+-----------------------------+---+------------------------+------------+
| ##### DEPARTMENT O          |   | #  510k Memo           |            |
| F HEALTH AND HUMAN SERVICES |   |                        |            |
+-----------------------------+---+------------------------+------------+
| **Division of General and   | * |                        |            |
| Restorative, and            | * |                        |            |
| Neurological Devices**      | F |                        |            |
|                             | o |                        |            |
| **General Surgery Devices   | o |                        |            |
| Branch, HFZ-410**           | d |                        |            |
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+-----------------------------+---+------------------------+------------+
| **Date: 1/9/04**            |   |                        |            |
+-----------------------------+---+------------------------+------------+
| **To: Richard Felten, Neil  |   |                        |            |
| Ogden, The file**           |   |                        |            |
+-----------------------------+---+------------------------+------------+
| **From: Michael J           |   |                        |            |
| Schlosser, M.D., Medical    |   |                        |            |
| Officer**                   |   |                        |            |
+-----------------------------+---+------------------------+------------+
| **Subject: Concentric       |   |                        |            |
| Retriever Clinical          |   |                        |            |
| consult**                   |   |                        |            |
+-----------------------------+---+------------------------+------------+
| **K033736**                 |   |                        |            |
+-----------------------------+---+------------------------+------------+

**Clinical Background:** The efficacy of thrombolytic therapy for acute
ischemic stroke is based on the restoration of blood flow to neurons
within the ischemic penumbra. The ischemic penumbra is a population of
viable neurons within a region of cerebral ischemia. These neurons are
stunned by limited blood flow, but can be salvaged by restoration of
flow within a time limit. Intravenous tissue-type plasminogen activator
(tPA) has been shown to improve the outcome of acute ischemic stroke
when given within the first 3 hours after onset of symptoms (4). Other
trials have failed to show an overall benefit when the treatment window
was extended to 6 hours (5, 7). While the PROACT I and II studies did
support an overall benefit of intra-arterial tPA given within 6 hours of
symptom onset, the drug was not approved by the FDA for this indication
(1, 6). As such, the only currently approved treatment for acute stroke
remains IV tPA. Due to the short time window, numerous
contraindications, and risk of intracranial hemorrhage (ICH), on average
only 2% of patients suffering from acute stroke receive this therapy.

Mechanical thrombectomy holds the promise of restoration of blood flow
to ischemic brain while limiting the risk of intracranial hemorrhage
(8). It also can be employed in patients with conditions that make them
poor candidates for IV or IA tPA. The success of thrombolytic therapy is
limited by the size of the clot. Evidence has shown that cohorts of
patients presenting with smaller, more distal occlusions fare better
with thrombolytic therapy than those with larger more proximal lesions.
Mechanical thrombectomy may allow the treatment of patients with larger
clots in more proximal arteries.

The Concentric Retriever is already legally marketed as a tool for
retrieving foreign bodies from the peripheral and neurovasculature. In
order to demonstrate the safety and efficacy of the device for removing
thrombus from the neurovasculature, a single-armed study was deemed
appropriate. This study would use the surrogate endpoint of successful
revascularization (evidenced by achieving TIMI II or III flow) as its
measure of efficacy. This was believed to be an appropriate surrogate
endpoint to demonstrate the effectiveness of this device for the
proposed indication because the NINDS stroke trial, the PROACT studies,
as well as subsequent studies of thrombolytics published in the
literature have provided some indication that revascularization of
ischemic cortex improves clinical outcome. At a previous meeting of the
FDA Neurological Devices advisory panel, the panel recommended that
devices indicated for treatment of stroke be studied in a randomized,
controlled trial with neurological improvement as the primary endpoint.
FDA agrees with this recommendation in general, however, we believe this
device, indicated for removal of thrombus, may be appropriately labeled
as a tool for assisting neurointerventionalists in managing patients
with acute stroke.

