# Presentation: 417077

## Clinical Review AbioCor® Implantable Replacement HeartH040006

**Julie Swain M.D.**
- Cardiovascular Surgeon
**Ileana Pi****ñ****a M.D.**
- Heart Failure Cardiologist

- DRAFT

**Notes:**
This Humanitarian Use Exemption request is being presented to the panel to obtain the panel’s assessment of the probable benefit of this request and to allow public presentation of the information for this high public interest device.

## Multicenter Single-Arm Feasibility Trial

**# pts**
**  ****per**
** ****center**

**Notes:**
No control prespecified because feasibility

## Indication For Use

**The AbioCor is designed to serve a subset of transplant-ineligible end-stage heart failure patients with biventricular failure not treatable by drugs, pacing devices, or approved cardiac assist devices.**** **

## Approved HUD Inclusion

**Heart failure patients who are on optimal medical therapy and meet all of the following:**
**< 75 years old  **
**not transplant candidates **
**estimated 30-day survival of <30%**
**in biventricular failure not supportable by an implantable left ventricular assist device (LVAD) alone  **
**multiple inotropes  **_**OR **_** those not weanable from a temporary BIVAD**

**Notes:**
Different from feasibility
How objective are the criteria for patient enrollment?
Experienced MD vs. those who do not use devices in practice regularly
Attitude and approaches to the patients
Consistent patient groups among centers with commonality of entry criteria

## Proposed Additional Inclusions(page 69, Post Approval Study)

** ****The Sponsor claims patients with contraindications to LVAD placement would be included in the indications for the device:**
**refractory arrhythmias**
**aortic regurgitation**
**prosthetic aortic valve**
**“****Massive MI”:  patients who are “...at risk of inlet cannula dislodgement due to fragility of the infarcted ventricular tissue.”**
**Mural thrombus in the ventricles**
**Ventricular septal rupture**
**Transplant rejection**
_**** It should be noted that none of the 14 patients in the feasibility study had any of the above conditions**_

**Notes:**
Sponsor proposed a postmarket study

## Post Hoc Proposed Controls

_**REMATCH control pts**_
**Changes in medical care **
**Different patients (LV failure, gatekeeper, OMM)****	**
**Subset analysis (61 pts, many withdrew from care)**
_**AMI-SHOCK Index**_
**No pts had acute MI**
_**AbioScore**_
**42 prospective and retrospective records**
**ICD-9 codes for heart failure and CPT and NDC codes for inadequate hemodynamics **
**age 20 - 79 years **
**26% were female **
**38% were on LVAD’s for bridge-to-transplant**** **

## AbioScore

**used to estimate survival for inclusion of > 70% mortality in 30 days**
**27 clinical items (renal function, NYHA class, etc.)**
**components include items normally used by clinicians**
**validation unproven**
**No known predictive system**
**Very ill, malnourished patients**

## Reasons for Non-transplant Candidacy

- # Pts

*****4 solely because of age

**Notes:**
The primary reason for non transplant eligibility was age (7/14), followed by renal insufficiency in six.  The baseline creatinine in the six patients diagnosed as renal insufficiency ranged from 1.5 to 3.0.  The Sponsor’s definition of renal failure as an adverse event is a creatinine of >3.5.

## Age at Implant

**# pts**

**Patient Age**

## Right-sided Pressures (mmHg)

**CVP**

**PAP**

**mean 9.6 ****mmHg**

**mean 34.5 ****mmHg**
**CI 2.1****L/min/M****2**

**Notes:**
The criteria used to determine the inability to tolerate only an LVAD are not provided in the protocol.  Review of the literature shows that in the majority of cases, an LVAD is sufficient support for patients with evidence of biventricular failure and highlights how difficult it is to make this assessment a priori.   It is unclear how RV failure was determined since the average CVP was 11 mmHg.

