurysm is 78% to 94%, making it crucial to prevent it (Brewster et al,

2003).

1.2: CAUSE

An abdominal aortic aneurysm can result from multiple factors, which leads to the progressive

breakdown of the structural components of proteins, elastin and collagen in the aortic wall.

These components provide structure and flexibility in the aortic wall. The exact cause, however,

is unknown (VD foundation, 2012).

Atherosclerosis, including the risk factors associated with it, is considered to play an important

role in aneurismal disease. Additional risk factors include:

• Increased risk with age

• Male

• History of cigarette smoking

• Family history

Page 1 of 38

• Atherosclerosis

• High blood pressure

• High cholesterol level

• Inherited conditions such as Marfan’s syndrome (CDC, 2011)

1.3: SYMPTOMS

There are generally no noticeable symptoms for AAA and they often grow silently. Occasionally,

aneurysms can expand rapidly or leak blood. This will cause pain in the abdomen, back or side

of the body. Patients with AAAs often have other signs of cardiovascular disease including a

previous heart attack, stroke or angina (O’Gara, 2003).

1.4: DIAGNOSIS

AAA can be detected by ultrasound scan or CAT scan. These exams are non-invasive and often

performed at an outpatient facility. The size of an AAA, which is significant in determining the

best treatment, is also measured (VD foundation, 2012). Aneurysms must be re-imaged when

symptoms develop, though it is important to have yearly checkups. This will allow the physician

to verify any change in size. If the physician recommends surgery, a CT scan or MRI of the

aorta is usually obtained. This will supply the surgeon with a “road map” for further action

(O'Gara, 2003).

1.5: TREATMENT

Depending on the physicians’ diagnosis of the patient’s AAA, there are two available primary

treatment options: open surgery or stent grafting (O’Gara, 2003).

Page 2 of 38

CHAPTER 2

CURRENT TREATMENTS OF ABDOMINAL AORTIC ANEURYSM

2.1: INTRODUCTION

When considering treatment options for Abdominal Aortic Aneurysms (AAAs) the best strategy

is prevention of aneurysm rupture. There are many contributing factors to treatment selection

that have to be taken into consideration such as: the size of aneurysm, risk of rupture, location

and shape of aneurysm, age of patient, life expectancy, and any other underlying medical

conditions that can impact treatment.

When patients are diagnosed with AAA, the abdominal aorta has ballooned to more than 1.5

times the normal diameter and patients are monitored for possible aneurysm enlargement, and

are at an increased risk for rupture. The most common standard of care is open surgical

removal via the Retroperitoneal approach and the Endovascular surgical approach via the

lumen of the abdominal aorta.

Most reported areas of research have focused on certain pathogenic mechanisms associated

with the disease such as the high presence of MMPs (metalloproteinase-9) levels in the aortic

wall, where studies using statin therapy have shown reduction in levels, inflammatory and

autoimmune mechanisms, molecular genetics of Abdominal Aortic Aneurysms, and analysis of

aortic wall stress distribution (Becquemin, et al.2011). Most recent approaches have

investigated patients who are more susceptible to rupture, by measuring the diameter of the

aneurysm and monitoring for growth.

Page 3 of 38

2.2: THE CURRENT TREATMENT OPTIONS

Open Surgery Repair

Open Surgery Repair is the established treatment for Abdominal Aortic Aneurysm. Patients are

generally asymptomatic and the aneurysm diameter is greater than 5cm. The repair is invasive

and occurs under general anesthesia. The procedure involves making a large incision in the

abdomen and replacing the diseased region of the aorta with a tube graft. Minimizing

techniques such as Laparoscopic techniques are utilized to minimize the extent of invasion.

Limitations in Open surgical repair

Post-surgical disadvantages include: longer stay in intensive critical care units (therefore longer

hospital stay), higher chance of surgical complications, and a higher 30-day mortality rate

(Becquemin et al, 2011). According to the Journal of vascular surgery, elderly patients at age 80

have a higher operative mortality risk to open AAA repair.

Open Surgery Repair excludes patients considered high risk and unfit for open surgery, as well

as patients that present with coexisting conditions such as atherosclerosis, cystic medial

necrosis, and vascilitic.

Endovascular Aneurysm repair (EVAR)

Endovascular Aneurysm Repair is the recommended option for patients who are considered

high risk or unfit for surgical repair due to other accompanying cardiovascular diseases.

Treatment is minimally invasive and occurs under local anesthesia. The procedure involves

making a small incision in the femoral artery in the groin. The stent graft (a Y-shape graft, with 2

branches for iliac arteries and proximal aorta) is delivered to the aorta using a single use,

disposable catheter (also delivers the bifurcated component and aortic extension). It is a

Page 4 of 38

favorable technique to open surgical repair due to shorter hospital stay (2 or 3 days), shorter

recovery time, and less blood loss.

Minor low occurrence procedural risks include; vascular injury and perforation, which can lead to

aneurysm, rupture (Becquemin et al, 2011). In cases where the procedure fails due to

complications, the open surgical repair is still possible. Significant RCTs (Randomized

Controlled Trials) have reported lower postoperative mortality rates after EVAR compared to

Open Surgery Repair (Greenhalgh et al, 2008).

Limitations in Endovascular Aneurysm Repair (EVAR)

There is a risk of late occurrence endovascular leaks (endoleaks) into the aneurysm, either due

to unsecure fixation on the organ site causing movement or backfilling from neighbouring small

vessels in aneurysm wall. Patients are required to meet specific anatomical criteria for EVAR

that would be advantageous, as it pertains to the axial length, shape and angulation of

aneurysm neck. If the criterion is not met, post-procedural risks include: graft migration, stenosis

or occlusion of graft, and widening of proximal aneurismal neck and iliac arteries (Becquemin et

al, 2011).

Minor postsurgical complications include allergic reactions to stent graft material (nitinol,

polyester, and platinum-iridium), and other effects on organs and systems such as bowel

complications, swelling in groin, tear in blood vessels, disruptions in blood flow, blood clot

formation and infections.