**Device Description**: The Concentric Retriever consists of a nitinol
wire with a helical shaped tip. The device is intended for retrieval of
thrombus within the neurovasculature in patients suffering from ischemic
stroke. The wire is passed through the thrombus within a microcatheter.
Once the microcatheter is beyond the occlusion, the catheter is
retracted and the wire within reforms the helical shape. The catheter
and the retriever are then pulled back to engage the thrombus. At this
point the entire apparatus is retracted back into the balloon guide
catheter, bringing the thrombus with it. The thrombus and guide catheter
can then be removed from the patient.

**Description of Clinical Protocol**:

*Trial design*: Prospective, multi-center, non-randomized, single arm
trial of 125 patients presenting with acute ischemic stroke. As this was
a single arm trial design, there was no control population prospectively
studied. Results were to be compared with the placebo group in the
PROACT II trial (1).

*Patient population*: The Patient population included individuals ≥ 18
years of age who presented with clinical symptoms suggestive of an acute
ischemic stroke. Patients were considered for enrolment if they
presented within 3 hours of symptom onset, but were not a candidate
(i.e. they possess one of the absolute contraindications) for
thrombolytic therapy. Alternatively, patients who presented after 3
hours, and in whom the thrombectomy procedure could be completed before
8 hours after symptom onset were also included. Only patients with a
presenting National Institute of Health Stroke Scale (NIHSS) score of ≥
8 and who signed informed consent were enrolled. Patients who met these
criteria received a selective cerebral angiogram. Patients with
occlusion (TIMI grade 0 or I flow) in the M1 or M2 segments of the
middle cerebral artery (MCA), internal carotid artery (ICA), basilar or
vertebral arteries were included in the study.

*Exclusion criteria*:

1)  pregnant

2)  Blood glucose \< 50.

3)  Arterial tortuosity that would prevent the device for reaching the
    target.

4)  Hemorrhagic diathesis, coagulation factor deficiency, or INR \> 3.0.

5)  PTT \> 2 time normal within the past 48 hours.

6)  Platelet count \< 30,000

7)  Severe allergy to IV contrast dye.

8)  Uncontrolled hypertension (systolic blood pressure \> 185 or
    diastolic \> 110)

9)  CT or MRI scan reveals mass effect

10) Arterial stenosis \> 50% proximal to the occlusion

11) Life expectancy is \< 3 months.

12) Participating in another investigational drug or device study.

*Study procedure*: Patients presenting with symptoms of acute ischemic
stroke were screened by the stroke team to determine potential entry
into the study. Patients who met all the inclusion and exclusion
criteria were then further assessed and NIHSS, modified Rankin Scale
(mRS), Barthel Index (BI), neurological exam and screen blood
chemistries obtained. A CT or MRI scan was then obtained (depending on
the routine of the treating center) to rule out intracranial hemorrhage
or mass effect. Patients who were found not to meet study criteria based
on pre-treatment screening were then excluded from the study and the
reasons documented. Informed consent was signed prior to
catheterization. After completion of informed consent, a selective
(anterior or posterior) cerebral angiogram was obtained based on
symptoms. Patients who lacked angiographic criteria for entry into the
study were then excluded. A patient was not considered enrolled in the
study unless the balloon guide catheter was placed.

Once the guide catheter was placed, the microcatheter was then advanced
through the identified occlusion and the anatomy distal to the thrombus
was studied via another injection through the microcatheter. The
Retriever was advanced through the microcatheter and deployed distal to
the thrombus. At this point the proximal balloon was inflated to arrest
blood flow during the retrieval process. The Retriever was then pulled
back to engage the clot. Then, the device and the thrombus were pulled
back together into the balloon guide catheter. Up to 6 attempts to
retrieve the thrombus were allowed by protocol. After treatment was
complete, another angiogram was obtained to document revascularization.
Antiplatelet agents could be administered prior to or immediately after
the procedure. No anticoagulation was allowed until the 24 hours
neuro-imaging was completed.