## 14 Patients

**6 patients**
**131, 128, 290, 105, 146, 132**

**Death <60 d**
**2**

**Op Death**
**	****2**

**Discharged**
**1**

** ****No Benefit                    ????           Probable Benefit**

**died <90 days**
**3**

## Days of Support

**Days of Support**

- Median 112 days

**Notes:**
Quality vs quantitiy

## Serious Adverse Events

**# SAE<60d**

- 181

- 512

- 293

- 1

- 0

- 100

- 53

- 109

- 115

- 86

- 146

- 164

- 142

- 56

**#’s above columns are days of survival**

**Notes:**
Definition of SAE’s in FDA review
How many days is quality of life acceptable considering the number of SAE’s

## Cause of Death

## Serious Adverse Events(out of 12 pts who survived op)

- # pts
- with
- SAE

**19****#**

**4****#**

**50****#**

**34****#**

**8****#**

**# = events**

**Notes:**
Renal failure was defined as (1) a requirement for dialysis or hemoconcentration for more than 3 days, or (2) creatinine greater than 3.5 mg/dL.  The incidence of reversible vs. irreversible renal failure cannot be determined from the data presented.
Difficulty in anticoagulation may be correlated with strokes
only 5/14 patients did not have a TIA or stroke.  Of the remaining 9 patients, they had 21 instances of TIA or stroke (3 TIA by my definition, 18 stroke). 
For example, Patient #11 was categorized as having a TIA, but the CT scan showed “two new non-hemorrhagic infarcts of the left thalamic region”.  Also, there was no evidence of systematic examination of these patients by a neurological expert, so the neurological event rate might have been larger than reported.

## Bleeding

**# bleeds**
**per pt**

**Patient #**

*** Survived <60 days**

*****

**Notes:**
Bleeding was defined as 1) blood loss exceeding 2000 ml in a 12-hour period; (2) bleeding requiring surgical exploration for resolution; (3) collection of clotted blood that requires aspiration or surgical intervention.  Based on the clinical reports, it appears that it was difficult to manage anticoagulation therapy in these patients since bleeding was an issue in all of the patients.  Difficulties in the management of anticoagulation in these patients might have had an effect on the number of neurological events that were seen in the feasibility study. Based on the clinical reports, it appears that it was difficult to manage anticoagulation therapy in these patients 

## Functional Measurements

**QOL**
**No validated measures**
**Occasional notes on walking or taking excursions out of the hospital**
**No functional measurements (6 min walk or MVO2 postop)**
**Difficult to understand functional level and to balance high mortality and SAE’s**

**Notes:**
It is not impossible to do QOL questionnaires on these patients.  The QOL measures that they say they used are completely unvalidated.  Depending on a post-market study to support the risk/benefit ration of this device is inappropriate.

## Summary of Clinical Data

**Implanted in patients who, in the judgment of the investigator, appeared not to have any other options to prolong survival**
**Provided physiological cardiac outputs and pressures**
**Some had improvement and/or stabilization of end-organ function**
**Some patients could sit, stand, walk, and take excursions outside of the hospital**

## Conclusion from Clinical Data

**	****The risk/benefit determination for this device is difficult due to the lack of validated QOL and functional data**

**Notes:**
patient #9 lived 53 days on the device.  However, the patient never regained consciousness after the implant operation and was kept alive in a comatose state for 53 days until the family requested withdrawal of support.

## Post Market Study Inclusion (page 69, Post Approval Study)

** ****The Sponsor claims patients with contraindications to LVAD placement would be included in the indications for the device:**
**refractory arrhythmias**
**aortic regurgitation**
**prosthetic aortic valve**
**“****Massive MI”:  patients who are “...at risk of inlet cannula dislodgement due to fragility of the infarcted ventricular tissue.”**
**Mural thrombus in the ventricles**
**Ventricular septal rupture**
**Transplant rejection**
_**It should be noted that none of the 14 patients in the feasibility study had any of the above conditions**_

**Notes:**
Sponsor proposed a postmarket study

## Post Market Study-Items for Discussion

**What should be measured?**
**Pre-implant status (demographics, hemodynamics, reason not Tx candidate)**
**Survival**
**Major adverse events (bleeding, stroke, renal failure, hepatic failure, infection)**
**Validated Function/QOL measurements**
**Rankin score**
**For how long?**
**To death or device removal**
**In how many patients?**
**20 (no statistics possible)**

**Notes:**
The Agency proposes that efficacy be tracked by assessing survival days with acceptable neurological status (modified Rankin scale or a disability scale), the ratio of in-hospital to out-of-hospital days,  validated QOL instruments (such as the Kansas City Cardiomyopathy Questionnaire), and a functional capacity assessment such as 6 min walk or MVO2.  Serious adverse events should be reported and the patients should have a standardized assessment of neurological status, including cognitive function.