Medical Management of Abdominal Aortic Aneurysm

Treatment of an Abdominal Aortic Aneurysm using beta blocker or angiotensin-converting-

enzyme inhibitors has been successful in treating small aneurysms with a diameter of less than

5cm. This form of pharmaceutical therapy is favourable because the risk of surgery to repair the

Page 5 of 38

smaller aneurysm outweighs the benefits, due to low risk of rupture. The recommended

medications are used to treat hypertension since patients with AAAs are also at risk for other

cardiovascular events. Extensive studies in RCTs have shown that this form of therapy

functions to reduce the growth of the aneurysm (Becquemin et al, 2011).

Other pharmaceutical agents include statins, a class of drugs that function to inhibit 3-hydroxy

3-methylglutaryl coenzyme A reductase. RCTs have shown a significant 50% reduction in

aneurysm growth (Colledge, Powell, 2007), as well as reduction in MMPs (contribute to

prevalence of aneurysm growth) concentration in the aortic wall. There is limited drug treatment

therapy targeted at reducing aneurysm growth due to cost, and unlimited uncertainties

associated with development.

Bare Metal stents

Bare Metal Stents (BMS) were first introduced as an alternative to balloon angioplasty in

maintaining blood vessel patency. During Bare Metal Stenting, a metal vascular stent without a

drug coating is inserted in place of the diseased aortic artery using a catheter. The technique

was highly favorable in managing the complicated system associated with the angioplasty

procedure such as “injury to the blood vessel, resulting in vascular elastic recoil, neointimal

proliferation and negative remodeling, often leading to restenosis…a more severe problem is

the collapse of the artery” (Ma et al, 2012). Extensive research in RCTs of BMS revealed it to

be significantly effective in reducing the rate of restenosis, with few adverse events reporting.

Limitations of Bare Metal Stents

The development of in stent restenosis due to cell proliferation became a contributing issue

associated with the procedure. New treatment options combining original stent with a carrier

Page 6 of 38

anti-restenotic agent to inhibit cell proliferation has been more effective in reducing the rate of

restenosis and late stage restenosis.

2.3: DRUG ELUTING STENTS (DES)

DEFINITION/DESCRIPTIONDES is based from bare metal stents and is a small mesh scaffolding (stent) that is placed in a

diseased and narrowed peripheral or coronary artery that slowly releases a drug to inhibit and

prevent tissue overgrowth. DES consists of three components: the stent platform, the carrier,

and the agent. The stent platform is characteristically flexible and allows for expansion. The

coating is typically a polymer coating, which is advantageous in preventing abrasions during

implantation, promotes high sterilization, and allows for maximum delivery of the active agent (a

drug) without other systemic interactions. Therefore, it is an efficacious, safe, and controlled

drug delivery system. Various types of coatings include: ‘‘phosphorylcholine, biocompatible

nonerodable, biodegradable, or bioabsorbable polymers, and ceramic layers” (Ma et al, 2012).

A successful drug agent includes immunosuppressive and anti-proliferative drugs that works to

inhibit restenosis (includes preventing neointimal hyperplasia and vessel remodeling).

Differences in drug eluting stents depend on their ability to inhibit restenosis. Components of

this device work to prevent stent thrombosis in patients with blocked coronary arteries that can

lead to myocardial infarction and death. DES is largely successful in treating patients with

coronary artery disease. Drug eluting stents have been recently approved by the FDA for re-

opening the femoropopliteral artery due to peripheral artery disease (PAD). DES has been

shown to be more effective in inhibiting and preventing tissue growth to avoid restenosis rate,

when compared to bare metal stents

Page 7 of 38

Limitations in Drug eluting stents

There is still a very small possibility for restenosis (renarrowing), but research shows significant

improvement to tissue growth inhibition. Approximately 1 in 5 patients develop restenosis after

stent placement without medication, but patients using DES have shown only 1 in 10, and half

the recurrent rate (Maisel et al, 2007).

Development of late stage stent thrombosis after implantation can be combated with anti-

clotting medication. There are limited studies of late stage safety and stability of drug eluting

stents associated with patients with other related conditions.

Other related Drug eluting stents

Sirolimus-eluting stent (SES)

Sirolimus-eluting stent, the first ever implanted drug eluting stent in 1999, is a stent coated with

sirolimus and an immunosuppressant drug. It functions to prevent the formation of neointimal

proliferation in diseased regions by inhibiting proliferation of T and B lymphocyte that promote

tissue growth, activate inflammatory response and smooth muscle cell.

RCTs studies have shown significantly less adverse events after procedure and lower rate of

restenosis and late luminal loss.

Paclitaxel-eluting stents (PES)

Paclitaxel eluting stents was developed simultaneously with SES also termed TAXUS. The stent

is coated with paclitaxel, an anti cancer agent used to inhibit stent migration and smooth muscle

cell hyperplasia.

RCTs showed similar favourable results as SES. Both the SES and PES are a better alternative

to Bare Metal Stenting.

Page 8 of 38

Second Generation Stents

Everolimus-eluting stents (EES)

Everolimus eluting stent is a stent coated with Everoliumus, an immunosuppressant drug that

has proven to be effective in reducing the rate of late-stage stent apposition.

Page 9 of 38

CHAPTER 3

RESEARCH EVIDENCE REQUIREMENTS

3.1: STRUCTURE OF THE PRE-CLINICALTRIALS

STUDY DESIGNPrimary purpose: To establish the safety of the AYASSE Drug Eluting Stent

Interventional model: Multi group dose ranging studies

Primary Objective: To evaluate the safety of the AYASSE Drug Eluting Stent

Secondary Objective:

1. To evaluate efficacy of the AYASSE Drug Eluting Stent

2. To study wound healing patterns and time following the AYASSE Drug Eluting Stent

insertion

3. Time to endothelial recovery in the injured vessels

Primary outcome measures:

Size and seriousness of post insertion arterial and vascular injuries

Time points for preclinical trials: Termination will be at 28, 90, 180 and 365 days

o These time points are chosen based on data from previous studies showing the

benefits of long term studies in preclinical trials. According to Ako et al., healing

time was studied for up to 480 days and relevant safety data was obtained even

at 480 days. To minimize cost, 365 days was chosen for this study.(Ako et

al,2005)

Important endpoints:

Thrombus formation

Inflammation

Page 10 of 38

Endothelialization and granulation tissue formation

Smooth muscle cells and matrix formation

Neo-intimal response over time

Death

ANIMALS USED IN THE STUDYFor cell culture studies, we will utilize porcine cell cultures. The cultures will contain vascular

endothelial and smooth muscle cells and will be treated over a range of doses in a logarithmic

scale. Although human cells are preferred it is more practical and ethical to use porcine cells.

