# Presentation: 498307

## Circulatory System Devices Advisory Panel

- LACI Review
- Introductions
- Outline of presentations
- Presentations

- Introductions & History

**Notes:**
CR assumes that he will be granted permission to speak at some point in the agenda.  This slide presentation is intended to introduce the people sitting at the sponsor’s table, to tell the panel what we would like to present, and to give some historical background to the main feature, the LACI results.

## Introductions

- Chris Reiser PhD
- VP Technology & Clinical Research, Spectranetics
- John Laird MD, Washington Hospital Center
- LACI Principal Investigator
- Bruce Gray DO, Greenville Memorial Hosp, SC
- LACI Steering Committee, Investigator
- Venkatesh Ramaiah MD FACS, Arizona Heart
- staff surgeon and LACI PI

- Introductions & History

**Notes:**
This slide speaks for itself.

## Outline of Presentations

- Background and history
- LACI Phase 2 results
- Benefits of LACI
- Why limb salvage is better than limb loss
- Alternative treatment strategies
- 	1 : medication		2 : primary amputation
- 	3 : PTA			4 : bypass surgery
- Summary of alternatives

- Introductions & History

**Notes:**
We have prepared several presentations based on our guesses of what the Panel would like to discuss.  The top three slide sets, highlighted in yellow, are the ones we would propose to give now.  I have about 10 slides on background and history, and then Dr. Laird will walk us through the LACI Phase 2 results.  In our computer are several other presentations on topics that may  be of interest to the Panel, but which we had intended to show only if requested by the Chairman.  The contents of these optional presentations are contained in the your panel packs in a more verbose format.

## Basic Technology

- Excimer laser atherectomy (ELA):
- XeCl excimer laser, 308 nm, pulsed at 40 pulses/second maximum
- Delivered via a fiberoptic catheter
- First approved by FDA in 1993 for use in coronary arteries
- Similar but slightly different than LASIK

- Introductions & History

**Notes:**
Without further ado...
Excimer laser atherectomy is an intravascular interventional treatment.  It uses a xenon chloride excimer laser to create pulses of ultraviolet light with a wavelength of 308 nanometers.  The laser pulses are launched into a bundle of optical fibers contained in a catheter specifically designed for this use.  The ultraviolet light emerges from the distal end of the catheter, where the light enters the blockage to be removed.  FDA granted our first PMA in early 1993, for indications in the coronary arteries.  LACI represents a new indication for a previously approved technology.
Most people in American have heard of LASIK and millions have improved eyesight from a LASIK procedure.  There are strong similarities between LASIK and atherectomy because they both rely on ultraviolet ablation of tissue to achieve clinically useful results.

## Quick Comparison

- _ELA_
- 308 nm
- fiber delivery
- catheters
- arteries & veins
- “cool” UV ablation

- _LASIK_
- 193 nm
- free-air propagation
- work station
- corneas
- “cool” UV ablation

- Introductions & History

**Notes:**
LASIK uses a slightly more ultraviolet wavelength than ELA.  The 193 nanometer wavelength can’t travel through fibers, but 308 nanometer UV light can.  Consequently our wavelength can be delivered by catheters wherease LASIK beams must travel through the air, essentially, inside a rather sizable workstation.  ELA is used in arteries and veins, does not work well with corneas.  LASIK lasers do work well with corneas but can’t be applied intravascularly.  Both use pulsed ultraviolet laser to achieve precise UV ablation without thermal side-effects.

## CVX-300 Laser System

- Gen 4 approved 1994?
- Same system used for all our applications:
- coronary atherectomy
- pacing lead removal
- peripheral atherectomy (EU only)
- A few facts...

- Introductions & History

**Notes:**
The laser system shown here has been in production since 1994?  This system has FDA approval for coronary atherectomy, for use with special catheters used in pacing lead removal, and in Europe for peripheral atherectomy.  The samesystem, without modification, was used in LACI.  For practical purposes, the system is merely a power supply for the catheters.
A few facts about the CVX-300:  it’s about as big as a console television set, weights 650 pounds, and has 4 wheels so it can be moved between labs.

## Excimer Laser Catheters

- 4th generation since first FDA approval
- Latest models are “legs-only” devices
- All have same basic features and work the same way

- Introductions & History

**Notes:**
The catheters that plug into the CVX-300 are what interest us today.  All our catheters have a coupler at the proximal end where the light enters the fiberoptic cable.  The whole catheter is about 3 meters long, with the distal 135 cm being the patient contact part.  As many as 250 individual fibers are used in each catheter; the proximal bundle shown at the lower left is rectangular because the beam from the laser is rectangular.  At the distal end, where the catheter tip contacts the vascular lesion, the fibers are arranged around the guidewire lumen.
Since the initial FDA approval, we have produced about 3 new generations of improved catheter designs.  The smaller catheters used in the LACI study were actually coronary catheter models, sized between .9 and 2.0 millimeters in diameter.  These catheters match the artery size below the knee rather well.  Also used in LACI were larger catheter models, designed specifically for use in the legs. These have sizes between 2.0 and 2.5 millimeters in diameter, and are used primarily in the superficial femoral and popliteal arteries.
Regardless of the catheter size, all our laser catheters share the same basic features and use excimer laser ablation to provide therapy.

## How ELA Works...

- Introductions & History

**Notes:**
Forgive me while I digress a moment into the nature of excimer laser ablation.  When the catheter contacts the tissue of the lesion, and the laser is fired, UV light exits from each fiber and penetrates a microscopic distance into the tissue.  Some of the photons break molecular bonds of the tissue, which weakens cellular structures.  This is a unique feature of ultraviolet ablation - smaller photons can’t break molecular bonds directly.  In less than a microsecond, the remaining photons are converted to heat.

## How ELA Works...

- Introductions & History

**Notes:**
When the heat is shared with intracellular water, the water vaporizes, or essentially explodes the weakened cells from the inside.  The tissue is reduced to subcellular debris.  In LASIK, the debris plume is sucked away by a gentle vacuum hose, but occasionally a LASIK patient will remark that he can smell smoke.  That’s the debris from his own cornea.  In ELA, the plume is carried away by the bloodstream.

## How ELA Works...

- Introductions & History

**Notes:**
About 200 microseconds after the laser pulse arrives, the event is completely over.  The ablated tissue vacates a shallow crater or void, a few microns deep, into which the catheter advances.  The next laser pulse arrives after a short wait of about 25 milliseconds, and the process repeats.  Essentially, the catheter nibbles or shaves its way through the tissue.
For LASIK, the property of precise sculpting by shaving thin layers of tissue is very important for achieving a precise optical shape in the cornea.  In ELA, we use the same property to controlably remove atheroma and thrombus.  The light does not travel to the side, or deeply ahead of the catheter, but affects only the tissue in contact with the tip.  In this way, there is no burning or charring, which would be very deleterious for LASIK or ELA.

## Coronary Indications

- Long, diffuse lesions
- Total occlusions crossable with a wire
- Moderately calcified lesions
- Ostial lesions
- Balloon angioplasty failures
- Vein grafts
- In-stent restenosis prior to brachytherapy

- Introductions & History

**Notes:**
Why did we get interested in treating peripheral vascular disease?  We have seven cornary indications, shown on this slide.  As we will see in the LACI study data, the first three indications, highlighted in yellow, are good descriptors of disease patterns expected in CLI patients.  We reasoned that if our technology were well matched to these patterns of disease in the coronaries, they would be well matched to the same patterns elsewhere.

## ELA Experience in the Legs

- Initial IDE work in the USA - early ‘90s
- Commercial experience in EU since ‘95?
- Anecdotal single-site experiences
- LACI Phase 1
- LACI Phase 2

- Introductions & History

**Notes:**
In the first part of the 1990’s we investigated ELA in the legs at several sites in the USA.  This study was not done according to modern standards, with prospectively designated endpoints harmonized with the current medical consensus documents.  We showed this data to FDA, and they advised us to do a pivotal study.  LACI phase 2 was designed to be that study.  Since we did not include our early data in our PMA submission, we won’t discuss that old data here.  Our favorable experience in Europe, including single-site experiences around the world, gave us further confidence that the LACI study would be successful.
This leads us the the LACI Phase 2 results, which Dr Laird is prepared to show us.

