October 26, 2016
Dear Transplant Surgeons and Cardiologists,
We are writing to provide an update and additional information regarding SynCardia Systems, Inc.'s Temporary Total Artificial Heart (TAH-t) Companion 2 Driver System (C2 Driver System), as well as to inform you of recent events with an additional SynCardia pneumatic driver system, the Freedom Driver System. The TAH-t functions as a bridge to a heart transplant in a small population of heart failure patients with severe bi-ventricular failure.
C2 Driver System
On June 15, 2015, FDA posted a letter informing the health care community that preliminary post-approval study information suggested a higher mortality rate for a subgroup of patients requiring pre-implant circulatory rescue interventions when using SynCardia's TAH-t C2 Driver System as compared to the previous generation driver, the Circulatory Support System (CSS) Console. Since then, additional interim post-approval study results have indicated a higher risk of neurological adverse events for patients supported by the C2 Driver System compared to patients supported by the CSS Console. We also have updated results regarding the mortality rate associated with the C2 Driver System.
ANALYSIS OF PROBLEM
As a condition of approval of the C2 Driver System, FDA required SynCardia to conduct a post-approval study assessing post-market performance. The study relies on data from the Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS), and compares outcomes for patients who were initially supported with the C2 Driver System and the CSS Console during the same time period (implanted on June 20, 2012 or after). CDRH's Post-Approval Studies Database provides the study protocol parameters and reporting schedule for the SynCardia post-approval study. The most recent results from the ongoing post-approval study regarding mortality and neurological adverse events are described below.
SynCardia has provided updated results from INTERMACS comparing mortality rates in patients who were initially supported with either the C2 Driver System or the CSS Console. There has continued to be a higher mortality rate for the subgroup of patients requiring pre-implant circulatory rescue interventions when using the C2 Driver System compared to those using the CSS Console. The mortality rates for patients who did not require pre-implant circulatory rescue interventions were similar for the C2 Driver System compared to the CSS Console.
In Table 1, the cumulative number and percentage of patients who required pre-implant circulatory rescue intervention and died within three months of TAH-t implant are stratified by the patients' initial support driver. Specifically, among the 80 patients with pre-implant circulatory rescue interventions, mortality was 39 percent in C2 Driver System users, compared to 25 percent in CSS Console users. For the 107 patients who did not require pre-implant rescue intervention (Table 2), the mortality rate up to three months post-implant was 27 percent in C2 Driver System users, compared to 21 percent in CSS Console users. It should be noted that statistical testing for mortality results is not appropriate at this time, given that the post-approval study is ongoing and the primary endpoint is survival rate.
As previously noted in our June 15, 2015 letter, there has been a higher mortality rate for the subgroup of patients requiring pre-implant circulatory rescue interventions when using SynCardia's C2 Driver System (60 percent) compared to those patients using the CSS Console (17 percent). For the subgroup of patients who did not require these pre-implant circulatory rescue interventions, mortality rates were similar (16 percent for C2 Driver System users vs. 15 percent for CSS Console users).
Table 1. Patients Who Received Pre-Implant Circulatory Rescue Intervention (January 2016 report)
|C2 Driver||CSS Console||Total|
|Died||17 (39%)||9 (25%)||26|
|Survived||27 (61%)||27 (75%)||54|
Table 2. Patients Who Did NOT Receive Pre-Implant Circulatory Rescue Intervention (January 2016 report)
|C2 Driver||CSS Console||Total|
|Died||21 (27%)||6 (21%)||27|
|Survived||58 (73%)||22 (79%)||80|
Stroke and Other Neurological Adverse Events
The most recent post-approval study results suggest that there is also a difference in clinical performance between the C2 Driver System and the CSS Console in terms of neurological adverse events.
