FDA Review Summary

**Device: 510(k) Number: K040429**

**CoolGard 3000/Icy Heat Exchanger Catheter**

> **Thermal Regulating System**
>
> **Alsius Corporation**

Introduction

This report presents the FDA summary of the clinical, statistical, and
pre-clinical testing review memorandums regarding K040429 for the
CoolGard 3000/Icy Heat Exchange Catheter Thermal Regulating System
submitted by Alsius Corporation.

510(k) Chronology

Information supporting the device was submitted as a 510(k) (K040429) on
March 8, 2004. Requests for additional information (AI Letters) were
issued by FDA to the sponsor on June 4, 2004 and October 5, 2005. The
sponsor submitted responses to these letters on July 2, 2004 and
November 8, 2004, respectively.

**Device Description**

The Alsius CoolGard™ 3000 thermal regulating system consists of the
Alsius CoolGard™ 3000 control unit and the Icy Catheter. The CoolGard™
3000 controller consist of a temperature monitor, a temperature
controller unit, a heat exchange unit, and a roller pump. The CoolGard™
3000 controller controls the temperature of the circulating saline that
flows through the Icy Catheter and is also responsible for monitoring
patient temperature. The Icy Catheter is a 3 lumen catheter with a
nominal diameter of 8.5 F. Two of the lumens are used to circulate the
saline and the third lumen is a standard guide wire lumen and could also
be used as an infusion lumen. The Icy catheter is a closed-loop catheter
system through which the cooled or warmed saline passes, allowing the
catheter to function as an internal heat exchanger. The catheter is
placed in the inferior vena cava through either the femoral, jugular or
subclavian vein. A more complete device description is included in **Tab
3** of your panel pack.

Device History

The CoolGard™ 3000 Thermal Regulating System has been previously cleared
by 510(k) for the following indications:

1.  The Alsius CoolGard™ 3000 and Cool Line™ Catheter Thermal Regulation
    System is indicated for use in fever reduction, as an adjunct to
    other antipyretic therapy, in patients with cerebral infarction and
    intracerebral hemorrhage who require access to the central venous
    circulation and who are intubated and sedated. (K014241)

2.  

3.  The Alsius CoolGard™ 3000 Catheter Thermal Regulation System, using
    either the Icy™ or Fortius™ model catheter, is indicated for use in
    cardiac surgery patients to achieve and/or maintain normothermia
    during surgery and recovery/intensive care, and, to induce, maintain
    and reverse mild hypothermia in neurosurgery patients in surgery and
    recovery/intensive care (K030421)

This current 510(k) application has been submitted to revise the
indications for use to include the following indication:

> "For use in the induction, maintenance, and reversal of mild
> hypothermia in the treatment of unconscious adult patients with
> spontaneous circulation after out-of-hospital cardiac arrest when the
> initial rhythm was ventricular fibrillation (VF)\".

The previous 510(k) clearances for the CoolGard™ 3000 were based on
clinical data that showed the device to perform equivalently to other
cooling devices for the same indications for use. The CoolGard™ 3000
System in this 510(k) is identical to the previously cleared device.

A Circulatory Systems Devices Advisory Panel meeting was held on
September 21, 2004, in part, to discuss the general clinical trial
issues related to devices indicated for delivering hypothermia to
victims of cardiac arrest who have return of spontaneous circulation. A
summary of the panel's deliberations at this meeting are given in **Tab
11** of this package. This previous panel meeting discussed general
clinical trial issues and did not consider specific data for any
manufacturer's device.

## Clinical Data 

In this 510(k) submission, the sponsor provided data and analyses that
were intended to address the following two objectives:

1.  To assess the effectiveness of mild therapeutic hypothermia,
    delivered via any method, in improving survival and neurological
    recovery in primary survivors of cardiac arrest.

2.  To assess the effectiveness and safety of mild endovascular
    therapeutic hypothermia, applied via Alsius CoolGard™ device, in
    improving survival and neurological recovery in primary survivors of
    cardiac arrest.