The structure and action of porcine cells is similar enough to correlate to human cells.

Combinations of two major models are used in stent pre-clinical trials: the ovine and the porcine

models using both sheep and pigs as the target animals.

These models were chosen based on data from previous clinical trials in similar fields which

suggests benefits from both models. The assumption is that a combination of data from two

animal models in one clinical trial will provide more accurate data predictive of performance of

the AYASSE Drug Eluting Stent in clinical trials.

According to Schwartz et al. (1380) no particular model fulfills the three objectives for evaluation

of endovascular treatments: device safety, device efficacy, and pathophysiology of

atherosclerosis. Although small animals are low cost and readily available, they have offered

only limited predictive clinical value. Large animals are more costly and less readily available

but porcine, ovine and rabbit models have proven useful for assessment of local toxicity and

determination of the margin of safety.

Sheep are chosen as the best candidate for evaluation of restenosis. Although they are docile,

their fibroyltic and coagulation system is similar to humans more so than other species and they

generally have blood vessels of a larger width.

Page 11 of 38

Pigs are chosen for their large vasculature which is suitable for the evaluation of performance of

the entire stent mechanism and for the study of wound healing and the inflammatory response.

Additionally, according to Perkins (2006), the local flow dynamics of porcine blood vessels

closely parallels those of humans allowing for greater confidence in the accuracy of

pharmacokinetic studies.

For both sheeps and pigs, there is also the added benefit of having large vessels that could

allow implantation of more than one device including overlapping of stents.

3.2: STRUCTURE OF CLINICAL STUDIES

PHASE I CLINICAL STUDYTitle: A Phase I Prospective, Non-randomized, Open label evaluation of the Safety of the

AYASSE Drug Eluting Stent when used for the treatment of Abdominal Aortic Aneurysm

Allocation: Non-randomized

Intervention model: Single Group Assignment

Masking: Open label

Primary purpose: Treatment

Number of participants: 25

Location: Sunnybrook Health Sciences Centre

2075 Bayview Ave Toronto, ON M4N 3M5

Sponsor: Johnson and Johnson Canada.

Primary outcome measures:

Page 12 of 38

Number of participants without a device related adverse event within 1 month of

procedure

o Adverse events to include stent graft migration, vessel dissection or perforation,

stent graft occlusion and aneurysm rapture

Number of participants without an endoleak within 1 month of procedure

o Endoleaks to include Type I endoleaks which are persistent perigraft blood flow

channels due to inadequate sealing at the graft ends, Type III endoleaks which

occur midgraft due to defect in graft fabric and Type IV endoleaks which emanate

from blood diffusion across the graft fabric due to holes caused by sutures or

stent struts

Secondary outcome measures:

Number of participants whose procedures are considered successful 5 hours after the

procedure is completed

Success is defined by this trial as a successful introduction of the drug eluting stent graft

into the blood vessel

Study duration: 6 months

Start date: March 2013

End date: August 2013

ELIGIBILITY

Inclusion criteria:

Male patients 18 years of age and above

Patients that are considered an appropriate candidate for open surgical repair of an AAA

at least one of the following:

Page 13 of 38

o Abdominal aneurysm above or equal to 4.5 cm in diameter

o Aneurysm has increased in size by 0.5cm in last 6 months

Have arteries that allow endovascular access to the aneurysmal site with a 17F Delivery

Catheter

Exclusion Criteria:

A dissecting, acutely ruptured, or leaking aneurysm

Acute vascular injury due to trauma

Need for emergent surgery

Congenital abnormalities in which the placement of the stent-graft will cause occlusion of

major arterial flow

Morbid obesity or other clinical conditions that inhibit visualization of blood vessels

Connective tissue disease (e.g., Marfan's or Ehlers-Danlos syndrome)

Contraindication for anticoagulation

Acute renal failure

Active systemic infection

less than 18 years of age

females

Life expectancy less than 1 year

Current, or anticipated participation within 1 year, in another research study involving an

investigational device or new drug

Page 14 of 38

PHASE II CLINICAL STUDYTitle: A Phase II Prospective, Multicentre, Non-randomized, Open label evaluation of the Safety

and Performance of the AYASSE Drug Eluting Stent when used for the treatment of Abdominal

Aortic Aneurysm

Allocation: Non-Randomized

Intervention Model: Single Group Assignment, Parallel Assignment

Masking: Open Label

Primary Purpose: Treatment

Number of Participants: 250

Locations: 1.Sunnybrook Health Sciences Centre, 2075 Bayview Ave Toronto, ON M4N 3M5

2. Toronto East General Hospital, 365 Gerrard Street East Toronto, ON M4C 4X5

3. Mount Sinai Hospital, 60 Murray St, Toronto, ON M5T 3L9

Sponsor: Johnson and Johnson Canada.

Primary Objective:

To determine the safety and efficacy of the AYASSE Drug Eluting Stent for the repair of

Abdominal Aortic Aneurysm

Primary Outcome Measure:

Overall Mortality

Incidence of Serious Adverse Event

Secondary Outcome Measure:

Evaluate the performance of the stent delivery system

Procedure related complications

Study Design: Prospective, Single arm, Non-randomized, Parallel and Open Label.

