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, 2013

WORD COUNT: 6,578
i

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.

CONTENTS

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 bodys 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

Atherosclerosis
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High blood pressure

High cholesterol level

Inherited conditions such as Marfans 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 (OGara, 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 patients AAA, there are two available primary
treatment options: open surgery or stent grafting (OGara, 2003).

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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.

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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

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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-convertingenzyme 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
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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 restenosisa 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

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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
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/DESCRIPTION
DES 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 reopening 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

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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 anticlotting 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)

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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.

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.

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CHAPTER 3
RESEARCH EVIDENCE REQUIREMENTS
3.1: STRUCTURE OF THE PRE-CLINICALTRIALS

STUDY DESIGN
Primary purpose: To establish the safety of the AYASSE Drug Eluting Stent
Interventional model: Multi group dose ranging studies
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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

Endothelialization and granulation tissue formation

Smooth muscle cells and matrix formation

Neo-intimal response over time

Death

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ANIMALS USED IN THE STUDY

For 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.
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.

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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 STUDY

Title: 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:

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

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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:

Abdominal aneurysm above or equal to 4.5 cm in diameter

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

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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

PHASE II CLINICAL STUDY

Title: 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
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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.
Study Duration: 24 months

Start Date: September 2013

End Date: September 2015

ELIGIBILITY
Inclusion

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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)

Safety & Effectiveness Endpoints

Proportion of subjects who experience a serious adverse event

Proportion of subjects that achieve treatment success

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PHASE III CLINICAL STUDY

Title: 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 Cte-Sainte-Catherine Road, Montral, 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

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:

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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)

Exclusion

Pregnant or lactating women

Ruptured or leaking abdominal aortic aneurysm

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

CHAPTER 4
REGULATORY CONSIDERATIONS
4.1: MEDICAL DEVICE CLASSIFICATION
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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

Precautions
Institutional Information

Names of Investigators

Names of Institutions

Research Ethics Board Approval

Protocol
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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

Bibliography
Labeling Material
Quality System Requirements
Risk Assessment
Quality Plan
Device specific detailed information, which includes:

Material specifications

Manufacturing process specifications

List of standards

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4.2: POSTMARKET SURVEILLANCE INFORMATION

The postmarket surveillance information that Health Canada might require would be the longterm 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
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

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Exclusion Criteria:

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

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

Lactating women

CHAPTER 5
THE VALUE ARGUMENT (HEALTH TECHNOLOGY ASSESSMENT)
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

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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
Canadas 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).

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).
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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).

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

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(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
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).

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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
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).

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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.
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
Page 33 of 38

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
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.
Page 34 of 38

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
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
Page 35 of 38

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
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 (Ryhnen, 1999). Therefore no special

Page 36 of 38

requirements are needed for the stent disposal. Also, it is preferable to avoid reusing stents to
avoid serious consequences, such as internal infection.

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