The sponsor used the following four sources of data in their analyses:

> 1\. Allgemeines Krankenhaus (AKH) Cardiac Arrest Registry (August
> 1991 - September 2003): This is an [observational study]{.underline}
> of patients treated after successful resuscitation from cardiac arrest
> at the Emergency Department of the Vienna General Hospital. Various
> methods of providing therapeutic hypothermia have been used at the
> AKH, and some patients in this cohort were treated with therapeutic
> hypothermia via the Alsius CoolGard System. [Patient-level data were
> made available to Alsius Corporation for analysis]{.underline}. A
> summary report of the analyses done using the AKH Cardiac Arrest
> Registry Data are located in Section 2.9 of the sponsor's clinical
> data summary (**Tab 4** of your package).
>
> 2\. The Hypothermia after Cardiac Arrest (HACA) Study (March 1996 -
> January 2001): This is a [randomized controlled international
> multicenter study that did not use the Alsius CoolGard™
> System.]{.underline} Patients enrolled in this study received either
> standard care with normothermia or mild therapeutic hypothermia by
> means of cool air. The results of this study were published and a copy
> of the article is available in **Tab** **7** of your panel pack. [The
> full data set for this study were made available to Alsius Corporation
> for analysis]{.underline}.
>
> 3\. Bernard Study (September 1996 - June 1999): This is an Australian
> [multicenter randomized controlled hypothermia study that did not use
> the Alsius CoolGard™ System]{.underline}. Patients enrolled in this
> study received either standard care (normothermia) or therapeutic
> hypothermia by ice packs around the neck. The results of this study
> were published and a copy of the article is available in **Tab 7** of
> your panel pack. [Alsius Corporation extracted data from this
> published report for their analysis.]{.underline}
>
> 4\. Hachimi-Idrissi Study (over six month period within 2000 and
> 2001): This is a [single-center randomized controlled feasibility
> study that did not use the Alsius CoolGard™ System]{.underline} .
> Patients enrolled in this study received either standard care
> (normothermia) or therapeutic hypothermia by means of a cooling
> helmet. The results of this study were published and a copy of the
> article is available in **Tab 7** of your panel pack. [Alsius
> Corporation extracted data from this published report for their
> analysis.]{.underline}

To evaluate the effectiveness (in general) of mild therapeutic
hypothermia in improving survival and neurological recovery in primary
survivors of cardiac arrest (the first objective), Alsius Corporation
performed a meta-analysis using the three randomized controlled trials
discussed above (HACA, Bernard, and Idrissi). A summary of the results
of this meta-analysis is discussed in Section 2.7 of the Sponsor's
clinical data summary provided in **Tab 4** of your panel package. A
copy of the complete meta-analysis report (including statistical tables)
is found in **Tab 5** of your panel package. In the meta-analysis, two
endpoints were evaluated: (1) Survival (for HACA trial, survival was
defined as 6-month mortality status, while for the other two trials,
survival was defined as hospital discharge); (2) Survival (alive after 6
months for HACA study and alive until hospital discharge for the other
two trials) [and]{.underline} good neurological recovery (cerebral
performance categories (CPC) 1 or 2). The sponsor used fixed effects
models to combine the point estimates from these three randomized
trials, and assessed statistical heterogeneity using Cochran\'s Q test.

As discussed above, the survival endpoints reported in the references
differed. In the HACA trial, mortality was assessed at 6 months, in the
Bernard study it was assessed at hospital discharge and in the Idrissi
trial, it was assessed at the end of the study (which was 4 hours after
applying therapeutic hypothermia). More over, the definitions of good
neurological recovery are also different in these three trials. The HACA
study used CPC score of 1 or 2 as good neurological recovery. (A
description of the CPC scale is found in **Tab 8** of your panel pack).
The Bernard study defined good neurological outcome as discharge home or
to a rehabilitation facility. The Hachimi-Idrissi trial did not
explicitly describe good neurological recovery. This difference in the
definitions of the two effectiveness endpoints (i.e., survival, survival
and good neurological recovery) among the three studies may affect the
validity of the meta-analysis.

Alsius Corporation also provided data from the Allgemeines Krankenhaus
(AKH) Cardiac Arrest Registry to evaluate the safety and effectiveness
of mild therapeutic hypothermia provided via the Alsius CoolGard™ 3000
System in improving survival and neurological recovery in primary
survivors of cardiac arrest (the second objective discussed above). In
this analysis, the sponsor used all patients from the AKH Cardiac Arrest
Registry who did not receive hypothermia as controls, and used all
patients from the same registry data who received hypothermia via Alsius
CoolGard™ device as treatment group. The endpoints for the analysis
were: (1) 30-day survival status; (2) 30-day survival status and good
neurological recovery (defined as CPC 1 or 2). Patients who died within
24 hours of treatment were excluded. Since the AKH Registry analysis was
an observational study, the sponsor used propensity scores (probit
model) to match the treated patients with control patients in the
effectiveness analysis. A summary of the AKH Registry analysis is found
in Section 2.9 of the Sponsor's clinical data summary (**Tab** **4** of
your panel package). A copy of the complete report (including
statistical tables) for the AKH registry analysis is found in **Tab**
**5** of your panel package. We are also including a summary report from
an audit done by Alsius Corporation personnel of the AKH site (**Tab**
**6** of your panel package). We have requested that the sponsor provide
(1) a description of how the registry data are collected (2) the
protocol used for data extraction for this analysis and (3) the clinical
protocol used to treat patients with hypothermia at this site. This
information will be provided to you in a second mailing when it is
available.