Page 15 of 38

Study Duration: 24 months

Start Date: September 2013

End Date: September 2015

ELIGIBILITY

Inclusion

Males and non-pregnant females above the age of 18 who have been diagnosed with

Abdominal Aortic Aneurysm

Abdominal aortic aneurysm with a diameter above or equal to 4.5 cm or with rapid

expansion (Matsumura et al)

The artery diameter and profile are capable of study device delivery

The vessels immediately proximal and distal to the lesion are capable of accommodating

the device

Aortic neck < 15mm in length (Blum et al, 1997)

Exclusion

Females that are pregnant or can be become pregnant during the course of the trial

Lactating women

Patients with vascular injury

Patients with allergy or intolerance to any components of the device or drug

Patients with connective tissue disease (Prinssen et al, 2004)

Patients participating in another investigational device or drug study within one year

(Matsumura et al, 2009)

Patients with Renal insufficiency

Patients with Aortic dissection (Matsumura et al, 2009)

Page 16 of 38

Safety & Effectiveness Endpoints

Proportion of subjects who experience a serious adverse event

Proportion of subjects that achieve treatment success

PHASE III CLINICAL STUDYTitle: A Phase III Prospective, Multicentre, Randomized, Open Label Clinical Evaluation of the

Safety and Performance of the AYASSE Drug Eluting Stent versus a Bare Metal Stent in the

treatment of Abdominal Aortic Aneurysm

Allocation: Randomized

Intervention Model: Two Treatment Arms, Parallel Assignment

Masking: Open Label

Primary Purpose: Treatment

Number of Participants: 1250 (625 per treatment arm)

Locations: 1.Sunnybrook Health Sciences Centre, 2075 Bayview Ave Toronto, ON M4N 3M5

2. Toronto East General Hospital, 365 Gerrard Street East Toronto, ON M4C 4X5

3. Mount Sinai hospital, 60 Murray St, Toronto, ON M5T 3L9

4. Montreal General Hospital, 1650 Cedar Avenue, Montreal, QC H3G 1A4

5. Jewish General Hospital, 3755 Côte-Sainte-Catherine Road, Montréal, QC H3T1E2

Sponsor: Johnson and Johnson Canada

Primary Objective:

To evaluate the safety and performance of the AYASSE Drug Eluting Stent compared to

a Bare Metal Stent in patients with Abdominal Aortic Aneurysm

Page 17 of 38

Primary Outcome Measure:

Compare aneurysm related mortality rates of the AYASSE Drug Eluting Stent to Bare

Metal Stent

Compare the incidence of serious adverse events

Secondary Outcome Measure:

Compare occurrence of device related adverse events

Study Design: Prospective, Non-randomized, Parallel, Multicenter, Open Label with two

treatment arms

Study Duration: 36 months

Start Date: October 2015

End Date: October 2018

ELIGIBILITY

Inclusion

Male and female above or equal to the age of 18

Adequate Infernal Neck (Prinseen et al, 2004)

Abdominal Aortic Aneurysm above 5.0cm OR increase of AAA diameter >0.5cm over

the last 6 months (Prinssen et al, 2004)

Artery diameter capable of study device delivery

Adequate femoral access

The vessels proximal and distal to the lesion are capable of accommodating the device

Patient is able to meet follow-up requirements

Patients must be considered suitable candidates for both procedures (Prinssen et al,

2004)

Page 18 of 38

Exclusion

Pregnant or lactating women

Ruptured or leaking abdominal aortic aneurysm

Patients who need to undergo emergency aneurysm repair (Prinssen et al, 2004)

Patients with vascular injury

Hypersensitivity

Renal insufficiency

Known allergy or intolerance to the components of the device

Patients with or a history of connective tissue disease (Prinssen et al, 2004)

Abdominal aortic dissection (Prinssen et al, 2004)

Coagulopathy or bleeding disorder (Prinssen et al, 2004)

Patients that are morbidly obese or have other conditions that inhibit visualization of

blood vessels

Existing AAA stent

Patients participating in another investigational device or drug study within one year

Patients with a life expectancy of less than two years (Prinssen et al, 2004)

Safety & Effectiveness Endpoints

Rate of mortality

Proportion of subjects that achieve treatment success

Proportion of subjects who experience a serious adverse event

Rationale for Phase II and III Clinical Trials: we elected these study designs for the evaluation of

the AYASSE Drug Eluting Stent for several reasons. First, we chose a multicentre approach to

increase our chances for patient recruitment. We chose prospective, parallel and open label

assignment because it is important to evaluate our medical device over an extended period of

Page 19 of 38

time, as to successfully assess the safety and effectiveness. It is unethical to choose any study

design other than parallel assignment and due to the fact that this device will be inserted into

patients under local anesthesia, blinding of the study would be very difficult to maintain. The

inclusion and exclusion criterion is based on results from previous studies, along with personal

suggestions.

3.3: FACTORS INFLUENCING DEVICE EFFECTIVENESS DATA

1. One of the factors influencing device effectiveness data is that there is a possibility that

results from preclinical data will not be translated similarly in humans. It is unclear

whether current animal models accurately reflect the human vascular response to Drug

Eluting Stents or whether other causes need to be sought. According to Schwartz et al.,

prior preclinical trials with positive results which did not translate to patients may be due

to improper or biased variable selection or confounding effects of vascular injury.

(Schwartz et al.,2004)

Solution: It is important to review data in respect of the limitations of the particular

preclinical model used. This understanding will enable conservative predictions to guide

the clinical research procedure.

Solution: Another solution for this problem is the planned use of two combined animal

models. This new approach hopes to minimize the limitations of the individual porcine

and ovine models and also maximize the amount of positive data collected.

2. Device implantation may be slightly different depending on technique of insertion. This

may make it hard to compare two devices.

Solution: The study will maintain only 1 personnel at each site responsible for insertion

of all stents so as to ensure uniformity of technique and therefore uniformity of data.

Page 20 of 38

CHAPTER 4

REGULATORY CONSIDERATIONS

4.1: MEDICAL DEVICE CLASSIFICATION

According to Health Canada Classification rules and Medical Device Regulations,

cardiovascular drug eluting stents are classified as Class IV. The primary mode of action of the

device is to treat Abdominal Aortic Aneurysm, a high risk, life-threatening disease of the

cardiovascular system. It does so by maintaining the patency of the abdominal aorta lumen

using a stent graft. The secondary mode of action introduces a drug (Ridaforolimus) into the

body via a coated stent to prevent restenosis, a related adverse event that is equally harmful.