*Outcome measures*:

Primary efficacy measure were the achievement of recanalization (TIMI
grade II or III flow in all major vessels) immediately post-procedure
without occurrence of serious adverse events including vessel
perforation or dissection, symptomatic intracranial hemorrhage, or
embolization into a previously uninvolved territory.

Secondary endpoint was the measurement of patient's neurologic condition
at 30 and 90 days post-procedure. NIHSS, Barthel Index and modified
Rankin scale scores will be collected at discharge (or 7 days), 30 and
90 days.

Study success was defined as revascularization rate that is
statistically different from the 18% spontaneous revascularization rate
seen in the placebo group of the PROACT II trial. Further, the actual
rate seen should be greater than 30%.

**Patient demographics**:

1412 patients presenting with symptoms of acute stroke were screened
across 25 centers. From this population, 144 patients were enrolled in
the study and 137 were treated. For comparison, in PROACT II, 12,323
patients were screened to treat 180. Complete acute data was available
for 121 patients at the time of this submission. Patients were
considered enrolled when the balloon guide catheter was inserted into
the patient. They were considered treated when the retriever was
deployed into the target vessel. In 7 patients out of the 121 with
available data the retriever was not deployed in the target vessel,
leaving 114 in the final analysis. Within these 7 patients who were
enrolled, but not treated, 1 was excluded due spontaneous recanalization
of the vessel prior to treatment, and another due to the occlusion
residing in a non-treatable vessel. The remaining 5 were due to an
inability to access the occlusion, place the balloon guide or advance
the retriever (resulting in a 4% failure to treat rate in patient who
met all inclusion and exclusion criteria). Of the 114 patients treated,
65 had occlusions in the MCA, 37 in the ICA or ICA termination and 12
had occlusions in the vertebral or basilar arteries.

The median time from symptom onset to groin puncture was 4.0 hours with
a range of 20 minutes to 9.5 hours. The median time to final angiogram
was 6.1 hours. The average time from symptom onset to randomization in
the PROACT II trial was 5.1 (range of 4.2-5.5) hours for the placebo
group and 4.7 (4.0-5.3) hours for the treatment group.

**Safety Data:**

The protocol for the MERCI trial based success on revascularization
while minimizing the rate of 4 serious adverse events: arterial
dissection or perforation, symptomatic ICH, or embolization of thrombus
into a previously uninvolved territory. Overall, there were 9 cases of
symptomatic ICH, 3 cases of arterial perforation, 3 cases of dissection,
and 2 cases of embolization into an uninvolved territory. If the
patients in whom the perforations lead to a symptomatic hemorrhage are
only counted once, the overall number of patients experiencing serious
adverse events was 15/114 (13%). These adverse events were individually
examined by the investigators and the DSMB to determine if they were
device or procedure related, or unlikely to be related to either the
device or the procedure. A total of 7 cases were determined to be device
or procedure related, serious adverse events (6%).

There were 4 serious adverse events that were determined by the
investigators and DSMB to be device-related. Two of these patients
experienced contrast extravasation after thrombectomy with the
Retriever. This finding was consistent with vessel dissection or
perforation. In one case the patient was treated with several other
mechanical therapies after unsuccessful treatment with the Retriever.
Both of these patients expired. Two additional patients, both with MCA
occlusions, experienced embolization of the clot into the ACA territory
during attempted thrombectomy resulting in occlusion of the A2 segment.
Both of these patients survived. The device-related serious adverse
event rate is 3.5% (4/114). One additional patient experienced diffuse
SAH and contrast in the subarachnoid space after unsuccessful
revascularization. This case was however determined to be procedure and
not device-related by the investigator and DSMB.