## Laser Angioplasty for Critical Limb Ischemia

- _L_aser _A_ngioplasty for _C_ritical Limb _I_schemia

***Results of the LACI Phase 2 Registry***

- LACI 2 Results

**Notes:**
We move into the results of the LACI Phase 2 study.

## Study Design

**Prospective, multi-center study**
**Patients with CLI**
- Rutherford Category 4-6
- poor surgical candidates
**Treatment:  ELA of SFA, popliteal and/or infrapopliteal arteries, with adjunctive PTA and optional stenting**
**Primary Efficacy Endpoint:  limb salvage at 6 mo.**
** **freedom from amputation at or above the ankle
**Primary Safety Endpoint:  death at 6 mo.**

- LACI 2 Results

**Notes:**
LACI was a prospective IDE study of patients with critical limb ischemia, that is Rutherford category 4, 5 or 6, who were poor surgical candidates.  The investigational treatment consisted of excimer laser atherectomy followed by balloon angioplasty and optional stenting.  Treatment was delivered from the SFA down to the ankle, with the objective of establishing straight-line blood flow to the foot.  The primary efficacy endpoint was limb salvage at 6 months, defined as freedome from amputation above the ankle.  The primary safety endpoint was death; the secondary safety endpoint was incidence of total SAEs.

## Study Design

**Included catheters:**
** ****2.2 - 2.5mm Spectranetics peripheral laser catheters **
** ****any Spectranetics coronary laser catheter**
**Poor surgical candidates because:**
**poor or absent vessel for outflow anastamosis, or**
**absence of venous conduit, or**
**significant co-morbidity**
**Enrollment period:   April ‘01 -  April ’02**
**Enrollment:  145 patients, 155 limbs**

- LACI 2 Results

**Notes:**
Investigational treatment was delivered with a variety of excimer laser catheters ranging in size from point 9 millimeters to 2.5 millimeters diameter.  The smaller sized catheters are actually approved coronary devices.  Patients in this study had to qualify as poor surgical candidates by meeting at least one of three criteria:
poor choices for distal anastomosis, that is, no artery, or diffusely diseased artery, or an artery less than 1 mm diameter
absences of a venous autologous conduit
American society of anethesiologists class 4 or higher, meaning signficant comorbidity with increased risk for surgical mortality
Enrolment of 145 patients with critically ischemic 155 limbs required a year.

## Historical Control Group

- Italian multicenter randomized study of Prostaglandin E1 in CLI patients
- 771 in alprostadil group
- 789 in control group
- Control group received variety of therapies (bypass, endarterectomy, medication, and a few PTAs)
- “the best you can do” for these patients
- Ann Intern Med 1999; 130:412-421
- Conforms to TASC definitions and GCP

**Notes:**
The control group for this study was the control group of a randomized trial published in 1999.  The control group of study of alprostadil in CLI patients contained 789 patients treated with a variety of therapies, including bypass, endarterectomy, mostly medication, and a few angioplasties.  Treatment was selected in each case according to the patient’s needs.  This study, done in Italy, conformed to the scientific principles of the trans-atlantic inter-society consensus, or TASC document, and good clinical practices.
Might mention a few words about TASC here.

## Enrollment by Site

**Enrollment by Site**

**Arizona Heart****	****	****23**
**Hertzentrum Leipzig****	****24**
**Hertzentrum Bad Kroz.****	****22**
**Greenville Memorial****	****19**
**Manatee Hospital****	****	****10**
**Lankanau Memorial****	****  8**
**Riverside Methodist****	****  7**

**Glendale Memorial****	****	****  7**
**St. Joseph’s Paterson****	****  7**
**Univ. Frankfurt****	****	****  6**
**Springhill Memorial****	****  5**
**Washington HC****	****	****  5**
**Ochsner Clinic****	****	****  1**
**St. Luke’s Milwaukee****	**_**  1**_
**total patients****	****	****145**
**total legs****	****	****	****155**

-  36% of sites enrolled 68% of patients

** ****145 patients at 14 sites**

- LACI 2 Results

**Notes:**
145 patients were enrolled at these 14 sites in the US and Germany.  Five sites contributed two-thirds of the patients.  About one-third of the patients were German.

## Patient  Descriptors

**	****	****	****	**** **_**LACI**_**	****	**_**Control**_**  ****	**** **_**p**_
**Mean age, years****	****	****72 ****±**** 10****	**** 72 ****±**** 10****	****ns**
**Men****	****	****	****	****    53%****	**** ****72%****	****	**** ***
**Risk factors**
**	****Smoking current****	****    14%****	**** ****25%****	****	**** ***
**	****Prior MI****	****	****    ****23%****	**** 15%****	****	**** ***
**	****Prior stroke****	****	****    ****21%****	**** 12%****	****	**** ***
**	****Diabetes mellitus****	****    ****66%****	**** 39%****	****	**** ***
**	****Hypertension****	****    ****83%****	**** 49%****	****	**** ***
**	****Dyslipidemia****	****    ****56%****	**** 16%****	****	**** ***
**	****Obesity****	****	****    ****35%****	****   7%****	****	**** ***
**	****	****	****	****	****	****	****     *****significant**

- LACI 2 Results

**Notes:**
When we designed the study, we expected that the LACI group would have more comorbidity than the control, since LACI enrolled only poor surgical candidates.  This slide shows that the control group had more men than LACI, and more current smokers, but LACI had higher statistics in all other categories of potential medical risk factors.  Notably, LACI had more patients with previous vascular events and diabetes.

## Leg Descriptors

**	****	****	****	****	**_**LACI**_**	****   **_**Control**_**	**_**p**_
**Rutherford Category**
**	****4****	****	****	****	****27%****	****      30%****	****ns**
**	****5 or 6****	****	****	****	****72%****	****      70%****	****ns**
**Reasons for poor surgical candidacy**
**     ****Absence of venous graft****	****32%**
**     ****Poor/no distal vessel****	****	****68%**
**     ****High surgical risk****	****	****46%****	****      11%****	*******
**     **
**     ****Only one reason****	****	****61%**
**     ****Any two reasons****	****	****33%**
**     ****All three reasons****	****	****  6%**

- LACI 2 Results

**Notes:**
Importantly, the comparison of peripheral clinical condition was very similar between the two groups.  There were a few patients in the control group who were had high surgical risk, but the percentage of high-risk patients was much higher in LACI.  This statistic, combined with the medical risk factors on the previous slide, vindicates our original assumption that LACI patients as a group would present with greater comorbidity.

## Case Profile

**61 year old Hispanic woman**
**Diabetic for > 20 years**
**ESRD; hemodialysis for 1 year**
**Non-smoker**
**Multiple ischemic ulcers on both feet**
**Bilateral ELA on 14 Aug 01**
**Skin grafts during follow-up period**
**Investigator:  Dr. Mitar Vranic at Arizona Heart**

- LACI 2 Results

**Notes:**
I would like to show you two case profiles.  This is the first.  It’s rather graphic.

## Case Profile : Right Foot  	1/4

**Prior to treatment**

- LACI 2 Results

**Notes:**
The patient’s right foot had a long history of infection.  Amputation might have been the only alternative.

## Case Profile : Right Foot  	2/4

**2.2 mm laser**
**3.0 mm balloon**
**no stent**
**popliteal also treated**

- LACI 2 Results

**Notes:**
A good result was obtained with laser, balloon, and no stent on the right side.

NOTE:  These graphics were not included in any filing.
?

## Case Profile : Right Foot  	3/4

**3 months post treatment**

- LACI 2 Results

**Notes:**
At three months, some healing is clearly evident.

## Case Profile : Right Foot  	4/4

**6 months post treatment**

- LACI 2 Results

**Notes:**
At six month, post skin grafting, the foot is in very good shape.

## Case Profile : Left Foot 

**baseline**

**3 months**

**6 months**

**laser**
**balloon**
**no stent**

- LACI 2 Results

**Notes:**
This patient was also treated on the left side.  A similar, rather startling recovery was observed at 6 months.

## LACI 2 Results

**Notes:**
Dr Laird wanted to make a point about recanalization of a long total occlusion in this example.

NOTE:  These graphics were not included in any filing.

- LACI 2 Results

**Notes:**
Another example of popliteal recanalization.

NOTE:  These graphics were not included in any filing.