The procedure involves permanent implantation of a vascular stent (Class IV device) and

follows the classification Rule 6 under a non-invasive medical device that requires the

modification of a biological or chemical composition of liquids, body fluids or tissues that may

lead to introduction of a potentially foreign substance.

Elements for a Class IV investigational testing authorization application

Introduction, which includes

Manufacturer Identification

Device Identification

Device Description

Design Philosophy

Marketing History

Risk Assessment and Risk Reduction Measures

Previous Studies

Alternate Treatments

Page 21 of 38

Precautions

Institutional Information

Names of Investigators

Names of Institutions

Research Ethics Board Approval

Protocol

Device Label

Investigator Agreements

Manufacturer and/or Device Sponsor Responsibilities

Record Keeping

Mandatory Problem Reporting

Other Obligations

Elements for Class IV Medical Device License Application

Executive summary

Table of contents

Background Information, which includes:

Device Description

Design Philosophy

Marketing History

Summary of Safety and Effectiveness Studies, which includes:

List of Standards

Method of Sterilization

Summary of Studies

Page 22 of 38

Bibliography

Labeling Material

Quality System Requirements

Risk Assessment

Quality Plan

Device specific detailed information, which includes:

Material specifications

Manufacturing process specifications

List of standards

4.2: POST‐MARKET SURVEILLANCE INFORMATIONThe post‐market surveillance information that Health Canada might require would be the long-

term safety of the AYASSE Drug Eluting Stent.

PHASE IV CLINICAL STUDY

Title: A Phase IV Study Evaluating the Long Term Safety and Effectiveness of the AYASSE

Drug Eluting Stent

Primary purpose: establish the long term safety and effectiveness of the AYASSE Drug Eluting

Stent through the endpoints previously determined in this protocol

Clinical purpose: assess the long term safety and effectiveness of the AYASSE drug eluting

stent evaluated at 4 years through devoid of Aneurysm-Related Mortality (ARM).

Allocation: Non-randomized

Intervention model: Single Group Assignment

Masking: Open label

Primary purpose: Treatment

Page 23 of 38

Number of participants: 300

Important endpoints: Safety/Efficacy Study

ELIGIBILITY

Inclusion

Males and non-pregnant females above the age of 18 who have been diagnosed with

Abdominal Aortic Aneurysm

Indication for elective surgical repair of AAA with the AYASSE drug eluting stent

Exclusion Criteria:

existing participation in a concurrent study which may confound the trial results

High possibility of the patient’s non-adherence to physician's follow-up requirements

Lactating women

CHAPTER 5

THE VALUE ARGUMENT (HEALTH TECHNOLOGY ASSESSMENT)

Page 24 of 38

5.1: THE DRUG-ELUTING ABDOMINAL STENTS VERSUS STANDARD OF CARE (CURRENT TREATMENT OPTIONS)

The traditional standard of care for AAA, as mentioned previously in this paper, is Open Surgery

Repair and therefore will be used to compare and contrast to drug-eluting abdominal stents

(DES) for the value argument. Factors that should be considered are device design, care,

handling, installation and risks associated with the device. Since treatment of AAA is more

frequently done with stents, a brief discussion will also ensue on the difference between Bare

Metal Stents (BMS) and DES and the potential impact this has on DES use in the Canadian

health care setting.

When comparing Open Surgery Repair to Endovascular Aneurysm Repair (EVAR) techniques

there are a few inherent similarities:

Both are surgically invasive procedures, however, open surgery carries a far greater risk

and requires the patient to be suitable for such a stress on the body (Moll et al 2011).

EVAR is far less invasive.

Both techniques require highly skilled surgeons and/or professionals

Both of the medical devices fall within Class IV of medical devices according to Health

Canada’s requirements

Both techniques have similar post-surgery risks and complications which include:

thrombus (blood clot) formation, recurrence of blood vessel narrowing which can lead to

restricted blood flow and increased pressure (restenosis) and extensive fibrosis (Walker

et al 2010).

Page 25 of 38

Efficacy in both cases is assessed based on clinical endpoints such as: rate of

revascularization, secondary blood clot formation, re-narrowing of blood vessels,

excessive growth of connective tissue and death (Walker et al 2009).

When looking at the differences between open surgery and EVAR procedures the following is

noted:

Open surgery is highly invasive requiring the surgeon to make a large incision to allow

access to the damaged aorta so that a prosthetic graft can be inserted (Chambers et al

2009).

With Endovascular Aneurysm Repair (EVAR), the procedure is much less invasion and

involves a small incision made in the femoral artery. The stent-graft is then carefully

guided through the abdominal aorta via a catheter, which is guided by radiography

methods (Moll et al 2011). Once the stent is in place, the catheter is removed.

EVAR when compared to Open Surgery results in less blood loss (total ml), less days

spent in intensive care and shorter hospital stays and has far shorter recovery times (in

days) (Brewster et al 1998).

Fewer local complications are seen with open surgery but the number of remote or

systemic complications is far greater than when compared to EVAR (May J et al 1998).

When looking at the design, DES consists of three parts: the stent platform, a coating

and a drug. The only true difference between DES and BMS is simply the presence of a

pharmacological substance, which aids to prevent further narrowing of the arteries

(Chambers et al 2009).

Page 26 of 38

In terms of clinical equivalence EVAR devices have shown an increasing growth of

safety and efficacy data when compared to Open Surgery Repair (Stone et at 2004).

EVAR also allows effective treatment of many patients that were unstable or did not

meet the requirements for Open Surgery Repair (Moll et al 2011, Walker et al 2010).

DES also helps to reduce the rate of repeat surgeries secondary to the risks associated

with endovascular stents.