The sponsor also provided two safety analyses. In the first safety
analysis, the sponsor used patients from the AKH Registry who received
Alsius CoolGard™ (treatment group) and those who did not receive
hypothermia and also met the inclusion criteria for the CoolGard™
patients (control group). In the second safety analysis, the sponsor
compared patients treated with Alsius CoolGard™ device in the AKH
Registry (treatment group) with patients treated in the HACA trial with
hypothermia via cool air (control group). Both safety analyses were
carried out using contingency tables and Fisher\'s exact tests, but were
not corrected for multiple testing. A summary of these safety analyses
are found in Section 2.9.4 of the Sponsor's clinical data summary (**Tab
4** of your panel package).

**FDA Analysis of Clinical Data Provided**

After reviewing the data provided in the 510(k) submission, FDA had the
following issues with the data submitted.

AKH Registry Data:

-   The AKH Registry data are observational and were not collected as
    part of a randomized trial. There is a possibility of introduction
    of bias in the selection of the non-hypothermic control group
    identified in the AKH data. Some control patients were those treated
    in the era before this institution used hypothermia, other patients
    were those who required cardiac or neurological imaging studies, but
    it is unclear why the remainder of the patients were chosen to not
    have hypothermia in a center where the standard of care is
    hypothermia. The possible role of selection bias and unknown
    covariates makes comparison of these two groups difficult.

-   FDA has requested additional information regarding the propensity
    score analysis, including:

    -   the list of covariates collected in the data set and used in the
        propensity score analysis

    -   the missing covariates in the propensity score analysis and how
        missing data was handled

    -   the distribution of the propensity scores in the treated and the
        control group (graphical presentation)

        Once this information is submitted by the sponsor, it will be
        provided to you in a second mailing, along with FDA's review of
        this information.

        .

-   Of the 66 subjects in the AKH database who received treatment with
    the CoolGard™ device, only 41 patients had 6 month outcome data
    available. Of these 41 patients, only 28 patients presented with
    documented VT/VF (the specific indication for which they are seeking
    FDA clearance).

    Meta-analysis:

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-   Uncertainty regarding the meta-analysis exists because:

    a.  The subject device was not used;

    b.  Different definitions were used for survival and neurological
        outcome in the studies;

    c.  Different methods of cooling were used;

    d.  Cooling was started at different times;

    e.  Inclusion and exclusion criteria were different;

    f.  Rewarming was different.

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-   Differences exist between endovascular and surface cooling with
    regard to the rates of cooling, heterogeneity of tissue
    temperatures, time to initiating cooling, and the expected adverse
    event profiles, making it difficult to apply the results of the
    meta-analysis to support the safety and effectiveness of
    endovascular cooling.

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-   In the Bernard study, patients were cooled to 33 Deg for 12 hours,
    while in the HACA study, patients were cooled to 32-34 degrees for
    24 hours. The minimum time needed for possible benefit from
    hypothermia is unknown.

**Supplementary Clinical Information**

The sponsor conducted a small feasibility study in the U.S. of the
CoolGard 3000/ICY catheter system in patients suffering out of hospital
cardiac arrest (IDE number G000207). This study enrolled 13 patients at
four institutions. A brief summary of the results is provided in Section
2.8 of the sponsor's clinical data summary in **Tab** **4** of your
panel pack.

During the course of our review, FDA asked the sponsor to address a
number of deficiencies regarding the clinical data provided in this
510(k). The responses to these deficiencies are found in **Tab 9** of
your panel pack.

The sponsor has recently submitted additional information prior to the
Panel Meeting including follow-up on additional subjects from the AKH
registry. That data will be sent to you in a second mailing, along with
FDA's review of the information.

**Proposed Labeling and Instructions for Use**

A copy of the proposed labeling and instructions for use are found in
**Tab 10** of your panel pack.