## Case Profile

**Case Profile**

- 45 year old female
- Diabetes mellitus, morbid obesity
- Distal popliteal occlusion, tibial disease
- Painful, ischemic 2nd toe

- LACI 2 Results

**Notes:**
The second case profile shows a wildly obese woman with a second toe in bad shape.  There is no evidence of a toenail; the first and second joints are necrotic.

## LACI 2 Results

- SITE 009-WHC
- PAT 005
- 6 MOS

**Notes:**
By six months, enough healing had occurred to warrant nail polish on the second toe.

## Vascular Lesion Locations

- 0%

- 5%

- 10%

- 15%

- 20%

- 25%

- 30%

- 35%

- 40%

- 45%

- SFA

- popliteal

- infrapopliteal

- other

- % of Identified Lesions

- LACI 2 Results

**Notes:**
Getting back to LACI statistics, about half of the treated lesions were in the SFA.  A bit more than half were at or below the knee.

## Lesion Types

- Mean # of treated lesions/pt:  2.7  1.4 (1-7)

- 0%

- 10%

- 20%

- 30%

- 40%

- 50%

- 60%

- 70%

- 80%

- stenoses

- occlusions

- stenoses and

- occlusions

**% of Limbs**

- LACI 2 Results

**Notes:**
The mix of stenoses and occlusions tells us that these patients had very diffuse disease throughout the leg.  In fact, the average number of lesions treated per patient -- 2.7, ranging up to 7 in on patient -- says that the disease was quite advanced in this patient group.  This is not simple disease, something that can be treated once with a simple balloon inflation, and then expected to remain patent for months.  This is complex, diffuse, extensive disease accumulation, with an average lesion length of 61 millimeters, or about 16 cm of target lesion per patient.  It was our hope that a technology that ablates or removes a critical portion of the plaque would make a clinically significant impact on these patients. 

## TASC Types

- LACI 2 Results

## LACI Procedure Results 

**Guidewire crossing success****	****	****	****92%**
**Laser treatment delivered****	****	****	****99%**
**Adjunctive balloon****	****	****	****	****96%**
**Stent Placement****	****	****	****	****	****45%**
**Procedure Success****	****	****	****	****85%**
**	****<50% residual stenosis at final**
**Straight line flow to foot established ****	****89%**
**Hospital stay (days):****	****	****mean****	****	****3.0**
**	****	****	****	****	****	****median****	****1.0**

- LACI 2 Results

**Notes:**
Guidewire crossing success was above 90%, and in some cases the laser assisted guidewire crossing with a step-by-step technique.  Laser treatement was delivered in all but 2 cases, and baloons were used virtually all the time.  A bit less than half of patients received at least one stent.
We defined procedure success as less than 50% residual stenosis at the end of all treatments, over the entire length of treated arteries.  This was achieved in 85% of legs.  Straight-line flow was established in 89% of legs.  Hospital stay was generally 1 day, but a few patients had long stays, and this skews the mean hospital stay up to 3 days.

## Angiographic ResultsVisual assessment 

**	****	****	****	**_**                    **__**%DS               **__**	**_
_**Location**_**	****	**_**Baseline**_**  **_**Post-laser**_**	**_**Final**__**	**_
**SFA****	****	****	****   91%****	****          56%****	**** 16%****	****   **
**Popliteal****	****  ****	****   94%****	****          53%****	**** 14%****	****    **
**Infrapopliteal****	****  ****	****   92%****	****          53%****	**** 24%****	****    **
-  Laser provided about half of the net luminal gain
-  Stenting was performed preferentially in larger    	vessels
-  Below the knee, final %DS was slightly higher

- LACI 2 Results

**Notes:**
On visual assessment, the treated arteries typically showed tight stenoses or occlusions.  The laser opened the arteries to about 50% residual stenosis, which was further reduced by balloon.  Below the knee, where the arteries are smaller, the final residual stenosis tended to be a bit higher.

## Control Treatments

- Bypass or endarterectomy	35%
- Angioplasty				  5%
- Thrombectomy				  3%
- Conservative therapies		 57%
- analgesics, vasoactive, antithrombotic, oxygen therapy, etc.

- LACI 2 Results

**Notes:**
By comparison, the treatments received by the control group were varied.  Most received a variety of conservative therapies, but 355 received a surgical intervention as their primary treatment.  This was not possible for LACI patients.  Angioplasty and thrombectomy were also delivered to a few percents of the control group population.

## Adjudicated SAEs

**	****	****	****	****  **_**LACI**__**	**_**	**_**Control**__**	**__**p**_
**Death****	****	****	****	****   10%****	****	****   14%****	****	****ns****	****   **
**Major amputation****	****	****     6%****	****	****   10%****	****	****ns**
**Nonfatal MI or Stroke****	****       .7%****	****     1.1%****	****ns**
**Reintervention****	****	****    ****17%****	****     4%****	****	**** ***
**Hematoma w/ surgery****	****       .7%****	****       .8%****	****ns**
**Acute limb ischemia****	****       .7%****	****   n/a**
**Perforation w/ surgery****	****      0****	****	****   n/a**
**Bypass****	****	****	****      2.1%****	****   n/a**
**Endarterectomy****	****	****       .7%****	****   n/a**
**Total SAEs****	****	****	****    38%****	****   30%****	****	****ns**

- LACI 2 Results

**Notes:**
On a per-patient basis, this slide shows rates of adjudicated serious adverse events.   Death and major amputation were similar between groups.  Bypass and endarterectomy were not considered adverse events in the control group, as these were primary therapies for some control group patients.  Reintervention was higher in LACI; this is the only category with a higher incidence in LACI.  Interestingly, reintervention was 11% in the control group among those patients who received an initial intervention.  Overall the total rate of SAEs was similar between groups.
We note that, according to both the LACI protocol and the Control publication, reintervention was not originally considered a serious adverse event.  Our Data Safety Monitoring Committee asked us to report reinterventions as SAEs after the study had been completed.  If we had classified reinterventions according to the protocol, the LACI SAE rate would be 21%, which would be nonsignificantly lower than the control group by about 5%.
A couple notes:  there was one in-hospital major amputation.  This patient had an unsuccessful procedure and an uncontrolable infection forced an amputation a week later.  Also, there were 3 bypasses; 2 of there were to new distal anastomosis sites made available by the LACI procedure.
One more thing.  All SAEs, even the few that were secondary to re-intervention, are included in this table.  Therefore this table represents the total risk to the patient population, and it’s not significantly different from the control.

## 6-Month Results: Patients

**Total enrollment****	****	****         145 patients**
**     ****death****	****	****	****	****	****  15**
**     ****lost to follow-up****	****	****	**_**  11**_
**Reached 6-month follow-up****	****119**
**Major amputation in survivors****	****    **_**9**_
**Patients with limb salvage****	****	****110**
**	****Intent-to-treat analysis****	****110/145 = 76%**
**	****Survival analysis****	****	****110/119 = 92%**

- LACI 2 Results

**Notes:**
Just to make things perfectly clear, this slide shows how the primary results are calculated on a per-patient basis.  OF 145 patients, 15 died and 11 were lost before6-month follow-up was completed.  Of the 199 with 6-month data, 9 had major amputation.  By intent-to-treat analysis, 76% had limb salvage; this is the statistic used in comparisons with the control group.  In a survival analysis, limb salvage was observed in 92% of patients for whom 6-month outcomes were known.

## 6-Month Results: Limbs

**Total enrollment****	****	****         155 limbs**
**     ****death****	****	****	****	****	****  17**
**     ****lost to follow-up****	****	****	**_**  11**_
**Reached 6-month follow-up****	****127**
**Major amputation in survivors****	****    **_**9**_
**Limbs salvaged****	****	****	****	****118**
**	****Intent-to-treat analysis****	****118/155 = 76%**
**	****Survival analysis****	****	****118/118 = 93%**

- LACI 2 Results

**Notes:**
Here is a similar analysis on a per-limb basis.  Of 155 limbs, 17 were attached to patients who died and 11 were lost to follow-up.  Nine were amputated on surviving patients.  Intent-to-treat and survival percentages are very close to the per-patient percentages.