When assessing risks associated with DES and BMS usage the Major Adverse

Cardiovascular Events (MACE) scale has been used as a tool to measure the clinical

outcome of trials on EVAR. DES has shown better outcomes in various endpoints

(death, myocardial infarction, and repeat surgery) when compared to their BMS

counterparts (Chavarri 2004, Lagerqvist et al 2007).

Another difference between BMS and DES is target vessel revascularization (TVR). TVR

is done when patients experience cardiovascular symptoms secondary to the lesions

originating along the site of the previous endovascular procedure. Generally, DES has a

lower risk of subsequent TVR when compared to BMS (Groeneveld 2012).

Briefly, as it will be discussed a bit more later on, BMS are less expensive than DES.

Cost per quality-adjusted life-year (QALY) gained is the primary outcome measure of

most cost-effectiveness analyses for EVAR (Ryan and Cohen 2006).

5.2: EFFICIENCY, COST AND EASE OF USE THROUGH THE HEALTH CARE SYSTEM

The main purpose in developing a new medical device should be to aim for increased efficiency

when it comes to treating a particular condition over current therapies/treatments. Two other

Page 27 of 38

important factors for a successful device are the product cost and the ease of use of the

product. Keeping the previously mentioned factors in mind, DES devices increase efficiency

through the health care system for the following reasons:

When compared to both Open Surgery Repair and BMS, DES devices reduce the

incidence of restenosis as well as the occurrence of stent thrombosis, smooth muscle

fibrosis, and the rate of scar tissue formation (Pfisterer et al 2006).

DES reduces TVR, which reduces the need for further revascularization surgeries by the

interventional cardiologist (Pfisterer et al 2009). Essentially DES devices decrease the

chances of repeat hospital visitations, which helps boost the QALY score for these

devices. (Decreased hospital visitations means decreased costs associated with

surgery, hospitalization stays, loss of patient work, etc).

Pivotal trials done on DES devices have shown significant effectiveness in the

management of AAA and a reduced risk of death has been associated with their use,

however these findings are controversial and there is much debate about the validity of

these statements in the literature (Hao et al 2010).

Another reason DES increase the efficiency of AAA treatment is their biodegradable

coating promotes endothelialisation, which aids in preventing restenosis and thrombosis

in patients (Lim et al 2008).

The procedure preformed for DES device implementation is nearly identical to that for

the previous generation BMS stents (Walker et al 2010). Since BMS stent usage in the

treatment of AAA is so widespread nowadays there are plenty of well trained cardiology

Page 28 of 38

surgeons who would be able to easily use the newer generation DES stents with only

minimal additional training required (training involved in the specifications of the new

devices, most importantly looking at the inherent differences between DES and BMS

stent and how the pharmaceutical drug and biodegradable coating works).

Overall, DES devices have the potential to increase and improve not only the efficiency of

treating AAA but may also be cost effective for the health care system in the long run, however,

in Canada the issue of cost effectiveness is questionable and will be discussed in more detail

further on. There is no question about the ease of use when it comes to DES devices as BMS

devices are inserted in an identical fashion so training will be minimal and again lead to

decreased costs.

By effectively improving AAA symptoms and reducing further risks of pathological progression

and repeat surgeries, DES can have a fundamental impact on increasing overall patient quality

of life. It would be beneficial for hospitals to adopt the use of DES devices as the overall benefits

outweigh the risks and typically, the use of DES has a “function of predicted benefit”

(Groeneveld 2012).

5.3: CHALLENGES IN BRINGING THIS NEW GENERATION OF TECHNOLOGY TO MARKET

As with any pharmaceutical product or medical device, there are always challenges associated

with bringing a new technology to market and accepted medical practice. Various factors such

as economics, consumer acceptance, ease of use, market competition, cost, technical

challenges, regulatory processes in difference countries, all must be considered when

developing a new product.

Page 29 of 38

From an economic standpoint for DES devices, there is a high cost-benefit ratio when compared

to Open Surgery Repair and the BMS counterpart. In an effort to control costs, healthcare

facilities are being more selective in how they evaluate and purchase new medical devices, this

is especially true in Canada where we have a publically accessible healthcare system and in

order for a new treatment to be widely accepted and used it has to not only be effective but

must also have a reasonable price associated with the product (Bowen et al 2005). The current

price of a BMS device in Canada is approximately $600 whereas that of a DES device is $1899

(Viminitz M 2005, Spears K 2005).

If a cheaper alternative is available and has similar efficacy, the cheaper product will most likely

always be used (especially if it is already well established and used). This is currently the

debate for the use of DES devices in Canada as the opinion seems to be that the cost-benefit

ratio is far too high when cheaper, equally effective treatments, open surgery and BMS, are

currently already available and widely used (Bowen et al 2005). Although DES reduces the

occurrence of restenosis and other medical conditions associated with AAA repair, many

experts in Canada feel the chances of many of these side effects are minimal and since BMS

are cheaper they should be used over DES, unless there is compelling evidence to suggest an

individual is at an increased risk for developing post-surgery complications (Walker et al 2010).

In Ontario specifically, a report was generated using “real-world” data, which was collected from

over 9,000 patients that compared the cost-effectiveness of DES versus BMS in terms of QALY.

The authors, Bowen et al, looked at factors such as revascularization probability, cost of health

resource utilization, initial cost of procedures, revascularization costs and quality of life. What

the report concluded was that there was only a difference of 15% in terms of revascularization

between BMS and DES devices within the selected patient population and as a result, based on

Page 30 of 38

the cost of each device, BMS were more cost effective in the long-term than their more

sophisticated DES counterparts (Bowen et al 2005).

Clearly in Canada, from an economic standpoint, brining DES devices into widespread usage

for AAA treatment is not necessarily very feasible unless there is high suspicion that a patient

will suffer complications following surgery.

Another factor that must be considered is consumer acceptance. There have not been

extensive studies done on DES compared to BMS in terms of safety and efficacy between the

two. It will be quite difficult to get a cardiology interventionist to use DES devices on their patient

for pilot studies due to the relatively low amount of information available.