The INTERMACS Neurological Adverse Event (AE) outcome is a composite of several separate adverse events including: transient ischemic attacks, confusion, ischemic/embolic stroke, hemorrhagic stroke, strokes from other causes, seizures, encephalopathy, and other events. The INTERMACS Neurological AE rates from the first three months after TAH-t implant were provided for patients initially supported by the C2 Driver System and for patients initially supported by the CSS Console (Table 3). The Neurological AE rate in the first three months post-implant is higher for patients initially supported with the C2 Driver System (31 percent) compared to patients initially supported with the CSS Console (16 percent; p =0.02).
These results are not adjusted for potential confounders, and they were not further stratified by pre-implant circulatory rescue intervention status. The Neurological AE rate will continue to be monitored, and additional analyses will be performed as appropriate in the future.
Table 3. All Patients (January 2016 report)
|C2 Driver||CSS Console||Total|
|Neurological Adverse Event||38 (31%)||10 (16%)||48|
|No Neurological Adverse Event||85 (69%)||54 (84%)||139|
Post-approval studies of the TAH-t and our investigation into these issues are ongoing. We do not know the root cause for these observed differences, and the existing data is limited. INTERMACS only captures information regarding the initial driver used to support TAH-t patients, and at this time, only unadjusted interim rates are available. Although we are concerned about the difference in outcomes between the C2 Driver System and the CSS Console, we recognize that the C2 Driver System may be the best option for circulatory support for some patients.
Freedom Driver System
In addition to the C2 Driver System and the CSS Console, a third pneumatic driver system, the SynCardia Freedom Driver System, is also available to power the SynCardia TAH-t. The Freedom Driver System is portable and can be used outside of the hospital, allowing some TAH-t patients to return home while on the device.
The FDA is aware of recent reports of serious, life-threatening TAH-t device malfunctions involving the Freedom Driver System. These reported malfunctions have included sudden cessation of TAH-t pumping without warning alarms or recognizable signs of impending malfunction (such as a change in sound during the Freedom Driver System's operation). The Freedom Driver System was also the subject of a Class 1 Recall initiated on August 7, 2015, but these recent reports appear to be unrelated to the issues that prompted the recall last year.
The FDA is working with SynCardia and clinicians to fully assess reports of malfunction involving the Freedom Driver System. In light of these recent reports, the FDA advises that clinicians review the Operator Manual's specific precautions regarding Freedom Driver System use outside of a hospital environment, and carefully consider individual patient circumstances when evaluating the Freedom Driver System as a treatment option.
The FDA has the following recommendations for health care providers:
- Carefully consider these mortality and neurological adverse event results, and device malfunction reports when making treatment decisions and device selection, and discuss the risks and benefits of these devices with your patients.
- Report any adverse events or suspected adverse events experienced with the SynCardia TAH-t Driver Systems (the C2 Driver, the CSS Console, or the Freedom Driver). Voluntary reports can be submitted through MedWatch, the FDA Safety Information and Adverse Event Reporting program. Device manufacturers and user facilities must comply with the applicable Medical Device Reporting (MDR) regulations. Health care personnel employed by facilities that are subject to FDA's user facility reporting requirements should follow the reporting procedures established by their facilities. Prompt reporting of adverse events can help the FDA identify and better understand the risks associated with medical devices.
- Return all devices associated with, or suspected to be associated with, any adverse events to the manufacturer for evaluation to help them and FDA better understand the issue.
The FDA has the following recommendations for facilities that participate in INTERMACS:
- Continue to enter high-quality data for these devices into INTERMACS, since this data is used to understand individual patient events and factors contributing to patient outcomes.
The FDA continues to work with SynCardia and INTERMACS to better understand these observations in patients using the C2 and Freedom Driver Systems, and will provide updates and additional information on all Syncardia TAH-t Driver Systems as it becomes available.
If you have questions about this communication, please contact the Division of Industry and Consumer Education (DICE) at DICE@FDA.HHS.GOV, 800-638-2041 or 301-796-7100.
William Maisel, MD, MPH
Deputy Center Director for Science
Center for Devices and Radiological Health
U.S. Food and Drug Administration