## Main Endpoints at 6 Months

**	****	****	****	****	****  **_**LACI**_**	**_**Control**_**	****  **_**p**_
**n****	****	****	****	****	****  145****	****	****   673**
**  ****Died****	****	****	****	****  10%****	****	****   14%****	****ns**
**  ****Survived with:**
**	****   ****Limb salvage****	****	****  76%****	****	****   73%****	****ns**
**	****   ****Persistent CLI****	****  30%****	****	****   31%****	****ns**
**  ****Any SAE*****	****          ****	****  38%****	****	****   30%****	****ns**
*** Including reinterventions not originally termed SAE’s under protocol****	****  **

- LACI 2 Results

**Notes:**
Here are the main outcomes.  The protocol hypothesized that LACI would show results equal to or better than the benchmarks established by the control publication.  That condition was met for all outcomes shown in this table.  We suggest that this implies that, if the control benchmarks define the statistical level of safety and effectiveness, then LACI is similarly safe and effective.  

.

## Ulcer Healing	

**	****	****	****	****	****	****     ****Area (Range)       % Healing**
**Mean area at baseline, cm****2****	****7 ******** 21 (0 to 263)        0%**
**Mean area at 3 months, cm****2****	****4 ********   8 (0  to 40 )      44%**
**Mean area at 6 months, cm****2****	****3 ********   9 (0  to  51)      50%**
**Wound Area data available **
**	****for 56/109 Ulcerated Limbs:****	****	****Improved ****	****23 **
**	****	****	****	****	****	****	****Healed****	****18**
**	****	****	****	****	****	****	****Worse****	****  7**
**	****	****	****	****	****	****	****Amputated     8**

- LACI 2 Results

**Notes:**
Ulcer healing was a secondary endpoint in LACI and was not an endpoint in the control publication.  On the average, ulcers reduced in size during the follow-up period.  
Can we get rid of this slide?  It really doesn’t give the data you want to see, which would be wound area reduction.  And, follow-up was rather low for this endpoint.  Perhaps we can get along merely with the next slide.

Refer in particular to Table 5, p18 of SSED, since this table did not appear in the Clinical Summary.  Data was not available at the original time of filing.

This table was changed to reflect what is no included in the SSED.

Note:  The labels on the data file spreadsheets for this data say 109 ulcers.  However, the improved/healed/worse/amputated data must be for ulcerated limbs.  The SSED did NOT clarify this point.

## Ulcer Sizes  	per-ulcer basis

**Most healing occurred in the first 3 months**

- LACI 2 Results

**Notes:**
Ulcer sizes were measured photographically at baseline, 3 months and 6 months.  This cumulative frequency plot shows that most healing occurred by the 3-month time point, although some large ulcers remained large throughout the study.

## Functional Outcomes

**Of surviving legs:**
**    ****69% Improved**
**    ****27% Stable**
**      ****4% Declined****  **

- LACI 2 Results

**Notes:**
Here we see clinical category outcomes plotted versus category at baseline.  Each row from front to back represents all patients in one particular Rutherford category at baseline.  Most of the category 4 patients were in a lower category at 6 months - they didn’t have CLI.  More than half of the category 5 patients healed by 6 months, as did a large fraction of the category 6 patients.  All the columns in green represent patients who improved; yellow signifies patients who exited the study at the same category they entered, and red means a category decline.  96% of patients for whom we know the 6-month category improved or remained stable.

## Predictors of Events

**   **_**Major Amputation**_**	****	****    ****	****	**_**p**_
**       ****Category 6****	****	****	****  ****	****	****.03**
**       ****Previous minor amputation****	****   ****	****.05**
**   **_**Death**_
**       ****Age****	****	****	****	****   ****	****	****.03**
** ****by Cox proportional hazards modeling**

- LACI 2 Results

**Notes:**
Statisticians at the Duke Clinical Research Institute ran a Cox proportional hazards model to find predictors of death and amputation.  Only age survived as a predictor of death, and only Category 6 at baseline was a predictor of major amputation.

## Stenting

**	****	****          ****Stented     Not Stented**
**	****	****	****   **_**n=70**_**	****  **_**n=85**__**	**_**         **_**p**_
**Procedure Success    93%****	****   79%****	****        .01**
**Straight-line flow****	****     96%****	****   84%****	****        .02**
**Limb Salvage****	****      83%****	****   71%****	****        .09**
**	****	****	****	****	****p-values by Fisher’s Exact**

* **Stents improved acute results*
* **Stents did not significantly affect limb salvage*
* **Sample size is small (low statistical power)*

- LACI 2 Results

**Notes:**
We looked at the effect of stenting in a subanalysis.  Stenting improved acute results, but only trended toward better 6-month outcomes.  Stented legs had the same rate of reintervention as nonstented legs.  

## LACI Phase 2 Summary

**Treatment of complex disease – multiple stenoses and occlusions**
**High risk patient population – poor candidates for surgical revascularization**
**High procedural success with few in-hospital SAE’s and short hospital stay**
**Excellent limb salvage rate despite this high-risk patient cohort**

- LACI 2 Results

**Notes:**
The text on this slide speaks for itself.

## LACI Phase 2 Summary

**Outcomes met all hypotheses in the protocol**
**Statistics meet the benchmarks of safety and effectiveness**

- LACI 2 Results

**Notes:**
From a regulatory perspective, we note that LACI met all the hypotheses set forth in the protocol.  The statistics we have just reviewed show that LACI meets the benchmarks for safety and effectiveness as set by the control publication.

## Clinical Benefit of LACI

- The LACI treatment strategy salvaged limbs...
- Efficacy endpoint equaled “the best” benchmarks in the literature
- ...without affecting patient’s chances of survival...
- Safety endpoint equaled “the best”
-  ...or significantly increasing patients’ risk of serious adverse events.

- Benefits

**Notes:**
In some pivotal trials, the added benefit of the investigational treatment is demonstrated by some success criterion, and the reduction of risk is shown by decreasing the incidence of complications or side-effects.  In LACI, the efficacy endpoint -- limb salvage -- is actually the inverse of the endpoint you would naturally choose as the one associated with risk -- major amputation.  In a sense, the benefit to CLI patients is the lack of amputation.  LACI achieved a high limb salvage success rate, as high as the best standards we could identify.  This success was attained without affecting the patients’ survivability and without significantly increasing the rate of serious adverse events, compared to the benchmark.
In short, the LACI data showed exactly what the protocol intended.  Limb salvage was achieved at a rate at least as high as the standard, without increasing risk to the patients, and with virtually no surgery.  If the benchmarks were chosen as representative of safe and effective therapy, then LACI must be just as safe and effective.

## Clinical Benefit of LACI

- LACI is an intravascular intervention
- avoids perioperative risks of surgery
- shortens initial hospital stay
- does not jeopardize future surgical options and may create new surgical options
- LACI Phase 2 results were achieved with virtually no surgery

- Benefits

**Notes:**
Perhaps this is obvious, but LACI is just not surgery.  If we use bypass surgery as the gold standard for treatment of CLI, we can expect a 1-4% perioperative mortality, some respiratory complications, and the occasional infection during a hospital stay of at least a week.  By contrast, LACI showed no in-hospital deaths, and a hospital stay of 3 days.  Further, delivering intravascular therapy does not preclude a bypass at some later date.  In fact, the LACI procedure may open arteries below the knee and provide a distal anastomosis site that was previously not available.  For some patients, the ones who were poor surgical candidates because they lacked a distal anastomosis site, LACI may create new options.

Having said that, we hasten to point out that patients did so well in LACI that surgery was virtually never used.  The data show that gold-standard limb-salvage results were achieved in LACI virtually without surgery.  

## Clinical Benefit of LACI

- The LACI strategy is applicable to a wide range of vascular disease states
- not limited to lesions amenable to PTA
- LACI Phase 2 enrolled essentially “all comers”
- useful in patients with no other options for limb salvage
- LACI results are predictable
- high rate of procedure success

- Benefits

**Notes:**
If you review the literature, you can find several reports on the use of PTA in CLI patients.  The results have been highly variable.  Those authors reporting high success rates with PTA picked their patients very carefully, typically those with short stenoses or single, short occluded segments.  They didn’t treat all comers, and a large proportion of their patients went to surgery or went home with medication.
The big benefit of LACI is that it provides a treatment strategy that can be applied to the vast majority of patients who don’t have a surgical option.  We didn’t “cherry pick” the patients enrolled in LACI; we enrolled patients with extensive, severe vascular disease.  The results were predictable, in the sense that there was a high procedure success with few complications, and the what complications occurred were precisely those expected from any angioplasty.