One also needs to consider competition for market shares. DES devices are in competition with

their cheaper BMS counterparts as well as themselves. There is more than one type of DES

device commercially available utilizing different drugs (Bowen et al 2005) and determining which

drug/stent combination is most effective may be difficult, especially if surgeons are

uncomfortable using a DES device in the first place due to additional safety concerns.

Technical challenges are also inherent for DES device usage. Handling of the DES needs

special care during a revascularization procedure in order to ensure that the biodegradable

layer of the stent is not damaged before it reaches its final destination (Walker et al 2010).

Training of personnel in handling and storage of the device is paramount and may generate

additional costs and time associated with the device.

Regulatory processes are also important to consider when developing new medical devices.

The regulatory requirements for Class IV medical devices in Canada are very stringent. Class IV

devices have the highest potential of risk and we have to prove a substantial equivalence of this

Page 31 of 38

new device to pre-existing devices. There are few literature reviews and software reviews on

abdominal DES devices as well as very few clinical studies on ridaforolimus.

In conclusion, although DES appears to have many potential benefits for patients, these

benefits and their associated cost ratios may not be good enough to surpass the widely

accepted use of BMS devices and Open Surgery procedures when it comes to treating and

managing AAA. In Canada, the wide-use of DES devices is unlikely as they cost nearly twice

the price of regular BMS devices and do not add significant improvements to the quality of life of

the patient. As with all new pharmaceutical and medical devices, continual on-going research

and post-marketing surveillance will be required before a more definite decision can be made

about DES device usage based on their safety and efficacy in order to gain more acceptance in

the medical community.

CHAPTER 6

ENVIRONMENTAL CONSIDERATIONS

There are no environmental considerations that influence the adoption of the new device.

However, the devices are manufactured for single use only. After use, the catheter used is

Page 32 of 38

disposed of in accordance with hospital, administrative, or government policies. They should

never be re-sterilized (Medtronic IFU, 2010).

The stent is made to stay inside a patient for their lifetime unless removed due to infection. The

composition of stent-grafts includes the delivery system, graft material and graft attachment

system (Donghoon, 2010).

The stents are composed of Ntinol, a metal alloy of nickel and titanium and sewn to a fabric

graft (Medtronic IFU, 2010).  Nitinol is biocompatible, which gives it the quality of not

having toxic or harmful effects on biological systems (Ryhänen, 1999).  Therefore no special

requirements are needed for the stent disposal. Also, it is preferable to avoid reusing stents to

avoid serious consequences, such as internal infection.

REFERENCES

Ako J, Morino Y, Honda Y, et al. Late Incomplete Stent Apposition after Sirolimus-Eluting Stent

Implantation: a serial intravascular ultrasound analysis. J Am Cardiol. 2005;46:1002-1005.

Page 33 of 38

Becquemin JP, et al. A Randomized Controlled Trial of Endovascular Aneurysm Repair Versus

Open Surgery for abdominal aortic aneurysms in low-to moderate-risk patients. Journal of

Vascular Surgery. 2001;53:1167-73.

Blum U, Voshage G, Lammer J, et al. Endoluminal Stent-Grafts for Infrarenal Abdominal Aortic

Aneurysms. The New England Journal of Medicine.1997;336:13-20.

Bowen J, Hopkins R, He Y, Blackhouse G, Lazzam C, Tu J, Cohen E, Tarride J-E,

Goeree R. Systematic review and cost-effectiveness analysis of drug eluting stents

compared to bare metal stents for percutaneous coronary interventions in Ontario.

Interim Report for the Ontario Ministry of Health and Long-term Care. Hamilton, ON:

Program for Assessment of Technology in Health, McMaster University; 2005 Dec. pp.

170. Report No.: HTA002-0512. Contract No.: 06129. Sponsored by St. Joseph’s

Healthcare Hamilton

Brewster DC, Cronenwett JL, Hallett J.W, et al. Guidelines for the treatment of abdominal aortic

aneurysms: Report of a subcommittee of the Joint Council of the American Association for

Vascular Surgery and Society for Vascular Surgery. Journal of Vascular Surgery.

2003;37:1106-1117.

CDC (2011). Aortic Aneurysm Fact Sheet. Retrieved from

http://www.cdc.gov/dhdsp/data_statistics/fact_sheets/fs_aortic_aneurysm.htm

Chambers, D., Epstein, D., Walker, S., Fayter, D., Paton, F., Wright, K., . . . Woolacott, N.

(2009). Endovascular stents for abdominal aortic aneurysms: a systematic review and economic

model. [Meta-Analysis Review]. Health Technol Assess, 13(48), 1-189, 215-318, iii.

Chávarri, M. Is Systematic Use of Drug-Eluting Stents Justified? Arguments in Favor. Revista

Española de Cardiología (Rev Esp Cardiol). 2004;57(2):99-108.

Cohen D, Ryan J. Will drug-eluting stents bankrupt the healthcare system. Are Drug-Eluting

Stents Cost-Effective? It Depends on Whom You Ask. Circulation. 2006;114:1745-1754.

Page 34 of 38

Edelman E, Rogers C. Stent-Versus-Stent Equivalency Trials. Are Some Stents More Equal

Than Others? CIRCULATION - Journal of the American Heart Association. Circulation.

199;100:896-898.

Endovascular stent-grafts for the treatment of abdominal aortic aneurysms. National Institute for

Health and Clinical Excellence (NICE), 2009.

Filipovic M, Goldacre MJ & Gill L. Elective surgery for aortic abdominal aneurysm: comparison

of English outcomes with those elsewhere. Journal of Epidemiology and Community Health.

2006;61:226–231.

Greenhalgh R, et al. Endovascular Repair of Abdominal Aortic Aneurysm. The New England

journal of Medicine. 2008;358:494-501.

Groeneveld W. How Drug-Eluting Stents Illustrate Our Health System's Flawed Relationship

With Technology; Comment on “Use of Drug-Eluting Stents as a Function of Predicted Benefit”.

