Device: 510(k) Number: K040429
CoolGard 3000/Icy Heat Exchanger Catheter
Thermal Regulating System
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.
The FDA review team for this file is as follows: Lead Richard
Felten, M.S. Clinical Julie Swain, M.D. Statistical Mary
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.
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
2 of your panel pack.
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)
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,
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
of this package. This previous panel
meeting discussed general clinical trial issues and did not consider specific
data for any manufacturer’s device.
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 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. 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
3 of your
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. 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
6 of your panel pack. The
full data set for this study were made available to Alsius Corporation for
3. Bernard Study (September 1996 - June
1999): This is an Australian multicenter randomized controlled hypothermia
study that did not use the Alsius CoolGard™ System. 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
of your panel pack. _
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 . 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
8 of your panel pack. _
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, Idrissi). A summary of the results of
discussed in Section 2.7 of the Sponsor’s clinical data summary provided in Tab 3 of your panel package. A copy of the complete meta-analysis report
(including statistical tables) is found in Tab
4 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 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
9 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
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 3 of your panel package). A copy of
the complete report (including statistical tables) for the AKH registry analysis
is found in Tab 4 of your panel
package. We are also including a
summary report from an audit done by Alsius Corporation personnel of the AKH
site (Tab 5 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
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
institutuin used hypothermia, other patients
were those who required cardiac or neurological imaging studies, but i 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:
o the list of covariates collected in the data set and used in the propensity score analysis
o the missing covariates in the propensity score analysis and how missing data was handled
distribution of the propensity scores in the treated and the control group
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).
the meta-analysis exists because
the fact that the subject device was not
different definitions were
used for survival and neurological outcome in the studies .
the use of fixed effects model
versus use of a random effects model.
· 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.
· 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
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
3 of your panel
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
10 of your
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
of your panel pack.