## Technical Benefit

- ELA reduces a complex lesion pattern into something that balloons and (optional) stents can handle...

- Benefits

**Notes:**
It’s natural to ask what the role of the laser might be in the LACI strategy.  That is what does the laser add to the strategy?  After all, some of the article referenced in the panel pack show remarkably good limb salvage in CLI patients using PTA alone.  Those articles showed that, if patients are pre-picked for simple disease patterns, then PTA can be successful and limb salvage will be high.  
The laser greatly relieves the need to pre-pick patients based on their disease pattern.  Laser atherectomy simplifies complex disease patterns into a simpler pattern, which can be successfully addressed by balloons and optional stents.  Laser catheters do this by drilling pilot holes through occlusions and by dissolving thrombus masses or plaque.  
The LACI treatment strategy uses a process of progressive simplification.  The laser turns occlusions into stenoses and tight stenosese into more focal lesions.  Balloons further open the arteries and  reveal the refractory flow-limiting stenoses.  Finally, stents are used to address only the most difficult sites.  

## Progressive Simplification

- Benefits

**Notes:**
The LACI treatment strategy uses a process of progressive simplification.  We’ve chosen a LACI patient to illustrate this point.  On the far left is an angiogram of normal below-the-knee arteries, showing widely patient anterior tibial, posterior tibial and peroneal arteries.  In this LACI patient, however, no artery below the knee is patent.  There is no distal target for bypass surgery.  How would you balloon or stent this patient?  At this point you don’t know, and so this patient has no options.  The laser opened the anterior tibial artery, and turned occlusions into stenoses and into more focal lesion patterns.  (Sorry, but the post-laser angiogram is from a slightly different flouro angle.)  Balloons further open the artery in the next angio and reveal the refractory  stenoses.  This patient had a mild dissection in the proximal anterior tibial artery, but did fine without a stent, although stenting may have been an option.

## Other Advantages

- ELA technology is mature
- ELA skills are based on standard interventional technique
- ELA uses “cool” UV laser ablation

- Benefits

**Notes:**
Finally we point out that this technology is well understood and widely accepted.  Excimer laser ablation has been used on perhaps millions of eyes and a hundred thousand arteries and veins.  Manufacturing and using fiberoptic catheters has been perfected over a 12 year period.  The same lasers that are used for coronary atherectomy can be used for LACI and there are already about 300 such lasers in US hospitals right now.  Using the laser catheter is a teachable art based on the same skill set already taught to our interventional fellows.  The technique is mature.

## Limb Salvage vs. Limb Loss

- Is limb salvage always the best goal?
- Or, stated another way:
- What patient groups benefit from limb salvage?
- What patients are better served by primary amputation?

- Benefits of Limb Salvage

**Notes:**
The cornerstone concept on which the LACI protocol is based is that limb salvage has greater benefit to the patient than major amputation.  A great body of medical literature to supports this concept.  Over the last 30 years, as data became available on the benefit of revascularizing limbs with CLI, the realization of the relative benefits of revascularization became so profound that direct comparisons with amputation became difficult. Sweeping generalizations about treatment options invariably ignore some segment of the patient population, and so it is prudent to ask about when primary amputation would be a more appropriate option.

## Clinical Outcomes

- In Class C patients*
- 					_revascularization_      _amputation_
- operative mortality			6%		16%
- hospital stay, days			14		31
- regained ambulation		72%		44%
- 3-year survival			76%		29%
- 	* Goldman score >9 or ASA class IV or V.  *Surgery 1988; 104:667-672*
- Promulgated “an aggressive approach to lower-extremity vascular reconstruction, irrespective of medical status”

- Benefits of Limb Salvage

**Notes:**
In 1988, Ouriel compared amputees against revascularized patients. He also further classified the patients into Class A (Goldman score <5 and ASA class I or II), Class B (Goldman score 5-9 or ASA class III), Class C (Goldman score >9 or ASA class IV or V).  Perioperative mortality was significantly greater for below the knee amputations than for revascularization (7.6% vs 2.9%, p<0.05). However, in Class C patients the difference was even more dramatic, 16% for amputation vs. 6% for revascularization. Length of hospital stay was reported as 14  2 days on average for revascularization and 31  3 days for amputation. Full ambulatory status was regained by 72% of Ouriel’s Class C revascularization patients, but only 44% of the Class C amputees. The Class C revascularization patients had a long term survival rate of 76%, while 29% of Class C amputees survived after 3 years (p<0.001). These data “reiterate the augmented mortality of amputation and promulgate the concept of an aggressive approach to lower-extremity vascular reconstruction, irrespective of medical status.”

## Quality of Life

- Comparing revascularized patients to primary amputees:
- Revascularization had significantly lower depression, lower impairment of social function, greater mobility
- QOL maintained after reintervention
- QOL similar between primary amputation and amputation after failed revascularization
- QOL always higher in limb salvage
*	**	**	**	**	**Eur J Vasc Surg 1995; 9:310-313*

- Benefits of Limb Salvage

**Notes:**
In comparing the quality of life (QOL) for patients who were revascularized against those with primary amputation, Thompson found no significant difference between the groups in anxiety, but the revascularized group was significantly lower in depression and impairment of social function and had significantly greater mobility. Further, QOL of the revascularized group was unaffected by a reintervention.  There was no difference in QOL between primary amputation patients and patients who received amputation after a failed revascularization. QOL was always higher in patients with limb salvage. This author concluded that “repeated interventions to maintain graft patency, either thrombectomy of a failed graft, or radiological or surgical angioplasty to treat vein graft stenoses, did not adversely affect the quality of life of patients following infragenicular arterial reconstruction."

## Elderly Patients

- In patients >80 years
- 			_revascularization_	   _amputation_
- survival	     44% @ 5 yrs        28%	 @ 4 yrs
- maintained
- residential status	88%			65%
- Elderly patients fare better with salvaged limbs
*	**	**	**	**	**J Vasc Surg 1998; 28:215-225*

- Benefits of Limb Salvage

**Notes:**
In Pomposelli’s  article on lower extremity reconstruction in the very elderly, he found that for patients at least 80 years old with reconstructed limbs, survival rate was nearly twice that of patients who had undergone major amputation: 44% at five years vs. 28% at four years. In the amputation group 65% retained their residential status.  Revascularized patients improved or remained the same 88%. Thus even patients of advanced age benefited from revascularization rather than amputation.
The point we are making from these references is that the relative benefit of limb salvage over primary amputation actually becomes greater as the patient becomes sicker and older.  However, once the patient’s condition becomes terminal or ambulation is impossible, a line is crossed and limb salvage is no longer a benefit.

## TASC Recommendation 103

- Primary amputation for CLI is indicated:
- Unreconstructable occlusive arterial disease
- Necrosis of significant areas of weight-bearing portions of the foot
- Fixed unremediable flexion contracture of the leg
- Terminal illness, limited life expectancy
*In how many patients does this apply?*

- Benefits of Limb Salvage

**Notes:**
The TASC document helps us understand where that line should be drawn.  TASC Recommendation 103 lists four conditions under which primary amputation is indicated.  LACI may impact the meaning of unreconstructable arterial disease, but clearly LACI will not benefit patients with the last three indications, such as terminal cancer or unremediable contracture of the leg.

We note that the LACI study excluded patients with the last three conditions.  LACI also excluded patients with no identifiable infrageniculate artery, which would have made them “unreconstructable”.  So, LACI harmonized with Recommendation 103.

One last question remains -- what proportion of CLI patients fit these indications for primary amputation?

## Delphi Consensus Study

- Physicians were presented with 596 hypothetical CLI patient scenarios
- Surgeons and radiologists indicated primary amputation in 9-10%
- _General consensus:_
- Vast majority should be revascularized
- Primary amputation should be reserved for the most hopeless cases
*	**	**	**	**Eur J Vasc Surg 2002; 24:411-416*

- Benefits of Limb Salvage

**Notes:**
The decision to revascularize should be made with the patient’s best interest in mind.  The pervasiveness of this treatment philosophy was tested in the Delphi Consensus Study, in which a variety of physicians were presented with 596 different hypothetical CLI patient scenarios with a wide range of disease severity, anatomic extent, coexistent conditions, etc.  "Both surgeons and radiologists thought primary amputation was indicated in approximately 9-10% of the scenarios."  This study does not quantitate an actual CLI patient population, but it does illustrate the current medical consensus. That is, primary amputation should be reserved for only the most hopeless of cases, perhaps 10% of the CLI population.  The majority will benefit from limb salvage attempts.  
This is the concept on which the LACI protocol was based.