Journal of the American Medical Association Internal Medicine formerly Archives of Internal

Medicine. 2012;172(15):1152-1153

Hao, P. P., Chen, Y. G., Wang, X. L., & Zhang, Y. (2010). Efficacy and safety of drug-eluting

stents in patients with acute ST-segment-elevation myocardial infarction: a meta-analysis of

randomized controlled trials. [Meta-Analysis Research Support, Non-U.S. Gov't Review]. Tex

Heart Inst J, 37(5), 516-524

Jefferys, D. Adverse Incident Reporting for Medical Devices - A Comparison with

Pharmacovigilance. Drug information Journal. 2005;39:73-80.

Kaiser C, Rocca H, Buser P, et al. Incremental Cost-Effectiveness of Drug-Eluting Stents

compared with a Thrid-Generation Bare-Metal Stent in real-world Settings: randomized Basel

Stent Kosten Effectiveness Trial (BASKET). The Lancet. 2005;366(9489):921-929.

Page 35 of 38

Katzen B, et al. Endovascular Repair of Abdominal and Thoracic Aortic Aneurysms. Circulation.

2005;112:1663-1675.

Lagerqvist B, James S, Stenestrand U, et al. Long-Term Outcomes with Drug-Eluting Stents

versus Bare-Metal Stents in Sweden. The New England Journal Of Medicine.2007;356(10):

1009-10.

Lim, S. Y., Jeong, M. H., Hong, S. J., Lim do, S., Moon, J. Y., Hong, Y. J., . . . Kang, J. C.

(2008). Inflammation and delayed endothelization with overlapping drug-eluting stents in a

porcine model of in-stent restenosis. [Comparative Study Research Support, Non-U.S. Gov't].

Circ J, 72(3), 463-468

May, J., White, G. H., Yu, W., Ly, C. N., Waugh, R., Stephen, M. S., . . . Harris, J. P. (1998).

Concurrent comparison of endoluminal versus open repair in the treatment of abdominal aortic

aneurysms: analysis of 303 patients by life table method. [Comparative Study]. J Vasc Surg,

27(2), 213-220; discussion 220-211.

Matsumura J, Katzen B, Sullivan TM, et al. Predictors of Survival following open and

endovascular repair of Abdominal Aortic Aneurysms. Annals of Vascular Surgery.

2009;23(2):153-158.

Medtronic (2010). Endovascular Stent Grafts: A Treatment for Abdominal Aortic Aneurysms.

Retrieved from http://www.accessdata.fda.gov/cdrh_docs/pdf10/P100021c.pdf.

Moll, F. L., Powell, J. T., Fraedrich, G., Verzini, F., Haulon, S., Waltham, M., . . . Ricco, J. B.

(2011). Management of abdominal aortic aneurysms clinical practice guidelines of the European

society for vascular surgery. [Practice Guideline Research Support, Non-U.S. Gov't Review].

Eur J Vasc Endovasc Surg, 41 Suppl 1, S1-S58.

O’Gara PT. Aortic Aneurysm. American Heart Association. 2003;107:43(45).

Page 36 of 38

Perkins LEL, Sheehy AS, Coleman LA, et al. XIENCE V,TAXUS and ENDEAVOR Drug Eluting

Coronary Stent Systems: Comparison in the Rabbit Iliac Arterial Model. Am J Cardiol.

2008;102:166.

Pfisterer, M., Brunner-La Rocca, H. P., Buser, P. T., Rickenbacher, P., Hunziker, P., Mueller, C.,

. . . Kaiser, C. (2006). Late clinical events after clopidogrel discontinuation may limit the benefit

of drug-eluting stents: an observational study of drug-eluting versus bare-metal stents.

[Randomized Controlled Trial

Research Support, Non-U.S. Gov't]. J Am Coll Cardiol, 48(12), 2584-2591

Preparation of an Application for Investigational Testing - Medical Devices and Preparation of a

Premarket Review. Document for Class III and Class IV Device License Applications, www.hs-

sc.gc.ca.

Prinssen M, Verhoeven E, Buth J, et al. A Randomized Trial Comparing Conventional an

Endovascular Repair of Abdominal Aortic Aneurysms. The New England Journal of Medicine.

2004;351:1607-1618.

Schwartz RS, Topol EJ, Serruys PW, et al. Artery Size, Neointima, and remodeling: Tim for

some standards. J Am Cardiol. 1998;32:2087-2094.

Spears K. Personal communication with Bowen J. Average selling price of

TAXUS® and bare metal stents over the past year. 4 Jul 2005

Stone GW, Ellis SG, Cox DA, Hermiller J, O'Shaughnessy C, Mann JT et al. One-year clinical

results with the slow-release, polymer-based, paclitaxel-eluting TAXUS stent: the TAXUS-IV

trial. Circulation 2004;109(16):1942-1947

Svensjö, S., et al. Low prevalence of abdominal aortic aneurysm among 65-year-old Swedish

men indicates a change in the epidemiology of the disease. Circulation. 2011;124(10):1118-123.

Page 37 of 38

Vascular Disease Foundation (2012). Abdominal Aortic Aneurysm. Retrieved from

http://vasculardisease.org/flyers/abdominal-aortic-aneurysm-flyer.pdf.

Viminitz M. Personal communication with Bowen J. Average selling price

of Cypher™ stents in Canada over past year. 24 Jun 2005

Ventola CL. Challenges in Evaluating and Standardizing Medical Devices in Health Care

Facilities. P & T Journal [Pharmacy and Therapeutics Community]. 2008;33(6):348–359.

Walker, T. G., Kalva, S. P., Yeddula, K., Wicky, S., Kundu, S., Drescher, P., . . . Cardella, J. F.

(2010). Clinical practice guidelines for endovascular abdominal aortic aneurysm repair: written

by the Standards of Practice Committee for the Society of Interventional Radiology and

endorsed by the Cardiovascular and Interventional Radiological Society of Europe and the

Canadian Interventional Radiology Association. [Practice Guideline Review]. J Vasc Interv

Radiol, 21(11), 1632-1655

Zeller JL, Burke AE, & Glass RM. Aortic Aneurysms. Journal of the American Medical

Association. 2009;302(8):2050.

Page 38 of 38