Procedure related adverse events were seen in 8 cases (7%). These fit
the criteria for serious adverse events in three cases. Two of these
cases involved dissection of the cervical ICA. In both cases this
complication was thought to be due to the placement of the Balloon guide
catheter. One of these patients expired due to complications associated
with the treatment of the dissection. The other had no sequelae. Another
case already mentioned above involved diffuse SAH that was though to be
due to manipulation of a guidewire and not the actual device. Five other
patients experienced groin hematomas that were procedure related. Two
required surgical evacuation and one a transfusion. No patients with
groin hematomas were reported as experiencing any long term impairment
as a result of that complication.

There was an overall symptomatic intracranial hemorrhage rate within 24
hours of treatment of 8% (9/114). Hemorrhages were deemed symptomatic if
the patient experienced a 4 point or greater decline in NIHSS with the
appearance of a hemorrhage on CT scan. Two of these hemorrhages were
considered device related (and are including above in the device related
adverse events). The hemorrhage rate in patients with MCA occlusions
(the population studied in PROACT II) was 6% (4/65). As is expected due
to the correlation between increased stroke volume and increased
hemorrhage rate, the hemorrhage rate among ICA occlusions in the MERCI
trial was higher (14%) than the rate seen for MCA occlusions. Increased
baseline NIHSS also corresponds to increase symptomatic ICH. In PROACT
II all symptomatic ICH occurred in patients with NIHSS \>10, and the
rate among patients with NIHSS \> 20 was 13%.

Table 1 compares the rates of the most common, serious adverse events
for both arms of the PROACT II trial and the MERCI study. Numbers for
the patients within the MERCI trial who presented with MCA occlusions
are expressed in the footnote. The symptomatic intracranial hemorrhage
rate associated with the use of IV tPA to treat stroke is between 6-8%
(4,5,7).

**Table 1**. Hemorrhage and mortality rates.

  -------------------- ---------------- ----------------- ----------------
                       **PROACT II      **PROACT II       **MERCI**
                       treatment**      placebo**         

  **Mortality**        25%              27%               38%\*

  **Symptomatic ICH    10%              2%                8%\*\*
  within 24 hours**                                       

  **Groin Hematoma**   7%               17%               4%
  -------------------- ---------------- ----------------- ----------------

\* Mortality rate for MCA strokes (population studied in PROACT II) in
MERCI was 32%

\*\* Hemorrhage rate in MCA strokes in MERCI was 6%.

**Primary Outcome Measures**:

Out of 114 patients treated with the retriever, 54% (n=61) patients had
TIMI grade II or III flow immediately post procedure. This is
statistically significant compared to the placebo group in PROACT II
(18% spontaneous revascularization in patients treated as randomized)
with P \<0.0001. It also is significantly greater than the target
success rate of 30% revascularization. If all patients enrolled in the
study are included (intent-to-treat success rate) the rate is 52%
(62/120). Four patients who were successfully revascularized went on to
have embolization of clot into a previously uninvolved territory (2
patients) or a symptomatic intracranial hemorrhage. Excluding these
patients with serious adverse events, the study success rate (as defined
as revascularization with the Retriever alone and without occurrence of
serious adverse events) is 47% (57/120) Out of the 61 patients who had
successful clot retrieval, 25% (15/61) went on to die prior to 90 day
follow-up. In seventeen patients where the MERCI Retriever was
unsuccessful in restoring flow, additional therapies were tried. Ten of
these patients were successfully revascularized with another therapy,
including 8 with IA thrombolysis and 2 with other mechanical devices

**Secondary Outcome**:

Secondary outcome measures included assessment of clinical outcome at 30
and 90 day follow-up. Modified Rankin scale scores and NIHSS scores were
assessed at both of these end points. Thirty day follow-up is presented
for 112 patients and 90 day follow-up for 70. Results are stratified by
baseline NIHSS score due to the known association between poor outcomes
and increasing baseline NIHSS (2). Comparisons are made to the clinical
outcome results of the PROACT II trial, though important differences in
the patient populations treated in PROACT II and MERCI make statistical
comparisons less informative. One important difference between these two
populations of patients is the severity of the strokes in the patients
treated. Table 2 presents the distribution of baseline NIHSS scores in
patients enrolled in MERCI as compared to the placebo group in the
PROACT II study. As is evident from the table, a larger percentage of
patients in the MERCI trial had NIHSS scores \>20 as compared to PROACT
II. Literature has shown that patients with baseline NIHSS \>22 have a
very poor prognosis with 98% experiencing poor outcome (3).