## Medication for CLI

- In the absence of LACI, patients at high risk of surgical mortality would receive medication and bed rest
- TASC recommends only prostanoids, and then only when
- revascularization has failed or is impossible
- alternative is amputation
- How would this subset of patients fare?

- Alternative Therapy: Medication

**Notes:**
LACI Phase 2 used a historical control to set benchmark values for the efficacy and safety endpoints.  It should be stressed that, if the LACI patients had not received LACI treatment, they would not have received the treatment plan given to the control group.  34% of the control group received surgery as their primary therapy; surgery was not a good option for LACI patients.
So, what would LACI patients have received instead of LACI?  It could be suggested that medication and bed rest would be the most probable treatment strategy for patients at high risk of surgical mortality.

## Recent Reports

- Selected reports of medication for treatment of CLI
- published in last 10 years
- at least 100 CLI patients
- poor surgical candidates
- follow-up to at least 6 months
- Compared to a subset of LACI patients who were at high risk of surgical mortality (ASA Class 4)

- Alternative Therapy: Medication

**Notes:**
Turning to the literature, we chose three articles for comparison based on large case series (>100 subjects), with 6-month follow-up statistics, published within the last 10 years.  Also, we chose publications on subjects who were not good surgical candidates, so that the subjects would be similar to LACI. Then we analyzed a subset of LACI patients who were American Society of Anethesiologists Class 4 or above and compared the results to literature values. 

## Literature Comparisons

- Alternative Therapy: Medication

**Notes:**
This table shows that conservatively treated patients typically have an initial hospital stay at least 10 days longer than LACI.  Limb salvage rates are lower than LACI, by at least 10% absolute.  Death at 6 months varies widely, and was lower than LACI in one report and higher than LACI in the others.  Major amputation was given to at least 37% of conservatively treated patients, compared to 6% of this LACI subset.  In the one article reporting this statistic, the incidence of surgical bypass was also higher, presumably as a desperate measure in patients who are poor surgical candidates.  Assuming that death, bypass, and major amputation are SAEs for the conservatively treated groups, total SAEs are much higher in the conservatively treated groups than in LACI.  

## Summary

- Outlook for conservatively-treated CLI is dismal
- 37% amputation in 6 months
- high incidence of adverse events
- LACI provided greater limb salvage, fewer SAEs, and shorter hospital stays

- Alternative Therapy: Medication

**Notes:**
In summary, the outlook for conservatively treated patients is dismal.  LACI provides increased benefit and reduced risk in all outcomes.

## Why not randomize vs. Meds?

- Randomizing against a treatment plan that promises 37% major amputation at 6 months has ethical issues

- Alternative Therapy: Medication

**Notes:**
Because the LACI results are so superior to conservative therapy, randomizing even a portion of patients in a potential study versus medication would be difficult to argue.

## Amputation for CLI

- It might be proposed that patients who are not at a high risk of surgical mortality may better benefit from primary amputation.
- Is this true for _all_ CLI patients who are not at a high risk of surgical mortality?
- How would this subset of patients fare?

- Alternative Therapy: Amputation

**Notes:**
Literature suggests approaching the decision of amputation vs. revascularization for CLI patients from a three-sided view: technical issues, foot wound healing issues and comorbidity.  Suppose we isolated the subset of LACI patients who were not at increased risk for surgical mortality, that is, not American Society of Anesthesiologists Class 4 or above.  How would they fare with primary amputation as the first treatment plan?

## Recent Reports

- Selected reports of amputation for treatment of CLI
- at least 100 CLI patients
- follow-up statistics for comparisons
- Compared to a subset of LACI patients who were not at high risk of surgical mortality (not ASA Class 4)

- Alternative Therapy: Amputation

**Notes:**
Turning to the literature, we chose four articles for comparison based on large case series (>100 subjects) with statistics on follow-up required for comparison. Then we analyzed a subset of LACI patients who were not ASA Class 4 or above and compared the results to literature values. 

## Literature Comparisons 1/2

- Alternative Therapy: Amputation

**Notes:**
In the two amputation case series shown here, the perioperative mortaltiy varies between 1% and 8%.  Ouriel also reported an index hospital stay of nearly three weeks.

## Literature Comparisons 2/2

**Literature Comparisons ****2/2**

- Alternative Therapy: Amputation

**Notes:**
Two additional studies show similarly long hospital stays for primary amputation, about 3 weeks, compared to 2.6 days for LACI.  Perioperative mortality ranges from 1% to 11% for amputation, whereas none was seen in LACI.  Death at 6 months was also higher for amputation.  Reintervention, in the form of a second surgery to convert from BKA to AKA, was required in 19% of amputations, whereas a second angioplasty was required in 15% of LACI cases.

The only benefit that might accrue to the primary amputation group is lack of persistent CLI, but this conclusion is somewhat clouded by the presence of up to 11% unhealed stumps at 6 months.

## Summary

- Patients receiving primary amputation are at risk for:
- perioperative mortality
- long hospital stay
- high incidence of secondary amputation,
- 	BKA 	    AKA
- LACI provided limb salvage with shorter hospital stays and decreased perioperative and post-operative mortality

- Alternative Therapy: Amputation

**Notes:**
In summary, LACI benefits include limb salvage, shorter hospital stay, no perioperative mortality and lower reintervention, while risks are no higher and of less serious types.

## Why not randomize vs. Amp?

- Randomizing against a treatment plan that promises 100% major amputation with a high death rate, both perioperative and long term, has ethical issues

- Alternative Therapy: Amputation

**Notes:**
Primary amputation should be reserved for only the most hopeless of cases.  Some groups of patients (the bedridden, immobile or terminally ill) may best be served by primary amputation to alleviate the pain of CLI.

## Bypass for CLI

- Bypass surgery is the “gold standard” for treatment of CLI.
- Outcomes after bypass could be used as a possible benchmark for safety and efficacy
- LACI patients were poor surgical candidates
- Bypass was not a treatment option
- How do LACI outcomes compare with the “gold standard”?

- Alternative Therapy: Bypass

**Notes:**
LACI patients were poor surgical candidates, indicated by at least one of the following conditions: a) absence of venous autologous grafts; b) poor (diffusely diseased or <1mm diameter) or no distal vessels available for graft anastamosis; c) high risk of surgical mortality, evidenced by American Society of Anesthesiologists Physical Class 4 or higher.  While bypass surgery is not a reasonable treatment option for LACI patients, it might be chosen in desperation prior to an amputation that was nearly inevitable.

## Recent Reports

- Selected reports of bypass for treatment of CLI
- patients treated with current bypass standards (treatment period 1987 - 2000)
- autogenous vein grafts
- infrainguinal revascularization
- Compared to all LACI patients

- Alternative Therapy: Bypass

**Notes:**
To check if LACI has advantage over expected outcomes in patients treated with bypass, literature references on bypass surgery were selected for comparison. The literature chosen for this comparison represent critically ischemic patients treated with current bypass standards, in a population treated between 1987 and 2000. The cited bypass strategies and anastomosis site selections are most suitable for the atherosclerotic disease pattern typically seen in this patient population. Additionally, all procedures cited were performed using the preferred conduit for infrainguinal revascularization, i.e. an autogenous vein graft instead of the less effective prosthetic graft.

## Literature Comparisons 1/2

- Alternative Therapy: Bypass

**Notes:**
These two bypass case series reported on mostly diabetic patients Surgical revision was necessary in up to 19% of patients.  Major amputation was not avoided in all patients.

## Literature Comparisons 2/2

- Alternative Therapy: Bypass

**Notes:**
Although direct comparison between the LACI poor surgical candidate population and bypass surgical patients is difficult, the early in-hospital complications, including reintervention and death at 30 days, favor LACI. Long term outcomes, including death and major amputation, are similar among the studies cited.

## Summary

- Patients receiving bypass are at risk for early in-hospital complications including:
- reintervention (graft revision or early re-operation)
- death at 30 days
- LACI provided limb salvage with very little need of bypass for patients who were poor surgical candidates

- Alternative Therapy: Bypass

**Notes:**
In summary, LACI achieved limb salvage comparable to the “gold standard” of bypass surgery, without higher SAE’s.

## Why not randomize vs. Bypass?

- LACI patients were poor surgical candidates
- high risk of surgical mortality, and/or
- lack of distal anastomosis site, and/or
- lack of venous conduit for bypass

- Alternative Therapy: Bypass

**Notes:**
Enough said?

## PTA for CLI

- Literature reports several single-center experiences since early ‘80s
- Results were variable
- patient selection criteria differed site-to-site
- pre-selected disease patterns
- adjunctive use or other treatments (atherectomy, thrombectomy, stents, etc) often not reported
- follow-up intervals varied widely
- No trials of PTA vs. anything in the past 15 years

- Alternative Therapy: PTA

**Notes:**
A possible alternative for LACI patients - patients with CLI who are poor surgical candidates -- might be balloon angioplasty, with or without stents.  The literature have several single-center reports going back 20 years on the use of PTA in CLI.  These reports tend to be small, single-center studies with patients selected according to each site’s criteria for suitability to PTA.  Consequently, results vary widely in the literature over the past 20 years.  Often these reports do not include all the necessary information you would hope to see, if your goal were to form an expectation about the value of PTA in CLI patients.  In fact, there have been no trials of PTA versus any other treatment modality published in the past 15 years. 

## Current Consensus

- TASC document recommends PTA for CLI only in simple lesions:
- Type A:  single stenoses <1 cm
- TASC does not recommend PTA in:
- Type B:  multiple short stenoses
- Type C:  long stenoses; short occlusions
- Type D:  occlusions >2cm; diffuse disease
- surgery is recommended for Type D

- Alternative Therapy: PTA

**Notes:**
The current medical consensus is authoritatively presented in the TASC document, the Trans-Atlantic inter-society consensus statement published in January 2000.  TASC makes recommendations for treatment plans based on the angiographic disease pattern for CLI patients.  Only the simplest patterns, or Type A lesions, are recommended for PTA.  Surgery is recommended for Type D disease, which is the most extensive.  TASC does not recommend PTA for Types B, C or D, and calls for more study of intervention in CLI.
The TASC document reviewed what information was available about PTA in CLI, but studies of PTA in the complex disease patterns were lacking.

## TASC Types in LACI

- _TASC Lesion Type_		_LACI legs __n=155_
- A : short stenoses		  3 (2%)
- B : multiple short lesions	13 (8%)
- C : complex patterns		44 (28%)
- D : long diffuse disease	93 (60%)
- insufficient data in 2/155 cases

- Alternative Therapy: PTA

**Notes:**
Analysis of the angiographic patterns of disease found in LACI patients showed that 88% of cases had TASC type C or D morphology.  These data make several points about the CLI patient population treated in LACI:
 the patients were not pre-selected for patterns recommended for PTA
 PTA would probably not be suitable for the large majority of this patient cohort, given the complex nature of the morphology
 since most of the patients treated in LACI would typically be declared ineligible for PTA, it would be inappropriate to consider that PTA would be the standard therapy for the LACI cohort, and it is unlikely that the literature would contain sizable case series of PTA in a similar cohort.

## Recent Reports of PTA in CLI

- Selected recent articles
- 8 years old
- 50 patients
- follow-up 6 months
- CLI in 90% of patients
- Inclusive of modern balloons, stents, anticoagulants, closure devices

- Alternative Therapy: PTA

**Notes:**
Nevertheless, because we wanted to know what one could reasonably expect from modern intravascular therapy in CLI, we selected reports from the literature that met four relevancy criteria:  the reports had to be focused primarily on CLI patients, be published recently, contain at least 50 patients, and include follow-up information.  Such studies could include all of the tools and drugs currently available in the interventional armamentarium.

## Literature Comparisons 1/2

- *30 day     ‡6 months    †1 year

- Alternative Therapy: PTA

**Notes:**
Five publications were selected for comparison with the LACI Phase 2 data.  In the first three, seen here, we note that the disease pattern is generally simpler than that treated in LACI.  Reintervention was a few percentage points lower in the literature reports, but bypass was higher.  Major amputation was much higher, ranging from 17% to 21%.  Rates of death were generally what one would expect in this population.

## Literature Comparisons 2/2

- ‡6 months    †1 year   a5 year, initial successes only

- Alternative Therapy: PTA

**Notes:**
Results from two other studies are shown here.  Interestingly, the frequency of bypass were higher in these two studies than in LACI, and this may have contributed to a limb salvage rate that nearly equaled LACI.  It should be noted that the Dorros article reported on successful interventions only; no mention was made about the fate of patients with unsuccessful initial procedures, nor did they mention the frequency of reintervention.  It should also be noted that 10% of the patients in the Danielsson article had claudication, not critical limb ischemia.

## Summary

- Literature reports patients pre-selected for PTA, not “all comers”
- Some articles report on initial successes only
- If the index procedure is successful, results may be comparable to LACI

- Alternative Therapy: PTA

**Notes:**
To summarize, the literature on PTA in CLI reports on patients pre-selected at each site as patients who have lesions amenable to PTA.  So, we don’t have a clear idea about how PTA would work in all comers, such as patients with TASC Type B or C or D lesions.  Some reports did not give intent-to-treat analyses; some did not report all treatments received by the patients.  However, it is clear that, if the index procedure were successful, then results were good.  Not better than LACI phase 2, and in some cases noticeably worse than LACI, but generally good.

## Summary

- Compared to these articles, LACI had
- lower incidence of bypass
- fewer major amputations
- similar rate of reintervention
- similar rate of death
- more complex disease
- more fragile patient set
- LACI outcomes equaled “the best” despite possible bias in the LACI population

- Alternative Therapy: PTA

**Notes:**
As we saw from the data tables, LACI showed fewer bypasses and major amputations than all the reports.  Similar rates of reintervention were observed.  Survival was similar.  LACI outcomes were equal to or better than these reference articles, even though the typical pattern of disease in LACI was more complex.

## Why not randomize vs. PTA?

- PTA is not recommended for all disease patterns in CLI (see TASC)
- Evidence that PTA can be successful in  CLI/poor surgical candidates is lacking; question of ethics in the control group
- No study has made PTA the “gold standard”

- Alternative Therapy: PTA

**Notes:**
If LACI were randomized against PTA, then half of the patients would receive PTA.  However, PTA is not indicated for most CLI patients, according to the TASC consensus.  Further, we have no evidence that PTA is efficacious in complex peripheral vascular disease patterns.  Randomizing patients with complex disease to a control group of undefined effectiveness poses a bit of an ethical issue.

## Study Design

- Randomized studies are easier to interpret than other controlled designs
- Could LACI have been randomized?
- Is there one control-group therapy that
- is the standard of care,
- is indicated for LACI patients, and
- avoids the ethical issue of substandard care in the control group?

- Why not randomize?

**Notes:**
One of the reasons we’re here today is to discuss the clinical evidence from the LACI study.  LACI was not randomized, and so it takes more thought to interpret.  We chose the LACI study design carefully, after considering randomization.  A critical consideration included finding a therapy strategy for a possible control group.  Such a therapy must be the current standard for the intended population, have indication for use in the LACI population, and avoid issues such as widespread expected amputation or mortality.

## Candidate Control Therapies

- Medication (conservative therapy)
- Primary amputation
- PTA + optional stents
- Bypass surgery

- Why not randomize?

**Notes:**
Four possible therapies were considered as possible controls for LACI:  medication, primary amputation, balloon angioplasty, and bypass surgery.

## Why not randomize vs. Bypass?

- LACI patients were poor surgical candidates
- Perioperative death is 1-10% higher for bypass than for LACI

- Why not randomize?

**Notes:**
My surgical colleagues might state that bypass surgery is the gold standard for CLI.  We decided not to go head-to-head with bypass.  LACI enrolled poor surgical candidates.  So bypass really isn’t an option for this patient population.