**Table 2**

  ------------------- ------------------- --------------------------------
  **Baseline NIHSS**  **MERCI**           **PROACT II placebo group**

  **4-10\***          3 (3%)              8 (14%)

  **11-20**           62 (55%)            37 (63%)

  **\>20\*\***        48 (42%)            14 (23%)
  ------------------- ------------------- --------------------------------

\* MERCI used 8 as the minimum NIHSS for enrolment

\*\* Patients with NIHSS \> 30 were excluded from PROACT II.

In PROACT II, a good outcome was defined as a mRS of ≤ 2 at follow-up.
Patients with mRS of ≤ 2 can have a slight disability and may not be
able to complete all previous activities, but are able to look after
their own affairs without assistance. This is an appropriate cutoff
point for a treatment of population of patients with more several
strokes. Table 3 compares the rate of good outcome in the PROACT II
treatment and placebo groups to all patients with 90 day data available
in the MERCI trial. As has been stated previously, MERCI included both
ICA strokes and posterior circulation strokes where was PROACT II
enrollment was limited to only stroke in the MCA (M1 and M2 segments).

**Table 3**. Rate of good outcome at 90 day follow-up.

PROACT II treatment PROACT II control MERCI

  ----------- ---------- ---------- ---------- ---------- ---------- ----------
  **NIHSS     **No.**    **mRS ≤    **No.**    **mRS≤ 2** **No.**    **mRS ≤
  strata**               2**                                         2**

  **\< 10**   16         10 (63%)   8          5(63%)     3          2(66%)

  **11-20**   75         34 (45%)   37         9 (24%)    34         10 (29%)

  **\>20**    30         4 (13%)    14         1 (7%)     32         5 (16%)

  **Total**   121        (40%)      59         (25%)      69         25%
  ----------- ---------- ---------- ---------- ---------- ---------- ----------

The rate of good outcome (mRS ≤ 2) in patients with MCA strokes (summing
all baseline NIHSS scores) treated with the MERCI Retriever at 30 days
was 24% (14/58). Patients with posterior circulation strokes faired much
worse, having only 17% good outcome at 30 days. As Table 4 indicates,
the treatment of MCA strokes in the MERCI trial showed no difference in
clinical outcome compared to the PROACT II placebo group though the
population treated in MERCI did have an increased severity of stroke at
presentation.

**Table 4**

  --------------------------------- ---------------- --------------------
                                    **MERCI MCA**    **PROACT II
                                                     placebo**

  **Baseline NIHSS median (range)** 19 (9-40)        17 (4-28)

  **mRS \< 3 at follow-up**         14/58 (24%)      15/59 (25%)
  --------------------------------- ---------------- --------------------

While there was no difference in clinical outcome when comparing all of
the patients treated in the MERCI trial to the outcomes of the PROACT II
placebo group, a comparison of outcome in patients in whom there was
successfully revascularization with the MERCI Retriever to those in whom
the procedure was unsuccessful (including those that went on to
successful revascularization with an alternative therapy as part of the
unsuccessful group) demonstrated a clinical benefit to
revascularization. Table 5 shows a comparison of the rate of good
outcome (mRS ≤ 2) at 90 days between patients with successful and
unsuccessful revascularization stratified by baseline NIHSS. While the
number of patients with 90 day follow-up available at the time of this
review was small, a substantial difference between the outcome of
patients with successful and unsuccessful revascularization is
demonstrated. In particular, the effect in patients with more severe
strokes at baseline is pronounced.