## Why not randomize vs. Amp?

- Patients receiving primary amputation are at risk for:
- perioperative mortality
- long hospital stay
- high incidence of secondary amputation,
- 	BKA 	    AKA
- Randomizing against a treatment plan that promises 100% major amputation with a high death rate, both perioperative and long term, has ethical issues

- Why not randomize?

**Notes:**
Primary amputation has similar difficulties as a control.  Surgical mortality is a few percent, hospital stays are weeks longer than in LACI.  Amputation does not definitively remove infection in all patients, as secondary amputations due to nonhealing stumps occur in many patients.  

Primary amputation should be reserved for only the most hopeless of cases, and we excluded such patients from LACI.  They needed amputation, and they got it.

## Why not randomize vs. Meds?

- Outlook for conservatively-treated CLI is dismal
- 37% amputation in 6 months
- high incidence of adverse events
- LACI provided greater limb salvage, fewer SAEs, and shorter hospital stays
- Randomizing against a treatment plan that promises 37% major amputation at 6 months has ethical issues

- Why not randomize?

**Notes:**
The outlook for conservatively treated patients who are poor surgical candidates is grim.  More than a third of such patients are amputated in 6 months, and mortality is high.  Because our results in the 1990’s was good,k and the LACI 1 results were so superior to conservative therapy, randomizing even a portion of patients in a potential study versus medication would be difficult to argue.

## PTA Summary

- Literature reports patients pre-selected for PTA, not “all comers”
- Some articles report on initial successes only
- There is no definitive study making PTA the standard in CLI
- We lack statistics needed to design a study using PTA as control
- Would an IRB allow a non-standard control?

- Why not randomize?

**Notes:**
The literature on PTA in CLI reports on patients pre-selected at each site as patients who have lesions amenable to PTA.  So, we don’t have a clear idea about how PTA would work in all comers, such as patients with TASC Type B or C or D lesions.  Some reports did not give intent-to-treat analyses; some did not report all treatments received by the patients.  
In cardiology we have clear-cut randomized trials such as TAXUS and SIRIUS.  There is no such trial of any sort that places balloon angioplasty in the position of an effective standard therapy for all types of CLI presentations.  We have no statistics to use, no evidence to cite to a hospital IRB that would assure them that patients randomized to PTA would receive standard-of-care.

## TASC Types in LACI

- _TASC Lesion Type_	    _LACI legs_
- A : short stenoses		  2%
- B : multiple short lesions	  8%
- C : complex patterns		 28%
- D : long diffuse disease	 60%

- _TASC says:_
-     PTA
-   Surgery

- Why not randomize?

**Notes:**
Analysis of the angiographic patterns of disease found in LACI patients showed that 88% of cases had TASC type C or D morphology.  These data make several points about the CLI patient population treated in LACI:
 the patients were not pre-selected for patterns recommended for PTA
 PTA would probably not be suitable for the large majority of this patient cohort, given the complex nature of the morphology
 since most of the patients treated in LACI would typically be declared ineligible for PTA, it would be inappropriate to consider that PTA would be the standard therapy for the LACI cohort, and it is unlikely that the literature would contain sizable case series of PTA in a similar cohort.
Imagine an investigator proposing a randomized trial with a PTA control in CLI.  The IRB asks, “Half of your patients will receive PTA.  Is that the standard for CLI patients?”  Answer:  “Not exactly.”  Next question:  “How will your control patients fare with PTA?”  Answer:  “We don’t really know.”  IRB’s final answer would be, “We don’t deliver substandard care to half our patients in this institution.  Request denied.”

## Why not randomize vs. PTA?

- PTA is not recommended for all disease patterns in CLI (see TASC)
- Evidence that PTA can be successful in  CLI/poor surgical candidates is lacking
- Question of ethics in a PTA control group

- Why not randomize?

**Notes:**
If LACI were randomized against PTA, then half of the patients would receive PTA.  However, PTA is not indicated for most CLI patients, according to the TASC consensus.  Further, we have no evidence that PTA is efficacious in complex peripheral vascular disease patterns.  Randomizing patients with complex disease to a control group of undefined effectiveness poses a bit of an ethical issue.

## Randomization Summary

- No one therapy is appropriate, ethical, and standard-of-care for this population
- Randomization would be unworkable
*What does that leave?*
- Self-controlled study designs
- Historical controls

- Why not randomize?

**Notes:**
After considering concurrent control designs, we found randomization to be an unworkable design for LACI.  And yet a control was needed.  
Self-controlled studies are also difficult.  Suppose the study plan was to give each patient Treatment A and then Treatment B.  In this case, if Treatment A fails, the patient loses a leg, and the ability to receive Treatment B.  It just doesn’t work.
That leaves historical controls. 

## Best-Case Historical Control

- Exact match in patient characteristics
- Huge enrollment
- Full statistics, excellent follow-up
- Treatment plan defines “standard”
- in this case, a mixed set of modalities that uses best-case therapy for each patient
- Conforms to TASC definitions

- Why not randomize?

**Notes:**
In a perfect scenario, we might have found a published study that enrolled patients exactly matched to the LACI population.  The mythic control would have enrolled a huge number of patients, be fully reported, and have zero lost patients.  The treatments delivered in the historical study would define a treatment standard, which in CLI patients, means the best treatment that each individual patient required.  And, the study would conform to all modern standards.

## ICAI Study

- Italian multicenter randomized study of Prostaglandin E1 in CLI patients
- 771 in alprostadil group
- 789 in control group
- Control group received variety of therapies (bypass, endarterectomy, medication, and a few PTAs)
- “the best you can do” for these patients
- Ann Intern Med 1999; 130:412-421
- Conforms to TASC definitions and GCP

- Why not randomize?

**Notes:**
We found such a study.  The ICAI study group performed a randomized trial of alprostadil in CLI patients in Italy.  Enrollment was very large, and the control group was treated with a wide variety of treatment modalities, according to what each required.  In a sense this is the best you can possibly expect, since one treatment modality was not forced on the entire population.  The study was published in a highly reputated journal, unusually long at 10 pages of text and tables.  The authors adhered to good clinical practice and the definitions in the TASC document.

## ICAI Study: Differences

- ICAI differs from LACI slightly
- ICAI enrolled CLI patients regardless of candidacy for surgery
- 35% of ICAI patients received surgery as their primary treatment option
- LACI enrolled only poor surgical candidates
- ICAI treatment plan is _not_ an alternative for LACI patients

- Why not randomize?

**Notes:**
The ICAI publication was not perfect for our needs, though.  ICAI enrolled good surgical candidates and bad surgical candidates.  In fact, 35% of the ICAI patients received surgery as their primary therapy at enrollment.  The LACI population is 100% poor surgical candidates.  So, the ICAI treatment plan is not an alternative for LACI patients -- LACI patients don’t get surgery.

The ICAI publication did not provide a subset analysis of just the poor surgical candidates.

## ICAI Study: Implications

- ICAI treatment plan is not a fall-back plan for LACI patients
- LACI population is not eligible for the same treatments, and hence may not enjoy the same outcomes as ICAI patients
- ICAI statistics represent the benchmark for “the best you can do”
- If ICAI statistics are safe and effective, then a treatment plan with equal statistics must also be safe and effective

- Why not randomize?

**Notes:**
This particular historical control takes away one assumption that is typically made in randomized trials.  In most randomized trials, the therapy plan used in the control group is typically given to patients who could have qualified for the study, but weren’t enrolled.  The control plan is the fall-back plan.  In this case, LACI-type patients can’t get the ICAI treatment plan because LACI patients won’t qualify for surgery.  Therefore, the ICAI control is just a benchmark.  It gives us the level of success we can expect when you deliver the best you can do.  If the benchmark is set at the best you can do, and that is by definition safe and effective, then an investigational result that meets that benchmark must also be safe and effective.  
And that’s exactly how the LACI protocol is worded.

## Implications for LACI

- ICAI sets the benchmark as high as possible
- “the best you can do”
- including surgery in 35% of patients
- We chose the highest benchmark we could find against which to measure LACI
- The control statistics are _benchmarks_, not a true measure of alternatives available to the LACI population

- Why not randomize?

**Notes:**
LACI uses the highest applicable benchmark we could find.  It defined the best you can do.  We reasoned that meeting that benchmark would be valid scientific evidence of safety and effectiveness.