**Table 5**

  --------------- --------------------- ------------- --------------------- -------------
  **Baseline      **Successful                        **Unsuccessful        
  NIHSS**         Revascularization**                 Revascularization**   

                  Total patients        mRS ≤ 2       Total patients        mRS ≤ 2

  **8-10**        2                     100%          1                     0%

  **11-20**       16                    56%           18                    6%

  **\>20**        12                    42%           20                    0%
  --------------- --------------------- ------------- --------------------- -------------

A comparison of all patients with successful revascularization to those
without showed a significant increase in the likelihood of a poor
outcome in those in whom flow was not restored (90% vs. 48%, P\<0.001).
The distribution of baseline NIHSS scores between successful and
unsuccessful populations was not statistically significantly different
(p=0.575); indicating that severity of stroke was not correlated with
difficulty in successfully completing the thrombectomy procedure.

**Summary:**

The MERCI trial data has been submitted to support a new indication for
use for the legally marketed Concentric Retriever. This indication is to
restore blood flow in the neurovasculature by removing thrombus in
patients experiencing acute ischemic stroke. The primary endpoint of the
study was to demonstrate successful revascularization of patients with
an acceptable adverse event rate. The study demonstrated 47% successful
revascularization of patients without occurrence of a serious adverse
event, which was significantly different than the spontaneous
revascularization rate of 18% seen in the placebo group of the PROACT II
study.

The mortality rate, while higher than that seen in PROACT II, likely
represents the expected mortality in the population treated, as the
acuity of the stroke patients treated in the MERCI trial was higher.
This is further confirmed by the low occurrence of device- and
procedure-related serious adverse events (6%) and fatal device- and
procedure- related adverse events (2%), indicating that the mortality
rate is likely due to the natural history of patients with severe stroke
and not a high rate of device or procedure related deaths. Similarly,
the symptomatic intracranial hemorrhage rate of 8% seen in the MERCI
trial is likely related to the inclusion of larger (ICA) strokes in the
treatment group. The rate of hemorrhage in patients with MCA strokes was
only 6%, half way between the 2% rate seen in the placebo group in
PROACT II and the 10% rate seen in the PROACT II treatment group. The
rate of 6% likely represents a combination of the 2 device related
vessel injuries leading to subarachnoid hemorrhage and a slightly
increased risk of hemorrhage in reperfused, injured brain.

The analysis of the clinical outcome of all patients treated in MERCI
did not show a significant improvement over the outcome of patients in
the PROACT II placebo group. Significant differences exist between these
populations. As is shown in Table 1, the population studied in the MERCI
trial had more severe strokes at presentation as compared to the
population treated in PROACT II. Very few patients treated with the
Retriever had NIHSS scores \<11, a population whose expected outcome is
quite good. As the trial was a single arm study and had different
inclusion and exclusion criteria than PROACT II, the chosen control
population, it was not deigned to demonstrate a clinical benefit of
treatment. However, comparisons of the patients with successful
revascularization to those in whom flow was not restored, and when
stratified for baseline stroke severity, demonstrated better clinical
outcomes are seen in patients in whom treatment was successful.

1)  
2)  
3)  
4)  

Michael J Schlosser, MD

Medical Officer

ODE/DGRND/GSBD

**References**:

1)  Furlan A, Higashida R, Wechsler L, Gent M, Rowley H, Kase C, Pessin
    M, Ahuja A, Callahan F, Clark WM, Silver F, Rivera F.
    "Intra-arterial prourokinase for Acute Ischemic Stroke. The PROACT
    II Study: A Randomized Controlled Trial." JAMA,
    1999;282(21):2003-11.

2)  H. P. Adams, P. H. Davis, E. C. Leira, K.-C. Chang, B. H.
    Bendixen, W. R. Clarke, R. F. Woolson, and M. D. Hansen. "Baseline
    NIH Stroke Scale score strongly predicts outcome after stroke: A
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